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The Toxicity of

PLUTONIUM, AMERICIUM AND CURIUM

A Report Prepared Under Contract for the Commission of the European Communities within its Research and

Development Programme on "Plutonium Recycling in Light Water Reactors''

J. C. Nenot Commissariat a PEnergie Atomique, Departement de Protection, CEN, Fontenay-aux-Roses, France

J. W. Stather National Radiological Protection Board, Harwell, Didcot, United Kingdom

Published for the

COMMISSION OF THE EUROPEAN COMMUNITIES

by

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First edition 1979

British Library Cataloguing in Publication Data

Nenot, J C The toxicity of plutonium, americium and curium. 1. Americium - Toxicology 2. Curium -Toxicology 3. Plutonium-Toxicology I. Title II. Slather, J W III. Commission of the European Communities 615.9'25'44 RA1231.R2 79-40429

ISBN 0-08-023440-2

EUR 6157 E N , FR

In order to make this volume available as economically and as rapidly as possible the authors' typescripts have been reproduced in their original forms. This method unfortunately has its typographical limitations but it is hoped that they in no way distract the reader.

Printed in Great Britain by Page Bros. (Norwich) Ltd.

SUMMARY

The objective of the report is to provide a biological basis for an

assessment of the radiological health problems resulting from human

exposure to plutonium, americium and curium.

Only limited data are available on the metabolism of these actinides

in man and there has been no recorded incidence of serious long-term

effects, such as cancer or hereditary effects, which might be related

to their incorporation into the body. Long term follow-up studies of

workers occupationally exposed to plutonium and other actinides will

eventually provide valuable data for improving the basis upon which stan-

dards of protection are determined. Current knowledge of the metabolism

and effects of plutonium, americium and curium is derived mainly from

animal experiments that have been conducted during the last 3 0 years in

many laboratories throughout the world.

Actinides may enter the body either by inhalation, by ingestion or

through wounds. The intact skin is an effective barrier to their entry

into the body. After inhalation of actinide dusts the amount deposited

in the three regions of the respiratory tract (nasopharynx, tracheo-

bronchial region, pulmonary region) depends on the particle size dist-

ribution and is not significantly influenced by the chemical form. Within

the first few days after exposure a fraction of the deposited activity

is rapidly cleared from the respiratory tract. This is due to transport

of particles to the oesophagus by the ciliated epithelium of the upper

regions of the respiratory tract and to absorption of soluble actinides

into the blood. The fraction of the deposited material which remains

in the alveolar region of the lung after the first few days is cleared

slowly. Clearance involves transport to the oesophagus in specialised

phagocytic cells named macrophages, transport to lymphatic tissue, and

slow transfer to the blood. Experimental studies have shown that for

plutonium dioxide the slow component is cleared exponentially with a

half-time of retention of about 5 0 0 days. For soluble forms of plutonium,

such as the nitrate and citrate, and for all compounds of americium and

curium, the half-time of retention is about 5 0 days. Absorption from tho

gastro-intestinal tract is low. The amount absorbed is estimated to

be about 1 x lO""2^ for soluble plutonium compounds, 1 x 1 0 ~ ^ % for plutonium

dioxide and 5 x 10~2% for all forms of americium and curium.

The behaviour of actinides at wound sites depends not only upon the

physico-chemical properties of the material deposited but also on

ix

X

biological factors such as the depth and site of deposition, the type of

tissue and the dispersion within the tissue. In general soluble forms

are cleared more readily than insoluble forms, subcutaneous deposits more

readily than intramuscular deposits and americium and curium more readily

than plutonium.

Upon reaching the circulation, plutonium, americium and curium are

accumulated in various tissues. For radiological protection purposes the

three sites of deposition that need to be considered are the skeleton,

liver and gonads. The skeleton and liver together accumulate about 90%

of the activity entering the blood (about U%% in the skeleton and k$% in

the liver) while approximately 3 x 1 0 ~ ^ % is accumulated by the testes and

1 x 1 C r ^ % by the ovaries. The human skeleton and liver are estimated to

retain actinides with half times of 1 0 0 years and i\0 years, respectively.

Animal studies suggest that there is no loss of activity from the gonads.

Acute or medium-term effects are due to very high radiation doses

which will only occur in extreme accidental situations. The level of

activity deposited in the pulmonary region of the lung which might cause

death of half an exposed population within one year is estimated to be

about 1 0 0 uCi ( 3 . 7 MBq). The main delayed effect found in experimental

animals has been the development of cancer which has occurred predominantly

in the lung and in the skeleton. Effects have generally been observed

at levels of activity in humans much greater than those equivalent to max-

imum permissible body burdens in man. The frequency of lung cancers

occurring after the inhalation of actinides increases with the dose up

to a maximum and then decreases at higher doses as a result of cell

sterilization and death. Most pulmonary cancers observed in experimental

animals have occurred in the peripheral regions of the lung. Actinides

deposited in the skeleton have induced bone cancers but various animal

species differ in their response, the dog exhibiting the highest

sensitivity. In addition to lung and bone cancers a small number of

liver cancers have been observed, and in animals exposed to readily

transportable forms of actinides some cancers have also occurred in other

soft tissues. No evidence of hereditary effects resulting from the

incorporation of actinides in the gonads has been demonstrated in any

of the animal species studied.

In evaluating the radiation effects that may occur in a population

exposed to actinides, estimates of risk coefficients are required for

xi

radiation induced cancers and for radiation induced hereditary diseases.

As the histological types of cancer seen in experimental animals may

differ from those commonly seen in man and as there are species differences

in radio sensitivity, only human data have been used for calculating risk

coefficients for late somatic effects of radiation. There are no data

on the development of cancers in humans as a result of incorporation of

plutonium, amercium or curium isotopes. Estimates of risk have therefore

been based mainly on the results of epidemiological studies on humans

exposed to external radiation. Some information is also available on

the development of bone and liver cancers as a result of intakes of other

alpha emitters. The recommended rounded values (based on the use of

a quality factor of 2 0 for alpha radiation) for the number of deaths per

1 0 ^ man gray (alpha) are: 1+00 from lung cancers, 1 0 0 from bone cancers,

1+00 from leukaemia, 1 0 0 from liver cancers and 1+00 from gastrointestinal

tract cancers; for serious hereditary diseases a total of 111+0 cases per

1 0 ^ man gray can be predicted over many generations. To assess the

biological consequences of intake of actinides these risk coefficients

must be weighted by the doses accumulated by the various tissues.

Furthermore the risk coefficients for radiation induced cancers are based

on the assumption that the full risk to the tissues is expressed. Because

of the long latent period for cancer induction this will only apply to

doses received early in life. The genetically significant dose is that

accumulated up to age about 3 0 .

At present the methods available for removing accidental intakes of

actinides from the body are only moderately successful. If insoluble

materials are inhaled, bronchopulmonary lavage is the only potentially

effective treatment. If activity is deposited at a wound site the most

satisfactory treatment is excision of as much of the contaminated tissue

as possible. For removing soluble forms of plutonium, americium and

curium, injection of the chelating agent DTPA is presently the best

method; it effectively clears actinides from the blood and extracellular

fluids and is rapidly excreted in the urine.

ACKNOWLEDGEMENTS The authors would like to acknowledge the valuable help given by many

of their colleagues during the preparation of this report. The authors

also wish to thank Miss R. A. Steggles for typing the manuscript.

xii

Chapter 1

I N T R O D U C T I O N

The Commission of the European Communities has initiated a programme

to evaluate the merits of using plutonium in light water reactor fuels.

As part of this programme, it is necessary to consider the implications

of handling materials containing increased quantities of plutonium,

americium and curium. This report provides a synthesis of current

knowledge on the metabolism and biological effects of these actinides

in animals and man, from which an assessment of radiological health

problems can be made. Relevant data are included from the many recent

studies that have been conducted both in the Member States of the

European Community and elsewhere.

In order to assess the consequences of humay, exposure to these

actinides it is necessary first to identify their routes of entry into

the body, second to understand the factors influencing their distribution

and retention in tissues, third to determine the tissues at risk and

fourth to define doss-response relationships for the critical tissues.

There is only a limited amount of information on the metabolism of

these actinides in humans although some data are available on the distri-

bution of plutonium in human autopsy samples. Published studies on the

behaviour of actinides in man. involve exposure to unknown physico-chemical

forms in most cases, often at unspecified times, and in many cases chelating

agents have been usfd which may have influenced their metabolism. Animal

studies are therefore necessary to elucidate those factors influencing

the metabolism of actinides in the body. A major limitation to the

value of many animal studies, however, is that the amounts of actinides

used hare been greatly in excess of those levels likely tc be encountered

in cases of human exposure. Since the behaviour of actinides in the body

is influenced by the mass deposited, studies on animals exposed to

relatively low doses have been considered wherever possible.

No detrimental biological effects in man can be unequivocably

attributed to exposure to actinides. Extensive animal studies have

shown that biological effects occur predominantly at the point of entry

(lungs or wound site) in regional lymphatic tissue draining the sites of

deposition and in the skeleton and liver following deposition in these

organs from the blood. Effects have generally been observed at levels of

activity in tissues much greater than those equivalent to maximum perm-

1

2

issible body burdens in man.

Depending upon the radiation dose to tissues both early and late

somatic damage could be anticipated in exposed individuals. Early

somatic effects are assumed to require a threshold ose before any damage

occurs and are unlikely except as a result of a mass.ive intake following

a major accident. The main late somatic effect is expected to be cancer,

although life-shortening may also occur as a result of non-specific

radiation effects. Cancer induction is assumed to be linearly related

to the close with no threshold. The histological types of radiation-

induced cancer that occur in experimental animals often differ from those

commonly seen in man and there exe species differences in radiosensitivity.

Only human data have therefore been used for calculating risk coefficients

for radiation induced cancer in the lung, bone, bone marrow, liver and

gastrointestinal tract. These estimates of risk have been based mainly

on the results of epidemiological studies on humans exposed to external

radiation but some information is also available on humans exposed to

incorporated alpha-emitters.

Radiation damage to the germ cells can result in spontaneous

abortion or hereditary disease. Hereditary effects may therefore be

expected to occur in the descendants of exposed individuals. No evidence

of genetic damage resulting from the incorporation of actinides in the

gonads has been demonstrated either in man or in animal studies. Estimates

of risk coefficients for radiation induced hereditary disease have been

extrapolated from studies on animals exposed to external radiation.

In the event of accidental contamination of humans by actinides,

therapeutic procedures may be used in an attempt to increase their rate

of elimination from the body. Current developments for treating intakes

of actinides have therefore been discussed.

Chapter 2

PHYSICAL AND CHEMICAL PROPERTIES OF BIOLOGICAL IMPORTANCE

1 • Introduction

Plutonium, americium and curium are produced in both thermal and

breeder reactors. The main civilian use of plutonium is in breeder

reactors and it may also be used as fissionable material in thermal

reactors. It has other uses in industry and medicine such as for power

sources and cardiac pacemakers. Americium and curium have few uses

although americium-21+1 has been used for transmission scanning studies in

tissues, in neutron sources, in smoke detectors, and in a-active foils with

applications in static eliminators.

2 . Plutonium

The chemistry of plutonium has been described by Katz and Seaborg

( 1 9 5 7 ) , Cleveland ( 1 9 7 0 ) and Taylor ( 1 9 7 3 a ) . It is a silvery white metal

which melts at 6 3 9 . 5°C and oxidises readily on warming in moist air. In

finely divided form the metal may be pyrophoric. When plutonium metal is

burnt in oxygen or when oxygen containing compounds such as Pu(lV) oxalate

or Pu(lY) peroxide are heated in vacuo to about 1000°C plutonium dioxide is

formed. Plutonium dioxide is a highly refractory material which melts at

2200-2 l+00°C and is difficult to dissolve by normal methods.

There are 1 5 known isotopes of plutonium having atomic weights between

2 3 2 and 2 l+6. Of these only 2 3 6 - 2 1 + 3 are of any biological interest either

as a result of their production in nuclear power programmes or because of

other uses. Table 2 . 1 shows the main physical properties of these isotopes.

The isotopes Pu - 2 3 9 and Pu-2l+1 are fissile and therefore of special

interest for fuel in both thermal and breeder reactors. In 1 9 7 5 the

estimated production of plutonium in the Countries of the European Community

was 3 « 0 tons and it was anticipated that this would rise to 5 - 7 tons by 1 9 8 0

(Haijtink, 1 9 7 6 ) . Pu - 2 3 9 and Pu-2l+0 emit an L X-ray of uranium in k% and

1 1 % of disintegrations respectively with an energy of about 1 7 keV. These

X-rays can penetrate a few centimetres of tissue thus allowing Pu - 2 3 9

(4Pu-2l+0)* to be detected in the lung or a wound site. The other a emitting

isotopes of plutonium also emit L X-rays in varying amounts. Pu - 2 3 8 is

used as a heat source in thermo-electric power generators such as cardiac

pacemakers and Pu - 2 3 6 and Pu - 2 3 7 are used.in tracer studies. Because of

*In the remainder of this report Pu - 2 3 9 + 21+0 are referred to as Pu - 2 3 9

Table

2.1

Physical properties of the manor isotopes of Plutonium, Americium and Curium

Isotope

Radioactive,

Half-live

W

(years)

Principal Mode

of Decay

Mean alpha

energy W

(MeV)

Specific Activity

^Ci g"

1

Mass per

Li

Ci

(«)

Relative

Mass

a

Plutonium-

236

2.8

5 E

0

0 a

5.7

5 5

.32

E

08

1.8

8 E

-09

1.1

5 E

-02*

Plutonium-

237

1.2

5 E

-01

E. C •

1.2

1 E

1

0 8.

28

E-1

1 5.

08

E-0

6

Plutonium-

2 38

8

.78

E 0

1 a, X-rays

5-2*

6 1

.71

E

07

5.82

* E

-08

3-58

E

-03

Plutonium

-239

2.

2*39

E

02*

a, X-rays

5.1

5 6

.13

E 0

2*

1.6

3 E

-05

1.0

0 E

0

0

Plutonium-

2i*0

6

.53

7 E

0

3 a

5.1

5 2

.28

E

05

U.3

8 E

-06

2.6

9 E

-01

Plutonium-

22*1

1

.50

2 E

01

P 9.

90

E

07

1.0

1 E

-08

6.1

9 E

-02*

Plutonium

-22*

2 3.

87

E

05

a U

.89

3.82

E

0

3 2

.62

E-0

2+

1.6

1 E

01

Plutonium

-22*

3 5

.66

E-01

* (3

2.60

E

12

3.82

* E

-13

2.3

6 E

-08

Americium-

22+1

2*

. 58

E

0

2 a, y-rays

5.2*

9 3

.25

E

06

3.08

E

-07

1.8

9 E

-02

Americium-

21*3

7.

2*0

E

03

a

5.2

7 1

.99

E

05

5.0

2 E

-06

3.08

E

-01

Curium-

21*2

2*

. 1*7

E

-01

a

6.1

0 3

.31

E

09

3.02

E

-10

1.8

5 E

-05

Curium-

214*

1

.79

E 0

1 a

5.80

8.

20

E

07

1.2

2 E

-08

7.2*

8 E

-02*

E.C.

-

Electron capture

a

-

In comparison with

1

^Ci of plutonium

-239 which is taken as

1

Reference:

A

- Harte

(1

97

6)

5

it,n short half-life ( 5 hrs) and low P energy ( 0 . 6 MeV) plutonium-21+3

is of little radiological importance.

Plutonium can exist in solution mainly in four valence states: Pu(lll),

Pu(lV), Pu(V) and Pu(Vl) and in some conditions as Pu(VIl). The individual

oxidation states can be stabilised by appropriate oxidising, reducing or

complexing agents. In concentrated acidic solutions a number of oxidation-

reduction reactions can occur leading to the formation of an equilibrium in

which the different oxidation states can co-exist.

There is little information on the oxidation state of plutonium in

biological systems. In neutral solutions the formation of the Pu(lV) state

is favoured and biological fluids contain ligands and complexing entities

that tend to stabilise the Pu(lV) state. Stable plutonium complexes can be

formed with citrate, ascorbate, amino acids and proteins. The stability of

these complexes decreases in the order Pu(lV) > Pu(lll) > Pu(Vl) > Pu(V).

It is, therefore, probable that most if not all plutonium in biological

systems is in the Pu(lV) state.

Of particular biological importance is the property of plutonium ions

in solution to rapidly hydrolyse and form polymers at high concentrations.

The tendency to hydrolyse decreases in the order Pu(lV) > Pu(Vl) > Pu(lll)

> Pu(v). Hydrolysis of Pu(lV) can result in the formation of relatively

insoluble polymers, a process which is only slowly reversible. The forma-

tion of plutonium polymers in the body leads to their phagocytic uptake by

macrophages and other cells that can accumulate particulate material.

Compounds of Pu(lll) and Pu(Vl) hydrolyse less rapidly at physiological pH

and can potentially be more readily absorbed from the gastrointestinal

tract, lung or other sites.

3 - Americium and Curium

The chemistry of the transplutonium elements americium and curium has

been reviewed by Katz and Seaborg ( 1 9 5 7 ) , Pascal ( 1 9 7 0 ) and Taylor ( 1 9 7 3 b ) .

Americium metal is silvery white, malleable and ductile and melts at

9 9 U + 7°C. It oxidises slowly in the air. Curium is a silvery, hard,

brittle metal with a melting point of 1 3 5 0 + 60°C. It oxidises rapidly

in the presence of oxygen. The oxides of both americium and curium are

more soluble than plutonium dioxide.

There are 1 3 known isotopes of americium ( 2 3 2 , 23I+ , 2 3 7 - 2 1 + 7 ) . Am-2l+1

is the most abundant isotope and is produced from Pu-2l+1 by P decay. It

6

subsequently decays by a emission also giving rise to a Y-ray with an energy

of 60 keV (1+0% of disintegrations) and if incorporated in the body can be

readily detected outside. Am-22|3 is the only other isotope of americium

produced in any quantity. Of the 12 known isotopes of curium only C111-2I4.2

and Cm—21+1+ are produced in significant amounts.

The main physical properties of these isotopes of americium and curium

are shown in Table 2.1. In solution the trivalent state is the most stable

oxidation state and the only one of importance in biological systems. The

general features of hydrolysis and complex ion formation are similar to

those found for plutonium. The trivalent transplutonics are however less

readily hydrolysed because of their lower ionic charge and larger ionic

radii (Am III = 99 pm, Cm III = 98 pm, Pu IV = 9 0 pm; Durbin, 1 9 6 2 ) . The

most important feature of their solution chemistry is that they form only

weak complexes with serum proteins and other ligands (Taylor, 1973*0 •

1|. General data relevant to problems in Radiological Protection

The relative amounts of the most important isotopes of plutonium,

americium and curium produced either in a thermal reactor (PWR) or in a

breeder reactor fuelled with plutonium from an SGHWR reactor are given in

Table 2 . 2 . Both inventories show that high levels of both americium and

curium isotopes are produced as well as plutonium. This is in contrast to

the fuel inventory after low burn-up times of say 1 0 0 0 MWD/Te when Pu - 2 3 9

+ 21+0 are the main isotopes produced (Dolphin, et al., 1 9 7 U ) • Although the

Cm-2i|2 isotope accounts for most of the alpha activity in fuel rods at the

end of long irradiation times it decays rapidly with a half-life of 1 6 3 days

to Pu-238.

Plutonium is used in fuel mainly in the oxide form. The chemical

separation procedures used in the reprocessing of fuel elements involve

their dissolution in nitric acid and subsequent separation of plutonium

from uranium and other fission products by extraction in organic solvents.

Plutonium i._ precipitated as the oxalate and then converted to the oxide.

In the preparation of plutonium metal an intermediate stage is the formation

of the fluoride compound. Accidental releases from chemical separation

plants may therefore involve numerous chemical forms of plutonium which

appear in various process streams during the separation procedures. The

higher actinides are normally removed during reprocessing but the release

of Pu-21+1 gives rise to Am-2l+1.

Actinides commonly enter the body by ingestion or inhalation as

particles. Depending upon the source of the release actinides may be taken

7

Table 2 . 2

Relative activities of isotopes in freshly discharged fuel3.

A b Inventory for PWR

at 3 3 , 0 0 0 MWD, Te"1

B c Inventory for CFR

with SGHWR plutonium at 8 0 , 0 0 0 MWD, Te~ 1

plutonium-236 1 . 1 0 E - 0 3 2 . 3 5 E-01+

Plutonium-2 3 7 < 3 . 1 U E -06 3 . 8 3 E - 0 3

Plutonium-238 8 . 5 5 E 0 0 2 . 9 U E 0 0

Plutonium-239 1 . 0 0 E 0 0 1 . 0 0 E 0 0

Plutonium-2l|0 1 . 5 0 E 0 0 2 . 1 5 E 00

Plutonium-2l+1 3 . 3 0 E 0 2 2 . 3 2 E 0 2

Plutonium-2U2 I+.3U E - 0 3 8 . 9 2 E - 0 3

Americium- 21+1 2 . 7 0 E - 0 1 6 . 9 1 E - 0 1

Americium-2l+3 5 . 6 9 E - 0 2 1+.00 E - 0 2

Curium-21+2 1 . 0 5 E 0 2 1 . 0 3 E 01

Curium-21+1+ 7 - 6 8 E 00 3 . 8 7 E 0 0

a In comparison with plutonium-239 taken as 1

b Pressurised Water Reactor (PWR)

c Commercial Fast Reactor (CFR)

d Steam Generating Heavy Water Reactor (SGHWR)

Reference: A. Bell ( 1 9 7 3 )

B. Kelly et al, ( 1 9 7 7 )

Relative activities of the major isotopes of plutonium, americium

and curium in irradiated fuel

8

in either as individual elements or in association with other active or

inactive materials. Following the inhalation of particles consisting of

mixtures of actinides and other elements the transportability of the

different actinides in the lung seems to depend largely on the element

present in greatest mass (Chapter 1+). Table 2.1 shows the relative masses

of the major isotopes of plutonium, americium and curium for unit amounts

of activity taking 1 jiCi (37 kBq) of plutonium-239 as 1. Thus in a dust

particle that contains oxides of both plutonium-239 (90% of the alpha

activity) and americium-21+1 ( 1 0 % of the alpha activity) the relative masses

of the two isotopes are kl& s 1 respectively and the low solubility of

plutonium dioxide limits the transport of americium from sites of deposition

in the body.

Another important physical parameter that influences the behaviour of

actinide particles in the body is their size. Table 2.3 shows both the

total number of atoms of Pu-239 in various sizes of spherical particles of

the oxide as well as the number of atoms at the surface. In particles

greater than 100 nm in diameter less than 2% of the atoms are at the

surface. These particles do not dissolve readily in biological fluids.

However, for 1 nm particles 89% of the atoms are at the surface where they

can be readily solubilised by biological ligands (this is discussed in

Chapter !+)•

9

Table 2.3

The theoretical relationship between particle size and number of

surface atoms in plutonium-239 dioxide spheres8.

Diameter in [xm

No. of atoms at surface (N T)

Total No. of atoms (N T)

Percentage of atoms at surface

0 . 0 0 1 2 1 . 5 21+. 1 89 0 . 0 0 2 8 6 11+6 5 8

0 . 0 0 3 191+ 1+56 k3 0 . 0 0 5 5 3 8 1 9 3 2 28

0 . 0 1 0 2 1 5 2 11+367 1 5

0 . 0 2 5 1.31+5 X 21.1+5 x 1oh 6

0 . 0 5 0 5 . 3 8 0 X 1 0 6 1 6 8 . 9 x ^oh

3 0 . 1 0 0 2 . 1 5 2 X 1 0 * 1 3 U . 1 x 1 0 ^ 2

a Assumes plutonium-239 dioxide crystal lattice structure

(Cleveland, 1 9 7 0 )

Reference: Smith et al ( 1 9 7 7 )

Chapter 3

HUMAN EXPERIENCE

1 . Introduction

In the United States it has been estimated that by 1 9 7 1 + about 1 7 * 0 0 0

persons had worked in the plutonium industry from the beginning of the

Manhattan project in 1 9 U 3 (Gillette, 1 9 7 U ) • There is no information on the

number of people that have worked with plutonium or the higher actinides

world wide. Accidental intakes of plutonium by humans have been recorded

since the discovery of plutonium in 1 9 U 2 . Despite this there is relatively

little information available on either the metabolism or effects of

plutonium in man that can be used to predict the potential consequences of

human exposure. The available human data frequently result from accidental

exposures, often at unspecified times and to compounds of unknown physico-

chemical form. The data is difficult to interpret because many

workers are also exposed to external radiation and possibly to other

internally incorporated radionuclides. Human metabolic data on the trans-

plutonium elements is even more fragmentary.

2 . Routes of Entry

The two principal routes of accidental entry of actinides in

occupationally exposed persons are either by inhalation or through cuts,

abrasions or other wounds. In a survey of 2 0 3 USAEC contractors1 personnel

with internal deposits of plutonium, Voelz ( 1 9 7 5 ) reported that 1 31 had

been contaminated by inhalation, 1+8 through wounds and 8 by both routes.

In 1 6 cases the cause of contamination was unknown.

Accidental intakes by inhalation have provided some information on

the retention of both plutonium and americium in the human lung. Lung

retention data have normally been obtained by chest counting. A limitation

of the technique is that measurements of actinides in the chest by external

counting do not distinguish between activity in lung and that in other

thoracic tissues such as lymph nodes. The limit of detection is between

5 and 1 0 nCi ( 1 8 5 and 3 7 0 Bq) of plutonium-239 or about 0 . 2 nCi ( 7 . 1 + Bq)

of americium-2l+1 depending upon the amount of absorbing tissue over the

rib cage of the individual. Americium-21+1 is detected more readily due to

the emission of 60 keV gamma-rays which are less readily absorbed in the

chest wall than the plutonium x-rays.

Plutonium dust particles that are accidentally inhaled frequently

contain some americium-2l+1. If the amount of americium in the inhaled

11

12

particles can be determined from samples of the dust collected on air

filters or from the source material then the amount of plutonium in the

chest can be inferred from the level of americium measured,

The number of incidents involving accidental inhalation of plutonium

or other actinides in man for which detailed in vivo and excretion

measurements have been made is small, Plutonium deposited in the upper

regions of the respiratory system is cleared with a half-time of 0 . 5 to

0 , 8 days (Ramsden et al, 1 9 7 0 ; Watts, 1 9 7 5 ) • Plutonium deposited in the

lower regions of the respiratory system is cleared more slowly. The

long term c -mponent of retention, obtained by measurements of activity

in the chest, in a man accidentally exposed to plutonium haa been reported

to be 2 9 0 days (Ramsden et al, 1 9 7 0 ) and in a second man 2'.|0 days

(Johnson et al, 1 9 7 2 ) . Watts ( 1 9 7 5 ) reviewed published data on the

clearance of insoluble plutonium-239 compounds from the lung. She

re-exanined the original data reported by Ramsden et al ( 1 9 7 C ) and showed

that the long term clearance from the chest could be represented by a two

component function with half-times of 1 7 and 6 5 0 days. The retention

data reported by Johnson et al ( 1 9 7 2 ) could be fitted by two components

with half-times of 2k and 3 2 0 days.

Oxides of americium are cleared more rapidly from the lung. Sanders

( 1 9 7 U & ) reported that in a man that had accidentally inhaled mixed oxides

of americium-2Ul and curium-2I4I4. the lung content of both nuclides after

the first seven days was cleared with a half-time of 2 8 days. This

difference between oxides of plutonium and the higher actinides has also

been found in animal experiments (Chapter U ) .

Fry ( 1 9 7 6 ) reported the long-term retention of americium-21+1 in the

chest of a subject who had inhaled the oxide was at least 9 0 0 days.

However, in vivo measurements were not started until about 21+0 days

after the accident and it seems likely that much of the activity measured

in the chest was in tissues other than the lung.

The other main route of entry of actinides into the body in occupa-

tionally exposed persons is through wounds. The majority of cases of

human exposure to transuranium elements through wounds have involved

plutonium either alone or in combination with americium. In most instances

either the oxide or metal has been involved (Pilleron et al, 1 9 6 1 ; ;

Lagerquist et al, 1 9 6 5 ; Schofield and Lynn, 1 9 7 3 ; Testa and Dellesite,

1 9 7 3 ; Johnson and Lawrence, 1 9 7 U ) • Cases of human contamination by

plutonium nitrate (Lafuma, 1 9 6 3 ; Schofield, 1 9 6 9 ; Jolly et al, 1 9 7 2 ) and

13

plutonium oxalate (Schofield et al, 1 9 7 U ) have also been reported. Accident

cases are frequently treated by surgical exision and/or chelation therapy

and often the nature of the material involved is not known. There may

also have been a history of accidental inhalation exposures. The data

available on humans are therefore not suitable for describing the be-

haviour of actinides that have entered the body through cuts or wounds

and use must be made of data from animal experiments (Chapter k)»

Transfer of actinides to man can also occur as a result of inhalation

or ingestion of actinides in the environment. Recently Bennett ( 1 9 7 ^ ) has

shown that estimated organ burdens of plutonium-239 in the United States

population are adequately accounted for by considering the inhalation

intake alone. The contribution to organ burdens by the ingestion route

was less than that from inhalation by about a factor of 1 0 0 0 .

3 . Distribution in Tissues

A number of studies have been reported on the tissue distribution of

plutonium in human autopsy samples arising from both occupational exposure

and fallout. The objective of measuring levels of activity in tissues

from occupationally exposed persons is to determine the body content of

plutonium or other actinides at death and subsequently to relate these to

the previous history of exposure and bioassay results. This should both

help to improve the accuracy of bioassay programmes and test the adequacy

of control procedures.

There are now more than 7 0 0 autopsy cases that have been studied for

plutonium concentrations (Campbell et al, 1 9 7 3 ; Lagerquist et al, 1 9 7 3 ;

Nelson et al, 1 9 7 2 ; Newton et al, 1 9 6 8 ; Norwood et al, 1 9 7 3 , 1 9 7 5 ;

Schofield and Dolphin, 1 9 7 U ; Maclnroy, 1 9 7 6 ; Popplewell, 1 9 7 7 ) , many of

the reported cases are from the general population but there are records

of more than $0 persons accidentally exposed at work. A major difficulty

in the assessment of organ or total body content from measurements on

autopsy samples is the necessity to extrapolate from measurements on a

relatively small sample of tissue. This is a particular problem with bone

when often only some vertebrae and ribs are removed. The tissues normally

analysed are lung, tracheo-bronchial lymph nodes, liver, kidney, gonads

and bone. Results from other tissues have normally shown much lower

concentrations. The results shown in Table 3 . 1 are for 2 2 autopsy

analyses with the highest concentration of plutonium. They have been

chosen on the basis that at least one tissue analysed has a concentration

of plutonium of 2 0 0 0 disintegrations per minute per kilogram. The results

Table 3*1

Distribution of plutonium in autopsy tissues of occupationally exposed workers

Time from possible

first exposure

to death

(years)

Concentration of plutonium in tissues

dis min"' kg"

1

Cause of Death

Reference

Time from possible

first exposure

to death

(years)

Lung

TBLN

Liver

Skeleton

Kidney

6

59

80

21 3

0 60

20

20

Cardiac embolism

pulmonary

A

NR

2800

16600

21+8

2

3 20

Suicide

A

12

1+07

0 3U

00

93

50

72

00

600

Complications of

heart surgery

A

25

351

3756

0 97

50

0 58

Coronary infarction

A

21

1U65

2 9

79

0 32

09

21+2

15

Coronary thrombosis

B

1+

2508

55

0 78

88

NA

Bronchitis

B

1 88

0 5

39

0 12

91+

21

3 15

Accident

B

9 39

60

330

867

181+8

1+1+

Coronary thrombosis

B

<1

2838

NA

672

130

NA

Coronary thrombosis

B

-39

00

NA

3900

0 1+

700

600

N.G.

C

-9

76

00

850

310

171

28

N.G.

D

-31

+100

11600

297

28

1+

N.G.

D

13

633U

8

50

96

98

36

23

89

1+7

N.G.

E

15

25

22

1+6000

U3U

3 NA

50

N.G.

E

15

8538

1

50

89

6 2866

612

7-1

N.G.

E

19

377

2681

+5

70

2 31

+ <MRL

N.G.

E

lU

Table

3

.1 (continued)

Time from possible

first exposure

to death

(years)

Concentration of plutonium in tissues

dis min"' kg"

1

Cause of Death

Reference

Time from possible

first exposure

to death

(years)

Lung

TBLN

Liver

Skeleton

Kidney

Cause of Death

Reference

25

NA

85

72

59

87

NA

N.G.

E

31

+ .

8U65

5

63

75

0 NA

3550

NA

Living

E

27

297

2298

<1

12

1

N.G.

E

29

375

10

35

2 53

8 85

10

N.G.

E

20

290

3678

Ik

18

1

N.G.

E

25

69

95

5 78

79U

9 38

U6

11

17

57

N.G.

E

+

Specimens obtained at biopsy

TBLN

Tracheobronchial lymph nodes

NA

Tissue not available

MRL

Minimum reporting level

Skeleton

Average concentration of results reported

NG

Cause of death not given

NR

Not recorded

References

A

Norwood et al,

19

73

B

Schofield and Dolphin,

19

7U

C

Popplewell,

1

97

7 D

Lagerquist et al,

19

73

E

Maclnroy,

19

76

Organ weights of Reference Man

ICRP Publication

2

3, 1

97

5

Lungs

TBLN

Liver

Skeleton

Kidneys

1000 g

15 g

1800 g

10

00

0 g

310

g

15

16

show that the concentration is highest in the tracheo-bronchial lymph

nodes in 13 of the cases and this reflects the fact that most exposures

were to plutonium oxide often more than 1 0 years prior to death.

The variation in the distribution of plutonium shows that each case

is unique. To relate these measurements to the previous history of

exposure and bioassay measurements, the chemical form, solubility and

particle size of the material involved must be know as well as its route

of entry, and the time and duration of exposure. Much of this information

is frequently not available and as a consequence the results of tissue

analyses have only a limited value.

Levels of fall-out plutonium have also been measured in human tissues.

This activity arises mainly from the estimated 3 2 5 k 0 i ( 1 2 PBq) of

plutonium-239 disseminated over the earth!s surface by weapons testing.

Smaller amounts of plutonium-238, plutonium-2l+1 and plutonium-21+2 have

also been produced by weapons testing (Bennett, 1 9 7 6 ) . Amercium-2l+1 is

the daughter isotope of plutonium-21+1. The amercium-2Ul : plutonium-239

activity ratio is currently about 0 . 2 5 in soil and will eventually

increase to 0 .1+ (Krey et al, 1 9 7 6 ) . Thus in addition to plutonium some

information on the tissue distribution of fall-out americium may even-

tually become available.

Data have been published by Maclnroy ( 1 9 7 6 ) on the distribution of

plutonium in human tissues from the general population. In a total of

2 0 0 or more specimens analysed the average concentrations of plutonium

1 1

found in tissues were: for lung 0 . 2 7 pCi kg" ( 1 0 mBq kg" ), liver 0 . 5 7 pCi — 1 — 1 1 1

kg"" ( 2 1 mBq kg" ), lymph nodes 1 . 3 5 pCi kg"* ( 5 0 mBq kg" ) and vertebrae —1 —1

0 . 2 3 pCi kg ( 8 . 5 mBq kg ). Levels in the kidneys and gonads were less

than the minimum recorded level ( 0 . 0 1 1 + pCi ( 0 . 5 mBq) per sample analysed).

The values for lung, liver and vertebrae are all within a factor of 2 or 3 .

Although measurements of total lymph node concentrations mask variation

between individual nodes the concentration of plutonium in them is about

5 times that found in the lungs. The variations found between the

different tissues are considerably less than those found in occupationally

exposed workers. 1+. Excretion

Estimates of the systemic body content of plutonium are normally made

from measurements of the daily excretion of plutonium in the urine.

Analysis of the data is based upon measurements made in the United States

IT

of urinary excretion of plutonium in 1 8 patients of relatively short life

expectancy who were intravenously injected with known amounts of plutonium

citrate or nitrate (Langham et al, 9 5 0 ; Langham, 1 9 5 7 ) . The studies were

under-oaken between 1 9 U 5 and 1 9 U 7 and 0 . 0 1 ; to 5 - 9 H c i 0 -5 t o 2 1 8 k B (l) o f

plutonium were injected. In the original analysis of data on 1 6 of the

patients Langham et a l , ( l 9 5 0 ) noted that? severe limitation m their use was

that only k cases were followed beyond H4O days after injection and only

two beyond 2 0 0 days (a series of U consecutive samples were collected from

the 5 2 3 r d and 1 6 1 0 t h day in one case - HP6 and from 1 6 1 0 days in the second

case - HP3). The data were therefore adjusted by including excretion data

from laboratory personnel accidentally contaminated with plutonium to

extend the excretion curve to 1 7 5 0 days. The adjusted expression was

Yua = 0 . 2 0 X~°'lk

where Yua is the percent of the injected dose excreted in a single

day and X is the time of observation in days post-injection.

Durbin ( 1 9 7 2 ) has recently reviewed the data from these studies and

discussed the limitations in its use. Apart from the short periods of

sample collection the data were collected after intravenous injection of

plutonium citrate or nitrate and this is not a normal route of occupational

exposure. In I4 cases hexavalent plutonium was injected which appears to be

more readily excreted than tetravalent plutonium. Also many of the

patients were severely ill with abnormal metabolism.

Durbin ( 1 9 7 2 ) used the plutonium excretion data given by Langham et al,

( 1 9 5 0 ) to obtain a five component exponential curve for urinary excretion

of plutonium thought to be representative of an adult human in reasonably

good health.

The plutonium excretion data reported by Langham et al, ( 1 9 5 0 ) have

also been modified by Beach and Dolphin (I96I4.) to take account of movement

from the lung as follows:

Y u = (b - 1 ) 0 . 1 6 Jr~b (x- tr0-68 d-\r

where Y^ is the urinary excretion rate expressed as a percentage of

the plutonium intake, is a function of time representing the transfer

of plutonium from the lung to the body, t is in days since contamination

and b is a constant.

To use this formula, a value of the function representing transfer

into the body, b, must be assigned if possible from knowledge of the intake

conditions.

18

Although these formulae are adequate for representing the excretion of

plutonium for short times after exposure the results from autopsy analysis

and from observation on occupationally exposed persons have shown that

their use at late times can lead to an over-estimation of the systemic

burden of plutonium, by up to a factor of 5 or more, (Lagerquist et al,

1 9 7 3 ; Maclnroy, 1 9 7 6 ; Popplewell, 1 9 7 7 ) .

Recently it has been found that of the 1 8 individuals given injections

of plutonium in 1 9 U 5 - 1 9 U 7 > 8 survived for eight years and 1+ are still

alive (Rowland and Durbin, 1 9 7 6 ) . The causes of death of 1 3 of these

individuals have been determined from death certificates and none appear

to be related to the administered plutonium. Rundo et al, ( 1 9 7 6 ) measured

the excretion of plutonium in the faeces and urine in some of the subjects.

For two subjects who had been injected intravenously with tetravalent

plutonium-239 as the citrate compound the urinary excretion rates were 7 . 6

and 1+.7 pCi ( . 2 8 and . 1 7 Bq) per day at approximately 1cA days after

injection. These rates corresponded to 2 . 5 2 x ^0~•tyo and 1 .1+1 x 1 0 " ^ of

the injected doses per day respectively. The faecal excretion rates were

about 1+0% of the urinary rates. These observed urinary excretion rates

were approximately an order of magnitude higher than those predicted by

Langham1s equation, and the estimated total excretion was 2 to 3 times

higher than the predictions obtained by integrating Langham1 s equations

for both urinary and faecal excretion (Langham et al, 1 9 5 0 ; Langham, 1 9 5 7 ) .

These results may therefore go some way to explaining over-estimates of

plutonium burdens from bioassay data.

In summary, body content estimates based on Langham1s equation are

likely to be an over-estimate of the true content at late times but many

more autopsy data correlated with urinary excretion data are required

before Langhamfs equation can be confidently amended or replaced.

5 . Effects

Voelz ( 1 9 7 5 ) has reviewed published information on the biological

effects of plutonium in man and concluded that no significant harmful

effects have been seen that can be definitely attributed to this radio-

nuclide. The only clinical or pathological finding reported has been the

development within a few months to several years of fibrous nodules around

the site of plutonium deposits of between about 1+ and 2 0 0 nCi ( 0 . 1 5 and

7 . 1 + kBq) in wounds. Eight cases have been reported (Lushbaugh et al, 1 9 ^ 7 )

which describe nodules not unlike those formed as a result of a foreign body

reaction. One of these lesions developed in the skin of the palm of the

19

hand of a person who had received a puncture wound contaminated with

plutonium four years previously. At the time of the excision the site

still contained 5 nCi ( 0 . 1 £ kBq) of plutonium-239 (Lushbaugh and Langham,

1 9 6 2 ) . Although the lesion was small the basal cells of the epidermis were

atrophic and dyskeratotic. The changes were similar to known precancerous

epidermal cytological changes but any potential development of the lesion

was prevented by its surgical excision. This is normal practice in the

case of superficial puncture wounds. Schofield ( 1 9 7 6 ) has reported that

at Windscale local deposits of alpha emitting radionuclides are surgically

removed if they are in excess of about 1+ nCi ( 0 . 1 5 kBq). A case of

synovial carcinoma allegedly associated with the handling of a leaking

carboy (Tamplin and Cochran, 1 9 7 U ) was not associated with a confirmed

plutonium intake, which would be a necessary prerequisite for establishing

a casual relationship (Voelz, 1 9 7 5 ) •

The most comprehensive follow-up available on workers exposed to

plutonium is that reported by Hempelman et al, ( 1 9 7 3 ) on 2 6 workers who worked

on the Manhattan Project at Los Alamos between 191+3 and 19^4-5- They were

exposed predominantly to aerosols of plutonium when they were involved in

purification and extraction of the metal. Despite uncertainties in body

content estimates exposures were estimated to be between 5 nCi and 1+20 nCi

( 0 . 1 9 and 1 5 - 5 kBq). The only observed signs of ill-health in the exposed

group were those that might be expected in any similar group of unexposed

United States males of this age. One of the men (aged 3 8 ) died of coronary

heart disease while another has recovered from a coronary. This study has

recently been extended and will include a further 2 3 2 persons with

estimated body contents of plutonium in excess of 1+ nCi ( 0 . 1 5 kBq).

In the United Kingdom the National Radiological Protection Board has

set up a National Registry for Radiation Workers. On the Register workers

that have been exposed to plutonium will be noted.

At the British Nuclear Fuel (BNPL) reprocessing plant at Windscale

(Cumbria, United Kingdom) where large quantities of radioactive materials

including plutonium, are processed each year, 11+ workers have an estimated

body content of plutonium of over a maximum permissible body burden (MPBB

= 1+0 nCi ( 1 . 5 kBq.))> mostly resulting from exposures during the first 1 0

years of operation of the plant. There are also 21+ workers with between

50% and 1 0 0 % of one MPBB. No pathological findings can be related to

exposure to plutonium in any of these cases (Schofield, 1 9 7 6 ) . In a recent

court action in the United Kingdom (November 1 9 7 7 ) it was agreed by BNFL

20

and the plaintiffs that, on the balance of probabilities in view of the

special factors in the case, the death from myeloma of an ex-radiation

worker who had been previously employed at BNEL, Windscale, was induced

by radiation at work. The factors included the dosages of irradiation

received and the amount of plutonium within his body, the latter of which

unusually, exceeded the prescribed international limit ( U O nCi ( 1 . 5 k Bq))

and some evidence of a causal relationship between myeloma and radiation.

In an opinion of the case by Dolphin (1 9 7 7 ) 9 it was noted that the man's

exposure history was both to external radiation and to plutonium. It was

likely that the myeloma had been induced by external radiation, the

plutonium contributing little to the risk.

6. Summary

A limited amount of information on the metabolism and effects of

plutonium and other actinides has been obtained from studies of

plutonium workers. The data is difficult to interpret because

many workers are also exposed to external radiation and possibly

to other internally incorporated radionuclides. Prom the small number

of workers who have incorporated plutonium and other actinides there

is no evidence of life shortening or malignant disease which can be

attributed to these intakes. The total number of persons in the

Nuclear Industry is increasing annually and long term follow-up

studies of those exposed to plutonium and higher actinides could

provide valuable information. A centralised system for the collec-

tion of such data in Europe would facilitate its use for improving

the basis upon which standards of protection are determined.

Chapter 4

METABOLISM IN ANIMALS

1. Introduction

In the last 3° years extensive animal studies on the metabolism of

plutonium have been published by workers in many countries including

France, The Federal Republic of Germany, the UK, USA and USSR. This work

has recently been reviewed in a number of publications: ICRP ( 1972b) , Bair

et al, ( 1 9 7 3 ) , Vaughan et al, (1973)> Bair ana Tnompson (197U), Bair (1971+a),

Bair et al, (197U), Dolphin et al, (197U), Durbin ( 1 9 7 5 ) , Bair ( 1 9 7 6 ) .

Animal studies have also been conducted on the metabolism of the higher

actinides americium and curium although data available are considerably

less extensive than for plutonium. This work has been reviewed by ICRP

(1972b) , Durbin (1973) and Bair ( 1 9 7 6 ) .

The object of this chapter is to review data on the metabolism of

plutonium, americium and curium, in animals that may be used to predict

their behaviour in man. However the levels of activity administered to

animals have frequently been greatly in excess of those likely to be

encountered in cases of human contamination, other than in the most severe

accident situations. The amount of actinide deposited in a tissue can

markedly influence its subsequent behaviour and therefore data from

animals given large amounts of activity must be interpreted with caution.

Where appropriate, some human data have also be included in this review.

2. Entry into the body

2.1 Routes of entry

Radioactive materials may enter the body either by inhalation, by

ingestion, through cuts, abrasions or other wounds, or by absorption

through the intact skin.

In the case of actinides any intake may be considered to consist of

two different fractions. Firstly a soluble (transportable) fraction that

rapidly enters the systemic circulation and is either deposited in tissues

or excreted. Although the size of this fraction depends upon the physico-

chemical form and on the route of entry in general its tissue distribution

and retention does not. Secondly there is a relatively insoluble (poorly

transportable) fraction due either to the formation of colloids after the

hydrolysis of soluble forms of actinides (eg, nitrate) at the site of entry

or resulting from an intake of actinide particles such as the oxide. A

number of physical and chemical factors influence the behaviour of this

21

22

second fraction. Polymers are formed more readily from plutonium compounds

than from the higher actinides (Chapter 2 ) and the extent of colloid

formation is also influenced by the mass of actinide deposited. For equal

activities of plutonium-239- plutonium-238, americium-2Ul and curium-2L|.2

deposited in a tissue the relative masses are 1 : 0 . 0 0 3 6 : 0 . 2 : 0 . 0 0 0 0 2

respectively and plutonium is therefore much more likely to form polymers.

In the case of intakes of particles of plutonium-239> plutonium-238,

americium-2i;1 and curium-22+2 the relative specific activities are approxi-

mately 1 : 3 0 0 : ^ 0 : 5 U » 0 0 0 respectively. The particles with a higher specific

activity would be expected to break up more readily in tissues as a result

of radiolytic activity. Radiolytic activity may also help to mobilise

americium and curium from any polymers formed in tissues.

When large amounts of activity are deposited, giving a high local dose

of radiation, fibrosis may develop preventing its transport to other

tissues. This may occur particularly at wound sites (Lushbaugh and Langham,

1 9 6 2 ) .

2 . 2 Inhalation

Retention in the lungs

Inhalation is the most likely route of accidental intake of signifi-

cant quantities of plutonium in man (Voelz, 1 9 7 5 ) • This would also be

expected to be the case for americium and curium. These actinides may be

deposited in the respiratory system either individually or in combination

with other active or inactive materials. It is important therefore to

understand factors influencing their deposition in and 'learance from the

lung both as individual species and as mixtures.

Animal experiments have shown that the regional deposition of an

aerosol in the respiratory system depends mainly on the particle size

distribution. The chemical form of the compound inhaled influences the

subsequent clearance from the lung (Report of the Task Group on Lung

Dynamics, ICRP, 1 9 6 6 a ) .

Lung retention curves for inhaled actinides in both man and animals

have generally been fitted by either two or three exponentials or a power

function. Within the first few days after exposure a fraction of the

deposited activity is rapidly cleared from the respiratory tract. In the

case of insoluble compounds such as plutonium dioxide the majority (> 99%)

of this fraction is activity deposited in the upper regions of the

respiratory tract which is subsequently cleared by the mucociliary

escalator up the bronchi and trachea swallowed and excreted in the faeces.

23

For soluble actinide compounds some activity is also rapidly translocated

to the blood. The first phase of clearance has a half-time of about one

day (Morrow et al, 1 9 6 7 ) .

Particles deposited in the pulmonary region of the lung and in the

terminal bronchioles below the ciliated epithelium are cleared slowly. In

a survey of published data on in vivo and bioassay measurements after

plutonium dioxide inhalation in large animals and man, Watts ( 1 9 7 5 ) showed

that the slower component of retention could be described by two components

with half times of 30 days and 5 0 0 days. The overall retention R(t) with

time (t) was described by the equation:-

R(t) = A exp ~ ( 2 ^ 2 S ) + B exp ~ ^ > + C exp "

The relative proportions of the three components A, B and C depend

considerably on the particle size distribution and the physico-chemical

form of the inhaled aerosol and therefore cannot be specified.

The retention half-time for the slower component of retention of

plutonium dioxide in the lungs of smaller animals varies from about 1 5 0 to

5 0 0 days in rodents and 2 0 0 to 1 2 5 0 days in dogs (Bair, 1 9 7 6 , Buldakov

et al, 1 9 6 9 ) . In the dog studies lung retention half-times of 1 0 0 0 days or

longer have been found following initial lung deposits of from 0 . 2 uCi

( 7 . 1 ; kBq) to about 5 0 uCi ( 1 . 9 MBq) of plutonium dioxide (Park et al, 1 9 7 2 ) .

These levels of activity may have influenced clearance mechanisms. In the

hamster alveolar clearance of plutonium dioxide is known to be inhibited

with an increase in the initial lung deposit (Sanders, 1 9 7 6 a ) .

The mechanism of clearance of these slower phases from the terminal

and respiratory bronchioles and alveoli is not clear but involves the

rapid phagocytosis of particles by alveolar macrophages which are

eventually cleared up the ciliary escalator or to lymph nodes. Some

material is also solubilised and translocated to the blood. The localisa-

tion of plutonium particles within macrophages has been demonstrated in

autoradiographs prepared from sections of lung tissue (Sanders, 1 9 6 9 ) . It

has been suggested that plutonium particles not phagocytosed by these cells

are found in type I alveolar wall cells (Sanders and Adee, 1 9 7 0 ) . However,

recent studies by Brightwell and Ellender ( 1 9 7 7 ) in hamsters have shown

that 90% of an initial lung deposit of plutonium dioxide can be removed

from the lungs by bronchopulmonary lavage (Chapter 8 ) and that most of this

activity (> 90%) has been accumulated by macrophages. Uptake of plutonium

particles by alveolar wall cells is therefore probably not of great

2k

significance.

The temperature of formation of inhaled plutonium particles affects

the retention of plutonium in the lung. This is illustrated by the

results shown in Table 1 + . 1 . At temperatures of 900°C or 1 1 5 0°C the

retention half-time of plutonium dioxide prepared from the chloride is

similar to values reported by Bair ( 1 9 7 6 ) for beagle dogs exposed to

plutonium dioxide. With lower temperatures of preparation the retention

half-times are more like those found for soluble plutonium compounds

(Mewhinney et al, 1 9 7 6 a ) . These changes are due to differences in solu-

bility of the aerosol caused by differences in the chemical form of

plutonium produced by heat treatment. At 325°C "^ne aerosol particles

would consist of a mixture of plutonium chloride, oxychloride and plutonium

dioxide. At higher temperatures of preparation the production of plutonium

dioxide, would be favoured. Particle size itself also influences retention.

For oxides of various sized particles calcined at similar temperatures

retention half-times are generally less for aerosols with a smaller part-

icle size distribution (Bair et al, 1 9 6 3 ) .

Following the inhalation of more soluble compounds of plutonium there

is a greater transfer of activity to the blood resulting in a faster rate

of clearance from the lung. The retention half-times for plutonium inhaled

as organic complexes, nitrate of fluoride range from about 30 to 3 0 0 days

in rats, hamsters and dogs (Buldakov et al, 1 9 6 9 , Bair, 1 9 7 6 ) .

Americium and curium compounds are generally cleared from the lungs

of rats and dogs more rapidly than plutonium compounds. Figure U . 1 shows

data obtained by Nenot et al, ( 1 9 7 2 ) in rats that had inhaled plutonium-

2 3 8 , plutonium-239> americium-2i+1 or curium-2l|.2 as the nitrates. Clearance

of both americium and curium was more rapid than plutonium. This may result

from the lesser tendency of americium and curium to form polymers in the

lung than plutonium and a greater rate of solubilisation of any polymers

that are formed. Figures U . 2 , 1+.3 and k»k show autoradiographs of sections

of lungs of rats exposed to americium, curium and plutonium nitrates.

These autoradiographs show the formation of plutonium polymers in the lung.

Alpha activity due to the presence of both americium and curium is more

uniformly distributed throughout the lung tissue.

Figure shows data obtained from studies in beagle dogs of the lung

retention of oxides of plutonium, americium and curium and also curium

chloride. Both americium and curium leave the lung more rapidly than

plutonium with little difference apparent in the pulmonary retention of the

Table

U.1

Distribution of plutonium in tissues of Beagle Dogs

56 days after inhalation of plutonium aerosols

Compound

Particle

Size

(MAD)

No. of

dogs

Percent of initial lung deposit

Tj of

Lung

Retention

(days)

Compound

Particle

Size

(MAD)

No. of

dogs

Lung

TBLN

Liver

Skeleton Urine

Faeces

Tj of

Lung

Retention

(days)

Plutonium

-239 dioxide

(3

25°C)

a

1.9

P

3 5k

o.

k 5

.9

7.6

1

.2

30

180

Plutonium

-239 dioxide

(6

00°C)

a

1.9

P

3 67

0.

6 1

.3

2.1

0.7

28

3U

0

Plutonium

-239 dioxide

(9

00°C)

a

1.9

P

3 80

o.

k ND

0.2

0

-3

19

> 5

00

Plutonium

-239 dioxide

(H

50°C)

a

1.9

P

3 87

ND

0.2

o.

h 11

>

50

0

Plutonium

-238 dioxide

(1

150°

C)

1.9

m

3 81

h.

2 0

.9

2.3

o.

k 9

.0

> 5

00

| Plutonium

-238 dioxide

(1

150°

C)

1.3

P 3

88

3.5

1

.0

2.2

0

.1

k.o

250

AMAD

Activity median aerodynamic diameter of the aerosol

TBLN

Tracheo-bronchial lymph nodes

ND

Activity not detected

p

Poly disperse aerosol, geometric standard deviation >

1.2

m

Mono disperse aerosol, geometric standard deviation <

1.2

a

Prepared by heating plutonium chloride at various temperatures

Ref: Mewhinney et al,

(1

97

6a)

25

. 2 6

1 0 0

ue

pjn

q

6u

n|

)D 1

1;u i

jo %

D a y s p o s t i n h a l a t i o n

Figure 1+.1 Retention of actinides in the lung after their inhalation as

nitrates (pH 1 . 5 ) . Redrawn from Nenot et al, ( 1 9 7 2 ) .

"Reproduced from Health Physics Vol. 2 2 , p. 6 5 9 , 1 9 7 2 , by

permission of the Health Physics Society."

27

Figure i+.2 Autoradiograph of a section of rat lung 7 days after inhalation

of americium-2U1 nitrate (Provided by R. Masse, Commissariat a

l'Energie Atomique, France).

28

Figure I 4 . 3 Autoradiograph of a section of rat lung 7 days after inhalation

of curium-2UU nitrate. (Provided by R. Masse, Commissariat a

l'Energie Atomique, France).

29

Figure U - U Autoradiograph of a section of rat lung 7 days after inhalation

of plutonium-239 nitrate. (Provided by R. Masse, Commissariat

a l'Energie Atomique, France).

30

1 0 0

2 3 9 Pu(N0 3 )£

0 1

2 U

C m C l 3 •

C m O 1 ? 3

_L

2 3 9 P u O o - 3 5 0 ° C

JL 4 0 0 8 0 0

T i m e a f t e r e x p o s u r e , d a y s

1 2 0 0

Figure U - 5 Lung retention of inhaled transuranic elements in beagle dogs.

Redrawn from McClellan et al, ( 1 9 7 2 c ) . "Reproduced from Health

Physics Vol. 22, p. 817 , 1972, by permission of the Health

Physics Society."

%

of

Init

ial

lun

g

bu

rd

en

o

o

31

two forms of curium. Similar results for the lung retention in dogs of

oxides of americium and curium have been obtained by Craig et al, ( 1 9 7 6 ) .

These results would be anticipated from the differences in solubility and

specific activity of the various oxides. It has also been shown that in

water particles of americium are unstable and become amorphous on ageing

(James et al, 1 9 7 8 ) .

The majority of experimental studies on the retention of actinides in

the respiratory system have used single actinide preparations in isolation.

In practice humans would normally be exposed to mixtures of actinides

either alone or in combination with fission products or other metals.

There is however little published work on the retention of such mixtures.

Data summarised by Bair ( 1 9 7 6 ) on the retention of americium and

plutonium in dogs after their inhalation in particles consisting of

mixtures of the oxides showed that separation of americium from plutonium

in the lung was barely detectable as long as 6 years after inhalation.

Studies in hamsters have also demonstrated that following the inhalation

of particles containing oxides of both plutonium and americium (americium

1 0 % by activity, 0 . 1 8 % by mass), the lung retention of the two nuclides

does not differ significantly up to a year after inhalation. With mixed

oxide aerosols of plutonium, americium and sodium oxides the amounts of

plutonium and americium translocated to the blood may increase by more

than a factor of a hundred but the lung retention of both nuclides is

similar (Stather et al, 1 9 7 7 b ; Brightwell and Carter, T 9 7 7 ) .

Some work has been reported on the retention of caesium-137 in the

lungs of beagle dogs following inhalation incorporated in fused alumino-

silicate particles (Boecker et al, 1 9 7 7 ) . The particles were relatively

insoluble in biological fluids and there was little leaching of caesium-137

from the particles. Actinides fused into such an insoluble matrix might be

expected to behave similarly.

The limited data available therefore suggest that following the

inhalation of particles consisting of mixtures of actinides either alone or

in combination with other materials the retention of actinides in the lung

will be influenced by the species present in greatest mass and its chemical

form.

Translocation from the lung to other tissues

Following deposition of actinides in the respiratory system the

activity may be removed by a number of processes. A fraction enters the

blood directly from the lungs after dissolving in tissue fluids. This

32

activity is either transported to other tissues, principally liver and

bone, or it is excreted. A second fraction is accumulated by macrophages

which are cleared from the lung by bronchial and tracheal clearance

mechanisms, swallowed and excreted. A third fraction is translocated via

the lymphatics to regional lymph nodes and some of this material may

ultimately reach the systemic circulation.

The amount of the soluble fraction entering the blood from the lung

either in the first few days after inhalation or as a result of a progres-

sive solubilisation of polymers or particles depends considerably upon the

chemical form of the inhaled material and in the case of relatively insolu-

ble aerosols such as plutonium dioxide on the particle size (Bair et al,

1 9 7 3 , Stather et al, 1 9 7 5 , Stradling et al, 1 9 7 7 ) . However, the distribu-

tion of actinides in the body following their entry into the systemic

circulation is in general independent of the physico-chemical form deposited

in the lungs.

Table 1+.2 shows the results from studies in which the distribution of

plutonium in extrapulmonary tissues of the rat was measured following the

pulmonary intubation of solutions or suspensions of various plutonium

compounds that had passed through a filter with a pore size of 1 0 0 nm or

less. In the case of citrate and nitrate forms more than 90% of the

original preparation passed through the filter but for a plutonium dioxide

suspension the comparable value was about 0 . 2 % . Despite these differences

the transportable fraction of each preparation distributed between the liver

and skeleton in a manner similar to that found for intravenous plutonium

citrate. It has been shown that measurements of the ultra-filterable

fraction of plutonium in an aerosol suspension can be used to give an

estimate of the transportable fraction of the aerosol (Kanapilly et al, 1 9 7 3 ,

Stather et al, 1 9 7 5 , Miglio et al, 1 9 7 7 ) .

The distribution of plutonium in the tissues of dogs and rats exposed

to two relatively soluble forms of plutonium (the citrate and the nitrate)

is shown in Table U . 3 « There is little retention in the thoracic lymph

nodes but appreciable amounts of activity are deposited in other extra-

pulmonary tissues. Because the major sites of deposition of plutonium

that has entered the systemic circulation are the skeleton and the liver

only the activity in the liver is given separately. The results in both

dogs and rats show that plutonium is more transportable in the lung when

administered as citrate than as nitrate probably as a result of the more

rapid hydrolysis of plutonium nitrate at physiological pH to form relatively

Table fr.g

d .

Tissue distribution of plutonium

in rats one week after pulmonary intubation in various chemical forms

Compound

No.

of

Animals

Pore size

of

filter (nm)

Percentage of

solution or

suspension

passing filter

(#)

% Administered Activity

Ref

Compound

No.

of

Animals

Pore size

of

filter (nm)

Percentage of

solution or

suspension

passing filter

(#)

Lung

Liver

Skeleton and

other soft

tissues

Total tissue

deposit (T)

x

10

0 (o

/o)

Ref

Plutonium dioxide

3.

h 10

0 0.

3k

59

.2

3.5

1

8.6

22

.1

15

.8

A

Plutonium dioxide

3.

8 10

0 0

.16

U3-

5 U

.2

27

.8

32.0

1

3.1

A

Plutonium nitrate

6 25

96

5

2.2

6

.5

30.8

2

7.3

1

7.

k A

Plutonium citrate

6 25

99

1

5.9

1

1.2

5

8.^

69

.6

16

.1

A

Plutonium dioxide

+ sodium oxide

a> ^

6 25

5k

5^

.9

3.1

15

.5

18

.6

16

.7

A

Plutonium citrate

0

6 25

99

0

.16

12

.9

69

.2

82.1

1

5-7

B

U)

a

Filtered aerosol suspension

b

Atomic ratio of plutonium and sodium in mixed aerosol

1

:19

.2

c

Administered by intravenous injection

d

Plutonium

-239

Re

f: A. Stather et al,

(1

97

5)

B. Stather and Howden

(1

97

5)

Table

U

* 3

Distribution of plutonium after inhalation as nitrate or citrate

Compound

Species

% Plutonium Administered (see footnote)

Reference

Species

Time

(days)

Lung

TBLN

Liver

Skeleton plus

other soft tissues

Faeces Urine

Reference

Dog

1 Ik

0

.05

1.U

6

Ballou and Park,

19

72

Dog

30

37

0.2

0 5

.3

38

10

0 29

o.

l+o

16

38

Rat

1 27

_

9.5

U

5 Stather and Howden,

19

75

28

9 -

U.3

59

1

82

1.8

-

2.5

58

Dog

1 88

0

.06

0.3

2 1

.8

Ballou and Park,

19

72

Dog

30

32

0.1+

9 U

3 1

00

U1

0.6

10

28

Rat

1 78

_

1.8

3

-2

0 0

Morin et al,

19

72

Rat

30

U0

-1

.0

7.7

1+

2 9

.2

90

1$

-0

.3

1+.1+

69

11

Rat

1 9

6 0.6

1.9

0

0.2

Morin et al,

19

72

Rat

30

53

-2

.2

18

.1

2k

2.5

Rat

30

32

-1

.5

11

Ballou,

19

75

10

0 12

-

o.5

9

20

0 k

-o.

l+

12

Rat

30

18

2.2

18

Ballou,

19

75

10

0 9

-1

.8

12

20

0 3

-0.6

21

Plutonium

-239 citrate

Plutonium

-239 citrate

Plutonium

-239 nitrate

Plutonium

-239 nitrate

Plutonium

-238 nitrate

Plutonium

-239 nitrate

Plutonium

-238 nitrate

a

% inhaled activity less faecal activity in first 6 days

b

Administered by pulmonary intubation

c

% inhaled activity less faecal activity in first

3 days

initial lung burden

35

insoluble polymers. In all these studies the proportion of the extra-

pulmonary deposit in the liver is relatively low indicating that plutonium

is entering the blood predominantly in a monomeric form (Lindenbaum et al,

1 9 6 8 ) . These results also show that in the dog there is no reduction in

the liver content of plutonium with time but that it is rapidly cleared

from the rat liver. Because of rapid loss of plutonium and other actinides

from the rat liver long term studies in this species are of little value

for extrapolation to man.

A number of other chemical forms of plutonium have also been studied.

Sodium plutonyltriacetate, ammonium plutonium pentacarbonate, plutonium

chloride (Lyubchanskii, 1 9 ^ 7 ) and plutonium oxalate (filtered through a

2 5 nm filter) (Stather and Howden, 1 9 7 5 ) all behave as relatively soluble

forms of plutonium in rats after their deposition in the lungs. When

administered as the fluoride to dogs plutonium was less readily translocated

to the blood ( 0 . 7 5 % of the initial lung deposit of plutonium was in extra-

pulmonary tissues at 9 0 days), although there was an appreciable deposit in

the tracheobronchial lymph nodes ( U - 5 % at 9 0 days) (Dilley, 1 9 7 0 ) .

Following the administration of a complex of plutonium with the

chelating agent diethylene triamine pentaacetic acid (DTPA) to rats by

pulmonary intubation only 0 . 5 % of the initial lung deposit of plutonium

remained in the lung at 7 days and less than 1 % in the extrapulmonary

tissues (Stather and Howden, 1 9 7 5 ) - This is a consequence of the high

stability of the chelate complex in body fluids and the rapid excretion

of DTPA in the urine.

Extensive information is available in the literature on the distribu-

tion of plutonium in animal tissues following the inhalation of plutonium

dioxide. With few exceptions these studies have shown the low solubility

of plutonium dioxide in the lung (ICRP, 1 9 7 2 b ) . The most comprehensive

data have been obtained in beagle dogs exposed to plutonium dioxide aerosols

with a mass median diameter of about 3 jjm (Park et al, 1 9 7 2 ) . Initial

alveolar deposits varied between less than 1 jiCi and about 5 0 ^iGi ( < 3 7 kBq

to about 1 . 9 MBq).

By 2 years after exposure the liver and skeleton each contained about

1 % of the initial alveolar deposit and the thoracic lymph nodes about 1 0 %

(Figure U « 6 ) . By 1 0 years, about 5% of the activity had translocated to

the skeleton, 1 5 % to the liver and 50% to the thoracic lymph nodes. The

relatively higher level of plutonium in the liver than in the skeleton

after about k years may have resulted from radiation damage to the lungs

36

TIME AFTER EXPOSURE, YEARS

Figure ij.,6 Retention and translocation of alveolar deposited plutonium-239

oxide in beagle dogs. Redrawn from Bair ( 1 9 7 6 ) .

239P

u

CO

NTE

NT

OF

TIS

SU

ES

(% O

F A

LV

EO

LA

R-D

EP

OS

ITE

D 239P

u0

2)

3T

allowing the entry of particles of plutonium directly into the blood or

alternatively some translocation from either bone or lymph nodes to liver

may have occurred. These studies have now been extended to include dogs

exposed to much lower initial lung deposits. It will, however, be more

than 10 years before the study is completed.

The method of preparation of plutonium dioxide can influence the trans-

portability of plutonium in the lung. Mewhinney et al, (1976a) reported

that the amount of plutonium translocated to extrapulmonary tissues was much

greater following the inhalation of low fired plutonium dioxide than of high

fired plutonium dioxide (Table U . 1 ) . Bair (l97Ub) has also reported studies

on beagle dogs that had inhaled plutonium dioxide prepared by heating either

the oxalate or the metal at different temperatures. Although all forms of

plutonium dioxide showed a low transportability in the lung the transport-

able fraction and the activity deposited in the tracheobronchial lymph nodes

varied considerably for different methods of preparation.

Other elements can also influence the behaviour of plutonium dioxide

in the lung. A series of studies have been reported on the lung clearance

of plutonium in rodents following their exposure to mixed aerosols of

plutonium and sodium oxides produced by an exploding wire technique

(Stather et al, 1975; Brightwell and Carter, 1977; Stather et al, 1 9 7 7 ) .

These studies have shown that with an excess of sodium the transportable

fraction of plutonium may be increased to values characteristic of relat-

ively soluble forms of plutonium (Table U.U). Figures !+• 7 and LL.8 show

autoradiographs of sections of lungs from hamsters that had inhaled either

an aerosol of plutonium dioxide particles or a mixed aerosol of plutonium

and sodium oxides (both aerosols had an activity median aerodynamic diameter

(AMAD) of about 1 0 3 Lim and a geometric standard deviation (GSD) of about

1 . 5 ) . In the lungs of animals exposed to plutonium dioxide the majority

of the activity is present as discrete particles but in animals that had

inhaled the mixed oxide aerosol a large proportion of the activity is

diffusely distributed throughout the lung volume indicating breakdown of

the inhaled particles. Filtration studies on aqueous suspensions of mixed

oxide aerosols have shown that the particle size distribution of plutonium

decreases with increasing sodium content of the aerosol. At sodium:

plutonium atomic ratios in excess of about 20:1 up to 50% of the plutonium

is in particles less than 100 nm in diameter whereas in an aqueous suspen-

sion of plutonium dioxide the comparable value is about 0.2% (Stather et

al, 1975 ; Brightwell and Carter, 1 9 7 7 ) . The particles of plutonium passing

the 100 nm filter have been shown to be about 1 nm in diameter and to

Table

k*

k

Distribution of plutonium in tissues of rodents after inhalation

c

or pulmonary intubation of various plutonium compounds

Compound

Species

Time after

exposure

(days)

Method of

administration

% Initial Lung Deposit

Reference

Compound

Species

Time after

exposure

(days)

Method of

administration

Lung

Extra Pulmonary Tissues

Reference

Plutonium dioxide

Rat

8U

Inhalation

11+.

8 0

.15

A

Plutonium citrate

Rat

91

P.I.

h.k

63.8

B

Plutonium nitrate

Rat

91

P.I.

9.6

ho

.Q

B

Plutonium dioxide

+ sodium oxide

3.

Rat

8h

Inhalation

5.7

3.

6 A

Plutonium dioxide

+ sodium oxide

a

Hamster

90

Inhalation

2h

26

C

P.I.

Pulmonary intubation

a

Atomic ratio plutonium:sodium in aerosol suspension

1:

20

c

Plutonium

-239

References: A. Stather et al,

(1

97

5)

B. Stather and Howden

(1

97

5)

C. Stather et al,

(1

97

7)

38

39

Figure 4.7 Autoradiograph of a section of hamster lung 6 months after

inhalation of an aerosol of plutonium dioxide. (Provided by

J. Brightwell, National Radiological Protection Board, U.K.)

ho

Figure 1+.8 Autoradiograph of a section of hamster lung 6 months after

inhalation of an aerosol of plutonium dioxide and sodium oxide

(Plutonium: Sodium atomic ratio 1:10J+)- (Provided by

J. Brightwell, National Radiological Protection Board, U.K.)

1+1

readily cross the lung cell membrane, subsequently dissolving in the blood

and behaving as soluble plutonium (Stradling et al, 1 9 7 7 ) . Particles of

this size can readily dissolve as about 90% of the atoms in the particle

are at the surface (Chapter 2 ) .

These results indicate, therefore, that in mixed oxide aerosols of

plutonium and sodium the high biological transportability of the plutonium

is predominantly due to the decreased particle size distribution of the

plutonium dioxide. Metivier (1976) has also suggested that in aerosols

produced by the combustion of plutonium and sodium in the presence of

oxygen some plutonium may be present as Pu(Vl) or Pu(VIl) and this may

influence the transportability of the plutonium in lung.

A number of studies have compared the tissue distribution of plutonium

following the inhalation of plutonium dioxide prepared from either

plutonium-238 or plutonium-239. In rats exposed to aerosols of plutonium-

238 dioxide or plutonium-239 dioxide with similar particle size character-

istics there was a greater translocation of plutonium from the lung to the

skeleton and other soft tissues with plutonium-238 (Table 1+.$). Similarly,

in dogs that had inhaled plutonium-238 dioxide between 2 and 6 years

previously the retention of plutonium in the liver and skeleton was about

10 times that found in dogs that had inhaled plutonium-239 dioxide (Park

et al, 1975 a and b). Further data showing the greater transportability of

plutonium-238 dioxide than plutonium-239 dioxide in animals have been

reported by Mewhinney et al, (1976a) (Table U .1 ) and Stather et al, ( 1 9 7 7 b ) .

An increased transportability of plutonium-238 compared with plutonium-239

has also been found in rats following inhalation as the nitrate (Table U«3)«

The increased transportability of plutonium-238 in lung compared with

plutonium-239 may be attributed to the higher specific activity of particles

containing plutonium-238 resulting in radiolytic activity causing more

rapid breakdown and solubilisation of the particles. The occurrence of a

fragmention process for plutonium dioxide particles in water has recently

been discussed by Fleisher and Raabe ( 1 9 7 7 ) .

Less information is available on the translocation of americium and

curium to other tissues. From studies in rats reported by Nenot et al,

(1971b),the translocation to tissues of americium-21+1 inhaled as the

nitrate (Table U.6) can be compared with the values found for plutonium-238

and plutonium-239 (Table U«3)« These results show that americium is

translocated more rapidly from the lung to extrapulmonary tissues than

plutonium. However as the liver deposit of actinides in rats is rapidly

Table

1+

.5

Comparative distribution of inhaled plutonium-238 dioxide and plutonium-239 dioxide in rats

% Body Activity

Plutonium

-238 dioxide

Plutonium

-239 dioxide

Days after exposure

20

127

U81

1

3 68

1

13

Tissue

Thoracic I#mph Nodes

O.h

3.

U 3

.3

0.3

1

.8

-Lung

82

78

68

97

97

99

Spleen

0.1

3 0.

2 0

.5

0 0.

0U

0

Kidneys

0.5

1

.1

0.5

0

0 0

Liver

2.h

1.7

3

.6

0.02

0

.3

0.3

Skeleton

11

.0

15

.0

23.O

0.01

0.

1 0

.16

Terminal Body

Burden (iCi)

9.5

0

.8

0.21

1

2.5

1

.5

0.6

Plutonium dioxide produced by calcining the oxalate in air at

3

50

CMD

2 =

0

.1, GSD was

1

.5-1

-9 for plutonium

-238

, 1

.7-2

.0 for plutonium

-239

Ref: Stuart et al,

(1

96

8)

quoted by Bair et al,

(1

97

3)

k2

Table

U.6

Distribution of americium

-2U

l in rat tissues after inhalation as the nitrate

Time

(days)

% Americium administered

3.

Time

(days)

Lung

Liver

Skeleton

Kidney

Muscle

Urine

Faeces

1 9

5 2

2.1

0.2

0

.2

0.5

0

10

8.7

22

. h

19

.9

1.8

1.3

1

1.5

3

2.7

45

k.k

2.1

18.1

--

10.0

61

.9

90

h.k

1.5

2

2.3

1

.9

-10.8

57

.9

a

% inhaled activity less faecal activity in first

3 days

Ref: Nenot et al,

(1

97

1b

)

^3

kk

lost from the body an accurate estimate of the total amounts of plutonium

and americium translocated to extrapulmonary tissues in these studies cannot

be obtained. This is a particularly important consideration in the case of

americium as about $0% of the activity entering the blood is deposited in

this tissue.

Studies by Crawley and Goddard (1976) on the tissue distribution of

americium following pulmonary administration as citrate showed that about

80% of the administered activity had translocated to extrapulmonary tissues

by one week after administration. This is a value similar to that reported

for plutonium administered as citrate by a similar technique (Stather and

Howden, 1 9 7 5 ) .

It could be expected that soluble forms of curium would behave

similarly to americium as it has been shown by Crawley and Goddard (1976)

and Stather and Priest (1977) that the lung clearance of these two nuclides

when administered as nitrates do not differ significantly.

A number of animal experiments with oxides of americium and curium

have shown they behave as relatively soluble materials in the lung. In

studies by Craig et al, (1976) in beagle dogs about h$% of the body burden

of americium-2[|.1 at 30 days after exposure was in extrapulmonary tissues.

For curium the comparable value was about 80%. The greater solubility of

curium-2i|l+ oxide than americium-2i|1 dioxide may partly be due to the

smaller particle size of the inhaled aerosol and greater specific activity

(Table U - 7 ) . Similar results have been reported by McClellan et al, (1972a)

on beagle dogs exposed to curium-2L|lL oxide. These studies also indicated

that americium and curium are translocated to liver and bone in fairly

comparable amounts. It is noteworthy that in the study by Craig et al,

(1976) about 30% of the extrapulmonary deposit of curium-2l4+ was accumu-

lated by muscle tissue (Table 1+.7). This result cannot be readily

explained.

Figure k*9 shows an autoradiograph of a section of rat lung from an

animal exposed to americium dioxide. Activity is more diffusely distri-

buted throughout the lung than is found for plutonium dioxide indicating

the breakdown of particles of americium dioxide. This no doubt contributes

to the increase in transportability as compared with plutonium dioxide.

Summary

A model for the deposition and retention of inhaled aerosols in the

human respiratory tract was described in the Report of the Task Group

on Lung Dynamics (ICRP, 1966a) for Committee 2 of the International

Table 1+.7

Tissue distribution of americium-2U1 and curium-21+1+ in beagle dogs after inhalation of

a

b

americium-21+1 dioxide

and curium-21+1+ oxide

% Final Body Activity

Tissue

10 days

30 days

90 days

270

days

Americium

Curium

Americium

Curium

Americium

Curium

Americium

Curium

Lung

78

.5

32

.9

55

.4

19

-9

29

.4

18

.0

13

.8

8.1

Liver

4.1

2

9.1

1

8.9

37

.1

38

.8

35

.5

32

.4

33

-6

Skeleton

5.1

18

.1+

10

.9

19

.8

18

.2

29

.7

45

.1

26

.6

Muscle

8.0

1

2.5

1

1.3

1

3.0

9

.9

10

.0

4.4

2

6.7

Other

Tissues

4.3

7

.1

3.5

1

0.2

3

-7

6.8

4

.3

5.0

a

AMAB

1

.35 GSD

1.7

1

b

AMAB

0

.52 GSB

2.

11+

Reference: Craig et al,

(1

97

6)

h5

1+6

Figure 1+-9 Autoradiograph of a section of rat lung 7 days after inhalation

of americium-2l+1 dioxide. (Provided by R. Masse, Commissariat

a l'Energie Atomique, France).

hi

REPORT OF TASK GROUP OF COMMITTEE 2

AMENDED CONSTANTS FOR U S E WITH T G L M CLEARANCE MoDEi/f

Region Pathway

Compound class

Region Pathway (D) (W) 00

N-P (a) 0.01 d/0.5 0.01 d/0.1 0.01 d/0.01 (b) 0.01 d/0.5 0.4 d/0.9 0.4 d/0.99

T - B (c) 0.01 d/0.95 0.01 d/0.5 0.01 d/0.01 (d) 0.2 d/0.05 0.2 d/0.5 0.2 d/0.99

P (e) 0.5 d/0.8 50 d/0.15 500 d/0.05 (0 — 1 d/0.4 1 d/0.4 (g) — 50 d/0.4 500 d/0.4 (h) 0.5 d/0.2 50 d/0.05 500 d/0.15

L (0 0.5 d/1.0 50 d/1.0 1000 d/0.9

(a)

(c)

(e)

(h)

Lymph nodes (L)

Nasopharynx Region (N-P)

Tracheo- bronchial Region (T-B) p-

Pulmonary Region (P)

(b)

(d) - ( f ) -

i (g)

t The first value listed is the biological half-life; the second is the regional fraction.

Figure U - 1 0 ICRP Task Group on Lung Dynamics model for describing the

respiratory tract retention of inhaled particles (as modified

in ICRP Publication 1 9 ) .

G. I.

T R A C T

B

L

O ! i

O

D

1+8

Commission on Radiological Protection and modified in ICRP Publication

1 9 > 1 9 7 2 (Figure 1+.10). In the model the respiratory tract has been

divided into three regions: the nasopharynx, the tracheobronchial

region and the pulmonary region. The regional deposition of an inhaled

aerosol is considered to be primarily a function of the particle size

distribution. The chemical form of the compound inhaled influences

the subsequent clearance from the lung. In the model retention in the

lung can be for days (Class'D), weeks (Class W) or years (Class Y).

The Task Group Lung Model predicts that following the inhalation of

an aerosol of a relatively soluble (Class W) compound (particle size

1 [im AMAD), 1 2 % of the activity will eventually be transferred to the

blood, and for a less soluble (Class Y) compound 5%. Retention is

exponential with half-times of retention of the long term component

in the lung of 5 0 and 5 0 0 days for Class W and Class Y compounds

respectively.

Studies in animals have shown that plutonium compounds generally

conform to this classification - the oxide is Class Y, the nitrate

and citrate are Class W and plutonium complexed with the chelating

agent diethylenetriaminepentaacetic acid (DTPA) is Class D.

Experimental studies have also shown that all compounds of americium

and curium, except for Class D category, but including the oxides,

are retained in the lung with half-time of a few weeks or months and

should be considered to be Class W. Following the inhalation of

particles consisting of mixtures of actinides or actinides in

combination with other elements, the retention in the lung of the

individual actinides will be similar to that of the material present

in the inhaled particles in greatest mass.

2 . 3 Ingestion

The majority of measurements on the gastrointestinal absorption of

actinides in animals have been made after their administration by gavage

(a technique by which solutions or suspensions are administered through a

tube passed into the stomach). Animals are normally given the actinide as

a single dose. Although this method would be expected to give an indication

of the level of absorption of actinides from the gut the large amounts of

activity that have to be administered may have resulted in the formation of

relatively insoluble polymers in the animals stomach causing a reduction in

the potential for absorption. This will be the case particularly for

plutonium administered as the nitrate. More realistic values for actinide

absorption are likely to be obtained from the continuous feeding of small

^9

concentrations of actinide incorporated in the diet.

Some studies on the absorption of actinides from the gut have used

the pig and dog as experimental animals. Most of the available data,

however, concerns uptake in rodents.

Values for the absorption of various compounds of plutonium-239

administered to adult hamsters by gavage are given in Table i |.8. The

amount of plutonium absorbed is greatest when given as the citrate

(1 x 1 0 " 2 % ) . A similar result in rats of 3 x 10"^% has been reported by

Weeks et al, (1956) and a higher value of 9 x 1 0 " % by Baxter and Sullivan

( 1 9 7 2 ) . The absorption of plutonium administered as the nitrate may

depend on its valency. For Pu(lV) nitrate values reported in rats have

varied between 1 x 1 0 _ 2 % and 1 x lO'^/o (ICRP, 1972b) . For Pu(Vl) uptake

of 1.9% was reported by Weeks et al, ( 1 9 5 6 ) . This result needs to be

further substantiated as the Pu(Vl) was fed to fasted animals in the presence

of an oxidising agent and these extreme conditions may have influenced

absorption. Plutonium dioxide is much less readily absorbed from the

gastrointestinal tract.' The value for hamsters in Table U . 8 (3.!+ x 10 % )

is similar to that found by Baxter and Sullivan (1971 ) in rats (6 x 10 % ) .

If plutonium dioxide is ingested as very small particles absorption may be

enhanced. Brightwell and Carter (1975) have shown that following admin-

istration to rats of a suspension of a mixed oxide aerosol of plutonium and

sodium (Pu:Na atomic ration about 1 :87) by gavage absorption of plutonium

was about 1 x 10~ 2 %. In these suspensions about 50% of the activity is in

particles about 1 nm in diameter (Stradling et al, 1977)•

A number of studies have been reported on the absorption of plutonium

incorporated into plant or animal tissues. Sullivan and Crosby (1976)

found that in rats that were fed on minced newborn rats previously

injected with plutonium-238 nitrate the proportion of the ingested

activity deposited in liver and bone (3 x 10"^%) was about a factor of

10 greater than the value found following the administration of plutonium-

238 nitrate solution. In similar studies with plutonium-238 oxide the

deposit in the liver and skeleton (9 x 1 0 ~ ^ of the ingested activity) was

about a factor of 2 greater than for plutonium-238 oxide suspension

administered by gavage. Sullivan and Garland (1977) have reported that

in rats fed plutonium-238 biologically incorporated into alfalfa (by

growth of the plants on soil containing plutonium) there appeared to be

about a tenfold increase in plutonium-238 gut absorption by the rat

(8.1; x 10 ^% absorbed) over the value found following its administration

as the inorganic nitrate. However, the number of animals in the study was

Table

1+

.8

Absorption of plutonium

-239 and americium-

21+1 from the gastrointestinal tract of the hamster

Compound

No. of

animals

Activity-

administered (iCi)

% Absorbed

3,

Plutonium citrate

6 0

.32

1.0

E-0

2

Plutonium nitrate

0.2

5 1

.6

E-0

3

Plutonium dioxide

6 2

.02

3.1+ E

-05

Plutonium in liver

0

6 1

.2

9.5

E-0

3

Americium citrate

13

0.9

0 1

.2

E-0

2

Americium nitrate

11

0.9

5 5

.6

E-0

2

Americium dioxide

6.1+

1 5

.9

E-0

3

Americium in liver

0

6 1

.0

3.5

E-0

3

a

Corrected for activity excreted in urine and faeces

b

Aged in water for

1+ months

c

Obtained from hamsters given plutonium or americium nitrate

1+ days

before being killed

d

3 to

1+ months old

Reference: Stather et al,

(1

97

8)

50

51

small. Similar studies with guinea pigs were inconclusive because of the

small numbers of animals used and a wide variation in results obtained.

The absorption of plutonium-239 from the hamster gut after its ingestion

in liver was 1 x 1 0 " ^ % (Table 1+.8) , a value similar to that for plutonium

citrate.

In young rats the absorption of plutonium-239 administered as nitrate

or citrate is one or two orders of magnitude greater than in adult rats

(Ballou, 1 9 5 8 ; Mahlum and Sikov, 1 9 6 7 ) .

Fewer data are available on the absorption of americium and curium but

both radionuclides appear to be more readily absorbed than plutonium. In

the hamster (Table 1+.8) absorption of americium-21+1 is a factor of 3 5

greater than plutonium after administration as the nitrate and after

administration as the oxide (aged in water suspension) a factor of 1 7 3

greater. Similar results have been obtained in rats and absorption is

again enhanced in young animals (Table 1+.9) . In rats fed on newborn rats

previously injected with americium nitrate the proportion of the intake

absorbed and deposited in tissues at 7 days ( 3 x 1 0 " ^ % ) was approximately

twice that obtained for the inorganic nitrate form (Sullivan, 1 9 7 7 ) . For

americium in liver absorption in the hamster was less than after adminis-

tration as the nitrate (Table U - 8 ) .

The gastrointestinal absorption of actinides appears to be related to

the absorption of iron. Iron absorption is high during growth (Bothwell

and Finch, 1 9 6 2 ) and absorption of actinides has been shown to be greater

in young animals than adults. Iron absorption is increased in iron-

deficient animals and Ragan et al, ( 1 9 7 U ) showed that the absorption of

plutonium citrate was increased by a factor of 1+-5 in iron deficient mice.

Summary

Studies in animals on the absorption of plutonium from the gastro-

intestinal tract have shown that this is not a major route of uptake

in the adult. For soluble plutonium compounds that have entered the

gut the amount of plutonium absorbed may be assumed to be about

1 x 1 0 - 2 % and for insoluble plutonium dioxide particles absorption

may be taken as 1 x 10""^%. Plutonium dioxide particles should be

treated as soluble if they are less than about 5 nm in diameter.

In some circumstances ingestion may become a significant route of

entry of actinides into the body. Americium and curium are absorbed

more readily from the gastrointestinal tract than plutonium and for

all compounds the amount absorbed can be taken to be about 5 x 1 0 ~ ^ % .

Table U>9

Chemical form

Adult rats

Young rats

0

Reference

Chemical form

Number

% Absorbed

3,

Number

% Absorbed

13

Reference

Americium-210 nitrate

11

1.5

E-0

2 8

5 A

Curium-2144 nitrate

1U

i+.O E

-02

7 2

A

Americium

-2U

1 oxide

6

1.3

E-0

2 10

1

.1

A

Curium

-2i4

i oxide

3 3

.0

E-0

3 5

1.7

vA

11

(U.O

E-0

2)C

h (1

.8)°

A

Americium

-2i|1 chloride

3.0

E-0

2 B

Curium-

21+2 chloride

5.0

E-0

2 ' C

a

Calculated as total activity deposited in liver and skeleton

b

Calculated as total activity in femur + liver + residual carcass

(excluding gastrointestinal tract)

c

Values obtained using curium oxide suspended in water for

k months

before administration

References: A. Sullivan and Crosby

(1

97

5)

B. Zalikin et al,

(1

96

8)

C

Semenov

(1

97

1)

52

Absorption of americium and curium from the gastrointestinal

tract of rats

7

days after administration by gavage

53

In young animals absorption of plutonium, americium and curium is

enhanced relative to the adult. Some studies on actinides incorpora-

ted into plant and animal tissues have shown that they may be absorbed

more readily than inorganic compounds but the results that have been

obtained so far are fragmentary and variable. Further studies are

urgently needed on the absorption of actinides from the gastro-

intestinal tract.

2 .1+ Wounds

Wound contamination with actinides has been simulated in animal

experiments by either intradermal, subcutaneous or intramuscular injection.

These studies have shown that both soluble material and particles may be

translocated from the site of deposition. Soluble complexes rapidly reach

the circulation while particles are essentially limited to slower movement

along lymphatic ducts, leading initially to accumulation in regional lymph

nodes. The principal forms of plutonium and higher actinides that have

been studied in animal experiments are the citrates, nitrates and oxides.

Injection as the citrate complex results in rapid translocation. The

amounts of americium and curium cleared by 1+ days after intramuscular

injection were: in rats, 97% of americium-2l+1 (Durbin et al, 1 9 ^ 9 ) and

9 7 . 3 % of curium-2l+2 (Williams et al, 1 9 6 1 ) , in mice 98% to 99% of americium-

21+1 (Parker et al, 1 9 ^ 2 ) and in monkeys 98 .1+% of americium-2l+1 (Durbin,

1 9 6 2 ) . Subcutaneous injection of americium-2l+1 citrate into the paw of

dogs resulted in the clearance of over 90% in the first day and approxi-

mately 9 5 % by the fourth day (Lloyd et al, 1 9 7 5 ) . Rapid clearance is

consistent with the presence of citrate ions in body fluids as natural

complexing ligands for actinides (Popplewell and Boocock, 1 9 6 8 ; Popplewell

et al, 1 9 7 5 ; Stradling et al, i 9 7 6 ) . The rate of clearance from the site

of injection can be expected to be directly related to the tissue fluid

flow at the site of deposition of either americium, curium or plutonium,

provided there is no binding to tissue components or hydrolysis. However,

a greater retention of plutonium after intramuscular injection in rats as

citrate - 1 9 % after 7 days (Taylor, 1 9 7 3 c ) and 18% after 9 0 days (Nenot et

al, 1 9 6 7 ) suggests that some polymer formation does take place despite the

presence of citrate.

The mineral salts of plutonium, americium and curium are stable in

acid solution but are hydrolysed at physiological pH. Clearance from a

wound site therefore depends either upon the formation of soluble complexes

with ligands in the tissue fluid such as citrate and transferrin (see later)

54

or the movement of particles. Although the concentration of many inorganic

ions are about the same in interstitial fluid as in the plasma, plasma

protein concentrations, including transferrin are only about one-sixth

those in plasma (Durbin, 1 9 7 5 ) • If therefore large masses of actinide are

deposited in a wound as soluble salts only a fraction can rapidly combine

with transferrin or other ligands and be transported, the remainder forms

polymers. This deposit may be slowly solubilised and translocated to the

systemic circulation while some particles may move to the regional lymph

nodes.

Nenot et al, ( 1 9 7 2 ) have studied the clearance of plutonium-238,

plutonium-239 9 americium-2i+1 and curium-2lj.2 from an intramuscular site of

deposition in the rat leg after injection as the nitrate. Values for the

retention of plutonium-238, curium-2lj.2 and americium-2l+1 were very similar

(Figure 1+.11) showing a fast clearance with a half-time ranging from 1 0 - 2 0

days during the first weeks. Plutonium-239 had a much slower rate of

clearance. Two factors will be contributing to the greater retention of

plutonium-239- Firstly polymer formation can be expected to be greatest

for the plutonium-239 deposit because of the greater mass in the injection

solution. An effect of mass has been demonstrated by Harrison et al,

( 1 9 7 7 ) following the intramuscular deposition of varying amounts of

plutonium-239 as nitrate into the thigh muscle of rats. The rate of trans-

location of plutonium was greatest after deposition of the smallest mass

(Figure 1+.12). Secondly the enhanced clearance of plutonium-238,

americium-2I4.I and curium-2i+2 may also have been partly due to their higher

specific activity (Table 2 . 1 ) .

Americium is also cleared more rapidly than plutonium from the paws of

dogs after subcutaneous deposition as the nitrate. 6 0 - 7 0 $ of americium-2Ul —1 —1

( 0 . 9 |iCi kg"" ( 3 3 kBq kg" ) administered) was cleared after one week and approximately 80% after h weeks (Lloyd et al, 1 9 7 5 ) . In a similar experi-

—1 —1

ment with plutonium-239 nitrate ( 0 . 2 p,Ci kg" ( 7 -U kBq kg" ) administered)

(Bistline et al, 1 9 7 2 ) , about 50% of the activity had been cleared by 2

weeks and approximately 7 0 $ by 1 year.

A limited number of studies have been reported on the movement of

oxides of plutonium from the subcutaneous tissue of the forepaws of beagle

dogs. These studies have shown that the translocation of plutonium dioxide

is generally characterised by its insolubility and slow rate of clearance

to other tissues, principally lymph nodes. Thus following the subcutaneous

deposition of air oxidised plutonium dioxide into the paw of dogs approxi-

mately 80% was retained at the injection site at one year (Watters and

55

D a y s p o s t i n j e c t i o n

Figure U«11 Retention of actinides at the site of administration after

intramuscular injection into rats as nitrates (pH 1 . 5 ) .

Redrawn from Nenot et al ( 1 9 7 2 ) . "Reproduced from Health

Physics Vol. 22, p. 6$8, 1972 , by permission of the Health

Physics Society."

%

of

in

itia

l in

jec

te

d

do

se

5 6

100H

TIME ( m o n t h s )

E r r o r b a r s r e p r e s e n t ± S . E . f o r g r o u p s o f 4

a n i m a l s

Figure U . 1 2 The effect of mass on the retention of plutonium-239 in the

extensor cruris muscle of the rat after injection as the

nitrate (Harrison et al, 1 9 7 7 ) .

% INJECTEC A C T I V I T Y

5 7

Lebel, 1 9 7 2 ) . This slow rate of clearance was, however, not found after

similar administration of high fired plutonium dioxide (Bistline et al,

1 9 7 2 ) . Approximately 7 0 $ of the plutonium was cleared after one year, a

rate of clearance similar to that found after deposition of the nitrate.

The greater rate of clearance of the high fired particles may have been

related to their smaller size (geometric mean diameter - 0 . 7 compared

with 7 for air-oxidised plutonium dioxide).

Surprisingly there appears to be no comprehensive information on the

clearance of plutonium dioxide from intramuscular sites of deposition. It

can be anticipated that clearance will be very slow. Studies of the

retention of plutonium dioxide produced by an exploding wire technique have

shown only a few per cent of the activity deposited translocated to other

tissues after k weeks (Harrison et al, 1 9 7 8 ) .

There are no animal data on the behaviour of pure oxides of either

americium or curium at wound sites. There is a greater rate of transloca-

tion of these actinides from the-lung compared with plutonium following

their inhalation as the oxides (see 2 . 2 ) . Similar results might there-

fore be expected following their deposition at a wound site.

Summary

The behaviour of actinide compounds in contaminated wounds depends

on physico-chemical characteristics such as chemical form, particle

size, mass injected and specific activity as well as biological

factors such as the depth and site of deposition, the type of tissue,

tissue fluid flow past the deposit and the dispersion within the

tissue. In general terms, soluble compounds are cleared more readily

than insoluble compounds, subcutaneous deposits more readily than

intramuscular deposits and americium and curium more readily than

plutonium.

2 . 5 Absorption through the intact skin

The few studies that have been reported on the percutaneous absorption

of actinides indicate that this is not a significant route of entry into

the body.

In experiments in animals Oakley and Thompson ( 1 9 5 6 ) found that 0 . 03>$

of plutonium nitrate in 10M HNO^ was absorbed in one hour and 1 - 2 $ in 5

days. Under these conditions severe skin damage would have been expected.

With plutonium nitrate in 0.1M HNO^ 0 . 1 - 0 . ; $ was absorbed in 5 days. In an

experiment in which 0 . 6 ^Ci ( 2 3 kBq) of plutonium nitrate in O . I4M nitric

58

acid were applied to the palm of the hand for 8 hours the amount absorbed

was no greater than 2 x 1 0 ~ ^ % per hour (Langham, 1 9 5 9 ) •

The amount of activity absorbed will depend upon the area contaminated

and may be increased if the skin is damaged or in the presence of solvents

that can penetrate the skin. In an accident in which a solution

containing about 1 \iOi ( 3 7 kBq) of plutonium in 9% HC1 containing EDTA and

a strong detergent was spilled onto a m a n ^ hand, absorption was estimated

to be about 1 0 ~ ^ % (Lister et al, 1 9 ^ 3 ) • Washing was started within about

5 minutes of the accident.

Summary

The results of both animal experiments and observations on humans

contaminated with plutonium indicate that the skin is an effective

barrier to the entry of plutonium into the body and probably to other

transuranics.

3 . Retention in lymph nodes

A proportion of plutonium or other actinides deposited in the

respiratory tract or a wound site translocate to regional lymph nodes.

The retention half-time of activity in these nodes varies markedly in

different experiments but because of their small mass the concentration of

plutonium or other actinides in them can increase to many times that at the

site of deposition or in other tissues and consequently they may receive

high radiation doses.

In a study reported by Bair (1971+a) in dogs that had inhaled plutonium

dioxide, the retention of plutonium in the thoracic lymph nodes after 1

year was about 1 0 % of the initial alveolar deposit, and 50% after 1 0 years.

The concentration of plutonium in the nodes at 1 0 years was approximately

2 0 0 0 times that in the lung and liver and about 2 0 0 0 0 times that in the

skeleton. This is the most extensive study on the retention of plutonium

in the lymph nodes. The amount of plutonium the dogs inhaled was, however,

high and radiation damage to the lung or lymph nodes could have influenced

the retention pattern.

Brightwell et al, ( 1 9 7 6 ) showed that plutonium was retained in the

thoracic lymph nodes of rats to a greater extent following inhalation of

plutonium dioxide ( 0 . 8 5 % of the initial lung deposit after 1 2 months) than

following inhalation of mixed oxide aerosols of plutonium and sodium

( 0 . 2 7 % ) . The difference was attributed to the smaller particle size

distribution of the plutonium in the mixed oxide aerosol. Whether the

59

difference resulted from a faster rate of removal from the nodes or from a

slower rate of translocation to them from the lung was not determined.

The retention of plutonium in the nodes of these rats was considerably-

less than at a comparable time in the experiment with dogs. This could have

resulted from differences in aerosol characteristics, the amount of activity

initially deposited in the respiratory system, or the rates of* clearance

from the lung or lymph nodes.

Craig et al, ( 1 9 7 6 ) compared the clearance of plutonium, americium and

curium from the lungs of beagles after inhalation as the oxides and showed

that accumulation in the thoracic lymph nodes was in the order plutonium-239

> plutonium-238 > americium-2Ul > curium-2144.. Tissues were analysed 3 5 0

days after inhalation of plutonium-238 dioxide and americium-2i|1 oxide,

lj.00 days after inhalation of plutonium-239 dioxide and J00 days after

inhalation of curium-2l4i oxide. The percentage of the translocated activity

accumulated by the lymph nodes was 9 5 • 2 2 , 1 . 5 and 0 . 1 5 $ for plutonium-239,

plutonium-238, americium-2^1 and curium-2l4j. respectively (values estimated

from graphs given in paper). These observations are consistent with

greater solubility of the americium and curium oxide particles.

A study on the translocation of plutonium from simulated subcutaneous

wounds in the dog forepaw showed that retention in the nodes depends upon

the chemical form deposited (Bistline et al, 1 9 7 2 ) . With air oxidised

plutonium dioxide (geometric mean diameter - 7 tim) deposition in the

cervical lymph node showed a continuous build-up to 1 7 % of the administered

activity at the end of one year. After deposition of plutonium nitrate

there was a rapid build-up in the nodes to a maximum of about 2 2 $ of the

administered activity at 1 0 days followed by a decline to about 7 $ at one

year. With high fired plutonium dioxide (geometric mean diameter - 0 . 7 pm)

a less rapid increase in concentration occurred in the nodes, deposition

reaching a maximum at about 5 0 days ( 1 5 $ of the amount administered)

followed by a decrease to about 1 0 $ over the subsequent 9 months.

Schallberger et al ( 1 9 7 6 ) have investigated the movement of plutonium

in the lymphatic system of dogs by cannulating afferent and efferent lymph-

atics of nodes draining the site of simulated subcutaneous wounds. They

collected lymph for up to k hours after injection and showed that there

were cellular and acellular components in both afferent and efferent lymph.

After deposition of plutonium nitrate the acellular component predominated

up to 1+ hours after administration but following deposition of polydisperse

plutonium dioxide particles acellular and cellular components were fairly

60

similar. Although the concentration of plutonium in efferent lymph was

always less than in afferent lymph the study showed that cellular and

acellular plutonium can pass through lymph nodes. This activity will

eventually deposit in other tissues in the body.

These observations suggest that particles accumulated in thoracic

lymph nodes from the lung may also be released and subsequently be

deposited in other tissues of the body. There are, however, no studies

that demonstrate this unequivocably.

There have been few detailed studies on the distribution of actinides

within lymph nodes. In rats (Brightwell et al, 1 9 7 6 ) and dogs (Bair et al,

1 9 7 3 ) exposed to plutonium dioxide the majority of th« plutonium in thoracic

lymph nodes was present as particles or aggregates. The deposits were

predominantly concentrated within and around the medullary region or

cortico-medullary junction but not generally in the germinal centres. In

the rats only some of the thoracic nodes from any one animal contained

activity, suggesting that only a proportion of the nodes drain

directly from the lung. The plutonium within the nodes was located

predominantly in macrophages within the medullary areas (Brightwell et al,

1 9 7 6 ) but it was not possible to identify whether the plutonium was

concentrated in migrating macrophages or the fixed phagocytic cells lining

the medullary sinuses.

Dagle et al, ( 1 9 7 5 ) have used autoradiographic methods to study the

distribution of plutonium in lymph nodes draining a simulated wound in the

hind paw of beagles. The work showed that after injection of high-fired

plutonium-239 dioxide the distribution of plutonium particles was related

to lymph flow through the popliteal node. In dogs sacrificed after k weeks

the plutonium particles were found in the subcapsular areas and areas

between the cortical nodules. From 8 to 3 2 weeks the plutonium particles

became more concentrated in the medullary areas near the efferent

lymphatics. Alpha activity was more pronounoed over regions where

haemosiderin was present. This observation was also made by Brightwell

et al, ( 1 9 7 6 ) in rats.

Summary

A fraction of the plutonium or other actinides deposited either in

the lungs or at a wound site may be translocated to regional lymphatic

tissue. Because of their small mass the radiation dose to these nodes

may greatly exceed that to the site of intake or to other tissues.

Some activity is subsequently released into efferent lymphatic ducts

6l

and will eventually deposit in other tissues of the body.

1+. Transport in the blood

Following the entry of soluble forms of plutonium into the systemic

circulation about 90% of the plutonium is rapidly bound to transferrin, the

protein that normally transports iron in the plasma (Popplewell and Boocock,

1968; Stevens et al, 1968; Turner and Taylor, 1968a) . The association of

americium and curium with transferrin has not been clearly demonstrated but

it is probable that the trivalent actinides also form complexes with

transferrin which, unlike the complex with plutonium, are not sufficiently

stable to withstand chemical separation procedures. Some plutonium in the

plasma remains associated with a small molecular weight species which is

probably citrate (Popplewell et al, 1975) and this may also be true of

americium and curium (Stradling et al, 1 9 7 6 ) .

Durbin (1972) has recently reviewed data on the clearance of plutonium

from the blood of man and 1+ other mammalian species after intravenous

injection as citrate (Table 1+-10). In man $2% of plutonium is cleared

with a half-time of 20 minutes and a further 27% with a half-time of 7

hours. The remaining 21% is cleared with a half-time in excess of one

day. Similar results are obtained for other species although the blood

clearance tends to be faster.

There is no comparable information on the blood clearance of americium

and curium in man. Results obtained in animals have shown that soluble

complexes of americium and curium reaching the circulation are cleared more

rapidly than plutonium. Thus intravenous injection of americium-21+1 in the

rat as the citrate or nitrate resulted in 97-98% clearance after one hour.

For curium-2l+l+ administered as the nitrate 96% was cleared by one hour but

in the case of plutonium-239 administered as nitrate or citrate clearance

was only about 57% and 31% respectively (Turner and Taylor, 1968b). In

beagles Atherton et al, (1973) showed clearance of 90% of americium-2l+1

and curium-2I4.I+ one hour after intravenous administration as citrate and

99% after 7 hours compared with 30% of plutonium-239 after 7 hours.

Polymeric plutonium is rapidly cleared from the blood and deposited

predominantly in cells of the reticuloendothelial system, primarily in the

liver, and to a lesser extent in the spleen and bone marrow (Rosenthal et

al, 1968) . Although the clearance of colloidal plutonium from the blood

has been studied extensively in animal experiments it seems likely that

this is not a chemical form likely to be of importance in the majority of

cases of human contamination.

Table 1

+.10

Disappearance from circulating blood of intravenously injected Pu(lY) citrate

Component

Species

A

B

C

D

E

Day of

last sample

Species

(min)

%

(hr)

%

(days)

%

(days)

(days)

Day of

last sample

Rat

60.3

58

3

7.3

8

.2

0.8

6

.0

8

Dog

hh

11 - i

+8

19

.5

7.3

30

1

.0

2.1

5

.0

0.08

1 2

20

a 3

,00

0

Sheep

68

2h

25

2 -

5 5

.8

1.6

1

.1

U.9

10

Man

52.U

20

27

.1

7.3

1

7.2

1

.2

3.3

5

.0

o.kh

88

U

2

An additional long term component emerged at

80

0 days

(0

.0U

5%, Tj- =

5

,$0

0 days)

Reference: Durbin (1972)

62

a

6 3

Recently Stradling et al, (1977) have shown that small particles of

plutonium dioxide less than about 1 nm in diameter can readily enter the

blood from the lungs. These particles have been found to associate with

citrate in the blood to form an "intermediate" complex. This complex has

a half-life of about 3 minutes in the blood but can pass through the kidney

glomerulus in the ultra-filtrate and be excreted, resulting in an enhanced

urinary excretion vsee later). Ultimately the plutonium particles not

excreted are solubilised, complexed by transferrin or citrate and deposited

in tissues in a manner similar to other soluble forms of plutonium.

After the entry of soluble forms of plutonium into the blood most of

it is rapidly bound to transferrin, a protein that normally transports

iron in the body. The remainder is bound to a smaller molecule which

is probably citrate. It is probable that americium and curium behave

similarly. Soluble complexes of americium and curium are cleared from

the blood more rapidly than plutonium.

5 . Deposition in tissues from the blood

The results of both animal and human studies have shown that for

radiological protection purposes three sites of deposition of plutonium,

americium and curium that have entered the systemic circulation must be

considered. The majority of activity entering the blood (> 90$) is

accumulated in either the liver or the skeleton. Much less is deposited

in other tissues. The retention and distribution of these actinides in

the gonads must also be known as any activity deposited in this tissue

will result in a genetic dose to exposed individuals or populations. Apart

from these 3 tissues activity will be deposited in all the other tissues of

the body but because of the generally lower radiation doses involved

retention in them is of considerably less importance and will not be

further considered.

5.1 Skeleton

Extensive studies in animals have shown that the skeleton is a major

site of deposition of actinides following their entry into the systemic

circulation. The amounts of plutonium, americium and curium deposited in

this tissue and their subsequent fate depend upon the route of administra-

tion, the physico-chemical form, the age of the animal and the amount

administered.

6k

Studies by Rosenthal et al, ( 1 9 6 8 ) have shown that the physico-

chemical form of plutonium entering the blood influences the pattern of

deposition in tissues. If plutonium particles or polymers enter the blood

most of the activity is deposited in the liver but for ultrafiltered

(monomeric) soluble forms of plutonium the majority of the activity is

deposited in the skeleton. The amount of plutonium accumulated by the

skeleton also depends on age. Thus 3 month old beagle dogs, in which

growth is rapid, accumulated about 70% of plutonium administered intraven-

ously as citrate at one to 2 weeks after injection whereas in dogs more

than 1 8 months old deposition in the skeleton was about 3U% (Stevens et al,

1 9 7 6 ) . In weanling rats 7 8 % of plutonium administered intravenously as

citrate was accumulated by the skeleton (skeletal retention taken to be

2 0 x femur concentration), whereas in adult rats only 5 3 % was accumulated

by the skeleton (Sikov and Mahlum, 1 9 7 2 ) . Similar results have been

obtained by Buldakov et al, ( 1 9 ^ 9 ) in lambs and sheep.

Since the first observation by Hamilton ( 1 9 U 7 ) of the deposition of

both plutonium and americium on bone surfaces, the distribution pattern of

plutonium in bone has been described in detail by a number of authors

(Arnold, 1 9 5 1 ; Arnold and Jee, 1 9 5 7 ; Jee and Arnold, 1 9 6 1 ; Jee, 1 9 7 2 ;

Nenot et al, 1 9 7 2 ; Vaughan et al, • 9 7 3 ; Priest, 1 9 7 7 ; Priest and Jackson,

1 9 7 7 ) - After the en-ury of soluble forms of plutonium into the blood much of

it is rapidly bound by the protein transferrin. Much of this activity is then

deposited on endosteal surfaces of bone and to a lesser extent on perio-

steal surfaces and surfaces of vascular channels in cortical bone. These

bone surface deposits irradiate cells within about 1+0 \w of the bone

surface (Figure k.13)•

Not all the plutonium reaching the skeleton is deposited in bone, some

is retained in the bone marrow. In animals given doses of plutonium less —1 —1

than about 1 |iCi kg"" ( 3 7 kBq kg"" ), the concentration of plutonium in the

marrow is highest at short times after plutonium has entered the blood,

when most of the activity is due to plutonium still circulating in the

blood and bone marrow spaces. As blood levels of plutonium fall so do

the levels in the bone marrow. At later times the level of plutonium in the

marrow may increase slightly due to the resorption of bone containing

plutonium (Jee, 1 9 7 2 ; Priest and Jackson, 1 9 7 7 ) .

The rate of disappearance of plutonium from the bone surface depends

upon the age of the animal and the amount of plutonium administered. In

65

Figure Plutonium-2U1 deposited upon a resorbing endosteal bone surface

of rat 2k hours after injection as the citrate. The plutonium

is present on the bone surface and in an osteoclast (bone

resorbing cell). However, no plutonium is present in other

cells in the marrow. (Provided by N. D. Priest, National

Radiological Protection Board, U.K.)

6 6

young, rapidly growing animals plutonium-239 deposited in the metaphyses

is rapidly displaced by endochondral ossification. Thus James and Taylor

( 1 9 7 1 ) showed that the long bone metaphysis of a 7 week old male rat was

completely replaced in less than 3 weeks. Concurrently with growth in

length of the bones the trabeculae are continually remodelling with the

result that plutonium bound to their surfaces is either buried or removed

by osteoblastic resorption and released within a few days of deposition

(Jee et al, 1 9 ^ 9 ; Priest and Jackson, 1 9 7 7 ) • Ultimately the processes of

apposition and resorption result in plutonium tending to become volume

distributed in the bone matrix. At high doses of plutonium (> 1 iCi kg""

( 3 7 kBq kg""1)) the a-radiation dose to bone surfaces results in an

inhibition of bone resorption (Polig, 1 9 7 6 ) and the accumulation of

plutonium by macrophages in the marrow (Arnold and Jee, 1 9 6 2 ; Jee, 1 9 7 2 ;

Priest and Jackson, 1 9 7 7 ) • In young adults the loss of plutonium from

bone surfaces is less rapid than in growing animals. Despite this surface

trabecular deposits of plu-conium, in 1 . 5 year old beagle& given i.v.injec-

1 —1

tions of plutonium-239 citrate (0.016 ..Ci kg"" (0.6 kBq kg ])

had virtually cleared by 6 months (Jee, 1 9 7 2 ) . In mature animals the rate

of removal of plutonium-239 from bone surfaces is slow (Jee, 1 9 7 2 ) . This

can be correlated with the reduction in bone remodelling rates in mature

animals. Frost ( 1 9 6 9 ) has given some values for normal bone formation

rates for cortical bone in the middle of the sixth human rib. Bone

formation rates were 1 . 8 - 1 + . ! $ per year in adults ( 3 0 - 9 0 years of age)

whereas in 1 - 9 year olds the rate was 38% per year and in the first year

of life 8 5 $ per year.

It might be anticipated therefore that provided the numbers of

sensitive osteoprogenitor cells per unit area remain fairly constant,

plutonium deposited on bone surfaces in mature bone would be potentially

more damaging than plutonium deposited in growing bones as the cells near

the surface will receive a greater radiation aose. In all ages, however,

there is significant burial of plutonium deposits in bone and therefore

calculations of dose to the sensitive osteoprogenitor cells on the bone

surface that are based on the assumption that plutonium remains at the

bone surface will be conservative.

The distribution of plutonium in bone is very different to the

alkaline earths. Radioactive isotopes of the alkaline earths can replace

calcium in the crystal lattice structure of bone and readily form a diffuse

deposit throughout the skeleton (ICRP, 1 9 6 8 ) . There are conflicting views

over the chemical form of the major binding sites for plutonium in bone.

67

Teseveleva ( i960) found that 87.5% of plutonium in bone was associated

with the organic matrix and 6% with bone mineral. The chemical procedures

used were, however, extreme and could have redistributed any plutonium

present. Contrary views were expressed by Foreman (1962) who showed that

bone mineral in vitro accumulated plutonium more readily than bone matrix,

and Jee and Arnold (1962) who concluded from studies on normal and

rachitic rats that plutonium was bound mainly to the mineral phase of

bone. However, Taylor and Chipperfield ( 1 9 7 1) showed that glycoprotein

fractions isolated from bovine bone bind plutonium more strongly than

transferrin, collagen or free chondroitin sulphate, suggesting that glyco-

proteins may play an important role in the binding of plutonium to bone.

Plutonium is retained in the skeleton with a long half-time in all

mammalian species studied. Data summarised by ICRP (1972b) suggest that

the half-time of plutonium in the skeleton of experimental animals is

approximately 1 to 2 times the average life expectancy of the species. On

this basis the half-time of plutonium in the skeleton of man was estimated

to range from 65 to 130 years with a mean of about 100 years.

The amounts of americium and curium which deposit in the skeleton

(ie, bone and bone marrow) after their entry in the blood in a soluble

form are very variable. Typical values for the percentage skeletal uptake

following their injection as a monomeric solution lie between 20 and 1+0%

(Durbin, 1973) - This is generally less than the skeletal deposition of

plutonium.

Few studies have directly compared the skeletal uptake of plutonium,

americium and curium. Seidel and Volf (1972) showed that in 3 groups of

rats given intravenous injections of these radionuclides as citrate, the

skeletal uptake of plutonium was approximately 3 times greater than the

value found for americium and curium (Table I4.ll).

In dogs the accumulation of these 3 actinides is more comparable.

Thus after the intravenous administration of plutonium, americium and

curium as citrate the proportions of the administered activity deposited

in the skeleton in the first 3 weeks after administration were 1+9%

(Stover et al, 1972a ) , 29% (Lloyd et al, 1970) and 1+1% (Lloyd et al, 1971+),

respectively.

In the long bones and vertebrae of mature and growing rats americium

becomes deposited on the endosteal and periosteal bone surfaces and around

cortical vascular canals (Hamilton, 191+7; Taylor et al, 1 9 6 1 ; Durbin et al,

Table

M1

Distribution of plutonium

-239. americium-

21+1 and curium-

21+2

in rat tissues

6

days after intravenous injection as citrate

Tissue

% Injected Activity (X, N =

1 + or

5

) Tissue

Plutonium

-239

Americium-

21+1

Curium

-21+

2

Skeleton

62

.0

18

.66

22

.3

Liver

1U

.6

U3

-33

U2

.7

Spleen

0.2k

0

.06

2 0

.07

Kidneys

1.0k

0

.82

3 0

.80

Lung

0.11

+ 0

.10

7 0

.12

Thyroid

0.0

22

0.02

1 0.

021+

Adrenals

0.0

12

0.0

05

0.0

04

Ovaries

0.0

17

0.0

09

0.0

13

Ref: Seidel and Volf (1972)

68

69

1969; Williamson, 1963; Nenot et al, 1 9 7 2 ) . Similar results have been

found in dogs (Herring et al, 1962; Lloyd et al, 1972), mice (Hammarstrom

and Nilsson, 1970a, 1970b) and cynomolgus monkeys (Durbin, 1 9 7 3 ) .

Herring et al, (19^2) showed that the distribution of americium on

bone surfaces in growing dogs varied with growth activity of the surfaces.

The highest amounts of americium were found on resorbing surfaces with

lower amounts on resting and actively growing bone surfaces. These results

are in apparent contrast to those of Williamson (1963) and most other

investigators who have shown that the greates t uptake of americium occurs

at sites of high growth activity among the trabeculae of the primary and

secondary spongiosae. Some americium deposits onto resorbing bone surfaces

and to a lesser extent onto resting surfaces. Its distribution can be

distinguished from plutonium mainly by a high level of deposition in

vascular channels but it is not concentrated in the bone marrow.

The mechanisms of uptake of americium and curium by the skeleton are

not known.

As with plutonium the skeletal uptake of americium and curium is lower

in older animals (Mahlum and Sikov, 1975; Stevens et al, 1976) and the

growth activity of the bone influences the temporal pattern of distribution.

They will also tend to become more evenly distributed throughout the bone

matrix with time. The limited data available for the retention half-times

of americium in the bones of experimental animals are similar to those for

plutonium (ICRP, 1972b) .

5 .2 Liver

The liver and skeleton together accumulate the majority of the

systemic deposit of plutonium, americium and curium which distribute

between these two tissues according to the relative affinities of hepatic

and skeletal tissue for each element. The liver uptake of monomeric

americium and curium from the systemic circulation in rodents is generally

greater than plutonium (ICRP, 1 9 7 2 b ) . In a study by Seidel and Volf (1972)

in rats the liver deposits of plutonium, americium and curium 6 days after

intravenous administration as the citrate were 1l+.6%, 1+3.3% and 1+2.7%

respectively of the administered activity (Table 1+.11) . In dogs deposition

of these actinides in liver is more comparable. Thus at 30 days after in-

halation of americium dioxide and curium oxide the liver accumulated about

1+1+% of the extrapulmonary tissue deposit (Table l+.7)> whilst for plutonium

dioxide it accumulated about 1+0% at 56 days (Table 1+.1). Similar results

are obtained in beagle dogs after intravenous administration. The liver

TO

accumulated about 30% of plutonium, 50% of americium and 35% of curium one

week after intravenous administration as citrate (Lloyd et al, 1971+)•

The half-time of retention of both plutonium and americium in the

liver was about 3 7 0 0 days when the administered activity was 0 . 1 ^Ci

kg""1 ( 3 - 7 kBq kg""1) or less (Stover et al, 1 9 7 1 ; Lloyd et al, 1 9 7 0 ) . With

increasing amounts of plutonium administered, the half-time of retention

was reduced, probably as a consequence of radiation damage to the liver and

the release of plutonium into the blood resulted in an increase in the

skeletal burden. A long half-time of retention of actinides (about 3 4 0 0

days) has also been found in the hamster liver (McKay et al, 1 9 7 2 ) . In the

mouse and rat the liver retention of plutonium after administration in a

monomeric form has a half-time of only about 2 0 days (Rosenthal et al,

1 9 6 8 ; Stather and Howden, 1 9 7 5 ) . In rats plutonium leaves the liver

predominantly in the bile (Ballou and Hess, 1 9 7 2 ) . A rapid rate of loss

of americium from the liver of mice, rats and monkeys has also been reported

(Durbin, 1 9 7 3 ) - Tne hamster and the dog are therefore the most suitable

animals for studies on the hepatic retention of plutonium that can be

related to man. There are no human data from which to estimate the half-

time of retention of plutonium in the liver in man but measurements of

the plutonium content of human livers obtained at autopsy suggest that it is

longer than a few years (Foreman et al, i 9 6 0 ; Magno et al, 1 9 ^ 9 ; Norwood et

al, 1 9 7 3 ; Schofield and Dolphin, 1 9 7 4 ; Mclnroy, 1 9 7 6 ; Voelz, 1 9 7 5 ) . Based

upon an extrapolation from the half-time of retention of plutonium in the

liver of experimental animals, a half-time of retention in the human liver

of 4 0 years has been estimated (lORP, 1 9 7 2 b ) . A similar half-time would be

expected for the higher actinides.

Autoradiographic studies of the distribution of plutonium in the livers

of beagle dogs after intravenous injection of plutonium-239 citrate showed

that the initial site of deposition was the hepatic cells. The uptake was

uniform and localisation within either the reticuloendothelial (RE) cells,

the biliary epithelium or the interstitial areas was very low within a few

days after injection (Taylor et al, 1 9 7 2 ) . By 2 to 3 months following the

injection 01 2 . 9 pCi/kg ( 1 0 7 kBq kg" ) (cumulative dose 3 4 0 to 4 9 4 rads

( 3 . 4 to 4 - 9 Gy) respectively) an increased activity in the RE cells lining

the sinusoids occurred and ultimately some cells became significant "hot

spots". The accumulation of activity by the RE cells appears to have

resulted from the death of hepatic cells and their subsequent uptake by

the phagocytic Kupffer cells lining the sinusoids (Taylor et al, 1 9 7 2 ) .

This movement was seen in dogs given varying levels of plutonium ( 0 . 0 1 7 - 2 . 9

71

1 1 p.Ci kg ( 0 . 6 - 1 0 7 kBq kg" )) but the latent period before l!hot spots11

developed became progressively longer as the injected dose decreased. The

pattern of distribution of americium-2l|1 in the liver of beagle dogs has

been shown to be similar to plutonium (Taylor et al, 1 9 6 9 ) .

A progressive aggregation of plutonium has also been shown in the

livers of mice given injections of polymeric plutonium (Lindenbaum et al,

1 9 6 8 ) . However, the progressive focalisation of activity was not

accompanied by a gradual shift of activity towards the Kupffer cells.

About 60% of the activity was associated with the hepatic cells and about

kO/o with the Kupffer cells between half an hour and 3 months after

administration. In mice injected with a monomeric plutonium preparation

about 70% of the deposit of plutonium was in the hepatic cells at 5 days.

In rats and hamsters the highest concentrations of plutonium are also

found in the hepatic cells up to one week after intravenous administration

as citrate (Priest, 1 9 7 7 ) •

Little is known of the mechanism by which plutonium, americium and

curium are taken up by liver cells. Differential centrifugation studies

of rat and beagle liver have shown that within the liver cells the

actinides are initially concentrated in the cytoplasm, principally in

association with the iron-storage protein, ferritin, (Boocock et al, 1 9 7 0 ;

Stover et al, 1 9 7 0 ; Stevens et al, 1 9 7 3 ) • They are subsequently transf-

erred from the cytoplasm to sub-cellular organelles, principally the mit-

ochondria and lysosomes. Association with nuclei has also been described

(Boocock et al, 1 9 7 0 ) . Autoradiographic studies have demonstrated the

accumulation of some plutonium-21+1 by the nuclei of rat and hamster liver

cells at one day after intravenous administration as citrate (James and

Rowden, 1 9 ^ 9 ; Priest, 1 9 7 7 ) (Figure h^h) although by one week these

deposits have reduced.

Some of the plifbonium and americium associated with beagle and rat

liver at short times after administration has been shown to be extra-

cellular and associated with connective tissue (Stover et al, 1 9 7 0 , 1 9 7 2 b ;

Grube et al, 1 9 7 5 - 1 9 7 6 ) . Perfusion of rat liver removed 6 - 7 % of the

incorporated Pu(lV) after one day and 1 % after 11+ days (Grube et al, 1 9 7 5 ) .

This fraction of the liver deposit may be removed by the intravenous admin-

istration of chelating agents (Chapter 8 ) .

The intracellular distribution of particles of plutonium taken up

by the liver is very different to that of soluble plutonium. Gurney and

72

Figure k*^k Hamster liver at 2k hours after the injection of plutonium-21+1.

Plutonium is concentrated by the liver celts surrounding a

small blood-vessel. Plutonium (B-tracks may be seen over both

the nuclei and the cytoplasm of cells. (Provided by

N. D. Priest, National Radiological Protection Board, U.K.)

73

Taylor (1975 ) showed that they were maximally concentrated in the lysosomes

of rat liver as soon as one hour after intravenous injection, A similar

uptake of particles of americium and curium can he expected.

5 - 3 Gonads

To estimate the human genetic dose resulting from an intake of

plutonium or other actinides, the uptake, distribution and retention in

the gonads must be known. Very little information is available in man and

use must be made of animal data.

Richmond and Thomas ( 1 9 7 5 ) have reviewed data on the deposition of

actinides in the gonads. Following the intravenous administration of

plutonium citrate or nitrate the percentage of the administered plutonium

accumulated by the testes (average for k species) was about k x 1 0 % with

less than a factor of 1 0 between the highest and lowest values (range 1 , 9 2 2

x 1 0 " % to 9 - 5 x 10~~ %). Only one result obtained in 3 dogs (Baxter et al,

1 9 7 3 ) following the intravenous administration of polymeric plutonium, was

below this range ( 1 . 6 x 10""-^%). This chemical form of plutonium is, how-

ever, mainly accumulated by the liver and is unlikely to be representative

of the transportable fraction of plutonium that has entered the blood in

cases of human contamination. The fractional accumulation of plutonium

by the testes is influenced by the relative weights of the testes and the

whole body. In animals in which the weight of the testes is a relatively

large proportion of the body weight (eg, rat and pig) the uptake of

plutonium is greater than in animals in which it is relatively small (eg,

man and dog). If the values for the uptake of plutonium by the testes are

normalised to take account of the differences in testis weight the values

obtained for 7 different species (mouse, rat, hamster, rabbit, dog, pig,

human) vary by only about a factor of 5 (Stather and Rodwell, 1 9 7 7 ) . The

average value for the accumulation of plutonium in these species would then

correspond to a deposition in the human testes of about 1 . 7 x 1 0 ~ 2 % . Until

more data is available 3 x 1 0 ~ 2 % can be taken as the amount of plutonium

or other actinides accumulated by the testes from the blood. If plutonium

was uniformly distributed throughout the body (weight 7 0 kg) the testes

(weight 3 5 g) would accumulate 5 x 1 0 ~ 2 % of the body activity (based on

organ weights given in ICRP Publication 2 3 , 1 9 7 5 ) .

The proportion of plutonium accumulated by the ovaries following

intravenous administration in soluble form was about 3 x 10"" % (average

of 6 species, range 1 . 3 x 1 0 " % to 9 . 8 x 1 0 ~ 2 % ) (Richmond and Thomas 1 9 7 5 ) .

7^

Data reported by Green et al, ( 1 9 7 7 ) gave an average uptake of 1 . 1 x 1 0 - 2 %

per ovary in the mouse in good agreement with these values. In general,

more activity is accumulated by the ovary in rodents than in larger animals.

This may be attributed to its larger fractional body mass in small animals.

Based on these values the amount of plutonium accumulated by the human

ovaries could be taken to be 1 x 1 0 ~ ^ % . If plutonium was distributed

uniformly throughout the body ( 5 8 kg) the ovaries ( 1 1 g) would accumulate

1 . 9 x ICf^ of the body activity (ICRP Publication 2 3 , 1 9 7 5 ) .

Values obtained for accumulation of americium and curium by the gonads

(Richmond and Thomas, 1 9 7 5 ) are similar to those obtained for plutonium.

Data on the retention of plutonium in the testes suggest that it is

retained with a long half-time. In a study reported by Taylor ( 1 9 7 7 ) no

significant change in the total activity in the testes of rats up to 5 7 5

days after intravenous injection as the nitrate was found. Similar results

have been reported in hamsters up to one year after administration as the

citrate (Stather and Rodwell, 1 9 7 7 ) and by Koshurnikova ( 1 9 6 1 ) in rabbits

up to 5 months after administration as the nitrate. The retention of

plutonium in the mouse ovary has been reported by Green et al, ( 1 9 7 7 ) .

Up to 1 8 0 days after intravenous administration as citrate there was no

significant variation in the retained activity.

There are no satisfactory long term data on the retention of americium

and curium in either the testes or ovaries.

Green et al, ( 1 9 7 5 ) have shown using autoradiographic techniques that

after intravenous injection as the citrate plutonium accumulated by the

rodent testes is associated mostly with cells in the interstitial tissue,

outside the seminiferous tubules. Similar findings have been reported by

Taylor ( 1 9 7 7 ) » Brooks et a l , ( 1 9 7 6 c ) , ana Priest ( 1 9 7 7 ) . As a consequence of

this localised accumulation the calculated average dose to the spermato-

gonial stem cells in the mouse in which genetic damage may accumulate, is

greater than the average dose to the whole testes by a factor of 2 to 2 . 5

(Green et al, 1 9 7 5 ) . This activity appears to be concentrated predominantly

in macrophages (Priest and Jackson, 1 9 7 8 ) . In the human about 50% of the

tissue of the testes is interstitial compared with 1 0 % and 1 6 % in the mouse

and hamster respectively. As a consequence no significant dose enhancement

factor for spermatogonia could be calculated when 90% of the plutonium-239

was assumed to be uniformly distributed in the interstitial tissue (Brooks

et al, 1 9 7 6 c ) .

75

Green et al, ( 1 9 7 7 ) have studied the distribution of plutonium in the

mouse ovary. At early times ( 1 and 2 days) after intravenous administration

of plutonium-239 citrate a-tracks were randomly distributed over all tissues

with concentrations of tracks occurring over some atretic follicles. A

second site of accumulation of plutonium-239 was within thecal rings, which

are the post-atretic remains of small follicles. At later times (up to 1 8 0

days) after injection plutonium accumulated in the macrophages of the

medullary stroma probably as a result of the phagocytic activity of these

cells. A similar deposition pattern of plutonium at early times has been

found in the ovaries of the rabbit and hamster (Priest and Jackson, 1 9 7 8 ) .

It is unlikely that this distribution of activity in the ovary would result

in any dose enhancement to developing ovarian follicles.

Summary

For radiological protection purposes there are three main sites of

deposition of actinides that have entered the blood: the skeleton,

the liver and the gonads. The skeleton and liver together accumulate

about 9 0 $ of the activity entering the blood and the activity can be

assumed to be equally divided between them. The half-time of

retention of actinides in the human skeleton is estimated to be 1 0 0

years and in the liver 1+0 years.

It is estimated that the testes will accumulate 3 x 1 0 " ^ %

and the ovaries 1 x lO""^ of the activity entering the

blood. The results of animal studies indicate that there is no

selective accumulation of actinides by the gonads but that any

activity deposited in them is retained indefinately.

6. Excretion

Following intakes of actinides, some of the activity is excreted in

the faeces and in the urine.

Activity in the faeces originates from two sources: either as

a result of activity deposited in the respiratory system being cleared

from the lung via the mucociliary escalator and swallowed, or by direct

secretion into the gut. In rats the main pathway of secretion is by

way of the bile (Ballou and Hess, 1 9 7 2 ) and accounts for the rapid loss

of plutonium from the liver. Non-biliary secretion into the gastro-

intestinal tract of rats have also been reported to account for the

greater rate of loss of plutonium in the faeces than in the bile following

the intravenous injection of plutonium (Astley and Sanders, 1 9 7 3 ) •

76

Plutonium excreted in the urine is derived from the systemic circula-

tion by ultrafiltration in the kidney glomerulus. The majority of plutonium

circulating in the blood following the administration of relatively soluble

forms of plutonium (citrate or nitrate) is bound either to transferrin or

to citrate and it has been shown that it is probably the citrate complex

that is excreted in the urine (Popplewell et al, 1 9 7 5 ) . This is also true

for americium and curium (Stradling et al, 1976) .

More americium and curium than plutonium is cleared into the urine

reflecting the relatively weak binding of the transplutonium elements to

plasma proteins. Thus the total urinary excretion of americium-2i|1 and

curium-2kh in beagle dogs over 3 weeks after intravenous injection as

citrate accounted for 10% and 8% of the injected dose, respectively (Lloyd

et al, 1970, 1 9 7 3 ) . This compares with a value of Iffi of the injected dose

of plutonium-239 obtained in similar studies (Stover et al, 1969). Faecal

excretion over this period accounted for 1%, y/o and 8% of the injected dose

of americium, curium and plutonium respectively. The fraction of the faecal

excretion in dogs that is due to biliary secretion has not been determined

but the high liver retention of the actinides in these animals indicates

that biliary excretion will be low.

Systemic deposits of actinides are difficult to detect by whole body

counting techniques and they are therefore normally assessed from measure-

ments of their rate of excretion in the urine. The results of these

measurements are interpreted on the basis of the equations developed by

Langham (Chapter 3)- Many studies have been reported on the urinary

excretion of actinides in animals that have been used as a guide for inter-

preting the results of bioassay data. For example the relatively high rate

of urinary excretion of both americium and curium indicates that the

application of equations based on the excretion of plutonium in man to

these higher actinides is likely to overestimate systemic deposits.

As a method for the assessment of plutonium entering the systemic

circulation it has been suggested that following accidental intakes of

plutonium, a constant relationship exists between the total urinary

excretion over a limited period of time following exposure and the amount

translocated to tissues (Lafuma, Nenot and Morin, 1 9 7 2 ) . The assumption

is that relatively constant fractions of the actinides entering the blood

are deposited in tissues and excreted in the urine. It has been shown in

studies with rats that the tissue distribution of plutonium following its

entry into the blood is largely independent of the original chemical form

deposited in the lung (Table U-2). Stradling et al, (1977) have, however,

77

demonstrated in rats that particles of plutonium dioxide about 1 nm in

diameter, can readily pass from the lungs into the blood to form an "inter-

mediate" species thought to be formed from the association of the plutonium

particles with citrate ions. This complex is readily excreted in the urine

and results in relatively high levels of urinary excretion. This "inter-

mediate" species is solubilised in the blood with a half-time of about 3

minutes which would suggest that at times later than a few days after

exposure the pattern of excretion should be similar to that found after

the administration of plutonium citrate.

Although it may be possible to make some estimate of the systemic

deposit of plutonium from urinary excretion data it cannot be used to

estimate activity in the lungs or at a wound site as the rate of movement

of activity from the site of deposition to the blood varies very widely

depending upon the chemical form of plutonium deposited.

Summary

Actinides incorporated into the body are excreted both in the faeces

and in the urine. Faecal excretion results from actinides entering

the gut either in mucous cleared from the respiratory system or in

gut secretions. Urinary excretion is due to ultrafiltration through

the kidney of actinide-citrate complexes formed in the blood.

Animal studies have shown that more americium and curium are excreted

in the urine than plutonium. The application of urinary excretion

data for plutonium in man to these higher actinides is therefore

likely to overestimate systemic deposits.

7. General conclusions

There are three main routes of entry of plutonium, americium and

curium into the body: by inhalation, by ingestion and through wounds.

A model for the deposition and retention of inhaled aerosols in the

human respiratory tract was described in the Report of the Task Group on

Lung Dynamics (1966) for Committee 2 of the International Commission on

Radiological Protection and modified in ICRP Publication 1 9 , 1972 . In the

model the respiratory tract has been divided into three regions: the

nasopharynx, the tracheobronchial region and the pulmonary region. The

regional deposition of an inhaled aerosol is considered to be primarily a

function of the particle size distribution. The chemical form of the

compound inhaled influences the subsequent clearance from the lung. In the

model retention in the lung can be for days (Class D), weeks (Class W) or

78

years (Glass Y). The Task Group Lung Model predicts that following the

inhalation of an aerosol of a relatively soluble (Class W) compound

(particle size distribution 1 un AMAD), 1 2 % of the activity will be trans-

ferred to the blood, and for a less soluble (Class Y) compound 5%. Reten-

tion is exponential with half-times of retention of the long term component

in the lung of $ 0 and 5 0 0 days for Class W and Class Y compounds respect-

ively.

Studies in animals have shown that plutonium compounds generally con-

form to this classification - oxides are Class Y, nitrates are Class W and

plutonium complexed with the chelating agent diethylenetriamine penta

acetic acid (DPTA) is Class D. Experimental studies have also shown that

all compounds of americium and curium, except Class D, but including the

oxides, are retained in the lung with half-times of a few weeks or months

and should be considered to be Class W. Following the inhalation of

particles consisting of mixtures of actinides the retention in the lung of

the individual actinides will be similar to that of the material present in

the inhaled particles in greatest mass.

For soluble plutonium compounds that have entered the gut the amount

of plutonium absorbed by adults is about 1 x 1 0 ~ ^ % and for insoluble

plutonium dioxide particles 1 x 1 0 " ^ % - Plutonium dioxide particles should

be treated as soluble if they are less than about 5 nm in diameter,

Americium and curium are absorbed more readily from the gut than plutonium

and a value of 5 x 1 0 " ^ % for all compounds is recommended. Absorption is

enhanced in the young and actinides incorporated in plant and animal tissue

may be absorbed more readily than inorganic compounds.

The behaviour of actinides compounds in contaminated wounds depends on

physico-chemical characteristics such as chemical form, particle size, mass

injected and specific activity as well as biological factors such as the

depth and site of deposition, the type of tissue, tissue fluid flow past

the deposit and the dispersion within the tissue. In general terms,

soluble compounds are cleared more readily than insoluble compounds,

subcutaneous deposits more readily than intramuscular deposits and americium

and curium more readily than plutonium.

The differences in behaviour between plutonium-239 and the higher

actinides can be attributed mainly to physical and chemical factors,

Plutonium forms polymers more readily than the higher actinides at physio-

logical pH and for equal amounts of activity a greater mass of plutonium-

2 3 9 than americium-2l+1 or curium-2U2 is deposited. Thus plutonium-239 is

7 9

more likely to be retained at sites of deposition than the higher actinides.

Particles of americium and curium have a higher specific activity than

plutonium-239 and this will also tend to mobilise them more readily from

any site of deposition.

The tissue distribution of actinides once they are in the blood is

largely independent of the initial physico-chemical form taken into the

body. For an assessment of the consequences of human exposure to these

actinides there are three important sites of deposition: the liver, the

skeleton and the gonads.

The liver and skeleton together accumulate about 90% of the systemic

deposit although the distribution of activity between these two tissues is

very variable. Overall 1+5% of the systemic activity can be considered to

deposit in each tissue. Retention is exponential with half-times in human

skeleton and liver estimated to be 1 0 0 and 1+0 years respectively.

Because of the potential genetic risk the third important site of

deposition from the blood is the gonads. Based upon both animal and human

data it has been estimated that the human testes will accumulate 3 x 1 0 " ^ %

of activity entering the blood and the ovaries 1 x 1 0 " ^ % . Although data on

the retention of actinides in the gonads is very limited animal studies

suggest that they are retained indefinitely.

Acknowledgement

The authors would like to thank Dr. N. Priest and Dr. J. D. Harrison

for their help in the preparation of this Chapter.

Chapter 5

T I S S U E S A T R I S K

1. The Concept of Critical Tissue in Relation to the Biological Effects

of Plutonium and Transplutonium Elements

It is extremely difficult to correlate the spatial distribution of the

dose in the tissues or organs following the deposition of plutonium or

transplutonium elements with the numerous observed biological effects. One

difficulty is caused by the large number of cell types that may be directly

or indirectly affected; this number can be reduced, however, as certain

determining factors also have to be taken into account, such as radiological

sensitivity, localization of the actinides in tissues and the number of

cells at risk. Factors relating to the radionuclide and its deposition in

the organism are equally important: the manner of deposition, whether the

distribution in the tissue is homogeneous or inhomogeneous, the size of the

particles, if the deposit is in a soluble or insoluble form, the specific

activity and the type of radioactive emission, the mobility of the deposit

including its rate of excretion, possible movements within the organ or

tissue itself, and the relationship with the various cell types of differing

radiosensitivities.

In addition, more fundamental factors play a part, such as the charact-

eristics of cell cycles, the variations in radiosensitivity associated with

growth, and cell differentiation and renewal.

This short list illustrates the difficulty in establishing a clear and

exact relationship between the physical features of contamination and a

biological assessment of the damage. Not only are many parameters still

unknown, but it is also practically impossible to apply a common standard

to the various biological effects that are observed; in fact, every type of

lesion seems to have its own dose-effect relationship. In the light of

present knowledge, this relationship may appear in forms that are appreci-

ably different. According to whether we are considering the effect on the

whole organism, a particular organ, a tissue or a cell type; a linear,

curvilinear or sigmoid relationship, or any other form, with or without an

apparent threshold may be obtained (UNSCEAR, 1972).

The tissues most exposed to contamination by plutonium or trans-

plutonium elements are the lung and skeleton. The former being the organ

through which the radionuclide may enter the body and the latter one of the

main organs for deposition, especially when the element is in a more soluble

form. Other organs exposed to significant amounts of activity include the

81

82

liver and lymphoid tissue. Finally, all the other organs and tissues may be

affected by the wide dispersion of the radionuclide in the organism.

1 . 1 Lung

All these introductory remarks can be applied to the lung. However,

certain other factors have to be taken into account, such as the duration

of alpha irradiation of particular cell types. Here a part is played both

by the kinetics of the radionuclide deposited in the lung and by the

kinetics of the cells that are exposed to risk; the fact that two kinetic

systems are involved produces more complex models. For example, a particle

taken up by a macrophage may move either inside an alveolus or even from

one alveolus to another. Furthermore, ventilatory movements of the

alveoli produce a more uniform dose distribution than might be assumed from

an autoradiograph of the particle which shows a "hot spot" that has every

appearance of being stationary (see Chapter 7 ) . This problem is related to

that concerning the number of cells affected by alpha irradiation (NCKP

Report No. 1+6, 1 9 7 5 ; Mayneord and Clarke, 1 9 7 6 ) . According to the nature

and manner of the deposit in the lung, the number of cells at risk varies.

This point underlines, among other things, the difficulty of extrapolating

from one species to another and, in particular, of making intercomparisons

between animals of very different sizes. However, some concepts are now

generally accepted, such as the fact that there will be a higher frequency

of lung cancer for a given radionuclide in a given form when the radio-

nuclide is distrioited more uniformly in the organ (Sanders, 1 9 7 2 , 1 9 7 6 b ;

Morin et al, 1 9 7 6 , 1 9 7 7 ; Bair et al, 'ISlh; Medical Research Council, 1 9 7 5 ) .

A large proportion of the activity in the lung will be phagocytosed by

macrophages. These mature cells form an isolated group with a highly

differentiated cellular type; they receive intense alpha irradiation at

very high dose rates from phagocytosed radioactive particles but their

precursor cells are only slightly affected. The situation is quite

different for the pulmonary cell types that are renewed in situ, such as

the epithelial cells, the cells of the blood and lymphatic vessels, the

lymphoid cells and the cells of the supportive tissue. The radiation

exposure of these different cell types depends on the manner in which

activity is deposited in the lung. The radioactive contaminant can be

transported through the pulmonary lymphatic vessels to the lymph nodes that

drain them; here the problem arises of the irradiation of the cells of the

lymph nodes. Most of the mature cells that circulate or remain in the

vessels, such as erythrocytes, granulocytes, and thrombocytes, are not

killed by low doses of radiation. The radiosensitivity of lymphocytes is

8 3

however well-established. In addition to the irradiation they receive in the

nodes they are also irradiated while passing throiigh the lung. This radio-

sensitivity can give rise to lymphopenia and to immunological consequences.

This effect may be pronounced due to the division rate of lymphocytes in the

capillaries of the lung, which seems much higher than in circulating blood

(Fritsch et al, 1 9 7 5 ) .

Although, anatomically, the bronchial and tracheo-bronchial lymph nodes

are not part of the lung, they do accumulate some of the inhaled radio-

nuclide. These deposits are cleared with a long half-time whatever the

selected reference model may be (Task Group on Lung Dynamics, ICRP 1 9 6 6 a ) .

The concentration of activity in the lymphoid tissue is sufficient reason

to pay it very close attention, although pathology associated with lymph

node irradiation is small or even non-existent. For this reason lymphatic

tissue will be examined in the same context as the other tissues which make

up the lung. This approach is especially appropriate as in the latest lung

model (ICRP 2 6 , 1 9 7 7 ) lymphoid tissue whether scattered in lung parenchyma

or concentrated in nodes, is grouped together with those tissues that are,

strictly speaking, lung tissues.

1 . 2 Skeleton

Among those organs other than the lung that are liable to develop or be

the origin of a pathological disorder resulting from alpha contamination,

the skeleton is of special significance. In this tissue, a number of cell

types are particularly liable to be sensitive to alpha irradiation because

they have a high rate of proliferation. The main types are:

- osteogenic cells in rapidly growing bone

- bone marrow with blood-forming cells (Loutit and vaughan, 1 9 7 1 )

As deposition of plutonium in the skeleton takes place in the marrow and on

the surface of the osteogenic tissue, the resultant pathology is particul-

arly complex. In a mature bone, in which absorption and apposition are

negligible, the number of osteoblasts and osteoclasts present on the surface

is very small. This is not the case with a young bone subject to extensive

remodelling, whose surface is covered with active osteoblasts and osteo-

clasts, all of which are mature differentiated cells; the precursor cells,

pre-osteoblasts and pre-osteoclasts, are also located on the bone surfaces

(Owen, 1 9 7 0 ) (Figure 5 . 1 ) .

In theory, tumours induced by alpha emitters deposited in bone can be

of various types (Vaughan, 1 9 7 3 ) s including osteo-sarcomas, chondro-

sarcomas, leukaemias and reticuloendothelial tumours. The former are by

8U

Figure 5*1 • Autoradiograph showing Pu deposited upon the trabecular surfaces of developing rat bone. Some plutonium has also been engulfed by a large osteoclast. In contrast very few or no (3-tracks are associated with the differentiating pre-osteoblasts within the intertrabecular spaces (Provided by N.D. Priest, National Radiological Protection Board, UK).

85

far the most frequent.

1 . 3 Liver

In view of the large deposits of plutonium in the liver that occur

after any contamination by plutonium or transplutonium elements, hepatic

tissue, composed primarily of hepatocytes and cells of the reticulo-

endothelial system, must be regarded as potentially at risk. This risk might

be higher in man and monkeys than in rats as the element is eliminated

more slowly. The fact that hepatic cancers induced by alpha emitters

oocur very rarely in experimental animals should not allow the potential

risk in man to be overlooked.

1 . 1 + Other tissues

Apart from the lung, bone and the liver every other tissue and organ

in the body is potentially at risk. Although following plutonium contamin-

ation tumours develop in other organs very infrequently, they may become

more significant in the case of elements that are particularly soluble,

such as americium or curium, as well as in the observed cases of synergy

involving many co-factors (Morin et al, 1 9 7 7 ) .

The potential risk from deposition in the gonads by an alpha emitter

constitutes a special case. Data on the genetic effects of plutonium and

the transplutonium elements are very sparse.

2 . Cells Affected by Alpha Irradiation; Cell Type, Function and Radio-

sensitivity

2 . 1 Criteria for defining tissues and cells exposed to risk

The criteria normally selected for assessing somatic risk are the

factors that have a harmful effect on the individual as a whole (ICRP 1 1 ; ,

1 9 6 9 ) . The most important effects, which have direct consequences for the

health of the contaminated person, are as follows:

( 1 ) shortening of the life-span;

( 2 ) anatomical or functional changes in the tissues directly exposed;

( 3 ) the induction of malignant tumours.

Those effects that are offset by a biological response and thus have

no apparent anatomical or functional repercussions are normally disregarded.

For example, the widespread destruction of macrophages by the inhalation of

plutonium particles is offset by the high reproduction rate of these cells,

with the result that the total population in the lung may be above normal

86

(Masse, 1 9 7 1 , 1 9 7 7 ) .

When an effect is studied in isolation, it must be borne in mind that

the same cause (contamination by alpha emitters) produces several effects,

that these effects are not normally simultaneous but consecutive, and that

the appearance of some may prevent the occurrence of others. For this

reason it is essential that these events are studied in sequence, viz. by

examining the effects of a large range of doses. Moreover, these effects

may not only conceal one another but also interfere with each other. Thus

a given frequency of cancers must influence the life-span, but it is just

as likely that other factors bearing no relation to the cancer may inter-

vene. Experiments have frequently shown that animals with cancers induced

by alpha emitters live longer on average than animals of the same exposure

group which have no cancers; this fact is simply related to the latent

period of cancer induction which is equivalent to a relatively large

fraction of their life-span (Morin et al, 1976; Lafuma et al, 1976 ) .

The interference of various pathological effects is most marked in the

lung. Hence the relative importance of each of the following factors in

causing early death is very difficult to gauge accurately:

( 1) respiratory insufficiency and its cardiovascular repercussions;

(2) a reduced resistance to respiratory infections;

( 3 ) any other pathological change in the pulmonary tissue.

In the light of histopathological knowledge, however, it is possible

to distinguish certain cell types according to their kinetics, function and

sensitivity. As direct exposure of cells to alpha radiation is the prime

consideration, the only cells and tissues discussed will be those whose dis-

tance from the primary site of radioactive deposition or from the particle

does not exceed the path travelled in the relevant tissue by the alpha

emission.

2.2 Cell types in relation to alpha irradiation

2.2 .1 Respiratory system

Retention of inhaled particles in the nasopharyngeal (N-P) region

(ICRP Task Group on Lung ])ynamics, 1966) increases very rapidly with the

size of the particle, for while less than 10% are retained in the case of

particles measuring 1 +un (AMAD) about 70% are retained for $ pm particles

and virtually 100% for particles measuring more than about $0 pm.

Elimination in the faeces is rapid and takes place in a few days but,

despite this brief stay in the nasopharynx, it is possible that a single

87

substantial contamination may deliver an appreciable dose to particular

regions of the nasopharynx, especially in the case of a radionuclide with

a high specific activity. In fact, no effect has ever been observed in

spite of the large number of cells that are liable to suffer damage from

alpha irradiation, such as the cells of the basal layer and of the ciliated

epithelium, chromaffin cells, and the serous and mucous acini cells.

It should be pointed out, however, that experimental data on the

effects of large particles are limited; if there is any risk, it is cert-

ainly much lower than the risk associated with the deposition of an equiva-

lent amount of activity in the lower respiratory tract. Elimination by the

gastrointestinal tract has not produced any pathological effects in cells

of the gut wall.

Tracheo-bronchial and pulmonary regions

In the ICRP lung model ( 1 9 6 6 ) the lower regions of the respiratory

tract are divided into the tracheo-bronchial (T-B) and pulmonary (P)

regions. About 5% of relatively large particles measuring, for example,

about 5 pni (AMAD) may be retained in the T-B compartment. These free,

non-phagocytosed particles may deliver significant doses in the space of a

few days, while retained in the T-B compartment. This is likely to be of

minor importance, however, for the following reasons:

( 1 ) no effect has ever been observed in relation to deposits in this

region which are rapidly eliminated via the upper airways and

swallowed;

(2) the dose is always small in comparison with the dose to the pulmonary

region of the lung.

However, it must be borne in mind that extrapolation of the dose-effect

relationship from animals to man is especially difficult where cancers in

this region are concerned. In fact, the upper bronchial tubes are normally

the most common sites for human cancers although some recent work has

suggested that up to £0% of human lung cancers may arise in the terminal

bronchioles (Wynder and Hecht, 1 9 7 6 ) . The trachea, on the other hand, is

affected only very rarely (Chretien and Masse, 1 9 7 5 ) • The preferential site

in animals is, in the main, the terminal bronchi, whereas the upper airways

are very seldom affected. This observation indicates clearly that cancer-

prone cells are located in different regions, depending on the species in

question (Lafuma et al, 1 9 7 U ; Chretien and Masse, 1 9 7 5 ; Bair et al, 1 9 7 U ;

Bair 197i+b).

Observations on animals (Masse, 1 9 7 6 ; Ducousso et al, 1 9 7 3 ) have shown

88

that there is direct breaching of the walls of the bronchioles and that

particles pass directly through the epithelium; this has not been quantified,

however. Observations have shown (Masse et al, 1 9 7 3 ) (Figure 5 . 2 ) that

there is penetration by the particles, followed by their retention in the

region of the bronchial cells, and that this is not affected by any phago-

cytosis. In view of the direct relationship which exists between the

presence of these particles in the ciliated epithelium and the basal cells

and retention in the bronchi, this phenomenon, if it occurs in man, might

contribute towards the neoplastic changes in this region.

Finally, it is in the deep lung that the deposited material remains

longest, and where the relationship between contaminants and biological

components is closest and has been studied most thoroughly. The pulmonary

epithelium appears to be simple, being composed of pneumocytes I and

pneumocytes II; the latter possibly giving rise to the former. There is no

longer any doubt about the origin of alveolar macrophages; they are derived

from the blood monocytes and therefore originate in marrow (Pinkett et al,

1 9 6 6 ) . They can multiply within the alveoli (Masse et al, 1 9 7 0 ) . In

pathological conditions, a stage of interstitial maturation may be observed

(Bowden et al, 19^9)> whereas, in physiological conditions, cellular

maturation occurs directly in the capillaries and alveoli (Masse et al,

1 9 7 7 ) .

With the possible exception of pneumocytes II, these different cell

types are able to accumulate foreign particles by phagocytosis and are

therefore liable to receive high radiation doses. The most actively

phagocytic of these cells is the alveolar macrophage which can ingest

several particles simulataneously, even when these are large. In general,

small particles aggregate within the cell and thus the dose rate to the

component parts of the cell directly adjacent to them is very high and

leads eventually to the death of the cell (Masse et al, 1 9 7 7 ) . Although

macrophages are radioresistant, it is difficult to compare the doses

delivered by external radiation and those received from an internal alpha

emitter. The epithelial cells situated at the bronchiolo-alveolar junction

seem to be especially sensitive to alpha radiation since many malignant

changes appear to originate in this area in animals (Chapter 6 ) .

Blood and Lymph Vessels of the Lung

The blood vessels of the lung are anatomically and physiologically of

special significance; the capillary endothelial cells represent about half

of all the alveolar cells of whatever origin (Miller, 1 9 5 2 ; Fritsch et al,

Figure 5.2 Formation of retention crypts in the monkey (baboon) with

penetration of the peribronchial alveoli after inhalation of

tantalum particles (information provided by R. Masse, CEA,

Departement de Protection, France).

89

90

1 9 7 7 ) » making them numerically the most important of the exposed cell

populations. They are irradiated directly since the endothelial cells of

the capillaries are within reach of the alpha irradiation coming from

actinides deposited in the deep lung, both when the contaminant is free in

the alveolus or when it is contained in macrophages (Figure 5 > . 3 ) . The

relationship between these vascular cells and the damage to them caused

by alpha radiation merits closer examination since the pathology is constant

and because the distribution of vascular tissue in the lung is uniform.

Pathological changes consist mainly of a chronic interstitial pneumonia with

slow, progressive obliteration (Masse et al, 1 9 7 5 ) * Malignant changes of

the haemangiosarcoma type are rare (Fritsch et al, 1 9 7 7 ) . The endothelial

cells probably have quite a higfr sensitivity to alpha radiation. They are

relatively sensitive to external radiation since 2 0 0 0 rad ( 2 0 Gy) delivered

by X-rays at a high dose-rate produces after a few months, cellular

necrosis of these elements (US NRDL, 1 9 ^ 6 ) ; moreover, they have the property

of accumulating certain soluble radionuclides (Masse et al, 1 9 7 5 ) *

It is probable that these changes to vascular tissue are soon

accompanied by a thrombosis in which the local blood platelets play an

important part (Cottier, 1 9 7 5 ) - These evolutive cell processes are a very

important contributory factor in the establishment of parenchymatous

fibrosis which appears as a final stage. Other contributory factors are

changes to the pneumocytes and the resultant fibrinous exudate.

Other vascular cells can be affected by alpha irradiation. These

include the endothelial cells of the terminal arterioles and the post-

capillary venules, as well as the components of the vascular supportive

tissue, such as fibroblasts and fibrocytes. Irradiation of some of these

components - elastic, collagenous, basilar and reticular fibres - might be

at the root of cardiovascular disorders, of which hypertension of the

pulmonary arteries is a typical case.

The mononuclear cells which circulate in these vessels and which make

up almost 20% of the cells of the alveolar wall (Fritsch et al, 1 9 7 7 ) are

liable, where clearance from the lungs is sufficiently slow and their life

span sufficiently long, to receive doses that produce appreciable effects.

Irradiation of the blood circulating within the lung is one of the elements

in the aetiology of the lymphopenia often observed experimentally in various

species, such as the dog (West and Bair, 1 9 6 I + ; Pa*k et al, 1 9 7 2 ; Buldakov

et al, 1 9 7 0 ) or, less often, in monkeys (Nolibe, 1 9 7 6 ) .

On the other hand, changes to other blood cells, such as polymorpho-

91

Figure 5 *3 Alpha emitters in an endothelial cell (information provided by

R. Masse, CEA, Departement de Protection, France).

92

nuclear leucocytes, are not observed when deposition is confined strictly to

the lung, but only when the actinides have migrated to bone; this distinc-

tion is particularly marked with high specific activity radionuclides, such

as plutonium-238 (Park et al, 1970) .

The presence of cellular infiltrates is sometimes observed after

pulmonary contamination by alpha emitters, especially if these are insoluble

(eg, plutonium dioxide); these infiltrates are composed principally of

granular leucocytes, lymphocytes, macrophages and plasma cells. They form

part of the response to the irradiation and there is still some doubt as

to the possible effect of the alpha radiation on these cells and, subse-

quently, on their defence mechanism function. Nevertheless, the total

number of cells affected is very small (Fritsch et al, 1 9 7 7 ) .

The pulmonary lymph vessels are also exposed as they are one of the

routes along which particles deposited in the lung are normally cleared.

Although dose-rates seldom reach high levels, the doses that are received

can be very high since in certain cases (for example, with non-transportable

compounds and others of low transportability) this particular route is

favoured (ICRP Task Group on Lung Dynamics, 1966) . Moreover, it is

conceivable that the dose-rates are subsequently increased as a result

of the obstruction of lymph vessels associated with local irradiation.

The resultant local oedema might then play a part in the formation of

pulmonary fibrosis.

Since the radiation induced lesions are replaced by scar tissue, the

risk incurred by the latter should also be examined. In fact, this replace-

ment tissue can appear well before most of the irradiating contaminant has

been removed. The component parts of the supportive tissue in the lung -

whether normal or replacement tissue - represent cell populations that are

exposed to risk (fibrocytes and fibroblasts). Information on the sensitivity

of different scar tissues is meagre. It is possible that the final effect

is relatively beneficial since scar tissue encapsulates the alpha emitter

to some extent and thus protects cell populations that are much more

sensitive. Obviously, this hypothesis does not preclude effects related to

the size of this replacement tissue which in extreme cases can be sufficient

to cause death.

Lymph Nodes

The consequences of the deposition of plutonium in the lymph nodes in

an insoluble form and, to a lesser extent, in a soluble form, or the

deposition of trivalent transplutonium elements constitutes one of the most

93

important areas of research into the radiotoxicity of alpha emitters. In

fact, for insoluble transuranium elements, the lymph nodes retain activity

with a long half-time; the slow clearance from the nodes can lead to very

high concentrations of the contaminant, whether contamination occurs

through a wound or by inhalation. In the latter case, the concentration

factor and consequently tissue doses can be very high in view of the

differences in mass of the pulmonary parenchyma and the lymph nodes (Pochin,

1 9 6 6 ) .

Routes followed by the lymphocytes circulating through the lymph nodes

are not straightforward and do not conform to any standard pattern. The

study of lymphocyte behaviour is made even more difficult by the presence

of several cell populations which seem to differ in origin, function,

sensitivity, and preferred localization. After entering the node by its

hilum, the lymphocyte carried in the blood can arrive in the parenchyma by

crossing the walls of the post capillary venules situated below the

capillary system; these vessels are found in the para-cortical region of

the node, on the inner edge of its cortical zone. It is in this zone that

the T lymphocytes, which represent about half of the total lymphocyte

population of the node, tend to concentrate. These T lymphocytes also make

up the majority of the lymphocytes that are released into blood circulation

which they reach after returning to the intranodal lymphatics. B lympho-

cytes, which are found mainly in the lymphoid follicles, make up the second

population of lymphocytes that are involved in radiation effects. The para-

cortical areas of the node contain quite large numbers of T and B lympho-

cytes; the large number of macrophages and granulocytes can be involved in

an anti-inflammatory response. Immune reactions lead to an increase in

the number of lymphocytes, probably by the two processes of migration and

local proliferation.

The presence of an alpha emitter in the node, whether or not in

particulate form, can therefore have an effect on its fixed cellular

components, and on the stock of sensitive cells circulating in the normal

way. It is possible that secondary reactions, due to quantitative and

qualitative changes to these lymphocyte populations; take place some

distance away in other lymphoid tissues such as splenic tissue or Peyer's

patches.

The^influence of radiation from alpha emitters on the immune response

is equivocal. On the one hand, it seems that a diffuse deposit, both in

the pulmonary parenchyma and in the nodes, is accompanied by a lessening

of the resistance to infection (Lafuma et al, 1 9 7 4 ) > and that there is a

9 ^

relationship between the homogeneity of distribution of the radioactive

deposit in the organ and the latterfs susceptibility to infection. On the

other hand, the only effects of localised irradiation, ie, not associated

with other, in general non-radioactive, harmful factors, are confined to

the site of irradiation. Moreover, the size of the local response is

proportional to the radiation dose. Present theories attributing radiation

carcinogenesis to a reduction in the general defence mechanisms have not

been conclusively demonstrated, although the lowering of cell-mediated

immunity leads to a large increase in the sensitivity of the rat to

carcinogenesis induced by alpha radiation (Nolibe et al, 1977a ) . It is

also possible that the replacement of the healthy node tissue by scar

tissue which scarcely functions, if at all, has an influence on the local

immune response.

Many other components of the node can be affected, but to a lesser

degree. This fact may be related to the greater radioresistance of the

macrophages and the reticular cells, of other blood cells, and the cells

of the capsule. This fact may also be related to the concentration of

the radionuclide in the area of the node where these components are

situated, such as in the para-cortical sinuses and in the medullary rays

which contain very few primordial lymphoid cells. This non-homogeneous

distribution is typical, even in the case of pulmonary contamination by

elements that are especially soluble. It is of particular importance

in the case of the formation of "hot spots" in the nodes.

Pulmonary Nervous Tissue

The components of the intra-pulmonary nervous tissue are much less

affected by intra-pulmonary irradiation if only because they are

quantitatively small in number. The very low frequency of tumours

arising in this nervous tissue in rats is not necessarily a sign of high

radioresistance, but may simply be related to the small populations

exposed to risk. This hypothesis could account in particular for the

absence in the rat of "oat cell" carcinomas which originate in the

neurosecretory cells of Kultschitsky as this cell type is found only

rarely in the rat (Pritsch et al, 1 9 7 7 ) .

2.2.2 Skeleton

It is well known that different transuranium elements deposit in

different component parts of adult bone. Distinctions should be made

first of all not on the basis of anatomical but of functional criteria.

95

Thus it is the type of tissue at risk which determines the nature of the

pathology. In this discussion, osteogenic tissue and bone marrow are of

central importance.

Bone

The main area of deposition of the transuranium elements in contrast

to the alkaline-earth elements, is the surface of the bone (Chapter i+).

Measurements made on a mature bone show that the distance separating the

bone cells (osteoblasts and osteoclasts) from the surface is in the region

of 10 pm (Vaughan, 1970; ICRP 1 1 , 1968) . This does not preclude the

presence of osteogenic cells in the marrow (Owen, 1970) . Irradiation of

the osteogenic population can give rise to neoplastic formations of the

osteosarcomatous, chondrosarcomatous or fibrosarcomatous type. The

temporal and spatial distribution of the doses delivered to the bone

depends partly on the form in which the radionuclide has been absorbed.

Different effects may therefore be expected, according to the elements

and compounds that are administered; this has in fact been confirmed in

experiments (Morin et al, 1976; Thomas et al, 1972; Ballou and Morrow,

1973)* Plutonium concentrates in large quantities in the osteolytic

periosteum, initially in the phagocytes and then in the fibrous part of

the tissue.

Trivalent elements, such as americium and curium,concentrate readily

in the walls of the vascular canals (Figure 5 » 4 ) ; they seem to be closely

associated with the cartilaginous matrix.

A crucial factor that has to be taken into account is the number of

the cells affected by alpha irradiation. Thus, whether a theoretical or

experimental approach is adopted, the large number of endosteal cells

assumes particular importance. In man, the periosteal and endosteal

surface areas are in the ratio of 8:100 (Sissons et al, 1967) which means

that the endosteal cells are more likely to be the site of malignant

changes. Experiments confirm this working hypothesis (Taylor et al, 1969;

Rosenthal and Lindenbaum, 19^9)• The observation that a uniform distribu-

tion of the element in this bony tissue is more carcinogenic that a non-

uniform distribution for a given level of activity shows the importance

of the number of cell components that are exposed to the risk of malignant

changes (Morin et al, 1977; Rosenthal and Lindenbaum, 1969) .

Bone Marrow

Bone marrow is a composite tissue, which in man and animals is the

origin of many types of tumour, each possibly deriving from a cell type in

9 6

Figure 5 - 4 Localization of curium-2i+2 in the vascular canals after

inhalation of curium-242 nitrate (Nenot et al, 1 9 7 2 ) .

97

the tissue (Vaughan, 1973)* Bone marrow is of mesenchymatous origin, and

contains precursors of the red blood cells, the granulocytes, the megakaryo-

cytes and of a part of the lymphocyte population (Owen, 1970) . Marrow is

in addition amply endowed with vessels (and hence endothelial cells) and

with supportive tissue.

The way in which transuranium elements are deposited in the skeleton

is certainly responsible for the consistently low frequency, or non-

existence, of tumours developing in tissue of mesenchymatous origin, with

the exception of leukaemias. In all animal experiments tumours such as

hemangiosarcomas or fibrosarcomas are always very rare (Taylor et al, 1969;

Masse, 1976) .

On the other hand, a certain number of leukaemias or, more precisely,

tumours arising from uncontrolled proliferation of the marrow cells, have

been observed in animal experiments, with various organs being secondarily

affected, such as the liver, the spleen and the kidney; these leucoblastic

processes are sometimes associated with severe anaemia (Vaughan, 1970) .

Leukaemias occur more frequently with plutonium than with transplutonium

elements (Nenot et al, 1972 ) .

2 .2 .3 Liver

A close study has been made of hepatic tissue with its two main

components, hepatocytes and reticuloendothelial cells; this is particularly

because the rates of hepatic clearance and the relative distribution between

the two component tissues differ enormously from one animal species to

another. In spite of the long residence time of plutonium in the dog and

monkey liver and the presence of large quantities of alpha emitters in the

organ, tumours are observed in it very infrequently, if at all. However,

despite the low incidence of liver tumours in experimental animals, the

liver in man must be considered potentially at risk from intakes of

actinides.

2*2.h Other tissues or organs

There has been a considerable increase in recent years in the number

of tissues or organs that have been found to be directly affected by alpha

irradiation and therefore at risk (without precluding the indirect effects

discussed above); this is due to the increasing number of studies carried

out and the increasing range of compounds and elements used. Thus in

animals that have inhaled plutonium-239 dioxide calcined at a high tempera-

ture the lung is the main organ at risk. Transportable compounds of the

same isotope also expose the skeleton and the liver to high doses. Much

98

more soluble elements such as americium-21+1, curium-21+2 and curium-21+1+,

califoxnium-2f>2 and einsteinium-253» of whatever physico-chemical form,

or even certain compounds of plutonium-238 (ultra-filterable microspheres,

for example) although depositing mainly in the bone and liver are dispersed

throughout the whole of the organism and therefore irradiate a considerable

number of cell types (Ballou and Morrow, 1 9 7 3 ; Nenot and Lafuma, 1 9 7 6 ;

Taysum and Taylor, 1 9 7 2 ; Morin et al, 1 9 7 1 + ; Nenot et al, 1 9 7 1 a ; Taylor

et al, 1 9 7 1 ) . It is impossible therefore to discuss all the tissues

potentially at risk. The main aim must be to determine the levels of

relative risk and to select the critical tissues.

The deposition of soluble elements in the gonads, which contain the

stem germ cells, theoretically exposes them to the dual risk of cancer and

a genetic effect. In experimental animals exposed to actinides no tumours

have been found in the gonads nor have genetic effects ever been demon-

strated. The risk of genetic effects in man must however still be considered.

Finally, it should be noted that the number or organs or tissues

exposed to risk and therefore, ultimately, the number of cell types, is

particularly important for elements which translocate readily in the body.

As cancerous changes are the most important long term pathological effects

that need to be considered, the important factor is no longer the individ-

ual risk to a cell type but the cumulative risk to all the cell types that

are exposed. In other words, in view of the seriousness of cancer the

important unit to take into account is neither the cell, nor the organ or

tissue, but the individual as a whole.

3 . Inter-relationships between effects of Alpha Emitters and Affected

Cells

3 . 1 Influence of cell kinetics on pathological effects

Consideration has to be given to cell kinetics since it is important

in the phenomena of both carcinogenesis and the repair of damage caused by

irradiation. Most of the models put forward are purely speculative, for we

still do not know enough about the mechanism of carcinogenesis, the main

cell types that are involved and the way in which they are renewed. Inter-

action of the various kinetic systems makes an experimental approach very

difficult. For example, a part of the macrophagic population which is

mobilized after respiratory contamination is of bone marrow origin; differ-

ences in response are to be expected, depending on whether the stem cells

of these macrophages were irradiated in situ, as is the case with trans-

portable transplutonium elements with large bone deposits, or not, as is

99

the case with the oxide of plutonium-239. The substantial accumulation of

alpha emitting elements in the macrophages would certainly account for the

rapid death of the cell rather than for any neoplastic changes. However,

it seems surprising that no tumour of this type has ever been described,

considering the constancy of dose delivered to this particular cell

population and the very large number of experiments carried out in very

many laboratories. It should be pointed out, however, that spontaneous

tumours derived from the mature macrophagic system are open to many

different interpretations with the probable exception of histiocytosis-X

in man.

Although our level of knowledge about lymphocytes and their variation

between species is much greater, it is still difficult to correlate their

kinetics with the observed effects if one takes into account both the

compartments in which they lodge and the residence times.

3 . 2 Influence of alpha emitters on certain cell populations

It is in the lung that the effects of alpha irradiation are most

apparent. The earliest effect observed is the death of a large number of

macrophages, associated with the great phagocytosing capability of these

cells.

Phagocytosis is very rapid and acts on a very large part of the inhaled

contaminant. Histologically, the surviving macrophages appear to be

abnormal, a reflection of the effects of radiation is shown, for example, by

their increased size and by the activity of their lysosomes (Masse, 1 9 7 7 ) .

There are also disruptions in the mechanisms in which they are normally

involved; thus, clearance may be affected (Nenot, 1 9 7 1 ) , there may be a

reduction in the mobilizable population that can be extracted from the lung

by lavage (Masse, 1 9 7 1 ) * The death of the macrophages releases the alpha

emitter into the air spaces; the actinide may then be rephagocytosed by a

healthy macrophage. This phenomenon may recur several times, but experi-

mental data does not at present allow a full understanding of all of the

factors involved in this mechanism, despite its apparent simplicity.

Phagocytosis by the endothelial cells in the pulmonary capillaries is

very limited. Lesions due to the presence of the alpha emitter are of the

exudate type. This exudate, rich in fibrin, is soon accompanied by an

increase in the fibrous supportive tissue with many breaks to the endothe-

lial layer. The thromboses in the arterioles and capillaries are similar

to the lesions observed after external radiation (Sanders et al, 1 9 7 1 ) .

100

Lesions in the lung will be described in Chapter 6 (Biological Effects).

Effects on the pneumocytes and the other main components of the deep lung

are direct and the inter-relationships between the physical behaviour of

the emitter and the biological behaviour of the cell are less clear.

i+. Discussion

It is extremely tempting to see a direct link between the alpha

radiation dose to tissues and the malignant or non-malignant changes which

result. The main direction followed by comprehensive work on the risk to

cell populations exposed to radiation is based on the supposition that the

dose must be received directly by a particular cell or cell population in

order to bring about pathological changes. This concept differs from the

hypothesis of a correlation between the seriousness of the effect and the

size of the cell population that is exposed. Experiments on animals and

observations on humans generally produce evidence in favour of the latter

theory. It is less easy to demonstrate that irradiation of a particular

tissue is needed in order to produce an effect. Substantial evidence in

favour of this concept is provided mainly by the almost total absence of

extra-pulmonary cancers after inhalation of insoluble plutonium, in contrast

to the widespread distribution of cancers found after inhalation of actini-

des that are readily transportable in the body. However, when the distri-

bution of these actinides in the organs that give rise to radiation-induced

cancers is studied, a number of anomalies emerge. For example, in animals

of the same strain elements which are deposited in completely different

ways would be expected to give rise to cancers whose site of initiation and

histological type would relate to the region of deposition. This is not so,

however, since analysis of the different types of pulmonary cancers induced

in the rat by such widely-differing alpha emitters as the transuranic

elements, which are deposited in the deep lung, and radon daughters which

are deposited in the upper airways, show a very similar distribution

pattern (Morin et al, 1 9 7 6 ) . This observation may partly result from the

fact that in the rat the frequency of spontaneous bronchial tumours is

practically nil; but it does not explain why the frequency of bronchiolo-

alveolar cancers due to inhalation of radon and its daughters (Chameaud

et al, 1976) should be practically identical to that due to parenchymatous

irradiation produced by the inhalation of plutonium-239 dioxide.

A second problem that needs further study arises from the lack of

consistency that is often observed between the cells that receive the

greatest dose and the histology of the observed tumours. It is very

difficult to arrive at a complete understanding of the histology of each

1 0 1

species and strain, particularly as the development of a "naturally"

occurring cancer may require a promoting agent. It is clearly very diffi-

cult to link the manner of the irradiation with the type of cancer when it

is observed that after inhalation of actinides giving approximately the

same radiation dose to the lung the frequency of pulmonary sarcomas is

2 .5% in one strain of rat and 17% in another (Morin et al, 1 9 7 6 ) . An

extra-ordinarily high frequency of a rare tumour (angiosarcoma) in the

dog has also been noted in dogs that had inhaled cerium-1I4+ in fused clay

particles (Hahn et al, 1973)* This second difficulty may be less discoura-

ging than it at first seems for just as it is essential that the kinetics

of cells at risk should be studied, it is equally important to carry out a

full study of the development of cancer. Two facts then become apparent:

( 1) Cellular changes follow one another in time, always in the same order,

and there is no break in the sequence. For example, in the rat lung

the stages of metaplasia and of adenomatosis precede that of adenoma

which, in turn, precedes that of carcinoma (Morin et al, 1 9 7 7 ) . For

a given dose the periods between the appearance of each effect are of

the same order, the rate of development of the various stages, however,

is a function of the dose. This phenomenon may be responsible for the

predominance of a certain type of cancer after medium doses and of

another type after high doses. For example, bronchiolo-alveolar

carcinoma predominates in rats at low doses, whereas bronchogenic

carcinoma predominates at high doses.

(2) Not only can the different stages in the development of cancer exist

at the same time in the same organ, but it is not unusual to observe

an inter-relationship between different types of cancer. If this

observation is extrapolated to the temporal development of tumours,

it could be concluded that there is really no standard type of lesion.

Thus, a simple lesion at a given time, as seen by histological

examination, becomes a composite lesion when its development with

time is taken into account.

The relative radiosensitivity of cells plays a large part in radiation-

induced pathology. Two points need to be made here: ( 1) The definition of

radiosensitivity is often vague; in fact the most sensitive cell populations

are not necessarily those which develop most cancers - on this basis the

cells in the pulmonary region that would be most liable to cancer induction

would be the epithelial cells. In practice this is not the case. This

phenomenon cannot be accounted for by sterilization (Fritsch et al, 1 9 7 7 ) .

102

It must therefore be concluded that the target cells are cells with a

higher potential for the development of cancer. This may correspond to a

form of ageing in the cell types involved: ciliated cells in the lower

bronchial tubes, Clara cells and pneumocytes II of the bronchioles and

alveoli (Fritsch et al, 1 9 7 7 ) • ( 2 ) Rather than considering the radio-

sensitivity of individual cells, it may be more appropriate to determine

the sensitivities at higher levels in the scale or organisation, whether

at the level of the organ or of the whole body. This concept, moreover,

is in line with current thinking about carcinogenesis.

Finally there are numerous co-factors that are involved in human

pathology and which may influence the development of radiation induced

cancers. Their influence cannot be quantified until more information is

available.

Acknowl e element

The authors would like to express their gratitude to Dr. Roland Masse

for agreeing to revise this chapter.

Chapter 6

P A T H O L O G I C A L EFFECTS IN ANIMALS

1 . Introduction

A substantial amount of experimental research work has been published

on the toxic effects of plutonium, transplutonium elements and other alpha

emitters in animals. These studies have examined different modes of

contamination using various animal species, and have been concerned both

with short- and medium-term toxicology and long-term toxicology. All the

laboratories involved in these studies have concentrated on long-term

effects; these are of major concern for the health of humans, since short-

and medium-term effects are only possible in accidental situations which by

their nature are exceptional. The scarcity or, indeed, the absence of human

data (Chapter 3 ) makes extrapolation of the results of animal studies to man

very difficult, whether for the estimation of lethal of sub-lethal doses,

or dose response relationships for the induction of cancer.

Due to technical difficulties only a limited number of laboratories

are concerned with research into low dose levels. This research is lengthy,

particularly when it entails examining animals with a long life span, such

as the dog or the monkey, it is expensive, and there are difficult problems

of interpretation of the results obtained. In addition to the studies which

concentrate on mortality there are a few studies on radiation-induced

diseases. These studies are, however, very limited because of the diffi-

culties of evaluation and quantification and of the importance for man of

the mortality studies on which emphasis has been placed.

Plutonium is the toxicological "model" for actinides, although from

the physico-chemical and, hence, metabolic point of view its behaviour is

the most complex (Chapter k)»

It is convenient to separate somatic effects into two distinct types:

( 1 ) early and medium-term effects;

( 2 ) delay effects.

These correspond to non-stochastic and stochastic effects (ICRP 2 6 , 1 9 7 7 ) .

2 . Early and Medium-Term Effects

2 . 1 Acute toxicity

There are few studies of the acute radiotoxicity of plutonium, probably

because they would have little relevance to radioprotection. In fact, the

L D ^ 0 o f intravenously-administered plutonium is in the region of

103

10k

— 1 —1 —1 —1

1 mg kg" or 6 1 . 3 p.Ci kg" ( 2 . 3 MBq kg ) in the rat and 0 . 3 mg kg" in the

dog (Moskalev, 1 9 7 2 ) ; extrapolation to man is too difficult for an exact

figure to be given, because of the great anatomical, physiological and

pathological differences between the three species. The L D ^ Q ^ Q °^ inhaled

plutonium-239 in man, which is easier to estimate by extrapolation from

animal studies, is probably about 5 0 mg, or 3 niCi ( 1 1 1 MBq). In this case,

death occurs as a result of massive pulmonary oedema and pulmonary

haemorrhage.

Clearly, it is very difficult to imagine a man inhaling amounts of

plutonium exceeding about 1 0 milligrams. On the other hand, it would be

more reasonable to envisage inhalation of an alpha emitter with a higher

specific activity; for example, the L D ^ Q ^ Q o f plutonium-238 would be

0 . 2 mg. However, even this amount is unlikely to be inhaled except in

exceptional accidental conditions.

The chemical toxicity of plutonium, americium and curium is sometimes

referred to, although no experimental result has demonstrated such an

effect. It is, however, possible to extrapolate from results obtained from

elements with very long physical half lives; very low specific activities

enable acute or subacute chemical toxicity to develop before any delayed

radiotoxic effects appear. This is the case, for example, with neptunium-

2 3 7 , with its physical half life of 2 . 2 million years and a specific activ-

ity 1 0 0 times smaller than that of plutonium-239 (Casey et al, 1 9 6 3 ) . By

comparing the toxic effects of neptunium-237 on the liver with those of the

stable isotope of cerium (Snyder et al, 1 9 5 9 ) , both of which are analogous

to plutonium in respect of their oxidation states and ionic radii ( 0 . 9 2 X ) ,

it has been shown that the maximum permissible body burden of plutonium-239

(k0 nCi, 1 . 5 kBq) (ICRP Publication 2 , 1 9 5 9 ) is smaller by a factor of about

3 3 0 0 0 0 than that which might produce a detectable chemotoxic effect in the

liver (Dolphin et al, 1 9 7 U ) • Thus it is clear that any chemotoxic effects

of plutonium or of the long-lived alpha emitters of the transplutonium

series will not manifest themselves since to a very large extent they are

masked by the radiotoxic effects.

2 . 2 Medium-term effects

Medium-term pathology results from radiation damage to a number of

organs or tissues. Usually it is found in one particular tissue and depends

upon the metabolism of the radionuclide and hence on the mode of contamina-

tion and the physico-chemical form of the contaminant.

Several tissues or organs may be affected at the same time or in

105

succession, provided that pathological changes in the first tissue or organ

affected do not produce rapid death. Any list of the main effects is there-

fore arbitrary, although some clearly predominate in certain conditions,

such as the development of pulmonary fibrosis after inhalation of actinides

or damage to the bone marrow after their intravenous injection.

2.2 .1 Respiratory insufficiency

The clinical symptoms of respiratory insufficiency are an increase in

respiratory rhythm, a drop in arterial oxygen concentration and an increase in

arterial carbon dioxide concentration; these indicate diffuse fibrosis of the

pulmonary parenchyma. The development of fibrosis has been considered in

Chapter 5 (section 2 . 2 . 1 ) . Radiation-induced changes have particular

characteristics which will be described later.

Pulmonary Function

The pulmonary radiation dose required to induce pathological changes

that can be detected clinically or biologically varies from one animal

species to another; it is unlikely that the only factor involved is the

differences in life spans, although a greater natural longevity allows a

larger radiation dose to be accumulated. Medium-term pathological changes

to the lung result in death from respiratory insufficiency within periods

varying on average from one to several months after exposure. In rats,

initial deposits of activity in the deep lung which exceed 0.1 iCi g

( 3 . 7 kBq g~^) bring about functional changes (Buldakov et al, 1970;

Koshurnikova et al, 1968a; Antonchenko et al, 19^9)- In beagles, pulmonary

—1 —1

deposits of similar amounts (0.1 uCi g (3*7 kBq g" )) bring about

death by fibrosis or oedema in less than one year, whether the plutonium is

in the form of a soluble salt (nitrate) or the dioxide (Park et al, 1968; 1970) . At lower dose levels, corresponding to pulmonary deposits of about

—1 —1

0.05 jiCi g ( 1 . 9 kBq g ) or less, fibrosis is more localised and causes

death after a longer interval of about four years (Yuile et al, 1970) . No

plutonium isotope produces fatal fibrotic lesions at less than 0.02 ^Ci g

(0 .7 kBq g 1 ) (Park et al, 1 9 7 5 a ) . In baboons contaminated with plutonium-

239 dioxide at different dose levels fibrosis appears after about three

years and is always in a localised form; it is variable and non-uniform,

and does not cause death (Metiyier, 1 9 7 6 ) .

Similar observations on respiratory function have been made with

transplutonium elements, in particular with americium-24l in dogs (Buldakov

et al, 1972; Thomas et al, 1 9 7 2 ) .

106

Lesion Survey

It is apparent that medium-term toxicity is related to the manner in

which the radionuclide is distributed in the lung (Figure 6 . 1 ) , The more

uniform the dispersal of the element, the greater and earlier the effect.

Table 6 . 1 compares the minimum dose levels that are required to produce

comparable lesions in the rat after inhalation of plutonium, americium and

curium nitrates (Masse et al, 1 9 7 5 ) . In the first month, the main patho-

logical changes are an alveolar oedema and heavy desquamation, accompanied

by many capillary and arteriolar thromboses.

Table 6 . 1

Comparison of doses causing pulmonary lesions in rats after inhalation

of alpha emitters (Masse et al, 1 9 7 5 )

Date of appearance

of pulmonary lesions

Plutonium-239 nitrate Americium-21+1 nitrate Curium-2U1+ nitrate Date of appearance

of pulmonary lesions

Dose (rad)

1st month 17 ,500 5,500 3,500

between 1st and

3 r d month 9,000 U,500 2,500

after 3 r d month

5,600 3,5oo 1,500

Desquamation of pneumocytes II can even lead to the appearance of

pseudo-pores. Very high doses produce widespread necrosis of the parenchyma

and the animals die by drowning in their own fluids. At lower doses the

lesions become established between the first and the third month after

inhalation, with an appreciable growth of elastic fibres and reticulin, and

with interstitial infiltration. There is an uncontrolled growth of the

vascular bed accompanied by a thickening of the alveolar membrane. These

pathological changes account for the clinical development of acute respira-

tory insufficiency and cardiac failure. After the third month, the lesions

have typical features although they vary slightly from one element to

another. They consist of a chronic interstitial pneumonia, accompanied by

foci of classic pneumonia with hyaline membranes and desquamative pneumonia

and disorganization of the interstitial tissue (Figure 6.2). Islets of

pseudo-adenomatosis begin to form. Lesions which appear at times in excess

of one year after exposure occur at much higher cumulative doses. They are

107

Figure 6 . 1 Rat lung 30 days after inhalation of plutonium-239 nitrate.

Non-uniform distribution of the radionuclide in the organ

(information supplied by R. Masse, Departement de Protection,

GEA, France).

Figure 6 . 2 Rat lung 1 5 0 days after inhalation of americium-2Ul nitrate.

Desquamative interstitial pneumonia, with destruction of the

fibrous interstitial tissue (R. Masse et al, 1 9 7 5 ) .

108

109

difficult to demonstrate; the only clear indication being an increased

amount of reticulin. However, refined anatomical and pathological techni-

ques reveal a decrease in the number of capillaries and a disturbance of

the vascular bed. An abnormal cell growth, responsible for an increase in

the weight of the lung but unrelated to changes in collagen content, is

frequently observed. Plutonium induces the most heterogeneous lesions;

necrotic foci are frequent and the interstitial tissue can exhibit all

forms from the normal state to atrophy, including a hyper vascular

condition, infiltration and emphysema.

Curium, in contrast, with its uniform distribution in pulmonary tissue,

produces lesions of atrophic interstitial pneumonia, causing emphysema and

there are large vascular lesions accompanied by oedema. These changes can

allow the entry of infections. It is probable that uniform high dose rate

irradiation from curium does not allow the mobilization of the cell pool

involved in the interstitial reaction that is observed with plutonium or

americium. All these late lesions are generally preceeded by lesions of

bronchiolar and bronchioloalveolar metaplasia. Epidermoid metaplastic

lesions appear in the rat at an early stage, within the first two months.

Adenomatosis occurs later, appearing on average towards the sixth month

(Figure 6 . 3 ) .

In the case of other rodents, such as hamsters and mice, the doses

needed to induce lesions identical to those observed in the rat are of the

same order. Thus, the L D ^ Q i n "the hamster after inhalation of plutonium-

2 3 9 dioxide is about 6 $ 0 0 rad ( 6 5 Gy) in about 7 5 days, and that of the

mouse about 1 1 0 0 0 rad ( 1 1 0 Gy) in about 6 5 days (Brightwell and Stather,

1 9 7 8 ) .

The lesions appearing in dogs are generally comparable (Thomas et al,

1 9 7 2 ) . Involvement of the pleura or sub-pleural localization of the lesions

seems to occur more frequently than in rats. Doses of 2 0 0 0 to $100 rad

( 2 0 to 9 1 Gy) are fatal when received over periods of between 2 and 11+

months ( 2 6 dogs out of 2 8 ) (Bair and Willard, 1 9 6 2 ) . In monkeys it appears

that lesions of chronic interstitial pneumonia are more uniform and largely

unrelated to the heterogeneous distribution in the lung of plutonium-239

dioxide (Masse et al, 1 9 7 5 ) . They appear at lower doses than those

producing the same lesions in rats. There are numerous explanations for

this, but none has been confirmed:

( 1 ) abundance of fibres and fibroblasts in the alveolar walls of monkeys;

( 2 ) the greater pulmonary clearance through interstitial tissue in monkeys

than in rats.

110

Figure 6 . 3 Rat lung six months after inhalation of plutonium. Adenomatosis

of the ciliated cells appears in an area adjacent to the

bronchi (information supplied by R. Masse, Departement de

Protection, CEA, France).

Ill

( 3 ) the greater lymphatic clearance in dogs as compared with that of

monkeys, since the integrity of this clearance route protects, in

particular, the lung against the appearance of fibrosis (Jennings

and Arden, 1 9 6 1 ) .

A comparison of the acute effects of plutonium-239 * cerium-1 hh and

strontium-90 has led some authors to advocate the use of an REE of 1 0 for

the early effects of the alpha emitters in the lung (Smith and Stather,

1 9 7 6 ) .

2 . 2 . 2 Blood

Observations relating to the biological effects on blood vary according

to the animal species studied. Rats and monkeys only show small blood

changes after inhalation, at all levels that have been studied. The deposi-

tion of 0 . 1 +xCi g" ( 3 . 7 kBq g~ ) of plutonium-239 dioxide in the lung of

the monkey is followed only occasionally by lymphopenia and only seems to

affect the B lymphocytes (Nolibe, 1 9 7 6 ) . On the other hand, observations

on beagles show changes to the normal composition of blood and to the blood

cell count in proportion to the dose.

The symptom that appears most invariably after inhalation of plutonium-

2 3 9 dioxide by beagles is lymphopenia. At doses corresponding to a

—1 —1

pulmonary deposition of 0 . 0 U +iCi g" ( 1 . 5 kBq g~ ), blood lymphocytes are

reduced to 3 0 - 5 0 % of the normal value from about one year after contamina-

tion and remain at this level during the whole life span of the dog (Park

et al, 1 9 7 2 ) . The other white blood cells are not affected so frequently.

At higher doses, (> 0 . 1 ^Ci g"1 ( 3 - 7 kBq g" 1)) the effect on the blood

appears much sooner and lymphopenia persists throughout the animal's life.

At much lower levels of respiratory contamination ( 0 . 0 0 1 jiCi ( 3 7 Bq

g~ 1)), lymphopenia occurs later, appearing on average after two years.

—1 —1

Levels as low as 0 . 0 0 0 3 ^Ci g~ ( 1 1 Bq g" ) are required if there are to be

no appreciable changes after three years (Park et al, 1 9 7 6 ) . As plutonium

deposits in the bone and in particular in haemopoietic tissues are very

small after inhalation of insoluble plutonium-239 dioxide, it is probable

that these changes to the blood are caused by the irradiation of the blood

circulating in the parenchyma of the lung and the nodes (Yuile et al, 1 9 7 0 ) .

This pathogenesis was discussed in Chapter 5 (in particular in section

2 . 2 . 1 ) .

This theory is in line with the effects on blood caused by soluble

forms of plutonium which irradiate in particular the haemopoietic tissues

after their translocation to the skeleton. Thus both the lymphocytes and

112

the neutrophils in the blood are depressed by inhalation of amounts of

plutonium citrate and plutonium nitrate that give doses to bone between

1 0 0 and I4OO rad ( 1 - 1 ; Gy) (Buldakov et al, 1 9 7 0 ; Ballou et al, 1 9 7 2 ) ,

Haematologic changes always appear earlier than with plutonium dioxide;

there is a drop in the total number of white cells towards the end of the

second week after exposure with widespread symptoms of lymphocyte and

neutrophil depression, leukopenia rapidly reaches 2$% of the normal value.

Apart from this, the erythrocytes, the haemoglobin count and the hematocrit

reading remain unchanged.

The effects of plutonium-238 dioxide are closer to those induced by

transportable forms of plutonium-239 than to those induced by its oxidized

forms, thus reflecting its relatively soluble nature (Park et al, 1 9 7 0 ) .

The effects on the blood after inhalation of transplutonium alpha

emitters are similar to those observed after inhalation of a transportable

form of plutonium. Their uniform distribution in the lung probably delivers

a higher dose to the blood cells than in the case of a non-uniform distribu-

tion; a fact which may explain why lymphopenia seems to be the most marked

phenomenon, overshadowing the effects on the other white cells despite the

large deposits of radionuclide in the blood-forming organs (Buldakov et al,

1 9 7 2 ; Thomas et al, 1 9 7 2 ) .

Einsteinium, is rapidly translocated from the lungs to the blood and

produces very large bone deposits giving high dose rates. With this radio-

nuclide the incidence of malignant changes to the primordial blood cells is

very high; these changes consist above all of lymphoid leukaemias and, to a

smaller extent, of myeloid leukaemias (Ballou et al, 1 9 7 2 ) .

Although qualitative changes to the blood have been widely studied,

observations on quantitative changes to the different cell types under

different experimental conditions are not sufficient to establish a dose

effect relationship. Determining such a relationship would pose considerable

problems in selecting the appropriate tissue or organ on which to base the

dose.

2 . 2 . 3 Lymph nodes

After contamination by inhalation or through a wound, some plutonium

is deposited in the regional lymph nodes which form the first drainage sites

from the point of entry into the body. The plutonium concentration in the

nodes may reach relatively high values, and in the case of pulmonary contam-

ination by plutonium dioxide, much higher values than the initial concentra-

tion in the lung. These deposits in the tracheo-bronchial and mediastinal nodes,

113

w i t h t h e i r s l o w c l e a r a n c e t o t h e b l o o d , p r o d u c e s i g n i f i c a n t p a t h o l o g i c a l

c h a n g e s . The p r i m i t i v e l e s i o n s c o n s i s t o f a d e p o p u l a t i o n o f t h e g e r m i n a l

c e n t r e s a n d a p r o g r e s s i v e e v o l u t i o n t o w a r d s f i b r o s i s , a c c o m p a n i e d b y a n

a b n o r m a l g r o w t h o f c e l l s . I t i s r e m a r k a b l e t h a t i n h i g h l y c o n t a m i n a t e d

a n i m a l s t h e l y m p h n o d e s w h i c h do n o t c o n t a i n p l u t o n i u m may a l s o b e t h e

s i t e o f a l y m p h o i d a t r o p h y ( B a i r e t a l , 1973) - B e c a u s e o f t h e t e c h n i c a l

d i f f i c u l t i e s a s s o c i a t e d w i t h s m a l l e r a n i m a l s , q u a n t i t a t i v e m e a s u r e m e n t s

h a v e b e e n made m a i n l y w i t h d o g s . I t s e e m s t h a t t h e b e s t c o r r e l a t i o n w i t h

t h e o b s e r v e d e f f e c t s i s o b t a i n e d w i t h t h e d o s e r a t e r a t h e r t h a n w i t h t h e

d o s e r e c e i v e d . P r e s e n t d a t a i n d i c a t e t h a t i n i t i a l a l v e o l a r d e p o s i t s —1 —1

e x c e e d i n g 0.001 | iCi g " (37 Bq g " ) o f p l u t o n i u m d i o x i d e a r e r e q u i r e d t o

i n d u c e a t r o p h i c l e s i o n s i n t h e i r r a d i a t e d n o d e s . At t h i s l e v e l l e s i o n s

r e q u i r e s e v e r a l y e a r s t o b e c o m e e s t a b l i s h e d ( B a i r e t a l , 1966) . H i g h e r

l e v e l s p r o d u c e l e s i o n s a t a n e a r l i e r s t a g e b u t v i s i b l e c h a n g e s i n l y m p h

n o d e s t r u c t u r e a r e f i r s t s e e n a t a c c u m u l a t e d p u l m o n a r y d o s e s o f a l p h a

r a d i a t i o n s l i g h t l y h i g h e r t h a n t h o s e w h i c h p r o d u c e o b v i o u s l u n g l e s i o n s

( Y u i l e , 1970) . D i f f e r e n c e s o b s e r v e d b e t w e e n p l u t o n i u m 238 a n d p l u t o n i u m -

239 w e r e n o t g r e a t a n d r e l a t e d m o r e t o k i n e t i c s t h a n t o a n a t o m o - p a t h o l o g y .

I n t h e c a s e o f c o n t a m i n a t e d w o u n d s , l y m p h n o d e l e s i o n s h a v e common

f e a t u r e s . A f t e r a n i n j e c t i o n o f p l u t o n i u m - 2 3 9 d i o x i d e i n t o t h e h i n d l e g s

o f d o g s , t h e p o p l i t e a l n o d e s e x h i b i t h y p e r p l a s i a w i t h m a c r o p h a g i c m o b i l i z a -

t i o n , z o n e s o f n e c r o s i s a n d f i b r o s i s , a n d t h e f i n a l t r a p p i n g o f t h e

p a r t i c l e s w i t h i n s c a r t i s s u e ( D a g l e e t a l , 1 9 7 5 ) .

2.2.1+ S k e l e t o n

A l t h o u g h t h e m a i n b o n e p a t h o l o g y f o u n d a f t e r d e p o s i t i o n o f a l p h a

e m i t t e r s i s o s t e o s a r c o m a - f o r m a t i o n , t h e r e i s a m e d i u m - t e r m p a t h o l o g y ,

p r o b a b l y o c c u r r i n g a b o v e a t h r e s h o l d d o s e a n d r e l a t e d t o t h e d o s e d e l i v e r e d .

T h e s e p a t h o l o g i c a l c h a n g e s a r e m o s t m a r k e d i f t h e a c t i n i d e d e p o s i t s r a p i d l y

i n t h e s k e l e t o n . The l e v e l s o f a c t i v i t y r e q u i r e d b e f o r e t h e s e e f f e c t s c a n

b e o b s e r v e d a r e a l w a y s h i g h , i r r e s p e c t i v e o f w h e t h e r t h e y a r e d e t e r m i n e d b y

c l i n i c a l , r a d i o l o g i c a l o r h i s t o l o g i c a l m e t h o d s .

H i g h d o s e s c a n i n d u c e f r a c t u r e s ; t h o s e m o s t f r e q u e n t l y o b s e r v e d

o c c u r r i n g i n t h e r i b s ( J e e e t a l , 1962; T a y l o r e t a l , 1962; Thomas e t a l ,

1 9 7 2 ) . I n b e a g l e s t h e maximum i n c i d e n c e o f f r a c t u r e s i s o b t a i n e d b y t h e 1 1

i n t r a v e n o u s i n j e c t i o n o f 1.0 t o 3.0 jiCi k g " (37 - 111 kBq k g " ) o f

p l u t o n i u m - 2 3 9 a s c i t r a t e . A f t e r t h e i n j e c t i o n o f a m e r i c i u m - 2 4 1 d i o x i d e t h e

d o s e t o t h e s k e l e t o n w h i c h c a u s e s r i b f r a c t u r e s i n d o g s a f t e r a p e r i o d o f

11U

a b o u t t h r e e y e a r s i s e s t i m a t e d t o b e 36OO r a d ( 3 6 G y ) . The f r a c t u r e s i t e s

d o n o t a p p e a r t o h a v e a t e n d e n c y t o c a n c e r - f o r m a t i o n .

S l i g h t r a d i o l o g i c a l c h a n g e s , r e l a t e d t o o s t e o p o r o t i c a n d n e c r o t i c

c h a n g e s a r e n o t e d m o r e f r e q u e n t l y . O s t e o p o r o s i s i s g e n e r a l i z e d b u t

m o d e r a t e , a n d i s a c c o m p a n i e d b y a c o n s o l i d a t i o n o f t h e g r o w t h c e l l s i n t h e

e p i p h y s i s a n d a c o r t i c a l t h i c k e n i n g o f t h e l o n g b o n e s (Langham e t a l , 1 9 5 1 ) -

T h e s e s k e l e t a l c h a n g e s a r e m o s t m a r k e d w h e n t h e c o n t a m i n a t e d a n i m a l i s

y o u n g ( B u s t a d e t a l , 1 9 ^ 2 ; C l a r k e , 1 9 6 2 ; F a b r i k a n t a n d S m i t h , 1 9 6 ! + ) . T h u s

a d m i n i s t r a t i o n o f p l u t o n i u m - 2 3 9 n i t r a t e a t l e v e l s o f 3 - 0 pCi k g " 1 ( 1 1 1 kBq

k g " ) o r a b o v e , g r e a t l y r e d u c e s b o n e g r o w t h ; t h i s o c c u r s a t much l o w e r

d o s e s t h a n w o u l d a p p e a r t o b e r e q u i r e d w i t h a m e r i c i u m . One y e a r a f t e r

i n j e c t i o n , a s h o r t e n i n g o f t h e l o n g b o n e s , a s c o m p a r e d w i t h t h e c o n t r o l s ,

i s o b s e r v e d ; t h i s s h o r t e n i n g c a n b e a s much a t 1 0 $ i n t h e c a s e o f t h e f e m u r .

T h i s d e f e c t i v e g r o w t h i s n o t c a u s e d b y e a r l y o s s i f i c a t i o n b u t p r o b a b l y b y

d i f f u s e s c l e r o s i s o f t h e b o n e . The p r i m i t i v e l e s i o n c a u s i n g t h i s d i s r u p t -

i o n o f o s s i f i c a t i o n a p p e a r s t o b e f i b r o t i c c h a n g e s i n t h e m e d u l l a r y b l o o d

v e s s e l s a n d t h e i n t e r f e r e n c e t o t h e c i r c u l a t i o n o f b l o o d w i t h i n t h e b o n e

t h a t r e s u l t s ( C l a r k e , 1 9 6 2 ) . N e c r o t i c l e s i o n s o f t h e H a v e r s i a n s y s t e m s

may o c c u r a f t e r t h e d e p o s i t i o n o f p l u t o n i u m a n d a r e c o m p a r a b l e t o t h o s e

p r o d u c e d b y r a d i u m . An a p p r e c i a b l e s e c o n d a r y c a l c i f i c a t i o n o c c u r s i n t h e

H a v e r s i a n c a n a l s ( J e e e t a l , 1 9 6 2 ) . F i b r o s i s o f t h e e n d o s t e u m i s c a u s e d

b y a h i g h a l p h a r a d i a t i o n d o s e t o t h e e n d o s t e a l c e l l s ; t h e d e a t h o f t h e s e

c e l l s may a c c o u n t f o r t h e l e s s f r e q u e n t o c c u r r e n c e o f o s t e o s a r c o m a s a t

t h e s e h i g h d o s e l e v e l s .

2 . 3 Summary

S t u d i e s o n t h e a c u t e e f f e c t s o f a c t i n i d e s a r e o f l i t t l e i n t e r e s t i n

t h e f i e l d o f r a d i a t i o n p r o t e c t i o n a s t h e y r e s u l t f r o m l a r g e r a d i a t i o n

d o s e s . The L D g 0 ^ 0 f ° r i n h a l e d p l u t o n i u m - 2 3 9 i s e s t i m a t e d t o b e a b o u t

3 mCi ( 1 1 1 MBq) .

M e d i u m - t e r m p a t h o l o g i c a l c h a n g e s i n t h e l u n g a r e a l s o c a u s e d b y

r e l a t i v e l y h i g h l e v e l s o f d o s e . The f i r s t l e s i o n s a p p e a r i n g a r e

m a i n l y a n a l v e o l a r o e d e m a f o l l o w e d b y a c h r o n i c i n t e r s t i t i a l

p n e u m o n i a ; f i b r o s i s o c c u r s l a t e r a s a r e s u l t o f damage t o t h e

v a s c u l a r b e d . E f f e c t s o n t h e b l o o d d e p e n d u p o n t h e s p e c i e s . I n

d o g s c h a n g e s t o t h e b l o o d c e l l c o u n t a n d i n b l o o d c o m p o s i t i o n o c c u r .

The m a i n c h a n g e o b s e r v e d i s t h e d e v e l o p m e n t o f l y m p h o p e n i a w h i c h i s

d i r e c t l y r e l a t e d t o t h e a m o u n t o f p l u t o n i u m d e p o s i t e d i n t h e l u n g s

o r e n t e r i n g t h e b l o o d . The d e p o s i t i o n o f l a r g e a m o u n t s o f p l u t o n i u m

115

i n t h e l y m p h n o d e s c a u s e s t h e d e p o p u l a t i o n o f g e r m i n a l c e n t r e s a n d

t h e d e v e l o p m e n t o f f i b r o s i s . M e d i u m - t e r m p a t h o l o g y i n t h e b o n e

a p p e a r s a f t e r i n t r a v e n o u s i n j e c t i o n o r i n h a l a t i o n o f t r a n s p o r t a b l e

a c t i n i d e c o m p o u n d s . F r a c t u r e s h a v e b e e n o b s e r v e d i n d o g s i n j e c t e d

w i t h h i g h d o s e s a n d o t h e r c h a n g e s i n t h e b o n e h a v e i n c l u d e d o s t e o -

p o r o s i s a n d n e c r o s i s .

3 . D e l a y e d E f f e c t s

The m e d i u m - t e r m e f f e c t s t h a t h a v e b e e n d e s c r i b e d a r e d u e t o v e r y h i g h

r a d i a t i o n d o s e s w h i c h o c c u r i n man o n l y i n e x c e p t i o n a l , a c c i d e n t a l

s i t u a t i o n s . D e l a y e d e f f e c t s c o m p r i s e m a l i g n a n t c h a n g e s t o v a r i o u s t i s s u e s

o r o r g a n s . T h e y o c c u r p r e d o m i n a n t l y i n t h e m o s t e x p o s e d t i s s u e s ( C h a p t e r

£ : t i s s u e s e x p o s e d t o r i s k ) ; t h e m o s t i m p o r t a n t o f w h i c h i s t h e l u n g ,

s i n c e i t i s b o t h a s i t e o f e n t r y i n t o t h e b o d y a n d a n o r g a n o f d e p o s i t i o n .

The s k e l e t o n , t h e l i v e r a n d a l l t h e o t h e r o r g a n s may a l s o b e a f f e c t e d a t a

f r e q u e n c y t h a t , b r o a d l y s p e a k i n g , v a r i e s a c c o r d i n g t o t h e t r a n s p o r t a b i l i t y

o f t h e p a r t i c u l a r a c t i n i d e a n d t h e a m o u n t d e p o s i t e d i n t h e t i s s u e . I n

a d d i t i o n t o t h e s e m a l i g n a n t c h a n g e s , i n c o r p o r a t i o n o f a c t i n i d e s c a n

i n f l u e n c e t h e l i f e s p a n o f a n i m a l s . As a r e s u l t o f many f a c t o r s o t h e r

t h a n c a n c e r t h e l i f e s p a n may b e l e s s t h a n i n u n e x p o s e d a n i m a l s . A l l t h e

o b s e r v e d e f f e c t s c a n h a v e a d i r e c t o r i n d i r e c t i n f l u e n c e o n t h e l i f e s p a n

( g r e a t e r s e n s i t i v i t y t o i n f e c t i o n r e s u l t i n g f r o m r a d i a t i o n - i n d u c e d i n t e r -

s t i t i a l p n e u m o n i a , s e c o n d a r y c a r d i o p a t h i a , p u l m o n a r y f i b r o s i s l e a d i n g t o

r e s p i r a t o r y d i s o r d e r s , e t c . ) . V e r y o f t e n , n o p a r t i c u l a r p a t h o l o g i c a l

c h a n g e i s o b s e r v e d a n d , a s t h e s h o r t e n i n g o f t h e l i f e s p a n c o u l d b e a n o n -

s t o c h a s t i c ( n o n - r a n d o m ) o c c u r r e n c e , i t i s a p p r o p r i a t e t o s t u d y i t a s a

w h o l e , w i t h o u t m a k i n g a n y d e c i s i o n s r e g a r d i n g i t s c a u s e s . The m a i n f a c t o r s

c a u s i n g t h i s e f f e c t a r e c o n s i d e r e d i n s e c t i o n k o f t h i s c h a p t e r .

3 . 1 Lung

A c o n s i d e r a b l e a m o u n t o f r e s e a r c h i n t o l u n g c a n c e r i n d u c t i o n b y a l p h a

e m i t t e r s h a s b e e n c o n d u c t e d i n e x p e r i m e n t a l a n i m a l s u s i n g s u c h v a r i e d

a n i m a l s p e c i e s a s m i c e , h a m s t e r s , r a t s , r a b b i t s , d o g s a n d m o n k e y s . A l t h o u g h

t h e m a j o r i t y o f t h e s e s t u d i e s h a v e i n v o l v e d r a t s a n d d o g s , i n f o r m a t i o n i s

a v a i l a b l e t h a t a l l o w s d o s e - e f f e c t r e l a t i o n s h i p s t o b e e s t a b l i s h e d i n a

n u m b e r o f s p e c i e s a n d d a t a f r o m s e v e r a l s p e c i e s t o b e c o m p a r e d . R e s e a r c h

c a r r i e d o u t o n m o n k e y s w i l l p r o d u c e u s e f u l r e s u l t s o n l y w h e n t h e a n i m a l s

a r e o l d e r b e c a u s e o f t h e l o n g l a t e n t p e r i o d f o r t h e d e v e l o p m e n t o f l u n g

c a n c e r i n t h i s s p e c i e s .

116

I n r a t s , t a k i n g i n t o c o n s i d e r a t i o n a l l t h e t r a n s u r a n i c e l e m e n t s a s a

w h o l e , t h e f r e q u e n c y o f p u l m o n a r y c a n c e r s r i s e s r a p i d l y w i t h t h e d o s e :

a b o u t 1 0 % f o r 1 $ 0 r a d ( 1 . 5 Gy) ( a v e r a g e l u n g d o s e ) , 26% f o r 3 5 0 r a d ( 3 . 5 Gy)

50% f o r 1 0 0 0 r a d ( 1 0 Gy) a n d 85% f o r 3 2 0 0 r a d ( 3 2 Gy) ( M o r i n e t a l , 1 9 7 7 ) .

At d o s e s a b o v e 5 0 0 0 r a d ( 5 0 Gy) t h e f r e q u e n c y d r o p s d u e t o c e l l s t e r i l i z a -

t i o n a n d b e c a u s e t h e r e i s i n s u f f i c i e n t t i m e f o r t h e c a n c e r t o m a n i f e s t

i t s e l f , d e a t h o f t e n o c c u r r i n g a t a n e a r l y s t a g e f r o m o t h e r c a u s e s . I n f a c t ,

l u n g c a n c e r f r e q u e n c y v a r i e s f r o m o n e r a d i o n u c l i d e t o a n o t h e r . The d o s e

w h i c h c o r r e s p o n d s t o t h e maximum f r e q u e n c y a l s o d e p e n d s o n t h e i n h a l e d

c o m p o u n d . F o r i n s t a n c e , t h e o p t i m a l d o s e i s l o w e r t h a n 5 0 0 r a d ( 5 Gy) f o r

c u r i u m - 2 4 ! | . n i t r a t e a n d a m e r i c i u m - 2 4 1 o x i d e , b e t w e e n 5 0 0 a n d 1 0 0 0 r a d ( 5 a n d

1 0 Gy) f o r p l u t o n i u m - 2 3 8 n i t r a t e o r o x i d e , b e t w e e n 5 0 0 a n d 5 0 0 0 r a d ( 5 a n d

5 0 Gy) f o r a m e r i c i u m - 2 1 + 1 n i t r a t e a n d o v e r 1 0 0 0 r a d ( 1 0 Gy) f o r b o t h

p l u t o n i u m - 2 3 9 o x i d e a n d n i t r a t e ( M o r i n e t a l , 1 9 7 7 ) •

The k i n e t i c s o f p u l m o n a r y c a n c e r d e v e l o p m e n t s e e m s t o b e r e l a t i v e l y

c o n s t a n t b u t t h e s p e e d o f d e v e l o p m e n t i s i n p r o p o r t i o n t o t h e d o s e .

R e g a r d l e s s o f t h e d o s e , t h e r e a r e a s e r i e s o f m o r p h o l o g i c a l c h a n g e s w h i c h

o c c u r o n e a f t e r a n o t h e r . An i d e n t i c a l o r d e r o f e v e n t s o c c u r s i n c o n t r o l

a n i m a l s , b u t i s s l o w e n o u g h f o r t h e c a n c e r t o a p p e a r o n l y i n a v e r y s m a l l

f r a c t i o n o f t h e a n i m a l s s i n c e t h e n o r m a l f r e q u e n c y i s l e s s t h a n 1 % . I f t h e

l i f e s p a n o f r a t s w i t h p u l m o n a r y c a n c e r i s c o n s i d e r e d ( w h i c h i s n o t

n e c e s s a r i l y e q u i v a l e n t t o t h e l a t e n c y o r d e v e l o p m e n t p e r i o d o f t h e c a n c e r ) ,

a c l e a r d i f f e r e n c e b e c o m e s a p p a r e n t b e t w e e n t h e a n i m a l s e x p o s e d t o

r e l a t i v e l y t r a n s p o r t a b l e e l e m e n t s s u c h a s t h e t r a n s p l u t o n i u m e l e m e n t s o r

p l u t o n i u m - 2 3 8 a n d a n i m a l s e x p o s e d t o e l e m e n t s w h i c h a r e s c a r s e l y , i f a t a l l ,

t r a n s p o r t a b l e , s u c h a s p l u t o n i u m - 2 3 9 o x i d e . T h e s e d i f f e r e n c e s a r e m o s t

m a r k e d a t l o w d o s e s . I n t h e c a s e o f t h e o x i d e , f o r e x a m p l e , a 25% m o r t a l i t y

i s r e a c h e d a f t e r a b o u t 3 5 0 d a y s , b u t i n t h e c a s e o f s a l t s g i v i n g a c o m p a r -

a b l e l u n g d o s e a f t e r a b o u t 5 0 0 d a y s . T h i s d i f f e r e n c e b e c o m e s l e s s a f t e r

a b o u t 5 5 0 d a y s , w h e n t h e r e i s a m o r t a l i t y o f a b o u t 50% ( M o r i n e t a l , 1 9 7 6 ) .

I n t e r p r e t a t i o n s a r e o f t e n d i f f i c u l t a s n u m e r o u s d i s t o r t i n g f a c t o r s may b e

i n v o l v e d o w i n g t o t h e e x p e r i m e n t a l d e s i g n . F o r e x a m p l e , t h e f r e q u e n c y o f

p u l m o n a r y c a n c e r s i n d u c e d b y i n h a l a t i o n o f curium-2hh i s n o t a s h i g h a s

m i g h t b e a n t i c i p a t e d ; t h e m o s t p r o b a b l e r e a s o n f o r t h i s i s t h e h i g h r a d i o -

t o x i c i t y o f t h e e l e m e n t , d u e t o i t s h o m o g e n e o u s d i s t r i b u t i o n i n t h e

p u l m o n a r y p a r e n c h y m a . T h i s c a u s e s a h i g h m o r t a l i t y r a t e a t a n e a r l y a g e ,

e i t h e r d i r e c t l y , o r i n d i r e c t l y a s a r e s u l t o f r a d i a t i o n damage p e r m i t t i n g

t h e d e v e l o p m e n t o f i n f e c t i o n . The s a m e i s t r u e o f e i n s t e i n i u m - 2 5 3 » w h o s e

s h o r t h a l f - l i f e r e q u i r e s t h e i n s t i l l a t i o n o f l a r g e q u a n t i t i e s o f a c t i v i t y

117

( B a l l o u a n d M o r r o w , 1 9 7 3 ) ; "the v e r y h i g h i n i t i a l d o s e r a t e s w h i c h r e s u l t

f r o m t h i s may p r o d u c e c e l l s t e r i l i z a t i o n , t h u s r e d u c i n g t h e i n c i d e n c e o f

c a n c e r d e s p i t e t h e w i d e r a n g e o f d o s e s r e c e i v e d b y t h e l u n g . W i t h d o s e s o f

b e t w e e n 38 a n d 1900 r a d (O .38 a n d 19 G y ) , t h e o b s e r v e d f r e q u e n c y o f l u n g

c a n c e r i s o n l y If/o a n d 1 2 . 5 % r e s p e c t i v e l y .

I n r a t s , l u n g c a n c e r s c a n b e d i v i d e d r o u g h l y i n t o t h r e e t y p e s a c c o r d i n g

t o t h e c e l l s i n w h i c h t h e t u m o u r o r i g i n a t e d : ( a ) b r o n c h i o l o - a l v e o l a r

c a r c i n o m a ( p n e u m o c y t e I I ) ; ( b ) b r o n c h o g e n i c c a r c i n o m a ( e p i d e r m o i d ) ; ( c )

s a r c o m a . I n a g i v e n s t r a i n o f r a t , i n s p i t e o f t h e v e r y d i f f e r e n t a r e a s

o f r e t e n t i o n , n o a p p r e c i a b l e d i f f e r e n c e i s o b s e r v e d b e t w e e n t r a n s p o r t a b l e

a n d n o n - t r a n s p o r t a b l e r a d i o n u c l i d e s .

S a r c o m a s r e p r e s e n t o n a v e r a g e 2% o f p u l m o n a r y c a n c e r s , t h e r e m a i n d e r

b e i n g made u p i n a b o u t e q u a l p r o p o r t i o n s o f b r o n c h i o l o - a l v e o l a r a n d b r o n c h o -

g e n i c c a r c i n o m a s ( M o r i n e t a l , 1 9 7 6 ) . At r e l a t i v e l y l o w d o s e s

a p r e d o m i n a n c e o f t h e b r o n c h i o l o - a l v e o l a r f o r m s i s o b s e r v e d a n d , a t h i g h

d o s e s , a p r e d o m i n a n c e o f b r o n c h o g e n i c f o r m s ; n o d o u b t t h i s m e r e l y

r e f l e c t s t h e d i f f e r e n t s p e e d s o f d e v e l o p m e n t o f d i f f e r e n t t u m o u r s . The

same d i s t r i b u t i o n i s a l s o f o u n d a f t e r i n h a l a t i o n o f r a d o n a n d i t s d a u g h t e r s ,

w h o s e mode o f d e p o s i t i o n i s q u i t e d i f f e r e n t (Chameaud e t a l , 1 9 7 6 ) . T h i s

p o i n t i l l u s t r a t e s t h e i m p o r t a n c e o f a s e n s i t i v i t y p e c u l i a r t o a c e l l t y p e

r a t h e r t h a n t o t h e r e g i o n i n w h i c h m o s t damage o c c u r s a n d h a s b e e n d i s c u s s e d

i n C h a p t e r 5 ( s e c t i o n !+)• F i g u r e 6.1+ t o F i g u r e 6.6 i l l u s t r a t e t h e

d i f f e r e n t f o r m s t h a t p u l m o n a r y c a n c e r s o r i g i n a t i n g i n t h e s e t h r e e c e l l t y p e s

c a n a s s u m e i n t h e r a t .

Much h a s b e e n l e a r n e d b y c o m p a r i n g v e r y many e x p e r i m e n t s o n r a d i a t i o n -

c a r c i n o g e n e s i s c a u s e d b y t h e p u l m o n a r y d e p o s i t i o n o f a c t i n i d e s . I n f a c t ,

v a r i o u s e x p e r i m e n t a l m e t h o d s h a v e b e e n u s e d : t r a c h e a l i n s t i l l a t i o n s w h i c h

g i v e a f a i r l y n o n - u n i f o r m d e p o s i t i o n , i n h a l a t i o n b y a c o n s c i o u s a n i m a l ,

p i n - p o i n t t r a n s - t h o r a c i c i n j e c t i o n s , a n d i n t r a v e n o u s i n j e c t i o n s o f p a r t i c l e s

t h a t l o d g e i n t h e p u l m o n a r y c a p i l l a r i e s . A l s o many r a d i o n u c l i d e s , i n

v a r i o u s p h y s i c o - c h e m i c a l f o r m s h a v e b e e n u s e d : t r a n s f e r a b l e c o m p o u n d s o f

t r i v a l e n t e l e m e n t s t h a t a r e r e a d i l y t r a n s p o r t a b l e a n d g i v e a v e r y u n i f o r m

d i s t r i b u t i o n i n t h e l u n g , h i g h l y i n s o l u b l e c o m p o u n d s w i t h a h i g h l y n o n -

u n i f o r m d i s t r i b u t i o n i n t h e l u n g , a n d e v e n i n s o l u b l e c o m p o u n d s t h a t h a v e a

p a r t i c l e s i z e d i s t r i b u t i o n , s u f f i c i e n t l y s m a l l t o p e r m i t t h e m t o b e

c l a s s i f i e d a s t r a n s p o r t a b l e r a d i o n u c l i d e s ( C h a p t e r !+)• A c o m p a r i s o n o f t h e

r e s u l t s o f t h e s e e x p e r i m e n t s s h o w s t h e h i g h t o x i c i t y o f a m o r e u n i f o r m

d i s t r i b u t i o n o f a c t i n i d e s i n t h e l u n g a n d w i t h t h e e x c e p t i o n o f t h e r e s e r v a -

t i o n s made a b o v e , t h e g r e a t e r f r e q u e n c y o f p u l m o n a r y c a n c e r s w h i c h i s

118

F i g u r e 6.I4. B r o n c h i o l o - a l v e o l a r p u l m o n a r y c a r c i n o m a w i t h p a p i l l o m a

c h a r a c t e r i s t i c s i n r a t ( i n f o r m a t i o n s u p p l i e d b y R. M a s s e ,

D e p a r t e m e n t d e P r o t e c t i o n , CEA, F r a n c e ) .

F i g u r e 6 . 5 N o n - k e r a t i n i z e d , d i f f e r e n t i a t e d e p i d e r m o i d p u l m o n a r y c a r c i n o m a

i n r a t ( i n f o r m a t i o n s u p p l i e d b y R . M a s s e , D e p a r t e m e n t d e

P r o t e c t i o n , CEA, F r a n c e ) .

119

120

F i g u r e 6.6 P u l m o n a r y a n g i o s a r c o m a i n r a t ( i n f o r m a t i o n s u p p l i e d b y R. M a s s e ,

D e p a r t e m e n t d e P r o t e c t i o n , CEA, F r a n c e ) .

121

n o r m a l l y a s s o c i a t e d w i t h i t . A d m i n i s t r a t i o n o f t h e o x i d e o f p l u t o n i u m - 2 3 8

i n t h e f o r m o f m i c r o s p h e r e s , ( u l t r a f i l t e r a b i l i t y 7 2 $ , CMD 0 . 0 2 , GSD 2 . 1 )

w h i c h l e a d s t o a m o r e u n i f o r m d i s t r i b u t i o n , i s o f p a r t i c u l a r i n t e r e s t

( S a n d e r s , 1 9 7 3 ) : d o s e s o f 9 r a d ( 0 . 0 9 G y ) g i v e a p u l m o n a r y c a n c e r f r e q u e n c y

o f 6 . 6 $ ; 3 2 r a d ( 0 . 3 2 Gy) g i v e 2 3 $ a n d 3 7 5 r a d ( 3 . 8 G y ) , 2 5 $ . T h e s e

i n c i d e n c e s a r e v e r y m u c h h i g h e r t h a n t h o s e o b t a i n e d w i t h a n i n s o l u b l e

p l u t o n i u m d i o x i d e a e r o s o l w i t h a n AMAD o f a b o u t 1 ^m. T h e s e c o n s i d e r a t i o n s

a r e r e l e v a n t t o t h e " h o t p a r t i c l e p r o b l e m " a n d a r e d i s c u s s e d f u r t h e r i n

C h a p t e r 7 .

O t h e r r o d e n t s p e c i e s h a v e b e e n u s e d f o r s t u d y i n g p u l m o n a r y c a n c e r s

i n d u c e d b y a c t i n i d e s , b u t a l w a y s o n a s m a l l e r s c a l e ; t h e s e e x p e r i m e n t s a r e

o f r e l e v a n c e , h o w e v e r , s i n c e t h e y a l l o w a n i n t e r c o m p a r i s o n o f r e s u l t s .

R e s u l t s o b t a i n e d i n m i c e g e n e r a l l y c o n f i r m t h o s e o b t a i n e d w i t h r a t s ,

a l t h o u g h t h e f a c t t h a t t h e s e s t u d i e s w e r e c o m p l e t e d some t i m e a g o m a k e s

c o m p a r i s o n d i f f i c u l t , m a i n l y b e c a u s e o f t h e d i f f e r e n t t e c h n i q u e s o f

a d m i n i s t e r i n g t h e a c t i n i d e s ( i n t r a t r a c h e a l i n s t a l l a t i o n o r i n h a l a t i o n )

( T e m p l e e t a l , 1 9 5 9 , i 9 6 0 ) . The l i f e s p a n d o s e s d e l i v e r e d t o t h e l u n g i n

a n i m a l s e x p o s e d t o p l u t o n i u m - 2 3 9 d i o x i d e r a n g e d f r o m 23OO t o 1+000 r a d ( 2 3

t o 2+0 G y ) . I n m i c e , l u n g c a n c e r s w e r e n o t o b s e r v e d i n g r o u p s o f m i c e w i t h

l u n g d o s e s o f s e v e r a l t e n s o f r a d s ( B a i r e t a l , 1 9 6 2 ) b u t t h e n u m b e r o f

m i c e s t u d i e d w a s m u c h l o w e r t h a n f o r r a t s e x p o s e d t o t h e same l e v e l o f

i r r a d i a t i o n a n d t h e r e f o r e n o c l e a r c o n c l u s i o n s c a n b e d r a w n .

R e s u l t s o b t a i n e d w i t h r a b b i t s a r e a l s o i n l i n e w i t h t h e c o n c l u s i o n s

d r a w n f r o m t h e v a r i o u s e x p e r i m e n t s c a r r i e d o u t o n r a t s a n d m i c e

( K o s h u m i k o v a e t a l , 1 9 7 1 ) . The d o s e s s t u d i e d r a n g e f r o m 1 0 0 0 t o 3 0 0 0 r a d

( 1 0 t o 3 0 G y ) , d e l i v e r e d t o t h e l u n g b y p l u t o n i u m - 2 3 9 a d m i n i s t e r e d a s

ammonium p l u t o n i u m p e n t a c a r b o n a t e . The i n c i d e n c e o f c a n c e r w a s 1 8 . 7 $ f o r a n

1 1

i n i t i a l d e p o s i t i o n o f 0 . 1 7 nCi g ~ ( 6 . 3 kBq g " ) ( 1 0 1 0 r a d ( 1 0 G y ) ) t o t h e

l u n g ) .

H a m s t e r s a r e e x c e p t i o n a l m e m b e r s o f t h e r o d e n t f a m i l y i n s o f a r a s

p l u t o n i u m - i n d u c e d p u l m o n a r y c a n c e r s a r e c o n c e r n e d . I n s t u d i e s c o n d u c t e d

t o d a t e t h e f r e q u e n c y o f n e o p l a s t i c c h a n g e s i n t h e l u n g i s , i n f a c t , much

l o w e r i n t h i s a n i m a l t h a n t h a t o b s e r v e d i n r a t s o r m i c e ; d o s e s c a u s i n g a

s i g n i f i c a n t r i s e i n t h e f r e q u e n c y o f p u l m o n a r y c a n c e r s i n r a t s h a v e n o

e f f e c t o n h a m s t e r s , w h e t h e r p l u t o n i u m - 2 3 9 o r p l u t o n i u m - 2 3 8 i s u s e d ( S a n d e r s

a n d M e i e r , 1 9 7 5 ; M e w h i n n e y e t a l , 1 9 7 6 b ) . E x p e r i m e n t s c o n d u c t e d o n

h a m s t e r s a r e r e l a t i v e l y r e c e n t a n d , i n many c a s e s , t h e r e s u l t s a r e s t i l l

i n c o m p l e t e a n d f r a g m e n t a r y .

122

R e s u l t s o f e x p e r i m e n t s o n b e a g l e d o g s a r e much m o r e r e l e v a n t f o r t h e y

h a v e i n v o l v e d l a r g e g r o u p s o f a n i m a l s t h a t h a v e b e e n f o l l o w e d f o r t h e i r

l i f e s p a n . H o w e v e r , n o e x p e r i m e n t h a s r e a l l y b e e n b r o u g h t t o a c o n c l u s i o n ,

s i n c e t h e o n l y s i g n i f i c a n t r e s u l t s a t p r e s e n t a v a i l a b l e a r e c o n c e r n e d w i t h

a n i m a l s t h a t h a v e b e e n e x p o s e d t o r e l a t i v e l y l a r g e i n i t i a l l u n g d e p o s i t s

a n d d i e d p r e m a t u r e l y ; d a t a o n d o g s c o n t a m i n a t e d a t v e r y l o w l e v e l s a n d

h a v i n g n o r m a l l o n g e v i t y a r e t o o i n c o m p l e t e t o b e u s e d . R e s u l t s a t p r e s e n t

a v a i l a b l e c o n c e r n r e l a t i v e l y h i g h d o s e l e v e l s , t h e d e p o s i t i o n s o f

p l u t o n i u m - 2 3 9 d i o x i d e a t p r e s e n t e m p l o y e d r a n g i n g f r o m 0.003 ^Ci g ~ —1 —1 —1

(1 kBq g " ) t o 0.04 ^iCi g"~ ( 1 . 5 kBq g~ ) ( c o r r e s p o n d i n g t o d o s e s o f

b e t w e e n 2000 a n d 12000 r a d (20 a n d 120 G y ) c a l c u l a t e d o n b l o o d l e s s l u n g s ) ;

t h e c o r r e s p o n d i n g s u r v i v a l t i m e s l i e b e t w e e n 2 .5 y e a r s a n d 11 y e a r s ( P a r k

e t a l , 1 9 7 2 ) , a n d t h e s e a n i m a l s e x h i b i t e d a h i g h r a t e o f p u l m o n a r y c a n c e r

(82%). A s m a l l g r o u p r e c e i v i n g a d o s e o f 1200 r a d (12 G y ) t o t h e l u n g

(0.007 tiCi g ~ 1 (0.26 kBq g " " 1 ) ) d u r i n g a n a v e r a g e l i f e s p a n o f 8 y e a r s ,

e x h i b i t e d a p a r t i c u l a r l y h i g h f r e q u e n c y o f p u l m o n a r y c a n c e r (87 .5%); h u t

t h e s m a l l n u m b e r o f a n i m a l s i n v o l v e d (7 d o g s w i t h l u n g c a n c e r o u t o f a n

i n i t i a l g r o u p o f 8) m a k e s t h i s r e s u l t l e s s s i g n i f i c a n t t h a n t h o s e o b t a i n e d

w i t h r a t s . A l l t h e p u l m o n a r y c a n c e r s o b s e r v e d i n b e a g l e s a r e o f t h e

a d e n o c a r c i n o m a t y p e . A f e w o t h e r h i s t o l o g i c a l t y p e s w e r e o b s e r v e d , b u t

t h e s e w e r e a l w a y s a s s o c i a t e d w i t h a f o c u s o f a d e n o c a r c i n o m a . Out o f 32

c o n t a m i n a t e d d o g s , 24 e x h i b i t e d p u l m o n a r y c a n c e r o f t h e a d e n o c a r c i n o m a

t y p e , a s s o c i a t e d i n 5 c a s e s w i t h a p e r i p h e r a l e p i d e r m o i d c a r c i n o m a , i n 2

w i t h a p u l m o n a r y l y m p h a n g i o s a r c o m a a n d i n 1 w i t h a h a e m a n g i o m a . M e t a s t a s i s

w a s f r e q u e n t . The r e s u l t s a r e s t i l l t o o f r a g m e n t a r y f o r p l u t o n i u m - 2 3 8

d i o x i d e , b e c a u s e o f t h e s h o r t t i m e s i n c e t h e s t a r t o f t h e e x p e r i m e n t s a n d

t h e s m a l l number o f d o g s u s e d ( P a r k e t a l , 1976) b u t t h e y a r e c o n s i s t e n t

w i t h t h o s e o b t a i n e d w i t h p l u t o n i u m - 2 3 9 . H o w e v e r , t h e s m a l l s i z e o f t h e

s a m p l e s (2 g r o u p s o f 10 d o g s ) , a n d t h e r e l a t i v e l y h i g h i n c i d e n c e o f o s t e o -

s a r c o m a s t h a t c a u s e d e a r l y d e a t h , i n t r o d u c e g r e a t u n c e r t a i n t y i n t o t h e

r e s u l t s .

A f e w e x p e r i m e n t s u s i n g p r i m a t e s h a v e b e e n s t a r t e d i n t h e l a s t f e w

y e a r s , b u t t h e y a r e a l l m u c h t o o r e c e n t t o a l l o w a s t u d y o f r a d i a t i o n -

i n d u c e d p u l m o n a r y c a n c e r t o b e m a d e . I n r h e s u s m o n k e y s , o n l y m e d i u m - t e r m

p a t h o l o g y , a f t e r a p e r i o d o f t h r e e y e a r s , h a s b e e n s t u d i e d ( B r o o k s e t a l ,

1976a) .

A f e w s t u d i e s o f p u l m o n a r y c a n c e r s i n b a b o o n s h a v e b e e n p u b l i s h e d

( M e t i v i e r e t a l , 1 9 7 2 ) , b u t m o s t o f t h e m s h o u l d b e r e g a r d e d w i t h e x t r e m e

c a u t i o n f o r , a l t h o u g h t h e l e s i o n s p r e s e n t e d h i s t o l o g i c a l f e a t u r e s t h a t w e r e

123

i n d i s p u t a b l y m a l i g n a n t t h e t u m o u r s r e p o r t e d w e r e i s o l a t e d a n d a b n o r m a l l y

e a r l y ( M e t i v i e r e t a l , 197U)• The f i r s t n e o p l a s t i c l e s i o n o c c u r r i n g i n

b a b o o n s a n d e x h i b i t i n g i n d i s p u t a b l e c l i n i c a l a n d h i s t o l o g i c a l s y m p t o m s o f

m a l i g n a n c y a p p e a r e d a f t e r a p e r i o d o f m o r e t h a n s i x y e a r s , w i t h a n i n i t i a l

1 1

l u n g d e p o s i t o f 0.01 jiCi g " (0.37 kBq g~ ) ( M a s s e , 1 9 7 7 ) . A v e r y h i g h d o s e

w a s t h e r e f o r e u s e d , b u t t h e f a c t t h a t t h i s c a n c e r w a s o f a b r o n c h i a l t y p e

m a k e s t h i s a n i m a l m o d e l o f g r e a t v a l u e f o r e x t r a p o l a t i o n t o man .

The r e s u l t s o f t h e s e e x p e r i m e n t s c a r r i e d o u t o n s e v e r a l s p e c i e s

c o n c l u s i v e l y d e m o n s t r a t e t h e c a r c i n o g e n i c a c t i o n o f a c t i n i d e s i n t h e l u n g .

To a c e r t a i n e x t e n t , a m a t h e m a t i c a l a n d s t a t i s t i c a l a n a l y s i s p e r m i t s a d o s e -

e f f e c t r e l a t i o n s h i p t o b e e s t a b l i s h e d . U n f o r t u n a t e l y , h o w e v e r , t h e s e d a t a

d o n o t p r o v i d e a n a d e q u a t e b a s i s f o r a p r e c i s e d e s c r i p t i o n o f t h e f o r m o f

t h e d o s e - e f f e c t r e l a t i o n s h i p a t l o w d o s e s . T h e r e a r e many r e a s o n s f o r

t h i s : i n c l u d i n g d i f f e r e n c e s i n e x p e r i m e n t a l d e s i g n , l a c k o f k n o w l e d g e o n

t h e a g e s p e c i f i c i n c i d e n c e o f c a n c e r i n c o n t r o l a n i m a l s , a n d i n a c c u r a c i e s

i n t h e d e t e r m i n a t i o n o f t h e i n i t i a l l u n g d e p o s i t . F u r t h e r m o r e , some

n e c e s s a r y b a s i c d a t a may n o t b e a v a i l a b l e ( f o r e x a m p l e w h e t h e r t h e c a n c e r

f r e q u e n c y w a s c a l c u l a t e d f r o m t h e t o t a l n u m b e r o f c o n t a m i n a t e d a n i m a l s o r

f r o m t h e a n i m a l s t h a t w e r e a t r i s k , o r w h e t h e r i t w a s b a s e d o n t h e n u m b e r

o f a n i m a l s w i t h c a n c e r o r o n t h e t o t a l n u m b e r o f c a n c e r s ) ; l a s t , b u t n o t

l e a s t , t h e r e a r e n o g r o u p s w i t h s u f f i c i e n t l y l a r g e n u m b e r s o f a n i m a l s t o

a l l o w s t a t i s t i c a l v a r i a t i o n s t o b e a p p r e c i a b l y r e d u c e d . I t i s a l s o v e r y

d i f f i c u l t t o u s e t h e e x p e r i m e n t a l r e s u l t s t o o b t a i n e s t i m a t e s o f t h e e f f e c t s

o n human h e a l t h a s a c e r t a i n n u m b e r o f h y p o t h e s e s h a v e t o b e i n t r o d u c e d t o

j u s t i f y t h e e x t r a p o l a t i o n t o man ( R o s e n b l a t t , G o l d m a n e t a l , 1 9 7 6 ) , a n d

c r o s s - c o m p a r i s o n t e c h n i q u e s h a v e t o b e u s e d ( B a i r e t a l , 1 9 7 6 ) .

The p r o b l e m o f t h e a s s o c i a t e d r i s k s o f r a d i a t i o n e x p o s u r e a n d o t h e r

e n v i r o n m e n t a l f a c t o r s h a s b e e n e x a m i n e d f o r many y e a r s , e s p e c i a l l y f o r

o c c u p a t i o n a l g r o u p s a t h i g h r i s k f o r t h e d e v e l o p m e n t o f l u n g c a n c e r s , s u c h

a s u r a n i u m m i n e r s , a s b e s t o s w o r k e r s , e t c . ( A r c h e r e t a l , 1 9 7 6 ) . N u m e r o u s

s t u d i e s a r e b e i n g c a r r i e d o u t t o e x a m i n e t h e a s s o c i a t i o n b e t w e e n t h e

a d m i n i s t r a t i o n o f a l p h a e m i t t e r s v i a t h e r e s p i r a t o r y t r a c t a n d t o b a c c o

smoke o r o t h e r c a r c i n o g e n i c s u b s t a n c e s , s u c h a s t h e a - b e n z p y r e n e ( L i t t l e a n d

o ' T o o l e , 1974; McGandy e t a l , 1974; S a n d e r s , 1975a ,1975b ; M o r i n e t a l , 1 9 7 7 ) .

A l t h o u g h i n t h e c a s e o f r a d o n a n d i t s d a u g h t e r p r o d u c t s t h e e x p e r i m e n t a l

a n i m a l s u s e d , w h e t h e r t h e y a r e r a t s (Chameaud e t a l , 1976) o r d o g s ( S t u a r t

e t a l , 1 9 7 6 ) , do n o t d e c i s i v e l y c o n f i r m t h e o b s e r v a t i o n s made o n m a n , t h e

p o t e n t i a l s y n e r g i s t i c e f f e c t o f c o m b i n a t i o n s o f c h e m i c a l s a n d r a d i o a c t i v e

t o x i c s u b s t a n c e s f o r t h e p r o d u c t i o n o f c a n c e r m u s t b e c o n s i d e r e d .

12k

The t h o r a c i c l y m p h n o d e s a r e a n i m p o r t a n t l i n k i n t h e t r a n s f e r o f

p l u t o n i u m f r o m t h e l u n g t o o t h e r o r g a n s o f d e p o s i t i o n . The m e d i u m - t e r m

e f f e c t s h a v e b e e n d i s c u s s e d p r e v i o u s l y ( s e c t i o n 2 . 2 . 3 ) . I n f o r m a t i o n o n

c a n c e r p a t h o l o g y i s v e r y l i m i t e d ; n o s i g n i f i c a n t i n c r e a s e h a s b e e n o b s e r v e d

i n t h e n u m b e r o f s a r c o m a s o r i g i n a t i n g i n n o d e s a f t e r c o n t a m i n a t i o n b y

a c t i n i d e s ( P a r k e t a l , 1 9 7 2 ; B a i r e t a l , 1 9 7 4 ; D o l p h i n , 1 9 7 1 ) a n d t h i s

r e i n f o r c e s s i m i l a r o b s e r v a t i o n s made i n d o g s a f t e r c o n t a m i n a t i o n b y w o u n d s

( D a g l e e t a l , 1 9 7 5 ) • A n u m b e r o f l y m p h o s a r c o m a s h a v e b e e n o b s e r v e d i n r a t s

( M o r i n e t a l , 1 9 7 6 ) , b u t t h e y h a v e o r i g i n a t e d i n t h e l u n g ; t h e s e t u m o u r s

d e v e l o p e d f r o m t h e l y m p h o i d t i s s u e d i f f u s e l y d i s t r i b u t e d i n t h e p u l m o n a r y

p a r e n c h y m a a n d n o t f r o m t h e n o d e s .

3 . 2 S k e l e t o n

The m o s t i m p o r t a n t e f f e c t o f a l p h a e m i t t e r s o n b o n e i s t h e i n d u c t i o n

o f n e o p l a s t i c c h a n g e s . The m o s t u s e f u l t e c h n i q u e f o r s t u d y i n g t h e i n d u c t i o n

o f b o n e c a n c e r b y a c t i n i d e s i s t h e i n t r a v e n o u s a d m i n i s t r a t i o n o f s o l u b l e

s a l t s o r c o m p l e x e s ; t h i s m e t h o d a l l o w s m e t a b o l i c , t o x i c o l o g i c , d o s i m e t r i c

a n d c l i n i c a l a s p e c t s t o b e i n v e s t i g a t e d . I n a d d i t i o n , t h i s m e t h o d f a c i l i t a -

t e s a n i n t e r c o m p a r i s o n b e t w e e n t h e d i f f e r e n t s p e c i e s , a s i t r e d u c e s t h e

n u m b e r o f v a r i a b l e s t o a min imum. F o r t h i s r e a s o n a g r e a t d e a l o f r e s e a r c h

d u r i n g t h e l a s t t h r e e d e c a d e s h a s b e e n b a s e d o n t h e i n t r a v e n o u s i n j e c t i o n

o f p l u t o n i u m c i t r a t e i n m i c e , r a t s a n d d o g s .

H o w e v e r , t h i s a p p r o a c h d o e s n o t p r o v i d e a r e a l i s t i c m o d e l f o r a l t h o u g h

i t a l l o w s t h e f e a t u r e s a n d m e c h a n i s m s o f r a d i a t i o n - i n d u c e d b o n e c a n c e r t o b e

a n a l y s e d , i t i s b y n o m e a n s r e p r e s e n t a t i v e o f t h e n o r m a l r o u t e s o f a c c i d e n -

t a l c o n t a m i n a t i o n i n man . F o r t h i s r e a s o n g r e a t i m p o r t a n c e m u s t b e a t t a c h e d

t o e x p e r i m e n t s i n w h i c h t h e r a d i o n u c l i d e r e a c h e s t h e s k e l e t o n a f t e r m i g r a t -

i n g f r o m t h e e n t r y p o i n t ( t h e l u n g , d i g e s t i v e t r a c t o r s k i n w o u n d s ) i n t o t h e

o r g a n i s m .

The s k e l e t o n i s made u p o f t w o d i s t i n c t t i s s u e s : t h e b o n e i t s e l f a n d

t h e b o n e m a r r o w . The s i t e s o f d e p o s i t i o n o f p l u t o n i u m a n d t h e t r a n s p l u t o n i u m

e l e m e n t s i n t h e s k e l e t o n r e s u l t i n t h e b o n e b e i n g a t g r e a t e s t r i s k f o r t h e

p r o d u c t i o n o f m a l i g n a n t c h a n g e s ( C h a p t e r 5> s e c t i o n 2 . 2 . 2 ) .

3 . 2 . 1 Bone

Bone c a n c e r s may i n c l u d e o s t e o s a r c o m a s , c h o n d r o s a r c o m a s ( V a u g h a n , 1 9 7 3 ;

V a u g h a n e t a l , 1 9 7 3 ) o r f i b r o s a r c o m a s o f o s t e o g e n i c o r i g i n ( B a r n e s a n d

K h r u s c h o v , 1 9 6 8 ) . Among t h e a c t i n i d e s p l u t o n i u m a p p e a r s t o c a u s e t h e

h i g h e s t i n c i d e n c e o f o s t e o s a r c o m a s , ( L i s c o e t a l , 1 9 4 7 ; F i n k e l , 1 9 5 9 ;

L a n g h a m , 1 9 5 9 ; D o u g h e r t y a n d M a y s , 1 9 6 9 ; M o s k a l e v e t a l , 1 9 ^ 9 ) • F o r

125

e x a m p l e , c o m p a r a b l e d e p o s i t s o f p l u t o n i u m - 2 3 9 a n d americium-21+1 i n r a t s

c a u s e v e r y d i f f e r e n t i n c i d e n c e s o f o s t e o s a r c o m a : 77% f o r p l u t o n i u m - 2 3 9 a n d

21% f o r americ ium -2 l+1 a d m i n i s t e r e d a s c i t r a t e ( T a y l o r a n d B e n s t e a d , 19^9)•

To r e a c h a n i n c i d e n c e o f 1+6% t h e a m o u n t o f americium -2l+1 h a d t o b e t r i p l e d .

The f a c t t h a t b o n e r e t e n t i o n i s l o w e r f o r a m e r i c i u m t h a n f o r p l u t o n i u m (1+0%

o f t h e i n j e c t e d q u a n t i t y f o r americium-21+1 c o m p a r e d w i t h 60% f o r p l u t o n i u m -

239) i s n o t s u f f i c i e n t t o a c c o u n t f o r t h i s d i f f e r e n c e , w h i c h i s p r o b a b l y d u e

t o d i f f e r e n t c o n c e n t r a t i o n s o n t h e b o n e s u r f a c e . The p h y s i c o - c h e m i c a l f o r m

o f t h e e l e m e n t i s a n i m p o r t a n t f a c t o r i n i t s r a d i o t o x i c i t y . T h u s f o r t h e

s a m e a v e r a g e b o n e d o s e t h e m o n o m e r i c f o r m o f p l u t o n i u m p r o d u c e s b o n e c a n c e r s

m o r e r a p i d l y i n m i c e t h a n t h e p o l y m e r i c f o r m a n d t h e t o t a l n u m b e r o f b o n e

c a n c e r s o b s e r v e d d u r i n g t h e w h o l e l i f e - s p a n i s h i g h e r b y a f a c t o r o f

a p p r o x i m a t e l y 2 ( R o s e n t h a l a n d L i n d e n b a u m , 19^9) • T h i s e x p e r i m e n t i l l u s t r -

a t e s o n c e a g a i n t h e d e c i s i v e r o l e p l a y e d b y t h e l o c a l i z a t i o n o f t h e

p l u t o n i u m , s i n c e t h e m o n o m e r i c f o r m i s d e p o s i t e d i n g r e a t e r q u a n t i t i e s o n

t h e s u r f a c e o f t h e e n d o s t e u m t h a n t h e p o l y m e r i c f o r m a n d t h e d o s e i s

d e l i v e r e d i n a m o r e u n i f o r m f a s h i o n .

A c o m p a r i s o n o f r e s u l t s o b t a i n e d i n v a r i o u s s p e c i e s b r i n g s o u t

a p p r e c i a b l e d i f f e r e n c e s . A p a r t f r o m t h e l o c a l i z a t i o n o f a c t i n i d e s i n t h e

v a r i o u s p a r t s o f t h e s k e l e t o n w h i c h a p p e a r s t o v a r y g r e a t l y f r o m o n e s p e c i e s

t o a n o t h e r ( F i n k e l a n d B i s k i s , 1962; C h r i s t e n s e n e t a l , 1 9 7 2 ) , s e n s i t i v i t y

t o a l p h a i r r a d i a t i o n s e e m s t o v a r y b e t w e e n s p e c i e s , t h e d o g a p p e a r i n g t o b e

t h e m o s t s e n s i t i v e o f t h e a n i m a l s c o m m o n l y u s e d i n e x p e r i m e n t s (Mays e t a l ,

1969) . I n m i c e , t h e l o w e s t l i f e s p a n d o s e t o t h e s k e l e t o n r e s u l t i n g i n a

s i g n i f i c a n t i n c i d e n c e o f o s t e o s a r c o m a s w a s 1+0 r a d (0.1+ Gy) ( a v e r a g e b o n e

d o s e ) w h e r e t h e f r e q u e n c y w a s 3-9% ( a f t e r i . v , p l u t o n i u m c i t r a t e ) ; t h e

f r e q u e n c y r e a c h e d a maximum o f 76.9% a t $60 r a d (5.6 Gy) ( F i n k e l a n d B i s k i s ,

1962) . Lower d o s e s h a v e b e e n r e p o r t e d t o c a u s e e x c e s s c a n c e r s i n r a t s

( B u l d a k o v e t a l , 1970) w i t h 1% o f a d d i t i o n a l o s t e o s a r c o m a s a t 3.6 r a d

(.036 Gy) a n d 3.1% a t 25 r a d (0.25 G y ) ; t h e r e a r e u n c e r t a i n t i e s o v e r t h e

t i m e d u r i n g w h i c h t h e d o s e s w e r e c a l c u l a t e d w h i c h may e x p l a i n t h e

d i s c r e p a n c y b e t w e e n t h e r e s u l t s o b t a i n e d i n t h e t w o r o d e n t g e n e r a . R e l a t -

i v e l y l o w d o s e s , a f t e r i n t r a v e n o u s i n j e c t i o n o f p l u t o n i u m c i t r a t e , h a v e

p r o d u c e d h i g h f r e q u e n c i e s o f b o n e c a n c e r i n b e a g l e s : 33% o s t e o s a r c o m a s f o r

78 r a d (O .78 Gy) t o t h e s k e l e t o n ( a v e r a g e b o n e d o s e , c a l c u l a t e d 1 y e a r

b e f o r e d e a t h ) , a n d 100% f o r 600 r a d (6 G y ) ; t h e r a t e o f i n c r e a s e o f o s t e o -

s a r c o m a s h a s b e e n e s t i m a t e d i n d o g s t o b e 0.38% r a d " 1 (0.00l+% G y " 1 ) , i n

m i c e 0.10% r a d " 1 (0.001% G y " 1 ) a n d i n r a t s , 0,06% r a d " 1 (0.0006% G y " 1 ) ,

w h i c h c o r r e s p o n d s t o a f a c t o r o f 6 t o t h e d o g s ' d i s a d v a n t a g e (Mays a n d

126

L l o y d , 1 9 7 2 ) . I n d o g s , o n t h e o t h e r h a n d , u n l i k e r a t s , n o s i g n i f i c a n t

d i f f e r e n c e h a s b e e n f o u n d b e t w e e n t h e e f f e c t s o f p l u t o n i u m a n d a m e r i c i u m

i n c a u s i n g r a d i a t i o n - i n d u c e d o s t e o s a r c o m a s ( L l o y d e t a l , 1 9 7 2 ) . No b o n e

c a n c e r h a s b e e n f o u n d i n m o n k e y s t h a t h a v e r e c e i v e d i n t r a v e n o u s i n j e c t i o n

o f a m e r i c i u m c i t r a t e d e l i v e r i n g d o s e s t o t h e s k e l e t o n r a n g i n g f r o m 2$0 t o

1000 r a d ( 2 . 5 t o 10 Gy) o v e r p e r i o d s o f t i m e v a r y i n g f r o m 2 t o 6 y e a r s

( D u r b i n , 1973) - I n t r a v e n o u s i n j e c t i o n s o f p l u t o n i u m n i t r a t e g i v e

c o r r e s p o n d i n g r e s u l t s ( M o s k a l e v e t a l , 1969; L e m b e r g , I96I4.).

I n f a c t , t o e x p r e s s t h e t r u e r i s k o f o s t e o s a r c o m a , t h e r a t e o f t r a n s -

l o c a t i o n o f t h e r a d i o n u c l i d e t o t h e b o n e f r o m t h e s i t e o f e n t r y i n t o t h e

b o d y m u s t b e t a k e n i n t o a c c o u n t . A c o m p a r i s o n o f v a r i o u s a c t i n i d e s

a d m i n i s t e r e d t o a n u m b e r o f s p e c i e s u s i n g t h e same r o u t e o f a d m i n i s t r a t i o n

w o u l d b e p a r t i c u l a r l y v a l u a b l e .

F o r r a t s , e x p e r i m e n t a l r e s u l t s a r e a v a i l a b l e w h i c h c o v e r a w i d e r a n g e

o f a c t i n i d e s i n h a l e d i n v a r i o u s f o r m s ; a c l e a r r e l a t i o n s h i p c a n u s u a l l y b e

s e e n b e t w e e n t h e t r a n s p o r t a b i l i t y o f t h e e l e m e n t i n t h e o r g a n i s m a n d i t s

t e n d e n c y t o i n d u c e o s t e o s a r c o m a s ( L a f u m a e t a l , 1975 ; M o r i n e t a l , 1976,

1977; B a l l o u e t a l , 1 9 7 5 ) .

T a b l e 6.2 s h o w s t h e p r o p o r t i o n o f b o n e c a n c e r s i n r e l a t i o n t o l u n g

c a n c e r s p r o d u c e d b y p l u t o n i u m , a m e r i c i u m a n d c u r i u m i n h a l e d i n v a r i o u s

c h e m i c a l f o r m s . Cur ium d o e s n o t c o n f o r m t o t h e t r e n d s h o w n b y t h e o t h e r

e l e m e n t s ; t h e p a u c i t y o f b o t h l u n g c a n c e r s a n d o s t e o s a r c o m a s may b e d u e t o

a g r e a t l y s h o r t e n e d l i f e s p a n o f t h e s e a n i m a l s . E i n s t e i n i u m , w i t h i t s

p h y s i c a l h a l f - l i f e o f 20 . 5 d a y s , i s a s p e c i a l c a s e ; c o m p a r i n g i t w i t h a

s o l u b l e f o r m o f p l u t o n i u m o r a m e r i c i u m may p r o v i d e a b a s i s f o r e s t i m a t i n g

t h e i n f l u e n c e o f h i g h d o s e r a t e s o n t h e i n d u c t i o n o f b o n e c a n c e r s . H e n c e ,

t h e i n c i d e n c e o f o s t e o s a r c o m a s i n r a t s a f t e r i n t r a t r a c h e a l i n j e c t i o n o f

e i n s t e i n i u m - 2 5 3 i s f o r d o s e s o f 600 r a d (6 Gy) d e l i v e r e d i n 5 m o n t h s ,

h a l f o f t h e d o s e b e i n g d e l i v e r e d i n 3 w e e k s ( D u r b i n , 1973) -

127

T a b l e 6 . 2

I n i t i a l Lung

D e p o s i t (+iCi g ~ 1 )

B o n e c a n c e r s / r a t s

Lung c a n c e r s / r a t s

B o n e c a n c e r s / L u n g

c a n c e r s

%

P l u t o n i u m - 2 3 9 d i o x i d e

0 . 0 1 - 0 . 7 3 0 / 1 0 8 6 5 / 1 0 8 0

P l u t o n i u m - 2 3 9 n i t r a t e

0 . 0 8 - 0 . 5 0 2 / 4 2 2 3 / 4 2 9

P l u t o n i u m - 2 3 8 d i o x i d e

0 . 0 1 5 - 0 . 0 9 1 / 4 5 8 / 4 5 1 2

P l u t o n i u m - 2 3 8 n i t r a t e

0 . 1 1 - 0 . 4 0 4 / 5 6 6 / 5 6 6 3

A m e r i c i u m - 2 i + 1 d i o x i d e

0 . 0 2 - 0 .1+8 1 0 / 1 1 4 6 1 / 1 1 4 1 7

A m e r i c i u m - 2 4 1 n i t r a t e

0 . 1 7 - 1 . 5 2 1 6 / 2 0 4 6 5 / 2 0 4 2 5

Curium-21+1+ n i t r a t e

0 . 0 3 - 0 . 2 8 1 / 4 8 9 / 4 8 1 0

E i n s t e i n i u m - 2 5 3 c h l o r i d e

0 . 2 5 - 1 2 . 0 * 2 0 / 9 6 8 / 9 6 2 6 2

* e x p r e s s e d a s pCi i n w h o l e l u n g

I n r a t s , o s t e o s a r c o m a s h a v e b e e n p r o d u c e d w i t h r e l a t i v e l y l o w b o n e

d o s e s : 1 5 r a d ( 0 . 1 5 Gy) r e s u l t e d i n a f r e q u e n c y o f 1 $ f o l l o w i n g i n h a l a t i o n

o f ammonium p l u t o n i u m p e n t a c a r b o n a t e ( g r o u p o f 2 5 0 r a t s a n d 5 0 0 c o n t r o l s )

( K o s h u r n i k o v a e t a l , 1 9 6 8 ) , 5 6 r a d ( 0 . 5 6 Gy) g a v e a f r e q u e n c y o f 1 . 1 %

f o l l o w i n g i n t r a t r a c h e a l a d m i n i s t r a t i o n o f p l u t o n i u m n i t r a t e ( g r o u p o f 9 3

r a t s ) ( B u l d a k o v e t a l , 1 9 7 0 ; K o s h u r n i k o v a , 1 9 6 8 b ) , 1 5 0 r a d ( 0 . 1 5 G y ) ( 0 . 0 9 —1 —1

+iCi g~ ( 3 . 3 kBq g~ ) ) g a v e a f r e q u e n c y o f 9*4% f o l l o w i n g a d m i n i s t r a t i o n o f

p l u t o n i u m - 2 3 8 t h a t w a s 70% u l t r a - f i l t e r a b l e ( S a n d e r s , 1 9 7 3 ) . I n t h i s l a s t

e x p e r i m e n t , i t i s i n t e r e s t i n g t o n o t e t h a t a l o w i n i t i a l p u l m o n a r y d e p o s i t

( 0 . 0 0 7 pCi g " 1 ( 0 . 2 6 kBq g " 1 ) ) g i v i n g 2 0 r a d ( 0 . 2 Gy) t o t h e b o n e d i d

n o t i n d u c e b o n e c a n c e r s b u t p r o d u c e d a h i g h f r e q u e n c y o f p u l m o n a r y c a n c e r s ,

v i z . 23% w i t h 3 2 r a d ( O . 3 2 Gy) t o t h e l u n g ; t h e s e r e s u l t s s h o u l d b e c o m p a r e d

w i t h t h o s e i n T a b l e 6 . 2 . The l o w f r e q u e n c i e s o b s e r v e d i n c e r t a i n e x p e r i m e n t s

C o m p a r i s o n o f t h e n u m b e r o f c a n c e r s i n r a t b o n e a n d l u n g a f t e r

i n h a l a t i o n o f v a r i o u s a l p h a e m i t t e r s

( L a f u m a e t a l , 1 9 7 5 ; B a l l o u e t a l , 1 9 7 5 )

128

i n v o l v i n g l o w d o s e s w h i c h a r e o n l y s l i g h t l y a b o v e t h e f r e q u e n c i e s n o r m a l l y

o c c u r r i n g i n u n e x p o s e d a n i m a l s i n d i c a t e t h e d i f f i c u l t y i n i n t e r p r e t i n g t h e

r e s u l t s ( T a b l e 6 . 2 ) .

A f e a t u r e common t o t h e s e b o n e c a n c e r s i s t h a t t h e y a r e o f t h e o s t e o -

g e n i c s a r c o m a t y p e ( F i g u r e 6 . 7 ) , a n d may m e t a s t a s i z e i n t o v a r i o u s o r g a n s ,

o f w h i c h t h e l u n g i s t h e m o s t i m p o r t a n t . I n a n i m a l s t h a t h a d i n h a l e d

a c t i n i d e s i t i s n o t u n u s u a l t o f i n d a p r i m a r y c a r c i n o m a a n d o s t e o s a r c o m a t o u s

m e t a s t a s i s ( L a f u m a e t a l , 1 9 7 5 ) -

R e s u l t s o b t a i n e d f r o m d o g s c o n f i r m t h e s e d a t a i n r a t s . No b o n e c a n c e r

h a s b e e n o b s e r v e d a f t e r i n h a l a t i o n o f i n s o l u b l e c o m p o u n d s , s u c h a s

p l u t o n i u m - 2 3 9 d i o x i d e ( P a r k e t a l , 1 9 7 6 ) . On t h e o t h e r h a n d , t h e

e f f e c t o f t h e s o l u b i l i t y o f p l u t o n i u m - 2 3 8 d i o x i d e i s t o i n d u c e a n a p p r e c i -

a b l e number o f b o n e c a n c e r s . The m i n i m a l i n i t i a l p u l m o n a r y a c t i v i t y i s o f

t h e same o r d e r a s t h a t o b s e r v e d i n r a t s . The r e s u l t s o f e x p e r i m e n t s c a r r i e d

o u t o n r a t s w i t h p l u t o n i u m - 2 3 8 d i o x i d e a r e c o n s i s t e n t : o s t e o s a r c o m a s h a v e

a p p e a r e d a t a v e r a g e b o n e d o s e s f r o m 5 0 t o 1 5 0 r a d ( 0 . 5 0 t o 1 . 5 Gy) ( S a n d e r s ,

1 9 7 3 ) > c o m p a r a b l e t o t h o s e d e l i v e r e d a f t e r i n t r a p e r i t o n e a l i n j e c t i o n s o f

p l u t o n i u m - 2 3 9 d i o x i d e g i v i n g s i m i l a r a v e r a g e b o n e d o s e s ( S a n d e r s e t a l , 1 9 7 2 ) .

The g r o w t h o f t h e b o n e t h a t o c c u r s d u r i n g a r e l a t i v e l y l a r g e p a r t o f

t h e l i f e o f t h e r a t p l a y s a r o l e i n t h e a g e - r e l a t e d v a r i a t i o n s o f b o n e

s e n s i t i v i t y t h a t h a v e b e e n o b s e r v e d i n t h e s e a n i m a l s .

T h u s , f o r t h e same d o s e s d e l i v e r e d t o b o n e b y a m e r i c i u m - 2 1 + 1 , a s s u m i n g

t h a t a l l o t h e r e x p e r i m e n t a l c o n d i t i o n s w e r e c o m p a r a b l e , t h e i n c i d e n c e o f

o s t e o s a r c o m a s w a s 29% i n y o u n g r a t s a n d o n l y 1 3 - 5 % i n a d u l t r a t s ( D u r b i n ,

1 9 7 3 ) « S i m i l a r r e s u l t s w e r e o b t a i n e d f o r p l u t o n i u m : 2 5 % f o r r a t s t h a t h a d

r e c e i v e d p l u t o n i u m - 2 3 9 a t 7 w e e k s a n d 5% a t 7 m o n t h s , a l t h o u g h t h e l e n g t h o f

t h e l a t e n t p e r i o d may h a v e d i s t o r t e d t h e r e s u l t o b t a i n e d i n o l d a n i m a l s

( F a b r i k a n t a n d S m i t h , 1 9 6 ! + ) . O t h e r s t u d i e s i n r a t s h a v e s h o w n t h e same

t r e n d a l t h o u g h d i f f e r e n c e s w e r e l e s s m a r k e d (Mahlum e t a l , 1 9 7 5 ) .

M i x t u r e s o f p l u t o n i u m a n d s o d i u m r e p r e s e n t a p o t e n t i a l c o n t a m i n a t i o n

r i s k i n c e r t a i n n u c l e a r p o w e r i n s t a l l a t i o n s . O n l y m e t a b o l i c d a t a i s a v a i l -

a b l e o n s u c h m i x t u r e s b u t p a r t i c u l a r a t t e n t i o n s h o u l d b e p a i d t o t h e r i s k

t o b o n e t h a t t h e y r e p r e s e n t . P l u t o n i u m i n p l u t o n i u m - s o d i u m m i x t u r e s i s

r e a d i l y t r a n s p o r t a b l e a n d r e s u l t s i n a h i g h b o n e d e p o s i t w h i c h i s n o t

r e a d i l y r e m o v e d b y c h e l a t i n g a g e n t s ( M e t i v i e r e t a l , 1 9 7 6 ) .

3 . 2 . 2 B o n e marrow

L e u k a e m i a ( s ) a r e t h e m o s t i m p o r t a n t g r o u p o f t u m o u r s o r i g i n a t i n g i n

129

F i g u r e 6.7 O s t e o g e n i c o s t e o s a r c o m a i n r a t s a f t e r i n h a l a t i o n o f a m e r i c i u m

( i n f o r m a t i o n s u p p l i e d b y R. M a s s e , D e p a r t e m e n t d e P r o t e c t i o n ,

CEA, F r a n c e ) .

130

t h e m a r r o w , o t h e r m e s e n c h y m a t o u r t u m o u r s o c c u r v e r y i n f r e q u e n t l y ( F i n k e l

a n d B i s k i s , 19&2). L e u k a e m i a s , a l t h o u g h t h e y a r e a p o t e n t i a l r i s k f r o m

a n y p l u t o n i u m d e p o s i t i n t h e h o n e , o c c u r much l e s s f r e q u e n t l y t h a n o s t e o -

s a r c o m a s ( M o s k a l e v e t a l , 1968) . To a g r e a t e r e x t e n t t h a n t h e t r a n s p l u t o n -

i u m e l e m e n t s , p l u t o n i u m may c a u s e l e u k a e m i c d i s e a s e s t h a t a r e m a r k e d b y a n

a b n o r m a l h y p e r p l a s i a o f t h e c e l l s i n t h e marrow w i t h e f f e c t s i n o t h e r

o r g a n s , s u c h a s t h e s p l e e n , t h e l i v e r o r t h e k i d n e y s a n d t h e d e v e l o p m e n t o f

a l e u c o - e r y t h o b l a s t i c a n a e m i a ( C h a p t e r $ , s e c t i o n 2 .2 ,2 ) ( V a u g h a n , 1970) .

A f e w l e u k a e m i a s h a v e b e e n o b s e r v e d i n r a t s a f t e r i n j e c t i o n s o f p l u t o n i u m

( B e n s t e d e t a l , 1 9 ^ 5 ) • The f r e q u e n c y o f l e u k a e m i a s i s a b o u t 2% o f t h a t o f

o s t e o s a r c o m a s o b s e r v e d i n b e a g l e s c o n t a m i n a t e d b y p l u t o n i u m - 2 3 9 c i t r a t e

a d m i n i s t e r e d i n t r a v e n o u s l y ( V a u g h a n e t a l , 1973) - Lymphomas h a v e b e e n

o b s e r v e d i n m i c e g i v e n i n t r a v e n o u s i n j e c t i o n s o f p l u t o n i u m - 2 3 9 c i t r a t e

( L o u t i t e t a l , 1 9 7 ^ ) • L e u k a e m i a s o c c u r v e r y r a r e l y i n a n i m a l s a f t e r

i n j e c t i o n o r i n h a l a t i o n o f a m e r i c i u m o r c u r i u m .

3- 3 L i v e r

E f f e c t s o n t h e l i v e r s h o u l d b e e x a m i n e d c l o s e l y , d e s p i t e t h e l a c k o f

c o n s i s t e n c y b e t w e e n t h e t h e o r e t i c a l e f f e c t s t h a t m i g h t b e e x p e c t e d a n d t h e

o b s e r v e d e f f e c t s . As p l u t o n i u m i s d e p o s i t e d , b r o a d l y s p e a k i n g , i n e q u a l

p r o p o r t i o n s i n t h e s k e l e t o n a n d i n t h e l i v e r , t h e r i s k o f m a l i g n a n t c h a n g e s

t o t h e l i v e r c o u l d e q u a l o r e v e n e x c e e d t h a t o f b o n e c a n c e r s (Mays e t a l ,

1970) . H o w e v e r , t h i s h a s n e v e r b e e n f o u n d e x p e r i m e n t a l l y i n a n i m a l s t u d i e s .

N u m e r o u s e x p e r i m e n t s h a v e d e s c r i b e d d e l a y e d b u t n o n - n e o p l a s t i c e f f e c t s

a r i s i n g f r o m t h e d e p o s i t i o n o f p l u t o n i u m o r o t h e r a c t i n i d e s i n t h e l i v e r .

—1 —1 L a r g e c o n c e n t r a t i o n s ( a b o u t 10 jiCi k g ~ (37O kBq k g ) ) o f p l u t o n i u m a r e r e q u i r e d t o e n a b l e t h e h e p a t i c d i s t u r b a n c e s , r e l a t e d t o a n e f f e c t o n t h e

h e p a t i c c e l l s t o b e d e t e c t e d c l i n i c a l l y . Lower c o n c e n t r a t i o n s ( l e s s t h a n —1 —1

2 jiCi k g (74 kBq k g ) ) may i n d u c e r e c i r c u l a t i o n o f q u a n t i t i e s o f p l u t o n i u m

i n t h e b l o o d s t r e a m ( L i n d e n b a u m a n d R o s e n t h a l , 1 9 7 2 ) . D i s p e r s e d f o r m s o f

p l u t o n i u m h a v e m o r e e f f e c t t h a n t h e p o l y m e r i c f o r m s , e s p e c i a l l y i n c h a n g i n g

p h a g o c y t i c f u n c t i o n ( K a s h i m a e t a l , 1 9 7 2 ) . H i s t o l o g i c a l c h a n g e s , s u c h a s

c o n c e n t r a t i o n s o f p i g m e n t i n t h e c e l l s o f t h e r e t i c u l o e n d o t h e l i a l s y s t e m

(RES) a r e o b s e r v e d w h e n t h e l o w e s t d o s e s a r e a d m i n i s t e r e d ( T a y l o r e t a l ,

1 9 7 2 ) . The r e l a t i v e d e p o s i t i o n o f p l u t o n i u m i n t h e h e p a t i c c e l l s a n d i n

t h e RES, w h o s e p r o p o r t i o n s v a r y a c c o r d i n g t o t h e s p e c i e s a n d t h e p h y s i c o -

c h e m i c a l f o r m o f t h e c o n t a m i n a n t , may p r o v i d e e x p l a n a t i o n s f o r t h e d i v e r s e

c h a n g e s o b s e r v e d i n t h e s e t w o t i s s u e s ( C o c h r a n e t a l , 19&2; T a y l o r e t a l ,

1966) .

131

On t h e o t h e r h a n d , t h e s e n o n - n e o p l a s t i c c h a n g e s t h a t h a v e b e e n

r e p o r t e d i n s e v e r a l a n i m a l s p e c i e s do n o t i n d i c a t e t h a t t h e l i v e r i s

p a r t i c u l a r l y r e s i s t a n t t o t h e d e v e l o p m e n t o f m a l i g n a n t c h a n g e , a l t h o u g h

t h i s h a s o f t e n b e e n o b s e r v e d ( G e r s h b e i m , 1956; R e e d a n d C o x , 1966) . M e t a -

b o l i c d a t a o b t a i n e d i n v a r i o u s a n i m a l s p e c i e s h a v e s h o w n t h a t r a t s a n d m i c e

r e p r e s e n t p o o r m o d e l s f o r m a n , u n l i k e d o g s a n d h a m s t e r s ( C h a p t e r 1+). One

w o u l d l o g i c a l l y e x p e c t t o f i n d a s i g n i f i c a n t n u m b e r o f c a n c e r o u s c h a n g e s ,

i n s p e c i e s i n w h i c h t h e b i o l o g i c a l h a l f - l i f e i n t h e l i v e r i s l o n g a n d

c o m p a r a b l e t o t h a t o f m a n . I n f a c t , l i v e r t u m o u r s c a u s e d b y h e p a t i c

d e p o s i t i o n o f p l u t o n i u m i n d o g s o n l y a f f e c t t h e b i l e d u c t s ( T a y l o r e t a l ,

1969; T a y l o r e t a l , 1 9 7 2 ) . A f t e r i n j e c t i o n o f p l u t o n i u m c i t r a t e i n d o g s ,

t h e i n c i d e n c e o f i n t r a h e p a t i c t u m o u r s w a s a b o u t 10% ( 1 0 / 9 6 ) , c o m p a r e d w i t h

a n i n c i d e n c e i n t h e c o n t r o l s o f !+%• T h e s e t u m o u r s o c c u r r e d a t 11 y e a r s o n

a v e r a g e (9 .2 - 11+) i n t h e c o n t a m i n a t e d d o g s a s c o m p a r e d w i t h 11+ y e a r s (1 3 -

16.1+) i n t h e c o n t r o l s . I n m o s t o f t h e d o g s , t h e s e t u m o u r s w e r e r e v e a l e d a t

a u t o p s y . A l o w p e r c e n t a g e ( a b o u t 20%) w e r e d i r e c t l y i n s t r u m e n t a l i n c a u s i n g

d e a t h ; i n t h e s e c a s e s , t h e l o w e s t l e v e l o f c o n t a m i n a t i o n t h a t c a u s e d a

t u m o u r (0.001+ p.Ci k g " 1 ( 0 .15 kBq k g " 1 ) ) g a v e a l i v e r d o s e o f 60 r a d (0.60

G y ) .

The q u e s t i o n a s t o why t h e r e a r e n o c a n c e r s i n t h e h e p a t i c t i s s u e s a n d

c e l l s r e m a i n s u n a n s w e r e d . The r e l a t i v e l y l o w r a d i o s e n s i t i v i t y o f t h e l i v e r

i s p r o b a b l y i n f l u e n c e d b y t h e s l o w r e n e w a l o f t h e h e p a t i c c e l l ( P a b r i k a n t ,

1967) ; i t c e r t a i n l y s e e m s t h a t s h o r t e n e d l i f e s p a n s o f c e l l s h e l p t o i n d u c e

c a n c e r o u s c h a n g e s ( W e i n b r e n e t a l , i960; C o l e a n d N o w e l l , 1961+; O o o d a l l ,

1966) . A t l o w c o n t a m i n a t i o n l e v e l s , s u c h a s t h o s e t h a t man m i g h t b e e x p e c -

t e d t o e n c o u n t e r , t h e r e w o u l d n o t b e a s u f f i c i e n t n u m b e r o f o s t e o s a r c o m a s

i n d u c e d t o mask t h e l a t e a p p e a r a n c e o f p r i m a r y l i v e r c a n c e r s ( M a y s e t a l , 19^9) •

M o r e o v e r , t h e d e v e l o p m e n t o f h e p a t i c c a n c e r s m i g h t b e h e l p e d b y t h e p r e s e n c e

o f o t h e r a d d i t i o n a l e n v i r o n m e n t a l f a c t o r s ( c h e m i c a l s , p h a r m a c e u t i c a l s , e t c . ) .

I t i s p r o b a b l e t h a t a m e r i c i u m a n d c u r i u m a r e m o r e t o x i c t h a n p l u t o n i u m s i n c e

t h e y a r e r e t a i n e d i n l a r g e r q u a n t i t i e s i n t h e l i v e r ( A t h e r t o n e t a l , 1968;

N e n o t e t a l , 1 9 7 1 a ) . T h u s , d e s p i t e t h e a b s e n c e o f c o n s i s t e n t s u p p o r t i n g

e x p e r i m e n t a l e v i d e n c e , t h e l i v e r s h o u l d b e r e g a r d e d a s a t i s s u e p o t e n t i a l l y

a t r i s k i n m a n .

3.1+ O t h e r o r g a n s

The p a t h o l o g i c a l e f f e c t s o f p l u t o n i u m o r o f a n y o t h e r a l p h a e m i t t e r i n

s o f t t i s s u e s , w h e r e s e c o n d a r y r e t e n t i o n t a k e s p l a c e , s e e m t o r e s u l t f r o m t h e

d e p o s i t i o n o f a c t i n i d e s i n t h e m . As i n t h e c a s e o f t h e b o n e ( s e c t i o n 3.2)

t h e r e s u l t s i n d i c a t e a n i n c i d e n c e o f c a n c e r s i n s o f t t i s s u e s o t h e r t h a n t h e

132

l u n g a n d t h e l i v e r t h a t i s p a r t i c u l a r l y h i g h w h e n t h e a c t i n i d e i s r e a d i l y

t r a n s p o r t a b l e i n t h e b o d y .

T h i s c a n b e i l l u s t r a t e d b y c o m p a r i n g r e s u l t s o b t a i n e d f o r "two

f o r m s o f p l u t o n i u m . A f t e r i n h a l a t i o n o f i n s o l u b l e p l u t o n i u m - 2 3 9 d i o x i d e b y

r a t s t h e i n c i d e n c e o f c a n c e r s i n s o f t t i s s u e s o t h e r t h a n t h e l u n g i s n e v e r

h i g h e r t h a n t h a t i n t h e c o n t r o l s ; i t i s n o r m a l l y l o w e r t h a n t h a t i n t h e

c o n t r o l s , b e c a u s e t h e l a t t e r l i v e l o n g e r a n d t e n d t o d e v e l o p c a n c e r s l a t e r

i n l i f e ( M o r i n e t a l , 1 9 7 7 ) . I n t h e s e c o n d c a s e , a f t e r i n h a l a t i o n b y r a t s

o f s o l u b l e p l u t o n i u m - 2 3 8 i n t h e f o r m o f c r u s h e d m i c r o s p h e r e s , t h e r e i s a

l a r g e i n c r e a s e i n t h e i n c i d e n c e o f p e r i p h e r a l c a n c e r s ( S a n d e r s , 1 9 7 3 ) • I n

a n i m a l s r e c e i v i n g a d o s e o f 9 r a d ( 0 . 0 9 Gy) t o t h e l u n g , c a n c e r s o f t h e s o f t

t i s s u e s a r e t h r e e t i m e s a s h i g h a s t h o s e i n t h e l u n g . T a b l e 6 . 3 s h o w s t h a t

t h e r e l a t i v e n u m b e r s o f p e r i p h e r a l c a n c e r s i n r e l a t i o n t o p u l m o n a r y c a n c e r s

i s i n v e r s e l y p r o p o r t i o n a l t o t h e d o s e a c c u m u l a t e d b y t h e l u n g ; t h e t w o

e f f e c t s o f r a d i a t i o n o f i n c r e a s i n g n u m b e r o f l u n g c a n c e r s a n d s h o r t e n i n g t h e

l i f e s p a n , m a s k s t h e a p p e a r a n c e o f o t h e r c a n c e r s .

T a b l e 6 . 3

F r e q u e n c y o f c a n c e r s a f t e r i n h a l a t i o n b y f e m a l e r a t o f p l u t o n i u m - 2 3 8

i n t h e f o r m o f c r u s h e d m i c r o s p h e r e s

( S a n d e r s , 1 9 7 3 )

D o s e t o l u n g ( r a d )

N o . o f

r a t s

L i f e s p a n

I n c i d e n c e o f t u m o u r s {%) D o s e t o

l u n g ( r a d )

N o . o f

r a t s

L i f e s p a n

Mammary Lung B o n e L i v e r L e u k a e m i a O t h e r s o f t

t i s s u e s

0 9 2 8 2 5 7 1 . 7 1 . 1 _ _ 2 . 2 1 . 1

9 30 6 5 0 7 3 . 3 6 . 6 - - - 1 9 . 8

3 2 30 5 7 5 6 0 . 0 2 3 . 2 - - - 1 3 . 2

3 7 5 3 2 5 5 0 6 2 . 5 2 5 . 0 9.k - - 1 2 . h

M o r e o v e r , p e r i p h e r a l c a n c e r s a p p e a r a t a l a t e s t a g e i n t h e a b s e n c e o f

a n y i r r a d i a t i o n ; f r e q u e n c i e s i n t h e c o n t r o l s o f 1 % b e f o r e t h e a g e o f 1 . 5

y e a r s , o f 5% b e t w e e n t h e a g e s o f 1 . 5 a n d 2 y e a r s , a n d 1 0 % a f t e r t h e a g e o f

2 a r e n o r m a l .

A m e r i c i u m , w h i c h i s r e a d i l y t r a n s p o r t a b l e i n t h e b o d y i n a l l i t s

c h e m i c a l f o r m s , i l l u s t r a t e s t h e r i s k o f c a n c e r i n d u c t i o n i n s o f t t i s s u e s ,

d u e t o t h e m o v e m e n t o f a c t i n i d e s i n t h e o r g a n i s m . T h u s , a f t e r i n h a l a t i o n o f

a m e r i c i u m d i o x i d e , a t h i r d o f t h e r a t s w i t h c a n c e r o f t h e l u n g a l s o h a v e a

c a n c e r o f t h e o t h e r s o f t t i s s u e s ( M o r i n e t a l , 1 9 7 7 ) . As h a s b e e n n o t e d i n

133

c o n n e c t i o n w i t h o s t e o s a r c o m a s , e i n s t e i n i u m h a s h i g h t o x i c i t y d u e t o i t s

r a p i d t r a n s l o c a t i o n i n t h e b o d y . Thus i n a g r o u p o f 1+8 r a t s t h a t r e c e i v e d

1900 r a d (19 G y ) t o t h e l u n g , 6 p u l m o n a r y c a n c e r s d e v e l o p e d t o g e t h e r w i t h

9 t u m o u r s i n t h e s o f t t i s s u e s a n d 2 l y m p h o i d l e u k a e m i a s , a s w e l l a s 20

o s t e o s a r c o m a s a n d 2 m y e l o i d l e u k a e m i a s ( B a l l o u e t a l , 1975) -

T h e r e f o r e t h e r i s k a s s o c i a t e d w i t h t h e i n h a l e d a c t i n i d e s d o e s n o t o n l y

a r i s e i n t h e l u n g a n d t h e b o n e b u t a l s o e x i s t s i n a number o f o t h e r o r g a n s .

As t h e l i v e r h a s a n i m p o r t a n t p a r t i n t r a n s u r a n i c e l e m e n t m e t a b o l i s m i t a l s o

h a s t o b e c o n s i d e r e d a s a n o r g a n p o t e n t i a l l y a t r i s k . The i n c r e a s e d i n c i d -

e n c e o f c a n c e r s i n o t h e r o r g a n s t h a t i s s o m e t i m e s o b s e r v e d d e p e n d s o n

t h e a n i m a l s t r a i n c h o s e n f o r t h e e x p e r i m e n t . O r g a n s o t h e r t h a n

t h e l u n g , b o n e a n d l i v e r r e c e i v e l o w d o s e s b u t a l t h o u g h t h e i r n u m b e r may

i n c r e a s e t h e o v e r a l l r i s k i t i s n o t p o s s i b l e t o i d e n t i f y a n y o f t h e m a s a

c r i t i c a l t i s s u e .

3.5 Summary

The d e l a y e d e f f e c t s t h a t h a v e t o b e c o n s i d e r e d i n a n i m a l s e x p o s e d t o

p l u t o n i u m , a m e r i c i u m a n d c u r i u m a r e m a l i g n a n t c h a n g e s i n t h e o r g a n s i n

w h i c h t h e y d e p o s i t . The t u m o u r f r e q u e n c y i n d i f f e r e n t t i s s u e s d e p e n d s

u p o n t h e t r a n s p o r t a b i l i t y o f t h e s e a c t i n i d e s i n t h e b o d y . The m a i n

o r g a n s o f d e p o s i t i o n a r e t h e l u n g , s k e l e t o n a n d l i v e r b u t a c t i n i d e s may

a l s o d e p o s i t i n a l l t h e o t h e r t i s s u e s o f t h e b o d y . I n r a t s t h e f r e q u -

e n c y o f r a d i a t i o n i n d u c e d l u n g c a n c e r i n c r e a s e s w i t h t h e d o s e u p t o a

maximum a n d t h e n d e c r e a s e s a s a r e s u l t o f c e l l s t e r i l i z a t i o n a n d d e a t h

o c c u r r i n g b e f o r e t h e d e v e l o p m e n t o f c a n c e r . T h i s maximum i n c i d e n c e

o c c u r s a t l u n g d o s e s a r o u n d 500 r a d (5 Gy) f o r americium-21+1 o x i d e a n d

curium-21+1+ n i t r a t e , b e t w e e n £00 a n d 10OO r a d (5 a n d 10 Gy) f o r p l u t o n -

ium-238 ( o x i d e a n d n i t r a t e ) , b e t w e e n £00 J Q O O r a d (5 a n d £0 Gy) f o r

americium-21+1 n i t r a t e a n d o v e r 1000 r a d (10 G y ) f o r p l u t o n i u m - 2 3 9

( o x i d e a n d n i t r a t e ) . E x p e r i m e n t a l r e s u l t s w i t h o t h e r s p e c i e s c o n f i r m

t h e s e r e s u l t s .

M a l i g n a n t t u m o u r s o f v a r i o u s t y p e s may d e v e l o p i n t h e s k e l e t o n a f t e r

t h e e n t r y o f a c t i n i d e s i n t o t h e b l o o d . T h e s e a r e o s t e o s a r c o m a s ,

c h o n d r o s a r c o m a s o r f i b r o s a r c o m a s . S e n s i t i v i t y t o r a d i a t i o n i n d u c e d

b o n e c a n c e r d e v e l o p m e n t v a r i e s w i t h t h e s p e c i e s c o n s i d e r e d . The d o g

a p p e a r s t o b e t h e m o s t s e n s i t i v e a n i m a l w i t h a n e s t i m a t e d i n d u c t i o n

r a t e o f 0.38% p e r r a d c o m p a r e d w i t h a r a t e o f 0.06% p e r r a d i n t h e r a t .

A f t e r i n h a l a t i o n o f a c t i n i d e s t h e d e v e l o p m e n t o f b o n e t u m o u r s c a n b e

c o r r e l a t e d w i t h t h e i r t r a n s p o r t a b i l i t y i n t h e b o d y a n d t h e a m o u n t

13U

d e p o s i t e d i n t h e s k e l e t o n . L e u k a e m i a s r e s u l t i n g f r o m i r r a d i a t i o n o f

t h e b o n e marrow h a v e b e e n s e e n o n l y r a r e l y i n a n i m a l s e x p o s e d t o

a c t i n i d e s .

L i v e r t u m o u r s h a v e b e e n s e e n o n l y i n f r e q u e n t l y i n a n i m a l s e x p o s e d t o

a c t i n i d e s . I n d o g s , l i v e r t u m o u r s d e v e l o p i n t h e b i l e d u c t s . M a l i g -

n a n t c h a n g e s may a l s o o c c u r o c c a s i o n a l l y i n o t h e r s o f t t i s s u e s i n

a n i m a l s e x p o s e d t o r e a d i l y t r a n s p o r t a b l e f o r m s o f a c t i n i d e s .

U. S h o r t e n i n g o f t h e l i f e s p a n

The s e p a r a t i o n o f t h e d e l a y e d e f f e c t s o n t h e o n e h a n d f r o m l i f e s p a n

s h o r t e n i n g o n t h e o t h e r h a n d i s t o some e x t e n t a r b i t r a r y , f o r t h e f o r m e r

c o n s i s t w h o l l y o f c a n c e r s w h i c h h a v e a s i g n i f i c a n t e f f e c t o n t h e l i f e s p a n .

I n p r a c t i c e , h o w e v e r , d e a t h may o c c u r a s a r e s u l t o f m a s s i v e t i s s u e damage

b e f o r e t h e c a n c e r s a p p e a r a n d t h i s e f f e c t i s n o n - s t o c h a s t i c u n l i k e i n t h e c a s e o f

c a n c e r s . As t h e h i g h e s t i n c i d e n c e o f c a n c e r o c c u r s a t t h e e n d o f l i f e , w i t h

o r w i t h o u t i r r a d i a t i o n , i t i s c l e a r t h a t t h e t w o p h e n o m e n a a r e r e l a t e d ,

p e r h a p s l i n k e d , b u t t h a t t h e a v e r a g e l i f e s p a n o f a g r o u p i s n o t d e t e r m i n e d

s o l e l y b y t h e n u m b e r o f c a n c e r s o r o f c a n c e r - b e a r i n g a n i m a l s i n t h a t g r o u p .

I t i s t h e r e f o r e p o s s i b l e t h a t a s t u d y o f l o n g e v i t y a n d i t s r e l a t i o n s h i p w i t h

i n t e r n a l i r r a d i a t i o n may n o t l e n d i t s e l f t o a p r o b a b i l i s t i c a p p r o a c h .

T a b l e 6.1+ s h o w s r e s u l t s o b t a i n e d i n a n u m b e r o f s t u d i e s o f t h e l e v e l s

o f p l u t o n i u m a n d t r a n s p l u t o n i u m e l e m e n t s t h a t i n f l u e n c e t h e l i f e s p a n o f

v a r i o u s s p e c i e s . The v a l u e o f t h e minimum d o s e p r o d u c i n g s i g n i f i c a n t l i f e

s h o r t e n i n g i s t o b e f o u n d b e t w e e n t h e t w o v a l u e s g i v e n i n t h e t a b l e :

( a ) t h e h i g h e s t d o s e a t w h i c h n o s h o r t e n i n g w a s o b s e r v e d , a n d ( b ) t h e l o w e s t

d o s e t h a t p r o d u c e d a s h o r t e n i n g . I t t h u s a p p e a r s t h a t t h e l o w e s t l e v e l o f

i n i t i a l p u l m o n a r y d e p o s i t i o n w h i c h s h o r t e n s t h e a v e r a g e l i f e s p a n o f r a t s i s

i n t h e r e g i o n o f 0 .01+ jiCi g 1 ( 1 . 5 kBq g 1 ) f o r p l u t o n i u m - 2 3 9 d i o x i d e , —1 —1

0 . 1 ^iCi g ~ ( 3 . 7 kBq g ) o r more f o r t h e t r a n s p o r t a b l e f o r m s o f p l u t o n i u m -

2 3 9 a n d p l u t o n i u m - 2 3 8 d i o x i d e , 0 . 0 5 pCi g ~ 1 ( 1 . 9 kBq g " 1 ) f o r t h e t r a n s -

—1 —1

p l u t o n i u m e l e m e n t s , a n d 0 . 0 0 2 jiCi g ~ ( 0 . 0 8 kBq g™ ) f o r u l t r a - f i l t e r a b l e

p l u t o n i u m - 2 3 8 , w h i c h w a s t h e m o s t s o l u b l e f o r m u s e d . A d o g s l i f e s p a n i s

a f f e c t e d l e v e l s a p p r o x i m a t e l y 3 "to 1 0 t i m e s l o w e r . As c l e a r a n c e r a t e s

d e p e n d u p o n p h y s i c o - c h e m i c a l f o r m s a n d s p e c i e s , i t i s v e r y d i f f i c u l t t o

d e t e r m i n e t h e minimum d o s e t h a t p r o d u c e s l i f e s h o r t e n i n g . The s i z e o f t h e

a n i m a l g r o u p s a l s o i n t r o d u c e s a f a i r l y l a r g e f a c t o r o f u n c e r t a i n t y i n t o t h e

d a t a , a n d m a k e s a n y i n t e r c o m p a r i s o n o f t h e s e many e x p e r i m e n t s d i f f i c u l t t o

i n t e r p r e t . I n r a t s t h e r e s u l t s s u g g e s t t h a t , b r o a d l y , t h e d o s e t o p r o d u c e

l i f e s h o r t e n i n g w o u l d a p p e a r t o b e a b o u t 1 5 0 0 t o 2 0 0 0 r a d ( 1 5 t o 2 0 Gy) t o

135

t h e l u n g f r o m p l u t o n i u m - 2 3 9 d i o x i d e , 5 0 0 t o 1 2 0 0 r a d ( 5 t o 1 2 Gy) f r o m

t r a n s p o r t a b l e p l u t o n i u m - 2 3 9 , 2 0 0 r a d ( 2 0 Gy) f r o m a m e r i c i u m - 2 4 1 , a n d o n l y a

f e w t e n s o f r a d f r o m t h e u l t r a - f i l t e r a b l e f o r m s o f p l u t o n i u m - 2 3 8 d i o x i d e .

T a b l e 6 . 4

S h o r t e n i n g o f l i f e s p a n , a f t e r i n h a l a t i o n o f a l p h a e m i t t e r s ,

i n d i f f e r e n t s p e c i e s

R a d i o n S p e c i e s

( a ) H i g h e s t l e v e l

a t w h i c h e f f e c t w a s n o t o b s e r v e d

( b ) L o w e s t l e v e l

a t w h i c h e f f e c t w a s o b s e r v e d

R a d i o n S p e c i e s ( L u n g ) ( L u n g )

R e x . R a d i o n S p e c i e s

N o . o f a n i m a l s

UCi g""1 Rad N o . o f

a n i m a l s UCi g ~ 1 Rad

P u - 2 3 9 Mouse 1 3 8 0 . 0 0 5 2 0 ( 1 ) d i o x i d e

R a t 6 0 0 . 0 1 7 9 3 2 0 . 0 1 9 ? ( 2 )

R a t 1 4 0 . 0 2 5 1 1 0 0 8 0 . 0 4 1 5 0 0 ( 3 )

D o g - ? ? 3 6 0 . 0 0 3 2 0 0 0 (h) Monkey - ? ? 3 2 0 . 0 5 3 3 0 0 ( 5 )

P u - 2 3 9 R a t 1 3 2 0 . 0 4 2 4 0 1 0 0 0 . 1 5 8 8 0 (6) c i t r a t e

(6)

P u - 2 3 9 R a t 6 5 0 . 0 6 ? 65 0 . 3 7 ? ( 7 ) n i t r a t e

R a t 1 2 0 . 0 1 6 2 2 5 1 8 0 . 1 2 2 8 0 0 ( 3 ) D o g - ? ? h 0 . 1 0 ? (h)

P u - 2 3 8 R a t 30 < 0 . 0 9 ? 2 7 O . 3 6 ? ( 2 ) d i o x i d e

H a m s t e r 4 5 0 . 0 1 ? U6 0 . 1 0 ? ( 8 )

D o g - ? ? 9 > 0 . 0 1 ? ( 9 ) P u - 2 3 8 R a t - 9 ? 30 > 0 . 0 0 2 9 ( 1 0 ) u l t r a f .

( 1 0 )

Am-21+1 R a t 5 0 . 0 3 1 5 0 9 0 . 1 3 7 5 0 ( 3 ) d i o x i d e

0 . 1 3 ( 3 )

Am-21+1 R a t 1 2 0 . 0 6 5 3 9 0 1 9 0 . 1 2 6 7 0 ( 3 ) n i t r a t e

( 3 )

C m - 2 4 4 R a t - 1 2 0 . 1 0 6 0 0 ( 3 ) n i t r a t e

( 3 )

E s - 2 5 3 R a t 4 8 0 . 0 5 3 8 U8 2 . 5 1 9 0 0 ( 1 1 ) c h l o r i d e

2 . 5 1 9 0 0 ( 1 1 )

( 1 ) B a i r e t a l , 1 9 6 2 ( 5 ) M e t i v i e r e t a l , 1 9 7 4 ( 9 ) P a r k e t a l , 1 9 7 6

( 2 ) S a n d e r s , 1 9 7 5 b ( 6 ) K o s h u r n i k o v a e t a l , 1 9 7 1 ( 1 0 ) S a n d e r s , 1 9 7 3

( 3 ) Lafuma e t a l , 1 9 7 5 ( 7 ) B a l l o u e t a l , 1 9 7 5 ( 1 1 ) B a l l o u a n d M o r r o w ,

( 4 ) P a r k e t a l , 1 9 7 2 ( 8 ) M e w h i n n e y e t a l , 1 9 7 6 b 1 9 7 3

136

A d i f f e r e n t a p p r o a c h c o n s i s t s o f c o m p a r i n g t h e L D ^ a t 1 y e a r f o r

d i f f e r e n t a c t i n i d e s i n t h e same s p e c i e s . H o w e v e r , t w o f a c t o r s m u s t t h e n b e

t a k e n i n t o a c c o u n t : ( a ) t h e $0% m o r t a l i t y r a t e o n l y t a k e s i n t o a c c o u n t t h e

s h o r t a n d m e d i u m - t e r m e f f e c t s , a n d i n v i e w o f t h e d e l a y e d e f f e c t s i t i s

s p e c u l a t i o n t o r e g a r d t h i s m o r t a l i t y r a t e a s r e p r e s e n t a t i v e o f t h e a v e r a g e

m o r t a l i t y r a t e o v e r a l i f e t i m e ; ( b ) t h i s L D ^ c o r r e s p o n d s t o t h e p l a t e a u o f

t h e s i g m o i d c u r v e l i n k i n g l i f e s p a n t o d o s e , a n d t h i s i n t r o d u c e s a f a c t o r

o f g r e a t u n c e r t a i n t y i n d e t e r m i n i n g t h e L D ^ Q ( L a f u m a e t a l , 1 9 7 4 , 1 9 7 6 ) .

The r e s u l t s i n T a b l e 6 . 5 s h o w t h a t t h e r e a r e l a r g e d i f f e r e n c e s b e t w e e n t h e

e l e m e n t s , t h e t w o e x t r e m e s b e i n g r e p r e s e n t e d b y c u r i u m n i t r a t e a n d

p l u t o n i u m - 2 3 9 d i o x i d e , w i t h a f a c t o r o f 5 * 5 b e t w e e n t h e t w o L D ^ n v a l u e s .

T a b l e 6 . 5

L D ^ Q a t 1 y e a r e s t i m a t e d f o r t h e r a t a f t e r

i n h a l a t i o n o f d i f f e r e n t a c t i n i d e s

Compound A v e r a g e d o s e t o l u n g

a t 1 y e a r ( r a d )

C u r i u m - 2 4 4 n i t r a t e 1 7 0 0

P l u t o n i u m - 2 3 8 d i o x i d e 2 5 0 0

P l u t o n i u m - 2 3 8 n i t r a t e 3 5 0 0

A m e r i c i u m - 2 4 1 d i o x i d e ) 4 0 0 0 - 5 0 0 0

A m e r i c i u m - 2 4 1 n i t r a t e )

P l u t o n i u m - 2 3 9 n i t r a t e 8 5 0 0

P l u t o n i u m - 2 3 9 d i o x i d e 9 5 0 0

Some a u t h o r s h a v e f a i l e d t o p o i n t t o t h e s e d i f f e r e n c e s i n e f f e c t w h i c h

may b e p r o d u c e d e i t h e r b y d i f f e r e n t a c t i n i d e s o r b y d i f f e r e n t i s o t o p e s o f

t h e same e l e m e n t a s f o r e x a m p l e p l u t o n i u m - 2 3 9 d i o x i d e a n d p l u t o n i u m - 2 3 8

d i o x i d e i n r a t s ( S t u a r t e t a l , 1 9 6 8 ) o r i n d o g s ( P a r k e t a l , 1 9 ^ 9 ) • The

r e a s o n s f o r t h i s a r e p r o b a b l y t w o f o l d : f i r s t l y , t h e d i f f e r e n t p u l m o n a r y

c l e a r a n c e r a t e s o f t h e t w o i s o t o p e s w e r e n o t t a k e n i n t o a c c o u n t a n d t h e

d o s e a n d t h e p u l m o n a r y d e p o s i t a t d e a t h w e r e c o n f u s e d i n t r o d u c i n g a l a r g e

f a c t o r o f e r r o r ; s e c o n d l y , t h e s u r v i v a l c u r v e s o n l y t a k e i n t o a c c o u n t e a r l y

e f f e c t s a t v e r y h i g h d o s e s .

An i n t e r s p e c i e s c o m p a r i s o n i s made d i f f i c u l t b y t h e l a c k o f d a t a a t

l o w d o s e s f o r d o g s a n d a b o v e a l l f o r m o n k e y s . F o r d o g s t h a t h a v e i n h a l e d

p l u t o n i u m - 2 3 9 d i o x i d e t h e e x p e r i m e n t a l d a t a c a n b e p l o t t e d o n l o g - l o g

s c a l e t o g i v e a s t r a i g h t l i n e r e l a t i o n s h i p b e t w e e n s u r v i v a l t i m e a n d l u n g

137

d o s e ( P a r k e t a l , 1 9 7 2 ) ( F i g u r e 6 . 8 ) , On t h e o t h e r h a n d , t h e n u m b e r o f

m o n k e y s t h a t h a v e d i e d a f t e r i n h a l a t i o n o f p l u t o n i u m - 2 3 9 i s s m a l l ( 3 5 ) a n d

m o s t o f t h e m d i e d e a r l y w i t h v e r y h i g h p l u t o n i u m b o d y b u r d e n s . M o r e o v e r ,

t h e o b s e r v e d g r e a t n o n - u n i f o r m i t y o f d i s t r i b u t i o n b e t w e e n o n e l u n g a n d

a n o t h e r h a s a n e n o r m o u s d i s t o r t i n g e f f e c t o n t h e r e s u l t s . H o w e v e r , i t d o e s

s e e m t h a t b a b o o n s a r e m o r e s e n s i t i v e t h a n d o g s t o l a r g e l u n g d o s e s , w i t h a

f a c t o r o f r e l a t i v e t o x i c i t y o f a b o u t 2 . 5 ( M e t i v i e r e t a l , 1 9 7 4 ) . The

s u r v i v a l c u r v e o f b a b o o n s a p p r o a c h e s t h a t o f t h e d o g s b y 2 o r 3 y e a r s

a f t e r i n h a l a t i o n a n d i t i s t h e r e f o r e p o s s i b l e t h a t t o x i c d o s e s a d m i n i s t e r e d

o v e r a l o n g p e r i o d p r o d u c e t h e same e f f e c t s o n t h e s u r v i v a l o f d o g s a n d

m o n k e y s ( B r o o k s e t a l , 1 9 7 6 a ) .

A l l t h e a l p h a e m i t t e r s c a n e f f e c t t h e l i f e s p a n , a l t h o u g h t h e r e i s

n o t a n y o b v i o u s c o r r e l a t i o n b e t w e e n t h e s u r v i v a l t i m e a n d t h e f o r m a t i o n o r

n o n - f o r m a t i o n o f c a n c e r s . On t h e o t h e r h a n d , t h e r e s e e m s t o b e a d e f i n i t e

c o r r e l a t i o n , a l b e i t d i f f i c u l t t o q u a n t i f y , b e t w e e n t h e d e g r e e o f l i f e

s h o r t e n i n g a n d t h e t r a n s p o r t a b i l i t y o f t h e e l e m e n t .

Summary

L i f e s p a n s h o r t e n i n g i n a n i m a l s e x p o s e d t o a c t i n i d e s i s a c o m p l e x

p h e n o m e n a i n v o l v i n g many c a u s e s . I t i s r e l a t i v e l y e a s y t o e s t i m a t e

l i f e s p a n s h o r t e n i n g r e s u l t i n g f r o m h i g h d o s e s a n d t o c o m p a r e d o s e s

f r o m v a r i o u s a c t i n i d e s . T h u s i n r a t s e x p o s e d t o c u r i u m - 2 4 4 t h e l u n g

d o s e r e q u i r e d t o p r o d u c e l i f e s p a n s h o r t e n i n g i n o n e y e a r w a s 1 7 0 0 r a d

( 1 7 Gy) b u t 9 5 0 0 r a d ( 9 5 Gy) i n r a t s e x p o s e d t o p l u t o n i u m - 2 3 9 d i o x i d e .

I t i s much m o r e d i f f i c u l t t o e v a l u a t e t h e d o s e s w h i c h r e s u l t i n a

s i g n i f i c a n t l i f e s p a n s h o r t e n i n g w h e n a n u m b e r o f c a u s e s a r e i n v o l v e d .

A c l e a r r e l a t i o n s h i p b e t w e e n l i f e s p a n s h o r t e n i n g a n d t h e i n d u c t i o n o f

c a n c e r s i s n o t a p p a r e n t .

5 . G e n e t i c E f f e c t s

T h e r e h a v e b e e n v e r y f e w e x p e r i m e n t s r e l a t i n g t o t h e p o s s i b l e e f f e c t s

o n h e r e d i t y o r f e r t i l i t y c a u s e d b y p l u t o n i u m o r a n y o t h e r a c t i n i d e s . No

e f f e c t h a s e v e r b e e n d e m o n s t r a t e d a n d t h e r e f o r e n o c o n c l u s i o n s c a n b e d r a w n .

D e s p i t e t h i s t h e p o t e n t i a l c o n s e q u e n c e s o f t h e d e p o s i t i o n o f a c t i n i d e s i n

t h e g o n a d s may b e i n f e r r e d b y c o m b i n i n g i n f o r m a t i o n o n t h e r a d i a t i o n s e n s i -

t i v i t y o f t h e g o n a d s ( C h a p t e r 9 ) w i t h t h e r e s u l t s o f s t u d i e s o n t h e m e t a -

b o l i s m a n d d o s i m e t r y o f a c t i n i d e s i n t h e g o n a d s ( C h a p t e r 4 ) .

6 . Summary a n d C o n c l u s i o n s

E x t e n s i v e a n i m a l s t u d i e d h a v e d e m o n s t r a t e d t h a t b i o l o g i c a l e f f e c t s f r o m

138

1000

100

S 10

1

f= r M I ^ I H J — » i 1 1 1 1 1 1 1 — i i 1 1 i i y

i s , .

O V v

V,' 15 :

YEARS"

^ © PULMONARY FIBROSIS

- • PULMONARY NEOPLASIA • * » ' i i 1 1 1 m l t i i li M i l

10 100 1000 3000

SURVIVAL TIME (DAYS AFTER EXPOSURE) F i g u r e 6.8 R e l a t i o n s h i p b e t w e e n q u a n t i t y o f p l u t o n i u m - 2 3 9 d e p o s i t e d a n d

s u r v i v a l t i m e o f d o g s ( r e d r a w n f r o m P a r k e t a l , 1 9 7 2 ) .

" R e p r o d u c e d f r o m H e a l t h P h y s i c s V o l . 22, p . 805, 1972 , b y

p e r m i s s i o n o f t h e H e a l t h P h y s i c s S o c i e t y . "

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139

i n t a k e s o f a c t i n i d e s may o c c u r p r e d o m i n a n t l y i n t h e l u n g , b o n e , l i v e r ,

b l o o d a n d l y m p h n o d e s . Many o f t h e a n i m a l s t u d i e s o n w h i c h t h e s e

o b s e r v a t i o n s a r e b a s e d h a v e u s e d l e v e l s o f a c t i v i t y t h a t a r e c o n s i d e r -

a b l y i n e x c e s s o f t h o s e t o w h i c h humans may b e e x p o s e d o t h e r t h a n i n

s e v e r e a c c i d e n t s i t u a t i o n s . I t m u s t b e a s s u m e d t h e r e f o r e t h a t t h e

c r i t i c a l t i s s u e s i d e n t i f i e d i n a n i m a l s e x p o s e d t o r e l a t i v e l y l o w d o s e s

o f a c t i n i d e s w i l l b e t h e same a s a f t e r e x p o s u r e t o h i g h d o s e s .

I n a p o p u l a t i o n e x p o s e d t o r a d i a t i o n o t h e r f a c t o r s may

i n f l u e n c e t h e d e v e l o p m e n t o f c a n c e r , I f , f o r e x a m p l e , t h e immune

r e s p o n s e o f i n d i v i d u a l s i s i m p o r t a n t i n t h e p r o d u c t i o n o f a l p h a

r a d i a t i o n i n d u c e d c a n c e r s t h e n t h e d o s e t o i n d i v i d u a l t i s s u e s may n o t

b e t h e o n l y f a c t o r t h a t n e e d s t o b e c o n s i d e r e d w h e n d e f i n i n g r i s k .

M o r e o v e r , o t h e r e n v i r o n m e n t a l f a c t o r s s u c h a s s m o k i n g o r c h e m i c a l

p o l l u t a n t s may h a v e a s y n e r g i s t i c e f f e c t i n t h e p r o d u c t i o n o f n e o -

p l a s t i c g r o w t h s . The o r g a n s t h a t w o u l d b e m o s t l i k e l y t o b e a f f e c t e d

b y s u c h f a c t o r s w o u l d b e t h e l u n g s a n d t h e l i v e r . A l t h o u g h h u m o r a l a n d

e n v i r o n m e n t a l f a c t o r s may i n f l u e n c e t h e d e v e l o p m e n t o f c a n c e r s i n man

t h e r e i s n o i n f o r m a t i o n f r o m w h i c h t h e i r e f f e c t c a n a t p r e s e n t b e

q u a n t i f i e d .

Lung

E a r l y e f f e c t s o f i n h a l e d a c t i n i d e s r e s u l t i n g i n d e a t h w i t h i n a b o u t a

y e a r h a v e b e e n o b s e r v e d i n d o g s a n d r o d e n t s t h a t h a v e i n h a l e d a m o u n t s

o f p l u t o n i u m e q u i v a l e n t t o m o r e t h a n a b o u t 1 0 0 uCi ( 3 « 7 MBq) i n m a n .

T h e s e c h a n g e s i n c l u d e o e d e m a , p n e u m o n i t i s a n d f i b r o s i s . A t l o w e r i n t a k e s

( e q u i v a l e n t t o a b o v e a b o u t 1 jiCi ( 3 7 k B q ) i n man) l u n g c a n c e r s h a v e

b e e n o b s e r v e d a s t h e m a i n l a t e e f f e c t i n t h e l u n g o f i n h a l e d a c t i n i d e s .

I n g e n e r a l c a n c e r s o b s e r v e d i n e x p e r i m e n t a l a n i m a l s h a v e d e v e l o p e d

p r e d o m i n a n t l y i n t h e p e r i p h e r a l r e g i o n s o f t h e l u n g . D i f f e r e n c e s h a v e

b e e n o b s e r v e d i n t h e d o s e - r e s p o n s e r e l a t i o n s h i p s f o r t h e d i f f e r e n t

a c t i n i d e s . I n g e n e r a l a m e r i c i u m a n d c u r i u m d i s t r i b u t e f a i r l y u n i f o r m l y

t h r o u g h o u t t h e l u n g t i s s u e a n d a r e more e f f e c t i v e a t i n d u c i n g c a n c e r

t h a n p l u t o n i u m - 2 3 9 w h i c h i s r e t a i n e d i n t h e l u n g m a i n l y i n l o c a l i s e d

d e p o s i t s .

B l o o d a n d b o n e marrow

C h a n g e s i n c i r c u l a t i n g b l o o d c e l l s h a v e b e e n s e e n i n d o g s a f t e r t h e

i n h a l a t i o n o f v a r i o u s p l u t o n i u m c o m p o u n d s . The m o s t f r e q u e n t c h a n g e

s e e n h a s b e e n a c h r o n i c r e d u c t i o n i n l y m p h o c y t e c e l l c o u n t t h a t o c c u r s

f o l l o w i n g a n i n i t i a l l u n g d e p o s i t e q u i v a l e n t t o m o r e t h a n a b o u t 1 jiCi

lUO

( 3 7 k B q ) i n man. The s i g n i f i c a n c e o f t h i s i s n o t k n o w n . I t m i g h t b e

a n t i c i p a t e d t h a t b e c a u s e a c t i n i d e s d e p o s i t i n t h e s k e l e t o n a n d i n l y m p h

n o d e s t h a t b l o o d s t e m c e l l n e o p l a s i a w o u l d b e a c o n s e q u e n c e o f a c t i n i d e

c o n t a m i n a t i o n . L e u k a e m i a h a s h o w e v e r b e e n f o u n d r a r e l y i n a n i m a l s a n d

a l m o s t e x c l u s i v e l y i n r o d e n t s g i v e n l a r g e a m o u n t s o f a c t i v i t y . B e c a u s e

o f t h e o b s e r v e d i n c r e a s e d i n c i d e n c e o f l e u k a e m i a i n humans e x p o s e d t o

e x t e r n a l r a d i a t i o n t h e b o n e marrow i n man m u s t b e c o n s i d e r e d p o t e n t i -

a l l y a t r i s k f r o m e x p o s u r e t o a c t i n i d e s d e p o s i t e d i n t h e s k e l e t o n .

B o n e a n d l i v e r

B o n e f r a c t u r e s h a v e b e e n o b s e r v e d i n d o g s g i v e n i n t r a v e n o u s i n j e c t i o n s

o f l a r g e d o s e s o f p l u t o n i u m - 2 3 9 ( > 1 jxCi ( 3 7 k B q ) k g " b o d y w t ) . A t

l o w e r d o s e s s t u d i e s i n a n i m a l s h a v e s h o w n t h a t b o n e c a n c e r i s t h e m o s t

f r e q u e n t f o r m o f m a l i g n a n c y i n d u c e d b y a c t i n i d e s t h a t h a v e e n t e r e d t h e

c i r c u l a t i o n . I n g e n e r a l t h e a p p e a r a n c e t i m e o f b o n e c a n c e r s i s

d e p e n d e n t u p o n t h e a m o u n t d e p o s i t e d i n b o n e . A v a r i a t i o n i n s e n s i t i v -

i t y b e t w e e n d i f f e r e n t a n i m a l s p e c i e s h a s b e e n d e m o n s t r a t e d a n d t h e r e

a r e t h e r e f o r e d i f f i c u l t i e s i n e x t r a p o l a t i n g t h e s e r e s u l t s t o man .

L i v e r c a n c e r s h a v e o c c u r r e d i n d o g s g i v e n i n t r a v e n o u s i n j e c t i o n s o f

p l u t o n i u m - 2 3 9 b u t t h e y h a v e o c c u r r e d much l e s s f r e q u e n t l y t h a n b o n e

c a n c e r s . D e s p i t e t h i s t h e l i v e r m u s t b e c o n s i d e r e d p o t e n t i a l l y a t

r i s k i n man.

Lymph n o d e s

Some o f t h e a c t i n i d e s d e p o s i t e d e i t h e r i n t h e l u n g s o r a t a w o u n d s i t e

may b e t r a n s l o c a t e d t o r e g i o n a l l y m p h a t i c t i s s u e . B e c a u s e o f t h e i r

s m a l l m a s s t h e r a d i a t i o n d o s e t o t h e s e n o d e s may g r e a t l y e x c e e d t h a t

t o t h e s i t e o f i n t a k e o r t o o t h e r t i s s u e s . E v i d e n c e f r o m s t u d i e s i n

e x p e r i m e n t a l a n i m a l s s u g g e s t h o w e v e r t h a t t h e o n l y s i g n i f i c a n t damage

t h a t o c c u r s i n t h i s t i s s u e i s f i b r o s i s o r n e c r o s i s a n d t h a t t h e y a r e

n o t a p r i m a r y s i t e f o r t h e d e v e l o p m e n t o f r a d i a t i o n i n d u c e d m a l i g n a n t

d i s e a s e . F o r t h i s r e a s o n l y m p h a t i c t i s s u e s h o u l d n o t b e c o n s i d e r e d a

c r i t i c a l t i s s u e f o r i n t a k e s o f a c t i n i d e s .

O t h e r t i s s u e s

R a d i a t i o n - i n d u c e d c a n c e r s h a v e b e e n o b s e r v e d i n o t h e r t i s s u e s f o l l o w i n g

i n t a k e s o f t r a n s p o r t a b l e f o r m s o f a c t i n i d e s b u t t h e y h a v e o c c u r r e d

i n f r e q u e n t l y i n e a c h t i s s u e a n d n e e d n o t b e c o n s i d e r e d i n d i v i d u a l l y

a s c r i t i c a l t i s s u e s .

G o n a d s

No e v i d e n c e o f h e r e d i t a r y e f f e c t s r e s u l t i n g f r o m t h e i n c o r p o r a t i o n o f

a c t i n i d e s i n t h e g o n a d s h a s b e e n d e m o n s t r a t e d i n a n y o f t h e a n i m a l

s p e c i e s s t u d i e d . E s t i m a t e s o f r a d i a t i o n - i n d u c e d h e r e d i t a r y d i s e a s e s

r e s u l t i n g f r o m t h e d e p o s i t i o n o f a c t i n i d e s i n t h e g o n a d s m u s t t h e r e -

f o r e b e o b t a i n e d b y e x t r a p o l a t i o n f r o m s t u d i e s o f t h e c o n s e q u e n c e s o f

e x p o s u r e t o e x t e r n a l r a d i a t i o n .

I n e s t i m a t i n g t h e r a d i a t i o n e f f e c t s i n a p o p u l a t i o n e x p o s e d t o

a c t i n i d e s e s t i m a t e s o f r i s k c o e f f i c i e n t s a r e t h e r e f o r e r e q u i r e d f o r

r a d i a t i o n i n d u c e d c a n c e r s o f t h e l u n g , b o n e , b o n e marrow a n d l i v e r a n d

f o r r a d i a t i o n i n d u c e d h e r e d i t a r y d i s e a s e s .

Chapter 7

T H E "HOT PARTICLE" PROBLEM

1 . T h e o r e t i c a l B a s i s

A number o f r i s k s a r e a s s o c i a t e d w i t h t h e i n c o r p o r a t i o n o f p l u t o n i u m

a n d o t h e r a c t i n i d e s b y t i s s u e s , t h e f o r e m o s t o f w h i c h i s t h e i n d u c t i o n o f

c a n c e r s ( C h a p t e r s 5 a n d 6 ) . The r i s k o f c a n c e r i s n o r m a l l y l i n k e d w i t h t h e

d o s e r e c e i v e d b y t h e t i s s u e e x p o s e d a n d d e p e n d s u p o n t h e d o s e - r e s p o n s e

r e l a t i o n s h i p . T h e r e a r e many m e t h o d s t h a t h a v e b e e n u s e d i n a n a t t e m p t t o

d e f i n e t h e f o r m o f t h e r e l a t i o n s h i p i n a s p r e c i s e a w a y a s p o s s i b l e .

The l u n g i s a t h i g h r i s k a f t e r t h e i n h a l a t i o n o f p l u t o n i u m d i o x i d e a s

i t i s b o t h a s i t e o f e n t r y a n d a n o r g a n o f l o n g - t e r m r e t e n t i o n ( s e e

C h a p t e r s k a n d 6 ) ( I A E A , 1 9 7 3 ; D u r b i n , 1 9 7 3 ; B a i r e t a l , 1 9 7 3 ; B a i r , 1 9 7 4 b ;

B a i r e t a l , 1 9 7 4 ) * I n v i e w o f t h e c o m p l e x i t y a n d d i v e r s i t y o f t h e m e c h a n -

i s m s c o n t r o l l i n g t h e b e h a v i o u r o f p l u t o n i u m i n t h e l u n g , i t i s d e s i r a b l e

t h a t t h e e s t i m a t i o n o f t h e d o s e d e l i v e r e d t o t h e o r g a n s h o u l d b e b a s e d o n

s i m p l e h y p o t h e s e s . The s i m p l e s t a p p r o a c h c o n s i s t s i n e s t i m a t i n g t h e a v e r a g e

d o s e d e l i v e r e d t o t h e o r g a n a s a w h o l e . A s e c o n d p o s s i b i l i t y i s t o t a k e

i n t o a c c o u n t o n l y t h e d o s e a b s o r b e d b y c e l l s a t t h e s u r f a c e o f t h e r a d i o -

a c t i v e d e p o s i t s . A t h i r d p o s s i b i l i t y , w h i c h l i e s b e t w e e n t h e s e f i r s t t w o ,

i s t o c a l c u l a t e t h e i n t e g r a t e d d o s e t o t h e f r a c t i o n o f t h e v o l u m e o f t h e

o r g a n a s s o c i a t e d w i t h t h e r a d i o a c t i v e d e p o s i t . The l a t t e r m e t h o d may a l s o

b e u s e d f o r a n y o r g a n o t h e r t h a n t h e l u n g , b u t i t b e c o m e s p a r t i c u l a r l y

r e l e v a n t i n t h e c a s e o f i n h a l a t i o n o f p l u t o n i u m i n p a r t i c u l a t e f o r m , s i n c e

i t p r o d u c e s a v e r y d i f f e r e n t r e s u l t t o t h e a v e r a g e l u n g d o s e . The m o s t

e x t r e m e e x a m p l e i s p r o v i d e d b y t h e o x i d e s o f p l u t o n i u m - 2 3 9 o r p l u t o n i u m - 2 3 8 .

F o l l o w i n g t h e i r i n h a l a t i o n t h e l o c a l d e p o s i t i o n o f l a r g e a m o u n t s o f e n e r g y

i n a v e r y s m a l l m a s s o f t i s s u e c o n s t i t u t e s t h e f i r s t damage c a u s e d b y t h e

p a r t i c l e . /

R a d i a t i o n p r o t e c t i o n s t a n d a r d s a r e g e n e r a l l y b a s e d o n t h e t w o h y p o -

t h e s e s : t h a t f o r t h e d e v e l o p m e n t o f c a n c e r s t h e r e i s n o t h r e s h o l d f o r t h e

a c t i o n o f i o n i z i n g r a d i a t i o n s a n d t h a t t h e r e i s a l i n e a r r e l a t i o n s h i p

b e t w e e n d o s e a n d e f f e c t ( ICRP 2 6 , 1 9 7 7 ; UNSCEAR, 1 9 7 2 ) . The a v e r a g e

a b s o r b e d d o s e i s a s t a t i s t i c a l c o n c e p t , a n d d o e s n o t t a k e i n t o a c c o u n t t h e

e n e r g y d i s s i p a t e d i n c e l l s o r g r o u p s o f c e l l s i s o l a t e d i n a n o r g a n . T h i s

f a c t i s c l e a r l y i n c o m p a t i b l e w i t h t h e v e r y c o n c e p t o f a " h o t p a r t i c l e " , a n d

t h i s i s why s e v e r a l m o d i f i c a t i o n s t o d o s e c a l c u l a t i o n s h a v e b e e n s u g g e s t e d

t o t a k e i n t o a c c o u n t t h e n o n - u n i f o r m d i s t r i b u t i o n o f a c t i v i t y i n a n o r g a n .

The c o n c l u s i o n f r o m t h e s e c o n s i d e r a t i o n s i s t h a t t h e c a l c u l a t i o n o f m e a n

lk3

Ikk

d o s e i s c o n s e r v a t i v e (ICRP 9 , 1 9 6 6 ; ICRP 1 i | , 1 9 6 9 ; BEIR, 1 9 7 2 ) . C l e a r l y a

u n i f o r m d i s t r i b u t i o n p r o d u c e s i r r a d i a t i o n o f a much g r e a t e r n u m b e r o f c e l l s

t h a n t h e same a m o u n t o f p l u t o n i u m d i s t r i b u t e d i n a n o n - u n i f o r m m a n n e r ; t h i s

i s p a r t i c u l a r l y t r u e w h e n t h e p a r t i c l e s a r e l a r g e . I t i s c o n c e i v a b l e ,

h o w e v e r , t h a t t h e r a d i o s e n s i t i v i t y o f t h e c e l l s i r r a d i a t e d b y t h e p a r t i c l e s

c o u l d b e g r e a t e r t h a n t h e a v e r a g e r a d i o s e n s i t i v i t y o f t h e c e l l s i n t h e

o r g a n , a n d t h e f r e q u e n c y o f r a d i a t i o n - i n d u c e d c a n c e r s w o u l d t h e r e f o r e

i n c r e a s e f a s t e r t h a n a l i n e a r r e l a t i o n s h i p w i t h d o s e w o u l d i n d i c a t e . I n

t h e c a s e o f t h e l u n g , t h e s e h y p o t h e s e s a r e u n t e n a b l e o w i n g b o t h t o t h e

n a t u r e o f t h e d i s t r i b u t i o n o f p a r t i c u l a t e p l u t o n i u m i n t h e l u n g a n d t o o u r

k n o w l e d g e a b o u t t h e r e l a t i v e s e n s i t i v i t i e s o f d i f f e r e n t c e l l p o p u l a t i o n s

t h a t a r e i n v o l v e d (NCRP N O . 1+6, 1 9 7 5 ) . T h i s i s n o t t h e c a s e w i t h b o n e ,

h o w e v e r , w h e r e p l u t o n i u m i s d e p o s i t e d n e a r t h e s e n s i t i v e c e l l s ( V a u g h a n ,

1 9 7 3 ; V a u g h a n e t a l , 1 9 7 3 ) .

I t i s i n f o r m a t i v e t o c a l c u l a t e t h e p r o p o r t i o n o f t h e l u n g t i s s u e t h a t

i s a f f e c t e d b y a l p h a i r r a d i a t i o n a s a f u n c t i o n o f p a r t i c l e s i z e ( T a b l e 7 - 1 )

( R i c h m o n d , 1 9 7 5 ; B a i r e t a l , 1 9 7 4 ) . I f t h e d i a m e t e r o f t h e p a r t i c l e s o f

p l u t o n i u m - 2 3 9 d i o x i d e i s d i v i d e d b y a f a c t o r o f 1 0 , t h e v o l u m e o f t h e l u n g

d i r e c t l y a f f e c t e d i s i n c r e a s e d b y a f a c t o r o f 1 0 0 0 . F o r a g i v e n p a r t i c l e

s i z e , t h e n u m b e r o f p l u t o n i u m - 2 3 8 d i o x i d e p a r t i c l e s r e s u l t i n g i n a g i v e n

a v e r a g e l u n g d o s e i s l o w e r b y a f a c t o r o f a b o u t 2 5 0 t h a n t h e n u m b e r o f

p l u t o n i u m - 2 3 9 d i o x i d e p a r t i c l e s n e e d e d t o g i v e t h e same d o s e ( o w i n g t o t h e i r

d i f f e r e n t s p e c i f i c a c t i v i t i e s ) ; t h i s i m p l i e s t h a t p l u t o n i u m - 2 3 8 d i o x i d e

p a r t i c l e s i r r a d i a t e a b o u t 1 / 2 5 0 o f t h e n u m b e r o f c e l l s i r r a d i a t e d b y

p l u t o n i u m - 2 3 9 d i o x i d e p a r t i c l e s , b u t a t a much h i g h e r d o s e r a t e . H o w e v e r ,

a s t h e s e t w o i s o t o p e s h a v e i n f a c t d i s s i m i l a r p u l m o n a r y c l e a r a n c e r a t e s ,

t h e c u m u l a t i v e d o s e s r e c e i v e d w i l l a l s o d i f f e r . The f u n d a m e n t a l p r o b l e m

w h i c h i s r a i s e d i s t h e r e f o r e t o e s t i m a t e t h e r i s k o f p u l m o n a r y c a n c e r i n

t e r m s o f t h e e x p o s u r e o f a r e l a t i v e l y s m a l l number o f c e l l s t o f a i r l y h i g h

d o s e r a t e s , t h e t w o p a r a m e t e r s - n u m b e r o f p a r t i c l e s a n d d o s e r a t e - v a r y i n g

i n i n v e r s e p r o p o r t i o n t o o n e a n o t h e r f o r a g i v e n t o t a l l u n g c o n t e n t . T h i s

p r o b l e m s h o u l d o n l y b e c o n s i d e r e d w i t h i n p h y s i o l o g i c a l l i m i t s s i n c e , i n a n

e x t r e m e c a s e , a b u r d e n o f 0 . 0 1 6 jiCi ( 5 9 2 B q ) c a n b e r e p r e s e n t e d b y a

s i n g l e p a r t i c l e o f p l u t o n i u m - 2 3 9 d i o x i d e w i t h a d i a m e t e r o f 3 6 ^m; c l e a r l y ,

t h i s s i z e o f p a r t i c l e i s n o t o n e t h a t Can b e i n h a l e d . On t h e o t h e r h a n d ,

t h i s e x t r e m e e x a m p l e s h o w s t h a t o t h e i ? e l e m e n t s w i t h v e r y h i g h s p e c i f i c

a c t i v i t i e s c a n b e c o n c e n t r a t e d i n a S m a l l n u m b e r o f p a r t i c l e s c o n t a i n i n g

r e l a t i v e l y h i g h l e v e l s o f a c t i v i t y .

Ih5

T a b l e 7 .1

R e l a t i o n s h i p o f p a r t i c l e s i z e t o n u m b e r

o f c e l l s a t r i s k f o r a s t a t i c l u n g

b u r d e n o f 0,016 uCi p l u t o n i u m - 2 3 9 d i o x i d e 8 ,

( B a i r e t a l , 197U; R i c h m o n d , 1 9 7 5 )

P a r t i c l e d i a m e t e r

(pm)

Number o f p a r t i c l e s

A c t i v i t y p e r p a r t i c l e

( p C i )

N o . o f i r r a d i a t e d

c e l l s

P e r c e n t o f l u n g

0.1 5 - 4 x 1 0 7 3 x 1 0 " ^ 3 x 1 0 1 1 30

0 . 3 2 . 0 x 1 0 6 0 . 0 1 1 . 3 x 1 0 1 0 1

0 . 7 1 . 8 x 1 0 5 0 . 0 8 1 . 2 x 1 0 9 0 . 1

1 . 0 5 - 4 x 10h

0 . 3 3 . 6 x 1 0 8 0 . 0 3

A s s u m i n g s t a t i c p a r t i c l e s i n a s t r u c t u r e l e s s human l u n g o f u n i f o r m

d e n s i t y 0 . 2 g cm J w i t h a n a v e r a g e c e l l v o l u m e o f 1 0 ^ an . C e l l s a t r i s k

a r e t a k e n t o b e t h o s e i n a s p h e r e o f r a d i u s e q u a l t o t h e a l p h a r a n g e

( 2 0 0 pm a t t h e a s s u m e d d e n s i t y )

The f i r s t a u t h o r s who e x a m i n e d t h e s e p r o b l e m s c l o s e l y c o n s i d e r e d t w o

o p p o s i n g r e s p o n s e s : a n i n c r e a s e i n t h e f r e q u e n c y o f c a n c e r s p e r i r r a d i a t e d

c e l l w i t h t h e d o s e a n d a r e d u c e d c a p a c i t y f o r c a n c e r o u s c h a n g e s w i t h t h e

l o s s o f r e p r o d u c t i v e c a p a c i t y i n t h e i r r a d i a t e d c e l l s ; t h e t i s s u e r e s p o n s e

w a s t h e r e f o r e t h e c o m b i n a t i o n o f t h e s e t w o f a c t o r s ( D e a n a n d Langham, 1 9 ^ 9 ) •

T h e i r h y p o t h e s i s w a s b a s e d o n s t u d i e s o n t h e p r o d u c t i o n o f b o t h b e n i g n a n d

m a l i g n a n t c u t a n e o u s t u m o u r s f o l l o w i n g i r r a d i a t i o n o f t h e s k i n o f r a t s w h i c h

s h o w e d a c l e a r c o r r e l a t i o n b e t w e e n t h e i n c i d e n c e o f c a n c e r a n d t h e n u m b e r

o f a t r o p h i e d h a i r f o l l i c u l e s ( A l b e r t e t a l , 1 9 6 7 a , 1 9 6 7 b , 1 9 6 7 c ) a n d

s u g g e s t e d t h a t t h e i r r a d i a t i o n o f a s i n g l e c e l l c o u l d g i v e r i s e t o a n

i r r e v e r s i b l e c a n c e r - f o r m a t i o n p r o c e s s . S e v e r a l m o d e l s t h a t d i s r e g a r d t h e

f a c t o r o f c e l l s t e r i l i z a t i o n a r e b a s e d o n t h i s i d e a ; t h e y c o n c l u d e t h a t

t h e r e i s a n i n c r e a s e i n r i s k i n t h e c a s e o f a n o n - u n i f o r m p a r t i c u l a t e

d i s t r i b u t i o n ( G e e s a m a n , 1 9 6 8 ; T a m p l i n a n d C o c h r a n , 1 9 7 U ) • T h e s e b a s i c

h y p o t h e s e s h a v e b e e n v e r y w i d e l y d i s c u s s e d a n d r e f u t e d i n t h e i r e n t i r e t y :

( B a i r e t a l , 1 9 7 U ; H e a l y , 1 9 7 4 ; D o l p h i n e t a l , 1 9 7 4 ; M e d i c a l R e s e a r c h

C o u n c i l , 1 9 7 5 ; A l b e r t e t a l , 1 9 7 6 ) ; f o r e x a m p l e , i t i s c l a i m e d t h a t t h e

r i s k w o u l d d e c r e a s e b y a f a c t o r o f 1 1 5 0 0 0 i f a p a r t i c l e c o n t a i n e d 0 . 1 ^iCi

( 3 . 7 k B q ) o f p l u t o n i u m w e r e t o b e b r o k e n i n t o t w o h a l v e s ( M e d i c a l R e s e a r c h

C o u n c i l , 1 9 7 5 ) .

1U6

The g e n e r a l t h e o r e t i c a l c o n c l u s i o n s c o m p a r i n g t h e r e l a t i v e r i s k s o f

u n i f o r m a n d n o n - u n i f o r m d i s t r i b u t i o n o f p l u t o n i u m i n t h e l u n g r e l a t e t o

s e v e r a l p o i n t s ( A l b e r t e t a l , 1 9 7 6 ) : ( a ) b a s i c f a c t o r s o t h e r t h a n j u s t t h e

d o s e ( e x p r e s s e d i n r a d o r r e m ) m u s t b e i n t r o d u c e d t o e x p l a i n t h e w a y s i n

w h i c h a l p h a p a r t i c l e s a c t o n c e l l s , e s p e c i a l l y w h e n t h e t a r g e t s i t e s a r e

s m a l l i n n u m b e r ; ( b ) t h e c o n c e n t r a t i o n o f a l p h a e m i t t e r s i n p a r t i c l e s

r e s u l t s i n o n l y a l i m i t e d n u m b e r o f c e l l s b e i n g i r r a d i a t e d , i r r e s p e c t i v e o f

t h e t o t a l a c t i v i t y d e p o s i t e d ; ( c ) t h e e x t r a p o l a t i o n o f r e s u l t s o b t a i n e d

f o l l o w i n g t h e i r r a d i a t i o n o f t h e h a i r f o l l i c l e o f t h e r a t t o t h e a n i m a l o r

human l u n g d o e s n o t h a v e a n y s c i e n t i f i c b a s i s ; ( d ) i t h a s n o t b e e n d e m o n -

s t r a t e d t h a t t h e i n d u c t i o n o f c a n c e r s i s i n d e p e n d e n t o f d o s e o r t h a t t h e

c o n c e n t r a t i o n o f d e a d c e l l s i s a c o n t r i b u t o r y f a c t o r i n t h e f o r m a t i o n o f

c a n c e r s ; ( e ) m o d e l s b a s e d o n r a d i o b i o l o g i c a l k n o w l e d g e s u g g e s t t h a t t h e

r i s k o f c a r c i n o g e n e s i s i s h i g h e r i n t h e c a s e o f u n i f o r m d i s t r i b u t i o n t h a n

i t i s i n t h e c a s e o f n o n - u n i f o r m d i s t r i b u t i o n . E x p e r i m e n t a l r e s u l t s a l s o

l e a d t o t h e same c o n c l u s i o n s ( s e c t i o n 2 ) .

A r e c e n t m a t h e m a t i c a l m o d e l , w h i c h t a k e s a c c o u n t o f v a r i o u s p a r a m e t e r s ,

c o m p a r e s t h e c o n v e n t i o n a l m o d e l , w h i c h a v e r a g e s d o s e o v e r t h e w h o l e o f t h e

o r g a n (ICRP P u b l i c a t i o n 9> 1966) , w i t h a m o d e l i n w h i c h t h e r i s k o f c a n c e r -

i n d u c t i o n i s r e l a t e d t o a f u n c t i o n o f t h e d o s e a n d t o t h e l o s s o f r e p r o d u c -

t i v e c a p a c i t y i n i r r a d i a t e d c e l l s ( M a y n e o r d a n d C l a r k e , 1 9 7 6 ) . T h i s c a n

o n l y b e a n a p p r o x i m a t i o n , s i n c e t h e m o v e m e n t s o f p a r t i c l e s i n s i d e t h e l u n g

a r e v e r y l i t t l e u n d e r s t o o d a n d t h e s l i g h t e s t m o v e m e n t o f a p a r t i c l e m a k e s

t h e d o s e c o n s i d e r a b l y m o r e u n i f o r m t h a n f o r a s t a t i o n a r y p a r t i c l e . I n t h e

m o d e l t h e e f f e c t s o f h i g h - r e n e r g y p a r t i c l e s m o v i n g r a p i d l y a r e a s s u m e d t o b e

i d e n t i c a l t o t h o s e o f l o w - e n e r g y p a r t i c l e s m o v i n g s l o w l y . No a c c o u n t i s

t a k e n o f t h e r e s p i r a t o r y m o v e m e n t s o f t h e a l v e o l i t h a t make t h e

d i s t r i b u t i o n o f d o s e m o r e u n i f o r m . A p a r t f r o m t h e s e r e s e r v a t i o n s ,

t h i s m o d e l g e n e r a l l y a r r i v e s a t c o n c l u s i o n s i d e n t i c a l t o t h o s e o f t h e

c l a s s i c a l m o d e l s : e s t i m a t i n g r i s k w i t h t h e h e l p o f t h e m e a n d o s e g i v e s t h e

b e s t e s t i m a t e o f t h e u p p e r r i s k l i m i t . I n e x c e p t i o n a l d i s t r i b u t i o n c a s e s

w h e n a l a r g e p r o p o r t i o n o f t h e c e l l s a r e e x p o s e d t o d o s e s i n t h e r e g i o n o f

t h e p e a k o f t h e d o s e - r e s p o n s e c u r v e t h e r i s k may b e u n d e r e s t i m a t e d b y u p t o

a f a c t o r o f $ .

2. E x p e r i m e n t a l A s p e c t s

T h e r e a r e a n u m b e r o f e x p e r i m e n t s w h i c h a l l o w t h e l o c a l e f f e c t s o f a

n o n - u n i f o r m d i s t r i b u t i o n o f a n a l p h a e m i t t e r i n t i s s u e t o b e c o m p a r e d w i t h

t h o s e o f a u n i f o r m d i s t r i b u t i o n o f a n e q u i v a l e n t a m o u n t o f a c t i v i t y .

M o s t a u t h o r s a r e a g r e e d t h a t r e s u l t s o b t a i n e d f r o m i r r a d i a t i o n o f t h e

s k i n c a n n o t b e e x t r a p o l a t e d t o t h e l u n g o r a n y o t h e r o r g a n b e c a u s e o f

d i f f e r e n c e s i n t h e s e n s i t i v i t y o f o r g a n s t o i r r a d i a t i o n ( A l b e r t , 1 9 6 7 a ,

1 9 6 7 b , 1 9 6 7 c ; B a i r e t a l , 1 9 7 4 ; NCRP, 1 9 7 5 ) .

The o n l y e x p e r i m e n t s t o b e c o n s i d e r e d a r e t h o s e t h a t d e a l w i t h a h i g h -

r i s k o r g a n c o n t a m i n a t e d b y a n a l p h a e m i t t e r , a l t h o u g h c e r t a i n e x p e r i m e n t s

c o n d u c t e d w i t h b e t a e m i t t e r s a r e r e l e v a n t t o t h e p r o b l e m ( C e m b e r a n d W a t s o n ,

1 9 5 8 a , 1 9 5 8 b ; Cember e t a l , 1 9 5 9 ; C e m b e r , 1 9 6 4 a , 1 9 6 4 b ) .

P o l o n i u m - 2 1 0 i s a g o o d e x p e r i m e n t a l t o o l , f o r i t c a n e x i s t i n a n

e x t r e m e l y s o l u b l e f o r m o r , o n t h e o t h e r h a n d , b e made i n s o l u b l e b y , f o r

e x a m p l e , f i x a t i o n o n i n e r t p a r t i c l e s o f h a e m a t i t e , ( P e g 0 ^ ) ( L i t t l e e t a l ,

1 9 7 0 a , 1 9 7 0 b ; G r o s s m a n e t a l , 1 9 7 1 ; L i t t l e e t a l , 1 9 7 3 ) . The e x p e r i m e n t s

a r e n o t s t r i c t l y c o m p a r a b l e a s t h e v e r y d i f f e r e n t c l e a r a n c e r a t e s f r o m t h e

l u n g o f t h e t w o f o r m s t h a t a r e b e i n g c o m p a r e d , r e s u l t i n q u i t e d i f f e r e n t

d o s e r a t e s f o r a g i v e n a m o u n t a d m i n i s t e r e d . H o w e v e r , c l e a r c o n c l u s i o n s c a n

b e d r a w n f r o m t h e s e s t u d i e s ; a l p h a i r r a d i a t i o n o f t h e l u n g i s m o r e c a r c i n o -

g e n i c w h e n t h e d o s e i s d e l i v e r e d i n a r e l a t i v e l y u n i f o r m f a s h i o n t o a l a r g e

p a r t o f t h e o r g a n t h a n w h e n t h e same a c t i v i t y i s d e p o s i t e d i n a n o n - u n i f o r m

f a s h i o n w i t h h i g h d o s e r a t e s d e l i v e r e d t o s m a l l v o l u m e s . T h i s d i f f e r e n c e

h o w e v e r d i s a p p e a r s a t q u i t e l o w d o s e s o f t h e o r d e r o f a f e w t e n s o f r a d

( L i t t l e a n d O ' T o o l e , 1 9 7 4 ) .

T r a n s t h o r a c i c i n j e c t i o n s o f p l u t o n i u m - 2 3 9 d i o x i d e i n r a t s d e l i v e r e d

l i f e s p a n d o s e s o f 2 0 0 0 0 0 r a d ( 2 0 0 0 Gy) t o 1 0 % o f t h e l u n g w h e n t h e i n j e c t e d

a c t i v i t y ( 0 . 7 ^Ci ( 2 6 k B q ) ) w a s d i s t r i b u t e d i n 1 0 0 mg o f p u l m o n a r y p a r e n -

chyma ( S a n d e r s a n d P a r k , 1 9 7 1 ) . The i n c i d e n c e o f p u l m o n a r y c a n c e r s w a s

h i g h : 5 o u t o f 1 6 i n s o m e t h i n g o v e r a y e a r . T h i s r e s u l t c a n n o t b e c o m p a r e d

w i t h t h e r e s p o n s e t o t h e same d o s e d i s t r i b u t e d t h r o u g h o u t t h e l u n g f o r

2 0 0 0 0 r a d ( 2 0 0 Gy) ( a l p h a ) w o u l d r e s u l t i n d e a t h f r o m f i b r o s i s i n l e s s t h a n

t h r e e m o n t h s . T h i s e x p e r i m e n t i s t h e o n l y o n e d e m o n s t r a t i n g t h e i n d u c t i o n

o f c a n c e r s w i t h l o c a l i s e d s o u r c e s d e l i v e r i n g v e r y h i g h d o s e r a t e s .

I n o r d e r t o c o m p a r e t h e e f f e c t s o f v a r y i n g a m o u n t s o f a c t i v i t y

d i s t r i b u t e d i n a v a r y i n g n u m b e r o f e m i t t i n g s o u r c e s , r e p r o d u c i n g e x p e r i m e n t -

a l l y t h e c o n d i t i o n s i n T a b l e 7 . 1 > i n t r a v e n o u s i n j e c t i o n s o f c a l i b r a t e d

s p h e r e s ( 1 0 i n d i a m e t e r ) w e r e made i n s u c h a w a y t h a t t h e y b e c a m e f i x e d

i n t h e p u l m o n a r y c a p i l l a r i e s ; t h e v a r i a b l e p a r a m e t e r s a r e t h e a c t i v i t y p e r

u n i t o f t h e m i c r o s p h e r e s , t h e i r n u m b e r , t h e i s o t o p e o f p l u t o n i u m u s e d a n d ,

c o n s e q u e n t l y , t h e a c t i v i t y d e p o s i t e d i n t h e l u n g a n d t h e p r o p o r t i o n o f t h e

l u n g a f f e c t e d ( R i c h m o n d , 1 9 7 5 ; S m i t h e t a l , 1 9 7 5 ? A n d e r s o n e t a l , 1 9 7 4 a ,

1 U 8

1 9 7 U h ) . A l l t h e e x p e r i m e n t s made w i t h t h e s e m i c r o s p h e r e s i r r a d i a t e b e t w e e n

1 a n d 3% o f t h e l u n g a n d c o r r e s p o n d t o d e p o s i t i o n s o f b e t w e e n 0 . 1 1 ; a n d

3 5 6 n C i ( 5 . 2 a n d 1 3 - 2 x 1 0 ^ B q ) ; t h e d o s e d e l i v e r e d t o t h e p o r t i o n o f t h e

l u n g t h a t i s i r r a d i a t e d i s 1 . 3 x 1 0 - 5 t o 1 0 r a d ( 1 . 3 x 1 0 t o 1 0 4 Gy) p e r

y e a r o r , i f i t i s e x p r e s s e d i n r e l a t i o n t o t h e w h o l e o f t h e l u n g , 1 3 t o

3 3 0 0 0 r a d ( 0 . 1 3 t o 3 3 0 G y ) . I n n o n e o f t h e s e e x p e r i m e n t s w a s t h e i n c i d e n c e

o f c a n c e r s i g n i f i c a n t l y h i g h e r t h a n t h a t o b s e r v e d i n t h e v a r i o u s c o n t r o l s ,

o f w h i c h some h a d n e v e r b e e n i n j e c t e d a n d o t h e r s h a d b e e n i n j e c t e d w i t h

i n e r t m i c r o s p h e r e s i n a m o u n t s e q u i v a l e n t t o t h o s e o f t h e e x p e r i m e n t a l

a n i m a l s . M o r e o v e r , t h e l i f e o f t h e a n i m a l s i s a p p a r e n t l y n o r m a l . When a

much l a r g e r p r o p o r t i o n o f t h e l u n g i s i r r a d i a t e d (36%) w i t h t h e same m i c r o -

1 1

s p h e r e s , a t a d o s e o f 1 3 0 0 0 r a d y " ( 1 3 0 Gy y " ) ( 7 0 0 0 0 s p h e r e s ) , t h e r e i s

a n a p p r e c i a b l e i n c r e a s e i n t h e i n c i d e n c e o f p u l m o n a r y c a n c e r ( 1 0 % ) ( T h o m a s ,

1 9 7 7 ) . I n c o n t r a s t t o t h i s , n o p a t h o l o g i c a l e f f e c t h a s b e e n o b s e r v e d i n

r a t s a f t e r t h e i n t r a v e n o u s i n j e c t i o n o f p a r t i c l e s o f p l u t o n i u m - 2 3 8 d i o x i d e

o f v e r y l a r g e d i a m e t e r ( 1 8 0 pm) w h i c h h a v e b e c o m e l o d g e d i n t h e p u l m o n a r y

—1 —1 c a p i l l a r i e s a n d d e l i v e r a d o s e r a t e c a l c u l a t e d a t 3 * 5 rem h ( 3 5 mSv h " , a s s u m i n g RBE f o r a l p h a r a d i a t i o n = 1 0 ) ( R i c h m o n d e t a l , 1 9 7 0 ) . The d o s e

8 —1 6 1 r a t e a t t h e s u r f a c e o f t h e p a r t i c l e , w h i c h i s a b o u t 1 0 r a d h~" ( 1 0 Gy h " )

w o u l d c o r r e s p o n d , i f a v e r a g e d o v e r t h e w h o l e o f t h e l u n g , t o a b o u t 2 x 1 0 ^

r a d ( 2 x 1 0 ^ G y ) i n t w o y e a r s . I t i s d i f f i c u l t t o u n d e r s t a n d why n o e f f e c t

h a s b e e n o b s e r v e d , a p a r t f r o m m i c r o l e s i o n s w i t h t o t a l c e l l u l a r d e g e n e r a t i o n

i n t h e i m m e d i a t e v i c i n i t y o f t h e p a r t i c l e ; h o w e v e r , t h e s e m i c r o l e s i o n s do

n o t c o r r e s p o n d t o n e c r o t i c s t a t e s , f o r t h e c o l l a g e n i n t h e m i s c o n s t a n t l y

b e i n g r e n e w e d . The same r e s u l t s h a v e b e e n o b s e r v e d i n d o g s ( R i c h m o n d e t a l ,

1 9 7 4 ) . A l l t h e s e e x p e r i m e n t s t h a t a r e b a s e d o n t h e i n t r a v e n o u s i n j e c t i o n

o f c a l i b r a t e d s p h e r e s t e n d t o i n d i c a t e t h a t t h e f r e q u e n c y o f l o c a l l y -

i n d u c e d c a n c e r s v a r i e s i n i n v e r s e p r o p o r t i o n t o t h e d e g r e e o f n o n - u n i f o r m i t y ,

a s s u m i n g t h a t t h e r e i s a d i r e c t r e l a t i o n s h i p b e t w e e n t h e i n d u c t i o n o f

c a n c e r s a n d t h e m a s s o f t i s s u e d i r e c t l y e x p o s e d t o r i s k . The m a i n c r i t i c i s m

t h a t c a n b e made o f t h i s s e r i e s o f e x p e r i m e n t s i s t h a t t h e y a r e u n r e a l i s t i c ,

f o r t h e y f a i l c o m p l e t e l y t o r e p r o d u c e t h e b a s i c c o n d i t i o n s o f c o n t a m i n a t i o n

a s t h e i r r a d i a t i n g p a r t i c l e s a r e t r a p p e d i n t h e p u l m o n a r y c a p i l l a r i e s .

H o w e v e r , a s r e g a r d s t h e r e s u l t i n g e f f e c t , i t w o u l d a p p e a r t o b e i r r e l e v a n t

w h e t h e r t h e c e l l i s i r r a d i a t e d f r o m t h e a i r s p a c e s ( a s i n c o n t a m i n a t i o n b y

i n h a l a t i o n ) , o r f r o m t h e b l o o d ( a s w i t h m i c r o s p h e r e s i n j e c t e d i n t r a v e n o u s l y ) .

The g r e a t e s t d i f f e r e n c e t h a t may b e n o t e d b e t w e e n t h e t w o e x p e r i m e n t a l

m e t h o d s c o n c e r n s t h e m o b i l i t y o f t h e p a r t i c l e i n t h e c a s e o f i n h a l a t i o n a n d

i t s l a c k o f m o v e m e n t i n t h e c a s e o f i n t r a v e n o u s i n j e c t i o n . I f t h i s i s t h e

b a s i c r e a s o n f o r t h e p a u c i t y o f p a t h o l o g y o b s e r v e d a f t e r t h e i n j e c t i o n o f

Ik9

m i c r o s p h e r e s , t h e n t h e n u m b e r o f i r r a d i a t e d c e l l s b e c o m e s a v e r y i m p o r t a n t

f a c t o r . I t i s a l s o p o s s i b l e t h a t t h e c e l l s w h i c h g i v e r i s e t o l u n g c a n c e r s

a r e n o t b e i n g i r r a d i a t e d .

F o r t h e s e r e a s o n s some o f t h e m o s t r e l e v a n t e x p e r i m e n t s a r e t h o s e w h i c h

d e a l w i t h v e r y u n i f o r m p u l m o n a r y d e p o s i t i o n s , a n d n o t w i t h n o n - u n i f o r m

p a r t i c u l a t e d e p o s i t i o n s , w h a t e v e r s i d e o f t h e a l v e o l a r w a l l t h e y may b e .

One o f t h e m o s t r e p r e s e n t a t i v e e x p e r i m e n t s d e a l s w i t h the . i n h a l a t i o n b y

r a t s o f f i n e l y c r u s h e d m i c r o s p h e r e s o f p l u t o n i u m - 2 3 8 d i o x i d e ( 7 2 % u l t r a -

f i l t e r a b l e , CMD 0 . 0 2 ) ( S a n d e r s , 1 9 7 2 ; 1 9 7 3 ) ; "the r e s u l t i n g d i s t r i b u t i o n i n

t h e p u l m o n a r y t i s s u e i s o n e o f t h e m o s t u n i f o r m t h a t c a n a t p r e s e n t b e

p r o d u c e d e x p e r i m e n t a l l y w i t h a n o x i d i z e d f o r m o f p l u t o n i u m .

T h e r e i s n o d o u b t t h a t t h e h i g h e s t n u m b e r o f p u l m o n a r y c a n c e r s i s

o b t a i n e d w i t h t h i s f i n e l y d i s p e r s e d f o r m a n d a t v e r y l o w l e v e l s o f a c t i v i t y :

6.6% a t 9 r a d ( 0 . 0 9 Gy) ( d e p o s i t i o n o f 5 n C i ( 1 8 5 B q ) ) , 2 3 . 2 % a t 3 2 r a d

( 0 . 3 2 G y ) ( 1 8 n C i (666 B q ) ) . The f l n o r m a l M f r e q u e n c i e s o b t a i n e d w i t h

p l u t o n i u m - 2 3 8 d i o x i d e a r e o f t h e o r d e r o f a f e w p e r c e n t u p t o a b o u t 1 0 0 r a d

( 1 G y ) a n d i n o r d e r t o o b t a i n f r e q u e n c i e s a l o t h i g h e r t h a n 1 0 o r 20%

l e v e l s o f 1 0 0 0 r a d ( 1 0 Gy) o r more h a v e t o b e r e a c h e d ( C h a p t e r 6 ) . The

c o m b i n a t i o n o f t h e t w o e f f e c t s , t h e i n d u c t i o n o f p u l m o n a r y c a n c e r s a n d t h e

s h o r t e n i n g o f t h e l i f e s p a n , i n s o f a r a s t h e y a r e n o t a s s o c i a t e d w i t h o n e

a n o t h e r , c a n o b v i o u s l y m i n i m i z e t h e e f f e c t i n t h e c a s e o f p a r t i c l e i n h a l a -

t i o n . T h i s p o i n t w a s d i s c u s s e d i n C h a p t e r 6, p a r a g r a p h s 3 - 1 a n d 3 * 4 . T h i s

e x p e r i m e n t u s i n g m i c r o s p h e r e s o f p l u t o n i u m - 2 3 8 d i o x i d e i s e s p e c i a l l y

i m p o r t a n t a l t h o u g h i t i s n o t t y p i c a l o f p l u t o n i u m c o n t a m i n a t i o n , e v e n w h e n

i t i s i n h a l e d i n t h e f o r m o f c i t r a t e o r n i t r a t e s o l u t i o n s . I n f a c t , e v e n

u n d e r t h e n o r m a l c o n d i t i o n s o f r e s p i r a t o r y c o n t a m i n a t i o n b y t h e f o r m s t h a t

a r e c o n s i d e r e d s o l u b l e , p l u t o n i u m i s n e v e r d i s t r i b u t e d i n a p e r f e c t l y u n i -

f o r m f a s h i o n i n t h e l u n g a s r a p i d f o r m a t i o n o f h y d r o x i d e s a s s o c i a t e d w i t h

a r a p i d r i s e o f t h e pH r e s u l t s i n p a r t i c l e f o r m a t i o n . D e p o s i t i o n s

o c c u r r i n g i n t h i s w a y l e a d t o h i g h l o c a l d o s e s , f a r e x c e e d i n g t h e d o s e

a v e r a g e d o v e r t h e t o t a l l u n g ( M o s k a l e v , 1 9 7 2 ) . More s o l u b l e a c t i n i d e s a r e

m o r e u n i f o r m l y d i s t r i b u t e d t h r o u g h o u t t h e l u n g . T h i s i s t r u e f o r e x a m p l e

o f r e s u l t s w i t h a m e r i c i u m - 2 1 + 1 > c u r i u m - 2 l i U * e i n s t e i n i u m - 2 5 3 > e v e n i n t h e i r

o x i d i z e d f o r m s ( C h a p t e r s 2 a n d i i ) . F o r t h i s r e a s o n a n a n a l y s i s o f t h e

r e s u l t s o b t a i n e d w i t h r e l a t i v e l y t r a n s p o r t a b l e a c t i n i d e s a s s u m e s s p e c i a l

i m p o r t a n c e . A c o m p a r i s o n w i t h p l u t o n i u m i s n o t w h o l l y v a l i d , f o r t w o

v a r i a b l e s a r e i n v o l v e d : f i r s t l y , a f a i r l y u n i f o r m d i s t r i b u t i o n , a n d

s e c o n d l y , c l e a r a n c e r a t e s t h a t v a r y f r o m o n e e l e m e n t t o a n o t h e r a n d s o

p r o d u c e v a r i a t i o n s i n t h e d o s e r a t e s ( f o r a g i v e n d o s e r e c e i v e d ) . The t w o

150

f o r m s o f a m e r i c i u m , o x i d e a n d n i t r a t e , p r o d u c e h i g h f r e q u e n c i e s o f l u n g

c a n c e r , i e , amer i c ium-2 l4 .1 n i t r a t e : a b o u t 20% f o r 5 0 0 r a d ( 5 G y ) a n d 80% f o r

l e s s t h a n 2 5 0 0 r a d ( 2 $ G y ) ; f o r a m e r i c i u m - 2 1 + 1 d i o x i d e : t h e r e s p o n s e o c c u r s

a t much l o w e r l e v e l s , 50% f o r l e s s t h a n 5 0 0 r a d ( 5 G y ) , 70% f o r 1 ^ 0 0 r a d

0 5 Gy) ( L a f u m a e t a l , 1 9 7 5 , 1 9 7 6 ; M o r i n e t a l , 1 9 7 6 , 1 9 7 7 ) . The h i g h

r a d i o t o x i c i t y i n o t h e r r a t t i s s u e s o f c u r i u m a n d e i n s t e i n i u m ( T a b l e 6 . 2 )

may a c c o u n t f o r t h e l o w e r f r e q u e n c i e s o f l u n g c a n c e r o b s e r v e d w i t h t h e s e

e l e m e n t s ( L a f u m a e t a l , 1 9 7 5 ; B a l l o u e t a l , 1 9 7 5 ) ; h o w e v e r , f o r a m e r i c i u m -

2l+1 t h e f r e q u e n c y o f p u l m o n a r y c a n c e r s i s h i g h e r a n d p e a k - f r e q u e n c y i s

o b t a i n e d a t a p p r e c i a b l y s m a l l e r d o s e s t h a n i n t h e c a s e o f t h e i n s o l u b l e

f o r m s o f p l u t o n i u m . The s h o r t h a l f - l i f e o f e i n s t e i n i u m - 2 5 3 a n d i t s r a p i d

d i f f u s i b i l i t y make a c o m p a r i s o n w i t h t h i s e l e m e n t v e r y d i f f i c u l t .

The c o m b i n a t i o n o f t h e r e s u l t s o f t h e s e many e x p e r i m e n t a l r e s e a r c h

p r o j e c t s u s i n g v e r y d i f f e r e n t a p p r o a c h e s a n d t e c h n i q u e s , g i v e s g r o u n d s f o r

t h i n k i n g t h a t d e p o s i t i o n i n t h e l u n g o f i n s o l u b l e a l p h a - e m i t t i n g p a r t i c l e s

d o e s n o t p r e s e n t a g r e a t e r r i s k o f l u n g c a n c e r t h a n d e p o s i t i o n o f t h e same

a l p h a a c t i v i t y d i s t r i b u t e d i n a m o r e u n i f o r m f a s h i o n i n t h e p u l m o n a r y

p a r e n c h y m a ( A l b e r t e t a l , 1 9 7 6 ; B a i r e t a l , 1 9 7 U ; NCRP U 6 , 1 9 7 5 ; D o l p h i n

e t a l , 1 9 7 J + ; M . R . C . , 1 9 7 5 ; I CEP 1 1 + , 1 9 6 9 ; M o s k a l e v , 1 9 7 2 ; Lafuma e t a l ,

1 9 7 5 ; M o r i n e t a l , 1 9 7 7 ) .

3 . O b s e r v a t i o n s o n Man

The number o f w o r k e r s e x p o s e d t o p l u t o n i u m o r t o t r a n s u r a n i u m e l e m e n t s

i s more t h a n s e v e r a l t h o u s a n d t h r o u g h o u t t h e w o r l d . A c e r t a i n p r o p o r t i o n

o f t h i s n u m b e r h a s i n c o r p o r a t e d a p p r e c i a b l e q u a n t i t i e s o f t h e s e a c t i n i d e s ,

s o m e t i m e s w i t h d o s e l e v e l s h i g h e r t h a n t h e s t a t u t o r y l i m i t s ; t h e t i m e t h a t

h a s e l a p s e d s i n c e c o n t a m i n a t i o n h a s i n many c a s e s b e e n m o r e t h a n 2 5 y e a r s

a n d a l l o w s c e r t a i n c o n c l u s i o n s t o b e d r a w n .

Some g r o u p s o f c o n t a m i n a t e d w o r k e r s a r e w e l l known ( R o s s , 1 9 6 8 ;

Hempelmann e t a l , 1 9 7 3 , 1 9 7 U ; B a i r e t a l , 1 9 7 U ; S c h o f i e l d a n d D o l p h i n ,

1 9 7 U ) • The g r o u p w h i c h h a s b e e n s t u d i e d m o s t i s t h a t o f t w e n t y - f i v e w o r k e r s

o n t h e " M a n h a t t a n P r o j e c t " ( C h a p t e r 3 ) - Of t h e s e 2 5 w o r k e r s , 11+ s t i l l h a v e

i n t e r n a l d e p o s i t i o n s o f p l u t o n i u m - 2 3 9 a m o u n t i n g t o b e t w e e n 0 . 0 0 5 a n d O.k +iCi

( 0 . 2 a n d 1 5 k B q ) a b o u t t h i r t y y e a r s a f t e r c o n t a m i n a t i o n . B a i r e t a l , ( 1 9 7 U )

h a v e c o m p a r e d t h e n u m b e r o f c a n c e r s a r r i v e d a t b y t h e v a r i o u s t h e o r e t i c a l

c a l c u l a t i o n s a n d t h e n u m b e r t h a t h a v e a c t u a l l y b e e n o b s e r v e d : ( a ) b a s e d o n

U . S . a g e s p e c i f i c m o r t a l i t y d a t a t h e number o f c a n c e r s e x p e c t e d i n t h i s

g r o u p w o u l d b e O . 7 6 f o r t h e l u n g , 0 . 1 5 f o r t h e l i v e r , 0 . 0 U f o r t h e b o n e ;

( b ) t h e n u m b e r , o n t h e p e s s i m i s t i c a s s u m p t i o n o f a r i s k e q u a l t o 5 x 1 0 ^

151

p e r p a r t i c l e ( T a m p l i n a n d C o c h r a n , 1 9 7 4 ) a n d a s s u m i n g 1 $ % o f t h e m a s s o f

t h e l u n g t o b e a f f e c t e d b y t h e p a r t i c l e s , w o u l d b e 2 0 0 m a l i g n a n t t u m o u r s

p e r i n d i v i d u a l , o r 5 0 0 0 i n t h e g r o u p ; ( c ) t h e n u m b e r o f c a n c e r s , o n t h e

same a s s u m p t i o n s b u t o n l y t a k i n g i n t o a c c o u n t t h e q u a n t i t i e s o f p l u t o n i u m

p r e s e n t i n t h e l u n g 30 y e a r s a f t e r c o n t a m i n a t i o n , w o u l d s t i l l b e 3 p e r

p e r s o n ; ( d ) t h e a c t u a l n u m b e r o b s e r v e d i n m o r e t h a n 30 y e a r s i s n i l .

A l t h o u g h n e g a t i v e r e s u l t s s h o u l d a l w a y s b e a n a l y s e d w i t h t h e g r e a t e s t c a r e ,

i t d o e s s e e m t h a t i f r a d i a t i o n f r o m p a r t i c u l a t e f o r m s o f p l u t o n i u m w a s

e x c e p t i o n a l l y h a z a r d o u s , some m a l i g n a n c i e s w o u l d a l r e a d y h a v e m a n i f e s t e d

t h e m s e l v e s .

A t u m o u r a l l e s i o n a r i s i n g f r o m c o n t a c t w i t h a c h i p o f m e t a l l i c

p l u t o n i u m b u r i e d i n t h e h a n d o f a w o r k e r h a s b e e n c l a s s i f i e d a s a " p r e -

c a n c e r o u s " s t a t e ( T a m p l i n a n d C o c h r a n , 1 9 7 4 ) ; t h e d o s e a r o u n d t h i s p i e c e

o f m e t a l w a s v e r y h i g h , b e i n g e s t i m a t e d a t 7 5 x 1 0 ^ r a d ( 7 5 x 1 0 ^ G y ) i n

a l i t t l e m o r e t h a n 4 y e a r s ( L u s h b a u g h e t a l , 1 9 & 2 , 1 9 ^ 7 ) . The e x c i s i o n o f

t h e l e s i o n w a s n o t f o l l o w e d b y a n y o f t h e s e c o n d a r y m a n i f e s t a t i o n s t h a t a r e

u s u a l w i t h c a n c e r o u s l e s i o n s . I n f a c t , t h i s u n i q u e c a s e , i n s o f a r a s i t i s

o n e o f a r e a l p r e - c a n c e r o u s c h a n g e , d o e s n o t p r o v i d e a n y p r e c i s e i n f o r m a t i o n :

t h e c o n c e p t o f r a d i a t i o n - i n d u c e d c a n c e r d o e s n o t n e e d f u r t h e r s u p p o r t i n g

a r g u m e n t s ; i n n o w a y d o e s t h i s human e x a m p l e d e m o n s t r a t e t h a t p l u t o n i u m i n

p a r t i c u l a t e f o r m i s p a r t i c u l a r l y d a n g e r o u s .

4 - Summary

W i t h t h e a i d o f a l l t h e r e c e n t d a t a f r o m v a r i o u s s o u r c e s i t i s e a s y t o

r e f u t e t h e a n a l y s e s o f e x p e r i m e n t s o r o f t h e o r e t i c a l s t u d i e s t n a t

t e n d t o t h e c o n c l u s i o n t h a t t h e r e i s a p a r t i c u l a r l y h i g h r i s k f r o m

n o n - u n i f o r m d i s t r i b u t i o n o f p l u t o n i u m i n t h e l u n g a s c o m p a r e d w i t h

u n i f o r m d i s t r i b u t i o n . The p r o b a b i l i t y t h a t a m a l i g n a n t t u m o u r w i l l

o c c u r i n a t i s s u e d e p e n d s o n t h e v o l u m e o f t h e i r r a d i a t e d t i s s u e a n d

h e n c e o n t h e n u m b e r o f c e l l s d i r e c t l y e x p o s e d t o r i s k w i t h o u t p r e -

j u d g i n g t h e m e c h a n i s m s i n i t i a t i n g a n d p r o m o t i n g t h e c a n c e r o u s p r o c e s s .

T h i s f a c t o r i s r e l a t e d t o t h e w a y i n w h i c h t h e a l p h a e m i t t e r i s

d i s p e r s e d i n t h e o r g a n . N o t o n l y d o e s i t a p p e a r t h a t t h e l o c a l r i s k

o f c a n c e r - f o r m a t i o n i s n o g r e a t e r i n t h e c a s e o f i n h a l a t i o n o f

a c t i n i d e s d i s t r i b u t e d i n a f i n i t e n u m b e r o f " h o t p a r t i c l e s " t h a n

i t i s i n t h e c a s e o f i n h a l a t i o n o f a d i s p e r s e d f o r m d i s t r i b u t e d i n a

l e s s h e t e r o g e n e o u s o r , i n d e e d , w h o l l y u n i f o r m w a y , b u t i t a l s o s e e m s

t h a t t h i s r i s k may b e s m a l l e r .

Chapter 8

T R E A T M E N T FOR ACCIDENTAL INTAKES

1 . I n t r o d u c t i o n

T r e a t m e n t s t h a t may b e u s e d t o a c c e l e r a t e t h e r a t e o f e l i m i n a t i o n o f

a c t i n i d e s f r o m t h e b o d y d e p e n d c o n s i d e r a b l y u p o n t h e s i t e o f d e p o s i t i o n ,

t h e p h y s i c o - c h e m i c a l f o r m i n v o l v e d a n d i n p a r t i c u l a r w h e t h e r t h e m a t e r i a l

i s s o l u b l e ( e g , p l u t o n i u m n i t r a t e o r c i t r a t e ) o r i n s o l u b l e ( e g , p l u t o n i u m

d i o x i d e ) •

2 . T r e a t m e n t f o r i n t a k e s o f i n s o l u b l e f o r m s o f a c t i n i d e s

2 . 1 D e p o s i t s i n t h e l u n g

F o l l o w i n g t h e a c c i d e n t a l i n h a l a t i o n o f p l u t o n i u m d i o x i d e a n y p a r t i c l e s

d e p o s i t e d i n t h e u p p e r r e g i o n s o f t h e l u n g s a r e r a p i d l y c l e a r e d u p t h e

c i l i a r y e s c a l a t o r . Any p a r t i c l e s r e m a i n i n g i n t h e l u n g s a f t e r t h i s e a r l y

c l e a r a n c e p h a s e a r e m a i n l y a c c u m u l a t e d b y m a c r o p h a g e s . Any t r e a t m e n t m u s t ,

t h e r e f o r e , a i m t o r e d u c e t h e l e v e l o f a c t i v i t y i n t h e l u n g b y r e m o v i n g

t h e s e c e l l s . The o n l y a p p r o a c h t h a t h a s b e e n d e m o n s t r a t e d t o b e p o t e n t i a l l y

o f v a l u e i s b r o n c h o p u l m o n a r y l a v a g e .

The p r o c e d u r e u s e d i n man a n d l a r g e a n i m a l s ( d o g s a n d b a b o o n s ) i n v o l v e s

p a s s i n g a c u f f e d d o u b l e - l u m e n t u b e t h r o u g h t h e m o u t h a n d i n t o t h e t r a c h e a o f

a n a n a e s t h e t i s e d s u b j e c t . The t u b e i s p o s i t i o n e d s o t h a t e a c h l u n g i s

i n d e p e n d e n t l y i n t u b a t e d a n d t h e s u b j e c t i s a l l o w e d t o b r e a t h e p u r e o x y g e n

t h r o u g h i t . One l u n g i s t h e n m a i n t a i n e d o n o x y g e n w h i l s t t h e o t h e r i s

f i l l e d w i t h s a l i n e w h i c h i s t h e n d r a i n e d o u t . The p r o c e d u r e i s r e p e a t e d a

n u m b e r o f t i m e s . A t t h e e n d o f t h i s " u n i l a t e r a l " l a v a g e t h e o p p o s i t e l u n g

c a n b e s i m i l a r l y l a v a g e d c o m p l e t i n g a " b i l a t e r a l l a v a g e " . S a l i n e i s

n o r m a l l y u s e d f o r l u n g w a s h i n g a s i t h a s b e e n s h o w n t o b e m o r e e f f e c t i v e

t h a n b a l a n c e d s a l t s o l u t i o n s i n r e m o v i n g p u l m o n a r y m a c r o p h a g e s ( N o l i b e e t a l ,

1 9 7 7 a ) . The p r e s e n c e o f C a + + a n d Mg"*^ i n h i b i t s t h e r e l e a s e o f m a c r o p h a g e s

f r o m t h e a l v e o l a r w a l l ( B r a i n a n d C o r k e r y , 1 9 7 7 ) .

O v e r t h e l a s t 1 0 y e a r s a s e r i e s o f s t u d i e s o n t h e u s e o f l a v a g e f o r

r e m o v i n g i n s o l u b l e r a d i o a c t i v e p a r t i c l e s f r o m t h e l u n g s o f a n i m a l s h a v e

b e e n r e p o r t e d f r o m F r a n c e , t h e U n i t e d S t a t e s a n d t h e U n i t e d K i n g d o m .

T a b l e 8 . 1 g i v e s some r e s u l t s o b t a i n e d i n man a n d k m a m m a l i a n s p e c i e s . I n

b o t h d o g s ( S i l b a u g h e t a l , 1 9 7 5 ) a n d b a b o o n s ( N o l i b e e t a l , 1 9 7 6 ) 5 0 - 6 0 %

o f a n i n h a l e d i n s o l u b l e a e r o s o l h a s b e e n r e m o v e d b y r e p e a t e d l a v a g e s c a r r i e d

o u t o v e r a p e r i o d o f 1 2 w e e k s a f t e r e x p o s u r e t o t h e a e r o s o l . B e t w e e n 8 5 a n d

90% o f t h e i n i t i a l l u n g c o n t e n t o f 2 ^ P u 0 9 h a s b e e n r e m o v e d f r o m h a m s t e r s

153

15U

g i v e n 7 s u c c e s s i v e l a v a g e s d u r i n g a 6 w e e k p e r i o d a f t e r e x p o s u r e , B r i g h t w e l l

a n d E l l e n d e r ( 1 9 7 7 ) . I n t h i s l a t t e r s t u d y t h e f i r s t 3 l a v a g e s r e m o v e d 7 3 %

o f t h e e s t i m a t e d i n i t i a l l u n g c o n t e n t . The s e v e n t h l a v a g e r e m o v e d o n l y

2 . 0 % o f t h e i n i t i a l l u n g c o n t e n t b u t t h i s w a s s t i l l a b o u t 20% o f t h e l u n g

c o n t e n t a t t h e t i m e o f t r e a t m e n t . I n r o d e n t s i t i s n o t p r a c t i c a b l e t o

w a s h o u t e a c h l u n g s e p e r a t e l y a n d t h e t e c h n i q u e u s e d i n v o l v e d a l t e r n a t i v e l y

f l o o d i n g b o t h l u n g s w i t h a v o l u m e o f s a l i n e r a t h e r l e s s t h a n t h e t o t a l

l u n g v o l u m e a n d t h e n d r a i n i n g t h e l u n g s .

B r o n c h o p u l m o n a r y l a v a g e h a s b e e n u s e d w i t h p a r t i a l s u c c e s s o n a man

who h a d i n h a l e d p l u t o n i u m f o l l o w i n g a g l o v e b o x a c c i d e n t ( M c C l e l l a n e t a l ,

1 9 7 2 b ) . A b o u t 1 3 % o f t h e i n i t i a l l u n g c o n t e n t w a s r e m o v e d i n t h e l a v a g e

f l u i d ( T a b l e 8 , 1 ) a n d t h e r e w a s some i n c r e a s e i n f a e c a l e x c r e t i o n t h a t

c o u l d h a v e r e s u l t e d f r o m t h e t r e a t m e n t . I n t h i s c a s e o n e l u n g w a s l a v a g e d

t w i c e a n d t h e o t h e r l u n g o n c e o n l y . The a c c u m u l a t e d e v i d e n c e f r o m a n i m a l

e x p e r i m e n t s s u g g e s t s t h a t m o r e l a v a g e s w o u l d h a v e f u r t h e r r e d u c e d t h e l u n g

c o n t e n t o f p l u t o n i u m .

N o l i b e e t a l , ( 1 9 7 7 a ) h a v e d e s c r i b e d t h e p a t h o l o g i c a l e f f e c t s o f

l a v a g e i n b a b o o n s . I m m e d i a t e l y a n d a f e w h o u r s a f t e r t r e a t m e n t t h e e f f e c t s

o n l u n g h i s t o l o g y i n c l u d e d h a e m o r r h a g e , p e r i b r o n c h i a l a n d p e r i v a s c u l a r

o e d e m a , a n d i n f i l t r a t i o n o f n e u t r o p h i l i c g r a n u l o c y t e s . C h a n g e s i n u l t r a -

s t r u c t u r e w e r e a l s o n o t e d i n c l u d i n g t h e s w e l l i n g o f some a l v e o l a r w a l l c e l l s ,

a n d i n p l a c e s t h e i r c o m p l e t e l o s s l e a v i n g a b a r e b a s a l m e m b r a n e . T w e n t y -

f o u r h o u r s a f t e r l a v a g e some a l v e o l i w e r e f i l l e d w i t h a f i b r i n o u s e x u d a t e

a n d f o a m y m a c r o p h a g e s , t h i s , w a s a s s o c i a t e d w i t h a n i n f i l t r a t i o n o f g r a n -

u l o c y t e s a n d o f t e n m e g a k a r y o c y t e s . N o n e o f t h e s e c h a n g e s w e r e e x t e n s i v e .

By 2 d a y s t h e r e w a s a l a r g e r e g r e s s i o n o f t h e s e p a t h o l o g i c a l c h a n g e s a n d

a f t e r h d a y s t h e l u n g s w e r e n o r m a l . No e v i d e n c e o f c h r o n i c l u n g p a t h o l o g y

w a s n o t e d s e v e r a l m o n t h s a f t e r a s c h e d u l e o f 1 5 l a v a g e s . S i m i l a r c h a n g e s

h a v e b e e n r e p o r t e d i n b e a g l e d o g s f o l l o w i n g l a v a g e t r e a t m e n t ( M u g g e n b u r g

e t a l , 1 9 7 2 ) .

A l t h o u g h t h e p r o c e d u r e h a s b e e n u s e d o n l y o n c e i n man f o r t h e r e m o v a l

o f i n h a l e d r a d i o a c t i v e m a t e r i a l i t h a s b e e n u s e d f r e q u e n t l y f o r t h e t r e a t -

m e n t o f a l v e o l a r p r o t e i n o s i s , b r o n c h i a l a s t h m a , c y s t i c f i b r o s i s , c h r o n i c

b r o n c h i t i s , a n d b r o n c h i e c t a s i s . I n a r e v i e w o f e x p e r i e n c e w i t h b r o n c h o -

p u l m o n a r y l a v a g e i n man R o g e r s e t a l , ( 1 9 7 2 ) s h o w e d t h a t i n 8 2 p a t i e n t s

g i v e n 2i+0 l a v a g e s o n l y o n e d e a t h d u r i n g o r p o s t - l a v a g e w a s r e p o r t e d . T h i s

w a s d u e t o a p u l m o n a r y e m b o l i s m w h i c h i s d i f f i c u l t t o r e l a t e t o t h e p r o c e d -

u r e p e r s e . A n u m b e r o f d e a t h s h a v e b e e n r e p o r t e d i n a n i m a l s t r e a t e d w i t h

l a v a g e ( N o l i b e e t a l , 1 9 7 6 , M u g g e n b u r g e t a l , 1 9 7 6 ) . H o w e v e r , t h e d e a t h s

h a v e o c c u r r e d p r e d o m i n a n t l y a s a r e s u l t o f e x p e r i m e n t a l e r r o r s a n d n o t

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b e c a u s e o f a n y a d v e r s e e f f e c t s o f l a v a g e u p o n t h e r e s p i r a t o r y s y s t e m .

I n c o n c l u s i o n , b r o n c h o p u l m o n a r y l a v a g e i s t h e o n l y e f f e c t i v e t r e a t m e n t

f o r r e m o v i n g i n h a l e d i n s o l u b l e r a d i o a c t i v e m a t e r i a l s . I t a p p e a r s t o b e a

s a f e p r o c e d u r e . The m a i n r i s k i s l i k e l y t o b e t h a t o f t h e r e p e a t e d

a n a e s t h e s i a r e q u i r e d r a t h e r t h a n t h e p r o c e d u r e i t s e l f . The o n l y l i m i t a t i o n

i n t h e u s e o f t h i s p r o c e d u r e f o r r e m o v i n g r a d i o a c t i v e m a t e r i a l s f r o m t h e

l u n g a p p e a r s t o b e t h e n u m b e r o f l a v a g e s r e q u i r e d a s e a c h l a v a g e may r e m o v e

o n l y 20% o r l e s s o f t h e l u n g c o n t e n t . The v a l u e o f t h e t e c h n i q u e w o u l d b e

i n c r e a s e d c o n s i d e r a b l y i f t h e e f f i c i e n c y c o u l d b e i m p r o v e d .

2 . 2 D e p o s i t s i n w o u n d s

D e p o s i t s o f p l u t o n i u m o r h i g h e r a c t i n i d e s i n w o u n d s i t e s c a n n o r m a l l y

b e r e m o v e d b y s u r g i c a l e x c i s i o n . S c h o f i e l d 0976) h a s r e p o r t e d t h a t a t

BNFL W i n d s c a l e p l u t o n i u m d e p o s i t s a r e s u r g i c a l l y e x c i s e d w h e n e v e r p o s s i b l e

i f t h e a c t i v i t y a t t h e s i t e i s i n e x c e s s o f a b o u t k n C i ( 0 . 1 5 k B q ) . E x c i s i o n

i s n o r m a l l y c o m b i n e d w i t h t h e u s e o f d i e t h y l e n e t r i a m i n e p e n t a a c e t i c a c i d

(DTPA) t o a c c e l e r a t e t h e e x c r e t i o n o f a n y s o l u b l e a c t i n i d e s t h a t h a v e

e n t e r e d t h e c i r c u l a t i o n o r r e m a i n a t t h e wound s i t e .

3 . T r e a t m e n t f o r i n t a k e s o f s o l u b l e f o r m s o f a c t i n i d e s

3 . 1 I n t r a v e n o u s a d m i n i s t r a t i o n o f DTPA

I n t a k e s o f a c t i n i d e s f r e q u e n t l y i n v o l v e c o m p o u n d s w i t h h e t e r o g e n e o u s

p h y s i c o c h e m i c a l p r o p e r t i e s . H o w e v e r a f r a c t i o n o f t h e d e p o s i t e d m a t e r i a l

w i l l b e h a v e i n a s o l u b l e m a n n e r ( t r a n s p o r t a b l e ) a n d t h e r e m a i n d e r a s

i n s o l u b l e ( n o n - t r a n s p o r t a b l e ) . I n t h e c a s e o f i n s o l u b l e f o r m s s u c h a s

p l u t o n i u m d i o x i d e t h e t r a n s p o r t a b l e f r a c t i o n may b e l e s s t h a n 0 . 1 % o f t h e

d e p o s i t b u t f o r s o l u b l e f o r m s ( n i t r a t e o r c i t r a t e ) i t may b e a t h i r d o r

m o r e ( C h a p t e r h)»

F o r i n c r e a s i n g t h e r a t e o f e l i m i n a t i o n o f t h e t r a n s p o r t a b l e f r a c t i o n

o f a n i n t a k e t h e c u r r e n t l y a c c e p t e d t r e a t m e n t i s t h e i n t r a v e n o u s a d m i n i s -

t r a t i o n o f t h e c a l c i u m s a l t o f t h e c h e l a t i n g a g e n t DTPA ( N o r w o o d , 1 9 6 2 ,

N o r w o o d a n d F u q u a , 1 9 6 9 , S c h o f i e l d a n d L y n n , 1 9 7 3 , S c h o f i e l d e t a l , 1 9 7 U ) .

The c h e l a t e c o m p l e x f o r m e d b e t w e e n a n y a v a i l a b l e p l u t o n i u m a n d DTPA i s

r a p i d l y a n d a l m o s t q u a n t i t a t i v e l y e x c r e t e d f r o m t h e b o d y ( N e n o t e t a l , 1 9 7 2 ,

S t a t h e r a n d H o w d e n , 1 9 7 5 ) . The d o s e u s e d i n man i s n o r m a l l y 3 . 5 t o 1 i + m g k g ~ " \

The v a l u e a n d l i m i t a t i o n s i n t h e u s e o f DTPA f o r t r e a t i n g a c c i d e n t a l

i n t a k e s o f p l u t o n i u m o r o t h e r a c t i n i d e s h a s r e c e n t l y b e e n r e v i e w e d b y

D o l p h i n ( 1 9 7 6 a ) . The m a i n d i s a d v a n t a g e a s s o c i a t e d w i t h t h e u s e o f DTPA i s

t h a t i t c a n o n l y p e n e t r a t e t h e c e l l s o f t h e b o d y t o a v e r y l i m i t e d e x t e n t

157

a n d t h e r e f o r e i n p r a c t i c e i s m a i n l y e f f e c t i v e i n r e m o v i n g p l u t o n i u m f r o m t h e

e x t r a c e l l u l a r s p a c e o r some o f t h a t w h i c h h a s r e c e n t l y b e e n d e p o s i t e d o n

b o n e o r l i v e r s u r f a c e s . As t h e r a t e o f c l e a r a n c e o f a m a j o r p o r t i o n o f

p l u t o n i u m f r o m t h e b l o o d i s r a p i d ( C h a p t e r h) i t i s i m p o r t a n t t o a d m i n i s t e r

DTPA a s s o o n a s p o s s i b l e a f t e r a s u s p e c t e d o r known i n t a k e o f a c t i n i d e s . A

n u m b e r o f s t u d i e s h a v e s h o w n t h a t t h e e f f e c t i v e n e s s o f t r e a t m e n t w i t h DTPA

d e p e n d s b o t h u p o n t h e t i m e o f a d m i n i s t r a t i o n a n d t h e a m o u n t . W i t h p r o m p t

t r e a t m e n t i t s e f f e c t i v e n e s s i n c r e a s e s w i t h t h e a m o u n t a d m i n i s t e r e d b u t a t

l a t e r t i m e s t h i s e f f e c t i s l e s s m a r k e d ( C a t s c h , 1 9 7 6 , S t a t h e r e t a l , 1 9 7 6 ) .

A m e r i c i u m a n d c u r i u m a r e c l e a r e d m o r e r a p i d l y f r o m t h e s y s t e m i c

c i r c u l a t i o n t h a n p l u t o n i u m ( C h a p t e r l i )» I t m i g h t b e e x p e c t e d , t h e r e f o r e ,

t h a t DTPA w o u l d b e l e s s e f f e c t i v e i n i n c r e a s i n g t h e e l i m i n a t i o n o f t h e s e

t r a n s p l u t o n i c e l e m e n t s c o m p a r e d w i t h p l u t o n i u m i f g i v e n a f e w h o u r s a f t e r

a n i n t a k e . No c o m p a r a t i v e d a t a a p p e a r t o b e a v a i l a b l e a t t h e s e t i m e s b u t

V o l f e t a l , ( 1 9 7 7 ) h a v e s h o w n t h a t t h e p r o m p t t r e a t m e n t w i t h t h e c a l c i u m

s a l t ( 1 5 \i m o l e k g 1 * a d m i n i s t e r e d 1 , 5 m i n u t e s a f t e r i s o t o p e i n j e c t i o n ) w a s

m o r e e f f e c t i v e i n r e d u c i n g t i s s u e l e v e l s o f a m e r i c i u m - 2 l ± 1 a n d c u r i u m - 2 l i 2

c o m p a r e d w i t h p l u t o n i u m - 2 3 9 * L e v e l s o f p l u t o n i u m i n t h e s k e l e t o n a n d l i v e r

w e r e r e d u c e d t o a b o u t 5 7 % o f t h e c o n t r o l s a t o n e w e e k w h e r e a s c u r i u m a n d

a m e r i c i u m l e v e l s i n t h e s k e l e t o n w e r e r e d u c e d t o a b o u t 27% o f c o n t r o l s a n d

i n t h e l i v e r t o 1 9 % . I f r e p e a t e d i n j e c t i o n s w e r e g i v e n a t l a t e r t i m e s

( 6 t h , 8 t h a n d 1 1 t h d a y a f t e r i s o t o p e i n j e c t i o n ) b u t a t a c o n s i d e r a b l y —1 —1

h i g h e r d o s e ( 1 m m o l e k g d a y ) , t h e e f f e c t o f t h e c a l c i u m s a l t i n

r e d u c i n g l e v e l s o f a c t i v i t y i n t h e s k e l e t o n w a s s i m i l a r f o r a l l t h r e e

r a d i o n u c l i d e s ( 7 7 % o f c o n t r o l s a t 1 3 d a y s a f t e r i s o t o p e a d m i n i s t r a t i o n ) b u t

w a s m o r e e f f e c t i v e a t r e d u c i n g a m e r i c i u m a n d c u r i u m i n t h e l i v e r (8% o f

c o n t r o l s ) t h a n p l u t o n i u m (20% o f c o n t r o l s ) ( S e i d e l a n d V o l f , 1 9 7 2 ) . The

i n c r e a s e d e f f e c t i v e n e s s o f DTPA i n r e d u c i n g t i s s u e l e v e l s o f t h e t r a n s -

p l u t o n i c e l e m e n t s p r o b a b l y r e s u l t s f r o m t h e i r w e a k e r b i n d i n g t o p r o t e i n s

i n t h e b l o o d a n d o t h e r t i s s u e c o m p o n e n t s .

I n a n i m a l e x p e r i m e n t s t h e e f f e c t i v e n e s s o f t r e a t m e n t c a n b e r e a d i l y

m e a s u r e d a s t h e a n i m a l s a r e n o r m a l l y k i l l e d a t t h e e n d o f t h e s t u d y . I t

i s c o n s i d e r a b l y l e s s e a s y t o e v a l u a t e t h e b e n e f i t s o f t r e a t m e n t i n man . An

e s t i m a t e o f t h e d e g r e e o f d e c o n t a m i n a t i o n a c h i e v e d d e p e n d s u p o n a k n o w l e d g e

b o t h o f t h e a m o u n t o f a c t i v i t y i n t h e b o d y s o o n a f t e r e x p o s u r e a n d t h e t o t a l

a m o u n t e x c r e t e d . T h e s e v a l u e s may n o t b e known w i t h a n y d e g r e e o f a c c u r a c y .

A n a l y s i s o f t h e a c t i v i t y e x c r e t e d i n t h e u r i n e o v e r a p e r i o d o f w e e k s

* 2 8 |i m o l e k g " DTPA = 1li mg k g " DTPA

158

p r o v i d e s p r o b a b l y t h e b e s t , b u t n o t a l w a y s a n a c c u r a t e e s t i m a t e o f t h e

e f f e c t i v e n e s s o f t r e a t m e n t . S p o o r ( 1 9 7 7 ) h a s r e v i e w e d 3 1 c a s e h i s t o r i e s

o f p e r s o n s t r e a t e d w i t h DTPA a f t e r a c c i d e n t a l i n t a k e s o f p l u t o n i u m ,

a m e r i c i u m o r c u r i u m c o m p o u n d s . Out o f t h e s e c a s e s t h e u s e o f DTPA w a s

c o n s i d e r e d t o h a v e h a d a n e g l i g i b l e e f f e c t i n a b o u t o n e t h i r d o f t h e c a s e s ,

a s l i g h t e f f e c t i n a f u r t h e r t h i r d a n d a c o n s i d e r a b l e e f f e c t i n t h e r e -

m a i n i n g c a s e s . I t w a s n o t e w o r t h y t h a t i n many c a s e s t h e u s e o f DTPA

e n h a n c e d t h e r a t e o f u r i n a r y e x c r e t i o n b y a f a c t o r o f 3 0 t o 1±0 o v e r t h e

v a l u e e x p e c t e d w i t h o u t t r e a t m e n t . D e s p i t e t h i s b e c a u s e t r e a t m e n t w a s

o f t e n i n i t i a t e d t o o l a t e o r b e c a u s e t h e o r i g i n a l i n t a k e i n v o l v e d p l u t o n i u m

d i o x i d e t h e o v e r a l l e f f e c t o f t h e t r e a t m e n t i n r e d u c i n g t h e b o d y a c t i v i t y

w a s i n many c a s e s s m a l l .

The e f f e c t i v e n e s s o f DTPA i s l i m i t e d b y i t s i n a b i l i t y t o r e m o v e

p l u t o n i u m t h a t h a s b e e n a c c u m u l a t e d b y c e l l s o r i n c o r p o r a t e d i n b o n e

m i n e r a l . R e c e n t l y , h o w e v e r , i t h a s b e e n r e p o r t e d t h a t a l i p o p h i l i c

d e r i v a t i v e o f DTPA (now t e r m e d P u c h e l ) h a s b e e n p r e p a r e d t h a t i s a b l e t o

r e m o v e 85% o f t h e l i v e r c o n t e n t o f p l u t o n i u m i n r o d e n t s ( B u l m a n e t a l ,

1 9 7 7 ) - T h i s m a t e r i a l w i l l n e e d e x t e n s i v e t o x i c o l o g i c a l t e s t i n g b e f o r e

i t c a n b e c o n s i d e r e d f o r u s e i n man .

3 . 2 E f f e c t s o f DTPA a f t e r i n t r a v e n o u s a d m i n i s t r a t i o n

T h e r e i s n o e v i d e n c e o f DTPA t o x i c i t y i n man p r o v i d e d i t i s g i v e n a s

s i n g l e i n t r a v e n o u s i n j e c t i o n s n o t e x c e e d i n g 11+ mg k g " 1 b o d y w e i g h t a t

i n t e r v a l s o f 2i+ h o u r s o r m o r e ( N o r w o o d a n d P u q u a , 1 9 ^ 9 ) • M o r g a n a n d S m i t h

( 1 9 7 U ) f a i l e d t o d e m o n s t r a t e a n y t o x i c e f f e c t s o f t h e c a l c i u m s a l t i n

a n i m a l s u n d e r a l l l i k e l y c o n d i t i o n s o f u s e . T h e r e i s e v i d e n c e f r o m a n i m a l

e x p e r i m e n t s o f l e t h a l a n d n o n - l e t h a l t o x i c e f f e c t s o r d e a t h w h e n t h e c a l c i u m

s a l t i s g i v e n a s m u l t i p l e i n j e c t i o n s ( 5 t i m e s a d a y ) o v e r a p e r i o d o f 2 l i

h o u r s f o r a f e w d a y s e v e n t h o u g h t h e a m o u n t i n j e c t e d d o e s n o t e x c e e d 1 l i mg

k g " d a y " ( T a y l o r e t a l , 1 9 7 U ) • I t i s t h o u g h t t h a t t h e a d v e r s e e f f e c t s

a r e c a u s a l l y r e l a t e d t o t h e r e m o v a l o f e s s e n t i a l t r a c e m e t a l s , m a i n l y Zn a n d

Mh ( G a b a r d , 1 9 7 U ; P l a n a s - B o h n e a n d O l i n g e r , 1 9 7 ^ ) • T h i s v i e w i s s u p p o r t e d

b y s t u d i e s w h i c h show t h a t t o x i c i t y c a n b e c o n s i d e r a b l y r e d u c e d b y t h e u s e

o f t h e z i n c s a l t ( T a y l o r e t a l , 1 9 7 U > C a t s c h a n d W e d e l s t a e d t , 1 9 6 5 * S e i d e l

a n d V o l f , 1 9 7 2 ) .

A d i s a d v a n t a g e i n t h e u s e o f t h e z i n c s a l t i s t h a t i t i s l e s s e f f e c t -

i v e t h a n t h e c a l c i u m s a l t i n r e m o v i n g i n t e r n a l l y d e p o s i t e d t r a n s u r a n i c

e l e m e n t s , w h e n t h e c h e l a t e i s a d m i n i s t e r e d w i t h i n a f e w d a y s a f t e r i n c o r p -

o r a t i o n o f t h e r a d i o n u c l i d e ( V o l f a n d S e i d e l , 1 9 7 4 , V o l f , 1 9 7 6 , C a t s c h ,

159

1 9 7 ^ , S m i t h e t a l , 1 9 7 6 ) . A d m i n i s t e r e d a t a l a t e r t i m e b o t h t h e c a l c i u m

a n d z i n c s a l t s a p p e a r t o b e e q u a l l y e f f e c t i v e ( L l o y d e t a l , 1 9 7 6 , S e i d e l

a n d V o l f , 1 9 7 2 , S e i d e l , 1 9 7 6 ) .

3 # 3 A e r o s o l a d m i n i s t r a t i o n o f DTPA

DTPA i s n o r m a l l y g i v e n b y i n t r a v e n o u s i n j e c t i o n b e c a u s e a b s o r p t i o n

f r o m t h e g a s t o - i n t e s t i n a l t r a c t i s l o w ( F o r e m a n e t a l , 1 9 5 6 ) . H o w e v e r , i t

i s n o t a l w a y s p r a c t i c a b l e t o i n j e c t DTPA s o o n a f t e r a n a c c i d e n t a n d a n u m b e r

o f a u t h o r s h a v e s u g g e s t e d t h a t i t c o u l d b e s e l f - a d m i n i s t e r e d a s a n a e r o s o l

( L y u b c h a n s k i i , 1 9 6 6 , N e n o t e t a l , 1 9 7 1 a , N e n o t e t a l , 1 9 7 1 h , J o l l y e t a l ,

1 9 7 2 , S m i t h e t a l , 1 9 7 6 , S t a t h e r e t a l , 1 9 7 6 ) . S t a t h e r e t a l , ( 1 9 7 6 ) h a v e

s h o w n t h a t t h e a d m i n i s t r a t i o n o f t h e c a l c i u m s a l t e i t h e r b y p u l m o n a r y i n -

t u b a t i o n o r b y i n t r a v e n o u s i n j e c t i o n w a s e q u a l l y e f f e c t i v e i n r e d u c i n g t i s s u e

l e v e l s o f p l u t o n i u m a d m i n i s t e r e d i n t r a v e n o u s l y a s c i t r a t e . S m i t h e t a l ,

( 1 9 7 6 ) h a v e s h o w n t h a t i n t r a v e n o u s DTPA ( 3 5 u m o l e k g " ) a n d i n h a l e d DTPA

a p p e a r t o b e t h e r a p e u t i c a l l y e q u i v a l e n t f o l l o w i n g i n t r a m u s c u l a r a d m i n i s t r a -

t i o n o f p l u t o n i u m n i t r a t e . I n t h e c a s e o f s o l u b l e f o r m s o f p l u t o n i u m

d e p o s i t e d i n t h e r e s p i r a t o r y s y s t e m e a r l y a d m i n i s t r a t i o n o f DTPA c a n b e

c o n s i d e r a b l y m o r e e f f e c t i v e t h a n i n t r a v e n o u s a d m i n i s t r a t i o n i n r e d u c i n g

t i s s u e d e p o s i t s o f p l u t o n i u m . F o r e x a m p l e w h e n r a t s w e r e e x p o s e d t o a e r o -

s o l s o f t h e c a l c i u m s a l t (5»U mg k g " ) U 5 m i n u t e s a f t e r t h e p u l m o n a r y

d e p o s i t i o n o f p l u t o n i u m c i t r a t e t h e l u n g c o n t e n t o f p l u t o n i u m m e a s u r e d a

w e e k l a t e r w a s r e d u c e d t o 8 . 5 % o f c o n t r o l a n i m a l s . I n a d d i t i o n t h e t o t a l

a c t i v i t y d e p o s i t e d i n t i s s u e s o t h e r t h a n t h e l u n g s w a s 60% o f c o n t r o l

a n i m a l s . F o l l o w i n g t h e i n t r a v e n o u s i n j e c t i o n o f s i m i l a r a m o u n t s o f DTPA

t h e c o m p a r a b l e f i g u r e s w e r e 96% a n d 68% r e s p e c t i v e l y ( S t a t h e r e t a l , 1 9 7 6 ) .

I f t r e a t m e n t i s d e l a y e d DTPA i s l e s s e f f e c t i v e . I n r a t s e x p o s e d t o a n

a e r o s o l o f t h e c a l c i u m s a l t ( 3 m g / r a t / e x p o s u r e ) 2 0 d a y s a f t e r i n h a l a t i o n o f

p l u t o n i u m n i t r a t e a n d a t f i v e s u b s e q u e n t w e e k l y i n t e r v a l s t h e r e w a s l i t t l e

e f f e c t o n p l u t o n i u m c l e a r a n c e f r o m t h e l u n g a l t h o u g h d e p o s i t i o n i n t h e

s k e l e t o n a n d l i v e r w a s r e d u c e d b y a b o u t 20% ( B a l l o u e t a l , 1 9 7 7 ) .

P a s q u i e r a n d D u c o u s s o ( 1 9 7 6 ) h a v e d e s c r i b e d a p e r s o n a l i n h a l a t i o n

s y s t e m f o r s e l f a d m i n i s t r a t i o n o f t h e c a l c i u m s a l t .

3 .U E f f e c t s o f DTPA a f t e r a e r o s o l a d m i n i s t r a t i o n

H i s t o l o g i c a l e x a m i n a t i o n h a s b e e n made o f t h e l u n g s o f r a t s a t i n t e r -

v a l s b e t w e e n 1 a n d 5 8 d a y s a f t e r e x p o s u r e t o a n a e r o s o l i s e d f o r m o f t h e

c a l c i u m s a l t o f DTPA (5.1+ mg k g " ) ( S t a t h e r e t a l , 1 9 7 6 ) . T h e r e w a s n o

e v i d e n c e o f a n y a b n o r m a l i t y i n t h e l u n g t i s s u e . T h i s i s i n c o n t r a s t t o

s t u d i e s r e p o r t e d b y S m i t h e t a l , (l3lG\ who d e s c r i b e d a t r a n s i t o r y

160

v e s i c u l a r e m p h y s e m a w i t h c o m p l e t e r e c o v e r y i n r a t s a n d h a m s t e r s e x p o s e d t o

a e r o s o l s o f t h e c a l c i u m s a l t f o r e i t h e r 1 o r 2 h o u r s 3 t i m e s i n 1 w e e k .

The d o s e i n t h e s e s t u d i e s r a n g e d f r o m 1 l i t o 2l± mg k g " 1 a t e a c h e x p o s u r e a n d

t h e t o t a l a m o u n t i n h a l e d i s a f a c t o r o f 8 t o 1 3 a b o v e t h e s t u d y b y S t a t h e r

e t a l , ( 1 9 7 6 ) . The r a t l u n g c a n r e c o v e r f r o m e v e n l a r g e r d o s e s o f t h e

c a l c i u m s a l t a s w a s s h o w n b y B a l l o u a n d B u s c h ( 1 9 7 2 ) who u s e d i n t r a t r a c h e a l - 1

i n j e c t i o n t o a d m i n i s t e r d o s e s o f b e t w e e n 1 7 0 a n d 3 9 0 mg k g t o r a t s . No

d e a t h s o c c u r r e d f r o m U d a i l y i n j e c t i o n s o f 1 7 0 mg k g . A t a c o n c e n t r a t i o n

o f 2 6 0 mg k g 90% s u r v i v e d e i t h e r t h e c a l c i u m o r z i n c s a l t o f DTPA; a t

d o s e s i n e x c e s s o f 2 6 0 mg k g " s u r v i v a l w a s a b o u t 50% a f t e r 3 d a i l y t r e a t -

m e n t s w i t h e i t h e r s a l t . A f t e r ii w e e k s r e c o v e r y , n o h i s t o l o g i c a l a l t e r a t i o n

w a s o b s e r v e d i n t h e l u n g s .

I n a f u r t h e r s t u d y ( S m i t h e t a l , 1 9 7 6 ) , d o g s w e r e e x p o s e d t o a n a e r o s o l

o f t h e c a l c i u m s a l t a t a n a v e r a g e e x p o s u r e d o s e o f 5 6 mg kg"" 1 g i v e n d a i l y f o r

5 d a y s . G r o u p s o f d o g s w e r e s a c r i f i c e d a t 1 , l i , 8 a n d 1 8 w e e k s a f t e r t h e

l a s t e x p o s u r e . H y p e r p l a s i a o f t h e g a s t r i c s u b m u c o s a l l y m p h o i d f o l l i c l e s

w a s o b s e r v e d i n 3 o u t o f k a n i m a l s t r e a t e d a t 1 w e e k f o l l o w i n g t h e l a s t

DTPA e x p o s u r e . No c h a n g e s w e r e s e e n a t l a t e r t i m e s a n d n o s i m i l a r c h a n g e s

w e r e s e e n i n c o n t r o l a n i m a l s . No e m p h y s e m a o f t h e t y p e o b s e r v e d i n r a t s

a n d h a m s t e r s w a s s e e n i n t h e d o g s a n d n o o t h e r s i g n i f i c a n t c h a n g e s w e r e

n o t e d .

I n human c a s e s i n w h i c h a e r o s o l DTPA h a s b e e n a d m i n i s t e r e d n o a d v e r s e

r e a c t i o n s h a v e b e e n n o t e d ( S a n d e r s , 1 9 7 4 a , J o l l y e t a l , 1 9 7 2 ) .

3 . 5 L o c a l t r e a t m e n t o f c o n t a m i n a t e d w o u n d s w i t h DTPA

F o r t h e t r e a t m e n t o f d e p o s i t s o f a c t i n i d e s i n wound s i t e s DTPA i s

u s u a l l y a d m i n i s t e r e d i n t r a v e n o u s l y . The p o s s i b i l i t y o f a g r e a t e r e f f e c t

a f t e r l o c a l a d m i n i s t r a t i o n i n c a s e s o f wound c o n t a m i n a t i o n h a s b e e n c o n -

s i d e r e d i n a n u m b e r o f e x p e r i m e n t a l s t u d i e s .

T a y l o r a n d Sowby ( 1 9 6 2 ) c o m p a r e d t h e e f f e c t o f i n t r a p e r i t o n e a l

i n j e c t i o n a n d l o c a l i n j e c t i o n o f DTPA o n t h e c l e a r a n c e o f P u - 2 3 9 f r o m a n

i n t r a m u s c u l a r s i t e o f i n j e c t i o n i n t h e h i n d l e g o f r a t s . DTPA ( 7 5 mg kg"" 1 )

w a s a d m i n i s t e r e d a t 1 h o u r a n d 21+ h o u r s a f t e r i n j e c t i o n o f 0 . 1 {iCi

( 3 . 7 k B q ) o f p l u t o n i u m - 2 3 9 n i t r a t e . The a m o u n t o f p l u t o n i u m - 2 3 9 r e m a i n i n g

a t t h e i n j e c t i o n s i t e a f t e r 7 d a y s w a s 63% o f c o n t r o l s a f t e r i n t r a -

p e r i t o n e a l i n j e c t i o n o f DTPA a n d 1 5 % o f c o n t r o l s a f t e r i n t r a m u s c u l a r

i n j e c t i o n . H o w e v e r , w h i l e s k e l e t a l u p t a k e w a s r e d u c e d t o 1 5 % o f c o n t r o l s

a f t e r l o c a l i n j e c t i o n c o m p a r e d w i t h 27% a f t e r s y s t e m i c i n j e c t i o n , l i v e r

161

u p t a k e w a s 58% o f c o n t r o l c o m p a r e d w i t h 2 1 % a f t e r s y s t e m i c i n j e c t i o n .

T h e s e r e s u l t s l e d t h e a u t h o r s t o d o u b t t h e v a l u e o f l o c a l i n j e c t i o n o f

DTPA.

More r e c e n t l y , V o l f ( 1 9 7 U > 1 9 7 5 ) h a s a d v o c a t e d t h e l o c a l

a d m i n i s t r a t i o n o f DTPA f o r t h e t r e a t m e n t o f p l u t o n i u m c o n t a m i n a t e d w o u n d s

o n t h e b a s i s o f f u r t h e r e x p e r i m e n t s w i t h r a t s . DTPA c a u s e d a n e n h a n c e d

c l e a r a n c e o f p l u t o n i u m f r o m t h e s i t e o f d e p o s i t i o n a n d a l o w e r l e v e l o f

d e p o s i t i o n i n o t h e r t i s s u e s i n a s e r i e s o f e x p e r i m e n t s . F o r i n s t a n c e ,

l o c a l i n j e c t i o n o f DTPA ( 5 0 0 mg k g " ) i n t o t h e t h i g h m u s c l e a t 1 h o u r a f t e r

i n j e c t i o n o f 0 . 5 \i0± ( 1 8 k B q ) o f p l u t o n i u m - 2 3 9 n i t r a t e r e s u l t e d i n a l e v e l

o f r e t e n t i o n a t t h e i n j e c t i o n s i t e a f t e r 8 d a y s o f 1 9 % o f c o n t r o l s a n d

l i v e r a n d s k e l e t a l u p t a k e o f 11+% a n d 16% o f c o n t r o l s , r e s p e c t i v e l y . Some

c o m b i n a t i o n s o f c h e l a t i n g a g e n t s w e r e f o u n d t o b e m o r e e f f e c t i v e t h a n DTPA

a l o n e . DTPA a n d c i t r a t e p r o v e d t h e m o s t e f f e c t i v e c o m b i n a t i o n t e s t e d i n

r e d u c i n g t h e o v e r a l l b o d y b u r d e n o f p l u t o n i u m - 2 3 9 * T h e i r i n j e c t i o n

( 2 5 0 mg kg"^ e a c h ) 1 h o u r a f t e r i n j e c t i o n o f 0 . 5 n-Ci ( 1 8 k B q ) o f p l u t o n i u m -

2 3 9 n i t r a t e r e s u l t e d i n r e t e n t i o n a t t h e i n j e c t i o n s i t e a f t e r 8 d a y s e q u a l

t o 1 2 % o f c o n t r o l s a n d l i v e r a n d s k e l e t a l u p t a k e o f 8% a n d 11% o f c o n t r o l s

r e s p e c t i v e l y .

S t u d i e s b y H a r r i s o n a n d D a v i d (19*77) u s i n g t h e c a l c i u m s a l t a t c o n -

c e n t r a t i o n s e q u i v a l e n t t o t h o s e u s e d i n human a c c i d e n t c a s e s h a v e a l s o s h o w n

t h a t l o c a l a d m i n i s t r a t i o n c a n b e m o r e e f f e c t i v e t h a n s y s t e m i c a d m i n i s t r a t i o n .

DTPA ( 1 5 mg k g " ; 0.1+ m l ) i n j e c t e d i n t o t h e t h i g h m u s c l e o f h a m s t e r s 1 5

m i n u t e s a f t e r i n j e c t i o n o f 8 n C i ( 3 0 0 B q ) o f p l u t o n i u m - 2 3 9 n i t r a t e r e d u c e d

t h e a c t i v i t y a t t h e s i t e o f i n j e c t i o n a t 7 d a y s t o 36% o f c o n t r o l s c o m p a r e d

w i t h 9l4% a f t e r i n t r a p e r i t o n e a l i n j e c t i o n . R e t e n t i o n i n t h e l i v e r a n d

s k e l e t o n w a s 65% a n d 38% o f c o n t r o l s , r e s p e c t i v e l y , c o m p a r e d w i t h 1 0 0 % a n d

66%, r e s p e c t i v e l y , a f t e r i n t r a p e r i t o n e a l i n j e c t i o n . The e f f e c t o f l o c a l

i n j e c t i o n w a s f o u n d t o b e much m o r e v a r i a b l e w h e n t h e same d o s e o f DTPA

w a s g i v e n i n a s m a l l e r v o l u m e o f s o l u t i o n ( 0 . 1 ml c o m p a r e d w i t h 0.1+ m l ) ,

p r e s u m a b l y d u e t o i n c o m p l e t e i n f i l t r a t i o n o f t h e p l u t o n i u m - 2 3 9 d e p o s i t b y

t h e DTPA. V o l f ( 1 9 7 6 ) h a s a l s o r e p o r t e d t h a t f o r t h e l o c a l a d m i n i s t r a t i o n

o f DTPA t o b e m a x i m a l l y e f f e c t i v e i t m u s t c o m p l e t e l y i n f i l t r a t e t h e wound

s i t e .

l+. Summary

B r o n c h o p u l m o n a r y l a v a g e i s t h e o n l y m e t h o d o f t r e a t m e n t t h a t h a s b e e n

s h o w n t o b e o f v a l u e f o r r e m o v i n g i n s o l u b l e r a d i o a c t i v e p a r t i c l e s

d e p o s i t e d i n t h e l u n g s . The t r e a t m e n t h a s b e e n s h o w n t o b e e f f e c t i v e

i n a n i m a l e x p e r i m e n t s b u t h a s b e e n u s e d o n l y o n c e i n man . The m a i n

l i m i t a t i o n i n t h e u s e o f t h i s t e c h n i q u e i s t h a t e a c h l a v a g e may r e m o v e

162

o n l y 20% o r l e s s o f t h e l u n g c o n t e n t . The v a l u e o f t h e t e c h n i q u e

w o u l d b e i n c r e a s e d c o n s i d e r a b l y i f t h e e f f i c i e n c y c o u l d b e i m p r o v e d .

F o r r e m o v i n g a c t i v i t y d e p o s i t e d a t a w o u n d s i t e t h e m o s t s a t i s f a c t o r y

t r e a t m e n t i s e x c i s i o n o f t h e c o n t a m i n a t e d t i s s u e .

I n t r a v e n o u s i n j e c t i o n o f DTPA i s t h e o n l y a c c e p t e d t h e r a p e u t i c m e t h o d

f o r r e m o v i n g s o l u b l e f o r m s o f a c t i n i d e s f r o m t h e b o d y . I t w i l l

e f f e c t i v e l y c l e a r a c t i n i d e s f r o m t h e s y s t e m i c c i r c u l a t i o n a n d some t h a t

h a s r e c e n t l y d e p o s i t e d i n b o n e a n d o t h e r t i s s u e s . I t i s u n a b l e t o

r e m o v e i n t r a c e l l u l a r d e p o s i t s o r a c t i v i t y t h a t h a s b e e n b u r i e d i n b o n e

a n d m u s t t h e r e f o r e b e a d m i n i s t e r e d s o o n a f t e r a n i n t a k e . The u s e o f

a n a e r o s o l i s e d f o r m o f DTPA may b e a c o n s i d e r a b l e a d v a n t a g e i n r e d u c i n g

t h e t i m e b e f o r e t r e a t m e n t i s g i v e n a n d f o r r e m o v i n g l u n g d e p o s i t s o f

s o l u b l e f o r m s o f a c t i n i d e s . L o c a l i n j e c t i o n o f DTPA i n t o c o n t a m i n a t e d

w o u n d s c a n r e m o v e m o r e p l u t o n i u m f r o m t h e b o d y t h a n t h e same a m o u n t

g i v e n i n t r a v e n o u s l y p r o v i d e d t h e DTPA c o m p l e t e l y i n f i l t r a t e s t h e wound

s i t e . A m e t h o d f o r r e m o v i n g b o t h i n t r a c e l l u l a r a n d s k e l e t a l d e p o s i t s

o f a c t i n i d e s i n man i s u r g e n t l y r e q u i r e d .

$ . A c k n o w l e d g e m e n t

The a u t h o r s w o u l d l i k e t o t h a n k D r . J . B r i g h t w e l l a n d D r . J . H a r r i s o n

f o r t h e i r h e l p i n t h e p r e p a r a t i o n o f t h i s C h a p t e r .

Chapter 9

A Q U A N T I T A T I V E ASSESSMENT OF T H E BIOLOGICAL CONSEQUENCES OF HUMAN EXPOSURE T O P L U T O N I U M , AMERICIUM

AND CURIUM

1 . I n t r o d u c t i o n

A p o p u l a t i o n may b e e x p o s e d t o p l u t o n i u m , a m e r i c i u m a n d c u r i u m i n

v a r i o u s w a y s f o l l o w i n g t h e i r r e l e a s e i n t o t h e e n v i r o n m e n t . P a r t i c l e s

c o n t a i n i n g t h e s e a c t i n i d e s c o u l d b e i n h a l e d , e i t h e r a s a r e s u l t o f

a i r b o r n e r e l e a s e s o r f o l l o w i n g t h e i r r e s u s p e n s i o n , o r c o n t a m i n a t e d f o o d -

s t u f f s o r w a t e r may b e c o n s u m e d . T h i s w o u l d r e s u l t i n i r r a d i a t i o n o f

e i t h e r t h e l u n g s o r g u t . A f r a c t i o n o f t h e s e i n c o r p o r a t e d r a d i o n u c l i d e s

w o u l d b e s o l u b l e i n t h e b o d y f l u i d s a n d t r a n s l o c a t e f r o m t h e s i t e o f e n t r y

t o b e d e p o s i t e d i n a n d i r r a d i a t e o t h e r t i s s u e s o f t h e b o d y i n p a r t i c u l a r t h e

l i v e r a n d s k e l e t o n . I n d i v i d u a l s a c c i d e n t a l l y e x p o s e d i n t h e c o u r s e o f t h e i r

w o r k may a l s o i n h a l e o r i n g e s t t h e s e a c t i n i d e s a n d i n some c a s e s t h e y may

e n t e r t h e b o d y t h r o u g h c u t s , a b r a s i o n s o r o t h e r w o u n d s .

D e p e n d i n g u p o n t h e r a d i a t i o n d o s e , b o t h e a r l y a n d l a t e s o m a t i c damage

c o u l d o c c u r i n t h e e x p o s e d p o p u l a t i o n , a n d h e r e d i t a r y e f f e c t s may o c c u r i n

t h e i r d e c e n d a n t s . T h i s d e v e l o p m e n t o f d o s e - e f f e c t r e l a t i o n s h i p s i s b a s e d

u p o n t h e l i m i t e d a m o u n t o f i n f o r m a t i o n a v a i l a b l e o n humans e x p o s e d t o

r a d i a t i o n s u p p l e m e n t e d b y e x p e r i m e n t a l d a t a o b t a i n e d f r o m a n i m a l s .

The s e v e r i t y o f damage t o t i s s u e s d e p e n d s u p o n t h e t y p e o f r a d i a t i o n .

The b i o l o g i c a l e f f e c t i v e n e s s o f r a d i a t i o n s w i t h a h i g h l i n e a r e n e r g y

t r a n s f e r (LET) ( e g , a l p h a p a r t i c l e s ) i s g e n e r a l l y g r e a t e r t h a n r a d i a t i o n s

w i t h a l o w LET ( e g , (3 p a r t i c l e s o r Y - r a y s ) . The r e l a t i v e b i o l o g i c a l

e f f e c t i v e n e s s (RBE) o f h i g h LET r a d i a t i o n c o m p a r e d w i t h l o w LET r a d i a t i o n

v a r i e s w i t h t h e s p e c i e s a n d t h e b i o l o g i c a l t e s t s y s t e m u s e d b u t i n g e n e r a l

i t i n c r e a s e s w i t h d e c r e a s i n g d o s e a n d d o s e r a t e ( I C R P , 1 9 7 2 ) . F o r t h e

c a l c u l a t i o n o f d o s e e q u i v a l e n t i n t i s s u e s f o r r a d i o l o g i c a l p r o t e c t i o n

p u r p o s e s t h e ICRP ( 1 9 7 7 ) h a s r e c o m m e n d e d t h a t t h e a b s o r b e d d o s e f r o m a l p h a

r a d i a t i o n s h o u l d b e m u l t i p l i e d b y a m o d i f y i n g f a c t o r ( q u a l i t y f a c t o r = Q)

o f 2 0 . A l t h o u g h t h i s m o d i f y i n g f a c t o r c a n n o t b e u s e d f o r a s s e s s i n g t h e

l i k e l y c o n s e q u e n c e s o f s e v e r e a c c i d e n t a l e x p o s u r e s , i t i s t o b e a p p l i e d f o r

e s t i m a t i n g t h e i n c i d e n c e o f b o t h l a t e e f f e c t s a n d h e r e d i t a r y e f f e c t s .

163

16k

2 . E a r l y s o m a t i c e f f e c t s

A i r b o r n e r e l e a s e s o f l a r g e a m o u n t s o f a c t i n i d e s may r e s u l t i n s e v e r e

l u n g d a m a g e . T h e r e a p p e a r s t o b e a t h r e s h o l d d o s e e q u i v a l e n t t o a n a v e r a g e

l u n g d o s e o f a b o u t 2000 r a d s (20 G y ; ( a l p h a ) i n a y e a r b e l o w w h i c h d e a t h

w o u l d n o t b e e x p e c t e d . Lung d o s e s i n excess o f t h i s may c a u s e o e d e m a , p n e u -

m o n i t i s a n d f i b r o s i s a n d e v e n t u a l l y r e s u l t i n d e a t h . D o s e s o f t h i s m a g n i t u d e

w o u l d n o t o c c u r e x c e p t a s a r e s u l t o f m a j o r a c c i d e n t a l r e l e a s e s a n d a r e

t h e r e f o r e n o t c o n s i d e r e d f u r t h e r . More i n f o r m a t i o n i s g i v e n i n C h a p t e r 6

o n t h e e a r l y e f f e c t s o f i n h a l e d a c t i n i d e s .

F o r d e p o s i t s o f a c t i n i d e s i n w o u n d s i t e s t h e r e i s i n s u f f i c i e n t i n f o r m -

a t i o n t o b e a b l e t o p r e d i c t t h e e f f e c t s t h a t may o c c u r a t t h e s i t e o f

d e p o s i t i o n . F i b r o u s n o d u l e s a r e t h e o n l y p a t h o l o g i c a l c h a n g e s t h a t h a v e

b e e n o b s e r v e d i n man a t s i t e s o f p l u t o n i u m d e p o s i t s i n w o u n d s o f b e t w e e n

a b o u t k a n d 200 n C i ( 0 . 1 5 kBq a n d 7 k B q ) ( C h a p t e r 3 ) .

3 . L a t e s o m a t i c e f f e c t s

3.1 I n t r o d u c t i o n

The m a j o r l a t e s o m a t i c e f f e c t o f r a d i a t i o n i n man i s c a n c e r . No

c l i n i c a l d i s t i n c t i o n c a n b e made b e t w e e n c a n c e r s i n d u c e d i n t h e p o p u l a t i o n

b y r a d i a t i o n a n d t h o s e r e s u l t i n g f r o m o t h e r c a u s e s .

The r i s k o f r a d i a t i o n - i n d u c e d m a l i g n a n t d i s e a s e h a s b e e n s u m m a r i s e d

i n v a r i o u s r e v i e w s ( I C R P , 1966c; D o l p h i n a n d M a r l e y , 1969; BEIR, 1972;

N a t i o n a l Academy o f S c i e n c e s , 197U; R a s m u s s e n , 1975; NCRP, 1975; MRC,

1975; T h o m e a n d V e n n a r t , 1976; S m i t h a n d S t a t h e r , 1976; ICRP, 1 9 7 7 ) .

T h e r e a r e c o n s i d e r a b l e d i f f i c u l t i e s i n v o l v e d i n a t t e m p t i n g t o e s t a b l i s h

e s t i m a t e s o f r i s k o f p r o d u c i n g c a n c e r i n d i f f e r e n t t i s s u e s . No d e f i n i t i v e

i n f o r m a t i o n i s a v a i l a b l e o n t h e m e c h a n i s m o f c a r c i n o g e n e s i s i n man a n d t h e

d a t a a v a i l a b l e o n c a n c e r i n c i d e n c e u s u a l l y r e l a t e t o r e l a t i v e l y s m a l l

g r o u p s o f p e o p l e e x p o s e d t o h i g h d o s e s o f r a d i a t i o n a t h i g h d o s e r a t e s .

I n m o s t c a s e s , t h e r e f o r e , i t i s n e c e s s a r y t o e x t r a p o l a t e t h e d a t a t o o b t a i n

some a s s e s s m e n t o f t h e a n t i c i p a t e d r i s k o f c a n c e r f r o m e x p o s u r e o f

r e l a t i v e l y l a r g e p o p u l a t i o n s t o l o w d o s e s o f r a d i a t i o n a t l o w d o s e r a t e s .

I n t h i s r e p o r t a l i n e a r , n o - t h r e s h o l d m o d e l h a s b e e n a d o p t e d i n w h i c h t h e

p r o b a b i l i t y o f c a n c e r d e a t h i s c o n s i d e r e d t o b e d i r e c t l y p r o p o r t i o n a l t o

t h e t o t a l d o s e ( I C R P , 1 9 7 7 ) .

N u m e r i c a l e s t i m a t e s o f r i s k a r e e x p r e s s e d i n a b s o l u t e t e r m s . The

a b s o l u t e r i s k i s t h e d i f f e r e n c e b e t w e e n t h e r i s k i n t h e i r r a d i a t e d p o p u l a -

t i o n a n d t h e r i s k i n a c o m p a r a b l e n o n - i r r a d i a t e d p o p u l a t i o n . U s i n g t h e

l i n e a r , n o - t h r e s h o l d , d o s e - i n c i d e n c e m o d e l , t h e a b s o l u t e c a n c e r r i s k c a n

165

b e e x p r e s s e d a s e i t h e r t h e n u m b e r o f e x c e s s c a n c e r s d e v e l o p i n g p e r u n i t o f

t i m e i n a n e x p o s e d p o p u l a t i o n p e r u n i t o f d o s e ( e g , c a n c e r s p e r 1 0 ^ man r a d

p e r y e a r ) o r t h e t o t a l n u m b e r o f e x c e s s c a n c e r s t h a t w o u l d b e e x p e c t e d t o

d e v e l o p d u r i n g t h e r e s t o f t h e i r r a d i a t e d p e r s o n ' s e x p e c t e d l i f e s p a n

( e g , c a n c e r s p e r 1 0 ^ man r a d ) . A l i m i t a t i o n o f t h i s a p p r o a c h i s t h a t i t

a s s u m e s t h a t t h e r e i s n o s y n e r g i s t i c e f f e c t b e t w e e n t h e r a d i a t i o n a n d a n y

o t h e r c a n c e r - i n i t i a t i n g o r p r o m o t i n g a g e n t . H o w e v e r , a b s o l u t e r i s k e s t i -

m a t e s p r o v i d e t h e m o s t a p p r o p r i a t e i n d i c a t i o n o f t h e i m p a c t o n a p o p u l a t i o n

r e s u l t i n g f r o m e x p o s u r e t o r a d i a t i o n b e c a u s e t h e y s p e c i f y d i r e c t l y t h e

n u m b e r o f p e r s o n s a f f e c t e d ( I C R P , 1 9 ^ 9 ) .

T h e r e i s e x t e n s i v e i n f o r m a t i o n a v a i l a b l e i n t h e l i t e r a t u r e o n c a n c e r

i n c i d e n c e i n a n i m a l s f o l l o w i n g e x p o s u r e t o r a d i a t i o n . H o w e v e r , a s t h e

h i s t o l o g i c a l t y p e s o f c a n c e r t h a t o c c u r i n e x p e r i m e n t a l a n i m a l s may d i f f e r

f r o m t h o s e c o m m o n l y s e e n i n m a n , a n d a s t h e r e a r e s p e c i e s d i f f e r e n c e s i n

r a d i o s e n s i t i v i t y , a n i m a l d a t a t o e s t i m a t e r i s k s f o r man m u s t b e u s e d w i t h

e x t r e m e c a u t i o n . O n l y human d a t a h a v e t h e r e f o r e b e e n u s e d f o r c a l c u l a t i n g

r i s k c o e f f i c i e n t s f o r l a t e s o m a t i c e f f e c t s o f r a d i a t i o n . T h e r e a r e n o d a t a

o n t h e d e v e l o p m e n t o f c a n c e r i n humans a s a r e s u l t o f i n c o r p o r a t i o n o f

p l u t o n i u m , a m e r i c i u m o r c u r i u m i s o t o p e s . E s t i m a t e s o f r i s k h a v e t h e r e f o r e

b e e n b a s e d m a i n l y o n t h e r e s u l t s o f e p i d e m i o l o g i c a l s t u d i e s o n humans

e x p o s e d t o e x t e r n a l r a d i a t i o n . Some i n f o r m a t i o n i s a l s o a v a i l a b l e o n t h e

d e v e l o p m e n t o f b o n e a n d l i v e r c a n c e r s a s a r e s u l t o f i n t a k e s o f a l p h a

e m i t t e r s .

E s t i m a t e s o f r i s k c o e f f i c i e n t s h a v e b e e n made f o r r a d i a t i o n - i n d u c e d

d e a t h s f r o m l e u k a e m i a a n d c a n c e r s o f l u n g , b o n e , l i v e r a n d g a s t r o i n t e s t i n a l

t r a c t . I n g e n e r a l , t h e v a l u e s g i v e n a r e r o u n d e d s o a s n o t t o i m p l y

g r e a t e r a c c u r a c y t h a n t h e d a t a a v a i l a b l e j u s t i f y . B e c a u s e o f t h e

l a c k o f human d a t a n o c o r r e c t i o n s a r e r e c o m m e n d e d f o r a n y p o s s i b l e

v a r i a t i o n i n e f f e c t i v e n e s s o f r a d i a t i o n w i t h d i f f e r e n t d o s e s a n d d o s e

r a t e s ( T a b l e 9 . 1 ) •

3 . 2 L e u k a e m i a

The i n d u c t i o n o f l e u k a e m i a b y i o n i s i n g r a d i a t i o n s h a s b e e n d e m o n s t r a t e d

i n a n u m b e r o f e p i d e m i o l o g i c a l s t u d i e s i n man.

I n t h e J a p a n e s e s u r v i v o r s , a t H i r o s h i m a a n d N a g a s a k i , J a b l o n a n d K a t o

( 1 9 7 2 ) f o u n d a n e x c e s s o f l e u k a e m i a s w a s a p p a r e n t b y 5 y e a r s a f t e r e x p o s u r e

s o t h a t t h e l a t e n t p e r i o d f o r r a d i a t i o n - i n d u c e d l e u k a e m i a i s 5 y e a r s o r

p o s s i b l y l e s s . B a s e d o n a n RBE o f 5 f o r n e u t r o n s , a r i s k e s t i m a t e

166

T a b l e 9 , 1

R i s k c o e f f i c i e n t s f o r d e a t h s f r o m c a n c e r

T i s s u e a t R i s k E f f e c t C a n c e r d e a t h s p e r

10° man r a d a l p h a

Lung

L i v e r

C e l l s o n e n d o s t e a l s u r f a c e s 1

B o n e marrow

G . I . t r a c t

Lung C a n c e r

L i v e r C a n c e r

B o n e C a n c e r

L e u k a e m i a

G . I . t r a c t c a n c e r

1*00°

1 0 0 d

1 0 0 d

1+00°

1+00°

a . T h e s e r i s k c o e f f i c i e n t s c a n b e c o n s i d e r e d t o a p p l y t o d o s e s r e c e i v e d o v e r a s h o r t p e r i o d ( e g , 1 y e a r ) c o m p a r e d w i t h t h e p l a t e a u p e r i o d f o r c a n c e r i n d u c t i o n .

b # The r i s k c o e f f i c i e n t a p p l i e s t o d o s e s t o t h e o s t e o -p r o g e n i t o r c e l l s , a s s u m e d t o b e w i t h i n 10 im o f t h e e n d o s t e a l s u r f a c e o f b o n e .

c . D e r i v e d f r o m f o l l o w - u p s t u d i e s o n humans e x p o s e d p r e d o m i n a n t l y t o l o w LET r a d i a t i o n . The r i s k c o e f f i c i e n t s c a l c u l a t e d h a v e b e e n m u l t i p l i e d b y a q u a l i t y f a c t o r o f 20 f o r a l p h a r a d i a t i o n .

d . D e r i v e d f r o m f o l l o w - u p s t u d i e s o n humans e x p o s e d p r e d o m i n a n t l y t o a l p h a i r r a d i a t i o n .

e . R i s k c o e f f i c i e n t s f o r d e a t h s f r o m c a n c e r s o f t h e l u n g , c e l l s o n e n d o s t e a l s u r f a c e s a n d b o n e marrow a r e c o n s i s t e n t w i t h t h o s e g i v e n i n ICRP P u b l i c a t i o n 2 6 , 1 9 7 7 * No s p e c i f i c r i s k c o e f f i c i e n t s a r e g i v e n b y ICRP f o r t h e l i v e r a n d t h e g a s t r o i n t e s t i n a l t r a c t .

167

e q u i v a l e n t t o a b o u t o n e l e u k a e m i a p e r y e a r p e r 1 0 ^ man r a d ( 1 0 ^ man Gy)

( l o w LET) o v e r a 2 0 - y e a r p e r i o d h a s b e e n c a l c u l a t e d ( B E I R , 1 9 7 2 ) . G o s s

( 1 9 7 U ) h a s c a l c u l a t e d a r i s k c o e f f i c i e n t o f 30 l e u k a e m i a s p e r 1 0 ^ man r a d

( 1 0 ^ man Gy) ( l o w LET) f o r a p o p u l a t i o n w i t h a s t a n d a r d a g e d i s t r i b u t i o n .

I n a s t u d y o f p a t i e n t s t r e a t e d w i t h X - r a y s f o r a n k y l o s i n g s p o n d y l i t i s ,

a n e x c e s s o f l e u k a e m i a w a s o b s e r v e d ( C o u r t Brown a n d D o l l , 1 9 6 5 ) . The

p e r i o d o f f o l l o w - u p r a n g e d u p t o 2 7 y e a r s w i t h a m e a n t i m e o f 1 1 . 5 y e a r s .

B a s e d o n a m e a n d o s e t o li0% o f t h e s p i n a l marrow o f a b o u t 8 8 0 r a d ( 8 . 8 G y )

( l o w L E T ) , a r i s k o f a b o u t 1 0 l e u k a e m i a s p e r 1 0 ^ man r a d ( 1 0 ^ man Gy) ( l o w

LET) h a s b e e n c a l c u l a t e d ( D o l p h i n a n d M a r l e y , 1 9 6 9 ) . T h i s e s t i m a t e w o u l d

b e e x p e c t e d t o i n c r e a s e w i t h a l o n g e r f o l l o w - u p . An e x c e s s o f l e u k a e m i a s

h a s a l s o b e e n f o u n d i n p a t i e n t s t r e a t e d b y X - i r r a d i a t i o n t o i n d u c e

a r t i f i c i a l m e n o p a u s e o r f o r o t h e r g y n a e c o l o g i c a l c o n d i t i o n s , S m i t h a n d

D o l l ( 1 9 7 6 ) . Prom t h e d a t a t h e y e s t i m a t e d a n e x c e s s r a t e o f l e u k a e m i a i n

women i n t h e f i r s t 2 0 y e a r s a f t e r t r e a t m e n t o f a b o u t 2 2 p e r 1 0 ^ man r a d

( 1 0 ^ man G y ) ( l o w L E T ) .

A l l t h e s e s t u d i e s a r e i n r e a s o n a b l e a g r e e m e n t a n d i n d i c a t e a r i s k

c o e f f i c i e n t o f a b o u t 2 0 l e u k a e m i a s p e r 1 0 ^ man r a d ( 1 0 ^ man Gy) ( l o w L E T ) .

F o r a l p h a i r r a d i a t i o n t h i s e s t i m a t e c o u l d b e m u l t i p l i e d b y 2 0 ( = Q)

3 . 3 Lung c a n c e r

The BEIR r e p o r t ( 1 9 7 2 ) g i v e s a n e s t i m a t e o f a b o u t 1 . 2 c a s e s o f l u n g

c a n c e r p e r 1 0 ^ p e r r a d ( 1 0 ^ p e r Gy) ( l o w LET) p e r y e a r f o r p a t i e n t s

t r e a t e d f o r a n k y l o s i n g s p o n d y l i t i s w i t h a m e a n f o l l o w - u p t i m e o f 1 1 . 5

y e a r s . I n f o r m a t i o n i s a l s o a v a i l a b l e o n r a d i a t i o n i n d u c e d l u n g c a n c e r i n

J a p a n e s e s u r v i v o r s . I n H i r o s h i m a a l l d o s e g r o u p s a b o v e 1 0 r a d s h a d h i g h e r

m o r t a l i t y r a t i o s t h a n t h e 0 - 9 r a d ( 0 - 0 . 0 9 Gy) d o s e g r o u p b u t i n N a g a s a k i

t h e 0 - 9 r a d ( 0 - 0 . 0 9 G y ) d o s e g r o u p h a d m o r t a l i t y f a r i n e x c e s s o f

e x p e c t a t i o n a t n a t i o n a l r a t e s ( a n i n c r e a s e o f 72%) a n d t h e r e w e r e n o

s i g n i f i c a n t d i f f e r e n c e s among t h e d o s e g r o u p s . I n t h e a b s e n c e o f d a t a o n

s m o k i n g a n d o n t h e e f f e c t s o f h i g h LET n e u t r o n i r r a d i a t i o n o n t h e r e s p i r a -

t o r y s y s t e m , t o w h i c h t h e p o p u l a t i o n a t H i r o s h i m a w a s e x p o s e d , i t i s t h e r e -

f o r e d i f f i c u l t t o i n t e r p r e t t h e d a t a . The BEIR r e p o r t ( 1 9 7 2 ) g i v e s a n

e s t i m a t e o f 0 . 6 c a s e s p e r 1 0 ^ p e r r a d ( 1 0 ^ p e r G y ) ( l o w LET) p e r y e a r

( b a s e d o n a n RBE f o r n e u t r o n s o f 5 ) f o r t h e J a p a n e s e s u r v i v o r s , i n r e a s o n -

a b l e a g r e e m e n t w i t h t h e e s t i m a t e o f 1 2 - i i O c a s e s p e r 1 0 ^ p e r r a d ( 1 0 ^ p e r

G y ) ( l o w LET) o v e r 2 5 y e a r s g i v e n i n t h e UNSCEAR r e p o r t ( 1 9 7 2 ) f o r

J a p a n e s e s u r v i v o r s .

168

R a d i a t i o n - i n d u c e d l u n g c a n c e r i n man h a s a l s o b e e n o b s e r v e d i n s t u d i e s

o n m i n e r s e x p o s e d t o r a d o n a n d i t s d a u g h t e r s ( A r c h e r a n d L u n d i n , 1967 , S e v c

e t a l , 1 9 7 6 ) . H o w e v e r , t h e r e a r e c o n s i d e r a b l e d i f f i c u l t i e s i n e s t i m a t i n g

r i s k c o e f f i c i e n t s f r o m t h e s e d a t a b e c a u s e o f p r o b l e m s i n a s s e s s i n g w h a t

e x p o s u r e s t o r a d o n d a u g h t e r s h a v e a c t u a l l y o c c u r r e d a n d b e c a u s e c a n c e r r i s k

i s u s u a l l y e x p r e s s e d i n t e r m s o f t h e d o s e t o t h e b r o n c h i a l e p i t h e l i u m

r a t h e r t h a n a v e r a g e l u n g d o s e . The i n c i d e n c e o f l u n g c a n c e r i n man i s a l s o

i n f l u e n c e d b y t o b a c c o s m o k i n g ( A r c h e r e t a l , 1973) a n d b y t h e i n h a l a t i o n o f

o t h e r e n v i r o n m e n t a l c o n t a m i n a n t s s u c h a s b e n z p y r e n e o r o c c u p a t i o n a l e x p o s u r e

t o a s b e s t o s f i b r e , a r s e n i c , n i c k e l , o r i r o n a n d i r o n o x i d e s ( S p e n c e r , 1 9 7 3 ) .

F u r t h e r m o r e , t h e h i s t o l o g i c a l t y p e s o f c a n c e r f o u n d i n t h e m i n e r s show a n

i n c r e a s e d i n c i d e n c e o f t h e s m a l l c e l l a n d u n d i f f e r e n t i a t e d t y p e s ( S a c c o m a n n o

e t a l , 1971) w h e r e a s t h o s e f o u n d i n t h e J a p a n e s e s u r v i v o r s a r e m a i n l y

s q u a m o u s c a r c i n o m a a n d a d e n o c a r c i n o m a s (UNSCEAR, 19^2) • I t i s n o t known

w h e t h e r l u n g t u m o u r s i n man i n d u c e d b y i n h a l e d a c t i n i d e s w o u l d o c c u r m a i n l y

i n t h e p e r i p h e r y o f t h e l u n g a s o c c u r s i n d o g s a n d r o d e n t s o r i n t h e m a i n

b r o n c h i , b u t r i s k c o e f f i c i e n t s b a s e d o n f o l l o w u p s t u d i e s i n m i n e r s a r e n o t

a p p r o p r i a t e f o r e s t i m a t i n g r i s k c o e f f i c i e n t s f o r t h e l u n g t h a t c a n b e

a p p l i e d t o a v e r a g e l u n g d o s e s c a l c u l a t e d f o r i n h a l e d l o n g - l i v e d r a d i o -

n u c l i d e s d e p o s i t e d i n t h e p u l m o n a r y r e g i o n o f t h e l u n g .

B a s e d o n t h e d a t a f r o m t h e J a p a n e s e s u r v i v o r s a n d p a t i e n t s t r e a t e d f o r

a n k y l o s i n g s p o n d y l i t i s , a r i s k c o e f f i c i e n t o f 20 c a n c e r s p e r 10^ man r a d

(10^ man Gy) ( l o w LET) i s r e c o m m e n d e d , a l t h o u g h i t i s p o s s i b l e t h a t t h i s

v a l u e may i n c r e a s e w i t h a l o n g e r f o l l o w - u p o f t h e e x p o s e d p o p u l a t i o n s . F o r

a l p h a i r r a d i a t i o n t h i s e s t i m a t e c o u l d b e m u l t i p l i e d b y 20 ( = Q ) .

3«U B o n e c a n c e r

Human d a t a o n b o n e c a n c e r i n d u c e d b y a l p h a i r r a d i a t i o n i s a v a i l a b l e

f r o m l o n g - t e r m s t u d i e s o n o v e r 1700 p e o p l e e x p o s e d t o r a d i u m b e t w e e n a b o u t

1910 a n d 1930 . The f o l l o w - u p o n t h e s e c a s e s now e x t e n d s t o m o r e t n a n 50

y e a r s a f t e r t h e i n i t i a l i n t a k e . I n t h e s t u d y p o p u l a t i o n , 5U b o n e c a n c e r s

a n d 27 c a n c e r s o f t h e p a r a n a s a l s i n u s e s o r m a s t o i d s h a v e o c c u r r e d ( f i v e

p e r s o n s d e v e l o p e d b o t h ) ( R o w l a n d , 1 9 7 5 ) . A l t h o u g h t h e r e a r e d i f f i c u l t i e s

i n e s t i m a t i n g t h e d o s e t o t h e s k e l e t o n f r o m d e p o s i t e d r a d i u m ( I C R P , 1968)

t h e d a t a h a v e b e e n i n t e r p r e t e d b y R o w l a n d (1975) u s i n g t h e N o r r i s r e t e n t i o n

f u n c t i o n (1955) a n d a v e r a g e b o n e d o s e s h a v e b e e n c a l c u l a t e d .

D o l p h i n (1976b) s h o w e d t h a t w h e n t h e d a t a a r e g r o u p e d i n t o d o s e r a n g e s

t h e r i s k c o e f f i c i e n t f o r b o n e c a n c e r i n t h o s e p e o p l e w i t h a n a v e r a g e b o n e

d o s e o v e r 1 0 , 0 0 0 r a d (100 G y ) ( a l p h a ) w a s a b o u t h a l f t h a t o f t h o s e i n t h e

l o w e r d o s e g r o u p . T h i s r e d u c t i o n c o u l d b e d u e t o t h e l o s s o f r e p r o d u c t i v e

169

c a p a c i t y o f p o t e n t i a l l y m a l i g n a n t c e l l s . By f i t t i n g a l i n e a r f u n c t i o n t o

t h e d a t a g i v e n b y R o w l a n d ( 1 9 7 5 ) o n a v e r a g e d o s e t o b o n e a n d b o n e s a r c o m a

i n c i d e n c e f o r t h e c a s e s w i t h a v e r a g e b o n e d o s e s b e l o w 1 0 , 0 0 0 r a d ( 1 0 0 Gy)

( a l p h a ) a r i s k c o e f f i c i e n t o f 5 3 b o n e s a r c o m a s p e r 1 0 ^ man r a d ( 1 0 ^ man Gy)

( a l p h a ) w a s o b t a i n e d . T h i s v a l u e i s i n a g r e e m e n t w i t h t h e v a l u e q u o t e d b y

Mays e t a l , ( 1 9 7 6 ) a n d i s e q u i v a l e n t t o a r i s k o f a b o u t 1 0 6 b o n e s a r c o m a s

p e r 1 0 ^ man r a d ( 1 0 ^ man G y ) ( a l p h a ) i f t h e r i s k c o e f f i c i e n t i s b a s e d o n

t h e d o s e t o t h e s e n s i t i v e c e l l s a d j a c e n t t o t h e e n d o s t e a l s u r f a c e o f b o n e

w h i c h r e c e i v e d a b o u t h a l f t h e a v e r a g e b o n e d o s e ( I C R P , 1 9 6 8 ) . W i t h a l o n g e r

f o l l o w - u p f u r t h e r t u m o u r s may o c c u r . H o w e v e r , m o r e t h a n 90% o f t h e 5 0 - y e a r

d o s e f r o m r a d i u m - 2 2 8 i s r e c e i v e d b y 1 5 y e a r s a f t e r e x p o s u r e a n d , i n t h e

c a s e o f r a d i u m - 2 2 6 , a b o u t o n e - t h i r d o f t h e 5 0 - y e a r d o s e i s r e c e i v e d i n t h e

f i r s t 8 y e a r s a n d a b o u t o n e - h a l f i n t h e f i r s t 1 5 y e a r s ( A d a m s , 1 9 7 6 ) . The

a p p e a r a n c e o f f u r t h e r c a n c e r s w o u l d t h e r e f o r e b e u n l i k e l y t o h a v e a s i g n i -

f i c a n t e f f e c t o n t h e o v e r a l l r i s k c o e f f i c i e n t . B a s e d o n t h e i n f o r m a t i o n

c u r r e n t l y a v a i l a b l e a r i s k c o e f f i c i e n t f o r b o n e c a n c e r o f 1 0 0 c a n c e r s p e r

1 0 ^ man r a d ( 1 0 ^ man G y ) ( a l p h a ) i s t h e r e f o r e r e c o m m e n d e d . I t s h o u l d b e

n o t e d t h a t t h e d o s e i s c a l c u l a t e d f o r t h e o s t e o p r o g e n i t o r c e l l s a s s u m e d

t o b e w i t h i n 1 0 ^m o f t h e e n d o s t e a l s u r f a c e s o f b o n e .

3 . 5 L i v e r c a n c e r

D a t a o n l i v e r c a n c e r i n d u c t i o n a s a r e s u l t o f a l p h a i r r a d i a t i o n i s

a v a i l a b l e f r o m p a t i e n t s t r e a t e d w i t h a n a q u e o u s s u s p e n s i o n o f t h e o x i d e s

o f t h o r i u m - 2 3 2 e n r i c h e d w i t h t h o r i u m - 2 3 0 ( T h o r o t r a s t ) . T h e s e d a t a c a n b e

u s e d t o o b t a i n a p r o v i s i o n a l e s t i m a t e o f l i v e r c a n c e r r i s k . T h o r o t r a s t

d o s i m e t r y i s a p r o b l e m o f g r e a t c o m p l e x i t y d u e t o i n c o m p l e t e k n o w l e d g e o f

t h e p h y s i c o c h e m i c a l a n d b i o l o g i c a l f a c t o r s a f f e c t i n g r a d i a t i o n d o s e t o t h e

l i v e r c e l l s . K a u l ( 1 9 7 3 ) h a s e s t i m a t e d m e a n o r g a n d o s e r a t e s i n man

f o l l o w i n g t h e i n j e c t i o n o f v a r y i n g v o l u m e s o f T h o r o t r a s t w h i c h make

a l l o w a n c e f o r s e l f - a b s o r p t i o n i n t h e T h o r o t r a s t p a r t i c l e s . F a b e r ( 1 9 7 3 a ,

1 9 7 3 ° ) n a s p u b l i s h e d d a t a o n a s e r i e s o f D a n i s h p a t i e n t s t r e a t e d w i t h

T h o r o t r a s t . A t o t a l o f 2 8 l i v e r c a n c e r s ( 1 7 h e p a t o c a r c i n o m a s a n d 1 1

h a e m a n g i © e n d o t h e l i o m a s ) w e r e r o u n d i n 7 5 6 p a t i e n t s w h e r e a s o n l y o n e w a s

e x p e c t e d . The a v e r a g e f o l o w - u p t i m e i n t h e s t u d y w a s a b o u t 30 y e a r s . The

r i s k o f d e v e l o p i n g l i v e r c a n c e r i n t h e s t u d y p o p u l a t i o n h a s b e e n c a l c u l a t e d

a s Ik c a n c e r s p e r 1 0 ^ man r a d ( 1 0 ^ man Gy) ( a l p h a ) ( S m i t h a n d S t a t h e r ,

1 9 7 6 ) .

B e c a u s e o f t h e p r o t r a c t e d d o s e f r o m T h o r o t r a s t , f u r t h e r c a n c e r s may

o c c u r w i t h a l o n g e r f o l l o w - u p t i m e . H o w e v e r , b e c a u s e o f t h e p r o g r e s s i v e

a g g r e g a t i o n o f T h o r o t r a s t p a r t i c l e s a n d t h e c o n s e q u e n t r e d u c t i o n i n t h e

170

m e a n a l p h a d o s e r a t e t o t h e l i v e r w i t h t i m e , a b o u t 65% o f t h e 2 0 - y e a r d o s e

i s a c c u m u l a t e d o v e r t h e f i r s t 1 0 y e a r s a f t e r a d m i n i s t r a t i o n ( K a u l , 1 9 6 ! + ) .

A f u r t h e r i m p o r t a n t f a c t o r i s t h a t e s t i m a t e s o f r i s k may b e f a l s e l y h i g h

i f t h e c h e m i c a l p r o p e r t i e s o f t h o r i u m make i t c a r c i n o g e n i c . I n v i e w o f t h i s

c o n s i d e r a t i o n , t o g e t h e r w i t h c o n s i d e r a b l e u n c e r t a i n t i e s i n T h o r o t r a s t d o s i -

m e t r y a n d t h e l a c k o f i n f o r m a t i o n o n t h e l a t e n t p e r i o d f o r r a d i a t i o n -

i n d u c e d l i v e r c a n c e r ( p o s s i b l y 1 0 - 2 0 y e a r s ) , a r i s k c o e f f i c i e n t w i t h a

r o u n d e d v a l u e o f 1 0 0 c a n c e r s p e r 1 0 ^ man r a d ( 1 0 ^ man G y ) ( a l p h a ) i s

r e c o m m e n d e d .

3 . 6 G a s t r o i n t e s t i n a l t r a c t c a n c e r

V e r y l i t t l e i n f o r m a t i o n i s a v a i l a b l e o n w h i c h t o e s t i m a t e t h e r i s k o f

c a n c e r i n t h e g a s t r o i n t e s t i n a l t r a c t .

B a s e d o n a f o l l o w - u p s t u d y o n t h e J a p a n e s e s u r v i v o r s , a r i s k c o e f f i -

c i e n t f o r t h e s t o m a c h a n d l a r g e b o w e l o f 0 . 5 2 c a n c e r s p e r y e a r p e r 1 0 ^ man

r a d ( 1 0 ^ man G y ) ( l o w LET) ( a s s u m i n g a n RBE f o r n e u t r o n s o f 5 ) h a s b e e n

c a l c u l a t e d ( B E I R , 1 9 7 2 ) . T h i s w o u l d b e e q u i v a l e n t t o a b o u t 1 3 c a n c e r s p e r

1 0 ^ man r a d ( 1 0 ^ man G y ) ( l o w LET) o v e r 2 5 y e a r s .

S m i t h a n d D o l l ( 1 9 7 6 ) h a v e r e p o r t e d a n e x c e s s o f c a n c e r s o f t h e

i n t e s t i n e s , e x c l u d i n g r e c t u m , i n a f o l l o w - u p s t u d y o n women t r e a t e d b y

X - i r r a d i a t i o n o f t h e l o w e r a b d o m e n t o i n d u c e m e n o p a u s e . No t i s s u e d o s e s

w e r e c a l c u l a t e d b u t a m e a n d o s e o f a b o u t 6 0 0 r a d ( 6 G y ) ( l o w LET) ( D o l l

a n d S m i t h , 1 9 6 8 ) , p o s s i b l y t o a b o u t o n e - t h i r d o f t h e i n t e s t i n e , g i v e s a n

e s t i m a t e d r i s k o f a b o u t 21+ c a n c e r s p e r 1 0 ^ man r a d ( 1 0 ^ man Gy) ( l o w LET)

( S m i t h a n d S t a t h e r , 1 9 7 6 ) .

B r i n k l e y a n d H a y b i t t l e ( 1 9 6 9 ) o b s e r v e d e x c e s s d e a t h s f r o m t u m o u r s o f

t h e r e c t u m a n d i n t e s t i n e i n a f o l l o w - u p o f p a t i e n t s g i v e n p r e v i o u s t h e r a -

p e u t i c i r r a d i a t i o n f o r t h e i n d u c t i o n o f a r t i f i c i a l m e n o p a u s e . B a s e d o n a n

e s t i m a t e d m e a n e x p o s u r e o f 8 0 0 r a d ( 8 Gy) t o t h e r e c t u m a n d o n e - h a l f o f

t h i s d o s e t o t h e l a r g e i n t e s t i n e , P o c h i n ( 1 9 7 2 ) h a s e s t i m a t e d a r i s k o f 2 7

c a n c e r s p e r 1 0 ^ man r a d ( 1 0 ^ man G y ) ( l o w L E T ) . F o r t h e r e c t u m a l o n e

( t h r e e o b s e r v e d c a s e s , 0 . 5 e x p e c t e d ) a n y e s t i m a t e w o u l d b e v e r y i m p r e c i s e .

S m i t h a n d D o l l ( 1 9 7 6 ) f o u n d a n e x c e s s o f c a n c e r s o f t h e r e c t u m i n a

f o l l o w - u p o f p a t i e n t s t r e a t e d b y X - i r r a d i a t i o n t o i n d u c e a r t i f i c i a l m e n o -

p a u s e . B a s e d o n a n e s t i m a t e d m e a n e x p o s u r e d o s e t o t h e r e c t u m o f a b o u t

6 0 0 r a d ( 6 Gy) ( D o l l a n d S m i t h , 1 9 6 8 ) , t h i s c o r r e s p o n d s t o a p o s s i b l e r i s k

o f a b o u t t w o c a n c e r s p e r 1 0 ^ man r a d ( 1 0 ^ man G y ) ( l o w LET) ( S m i t h a n d

S t a t h e r , 1 9 7 7 ) .

171

The e v i d e n c e o n w h i c h t o b a s e e s t i m a t e s o f t h e r i s k c o e f f i c i e n t f o r

r a d i a t i o n - i n d u c e d c a n c e r o f t h e g a s t r o i n t e s t i n a l t r a c t i s t h e r e f o r e very -

l i m i t e d . H o w e v e r , t h e s e d a t a w o u l d s u g g e s t t h a t , u n t i l f u r t h e r e v i d e n c e

i s a v a i l a b l e , i t w o u l d b e a p p r o p r i a t e t o u s e a v a l u e o f 2 0 c a n c e r s p e r 1 0

man r a d ( 1 0 ^ man G y ) ( l o w L E T ) . F o r a l p h a i r r a d i a t i o n t h i s e s t i m a t e c o u l d

b e m u l t i p l i e d b y 2 0 ( = Q ) . D o s e s a r e t h o s e a b s o r b e d b y t h e m u c o s a l c e l l

l a y e r . F o r a l p h a a c t i v i t y i n t h e g u t l u m e n t h e d o s e t o t h e m u c o s a l l a y e r

may b e t a k e n t o b e 1 % o f t h a t a t t h e s u r f a c e o f t h e g u t c o n t e n t s . A l t h o u g h

t h i s i s a r a t h e r a r b i t r a r y v a l u e t h e r e i s some e x p e r i m e n t a l e v i d e n c e t h a t

i t s u s e i s w a r r a n t e d ( S u l l i v a n e t a l , i 9 6 0 ) .

1+. H e r e d i t a r y E f f e c t s

i | . 1 The o c c u r r e n c e o f h e r e d i t a r y d i s e a s e s

Damage t o t h e g e r m c e l l s c a n r e s u l t i n s p o n t a n e o u s a b o r t i o n o r

h e r e d i t a r y d i s e a s e . The r i s k o f a b o r t i o n i s d i f f i c u l t t o q u a n t i f y b e c a u s e

many o c c u r s o e a r l y i n p r e g n a n c y a s t o b e u n d e t e c t a b l e . F o r t h i s r e a s o n ,

a b o r t i o n s a r e n o t c o n s i d e r e d i n t h i s r e p o r t . H e r e d i t a r y d i s e a s e s may b e

c l a s s i f i e d i n t o t h r e e t y p e s w h i c h a r e a s s o c i a t e d w i t h damage t o s i n g l e

g e n e s , s e v e r a l g e n e s o r c h r o m o s o m e s .

Damage t o a s i n g l e g e n e may a p p e a r a s a m u t a t i o n ( d o m i n a n t o r

r e c e s s i v e ) o n e i t h e r n o n - s e x c h r o m o s o m e s ( a u t o s o m e s ) o r s e x c h r o m o s o m e s .

D o m i n a n t m u t a t i o n s c a n b e t r a n s m i t t e d t o c h i l d r e n b y e i t h e r p a r e n t a n d t h e

f r e q u e n c y o f t h e o b s e r v e d d i s e a s e i s t h o u g h t t o b e d i r e c t l y p r o p o r t i o n a l t o

t h e m u t a t i o n r a t e . B a s e d u p o n a n i m a l s t u d i e s , i t h a s b e e n c a l c u l a t e d t h a t

a b o u t o n e - f i f t h o f t h e s e m u t a t i o n s a p p e a r a s d i s e a s e i n t h e f i r s t g e n e r a t i o n

a n d t h e y a r e e l i m i n a t e d a t t h e r a t e o f a b o u t 20% i n e a c h s u c c e e d i n g

g e n e r a t i o n ( B E I R , 1 9 7 2 ) . T h e r e c e s s i v e m u t a t i o n i s a l s o t r a n s m i t t e d b u t

a p p e a r s a s d i s e a s e o n l y i f b o t h p a r e n t s c o n t r i b u t e t h e same t y p e o f

d e f e c t i v e g e n e . L i t t l e i s k n o w n a b o u t t h e i n c i d e n c e o f r e c e s s i v e - l i n k e d

d i s e a s e s e x c e p t t h a t t h e y a r e l o w ( l e s s t h a n 0 . 1 % ( S a n k a r a n a r a y a n a n , 1 9 7 6 ) )

a n d may n o t b e c o m e a p p a r e n t f o r many g e n e r a t i o n s . D i s e a s e s l i n k e d t o

d a m a g e d g e n e s i n s e x c h r o m o s o m e s s h o w a p a t t e r n s i m i l a r t o t h a t o b s e r v e d

i n t h e a u t o s o m a l d o m i n a n t d i s e a s e s b u t t h e i r i n c i d e n c e i s a b o u t o n e - t e n t h

o f t h a t o f t h e d o m i n a n t d i s e a s e s . The g r o u p o f s i n g l e g e n e ( m o n o g e n i c )

d i s e a s e s , o f w h i c h t h e a u t o s o m a l d o m i n a n t d i s e a s e s a r e t h e m o s t common,

o c c u r w i t h a f r e q u e n c y o f a b o u t 1 % o f a l l l i v e b i r t h s ( S t e v e n s o n , 1 9 5 9 ,

BEIR, 1 9 7 2 ) .

A n o t h e r g r o u p o f h e r e d i t a r y d i s e a s e s , t h e m u l t i - g e n e o r p o l y g e n i c

d i s e a s e s , a r e m u c h m o r e c o m p l e x i n a e t i o l o g y . T h e y r e f l e c t damage t o m o r e

172

t h a n o n e g e n e a n d t h e i r i n c i d e n c e i s e s t i m a t e d t o b e a b o u t k% o f a l l l i v e

b i r t h s ( B E I R , 1 9 7 2 ) , Some o f t h e s e d i s e a s e s a r e s e e n a s m a l f o r m a t i o n s a t

b i r t h , b u t o t h e r s a p p e a r i n l a t e r l i f e . T h e y c o u l d i n c l u d e m a j o r c a t e g o r i e s

o f c o n s t i t u t i o n a l a n d d e g e n e r a t i v e d i s e a s e s u c h a s d i a b e t e s , s c h i z o p h r e n i a

a n d h e a r t d i s e a s e . H o w e v e r t h e r e l a t i o n s h i p b e t w e e n t h e i r i n c i d e n c e a n d

m u t a t i o n r a t e i s n o t u n d e r s t o o d ; some g e n e t i c i s t s b e l i e v e t h a t t h e y a r e

m a i n t a i n e d m a i n l y b y s e l e c t i o n a n d t h a t a n i n c r e a s e i n m u t a t i o n r a t e w o u l d

n o t i n f l u e n c e t h e p r e v a l e n c e o f t h e s e d i s e a s e s . The m u t a t i o n a l c o m p o n e n t

i s u n l i k e l y t o b e m o r e t h a n 50% a n d i s p r o b a b l y much l o w e r ( B E I R , 1 9 7 2 ) .

I t i s a s s u m e d t h a t s e l e c t i o n i s t h e m a i n m e c h a n i s m o f t r a n s m i s s i o n a n d t h a t

o n l y 5% o f t h e d i s e a s e s a r e m a i n t a i n e d b y m u t a t i o n . The m a g n i t u d e o f

i n d i v i d u a l g e n e e f f e c t s c a u s i n g d i s e a s e i s l i k e l y t o b e l e s s t h a n t h a t o f

t h e s i n g l e g e n e d o m i n a n t m u t a t i o n s a n d a s m a l l e r f r a c t i o n o f t h e t o t a l

i m p a c t w o u l d t h e r e f o r e b e e x p e c t e d i n t h e f i r s t g e n e r a t i o n . I t may t h e r e -

f o r e b e a s s u m e d t h a t 10% o f p o l y g e n i c d i s e a s e s w i l l a p p e a r i n t h e f i r s t

g e n e r a t i o n a n d t h e r a t e o f e l i m i n a t i o n w i l l b e 10% i n e a c h s u c c e e d i n g

g e n e r a t i o n (BEIR, 1 9 7 2 ) .

The t h i r d g r o u p o f h e r e d i t a r y d i s e a s e s i s a s s o c i a t e d w i t h a b e r r a t i o n s

i n t h e c h r o m o s o m e s . T h i s damage m a n i f e s t s i t s e l f a s c h a n g e s i n t h e n u m b e r

o r s t r u c t u r e o f t h e C h r o m o s o m e s . M o s t c h r o m o s o m e a b e r r a t i o n s t e r m i n a t e i n

a b o r t i o n . T h o s e e n d i n g i n a s u c c e s s f u l p r e g n a n c y p r o d u c e c h i l d r e n w h o , i f

t h e y s u r v i v e t h r o u g h a d o l e s c e n c e , a r e m a i n l y s t e r i l e . T h u s , f o r p r a c t i c a l

p u r p o s e s , d i s e a s e s l i n k e d t o c h r o m o s o m e a b e r r a t i o n s a r e e l i m i n a t e d i n t h e

f i r s t a n d s e c o n d g e n e r a t i o n s . T h e i r i n c i d e n c e i s e s t i m a t e d t o b e a b o u t

0.6% o f a l l l i v e b i r t h s ( N e i l s e n a n d S i l l e s e n , 1 9 7 5 ) .

The s e v e r i t y o f h e r e d i t a r y d i s e a s e i s a f a c t o r w h i c h c a n n o t b e

m e a s u r e d . I t may v a r y f r o m d e a t h i n e a r l y c h i l d h o o d t o d i s e a s e s w h i c h a r e

l a t e n t t h r o u g h o u t l i f e a n d c a n b e d e t e c t e d o n l y b y s o p h i s t i c a t e d l a b o r a t o r y

t e s t s .

l i . 2 R a d i a t i o n - i n d u c e d e f f e c t s

R a d i a t i o n - i n d u c e d h e r e d i t a r y d i s e a s e d i f f e r s i n n o known w a y f r o m

h e r e d i t a r y d i s e a s e w h i c h o c c u r s s p o n t a n e o u s l y . The g e n e t i c c o n s e q u e n c e s o f

r a d i a t i o n h a v e b e e n d i s c u s s e d i n r e c e n t r e v i e w s (UNSCEAR, 1972; BEIR, 1972;

R a s m u s s e n , 1975; S a n k a r a n a r a y a n a n , 1976; S m i t h a n d S t a t h e r , 1976; ICRP,

1 9 7 7 ) .

T h e r e i s n o i n f o r m a t i o n o n r a d i a t i o n - i n d u c e d h e r e d i t a r y d i s e a s e i n man

o r a n i m a l s r e s u l t i n g f r o m t h e d e p o s i t i o n o f a c t i n i d e s i n t h e g o n a d s . The

g e n e t i c c o n s e q u e n c e s o f a c t i n i d e a c c u m u l a t i o n i n t h e g o n a d s m u s t t h e r e f o r e

173

b e e x t r a p o l a t e d f r o m i n f o r m a t i o n o n t h e e f f e c t s o f l o w LET r a d i a t i o n .

I n a s t a n d a r d p o p u l a t i o n e x p o s e d t o i o n i s i n g r a d i a t i o n s f r o m r a d i o -

a c t i v i t y r e l e a s e d i n t o t h e e n v i r o n m e n t a t o t a l o f 5 7 c a s e s o f s e r i o u s

h e r e d i t a r y d i s e a s e p e r 1 0 ^ man r a d ( 1 0 ^ man Gy) ( l o w LET) h a v e b e e n

p r e d i c t e d o v e r many g e n e r a t i o n s ( S m i t h a n d S t a t h e r , 1 9 7 6 ) o f w h i c h 1 5 a n d

9 c a s e s p e r 1 0 ^ man r a d ( 1 0 ^ man Gy) ( l o w LET) w o u l d a p p e a r i n t h e f i r s t

a n d s e c o n d g e n e r a t i o n s r e s p e c t i v e l y . The j u s t i f i c a t i o n f o r t h e s e v a l u e s i s

b a s e d u p o n s t u d i e s c a r r i e d o u t m a i n l y i n t h e m o u s e b e c a u s e t h e r e i s l i t t l e

d i r e c t e v i d e n c e o f t h e e f f e c t s o f r a d i a t i o n - i n d u c e d h e r e d i t a r y d i s e a s e i n

man . T h e s e v a l u e s a r e b r o a d l y c o n s i s t e n t w i t h t h o s e g i v e n i n ICRP

P u b l i c a t i o n 2 6 ( 1 9 7 7 ) f o r o c c u p a t i o n a l l y e x p o s e d w o r k e r s a n d f o r m e m b e r s

o f t h e g e n e r a l p u b l i c . The v a l u e s g i v e n b y ICRP a r e 1+0 c a s e s o f h e r e d i t a r y

d i s e a s e p e r 1 0 ^ man r a d ( 1 0 ^ man Gy) f o r t h e f i r s t t w o g e n e r a t i o n s a n d a

f u r t h e r 1+0 c a s e s p e r 1 0 ^ man r a d ( 1 0 ^ man Gy) f o r a l l f u t u r e g e n e r a t i o n s .

B a s e d o n a q u a l i t y f a c t o r o f 2 0 f o r a l p h a i r r a d i a t i o n t h e o v e r a l l r i s k

w o u l d b e e q u i v a l e n t t o 111+0 c a s e s o f s e r i o u s h e r e d i t a r y d i s e a s e p e r 1 0 ^ man

r a d a l p h a (10^" man G y ) . D e r i v e d v a l u e s f o r t h e n u m b e r s o f r a d i a t i o n i n d u c e d

s i n g l e g e n e , m u l t i g e n e a n d c h r o m o s o m e d i s o r d e r s nxe g i v e n i n T a b l e 9 . 2 .

No e s t i m a t e s o f r i s k o f s p o n t a n e o u s a b o r t i o n s h a v e b e e n made f o r

a l t h o u g h t h e y may b e a s o u r c e o f human d i s t r e s s t h e y w i l l b e o f much l e s s

c o n c e r n t h a n c o n g e n i t a l a b n o r m a l i t i e s i n t h e l i v e - b o m a n d w i l l n o t h a v e

a n a p p r e c i a b l e e f f e c t o n human w e l l - b e i n g .

5 . B i o l o g i c a l e f f e c t s i n man

I n o r d e r t o a s s e s s t h e b i o l o g i c a l c o n s e q u e n c e s o f i n t a k e s o f a c t i n i d e s

b y e i t h e r i n d i v i d u a l s o f p o p u l a t i o n s t h e r i s k c o e f f i c i e n t s f o r b o t h r a d -

i a t i o n i n d u c e d c a n c e r a n d h e r e d i t a r y d i s e a s e s m u s t b e w e i g h t e d b y t h e d o s e s

a c c u m u l a t e d b y t h e v a r i o u s t i s s u e s o f t h e b o d y . B e c a u s e o f t h e l o n g h a l f -

t i m e o f r e t e n t i o n o f a c t i n i d e s i n t i s s u e s t h e d o s e s r e c e i v e d w i l l d e p e n d

u p o n t h e a g e a t e x p o s u r e . F u r t h e r m o r e r a d i a t i o n i n d u c e d c a n c e r s d e v e l o p

f o l l o w i n g a l a t e n t p e r i o d a f t e r e x p o s u r e w h e n n o e f f e c t i s s e e n . The l e n g t h

o f b o t h t h e l a t e n t p e r i o d a n d t h e s u b s e q u e n t p e r i o d o f r i s k w i l l t h e r e f o r e

a l s o i n f l u e n c e t h e c o n s e q u e n c e s o f e x p o s u r e . An i d e a l i s e d m o d e l may b e

u s e d f o r c a l c u l a t i n g c a n c e r m o r t a l i t y i n a p o p u l a t i o n f r o m e s t i m a t e d v a l u e s

o r r i s k c o e f f i c i e n t s . I n t h i s m o d e l t h e l a t e n t p e r i o d , i n w h i c h t h e r e i s

a n e g l i g i b l e i n c r e a s e i n c a n c e r i n c i d e n c e , i s f o l l o w e d b y a p e r i o d w i t h a n

i n c r e a s e d i n c i d e n c e o f c a n c e r a t a u n i f o r m r a t e w h i c h l a s t s f o r a n u m b e r

o f y e a r s . F o r l e u k a e m i a i t may b e a s s u m e d t h a t n o n e o c c u r d u r i n g t h e f i r s t

5 y e a r s a f t e r i r r a d i a t i o n a n d t h a t t h e r e i s a c o n s t a n t i n c i d e n c e d u r i n g t h e

Ilk

N u m b e r s i ^ 6 p e r 1 0 man r a d a l p h a e

C l a s s o f d i s e a s e F i r s t

g e n e r a t i o n S e c o n d

g e n e r a t i o n T o t a l f o r

a l l g e n e r a t i o n s

S i n g l e g e n e 0

( m a i n l y a u t o s o m a l d o m i n a n t ) 1 6 0 11+0 81+0

M u l t i - g e n e 0 2 0 2 0 1 6 0

Chromosome^" 1 2 0 2 0 1 4 0

TOTAL 300 1 8 0 111+0

N o t e s : a . B a s e d u p o n 4 2 0 , 0 0 0 l i v e b i r t h s p e r 1 0 p o p u l a t i o n i n o n e g e n e r a t i o n ( 3 0 y e a r s ) .

b . The r a d i a t i o n d o s e r e c e i v e d i n o n e y e a r .

c . A d o u b l i n g d o s e o f 1 0 0 r a d ( l o w LET) t o t h e s p e r m a t o c y t e i s a s s u m e d i n t h e c a l c u l a t i o n s .

d . C o n f i n e d t o t r a n s l o c a t i o n - l i n k e d d i s e a s e s b a s e d u p o n a n i n d u c t i o n r a t e o f 7 7 0 b a l a n c e d t r a n s l o c a t i o n s p e r 1 0 man r a d ( l o w LET) a n d e q u a l s e n s i t i v i t y o f t h e s p e r m a -t o x y t e a n d o o c y t e .

e . B a s e d o n a q u a l i t y f a c t o r o f 2 0 f o r a l p h a r a d i a t i o n .

R e f e r e n c e : S m i t h a n d S t a t h e r ( 1 9 7 6 ) .

R i s k c o e f f i c i e n t s f o r h e r e d i t a r y d i s e a s e s 8 * '

T a b l e 9 . 2

175

n e x t 2 0 y e a r s . F o r a l l o t h e r c a n c e r s t h e i n i t i a l p e r i o d o f n o r i s k c a n b e

t a k e n t o b e 1 5 y e a r s f o l l o w e d b y a p e r i o d o f 3 0 y e a r s a t c o n s t a n t r i s k . I t

i s t h e r e f o r e o n l y a p p r o p r i a t e t o a p p l y t h e f u l l r i s k c o e f f i c i e n t s t o r a d -

i a t i o n d o s e s r e c e i v e d e a r l y i n l i f e .

F o r r a d i a t i o n i n d u c e d h e r e d i t a r y d i s e a s e s t h e e f f e c t o f a n i n t a k e o f

a c t i n i d e s w i l l a l s o d e p e n d u p o n t h e a g e a t e x p o s u r e . R e p r o d u c t i v e l i f e i s

n o r m a l l y a s s u m e d t o c e a s e a t a n a v e r a g e a g e o f 3 0 a n d a n y r a d i a t i o n d o s e

r e c e i v e d b y t h e g o n a d s a f t e r t h i s a g e w i l l h a v e n o e f f e c t o n f u t u r e

g e n e r a t i o n s .

T a b l e 9 * 3 s h o w s t h e 5 0 y e a r c o m m i t t e d d o s e t o t h e t i s s u e s o f i n t e r e s t

f o l l o w i n g t h e i n h a l a t i o n o f 1 u C i ( 3 7 kBq.) o f e i t h e r i n s o l u b l e o r s o l u b l e

c o m p o u n d s o f p l u t o n i u m . The t i s s u e d o s e s h a v e b e e n c a l c u l a t e d ( A d a m s , 1 9 7 8 )

u s i n g t h e m e t h o d s a n d t r a n s f e r f a c t o r s a d o p t e d b y ICRP C o m m i t t e e I I i n

t h e i r f o r t h c o m i n g r e p o r t ( ICRP i n p r e s s ) . The e n d o s t e a l c e l l s o n t h e

s u r f a c e o f t h e b o n e r e c e i v e t h e h i g h e s t d o s e . The d o s e s t o t h e g o n a d s a n d

t o t h e m u c o s a l c e l l l a y e r a r e o n l y a b o u t 1 % a n d 0 . 0 0 2 % o f t h e d o s e t o t h e

e n d o s t e u m .

T a b l e 9»U g i v e s t h e 5 0 y e a r c o m m i t t e d d o s e t o t h e t i s s u e s o f i n t e r e s t

f o l l o w i n g t h e i n g e s t i o n o f 1 u C i ( 3 7 kBq.) o f e i t h e r i n s o l u b l e o r s o l u b l e

p l u t o n i u m c o m p o u n d s . B e c a u s e o f t h e l o w a b s o r p t i o n f r o m t h e g u t t h e t i s s u e

d o s e s a r e c o n s i d e r a b l y l e s s t h a n t h o s e o b t a i n e d f o l l o w i n g i n h a l a t i o n . The

e n d o s t e a l c e l l l a y e r a g a i n r e c e i v e s t h e h i g h e s t d o s e w h i l s t t h e l o w e s t i s

r e c e i v e d b y t h e g o n a d s .

The d o s e s g i v e n i n T a b l e s 9 * 3 a n d 9 * 4 a r e c l e a r l y t h e maximum d o s e s

t h a t a r e l i k e l y t o b e r e c e i v e d . The a c t u a l d o s e s a n d t h e c o n s e q u e n c e s o f

e x p o s u r e w i l l d e p e n d u p o n t h e a g e o f t h e i n d i v i d u a l o r t h e a g e d i s t r i b u t i o n

o f t h e p o p u l a t i o n . The d a t a i n T a b l e s 9 * 3 a n d 9 * 4 d o d e m o n s t r a t e h o w e v e r

t h a t f o l l o w i n g t h e i n h a l a t i o n o f a c t i n d e s t h e t i s s u e s r e c e i v i n g t h e h i g h e s t

d o s e s a r e t h e l u n g , t h e e n d o s t e a l c e l l s o f b o n e , t h e b o n e marrow a n d l i v e r .

The d o s e s t o t h e s e t i s s u e s f o l l o w i n g i n g e s t i o n o f p l u t o n i u m c o m p o u n d s a r e

a b o u t a t h o u s a n d t h o f t h o s e r e c e i v e d f o l l o w i n g t h e i n h a l a t i o n o f c o m p a r a b l e

a m o u n t s o f a c t i v i t y .

6. Efamrnary

To p r o v i d e a b a s i s f o r a n a s s e s s m e n t o f t h e e f f e c t s o n a p o p u l a t i o n o f

e x p o s u r e t o a c t i n i d e s , e s t i m a t e s o f r i s k c o e f f i c i e n t s h a v e b e e n made

f o r a l p h a r a d i a t i o n - i n d u c e d d e a t h s f r o m l e u k a e m i a (1+00 c a s e s p e r 1 0 ^

man r a d a l p h a (1+00 p e r 1 0 ^ man G y ) ) a n d f r o m c a n c e r s o f t h e b o n e ( 1 0 0

c a n c e r s p e r 1 0 ^ man r a d a l p h a ( 1 0 0 p e r 10^" man G y ) ) , l i v e r ( 1 0 0 c a n c e r s

176

p e r 10^ man r a d a l p h a (100 p e r 10^ man G y ) ) , l u n g (1+00 c a n c e r s p e r W

man r a d a l p h a (1+.00 p e r 10^ man G y ) ) a n d g a s t r o i n t e s t i n a l t r a c t (1+00

c a s e s p e r 10^ man r a d a l p h a (1+00 p e r 10^ man G y ) ) , T a b l e 9,1. F o r

s e r i o u s h e r e d i t a r y d i s e a s e s a t o t a l o f 111+0 c a s e s p e r 10^ man r a d

a l p h a (111+0 p e r 10^ man Gy) i s p r e d i c t e d o v e r many g e n e r a t i o n s ( T a b l e

9.2). T h e s e v a l u e s a r e b a s e d o n t h e u s e o f a q u a l i t y f a c t o r o f 20

f o r a l p h a r a d i a t i o n .

ITT

T a b l e 9 . 3

T i s s u e

- 1 r a d u C i i n h a l e d

T i s s u e C l a s s Y

( i n s o l u b l e ) C l a s s W

( s o l u b l e )

b L u n g 5 . 9 E 01 3 . 1 E 00

L i v e r ' 3 . 9 E 01 9 , 8 E 01

E n d o s t e a l c e l l s 0 ' 6 1 . 8 E 0 2 1+.6 E 0 2

B o n e marrow 1.1+ E 01 3 . 7 E 01

f L o w e r l a r g e i n t e s t i n e 5 . 9 E - 0 3 5.U ^ 0 3

G o n a d s 0 ' ^ 2 . 2 E 0 0 5 . 9 E 0 0

L u n g d e p o s i t i o n a n d c l e a r a n c e p a r a m e t e r s a s d e f i n e d i n t h e ICRP

T a s k Group L u n g M o d e l ( ICRP 1 9 6 6 a , 1 9 7 2 ) .

A v e r a g e d o s e t o l u n g a n d a s s o c i a t e d l y m p h n o d e s ( I C R P , 1 9 7 7 ) .

A s s u m e s t h a t o f t h e a c t i v i t y e n t e r i n g t h e b l o o d 1+5% i s d e p o s i t e d i n t h e s k e l e t o n (T£ 100 y e a r s ) 45% i n t h e l i v e r (T£ 1+0 y e a r s ) 0.011% i n t h e o v a r i e s a n d 0.035% i n t h e t e s t e s . The a c t i v i t y d e p o s i t e d i n t h e g o n a d s i s a s s u m e d t o b e r e t a i n e d i n d e f i n i t e l y .

A v e r a g e o r g a n d o s e s .

D o s e c a l c u l a t e d t o t h e o s t e o p r o g e n i t o r c e l l s a s s u m e d t o b e w i t h i n 1 0 urn o f t h e e n d o s t e a l s u r f a c e o f d o s e ( ICRP 1 9 7 7 ) .

A v e r a g e d o s e a b s o r b e d b y t h e m u c o s a l c e l l l a y e r t a k e n t o b e 1 % o f t h a t a t t h e s u r f a c e o f t h e g u t c o n t e n t s .

R e f e r e n c e Adams 1 9 7 8 .

a )

b )

o )

d )

e )

f )

50 y e a r c o m m i t t e d d o s e t o t i s s u e s i n man f o l l o w i n g i n h a l a t i o n o f p l u t o n i u m a e r o s o l s ^AMAD 1 u m j 3 ^ "

178

T a b l e 9.1+

T i s s u e

r a d u C i " 1

i n g e s t e d

T i s s u e cidjs -f-

( i n s o l u b l e ) C l a s s W b

( s o l u b l e )

L i v e r 7

E n d o s t e a l c e l l s 0

B o n e marrow

L o w e r l a r g e i n t e s t

G o n a d s 0 ' d

8 . 1 E - 0 3

3 . 9 E - 0 2

3 . 1 E - 0 3

i n e 1 . 0 E - 0 2

J+.8 E-01+

8 . 1 E - 0 2

3 . 9 E - 0 1

3 . 1 E - 0 2

1 . 0 E - 0 2

1+.8 E - 0 3

0 . 0 0 1 % a b s o r b e d .

0 . 0 1 % a b s o r b e d .

A s s u m e s t h a t o f t h e a c t i v i t y e n t e r i n g t h e b l o o d 1+5% i s d e p o s i t e d i n t h e s k e l e t o n (T£ 1 0 0 y e a r s ) 1+5% i n t h e l i v e r ( T j 1+0 y e a r s ) 0 . 0 1 1 % i n t h e o v a r i e s a n d 0 . 0 3 5 % i n t h e t e s t e s . The a c t i v i t y d e p o s i t e d i n t h e g o n a d s i s a s s u m e d t o b e r e t a i n e d i n d e f i n i t e l y .

A v e r a g e o r g a n d o s e s .

D o s e c a l c u l a t e d t o t h e o s t e o p r o g e n i t o r c e l l s a s s u m e d t o b e w i t h i n 1 0 urn o f t h e e n d o s t e a l s u r f a c e o f b o n e ( ICRP 1 9 7 7 ) .

R e f e r e n c e Adams , 1 9 7 8 .

a )

b )

c )

a)

e )

5 0 y e a r c o m m i t t e d d o s e t o t i s s u e s i n man f o l l o w i n g i n g e s t i o n o f p l u t o n i u m

Chapter 10

S U M M A R Y A N D C O N C L U S I O N S

1 . I n t r o d u c t i o n

The o b j e c t o f t h i s r e v i e w h a s b e e n t o s u m m a r i s e t h e a v a i l a b l e i n f o r m a -

t i o n o n t h e m e t a b o l i s m a n d b i o l o g i c a l e f f e c t s o f t h e a c t i n i d e s p l u t o n i u m ,

a m e r i c i u m a n d c u r i u m r e l e v a n t t o a n a s s e s s m e n t o f t h e r a d i o l o g i c a l h e a l t h

p r o b l e m s r e s u l t i n g f r o m t h e u s e o f m i x e d o x i d e f u e l s o f p l u t o n i u m a n d

u r a n i u m i n l i g h t w a t e r r e a c t o r s .

2. M e t a b o l i s m

2.1 M e t a b o l i s m a t t h e s i t e o f e n t r y

A c t i n i d e s may e n t e r t h e b o d y b y i n h a l a t i o n , t h r o u g h c u t s , a b r a s i o n s o r

o t h e r w o u n d s , o r b y i n g e s t i o n . I f d e p o s i t e d e i t h e r a t a w o u n d s i t e o r i n

t h e r e s p i r a t o r y s y s t e m t h e r e i s a l w a y s a t r a n s p o r t a b l e ( s o l u b l e ) f r a c t i o n

o f m a t e r i a l t h a t r a p i d l y e n t e r s t h e s y s t e m i c c i r c u l a t i o n a n d i s e i t h e r

d e p o s i t e d i n t i s s u e s o r e x c r e t e d . A s e c o n d f r a c t i o n f o r m e d e i t h e r b y r a p i d

h y d r o l y s i s a n d p o l y m e r i s a t i o n o f s o l u b l e a c t i n i d e c o m p o u n d s o r r e s u l t i n g

f r o m a n i n t a k e o f i n s o l u b l e p a r t i c l e s o r c o l l o i d s r e m a i n s a t t h e s i t e o f

e n t r y * Much o f t h i s s e c o n d ( i n s o l u b l e ) f r a c t i o n i s e n g u l f e d b y m a c r o p h a g e s

a n d e v e n t u a l l y may e i t h e r b e t r a n s l o c a t e d t o r e g i o n a l l y m p h a t i c t i s s u e o r i n

t h e c a s e o f d e p o s i t s i n t h e l u n g c l e a r e d u p t h e m u c o c i l i a r y e s c a l a t o r ,

s w a l l o w e d a n d e x c r e t e d i n t h e f a e c e s . Some i n s o l u b l e p a r t i c l e s w i l l a l s o

b e d i s s o l v e d i n b i o l o g i c a l f l u i d s a n d g r a d u a l l y e n t e r t h e s y s t e m i c c i r c u l a -

t i o n . F o r a n y i n t a k e t h e r e l a t i v e p r o p o r t i o n s o f t h e s e t w o f r a c t i o n s d e p e n d

u p o n t h e m a t e r i a l i n i t i a l l y d e p o s i t e d . F o r e x a m p l e , i n t h e c a s e o f a p o l y -

d i s p e r s e a e r o s o l o f h i g h t e m p e r a t u r e c a l c i n e d p l u t o n i u m d i o x i d e d e p o s i t e d i n

t h e l u n g s t h e a m o u n t r a p i d l y m o v i n g t o b l o o d i s n o r m a l l y l e s s t h a n 0.1+%

w h e r e a s f o r a p l u t o n i u m c i t r a t e a e r o s o l i t may b e g r e a t e r t h a n 1+0%.

2.2 E n t r y b y i n h a l a t i o n

A m o d e l f o r t h e d e p o s i t i o n a n d r e t e n t i o n o f i n h a l e d a e r o s o l s i n t h e

human r e s p i r a t o r y t r a c t w a s d e s c r i b e d i n t h e R e p o r t o f t h e T a s k G r o u p o n

Lung I t y n a m i c s (1966) f o r C o m m i t t e e 2 o f t h e I n t e r n a t i o n a l C o m m i s s i o n o n

R a d i o l o g i c a l P r o t e c t i o n a n d m o d i f i e d i n ICRP P u b l i c a t i o n 19> 1972 . I n t h e

m o d e l t h e r e s p i r a t o r y t r a c t h a s b e e n d i v i d e d i n t o t h r e e r e g i o n s ; t h e n a s o -

p h a r y n x , t h e t r a c h e o b r o n c h i a l r e g i o n a n d t h e p u l m o n a r y r e g i o n . The r e g i o n a l

d e p o s i t i o n o f a n i n h a l e d a e r o s o l i s c o n s i d e r e d t o b e p r i m a r i l y a f u n c t i o n o f

t h e p a r t i c l e s i z e d i s t r i b u t i o n . The c h e m i c a l f o r m o f t h e c o m p o u n d i n h a l e d

i n f l u e n c e s t h e s u b s e q u e n t c l e a r a n c e f r o m t h e l u n g . I n t h e m o d e l r e t e n t i o n

179

180

i n t h e l u n g c a n b e f o r d a y s ( C l a s s D ) , w e e k s ( C l a s s W) o r y e a r s ( C l a s s Y ) .

The T a s k G r o u p Lung M o d e l p r e d i c t s t h a t f o l l o w i n g t h e i n h a l a t i o n o f a n

a e r o s o l o f a r e l a t i v e l y s o l u b l e ( C l a s s W) c o m p o u n d ( p a r t i c l e s i z e d i s t r i b u -

t i o n 1 [im AMAD), 1 2 % o f t h e a c t i v i t y w i l l e v e n t u a l l y b e t r a n s f e r r e d t o t h e

b l o o d , a n d f o r a l e s s s o l u b l e ( C l a s s Y) c o m p o u n d 5%. R e t e n t i o n i s e x p o n e n -

t i a l w i t h h a l f - t i m e s o f r e t e n t i o n o f t h e l o n g t e r m c o m p o n e n t i n t h e l u n g o f

$ 0 a n d 5 0 0 d a y s f o r C l a s s W a n d C l a s s Y c o m p o u n d s r e s p e c t i v e l y .

S t u d i e s i n a n i m a l s h a v e s h o w n t h a t p l u t o n i u m c o m p o u n d s g e n e r a l l y c o n -

f o r m t o t h i s c l a s s i f i c a t i o n - o x i d e s a r e C l a s s Y , n i t r a t e s a r e C l a s s W a n d

p l u t o n i u m c o m p l e x e d w i t h t h e c h e l a t i n g a g e n t d i e t h y l e n e t r i a m i n e p e n t a a c e t i c

a c i d (DTPA) i s C l a s s D .

E x p e r i m e n t a l s t u d i e s h a v e a l s o s h o w n t h a t a l l c o m p o u n d s o f a m e r i c i u m

a n d c u r i u m , e x c e p t C l a s s D , b u t i n c l u d i n g t h e o x i d e s , a r e r e t a i n e d i n t h e

l u n g w i t h h a l f - t i m e s o f a f e w w e e k s o r m o n t h s a n d s h o u l d b e c o n s i d e r e d t o

b e C l a s s W.

F o l l o w i n g t h e i n h a l a t i o n o f p a r t i c l e s c o n s i s t i n g o f m i x t u r e s o f

a c t i n i d e s o r a c t i n i d e s i n c o m b i n a t i o n w i t h o t h e r e l e m e n t s t h e r e t e n t i o n i n

t h e l u n g o f t h e i n d i v i d u a l a c t i n i d e s w i l l b e s i m i l a r t o t h a t o f t h e m a t e r i a l

p r e s e n t i n t h e i n h a l e d p a r t i c l e s i n g r e a t e s t m a s s .

2 . 3 E n t r y t h r o u g h c u t s a n d w o u n d s

The b e h a v i o u r o f a c t i n i d e c o m p o u n d s i n c o n t a m i n a t e d w o u n d s d e p e n d s o n

p h y s i c o - c h e m i c a l c h a r a c t e r i s t i c s s u c h a s c h e m i c a l f o r m , p a r t i c l e s i z e , m a s s

i n j e c t e d a n d s p e c i f i c a c t i v i t y a s w e l l a s b i o l o g i c a l f a c t o r s s u c h a s t h e

d e p t h a n d s i t e o f d e p o s i t i o n , t h e t y p e o f t i s s u e , t i s s u e f l u i d f l o w p a s t

t h e d e p o s i t a n d t h e d i s p e r s i o n w i t h i n t h e t i s s u e . I n g e n e r a l t e r m s , s o l u b l e

c o m p o u n d s a r e c l e a r e d m o r e r e a d i l y t h a n i n s o l u b l e c o m p o u n d s , s u b c u t a n e o u s

d e p o s i t s m o r e r e a d i l y t h a n i n t r a m u s c u l a r d e p o s i t s a n d a m e r i c i u m a n d c u r i u m

m o r e r e a d i l y t h a n p l u t o n i u m .

2 .1+ I n g e s t i o n

S t u d i e s i n a n i m a l s o n t h e a b s o r p t i o n o f p l u t o n i u m , f r o m t h e g a s t r o -

i n t e s t i n a l t r a c t , h a v e s h o w n t h a t t h i s i s n o t a s i g n i f i c a n t r o u t e o f u p t a k e

i n t h e a d u l t . F o r s o l u b l e p l u t o n i u m c o m p o u n d s t h a t h a v e e n t e r e d t h e g u t t h e

i n s o l u b l e p l u t o n i u m d i o x i d e p a r t i c l e s 1 x 1 0 y o . P l u t o n i u m i n p a r t i c l e s o f

t h e d i o x i d e l e s s t h a n a b o u t 5 nm i n d i a m e t e r s h o u l d b e t r e a t e d a s s o l u b l e .

I n some c i r c u m s t a n c e s i n g e s t i o n may b e a s i g n i f i c a n t r o u t e o f e n t r y

i n t o t h e b o d y . A m e r i c i u m a n d c u r i u m a r e a b s o r b e d m o r e r e a d i l y f r o m t h e

a m o u n t o f p l u t o n i u m a b s o r b e d may b e a s s u m e d t o b e a b o u t 1 x 1 0 " ^ % a n d f o r

181

g a s t r o i n t e s t i n a l t r a c t t h a n p l u t o n i u m a n d f o r a l l c o m p o u n d s t h e a m o u n t

a b s o r b e d c a n b e t a k e n t o b e a b o u t 5 x 1 0 ~ 2 % . I n y o u n g a n i m a l s a b s o r p t i o n

o f p l u t o n i u m , a m e r i c i u m a n d c u r i u m i s e n h a n c e d r e l a t i v e t o t h e a d u l t . Some

s t u d i e s o n a c t i n i d e s i n c o r p o r a t e d i n t o p l a n t a n d a n i m a l t i s s u e s h a v e s h o w n

t h a t t h e y may b e a b s o r b e d m o r e r e a d i l y t h a n i n o r g a n i c c o m p o u n d s b u t t h e

r e s u l t s t h a t h a v e b e e n o b t a i n e d s o f a r a r e f r a g m e n t a r y a n d v a r i a b l e . More

s t u d i e s a r e n e e d e d o n t h i s r o u t e o f i n t a k e .

2 . 5 T r a n s p o r t i n t h e b l o o d a n d d e p o s i t i o n i n t i s s u e s

A f t e r t h e e n t r y o f p l u t o n i u m i n t o t h e b l o o d m o s t o f i t i s r a p i d l y b o u n d

t o t r a n s f e r r i n , a p r o t e i n t h a t n o r m a l l y t r a n s p o r t s i r o n i n t h e b o d y . The

r e m a i n d e r i s b o u n d t o a s m a l l e r m o l e c u l e w h i c h i s p r o b a b l y c i t r a t e . I t i s

p r o b a b l e t h a t a m e r i c i u m a n d c u r i u m b e h a v e s i m i l a r l y o n e n t r y i n t o t h e b l o o d .

The t i s s u e d i s t r i b u t i o n o f a c t i n i d e s f o l l o w i n g t h e i r e n t r y i n t o t h e

b l o o d i s l a r g e l y i n d e p e n d e n t o f t h e i n i t i a l p h y s i c o - c h e m i c a l f o r m t a k e n i n t o

t h e b o d y . F o r a n a s s e s s m e n t o f t h e c o n s e q u e n c e s o f human e x p o s u r e t o t h e s e

a c t i n i d e s t h e r e a r e t h r e e i m p o r t a n t s i t e s o f d e p o s i t i o n : t h e l i v e r , b o n e

a n d g o n a d s . A p a r t f r o m t h e s e t h r e e t i s s u e s a c t i n i d e s a r e d e p o s i t e d i n a l l

t h e o t h e r t i s s u e s o f t h e b o d y b u t b e c a u s e o f t h e g e n e r a l l y l o w r a d i a t i o n

d o s e s i n v o l v e d t h e y n e e d n o t b e c o n s i d e r e d a s c r i t i c a l t i s s u e s .

The l i v e r a n d b o n e t o g e t h e r a c c u m u l a t e a b o u t 90% o f t h e s y s t e m i c

d e p o s i t a l t h o u g h t h e d i s t r i b u t i o n o f a c t i v i t y b e t w e e n t h e m i s v e r y v a r i a b l e .

O v e r a l l 1+5% o f t h e s y s t e m i c a c t i v i t y c a n b e c o n s i d e r e d t o d e p o s i t i n e a c h

t i s s u e . R e t e n t i o n i s e x p o n e n t i a l w i t h h a l f - t i m e s i n human b o n e a n d l i v e r

e s t i m a t e d t o b e 1 0 0 a n d 1+0 y e a r s r e s p e c t i v e l y .

B e c a u s e o f t h e p o t e n t i a l g e n e t i c r i s k t h e t h i r d i m p o r t a n t s i t e o f

d e p o s i t i o n f r o m t h e b l o o d i s t h e g o n a d s . B a s e d u p o n b o t h a n i m a l a n d human

d a t a i t h a s b e e n e s t i m a t e d t h a t t h e human t e s t e s w i l l a c c u m u l a t e 3 x 1 0 " ^ %

o f a c t i v i t y e n t e r i n g t h e b l o o d a n d t h e o v a r i e s 1 x 10~"^%. A l t h o u g h d a t a o n

t h e r e t e n t i o n o f a c t i n i d e s i n t h e g o n a d s i s v e r y l i m i t e d a n i m a l s t u d i e s

s u g g e s t t h a t t h e y a r e r e t a i n e d i n d e f i n i t e l y .

2 . 6 E x c r e t i o n

A c t i n i d e s i n c o r p o r a t e d i n t o t h e b o d y a r e e x c r e t e d b o t h i n t h e f a e c e s

a n d i n t h e u r i n e . F a e c a l e x c r e t i o n r e s u l t s f r o m a c t i n i d e s e n t e r i n g t h e g u t

e i t h e r i n m u c o u s c l e a r e d f r o m t h e r e s p i r a t o r y s y s t e m o r i n g u t s e c r e t i o n s .

U r i n a r y e x c r e t i o n i s d u e t o u l t r a f i l t r a t i o n t h r o u g h t h e k i d n e y o f a c t i n i d e -

c i t r a t e c o m p l e x e s f o r m e d i n t h e b l o o d .

A n i m a l s t u d i e s h a v e s h o w n t h a t m o r e a m e r i c i u m a n d c u r i u m a r e e x c r e t e d

182

i n t h e u r i n e t h a n p l u t o n i u m . The a p p l i c a t i o n o f u r i n a r y e x c r e t i o n d a t a f o r

p l u t o n i u m i n man t o t h e s e h i g h e r a c t i n i d e s i s t h e r e f o r e l i k e l y t o o v e r -

e s t i m a t e s y s t e m i c d e p o s i t s .

3 - B i o l o g i c a l E f f e c t s

From t h e s m a l l n u m b e r s o f w o r k e r s who h a v e i n c o r p o r a t e d p l u t o n i u m o r

o t h e r a c t i n i d e s t h e r e i s n o e v i d e n c e o f l i f e s h o r t e n i n g o r m a l i g n a n t d i s e a s e

w h i c h c a n b e a t t r i b u t e d t o t h e s e i n t a k e s . E x t e n s i v e a n i m a l s t u d i e s h a v e

d e m o n s t r a t e d t h a t b i o l o g i c a l e f f e c t s may o c c u r p r e d o m i n a n t l y i n t h e l u n g ,

b o n e , l i v e r , b l o o d a n d l y m p h n o d e s b u t g e n e r a l l y a t h i g h e r l e v e l s o f

i n c o r p o r a t i o n t h a n h a v e b e e n o b s e r v e d i n man . E f f e c t s h a v e a l s o o c c u r r e d a t

w o u n d s i t e s c o n t a m i n a t e d w i t h a c t i n i d e s . No e f f e c t s h a v e b e e n s e e n i n t h e

g a s t r o - i n t e s t i n a l t r a c t a s a r e s u l t o f i n g e s t i o n o r i n h a l a t i o n o f a c t i n i d e s .

3 . 1 Lung

E a r l y e f f e c t s o f r a d i a t i o n r e s u l t i n g i n d e a t h w i t h i n a b o u t a y e a r h a v e

b e e n s e e n i n d o g s a n d r o d e n t s t h a t h a v e i n h a l e d l a r g e a m o u n t s o f p l u t o n i u m -

2 3 9 d i o x i d e e q u i v a l e n t t o m o r e t h a n a b o u t 100 uCi ( 3 - 7 MBq) i n man . T h e s e

c h a n g e s i n c l u d e o e d e m a , p n e u m o n i t i s a n d f i b r o s i s . A t l o w e r i n t a k e s

( e q u i v a l e n t t o a b o v e a b o u t 1 jiCi ( 3 7 k B q ) i n man) l u n g c a n c e r s h a v e b e e n

o b s e r v e d a s t h e m a i n l a t e e f f e c t o f i n h a l e d p l u t o n i u m - 2 3 9 d i o x i d e . S i m i l a r

e f f e c t s h a v e b e e n s e e n f o r t h e h i g h e r a c t i n i d e s r e t a i n e d i n t h e l u n g s

a l t h o u g h b e c a u s e o f t h e m o r e u n i f o r m d i s t r i b u t i o n o f t h e a m e r i c i u m a n d

c u r i u m i n t h e l u n g e f f e c t s h a v e b e e n p r o d u c e d a t l o w e r t i s s u e d o s e s . I n

g e n e r a l c a n c e r s o b s e r v e d i n e x p e r i m e n t a l a n i m a l s o c c u r i n t h e p e r i p h e r a l

r e g i o n o f t h e l u n g s . I n man n a t u r a l l y o c c u r r i n g c a n c e r s o r c a n c e r s o c c u r r -

i n g a f t e r e x p o s u r e t o t o b a c c o smoke o r t o r a d o n a n d i t s d a u g h t e r s i n m i n e s

a r e f o u n d m a i n l y i n t h e p r i m a r y a n d s e g m e n t a l b r o n c h i . I t i s n o t k n o w n

w h e t h e r p l u t o n i u m i n d u c e d c a n c e r i n man w o u l d o c c u r p e r i p h e r a l l y o r i n t h e

m a i n b r o n c h i . Much w o r k h a s s t i l l t o b e d o n e i n d e f i n i n g t h e l u n g c e l l s

m o s t a t r i s k .

3 . 2 B l o o d a n d b o n e m a r r o w

C h a n g e s i n c i r c u l a t i n g b l o o d c e l l s h a v e b e e n s e e n a f t e r t h e i n h a l a t i o n

o r i n t r a v e n o u s i n j e c t i o n o f p l u t o n i u m c o m p o u n d s . The m o s t f r e q u e n t c h a n g e

s e e n h a s b e e n a c h r o n i c r e d u c t i o n i n l y m p h o c y t e c e l l c o u n t . L y m p h o p o e n i a

h a s o c c u r r e d i n d o g s f o l l o w i n g t h e i n h a l a t i o n o f q u a n t i t i e s o f p l u t o n i u m

e q u i v a l e n t t o m o r e t h a n a b o u t 1 [iCi ( 3 7 k B q ) i n man. The s i g n i f i c a n c e o f

t h i s i s n o t k n o w n . I t m i g h t b e a n t i c i p a t e d t h a t b e c a u s e p l u t o n i u m d e p o s i t s

i n b o n e a n d l y m p h n o d e s , b l o o d s t e m c e l l n e o p l a s i a s h o u l d b e a c o n s e q u e n c e

o f p l u t o n i u m c o n t a m i n a t i o n . L e u k a e m i a h a s h o w e v e r b e e n f o u n d r a r e l y i n

183

a n i m a l s a n d a l m o s t e x c l u s i v e l y i n r o d e n t s a d m i n i s t e r e d w i t h l a r g e a m o u n t s o f

a c t i v i t y . B e c a u s e o f t h e o b s e r v e d i n c r e a s e d i n c i d e n c e o f l e u k a e m i a i n

h u m a n s e x p o s e d t o e x t e r n a l r a d i a t i o n t h e b o n e m a r r o w i n man m u s t b e c o n s i d -

e r e d p o t e n t i a l l y a t r i s k f r o m e x p o s u r e t o a l p h a i r r a d i a t i o n f r o m a c t i n i d e s

d e p o s i t e d i n b o n e .

3 . 3 B o n e a n d l i v e r

B o n e f r a c t u r e s h a v e b e e n o b s e r v e d i n a n i m a l s g i v e n i n t r a v e n o u s i n j e c -

t i o n s o f l a r g e d o s e s o f p l u t o n i u m - 2 3 9 ( e q u i v a l e n t t o m o r e t h a n 7 0 +iCi

( 2 . 6 MBq) i n m a n ) . A t l o w e r d o s e s s t u d i e s i n a n i m a l s h a v e s h o w n t h a t b o n e

c a n c e r i s t h e m o s t f r e q u e n t f o r m o f m a l i g n a n c y i n d u c e d b y p l u t o n i u m - 2 3 9 t h a t

h a s e n t e r e d t h e s y s t e m i c c i r c u l a t i o n . I n g e n e r a l t h e a p p e a r a n c e t i m e o f

t h e s e c a n c e r s i s d e p e n d e n t u p o n t h e a m o u n t o f p l u t o n i u m d e p o s i t e d i n b o n e .

A v a r i a t i o n i n s e n s i t i v i t y b e t w e e n d i f f e r e n t a n i m a l s p e c i e s h a s b e e n d e m o n -

s t r a t e d a n d t h e r e a r e t h e r e f o r e p r o b l e m s i n e x t r a p o l a t i n g t h e s e r e s u l t s t o

man. B o n e c a n c e r s h a v e a l s o o c c u r r e d i n d o g s g i v e n i n t r a v e n o u s i n j e c t i o n s

o f a m e r i c i u m - 2 1 + 1 , i n d o g s t h a t h a d i n h a l e d p l u t o n i u m - 2 3 8 o x i d e , a n d i n r a t s

t h a t h a d i n h a l e d a m e r i c i u m a n d c u r i u m c o m p o u n d s .

L i v e r c a n c e r s h a v e b e e n o b s e r v e d i n d o g s g i v e n i n t r a v e n o u s i n j e c t i o n s

o f p l u t o n i u m - 2 3 9 b u t t h e y h a v e o c c u r r e d m u c h l e s s f r e q u e n t l y t h a n b o n e

c a n c e r s . D e s p i t e t h e l o w i n c i d e n c e o f l i v e r c a n c e r s f o u n d i n a n i m a l s t h i s

t i s s u e m u s t b e c o n s i d e r e d p o t e n t i a l l y a t r i s k i n man u n t i l s h o w n t o b e

o t h e r w i s e .

3»U Lvmph n o d e s

Some o f t h e p l u t o n i u m o r o t h e r a c t i n i d e s d e p o s i t e d e i t h e r i n t h e l u n g s

o r a t a w o u n d s i t e may b e t r a n s l o c a t e d t o r e g i o n a l l y m p h a t i c t i s s u e .

B e c a u s e o f t h e i r s m a l l m a s s t h e r a d i a t i o n d o s e t o t h e s e n o d e s may g r e a t l y

e x c e e d t h a t t o t h e s i t e o f i n t a k e o r t o o t h e r t i s s u e s . H o w e v e r , e v i d e n c e

f r o m s t u d i e s i n e x p e r i m e n t a l a n i m a l s i s t h a t t h e o n l y s i g n i f i c a n t damage

t h a t o c c u r s i n t h i s t i s s u e i s f i b r o s i s o r n e c r o s i s a n d t h a t t h e y a r e n o t

a p r i m a r y s i t e f o r t h e d e v e l o p m e n t o f r a d i a t i o n i n d u c e d m a l i g n a n t d i s e a s e .

Prom t h i s r e a s o n l y m p h a t i c t i s s u e s h o u l d n o t b e c o n s i d e r e d a c r i t i c a l t i s s u e

f o r i n t a k e s o f a c t i n i d e s .

3 - 5 Gut

No e f f e c t s o n t h e g a s t r o - i n t e s t i n a l t r a c t h a v e b e e n o b s e r v e d e i t h e r

i n man o r a n i m a l s f o l l o w i n g e x p o s u r e t o a c t i n i d e s . I t i s u n l i k e l y , b u t

n e v e r t h e l e s s p o s s i b l e , t h a t c a n c e r s o f t h e g a s t r o - i n t e s t i n a l t r a c t c o u l d

o c c u r a s a r e s u l t o f i n g e s t i o n o f l a r g e a m o u n t s o f a c t i n i d e s .

181;

3 . 6 G o n a d s

No t u m o u r s o r e v i d e n c e o f h e r e d i t a r y e f f e c t s r e s u l t i n g f r o m t h e

i n c o r p o r a t i o n o f a c t i n i d e s i n t h e g o n a d s h a s b e e n d e m o n s t r a t e d i n a n y o f

t h e a n i m a l s p e c i e s s t u d i e d . I n o r d e r t o a s s e s s t h e h e r e d i t a r y e f f e c t s o f

a c t i n i d e s i n c o r p o r a t e d i n t h e g o n a d s i t i s t h e r e f o r e n e c e s s a r y t o e x t r a -

p o l a t e f r o m s t u d i e s o n a n i m a l s e x p o s e d t o e x t e r n a l r a d i a t i o n .

3 . 7 Wounds

The o n l y c l i n i c a l o r p a t h o l o g i c a l c h a n g e r e p o r t e d i n man h a s b e e n t h e

d e v e l o p m e n t a f t e r a f e w m o n t h s o r y e a r s o f f i b r o u s n o d u l e s a r o u n d t h e s i t e

o f p l u t o n i u m d e p o s i t s o f b e t w e e n k a n d 200 n C i (0.15 a n d 7 -4 k B q ) .

3 . 8 The h o t p a r t i c l e p r o b l e m

The h y p o t h e s i s t h a t n o n - u n i f o r m i r r a d i a t i o n o f t h e l u n g b y p a r t i c l e s o f

p l u t o n i u m o r o t h e r a c t i n i d e s i s l i k e l y t o b e m o r e c a r c i n o g e n i c t h a n u n i f o r m

i r r a d i a t i o n o f t h e l u n g i s n o t s u p p o r t e d b y t h e e v i d e n c e a v a i l a b l e . F o r a

g i v e n a m o u n t o f a c t i v i t y u n i f o r m i r r a d i a t i o n o f t h e l u n g i n c r e a s e s t h e

n u m b e r o f c e l l s a t r i s k a n d i s p o t e n t i a l l y m o r e c a r c i n o g e n i c .

U. T h e r a p y

B r o n c h o p u l m o n a r y l a v a g e i s t h e o n l y m e t h o d o f t r e a t m e n t t h a t h a s b e e n

s h o w n t o b e e f f e c t i v e i n a n i m a l s f o r r e m o v i n g i n s o l u b l e r a d i o a c t i v e p a r t i -

c l e s d e p o s i t e d i n t h e l u n g s . The t r e a t m e n t h a s b e e n u s e d o n l y o n c e i n man

f o r r e m o v i n g a n i n t a k e o f p l u t o n i u m a n d w a s n o t v e r y e f f e c t i v e . The

a c c u m u l a t e d e v i d e n c e f r o m a n i m a l e x p e r i m e n t s s u g g e s t s t h a t e x t e n d i n g t h e

c o u r s e o f t r e a t m e n t w o u l d h a v e f u r t h e r r e d u c e d t h e l u n g c o n t e n t o f p l u t o n i u m .

F o r r e m o v i n g a c t i v i t y d e p o s i t e d a t a wound s i t e t h e m o s t s a t i s f a c t o r y

t r e a t m e n t i s e x c i s i o n o f a s much o f t h e c o n t a m i n a t e d t i s s u e a s p o s s i b l e .

I n t r a v e n o u s i n j e c t i o n o f t h e c a l c i u m s a l t o f t h e c h e l a t i n g a g e n t

d i e t h y l e n e t r i a m i n e p e n t a a c e t i c a c i d (DTPA) i s t h e o n l y p r e s e n t l y u s e d

m e t h o d f o r r e m o v i n g s o l u b l e f o r m s o f a c t i n i d e f r o m t h e b o d y . I t w i l l

e f f e c t i v e l y c l e a r a c t i n i d e s f r o m t h e b l o o d a n d e x t r a c e l l u l a r f l u i d a n d some

t h a t h a s r e c e n t l y d e p o s i t e d i n b o n e a n d o t h e r t i s s u e s . I t i s u n a b l e t o

r e m o v e i n t r a c e l l u l a r d e p o s i t s o r a c t i v i t y t h a t h a s b e e n b u r i e d i n b o n e a n d

m u s t t h e r e f o r e b e a d m i n i s t e r e d s o o n a f t e r a n i n t a k e . The u s e o f a n a e r o s o l -

i s e d f o r m o f DTPA may b e a c o n s i d e r a b l e a d v a n t a g e i n r e d u c i n g t h e t i m e

b e f o r e t r e a t m e n t i s g i v e n a n d f o r r e m o v i n g l u n g d e p o s i t s o f s o l u b l e f o r m s o f

a c t i n i d e s . L o c a l i n j e c t i o n o f DTPA i n t o c o n t a m i n a t e d w o u n d s c a n r e m o v e m o r e

p l u t o n i u m f r o m t h e b o d y t h a n t h e same a m o u n t g i v e n i n t r a v e n o u s l y p r o v i d e d

t h e DTPA c o m p l e t e l y i n f i l t r a t e s t h e w o u n d s i t e . A m e t h o d f o r r e m o v i n g b o t h

185

i n t r a c e l l u l a r a n d s k e l e t a l d e p o s i t s o f a c t i n i d e s i s u r g e n t l y r e q u i r e d .

5 . H e a l t h E f f e c t s i n Man

A s t h e h i s t o l o g i c a l t y p e s o f c a n c e r s e e n i n e x p e r i m e n t a l a n i m a l s

may d i f f e r f r o m t h o s e c o m m o n l y s e e n i n man a n d a s t h e r e a r e s p e c i e s

d i f f e r e n c e s i n r a d i o s e n s i t i v i t y , o n l y human d a t a h a v e b e e n u s e d f o r

c a l c u l a t i n g r i s k c o e f f i c i e n t s f o r l a t e s o m a t i c e f f e c t s o f r a d i a t i o n .

T h e r e a r e n o d a t a o n t h e d e v e l o p m e n t o f c a n c e r s i n h u m a n s a s a r e s u l t

o f i n c o r p o r a t i o n o f p l u t o n i u m , a m e r i c i u m o r c u r i u m i s o t o p e s . E s t i m a t e s

o f r i s k h a v e t h e r e f o r e b e e n b a s e d m a i n l y o n t h e r e s u l t s o f e p i d e m i l o g i c a l

s t u d i e s o n h u m a n s e x p o s e d t o e x t e r n a l r a d i a t i o n . Some i n f o r m a t i o n i s

a l s o a v a i l a b l e o n t h e d e v e l o p m e n t o f b o n e a n d l i v e r c a n c e r s a s a r e s u l t

o f i n t a k e s o f o t h e r a l p h a e m i t t e r s .

To p r o v i d e a b a s i s f o r a n a s s e s s m e n t o f t h e e f f e c t s o n a p o p u l a t i o n

o f e x p o s u r e t o a c t i n i d e s , e s t i m a t e s o f r i s k c o e f f i c i e n t s h a v e b e e n made

f o r a l p h a r a d i a t i o n - i n d u c e d d e a t h s f r o m l e u k a e m i a (1+00 c a s e s p e r 10^ man

r a d a l p h a (1+00 p e r 10^ man G y ) ) a n d f r o m c a n c e r s o f t h e b o n e (100 c a n c e r s

p e r 10^ man r a d a l p h a (100 p e r 10^ man G y ) ) , l i v e r (100 c a n c e r s p e r 10^

man r a d a l p h a (100 p e r 10 " man G y ) ) , l u n g (1+00 c a n c e r s p e r 10^ man r a d

a l p h a (1+00 p e r 10 " man G y ) ) a n d g a s t r o i n t e s t i n a l t r a c t (1+00 c a s e s p e r

10^ man r a d a l p h a (1+00 p e r 10^ man G y ) ) . F o r s e r i o u s h e r e d i t a r y d i s e a s e s

a t o t a l o f 111+0 c a s e s p e r 10^ man r a d a l p h a (111+0 p e r 10^ man Gy) i s

p r e d i c t e d o v e r many g e n e r a t i o n s . T h e s e v a l u e s a r e b a s e d o n t h e u s e o f a

q u a l i t y f a c t o r o f 20 f o r a l p h a r a d i a t i o n .

To a s s e s s t h e b i o l o g i c a l c o n s e q u e n c e s o f i n t a k e s o f a c t i n i d e s t h e s e

r i s k c o e f f i c i e n t s m u s t b e w e i g h t e d b y t h e d o s e s a c c u m u l a t e d b y t h e

v a r i o u s t i s s u e s . F u r t h e r m o r e t h e r i s k c o e f f i c i e n t s f o r r a d i a t i o n i n d u c e d

c a n c e r s a r e b a s e d o n t h e a s s u m p t i o n t h a t t h e f u l l r i s k t o t h e t i s s u e s i s

e x p r e s s e d . B e c a u s e o f t h e l o n g l a t e n t p e r i o d f o r c a n c e r i n d u c t i o n t h i s

w i l l o n l y a p p l y t o d o s e s r e c e i v e d e a r l y i n l i f e . The g e n e t i c a l l y s i g n -

i f i c a n t d o s e i s t h a t a c c u m u l a t e d u p t o a g e a b o u t 30.

A P P E N D I X N o t e o n U n i t s

1 . The u n i t s m o s t f r e q u e n t l y u s e d i n t h e t e x t a r e :

U n i t o f a c t i v i t y : t h e c u r i e ^ i s t h a t q u a n t i t y o f r a d i o a c t i v e m a t e r i a l

g i v i n g 3*1 x 1 0 " ^ d i s i n t e g r a t i o n s p e r s e c o n d , a n d c o r r e s p o n d s t o t h e

a m o u n t o f r a d o n i n e q u i l i b r i u m w i t h l g o f r a d i u m . Some s u b - u n i t s a r e :

1 m i l l i c u r i e ( m C i ) = l c f ^ C i

1 m i c r o c u r i e ( | i C i ) = 10~^ C i

1 n a n o c u r i e ( n C i ) = 10~^ C i

—12 1 p i c o c u r i e ( p C i ) = 10*" C i

U n i t o f a b s o r b e d d o s e : t h e r a d , w h i c h c o r r e s p o n d s t o a n a b s o r b e d —2 —1

e n e r g y o f 10 j o u l e s p e r k i l o g r a m o f t i s s u e ( = 100 e r g . g ) .

U n i t o f d o s e e q u i v a l e n t : t h e r e m . The b i o l o g i c a l e f f e c t i v e n e s s o f

t h e a b s o r b e d d o s e d e p e n d s u p o n s u c h f a c t o r s a s t h e s p a t i a l d i s t r i b u t i o n

o f t h e d o s e a n d t h e l i n e a r e n e r g y t r a n s f e r o f t h e r a d i a t i o n . The rem

i s t h e p r o d u c t o f t h e a b s o r b e d d o s e m u l t i p l i e d b y o n e o r m o r e w e i g h t i n g

f a c t o r s w h i c h t a k e a c c o u n t o f t h e s e d i f f e r e n t i r r a d i a t i o n c o n d i t i o n s .

2. T h e s e u n i t s a r e b e i n g p r o g r e s s i v e l y r e p l a c e d b y t h e I n t e r n a t i o n a l

S y s t e m o f U n i t s ( S i )

U n i t o f a c t i v i t y : t h e B e c q u e r e l ( B q )

1 Bq = 1 d i s i n t e g r a t i o n p e r s e c o n d

U n i t o f a b s o r b e d d o s e : t h e G r a y ( G y ) _ 1

1 Gy = 1 j o u l e k g

U n i t o f d o s e e q u i v a l e n t : t h e S i e v e r t ( S v )

1 S v = 100 r em

187

188

The r e l a t i o n s h i p b e t w e e n t h e n e w S I u n i t s a n d t h e p r e v i o u s u n i t s a r e

s h o w n i n t h e t a b l e b e l o w :

Q u a n t i t y New n a m e d u n i t

a n d s y m b o l I n o t h e r S I u n i t s

O l d s p e c i a l u n i t a n d s y m b o l

C o n v e r s i o n f a c t o r

A b s o r b e d d o s e

g r a y ( G y ) J k g " 1 r a d ( r a d ) 1 Gy = 100 r a d

D o s e e q u i v a l e n t

s i e v e r t ( S v ) J k g " 1 r e m ( r e m ) 1 S v = 100 rem

A c t i v i t y b e c q u e r e l ( B q ) - 1

s c u r i e ( C i ) 1 B q * 2 . 7 x 1 0 " 1 1

C i

R E F E R E N C E S

Adams , N . ( 1 9 7 6 ) N a t i o n a l R a d i o l o g i c a l P r o t e c t i o n B o a r d , H a r w e l l . P e r s o n a l

c o m m u n i c a t i o n .

A d a m s , N . , ( 1 9 7 8 ) N a t i o n a l R a d i o l o g i c a l P r o t e c t i o n B o a r d , H a r w e l l .

P e r s o n a l c o m m u n i c a t i o n

A l b e r t , R. E . , B u r n s , F . J . a n d H e i m b a c h , R. D . ( 1 9 6 7 a ) The e f f e c t o f

p e n e t r a t i o n d e p t h o f e l e c t r o n r a d i a t i o n o n s k i n t u m o r f o r m a t i o n i n t h e

r a t . R a d i a t . R e s . , JO, 5 1 5 .

A l b e r t , R. E . , B u r n s , F . J . a n d H e i m b a c h , R. B . ( 1 9 6 7 b ) S k i n damage a n d

t u m o r f o r m a t i o n f r o m g r i d a n d s i e v e p a t t e r n s o f e l e c t r o n a n d b e t a

r a d i a t i o n i n t h e r a t . R a d i a t . R e s . , JO, 5 ^ 5 -

A l b e r t , R. E . , B u r n s , F . J . a n d H e i m b a c h , R. D . ( 1 9 6 7 c ) The a s s o c i a t i o n

b e t w e e n c h r o n i c r a d i a t i o n damage o n t h e h a i r f o l l i c l e s a n d t u m o r

f o r m a t i o n i n t h e r a t . R a d i a t . R e s . , JO, 5 9 0 .

A l b e r t , R. E . , A l p e n , E . L . , B a i r , W. J . , C a s a r e t t , G. W . , E p p , E . R . ,

G o l d m a n , M . , G r e g g , E . C . , L e w i s , E . B . , M c C l e l l a n , R. 0., R a d f o r d , E . P .

a n d H i l b e r g , A . W. ( 1 9 7 6 ) H e a l t h e f f e c t s o f a l p h a - e m i t t i n g p a r t i c l e s i n

t h e r e s p i r a t o r y t r a c t , r e p o r t o f Ad Hoc C o m m i t t e e o n "Hot p a r t i c l e s " ,

N a t i o n a l Academy o f S c i e n c e s , NRC, U . S . E . P . A . , EPA 5 2 0 / 4 - 7 6 - 0 1 3 «

A n d e r s o n , E . C. e t a l ( 1 9 7 4 a ) E f f e c t s o f i n t e r n a l r a d i a t i o n o n t h e l i v i n g

o r g a n i s m . A n n u a l r e p o r t o f t h e LASL H e a l t h D i v i s i o n , L A - 5 8 8 3 - P R , L o s

A l a m o s S c i e n t i f i c L a b o r a t o r y , p 2 .

A n d e r s o n , E . C , H o l l a n d , L . M . , P r i n e , J . R. a n d R i c h m o n d , C . R. ( 1 9 7 4 " D )

Lung i r r a d i a t i o n w i t h s t a t i c p l u t o n i u m m i c r o s p h e r e s . I n : E x p e r i m e n t a l

l u n g c a n c e r , c a r c i n o g e n e s i s a n d b i o a s s a y s , I n t e r n a t i o n a l s y m p o s i u m ,

S e a t t l e - , 2 3 - 2 6 J u n e 1 9 7 4 , E . K a r b e , J . F . P a r k E d s , B e r l i n , S p r i n g e r -

V e r l a g , p 4 3 0 .

A n t o n c h e n k o , G. P . , K o s h u r n i k o v a , N . A. a n d L y u b c h a n s k i i , E . R. ( 1 9 ^ 9 )

M o r p h o l o g i c a l c h a n g e s i n t h e l u n g s o f r a t f o l l o w i n g i n h a l a t i o n o f l a r g e

d o s e s o f p l u t o n i u m - 2 3 9 c o m p o u n d s . R a d i o b i o l o g i y a £ , 7 5 .

A r c h e r , V . E . a n d L u n d i n , F . E . J r . ( 1 9 ^ 7 ) R a d i o g e n i c l u n g c a n c e r i n ^ a n .

e x p o s u r e - e f f e c t r e l a t i o n s h i p . E n v i r o n . R e s . , 1_, 3 7 0 .

A r c h e r , V . E . , J o s e p h , K . , W a g o n e r , S . D . , F r a n k , E . a n d L u n d i n , F . E . J r .

( 1 9 7 3 ) U r a n i u m m i n i n g a n d c i g a r e t t e s m o k i n g e f f e c t s o n man . J . O c c u p .

M e d . , l £ , 2 0 4

A r c h e r , V . E . , D e a n G i l l a m , J . a n d W a g o n e r , J . K. ( 1 9 7 6 ) R e s p i r a t o r y

d i s e a s e m o r t a l i t y among u r a n i u m m i n e r s . A n n a l s o f t h e New Y o r k A c a d .

S c i . , 2 7 1 , O c c u p a t i o n a l C a r c i n o g e n e s i s , V . S a f f i o t i a n d J . K. W a g o n e r

E d s , p 2 8 0 .

189

190

A r n o l d , J . S . ( 1 9 5 0 M e t a b o l i s m o f B o n e a s s t u d i e d b y r a d i o a u t o g r a p h i c

d i s t r i b u t i o n o f c a l c i u m , p l u t o n i u m a n d r a d i u m . Am. J . P h y s i o l . , 1 6 7 ,

7 6 5 .

A r n o l d , J . S . a n d J e e , W. S . S . ( 1 9 5 7 ) B o n e g r o w t h a n d o s t e o c l a s t i c

a c t i v i t y a s i n d i c a t e d b y r a d i o a u t o g r a p h i c d i s t r i b u t i o n o f p l u t o n i u m .

Amer . J . A n a t . 1 0 1 , 3 6 7 .

A r n o l d , J . S . a n d J e e , W. S . S . ( 1 9 6 2 ) P a t t e r n o f l o n g - t e r m s k e l e t a l

r e m o d e l l i n g r e v e a l e d b y r a d i o a u t o g r a p h i c d i s t r i b u t i o n o f p l u t o n i u m - 2 3 9

i n d o g s . H e a l t h P h y s . , Q, 7 0 5 -

A s t l e y , C. a n d S a n d e r s , C . L . ( 1 9 7 3 ) B i l i a r y e x c r e t i o n o f i n j e c t e d

p l u t o n i u m - 2 3 8 . B a t t e l l e P a c i f i c N o r t h w e s t L a b o r a t o r y . A n n u a l R e p o r t

f o r 1 9 7 2 . V o l u m e 1 . L i f e S c i e n c e s P a r t 1 . B i o l o g i c a l S c i e n c e s . BNWL

1 7 5 0 P T 1 p 3 5 .

A t h e r t o n , D . R . , L l o y d , R. L . , T a y l o r , G. N . , S t o v e r , B . J . a n d M a y s , C. W.

( 1 9 6 8 ) D i s t r i b u t i o n o f a m e r i c i u m - 2 l + 1 i n t h e b e a g l e . R e s e a r c h i n

R a d i o b i o l o g y . A n n u a l R e p o r t o f t h e I n t e r n a l I r r a d i a t i o n P r o g r a m ,

U n i v e r s i t y o f U t a h , C 0 0 - 1 1 9 - 2 3 9 , P 1 1 7 .

A t h e r t o n , D . R . , S t e v e n s , W. a n d B r u e n g e r , F . W. ( 1 9 7 3 ) E a r l y r e t e n t i o n

a n d d i s t r i b u t i o n o f c u r i u m i n s o f t t i s s u e s a n d b l o o d o f t h e b e a g l e .

I n : R e s e a r c h i n R a d i o b i o l o g y . A n n u a l R e p o r t o f t h e I n t e r n a l I r r a d i a t i o n

P r o g r a m , U n i v e r s i t y o f U t a h , C 0 0 - 1 1 9 - 2 1 + 8 , p 1 7 8 .

B a i r , ¥ . J . a n d W i l l a r d , D . H . ( 1 9 ^ 2 ) P l u t o n i u m i n h a l a t i o n s t u d i e s : I V .

M o r t a l i t y i n d o g s a f t e r i n h a l a t i o n o f p l u t o n i u m - 2 3 9 d i o x i d e . R a d i a t .

R e s . , 1 6 , 8 1 1 .

B a i r , W. J . , W i g g i n s , A . D . a n d T e m p l e , L . A. ( 1 9 6 2 ) The e f f e c t o f i n h a l e d

p l u t o n i u m - 2 3 9 d i o x i d e o n t h e l i f e s p a n o f m i c e . H e a l t h P h y s . , 8 , 6 5 9 -

B a i r , W. J . , T o m b r o p o u l o s , E . G. a n d P a r k , J . F . ( 1 9 6 3 ) D i s t r i b u t i o n a n d

r e m o v a l o f t r a n s u r a n i c e l e m e n t s a n d c e r i u m d e p o s i t e d b y t h e i n h a l a t i o n

r o u t e . I n : P r o c . Symp. D i a g n o s i s a n d T r e a t m e n t o f R a d i o a c t i v e P o i s o n i n g

V i e n n a 1 9 6 2 . V i e n n a IAEA, p 3 1 9 -

B a i r , W. J . , P a r k , J . F . a n d C l a r k e , W. J . ( 1 9 6 6 ) L o n g - t e r m s t u d y o f

i n h a l e d p l u t o n i u m i n d o g s . T e c h n . r e p o r t n o . A E W L - T R - 6 5 - 2 1 1 + .

B a i r , W. J . , B a l l o u , J . E . , P a r k , J . F . a n d S a n d e r s , C . L . ( 1 9 7 3 ) P l u t o n i u m

i n s o f t t i s s u e s w i t h e m p h a s i s o n t h e r e s p i r a t o r y t r a c t . I n : U r a n i u m ,

p l u t o n i u m , t r a n s p l u t o n i c e l e m e n t s , H . C . H o d g e , J . N . S t a n n a r d ,

J . B . H u r s h E d s . , S p r i n g e r - V e r l a g , B e r l i n , p 5 0 3 -

B a i r , W. J . ( 1 9 7 1 + a ) T o x i c o l o g y o f p l u t o n i u m . A d v a n . R a d i a t . B i o l . , 1±, 2 5 5 *

191

B a i r , W. J . ( l 9 7 U b ) The b i o l o g i c a l e f f e c t s o f t r a n s u r a n i u m e l e m e n t s i n

e x p e r i m e n t a l a n i m a l s . I n : P l u t o n i u m a n d o t h e r t r a n s u r a n i u m e l e m e n t s :

s o u r c e s , e n v i r o n m e n t a l d i s t r i b u t i o n a n d b i o m e d i c a l e f f e c t s . WASH 1 3 5 9 ,

HSAEC.

B a i r , W. J . a n d T h o m p s o n , R. C. ( 1 9 7 U ) P l u t o n i u m : B i o m e d i c a l R e s e a r c h .

S c i e n c e , 1 8 3 , 7 1 5 .

B a i r , W. J . , R i c h m o n d , C. R. a n d W a c h h o l z , B . W. ( 1 9 7 U ) A r a d i o b i o l o g i c a l

a s s e s s m e n t o f t h e s p a t i a l d i s t r i b u t i o n o f r a d i a t i o n d o s e f r o m i n h a l e d

p l u t o n i u m . W A S H - 1 3 2 0 , USAEC.

B a i r , W. J . ( 1 9 7 6 ) R e c e n t a n i m a l s t u d i e s o n t h e d e p o s i t i o n , r e t e n t i o n a n d

t r a n s l o c a t i o n o f p l u t o n i u m a n d o t h e r t r a n s u r a n i c c o m p o u n d s . I n : P r o c .

S e m i n a r , D i a g n o s i s a n d T r e a t m e n t o f I n c o r p o r a t e d R a d i o n u c l i d e s . V i e n n a ,

1 9 7 5 , V i e n n a IAEA, p 5 1 .

B a i r , W. J . a n d T h o m a s , J . M. ( 1 9 7 6 ) P r e d i c t i o n o f t h e h e a l t h e f f e c t s o f

i n h a l e d t r a n s u r a n i u m e l e m e n t s f r o m e x p e r i m e n t a l a n i m a l d a t a . I n : P r o c . i

Symp. T r a n s u r a n i u m n u c l i d e s i n t h e E n v i r o n m e n t , S a n F r a n c i s c o , 1 9 7 5 -

V i e n n a IAEA, p 5 6 9 -

B a l l o u , J . E . ( 1 9 5 8 ) E f f e c t s o f a g e a n d mode o f i n g e s t i o n o n a b s o r p t i o n

o f p l u t o n i u m . P r o c . S o c . E x p . B i o l . M e d . , 28» 7 2 6 .

B a l l o u , J . E . a n d B u s c h , R . H . ( 1 9 7 2 ) A c u t e t o x i c i t y o f DTPA a d m i n i s t e r e d

i n t r a t r a c h e a l l y . B a t t e l l e P a c i f i c N o r t h w e s t L a b o r a t o r y . A n n u a l R e p o r t

f o r 1 9 7 1 . V o l u m e 1 . L i f e S c i e n c e s P a r t 1 , B i o l o g i c a l S c i e n c e s . BNWL

1 6 5 0 ( P t 1 ) p 1 6 U .

B a l l o u , J . E . a n d H e s s , J . 0 . ( 1 9 7 2 ) B i l i a r y p l u t o n i u m e x c r e t i o n i n t h e

r a t . H e a l t h P h y s . , 2 2 , 3 6 9 .

B a l l o u , J . E . a n d P a r k , J . F . ( 1 9 7 2 ) The d i s p o s i t i o n o f i n g e s t e d , i n j e c t e d

a n d i n h a l e d p l u t o n i u m - 2 3 9 c i t r a t e a n d p l u t o n i u m - 2 3 9 n i t r a t e . B a t t e l l e

P a c i f i c N o r t h w e s t L a b o r a t o r y . A n n u a l r e p o r t f o r 1 9 7 1 • V o l u m e 1 . L i f e

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I n t e r n a t i o n a l C o m m i s s i o n o n R a d i o l o g i c a l P r o t e c t i o n ( 1 9 5 9 ) R e p o r t o f

C o m m i t t e e I I o n P e r m i s s i b l e B o s e f o r I n t e r n a l R a d i a t i o n , ICRP

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I n t e r n a t i o n a l C o m m i s s i o n o n R a d i o l o g i c a l P r o t e c t i o n ( 1 9 6 6 a ) T a s k Group

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I n t e r n a t i o n a l C o m m i s s i o n o n R a d i o l o g i c a l P r o t e c t i o n ( 1 9 6 6 c ) R e c o m m e n d a -

t i o n s o f t h e I n t e r n a t i o n a l C o m m i s s i o n o n R a d i o l o g i c a l P r o t e c t i o n .

ICRP P u b l i c a t i o n 9 , P e r g a m o n P r e s s , O x f o r d .

I n t e r n a t i o n a l C o m m i s s i o n o n R a d i o l o g i c a l P r o t e c t i o n ( 1 9 6 8 ) A r e v i e w o f

t h e r a d i o s e n s i t i v i t y o f t h e t i s s u e s i n b o n e . ICRP P u b l i c a t i o n 1 1 ,

P e r g a m o n P r e s s , O x f o r d .

I n t e r n a t i o n a l C o m m i s s i o n o n R a d i o l o g i c a l P r o t e c t i o n ( 1 9 ^ 9 ) T a s k Group

o f C o m m i t t e e 1 o f t h e I n t e r n a t i o n a l C o m m i s s i o n o n R a d i o l o g i c a l P r o t e c t i o n

R a d i o s e n s i t i v i t y a n d s p a t i a l d i s t r i b u t i o n o f d o s e . ICRP P u b l i c a t i o n 1l+,

P e r g a m o n P r e s s , O x f o r d .

I n t e r n a t i o n a l C o m m i s s i o n o n R a d i o l o g i c a l P r o t e c t i o n ( 1 9 7 2 a ) The RBE

f o r H i g h - L E T R a d i a t i o n s w i t h R e s p e c t t o M u t a g e n e i s . ICRP P u b l i c a t i o n

18 , P e r g a m o n P r e s s , O x f o r d .

I n t e r n a t i o n a l C o m m i s s i o n o n R a d i o l o g i c a l P r o t e c t i o n ( 1 9 7 2 b ) M e t a b o l i s m o f

Compounds o f P l u t o n i u m a n d O t h e r A c t i n i d e s . ICRP P u b l i c a t i o n 19,

P e r g a m o n P r e s s , O x f o r d .

I n t e r n a t i o n a l C o m m i s s i o n o n R a d i o l o g i c a l P r o t e c t i o n ( 1 9 7 5 ) R e p o r t o f t h e

T a s k Group o f C o m m i t t e e I I o n R e f e r e n c e Man. ICRP P u b l i c a t i o n 23,

P e r g a m o n P r e s s , O x f o r d .

2 0 2

I n t e r n a t i o n a l C o m m i s s i o n o n R a d i o l o g i c a l P r o t e c t i o n ( 1 9 7 7 ) R e c o m m e n d a t i o n s

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