POSTGRAD. MED. J. (1966), 42, 437

THE BIOLOGICAL EFFECTS OF IONISINGRADIATION ON THE THYROID GLAND

J. R. PHILP, B.Sc., M.B., Ch.B.

Research Fellow, Department of Materia Medica and Therapeutics, University of Aberdeen.

SINCE the high incidence of iatrogenic hypo-thyroidism (40%/. eight years after treatment) inthyrotoxic patients treated with radioiodine wasappreciated, the radiobiology of the thyroidgland has 'become a subject of great clinicalimportance. The method of treatment in itsorthodox form and dosage is clearly unsatis-factory and efforts are being made to improveit in various centres. Unfortunately, theseefforts are having to take place against a back-ground of inadequate iniformation ajbout funda-mental radiobiological mechanisms.

It is my intention to review some of theliterature relevant to the radiobiology of thethyroid but before doing so I would like tomention some common radiobiological concepts.The events following bombardment of a tissue

by ionising radiation are discussed by Bacq andAlexander (1961). When X-rays or y-rays entera tissue they eject electrons from the atoms bywhich they are absorbed. These ejected electronsin turn eject electrons from other atoms and areresponsible for most of the ionisations whichoccur. In the case of a-rays, P-rays, protonsand neutrons electrons are again ejected withsimilar consequences.

It should be noted that molecules can bedamaged directly or indirectly by ionisation.Direct damage results when the molecule isionised by the passage of an ionising particlethrough it. Indirect damage can also result ifthe molecules are dissolved in water which canbe ionised to form free radicals which react withthe molecules with consequent chaniges in theirnhysico-chemical nature and function. In bio-logical systems where water is the universalsolvent indirect damage from free radicals isprobalbly the most important.Doses of radiation are measured by the

amount of radiation absorbed by the tissue inrads where one rad is equivalent to 100 ergs ofabsorbed energy per gram of tissue. Doseresponses are often expressed in terms of theD37 dose where one D37 leaves 370/s of the radio-

biological targets undamaged, e.g. 370/% of cellsin a population able to divide or function etc.In theory loss of ability to survive or function ordivide may result from entirely different combi-nations of damaged molecular sites within thecell. In general it seems reasonable to supposethat for reproduction, long term survival andfunction chromosal damage is important. Pre-sumably, damage to individual enzymes andother cytoplasmic structures can be made goodproviding the appropriate genes remain intact.

Human and Clinical StudiesExternal radiation was once used extensively

in the treatment of thyrotoxicosis and manyreports exist claiming that the disease could becured by this means. Hayes (1927) claimed 620/,of his cases were cured and that 140/n wereimproved. Groover, Christie, Merritt, Coe &McPeak (1929) claimed an 89%0/ cure rate and90/, improved. Hayes (1927) warned of the possi-bility of indiucing hypothyroidism iby radiationoverdosage but gives no ind'ication of the inci-dence of this occurrence. Unfortunately it isimpossible in 'many cases to ascertain what raddose the natients received as often completephysical details of the X-ray machine andprocedure are not supplied. Furthermore, in allcases the total doses were fractionated over sev-eral weeks and calculation of the one doseequivalent is imnossible. It is estimated byGoolden (1964) that the cumulative dose couldnot have exceeded 3,500 roentgens. It is ofinterest that in twenty cases of laryngeal cancertreated bv large doses of X-ravs in which therewas inevitable exposure of the thyroid glandthere were no cases of hynothvroidism 11 to 12vears later. (Greig, Boyle, Buchanan and Fulton.1,965).

Radioiodine when it was introduced by Hertzin 1941 offered a golden therapeutic onnor-tunitv. Here was an agent which cojuld seek outits own target and then destrov it. the decree ofdestruction, it was thought, being proportional

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to the millicurie dose administered. Numeroustrials of this agent have ibeen reported. In theseries reported by Greig, Crooks & Macgregor,(1966), 318% remained thyrotoxic and 25°/became hypothyroid with one dose. Of thoserequiring a second dose (3'8%), 37% remainedthyrotoxic, 29% became euthyroid, and 27%became hypothyroid. Occasionally three or fourdoses were required. The incidence of recur-rence of hyperthyroidism with radioiodinetherapy is therefore low but the incidence ofhypothyroidism is very high and increases withthe number of doses given and the length oftime after treatment. The same pattern has beenreported bv Beling & Einhorn (1961), Dunn &Chatnman (1964), Green & Wilson (1964) andMcGirr, Thompson & Murray (1964). The situ-ation was sum,marised by Crooks (1965). In hisseries of patients 40%/, were hvnothyroid some 8vears after therapy with no evidence of a plateauihaving been reached in the cumulative inci-dence. A trial of a lower dose regime of 1311 hasbeen reported bv Smith & Wilson (1965). Theygave "calculated rad doses" of "3.500 rads" incontrast to orthodox levels of "7.000 to 10.000rads". This nrocedure lowered the incidence ofhvnothyroidism at 4 years after therapy from280YA to 90/O. However it remains to be seen if astaible olateau will be reached. Furthermore. asa result of the lower dose employed there is adelay in the attainiment of the euthyroid stateand antithyroid drugs have been required in ahigher proportion (600%,) of patients.

These clinical observations point to the basicconflict in radioiodine therapy, i.e. that highdoses effect rapid control but cause a high hypo-thyroid rate; lowering the dose decreases thehypothyroid rate but lengthens the period forcontrol of symptoms unless antithyroid drugsare used. In the case of deliberately inducedmild hypothyroidism in patients with anginapectoris the conflict disanpears as this result canalmost be guaranteed (Blumgart, Freediburg &Buka, 1948; Blumgart, Freediburg & Kurland,1955). In general, however, the dose required ishuge (e.g. 50 ,millicuries) compared to that norm-allv used in the treatment of thyrotoxicosis (5-15millicuries). This difference probalbly resultsfrom the higher nercentage untake of the admin-istered dose by the cells of the thyrotoxic gland.On the other hand as yet unknown biologicalnhenomena may be operating to produce thisdisparity in apparent radiosensitivity.

These clinical effects are in line with studiesof the function and histology of the radioiodine-treated human thyroid gland. The functional

changes have been described by Dobyns,Vickery, Maloof & Chapman (1953) and Eckert,Green, Kilpatrick & Wilson (1960). In patientsrendered euthyroid the aibsolute uptake of atracer dose of radioiodine is within the normalrange although the residual tissue remains over-active as evidenced by a high turnover rate ofthe tracer. The response to TSH is red,uced andthere is little suppression of -thyroid function bytriiodothyronine. That the functional reserve isreduced is demonstrated by the ease with whichthe serum PBI can be lowered by antithyroiddrug administration. These findings are in sharpcontrast to the behaviour of the remnant afterpartial thyroidectomy which after a period offive years often comes to resemble the normalthyroid both functionally and histologically. Thehistological changes in the rad'ioiodine-treatedcases are comnatible with the observations onfunction and have been described bv Dobynsand others (1953), Freedburg. Kurland & Blum-Part (1953), Lindsay, Dailey & Jones (1954) andCurran, Eckert & Wilson (1958). The acutechanges consist of nuclear pvknosis, cell death,small vessel thrombosis and oedema of thestroma. In the long term there are small islandsof fuinctioning cells embedded in large volumesof fibrous tisssuie. The follicles are small andirregular with little colloid storage; 'the follicularcells are large and many of them have bizarrenuclear forms.

Tn none of these series were malignant cellsdbserved in the histological sections. Tn adultsno significant incidence of thyroid cancer hasbeen found either after external X-ray therany(Quim1by & Werner, 1949), or after radioiodinetherapy i(Hollingworth, Hamilton, Tamagaki &Beebe, 1963). In children and adolescents, how-ever, a definite association between externalirradiation of the neck and the subsequent devel-opment of thyroid cancer has been established(Goolden, 1964). It has also been suggested bySheline, Lindsay and Bell (1959) that thyroidcancer may follow the use of radioiodine fortreating hyperthyroidism in childhood. InDoniach's animal experiments (1953) a signifi-cant nu'mber of rats developed thyroidcarcinoma after being treated with low doses(5 to 30 Ac) of 131 I followed by methylthiouracil.No such tumours were found in a group of ratsaiven 100 tic 13'I. One possible interpretation ofthis phenomenon is that all doses of radiationcause cancerous mutations but with really highdoses the cancer cells are rendered incapalbleof division. It should -be noted, however, thatGoldberg and Chaikoff (1952) described thy-

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JPHILP: Efgects of Radiation on the Thyroid

roid cancer in rats within two years of theirreceiving 400 pc of 1'I1.Another possible biological hazard of radio-

iodine therapy is leukaemogenesis but as yet nosignificant incidence of this has been reported(Pochin 1960; Green, Fisher, Miller & Wilson,1961; and Werner, Gittelshon & Brill, 1961).Similarly no significant 'incidence of congenitalmalfunctions has been found in the children ofmothers treated with radioiodine (rMeans, De-groot & Stanbury, 1963). Clearly, however, boththese hazards merit further iinvestigation.The idea of radioiodine therapy is to achieve

a "radiation partial thyroidectomy", but itremains to be seen if this is possible within areasonable period of time. Clinical trials so farhave not been conclusive and it is more likelythat the solution will come from purer radiobio-logical situations in which fundamental changesin cell behaviour following irradiation can beassessed in a quantitative manner.

In Vivo Studies of the Radiobiology of theThyroid in Animals

Very little truly quantitative information isavailable on the radiobiology of organisedtissues. Walters, Anson & Ivey (1931) found nochanges in the thyroids of dogs treated withdoses of X-rays similar to those used in thetreatment of thyrotoxicosis. Levene, Gould &Kniseley (1955) studied the qualitative histologi-cal effects of large doses of 1311 given to dogs.From tihe fourth day onwards after the admini-stration of 1311 there was a rapid loss ofradioactivity froim the gland and a rise in thebound plasma radioactivity. By the twelfth daythere was very little radioactivity left in thegland. These changes were explained by thehistological and radioautographic observations.As found in humans there was an initial patchydistribution of 1311 throughout the gland. Nohistological changes were observed during thefirst three days after radioiodine administration.By the sixth day there was massive necrosis inthe central part of the gland from which nearlyall radioactivity had been lost. However theisotope was still concentrated in a peripheralrim of histologically intact follicles. From thetwelfth day even this rim of "intact" tissue haddisappeared and the radioiodine was only con-centrated in small islands of functioning cellsthroughout the gland. In this complex situationno accurate assessment of radiation dose ispossible. Similar studies in rats by Findlay &Leblond (1948) and Goldberg, Chaikoff, Lind-

say & Feller (1950) have yielded similar results.In order to quantitate the dose of radiation, St.Aubin, Kniseley and Andrews (1955) studied theeffect of external radiation in the thyroid histol-ogy and 1311 metabolism in the dog. With a doseot 21,000 rads they found almost identicalresults to those obtained by Levene and others(1955), i.e. accelerated release of 13\1 (tracerdose) from the fourth day onwards accompaniedby gross central necrosis with the same sur-viving rim of follicles at the periphery of thegland. This suggests a biological explanation(e.g. blood vessel necrosis) for these phenomena.The latent period of ithree days in both casesbefore histological and functional changes occurargues against the theory that in the case of131J, time is needed for the cumulative radiationdose to build up. Although changes similar tothese were observed with 10,000 rads theywere surprisingly of minimal degree. This smallhistological and functional response to a mas-sive dose (10,000 rads) of X-rays is borne outby the electron microscope studies of McQuade,Seaman & Porporis (1956) in which no changeswere found within 6 hours of a 17,200 rad doseor within 5 days of a 6,800 rad dose.Skanse (1948) discovered that the goitrogeniic

response of the chicken to TSH and thiouraciladministration could be inhibited by large(50 lic) but not small (10 tic) doses of radio-iodine. Doniach & Logothetopoulos (1955) usedthis inhiibition of the goitrogenic response tostudy the effects of ionising radiation on the ratthyroid. In rats simply given 30 ,fc 1311 therewas a decrease in thyroid weight and an in-crease in follicular cell height indicating thatcell hypertrophy had occurred presumablyunder a TSH stimulus secondary to radioiodineinduced thyroid failure. The 1311 uptake of these"compensated" glands was normal. If the ratswere hemithyroidectomised there was a similartracer 13111 uptake but greater "compensatory"follicular cell hypertrophy than in the controls.Finally the normal goitrogenic response to pro-pylthiouracil was decreased in the irradiatedgroup and was accompanied by a markedreduction in mitosis although cell hypertrophywas not reduced. The high incidence ofabnormal nuclear forms suggested that theloss of the ability to divide was due to chromo-some damage.

Crooks, Greig, Macgregor & iMcIntosh (1964)measured the degree of inhibition of the goitro-genic response in the rat brought about byvarious accurately 'measured doses of X-raysfrom an external source. They found progressive

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inhibition with increasing doses of X-raysalthough 1311 uptake was unaffected by dosesup to 1,600 rads. Histological examination ofttese glands was not carried out so that thecontrilbution of cell division and cell hyper-trophy to the total gland weight could not beassessed. However, their observations were inkeeping with those of Doniach & Logotheto-poulos (1955) and their dose-response curvecomipatible with those obtained in vitro by Puck,Morkovin, Marcus & Ceicura (1957) and invivo by Hewitt & Wilson (1961). Observationsakin to those of Crooks and others (1964) weremade by Al;Hindawi & Wilson (1965) whoalso showed 'by tritiated-thymidine labelling thatDNA synthesis was decreased in the irrad'iatedcells which also had had a shortened half-life.In this connection the work of Weinbren,Fitschen & Cohen (1960) is worthy of mention.They irradiated rat livers with doses of X-raysinsufficienit to cause immediate cell death. Manymonths later the animalis were subjected topartial hepatectomy. When the irradiated cellsattempted to make good the functioning hepaticcell mass by cell division they immediately dieda "mitotic death". All those observations indi-cate that doses of radiation which markedlyreduce reproductive capacity do not significantlyimpair the ability of the follicular cells tosurvive and hypertrophy and the capacity ofthe whole gland to function normally. There-fore the mechanisms involved in cell divisionare 'more radiosensitive than those responsiblefor cellular viability, hypertrophy, and function.The clinical implications of these observa-

tions are clear if extrapolation to the humansituation is justified. A dose of radiation suffi-cient to have a significant rapid effect on totalgland function, either 'by killing cells or render-ing them functionless will leave exceedinglyfew cells reproductively intact. In tihese circum-stances indefinite continuance of an adequatefunctioning cell mass is impossible. In otherwords, a dose of 1311 sufficient to bring abouta rapid decrease in thyroid function is likelyto bring about thyroid gland failure in the lIongterm due to accelerated cell death and failureof cell replacement.The conflict between the slow control of

symptoms and late onset of hypothyroidismdescribed by Crooks (1965) can therefore beexplained on the basis of the above observa-tions. However they still do not answer thecritical question of whether a radiation-inducedpartial thyroidectomy or its functional equiva-lent can be achieved or not. More detailed

quantitative information about the post-irradiation patterns of cell behaviour is needed.However, for an insight into the pssible pat-terns of cell behaviour after irradiation we canturn briefly to the more ideal ((but less realistic)radiobiological studies carried out in vitro.

In Vitro ObservationsPuck (1959) put tissue culture on a new

footing witn tne development o0 methods lorma,namning cells in vitro whose chromosomestructure, oiochemical behaviour and geneticrelationships can ibe compared with normalcells in their normal environment. On this basishe was able to construct dose-response curvesfor reproductive integrity for a variety of humancells grown in vitro. Hewitt & Wilson (1961)reported their dose-response curves for varioustumour cells in animals. I'he cells wereirradiated in vivo and cultured in vivo byinjection into test animals. The dose-responsecurves for all the tumour cells tested by Herwittand Wilson (1961) were all very similar to oneanother and to those found by Puck, Morkovin,Marcus & Ceicura (1957) and Morkovin &Feldman (1960). The fact that similarquantitative responses were obtained by differentinvestigators working with different cell typesunder different conditions argues that thephenomena are of such a fundamental natureas to be applicable to the human situation.

I;t must be appreciated however that the situa-tion is more complex than is indicated by theexperiments quoted above which concernthemselves in the main with the effect ofradiation on one aspect of cell activity, 'i.e.the ability to divide an indefinite numlberof times. in contrast Sinclair (1964) reportedthe induction of cell mutants which survivedbut grew more slowly than the reproductivelyintact cells and unirradiated controls. Thusafter irradiation there exists a heterogeneouspopulation with respect to cell division andthis probably applies to every aspect of cellactivity. This heterogeneity was also demonst-rated by the experiments of Puck & Marcus(1956), Tolmach & Marcus (1960) and Tolmach(1961). They sihowed that radiation damagedcells may lyse before division, grow withoutdivision to form giant cells which ultimatelydie, or divide a limited numlber of times.Elkind, Han & Volz (1960) also found thatmany of the damaged cells could divide alimited numnber of times, the number beinginversely related to the dose of X-rays.

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July, 1966 PHILP: Effects of Radiation on the Thyroid 441

ConclusionsIf nothing else the preceding discussion

illustrates the complexity of dynamic eventswhich follow irradiation of the cell populationof a whole organ. Each individual effect suchas immediate cell death; or loss of reproductivecapacity will have its own dose-responsecharacteristics. However, many radiation effectsare probably interrelated in terms of combina-tions of genetic damage so that as the dose ofradiation increases it is unlikely that the pro-portions of the various types of damaged cellswill follow a simple pattern.

Philp (1965) reported a model in which thecells of the rat thyroid divide expotentiallyafter goitrogen administration. This providesfor the first time a population of normalmammalian cells in their normal environmentundergoing division at a constant and measur-able rate. Similar experimental conditions havepreviously only been available in bacterial ortissue culture. This model is now being usedto study the various vatterns of cell behaviourafter graded doses of X-rays. It is anticipatedthat the results of these investigations willindicate the feasibility of a radiation-inducednartial thvroidectomy or its functional eauiva-lent. On the answer to this question hinges thefuture nattern of anplications of radioiodine asa therapeutic agent.

REFERENCESAL,HINDAWI, A. Y., and WILSON, G. M. (1965):The Effect of Irradiation on the Function andSurvival of Rat Thyroid Cells, Clin. Sci., 28, 555.

BACQ, IM., and ALEXANDER, P. (1961): Fundamentalsof Radiobiology, 2nd Ed., Chaps. 1-6. Oxford,London, etc.: Pergamon Press.

BELING, U., and EINHORN, J. (1961)): Incidence ofHypothyroidism and tRecunrences Following "'ITreatment of Hyperthyroidism, Acta. radiol.(Stockh.), 56, 275.

BLUMGART, H. L., FREEDBURG, A. S., and BUKA, R.(1948): Treatment of Euthyroid Cardiac Patientsby Producing Myxoedema with Radioactive Iodine,Proc. Soc. exp. Biol. (N.Y.), 67, 190.

BLUMGART, H. L., FREEDBURG, A. S., and KURLAND,G. S. (1955): Treatment of Incapacitated EuthyroidCardiac Patients with Radioactive Iodine, J. Amer.med. Ass., 157, 1.

CROOKS, J., GREIG, W. R., MACGREGOR, A. G., andMCINTOSH, J. A. !R. (1964): A Quantitative Methodof Measuring the Effects of X4Irradiation on theGrowth and Function of the Rat Thyroid Gland,Brit. J. Radiol., 37, 380.

CROOKS, J. (1965): Radioactive Iodine Therapy inthe Treatment of Thyrotoxicosis, Proc. Fifth Inter.Thyroid Conf. (Rome), p. 1208. Edited by Cassano,C., and Andreoli, ,M. New York and London:Academic ,Press.

CURRAN, R. C., ECKERT, H., and WILSON, G. M.(1958): The Thyroid Gland after Treatment ofHyperthyroidism by Partial Thyroidectomy or"'Iodine, J. Path. Bact., 76, 54.

DOBYNS, B. M., VICKERY, A. L., MALOOF, F., andCHAPMAN (1 953): Functional and HistologicalEffects of Therapeutic Doses of IRadioactive Iodineon the Thyroid of Man, J. clin. Endocr., 13, 548.

DONIACH, I. (1'953): Effect of Radioiodine Alone andin Combination with IMethylthiouracil uponTumour Production in the Rat's Thyroid Gland,Brit. J. Cancer, 7, 181.

DONIACH, I., and LOGOTHETOPOULOS, J. H. (1955):Effect of Radioactive Iodine on the Rat's ThyroidFunction, Regeneration and Response to Goitro-gens, Brit. J. Cancer, 9, 1'17.

DUNN, J. T., and CHAPMAN, E. M. (1964): RisingIncidence of Hypothyroidism after RadioactiveIodine Therapy in Thyrotoxicosis, New Engl. J.Med., 271, 1037.

ECKERT, H., GREEN, M., KILPATRICK, R., and WILSON,G. M. (1960): Thyroid Function after the Treat-ment of Thyrotoxicosis by Partial Thyroidectomyor ''Iodine, Clin. Sci., 20, 87.

ELKIND, M. M., HAN, A., and VOLZ, K. W. (1963):Radiation Response of Mammalian Cells grown inCulture, J. nat. Cancer Inst., 30, 705.

FINDLAY, D., and LEBLOND, C. F. (1948): PartialDestruction of the IRat Thyroid with large Dosesof Radio-iodine, Amer. J. Roentgenol, 59, 387.

FREEDBURG, A. S., KURLAND, G. S., and BLUMGART,H. L. (1952): The Pathologic Effects of 131I onthe Normal Thyroid Gland in Man, J. clin. Endocr.,12, 1315.

GOLDBERG, R. C., CHAIKOFF, I. L., LINDSAY, S., andFELLER, D. D. (1950): Histopathological Changesinduced in the Normal Thyroid and Other Tissuesof the Rat by Internal Rad,iation with various dosesof Radioactive Iodine, Endocrinology, 46, 72.

GOLDBERG, R. C., and CHAIKOFF, I. L. (1952): In-duction of Thyroid Cancer in the Rat by Radio-active Iodine, Arch. Path., 53, 22.

GOOLDEN, A. W. G. (1964): 'Radioactive Isotopesof Iodine and their Aepplication in "The ThyroidGland" vol. 1, Edited by fPitt-Rivers, R., andTrotter, W. R. London: tButterworth.

GREEN, M., FISHER, M., MILLER, H., and WILSON,G. M. (1961): Blood Radiation Doses after '1ITherapy of Thyrotoxicosis: Calculations withReference to Leukaemia, Brit. med. J., ii, 211.

GREEN, M., and WILSON, G. M. (1964): Thyrotoxi-cosis treated by Surgery or Iodine-4l31. With SpecialReference to the Development of Hypothyroidism,Brit. med. J., i, 1005.

GREIG, W. R., BOYLE, J. A., ,BUCHANAN, W. W., andSHEENA FULTON (1965): Clinical and Radiobio-logical Observations on Latent Effects of X-irradia-tion on the Thyroid Gland, J. clin. Endocr., 25,1009.

GREIG, W. R., CROOKS, J., and MACGREGOR, A. G.(1966): Clinical and Radiobiological Consequencesof Thyroid Irradiation, Proc. roy. Soc. Med. (To bePublished).

GROOVER, R. A., CHRISTIE, A. C., MERRITr, E. A.,COE, F. 0., and MCPEAK, E. M. (1929): RoentgenIrradiation in the Treatment of HyperfhyroidismJ. Amer. med. Ass., 92, 1730.

HAYES, M. R. J. (1927): A Study of X-ray Treat-ment of One Hundred Cases of Graves Disease,Brit. J. Radiol., 32, 64.

HEWITr, H. B., and WILSON, C. W. (1961): Sur-vival Curves for Tumour Cells Irradiated in vivo.,Ann. N.Y. Acad. Sci., 95, 818.

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HOLLINGWORTH, D., HAMILTON, H. D., TAMAGAKI, H.,and IBEEBE, G. W. (1963): Thyroid Disease: AStudy in Haroshima, Japan. Medicine (Baltimore),42, 47.

LEVENE, M. B., ANDREWS, G. A., and KNISELEY,R. M. (1955): Large Doses of '^I in Dogs:Radiation Dosage Correlated with Histologic andAutoradiographic Changes, Amer. J. Roentgenol,73, 88.

LINDSAY, S., DAILEY, M. E., and JONES, M. D. (1954):Histologic Effects of Various Types of IonisingRadiation on Normal and Hyperplastic HumanGlands, J. clin. Endocr., 14, 1179.

McGIRR, E. M., THOMPSON, J .A., MURRAY, I. P. C.(1964): RaJdioiodine Therapy in Thyrotoxicosis:A Review of 908 Cases, Scot. med. J., 9, 505.

MCQUADE, H. A., SEAMAN, W. B., PORPORIS, A. A.(1956): Electron Microscopy of Irradiated Cellsof the Follicular Cells of the Rat Thyroid, Radiat.Res., 4, 532.

MEANS, J. H., DEGROOT, L. J., and STANBURY, J. B.in The Thyroid and its Diseases p. 233, Published bythe Blakiston Division. New York, Toronto andLondon: McGraw-Hill Book Company.

MORKOVIN, D., and FELDMAN, A. (1960): End Pointof One of the Actions of Radiation on LivingTissue important in Radiation Therapy and inAcute Radiation Syndrome, Brit. J. Radiol., 33,197.

PHILP, J. R. (1965): The Growth Pattern ofThyroid Follioular Cells under a GoitrogenicStimulus, Scot. med. J., 10, 488.

POCHIN, E. E. (1960): Leukaemia Following Radio-iodine Treatment of Thyrotoxicosis, Brit. med. J.,ii, 1545.

PUCK, T. T., and IMARCUS, P. I. (1956): Action ofX-rays on Mammalian Cells, J. exp. Med., 103,653.

PUCK, T. T., MORKOVIN, D., MARCUS, P. I., andCEICURA, S. J. (1957): Action of X-rays on Mam-malian Cells. II. Survival Curves of Cells fromNormal Human Tissues, J. exp. Med., 106, 485.

PUCK, T. T. (1959): Quantitative Studies on Mam-malian Cells in Vitro, Rev. mod. Physics, 31, 433.

QUIMBY, E. H., and WERNER, S. C. (1949): LateRoentgen Radiation Effects in Roentgen RayTherapy for Hyperthyroidism, J. Amer. med. Ass.,140, 1046.

SHELINE, G. E., LINDSAY, S., and BELL, H. G. (1959):Occurrence of Thyroid Nodules in Children follow-ing Therapy with Radioiodine for Hyperthyroid-ism, J. clin. Endocr., 19, 127.

SINCLAIR, W. K. (1964): X-ray Induced HeritableDamage (Small Colony Formation) in CulturedMammalian Cells, Radiat. Res., 21, 584.

SKANSE, B. N. (1948): Biologic Effect of Irradiationby Radioactive Iodine, J. clin. Endocr., 8, 707.

SMITH, R. N., and WILSON, G. M. (1965): A ClinicalTrial of Different Doses of 13' in the Treatment ofThyrotoxicosis. Proc. Fifth International ThyroidConference (Rome), p. 1152. Edited by Cassano,C., and Andreoli, M. New York and London:Academic Press.

ST. AUBIN, P. M., KNISELEY, R. M., and ANDREWS,G. A. (1957): External Irradiation of the Thyroidin Dogs, Amer. J. Roentgenol, 78, 804.

TOLMACH, L. J., and MARCUS, P. I. (1960): Develop-ment of X-ray Induced Giant Hela Cells, Exp.Cell Res., 20, 350.

TOLMACH, L. J. (1961): Growth Patterns in X-irradiated Hela Cells, Ann. N.Y. Acad. Sci., 95, 743.

WALTERS, A. M., ANSON, B. J., and IVEY, A. C.(1931): The Effects of X-rays on the Thyroid andParathyroid Glands, Radiology, 16, 52.

WEINBREN, K., FITSCHEN, W., and COHEN, M. (1960):The Unmasking by Regeneration of Latent Irradia-tion Effects in the Rat Liver, Brit. J. Radiol., 33,419.

WERNER, S. C., GITrELSHON, A. M., and BRILL, A. B.(1961): Leukaemia Following Radioiodine Therapyof Thyrotoxicosis, J. Amer. med. Ass., 177, 646.

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