…een vruchtbare combinatie

Dutch Approach to RA of GCTechnical Assistance in the Field of Chemicals

Slide 1TeACH

…een vruchtbare combinatie

Beoordeling van beroepsmatige blootstelling in de praktijk van de regelgeving

The skin is not the limit……..

Joop J. van Hemmen

TNO Senior Research Fellow in Occupational Toxicology

TNO Chemistry, Food & Chemical Risk Analysis

Chemical Exposure assessment

TNO | Knowledge for Business

Dutch Approach to Risk Assessment of Genotoxic Carcinogens

Dinant Kroese

Dutch Approach to RA of GC 2

TNO: Netherlands Organisation for Applied Scientific Research

• Knowledge and Technology Provider• Established in 1932 (by Act of Parliament)• Independent from Government • Revenue Generating Not for Profit• Second largest of its kind in Europe• 5500 employees• Serving 5 Core Areas


5 core areas

• Quality of Life (Life Sciences)

• Defence, Security & Safety

• Science & Industry (Processes)

• Built Environment & Geosciences

• Information & Communication Technology


Setting of OELs for carcinogens

Comprises 3 activities (“three-step procedure”):

The Subcommittee on Evaluating Carcinogenic Substances of The Health Council

performs evaluations on the carcinogenic properties of substances at request of the

Ministry of Social Affairs and Employment.

The Dutch Expert Committee on Occupational Safety (DECOS) of The Health

Council subsequently recommends concentrations in the air, which correspond to

certain reference values of excess cancer risk for substances that are shown to be

carcinogenic and genotoxic,

The OEL subcommittee of The Social and Economic Council advices the Ministry of

Social Affairs and Employment on the feasibility of these reference values.

The Minister finally sets legally binding occupational exposure limits.


Health Council of The Netherlands

Independent advisory board of the government of which members are selected from

the scientific and healthcare communities. The areas of activity are health and

healthcare, health and nutrition, and health and environment. Advisory reports are

produced in autonomous, multidisciplinary ad-hoc or semi-permanent committees

comprising both members of the council and external experts.


Social and Economic Council of The Netherlands

The SER is an independent advisory board to the government in which employers

and employees are participating. Committees are responsible for the advices to the

government.


Activity 1 Classification - cf EU Dir. - and assessment of mechanism of action

Activity 2 Calculating reference risk values for genotoxic carcinogens

Activity 3 Deriving of a limit value via a feasibility assessment


Genotoxic carcinogens Chemical agents that have the capacity to damage and change DNA directly. As a

result they generate mutations in DNA, which may ultimately lead to cancer.

Genotoxic carcinogensChemical agents that inhibit enzymes involved in the synthesis and repair of

damaged DNA, but do not cause mutations themselves. They indirectly promote

permanent DNA damage.

Non-genotoxic carcinogensChemical agents that have no capacity to change DNA directly, but promote cancer

by other mechanisms than inhibiting DNA-repair enzymes etc. Many of these agents

do so by direct or indirect stimulation of cell division.

Activity 1 Classification (cf EU Dir.) and assessment of mechanism of action

acting by a stochastic mechanism

acting by a non-stochastic mechanism


Genotoxic carcinogens acting by a stochastic mechanismNon-threshold approach: calculation of a HBC-OCRV

Genotoxic carcinogens acting by a non-stochastic mechanism

Threshold approach like for non-carcinogens: calculation of a HBROEL

Non-genotoxic carcinogensThreshold approach like for non-carcinogens: calculation of a HBROEL

HBC-OCRV: Health-Based Calculated-Occupational Cancer Risk Value

HBROEL: Health-Based Recommended Occupational Exposure Limit

Approach for deriving a limit value



Principle One-hit kinetics, assuming:

One cell may transform in a cancer cell by one hit of a carcinogen; Exposure-response relationship at low exposure levels assumed linear.





Threshold approach like for non-carcinogens: calculation of a HBROEL

Non-genotoxic carcinogensThreshold approach like for non-carcinogens: calculation of a HBROEL

(Formaldehyde)

In case of ???



Report cover


Some examples

Genotoxic carcinogens acting by a stochastic mechanismAflatoxin, 1,3-Butadiene, Azathioprine, Bariumchromate, Benzo[a]pyrene …..


Arsenicum, ……

Non-genotoxic carcinogensHexachlorobenzene, …….



Step 1 Selection of key study

Step 2 Calculating carcinogenic activity Iconcentration

Step 3 Calculating cancer risk for workplace exposure: HBC-ORCV

Step 4 Calculating reference values of excess cancer



Preferably human cancer mortality data. However, in most cases it has to be

based on animal data.





There is as yet no guidance for calculating a HBC-OCRV based on human data

In practice different approaches have been applied: - A simple linear extrapolation using life tables if appropriate,

- Using available dose response (using life tables if appropriate)

See Goldbohm et al., (2006) Risk estimation for carcinogens based on epidemiologi-cal data: A structural approach, illustrated by an example chromium. Regul.Toxicol. and Pharmacol., 44, 294-310.





Criteria for animal studies:

duration of exposure: at least one fourth of the standard lifespan &

observation period: at least one half of the standard lifespan; animal studies are preferred that are most relevant for the occupational

situation (inhalation studies over oral studies); only data on malignant tumours are used, unless, according to the present

scientific views, benign tumours or neoplasms are known to develop into

malignancy.


Tumor frequency

TDsign

Dose

• ••

•

0.05

0.10

0.20

0.30

Ic

Ie

Ie = incidence exposed

Ic = incidence control

Step 2 Calculating carcinogenic activity Iconcentration

Ie - Ic

Iconc = (mg/m3)-1

TDsign x Xe/L x Xo/L x h/24 x d/week

Xe = exposure (days)

Xo = observation (days)

L = 1000 (days)


Step 3 Calculating cancer risk for workplace exposure: HBC-ORCV

Ie - Ic

Iconc = (mg/m3)-1

TDsign x Xe/L x Xo/L x h/24 x d/week

40 48 5 10 HBC-OCRV = Iconc x x x x (mg/m3)-1

75 52 7 18

years weeks/year days / week inhalation volume / day


Step 4 Calculating reference values of excess cancer

Two reference excess risk values per worker life are derived from this

HBC-OCRV {(mg/m3)-1}

4 per 1000 (4 x 10-3) (cf 40 times a 10-4 risk per worker year)

‘prohibitive risk level’

4 per 100.000 (4 x 10-5) (cf 40 times a 10-6 risk per worker year)

‘target risk level’


Report cover


It is assumed that no differences exist between experimental animals and humans with respect to kinetics, mechanism of tumour induction, target

susceptibility etc.

Some remarks

However, in case relevant data on differences between experimental animals and humans are available, these will be taken into account.


Activity 3 Derivation of a limit value via a feasibility assessment

second step in “three-step procedure”

Substances that are genotoxic carcinogenic will be subjected to a feasibility evaluation (technical and economical), which is given as an

advice to the Minister of Social Affairs


exposure reduction obligations

4 per 10-3 risk

4 per 10-5 risk

Activity 3 Derivation of a limit value via a feasibility assessment

third step in “three-step procedure”

the Minister of Social Affairs sets the legal OEL

Discussion on whether there should be use of PPE above 4 per 10-5 risk

No PPE obligation


References

Calculating Cancer Risk. Health Council of the Netherlands: Dutch Expert Committee on

Occupational Standards (DECOS). The Hague, 1995. Publication No. 1995/06WGD

www.gr.nl

www.healthcouncil.nl

DECOS is currently revising its Guidelines; Publication is expected end 2009.


Special thanks to:

Ms Aafje van der Burght

Scientific secretary of

Subcommittee Evaluating Carcinogenic Substances & DECOS

Both Committees of the Health Council of the Netherlands


Thank you for your attention!


Dose

•••

10-1

10-6

10-2

10-3

10-4

10-5

10-6 110-5 10-4 10-3 10-2 10-1

1

ELR

Tumor frequency

Simple straight line!

10-6 risk dose

From a net TD sign value

‘T25’


Example: 1,2 dibromoethane [Cas No. 106-93-4]

Use, fumigant; EU-classification, carc cat 2; R45, may cause cancer. Key study: long-term inhalation study using male and female rats (exposure duration, 721

days; observation period, 721 days; lifespan rats, standard value 1000 days) Type of tumours observed: adenomas and carcinomas in nasal cavity,

hemangiosarcomes of the spleen, and mammary tumours (number of animals with

tumours: no-exposure 7/100; exposure to 77 mg/m3, 87/100)

87/100 – 7/100 Iconcentration = 77 [mg/m3] x 721/1000 x 721/1000 x 8/24 x 5/7 = 8.4 x 10-2 [mg/m3]-1

A case example

HBC-OCRV = 8.4 x 10-2 x 40/75 x 48/52 x 5/7 x 10/18 = 1.64 x 10-2 [mg/m3]-1


Threshold level: HBR-OEL

Which carcinogens? Genotoxic carcinogens acting by a non-stochastic mechanism. Non-genotoxic carcinogens.

PrincipleBoth groups of carcinogens act by a non-stochastic mechanism, and therefore are

assumed to have a threshold level below which no relevant adverse effect is

expected.

MethodDerivation of a health-based recommended occupational exposure limit (HBR-

OEL), based on a ‘no-observed adverse effect level (NOAEL)’, and applying

uncertainty factors.


Assessment factor Specifics Default value

Interspecies metabolic rate / bw AS

remaining difference -

Intraspecies worker -

consumer -

Exposure duration sub- to semi

sub- to chronic other formula

semi to chronic

Route-to-route absorption 1

Dose response reliability -

L → NOAEL NA

severity effect -

Extrapolation of animal to human

Default assessment factors / without threshold

…een vruchtbare combinatie

Documents

ra of gchealth council

core areasdutch approach

ra of gcsetting

ra of gcactivity

ra of gcsocial

genotoxic carcinogens

assessment of mechanism

economic council advices