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
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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
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5 core areas
• Quality of Life (Life Sciences)
• Defence, Security & Safety
• Science & Industry (Processes)
• Built Environment & Geosciences
• Information & Communication Technology
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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.
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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.
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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.
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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
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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
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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
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Genotoxic carcinogens acting by a stochastic mechanismNon-threshold approach: calculation of a HBC-OCRV
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.
Approach for deriving a limit value
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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
(Formaldehyde)
In case of ???
Approach for deriving a limit value
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Report cover
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Some examples
Genotoxic carcinogens acting by a stochastic mechanismAflatoxin, 1,3-Butadiene, Azathioprine, Bariumchromate, Benzo[a]pyrene …..
Genotoxic carcinogens acting by a non-stochastic mechanism
Arsenicum, ……
Non-genotoxic carcinogensHexachlorobenzene, …….
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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
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Activity 2 Calculating reference risk values for genotoxic carcinogens
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
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Step 1 Selection of key study
Preferably human cancer mortality data. However, in most cases it has to be
based on animal data.
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Step 1 Selection of key study
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.
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Step 1 Selection of key study
Preferably human cancer mortality data. However, in most cases it has to be
based on animal data.
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.
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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)
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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
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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’
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Report cover
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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.
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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
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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
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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
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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.
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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
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Thank you for your attention!
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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’
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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
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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.
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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