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www.ifado.deBrasilian Benzene Seminar, 5th December 2012
DERIVATION OF OELs ......
The German risk-based approach for minimizing exposure to carcinogens
Gisela H. Degen
Leibniz Research Centre for Working Environment and Human Factors at the TU Dortmund (IfADo); Chairperson of ’AK CM’ of Subcommittee III in the AGS
www.ifado.de
0 OVERVIEW – CONTENTThe German Risk-based Approach for minimizing exposure to carcinogens
Brasilian Benzene Seminar, 5th December 2012
1 German Legislation & COMMITTEES
2 The new German Hazardous Substances Ordinance
3 Risk-based OELs for carcinogens? (C1, 2 or CLP 1A, B)
Two values ! for ‘acceptable‘ and ‘tolerable‘ risk
4 Traffic Light concept & Graded Intervention Measures
(RA & RM)
5 Guidance document on deriving cancer risk figures
6 Evaluation of carcinogenic substances - examples ..
7 Present experience – Concluding Remarks
1 OCCUPATIONAL SAFETY & HEALTH .. in GERMANYThe German Risk-based Approach for minimizing exposure to carcinogens
Brasilian Benzene Seminar, 5th December 2012
OSH legislation & „downstream“ regulations: responsibility of the German Federal Ministry of Labour and Social Affairs (BMAS)
in 2005: the new German Hazardous Substances Ordinance
The Committee for Hazardous Substances (AGS, Ausschuss für Gefahrstoffe) advice to the Ministry on OSH measures ...
AGS subcommittes (UA I to III) + project groups (AK, Arbeitskreise)
Subcommittee III (hazard risk assessment) launched the ’AK CM’ to formulate proposals for limit values for
carcinogenic/mutagenic (CM) substances and for their classification ...
Several members of the German MAK-Commission (an independent scientific body) also members in working groups of the AGS.
AGS: a ‘tripartite‘ committee ... (political/social partners & academia)
2-1 The GERMAN HAZARDOUS SUBSTANCES ORDINANCE The German Risk-based Approach for minimizing exposure to carcinogens
Brasilian Benzene Seminar, 5th December 2012
Introduced in 2005; permits only health-based OELs ...
Deletion of numerous hazardous substances ... from ‚limit value‘ lists:
– carcinogens (until then technically-based ‚limit value‘)
– substances for which thresholds of toxicological action cannot be determined with adequate reliability ...
The Dilemma: virtually impossible to define health-based OELs for mutagenic carcinogens, but the necessity for protecting workers ...
The Ministry (BMAS) instructed the AGS to develop a concept for the deduction of risk-based atmospheric limit values for carcinogens (categories 1 and 2; CLP 1A and 1B)
AGS launched the ’Risk Acceptance’ project group ... to propose levels of ‘acceptable‘ and ‘tolerable‘ risk at the
workplace:
Task involving representatives from all affected social groups
2-2 RATIONALE AND OBJECTIVES The German Risk-based Approach for minimizing exposure to carcinogens
Brasilian Benzene Seminar, 5th December 2012
Starting point…
If substitution of a carcinogenic substance is not possible any exposure must be minimized (or EU directive 90/394/EC)
Germany had introduced TRK = technically-based threshold limit values which should not be exceeded (from 1991 until 2005)
… minimization of exposure is not a new obligation – so why introduce a new concept?
Minimization of carcinogenic substances with the former TRK concept did not work in practice: overall cap - yes but further reduction below the TRK value - no
At a workplace continuous minimization is difficult to verify if only one single ‘threshold’ exists
Minimization ”to zero“ is not possible in reality
3-1 RISK LIMITS FOR CARCINOGENS AT THE WORKPLACE The German Risk-based Approach for minimizing exposure to carcinogens
Brasilian Benzene Seminar, 5th December 2012
Upper risk level
Lower risk level
Tolerable risk of 4 : 1,000
Acceptable risk of 4 : 10,000 (prov.) then 4 : 100,000
Risk limits agreed on by social partners,
independent of the agent
From concept to application: How to get from risk limits to air concentrations?
for each individual substance an exposure-risk-relationship (ERB) must be determined
from there a substance-specific acceptable concentration and a tolerable concentration are derived
Exposure-risk-relationship – for 2 substances X und Y
tolerable risk
acceptable risk
risk
AK-X TK-X AK-Y TK-Y exposure
AK: acceptable concentration TK: tolerable concentration
Exposure-risk graph linear for X
Exposure-risk graph non-linear for Y „hockey stick“
Brasilian Benzene Seminar, 5th December 2012
3-2 FROM CONCEPT TO APPLICATION – GENERAL PRINCIPLES
The German Risk-based Approach for minimizing exposure to carcinogens
4 The TRAFFIC-LIGHT CONCEPT & MORE ...The German Risk-based Approach for minimizing exposure to carcinogens
Brasilian Benzene Seminar, 5th December 2012
Three areas: Graded Intervention (action) for areas of risk
risk of cancer (disease)
tolerable risk
acceptable risk
High risk:most stringent measures
Medium risk:less stringent measures
Low risk:least stringent measures
---> Risk management (RM) based on risk assessment (RA)
5 GUIDANCE on DERIVING CANCER RISK FIGURES ...The German Risk-based Approach for minimizing exposure to carcinogens
Brasilian Benzene Seminar, 5th December 2012
To enable application of the ‚traffic-light-concept‘ the AGS subcommitee III charged the Project group ‘Risk Deduction‘ to produce a guidance document:
Procedure for quantifying cancer risk figures from animal and/or human data
Default assumptions to bridge data gaps ...
Extrapolation to low doses based on MoA information
Exposure-Risk-Relationships (ERB) for carcinogens
Include non-cancer endpoints in overall evaluation
Full transparent documentation; adress uncertainties
Update/revise G. when more experience is available
http://www.baua.de/en/Publications/Expert-Papers/Gd34.html
6-1 EVALUATION OF CARCINOGENS - EXAMPLES The German Risk-based Approach for minimizing exposure to carcinogens
Brasilian Benzene Seminar, 5th December 2012
1,3-Butadiene: K1; M2 --> ERB
human data - epidemiology - risk extrapolation - genotoxic
Ethylene oxide: K2; M2 --> ERB
animal data - risk extrapolation - genotoxic
Trichloroethylene: EU K2 / MAK K1 --> ERB
human data - epidemiology - sublinear risk extrapolation - nephrotoxicity - peak exposures !
Acrylamide: K2; M2 --> ERB
animal data - extrapolation - mechanism? - neurotoxic --> AGW
Methylene chloride (DCM): EU K3 / MAK K5 --> AGW
animal (tumour) data - human (CO-Hb)
1,3-Butadiene *
• EU: Category 1, M2; DFG: K1, KMut2 „old“ TRK-Value of 15 or 5 ppm
• Lymphosarcoma, Leukemia (animal data)
• genotoxic carcinogen (Oxiran-Metabolite)
• Cohort study (Graff et al. 2005) synthetic rubber industry & Leukemia
class midpoint of 4 exposure categories (cumul.expo) : 35 years =>Long-term mean value of the exposure; then compared to rel. risk- straight line of regression slope 0.16 (rounded): per 1 ppm exposure increase, the rel. risk of contracting cancer increases by 0.2
• Background leukemia risk in males about 1% x rel. risk of 0.2 per ppm --> an “excess-working life risk“ of 0.2% (2:1,000) after 35 years workplace exposure to a long-term mean value of 1 ppm
► Exposure Risk Relationship (ERB) :4 : 1,000 at 2 ppm Butadiene (full shift, 5d week, 35-40 y)
4 : 10,000 at 0.2 ppm Butadiene
* Degen & Nies (2008) Gefahrstoffe - Reinhaltung der Luft 68: 299-302
6-2
Ethylene oxide • EU: Category 2; DFG: K2 old TRK-value 1 ppm = 2 mg/m3
• Peritoneal mesotheliomas, MNC-leukemia, lung-, brain tumors
• genotoxic carcinogen; endogenous EtO production
• Epidemiological data insuffient ...
• POD for Risk calculation (linear extrapolation): Sum (BMD10) alveolar & bronchiolar carcinoma
(rodent) 19.44 ppm --> conservative approach
► Exposure Risk Relations (ERB) Occup. Tumor Risk:4 : 1,000 at 1.18 ppm EO (full shift, 5 d week, working life 40y)
4 : 10,000 at 0.12 ppm EO
• Non-cancer (neurotoxic) effects only at much higher concentration: NOAEL 50 ppm in primates
CH2
O
CH2
6-3
Trichloroethylene
• EU CLP: K1B; M2 DFG: K2 old TRK-value 50 ppm
• Kidney tumors in rats
• Human data: Kidney tumors (5% excess risk at 75 ppm)
– and possibly liver and NHL
• Nephrotoxic: NOAEL at 6 ppm
• POD for Risk calculation :
See graphical depiction
► Exposure Risk Relations (ERB) Occup. Tumor Risk:4 : 1,000 at 11 ppm TRI (full shift, 5 d week, working life 40y)
4 : 10,000 at 6 ppm TRI
• Non-cancer (nephrotoxic) effects; but no AGW due to genotox
• Dermal absorption of liquid TRI - and peak exposures ?
6-4
Brasilian Benzene Seminar, 5th December 2012
Trichloroethylene
Exzess-Lebenszeit-Krebsrisiko
15ppm
1%
0,69%
6 ppm
0,4%
0,04%
Knickstelle
0,2%
0,4%
0,6%
0,8%
1 %
Schnittpunkt der Geraden bei 75 ppm (5%Excess Risiko) = POD
Point of Departure: 5%-Excess risk at 75 ppm(Kidney tumor, Human)
Excess-Lifetime-cancer riskocc. expos
6 ppm
1% NOAELNephrotoxicity(Human)
11 ppmTolerance level !
15 ppm
6-5
Brasilian Benzene Seminar, 5th December 2012
Cl
Cl
Cl
H
Acrylamide
• EU: K2; M2; R3 DFG: K2 and „H“
• Mesothelioma of TV; mammary tumors, thyroid, CNS (rat) after oral administration
• Mechanisms unclear; genotoxic metabolite (glycide amide)
• POD: Johnson et al (1986), Friedman et al (1995)
Mammary tumors rats in d.w. study --> BMD10 1.1 mg/kg/d
BMD10 Rat (p.o.) extrapolated Human extra risk = 2.6 mg/kg/d
• ► Exposure - Risk relations - Occup. cancer convert Lifelong Exposure > Worklife Exposure:
Risk 10% at POD 18 mg/m3 or4 : 1,000 at 0.7 mg/m3 AA (full shift, 5 d per week, 40 y) 4 : 10,000 at 0.07 mg/m3 Acrylamide
• BUT: Protection against Neurotoxicity: 0.15 mg/m3 (OEL)• Biological Monitoring indicated („H“)
6-6
Brasilian Benzene Seminar, 5th December 2012– old splitted TRK: 30 or 60 µg/m3
6-7 Methylene chloride - Dichloromethane
• Classification: EU: K3; DFG: 3A
• Lung, Liver tumors (Mice), Mammary tumors (Rat) upon Inhalation
• Mechanisms: Glutathione-dependent metabolites in rodents, but formed in minor amounts in humans
• Basis for Risk figures: Calculations of Starr et al. (2006) PBPK Modelling (Bayes‘s with Markov-Chain-Monte-Carlo- Techniques) and considerations on GST-Polymorphisms (U.S.)
mean extra risk (Human) = 1.05 x 10-9 pro 1 µg/m3
► Exposure rel. cancer risk at the 75 ppm ‚AGW‘ ??Lifetime: 2.6 x 10-4 Working life: 4.3 x 10-5 (i.e. „acceptable“ !)
Cl
Cl HH
• German OEL: 75 ppm = 260 mg/m3 (AGW, 2007)
Brasilian Benzene Seminar, 5th December 2012
K3 compound in TRGS 900
SOME SUBSTANCES and ERBs
0,0
0,1
1,0
10,0
100,0
1.000,0
10.000,0
100.000,0
1.000.000,0
µg/m3
NDMA
0,750
0,075
Acrylamid
700
70
700
70
2640
260
5000
500
60.00033.000
MDA Acrylnitril 1,3-Butadien TRI
0,70
0,07
BaP Ethylenoxid
2000
200
Exposure level(logarithmic)
Upper Risk 4:1.000
Lower Risk 4:10.000
Data Base – Scenarios
2 1 30 2000 4500 11 000 270 000Former TRK value: µg/m³
Yellow area:
100*
MDA: 4,4‘-Methylenedianiline, NDMA: Nitrosodimethylamine,TRI: Trichloroethylene
Brasilian Benzene Seminar, 5th December 2012
7-1
Brasilian Benzene Seminar, 5th December 2012
7-2 CONCLUDING REMARKS
Introduction of three bands(intervention measures/risk bands)compared to two bands in the former TRK-concept
Substance-independent tiered control schemeto minimize exposure: Grading of the individual measures in three risk bands
Quantified risks: two substance-independent risk limits:acceptable risk and tolerable risk
Derivation of substance-specific concentration values based on those two risk limits:acceptable concentration and tolerable concentration
www.ifado.de
THANK YOU FOR THE INTEREST !
..........
Many thanks to Dr. E. Nies and Dr. H. Wriedt who shared some slides for this presentation
Brasilian Benzene Seminar, 5th December 2012
Position papers on Expo-Risk-Relations for carcingens (in German) available at:
http://www.baua.de/de/Themen-von-A-Z/Gefahrstoffe/TRGS/Begruendungen-910.html