05 gisela degen

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


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


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


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


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“


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


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


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


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


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


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)


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


7-1


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


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

05 gisela degen

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