1st day HM Bolt

Derivation of OELs for carcinogens and mutagens

Strategy regarding carcinogens/mutagens of the

Scientific Committee on Occupatinal Exposure Limits

(SCOEL) of the European Union, with a view on benzene

Hermann M. Bolt, Dortmund/Germany

Leibniz-Institut für Arbeitsforschung an der TU DortmundLeibniz Research Centre for Working Environment and Human Factors

WHO Collaborating Centrefor Occupational Health

The Positioning of Advisory Bodies

The general discourse and interplays leading to OEL/BLV regulations are similar at national and EU levels :

Legislation onoccupational standards

Politicalauthorities

Scientific experts

Social partners:employers/industry,

trade unions

Chemical desasters with long-term influence on policy and legislation on chemicals in the EU

OELs and BLVs: Development of the SCOEL Mandate

Council Directive 80/1107/EEC protection of workers from the risk related to exposureto chemical, physical and biological agents at work

Council Directive 88/642/EEC amending the Directive of 1980

Commission Decision 95/320/EC setting up SCOEL

EUR 19253“Methodology of derivation of OELs“

Council Directive 89/391/EEC introduction of measures/safety and healthof workers

Council Directive 90/394/EEC protection of workers to carcinogens

Revision/extension of„Biological Monitoring“

1980 1988 1989 1990 1995 1997 2004 2007SCOEL strategy for carcinogens

2013: New mandate

Commission Decision (95/320/EC) of 12 July 1995,setting up a Scientific Committee for Occupational

Exposure Limits to Chemical Agents (SCOEL)

Article 2 (1)... „The Committee shall in particular give advice on the setting of OccupationalExposure Limits (OELs) based on scientific data and, where appropriate, shallpropose values which may include:

• the eight-hour time-weighted average (TWA),• short-term limits/excursion limits (STEL),• biological limit values.

The OELs may be supplemented, as appropriate, by further notations.The Committee shall advise on any absorption of the substance in questionvia other routes (such as skin and/or mucous membranes) which is likelyto occur.“ [Nota bene: no explicit reference to carcinogens!]

Review: European aspects of standard setting inoccupational hygiene and medicine. Rev.Environ.Health 16:81-86

8

SCOEL Methodology (see SCOEL website)

✽ Evaluations on a “case by case“ basis

✽ Recommendations with clear justifications

✽ Critical effects and mechanisms of action to be described as detailed as possible

✽ NOAEL and/or LOAEL, extrapolation model used and quantitative considerations

✽ Systematic update of key scientific criteria (e.g. genotoxicity)

Two kinds of OELs:

Indicative OELs

[majority of OELs]

Binding OELs

[traditionally for

genotoxic carcinogens

and for Pb]

10

Official performance data in 2008(introduction of SCOEL carcinogen strategy)

✽ 156 Recommendations in total

✽ 18 Carcinogens✽ 96 IOELVs (+10) D2000/39/CE & D2006/15/CE (91/322/CE)

• “Binding Values”: Benzene VCM D 2004/37/CE

Wood dustLead D 98/24/CE

Asbestos D2003/18/CE

Binding Limit Values in the EU and in Germany

(binding)(in Germany)

Triggering Discussions for new Criteria (2000-2007) (Threshold Effects for Carcinogens ?)

Induction of aneuploidy Topoisomerase II poisons Oxidative stress Inhibition of DNA synthesis Steep dose-effect curve, cytotoxicity involved

Endogenous carcinogens, within limits of homeostasis Clastogens (being discussed)

Kirsch-Volders et. al: Mutation Res. 464:3-11, 2000Madle et. al: Mutation Res. 464:117-121, 2000Pratt & Baron: Toxicol. Lett. 140/141: 53-62, 2003

„The dose-response relationship for a number of suchagents is generally accepted to show a threshold, however,the degree of acceptance of the threshold effect differs indifferent EU regulatory systems.“

Dose-Effect Relations in the Low Dose Range and Risk Evaluation (Concept adopted by SCOEL - see Archives of Toxicology 82: 61-64, 2008)

Chemical carcinogen,causing tumours in humans and/or experimental animals

Non-genotoxicGenotoxic

DNA reactive,causing mutations

Genotoxicity only on chromosomelevel (e.g. spindle, topoisomerase)

Weak genotoxin,secondary mecha-nisms important

Borderlinecases

ClearlyDNA-reactive& initiating

C: Practical/apparent threshold likely

D: Perfect/statistical threshold likely

A: No threshold,LNT model to apply

Numerical risk assessment, risk management procedures

NOAEL health-based exposure limits

B: Situation not clear LNT as default

Summary of the SCOEL Strategy for Carcinogens

• The scientific development allows to identify carcinogens with a threshold-type mode of action. For these compounds health based OELs (and BLVs, where appropriate) can be derived.

• Such a mechanism-based assignment is independent of the formal classification of carcinogens (i.e., former EU cate- gories 1, 2 or 3, equivalent to GHS categories 1A, 1B, 2)!

• When derivation of a health-based OEL/BLV is not possible, SCOEL assesses the quantitative cancer risk, whenever data are sufficient.

• When data are not sufficient for a risk assessment, SCOEL gives recommendations on possible strategies for risk minimisation, if possible.

Results of SCOEL Discussions (Examples)

vinyl chloride / vinyl bromide (risk assessment) MDA dimethyl / diethyl sulfate 1,3-butadiene (risk assessment)

No threshold, LNT (Linear Non-Threshold) model to apply:

A

LNT as default assumption:

acrylonitrile benzene (provisional assignment) arsenicnaphthalene hexavalent chromium o-anisidine 2,6-dimethylaniline (insuff. Data)

Practical/apparent threshold:vinyl acetate nitrobenzene pyridinelead (provisional OEL); lead chromate TRI DCMglyceryl trinitrate

Perfect/statistical threshold:

carbon tetrachloride chloroform

B

C

D

SCOEL: Formaldehyde - B oder C ?Major points of general discussion

- Classical case since the 1980s of nasal tumours in rats- Sublinear dose-response curve (accepted since the 1980s)- Cytotoxicity as relevant/necessary influencing factor - IARC (2005): Sufficient evidence of human nasopharyngeal carcinomas (local effect in humans)

• A: Cell profiferation/irritation necessary for tumour formation• B: No straightforward evidence for systemic effects

Group C: Carcinogen with practical threshold, OEL=0.2 ppm

Discussions by SCOEL (2005-2007):

Case Discussion: Vinyl Acetate, B oder C ?

- Local carcinogenesis upon inhalation and drinking water application- Locally hydrolysed to acetaldehyde and acetic acid- Local genotoxicity of acetaldehyde plus cytotoxicity due to acidification of cells (M. Bogdanffy, EUROTOX Budapest 2002)

• Cell proliferation/irritation necessary for tumour formation• No straightforward evidence for systemic effects

Group C: OEL of 5 ppm recommended

Argumentations by SCOEL (2005)

Case: Acrylonitrile, B or C ?- Carcinogenic to rats (oral and inhalation studies)- Weakly mutagenic in vitro, but mutagenic epoxide metabolite

• Absence of DNA adducts in brain• Oxidative DNA damage in astrocytes in vitro• Reversible loss of gap junction communication in exposed astrocytes• Dose-response curve sublinear• Genotoxicity in vivo not straightforward

But: multi-organ carcinogen[brain, spinal cord, Zymbal gland, GI tract (upon oral dosing),mammary gland]

High acute toxicity, due to cyanide formation !Group B; no health-based OEL

Argumentations for brain tumours discussed by SCOEL:

Special Case: Acrylamide, B or C ?

- Carcinogenic to rats (similar to acrylonitrile)- Weakly mutagenic in vitro, but mutagenic epoxide metabolite

Similar to acrylonitrile: multi-organ carcinogen[brain, mammary gland, mesotheliomas]

High neurotoxicity!Group B; no health-based OEL

Argumentations discussed by SCOEL:

But: derivation of a „practical“ OEL and BLV, to prevent neurotoxicity!

Case: Trichlorethylene, B oder C ?

- Renal cell carcinomas in humans exposed to very high peak concentrations over several years (studies in Germany and France)- -Lyase pathway involved in local bioactivation- Specific VHL mutation patterns in highly exposed persons- Nephrotoxicity involved (1-microglobulin, GST, other markers)

Toxicol. Lett. 140-141: 43-51, 2003

SCOEL Recommendation

Group C: Proposal of an OEL of 10 ppm based on avoidance of nephrotoxicity

Further examples: Recent SCOEL recommendations on inorganic compounds

A (no threshold): Cr(VI) - numerical risk assessment

B (situation not clear): Be – no OEL recommended

C (practical threshold):• Crystalline silica, resp. dust: OEL = 50 µg/m3

• Cd: OEL = 4 µg/m3; BLV = 2 µg/g creatinine• Ni: OEL = 10 µg/m3 inh., 5 µg/m3 resp. dust; BLV = 3 µg/L

D (perfect threshold): RCF; OEL = 0.3 fibres/mL

General conclusions:There has been consistent progress in research on modes of carcinogenic action. Secondary geno-toxicity is receiving more attention!

The recognition of genotoxic and carcinogenic thresholds will allow the assignment of health-based limit values for an increasing number of relevantcarcinogens. However: SCOEL/SEG discussions on benzene dated prior to the introduction of the SCOEL system for carcinogens!

SCOEL recommendation on benzene (I)(1991, with addendum on biomonitoring 2006)

Benzene induces myelogenous leukemia Growing evidence for lymphomas and multiple myelomasClastogenic in humans and animals, with growig evidence for mutagenicity in vitroCovalent binding of metabolites to DNA

-> No threshold can be identified at the present time (equivalent to SCOEL Carcinogen Group B)-> However: by lowering exposure risk can be reduced

SCOEL recommendation on benzene (II)Risk assessment based on 1980s literature

Benzene ExposureRange of additional leuk. conc. (ppm) ppm x years risk per 1000 workers

0.1 40.05 – 0.7

0.5 200.25 – 3.3

1.0 400.5 – 6.6

3.0 1202.0 – 19.8

SCOEL recommendation on benzene (III)

An OEL of 0.5 ppm (20 ppm-years): reduction to 0.25-3.3 additional leukaemia cases per 1000 Non-genotoxic effects on the haematopoietic system in animals: LOAEL 10 ppm LOAEL for chromosomal damage (SCE, micronuclei) in blood cells and bone marrow of rodents: 1-10 ppm

„If haematotoxic effects play a role in leukaemia induction, avoidance of these will minimise leukaemia risk. A limit value should be below 1.0 ppm; this should also avoid chromosomal effects.“

Biological monitoring parameters (addendum 2006)

Benzene metabolism considered

t,t-Muconic acidin urine

Benzenein blood

S-Phenyl mercapturic acidin urine

Biological monitoring parameters - evaluation

Benzene in blood: invasive sampling Evironmental influences of t,t-muconic acid excretion (e.g. sorbic acid as food preservative) S-Phenylmercapturic acid recommended for low benzene exposures

Benzene (ppm): 0.3 0.61.0 2 4 6

t,t,-Muconic acid (mg/L): 0.8 1.6 23 5 7

Present Binding Limit Values: Discussion goes on!

(binding)(in Germany)

PS: Benzene may be a problem inside automobiles

Toxicol Lett. 2006; 160(2):93-104. Benzene and its methyl-derivatives: derivation of maximum exposure levels in automobiles.Schupp T, Bolt HM, Jaeck R, Hengstler JG.:

„A systematic toxicological evaluation of the risk associated with benzene exposure in cars seems necessary.“

This keeps us busy.

Thank you for your attention!

Acknowledgement

Scientific Committee for

Occupational Exposure Limits, DG

Employment, European Union,

Luxembourg,

and the

German MAK Commission of the

Deutsche

Forschungsgemeinschaft (DFG)

La vallée des moulins (Müllerthal), Luxemburg