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 Dortmund Leibniz Research Centre for Working Environment and Human Factors WHO Collaborating Centre for Occupational Health
The Positioning of Advisory Bodies The general discourse and interplays leading to OEL/BLV regulations are similar at national and EU levels : Political Legislation on authorities occupational standards Scientific experts Social partners: employers/industry, trade unions
Chemical desasters with long-term influence on policyand legislation on chemicals in the EU 1974 Flixborough/UK Cyclohexane explosion: 28 deaths,89 wounded 1976 Seveso/I TCDD desaster 1984 Bhopal/IND Methylisocyanate desaster 1986 Schweizerhalle/CH Environmental desaster; Rhine pollution 1993 Frankfurt-Höchst/D Accidents: communication desaster 2000 Baia Mare/RO Cyanide (50-100 t) in Tisa and Danube 2000 Enschede/NL Explosion: 23 deaths, 947 wounded 2001 Toulouse/F Ammonium nitrate explosion: 31 deathshttp://www.sust-chem.ethz.ch/teaching/courses/MaterialCuG/Unfaelle.pdf (modified)
OELs and BLVs: Development of the SCOEL Mandate 2013: New mandate1980 1988 1989 1990 1995 1997 2004 SCOEL strategy 2007 for carcinogens Revision/extension of „Biological Monitoring“ EUR 19253“Methodology of derivation of OELs“ Commission Decision 95/320/EC setting up SCOEL Council Directive 90/394/EEC protection of workers to carcinogens Council Directive 89/391/EEC introduction of measures/safety and health of workers Council Directive 88/642/EEC amending the Directive of 1980 Council Directive 80/1107/EEC protection of workers from the risk related to exposure to chemical, physical and biological agents at work
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
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) 8
Two kinds of OELs: Indicative OELs [majority of OELs] Binding OELs [traditionally for genotoxic carcinogens and for Pb]
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 dust Lead D 98/24/CE Asbestos D2003/18/CE 10
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 Endogenous carcinogens, within Topoisomerase II poisons limits of homeostasis Oxidative stress Clastogens (being discussed) Inhibition of DNA synthesis Steep dose-effect curve, cytotoxicity involved Kirsch-Volders et. al: Mutation Res. 464:3-11, 2000 Madle et. al: Mutation Res. 464:117-121, 2000 Pratt & Baron: Toxicol. Lett. 140/141: 53-62, 2003 „The dose-response relationship for a number of such agents is generally accepted to show a threshold, however, the degree of acceptance of the threshold effect differs in different 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 Genotoxic Non-genotoxic DNA reactive, Genotoxicity only on chromosome causing mutations level (e.g. spindle, topoisomerase)Clearly Weak genotoxin,DNA-reactive Borderline secondary mecha-& initiating cases nisms importantA: No threshold, B: Situation not clear C: Practical/apparent D: Perfect/statisticalLNT model to apply LNT as default threshold likely threshold likely Numerical risk assessment, NOAEL risk management procedures health-based exposure limits
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.
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) Discussions by SCOEL (2005-2007):• 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
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) Argumentations by SCOEL (2005)• Cell proliferation/irritation necessary for tumour formation• No straightforward evidence for systemic effects Group C: OEL of 5 ppm recommended
Case: Acrylonitrile, B or C ?- Carcinogenic to rats (oral and inhalation studies)- Weakly mutagenic in vitro, but mutagenic epoxide metaboliteArgumentations for brain tumours discussed by SCOEL:• 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
Special Case: Acrylamide, B or C ?- Carcinogenic to rats (similar to acrylonitrile)- Weakly mutagenic in vitro, but mutagenic epoxide metabolite Argumentations discussed by SCOEL: Similar to acrylonitrile: multi-organ carcinogen [brain, mammary gland, mesotheliomas] High neurotoxicity! Group B; no health-based OEL 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) SCOEL Recommendation Group C: Proposal of an OEL of 10 ppm based on avoidance of nephrotoxicity Toxicol. Lett. 140-141: 43-51, 2003
Further examples: Recent SCOEL recommendations on inorganic compoundsA (no threshold): Cr(VI) - numerical risk assessmentB (situation not clear): Be – no OEL recommendedC (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/LD (perfect threshold): RCF; OEL = 0.3 fibres/mL
General conclusions:There has been consistent progress in research onmodes of carcinogenic action. Secondary geno-toxicity is receiving more attention!The recognition of genotoxic and carcinogenicthresholds will allow the assignment of health-basedlimit values for an increasing number of relevantcarcinogens.However: SCOEL/SEG discussions on benzenedated prior to the introduction of the SCOELsystem for carcinogens!
SCOEL recommendation on benzene (I) (1991, with addendum on biomonitoring 2006)Benzene induces myelogenous leukemiaGrowing 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 literatureBenzene Exposure Range of additional leuk.conc. (ppm) ppm x years risk per 1000 workers 0.1 4 0.05 – 0.7 0.5 20 0.25 – 3.3 1.0 40 0.5 – 6.6 3.0 120 2.0 – 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 acid in urine Benzene in blood S-Phenyl mercapturic acid in urine
PS: Benzene may be a problem inside automobilesToxicol 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 associatedwith 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