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Seminrio Nacional do Benzeno ( 5 e 6 dez/12) - Derivao de Limites de Exposio Ocupacional para Substncias Carcinognicas e Mutagnicas - Experincias Internacionais e Nacional


<ul><li> 1. 1st day HM Bolt</li></ul> <p> 2. 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/GermanyLeibniz-Institut fr Arbeitsforschung an der TU DortmundLeibniz Research Centre for Working Environment and Human Factors WHO Collaborating Centrefor Occupational Health 3. The Positioning of Advisory Bodies The general discourse and interplays leading to OEL/BLVregulations are similar at national and EU levels : Political Legislation onauthoritiesoccupational standardsScientific experts Social partners:employers/industry,trade unions 4. Chemical desasters with long-term influence on policyand legislation on chemicals in the EU 1974 Flixborough/UKCyclohexane explosion: 28 deaths,89 wounded 1976 Seveso/ITCDD desaster 1984 Bhopal/INDMethylisocyanate desaster 1986 Schweizerhalle/CH Environmental desaster; Rhine pollution 1993 Frankfurt-Hchst/DAccidents: communication desaster 2000 Baia Mare/ROCyanide (50-100 t) in Tisa and Danube 2000 Enschede/NL Explosion: 23 deaths, 947 wounded 2001 Toulouse/FAmmonium nitrate explosion: 31 deathshttp://www.sust-chem.ethz.ch/teaching/courses/MaterialCuG/Unfaelle.pdf (modified) 5. OELs and BLVs: Development of the SCOEL Mandate2013: New mandate1980 1988 1989 1990 1995 19972004SCOEL strategy 2007for carcinogens Revision/extension of Biological Monitoring EUR 19253Methodology of derivation of OELs Commission Decision 95/320/EC setting up SCOEL Council Directive 90/394/EEC protection of workers to carcinogensCouncil Directive 89/391/EEC introduction of measures/safety and healthof workers Council Directive 88/642/EECamending 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 6. Commission Decision (95/320/EC) of 12 July 1995,setting up a Scientific Committee for OccupationalExposure 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 7. SCOEL Methodology (see SCOEL website) Evaluations on a case by case basis Recommendations with clear justifications Critical effects and mechanisms of action to bedescribed as detailed as possible NOAEL and/or LOAEL, extrapolation model usedand quantitative considerations Systematic update of key scientific criteria (e.g.genotoxicity) 8 8. Two kinds of OELs: Indicative OELs[majority of OELs] Binding OELs[traditionally forgenotoxic carcinogensand for Pb] 9. Official performance data in 2008(introduction of SCOEL carcinogen strategy) 156 Recommendations in total 18 Carcinogens 96 IOELVs (+10) D2000/39/CE &amp; D2006/15/CE (91/322/CE) Binding Values: Benzene VCMD 2004/37/CE Wood dust LeadD 98/24/CE AsbestosD2003/18/CE 10 10. Binding Limit Values in the EU and in Germany (binding) (in Germany) 11. Triggering Discussions for new Criteria (2000-2007)(Threshold Effects for Carcinogens ?) Inductionof aneuploidy Endogenous carcinogens, within Topoisomerase II poisonslimits of homeostasis Oxidative stress Clastogens (being discussed) Inhibition of DNA synthesis Steep dose-effect curve,cytotoxicity involvedKirsch-Volders et. al: Mutation Res. 464:3-11, 2000Madle et. al: Mutation Res. 464:117-121, 2000Pratt &amp; Baron: Toxicol. Lett. 140/141: 53-62, 2003The 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. 12. 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 GenotoxicNon-genotoxic DNA reactive, Genotoxicity only on chromosome causing mutations level (e.g. spindle, topoisomerase)ClearlyWeak genotoxin,DNA-reactive Borderlinesecondary mecha-&amp; initiating cases nisms importantA: No threshold,B: Situation not clear C: Practical/apparent D: Perfect/statisticalLNT model to applyLNT as defaultthreshold likelythreshold likelyNumerical risk assessment,NOAEL risk management procedureshealth-based exposure limits 13. Summary of the SCOEL Strategy for Carcinogens The scientific development allows to identify carcinogenswith a threshold-type mode of action. For these compoundshealth based OELs (and BLVs, where appropriate) can bederived. Such a mechanism-based assignment is independent of theformal 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, wheneverdata are sufficient. When data are not sufficient for a risk assessment, SCOELgives recommendations on possible strategies for riskminimisation, if possible. 14. Results of SCOEL Discussions (Examples)No threshold, LNT (Linear Non-Threshold) model to apply:A vinyl chloride / vinyl bromide (risk assessment) MDAdimethyl / diethyl sulfate 1,3-butadiene (risk assessment)LNT as default assumption:B acrylonitrile benzene (provisional assignment) arsenicnaphthalene hexavalent chromium o-anisidine 2,6-dimethylaniline (insuff. Data)Practical/apparent threshold:vinyl acetate nitrobenzene pyridineClead (provisional OEL); lead chromate TRI DCMglyceryl trinitratePerfect/statistical threshold:D carbon tetrachloride chloroform 15. 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 nasopharyngealcarcinomas (local effect in humans) Discussions by SCOEL (2005-2007): A: Cell profiferation/irritation necessary for tumour formation B: No straightforward evidence for systemic effectsGroup C: Carcinogen with practical threshold, OEL=0.2 ppm 16. Case Discussion: Vinyl Acetate, B oder C ?- Local carcinogenesis upon inhalation and drinking waterapplication- Locally hydrolysed to acetaldehyde and acetic acid- Local genotoxicity of acetaldehyde plus cytotoxicity due toacidification 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 17. 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 straightforwardBut: 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 18. 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! 19. Case: Trichlorethylene, B oder C ?- Renal cell carcinomas in humans exposed to very high peakconcentrations 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 nephrotoxicityToxicol. Lett. 140-141: 43-51, 2003 20. 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 g/m3 Cd: OEL = 4 g/m3; BLV = 2 g/g creatinine Ni: OEL = 10 g/m3 inh., 5 g/m3 resp. dust; BLV = 3 g/LD (perfect threshold): RCF; OEL = 0.3 fibres/mL 21. 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! 22. 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-&gt; No threshold can be identified at the present time (equivalent to SCOEL Carcinogen Group B)-&gt; However: by lowering exposure risk can be reduced 23. SCOEL recommendation on benzene (II)Risk assessment based on 1980s literatureBenzene ExposureRange of additional leuk.conc. (ppm) ppm x years risk per 1000 workers 0.14 0.05 0.7 0.5200.25 3.3 1.0400.5 6.6 3.0120 2.0 19.8 24. SCOEL recommendation on benzene (III) An OEL of 0.5 ppm (20 ppm-years): reduction to 0.25-3.3additional leukaemia cases per 1000 Non-genotoxic effects on the haematopoietic systemin animals: LOAEL 10 ppm LOAEL for chromosomal damage (SCE, micronuclei) inblood cells and bone marrow of rodents: 1-10 ppmIf 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. 25. Biological monitoring parameters (addendum 2006)Benzene metabolism consideredt,t-Muconic acidin urineBenzenein bloodS-Phenyl mercapturic acidin urine 26. Biological monitoring parameters - evaluation Benzene in blood: invasive sampling Evironmental influences of t,t-muconic acidexcretion (e.g. sorbic acid as food preservative) S-Phenylmercapturic acid recommended for lowbenzene exposuresBenzene (ppm):0.3 0.6 1.0 2 4 6t,t,-Muconic acid (mg/L): 0.8 1.6 2 3 5 7 27. Present Binding Limit Values: Discussion goes on!(binding) (in Germany) 28. 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! 29. AcknowledgementScientific Committee forOccupational Exposure Limits,DG Employment, EuropeanUnion, Luxembourg,and theGerman MAK Commission ofthe DeutscheForschungsgemeinschaft (DFG)La valle des moulins (Mllerthal), Luxemburg </p>