An Overview of Methods to Develop XX Word Congress on Safety and Health at Work 2014 Symposium on Threshold Limit Values for Chemical Substances and Nanomaterials An Overview of Methods to Develop Occupational Exposure Limits in Europe Hermann M. Bolt Leibniz Research Centre for Working Environment and Human Factors, TU Dortmund (IfADo) Chair, Scientific Committee for Occupational Exposure Limits (SCOEL), Luxemburg WHO Collaborating Centre for Occupational Health Aug. 25, 2014

The Position of Scientific Advisory Bodies The general discourse and interplay leading to OEL/BLV regulations is similar at national and EU levels: Political authorities Legislation on occupational standards Scientific experts Social partners: employers/industry, trade unions

OELs and BLVs: Development of the SCOEL Mandate 1990: SEG established SCOEL strategy for carcinogens 1980 1988 1989 1990 1995 1997 2004 2007 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 Occupational Exposure Limits (OELs) based on scientific data and, where appropriate, shall propose 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 question via other routes (such as skin and/or mucous membranes) which is likely to occur.“ Review: European aspects of standard setting in occupational hygiene and medicine. Rev.Environ.Health 16:81-86

„Indicative Values“ vs. „Binding Values“ Two ways for the legal implementation of values D 98/24/CE on chemical agents (indicative and binding values) D 2004/37/CE on carcinogens and mutagens (only binding) - IOELVs : Based on health criteria, derived from the assessment of updated and validated scientific data Below this exposure no adverse effects are expected. - BOELVs : Take also into account practical and socio-economical factors and the risk accepted by society They are considered “political-type” values*. * Political decision: to define “acceptable” versus “non-acceptable” risk Aug. 25, 2014

Formal Procedures Development of limit values Prioritisation of chemicals Collection of existing data (by SCOEL members, contractor or JRC) Evaluation of scientific data Recommendation of limit value(s) Scientific discussion (including 6 months consultation) and final recommendation (including analytical methods) Consultation of social partners Adoption (Commission/EP + Council) Transposition (national) and use Aug. 25, 2014

SCOEL’s Mandate Scientific assessment to the EC ( D 95/320/CE) , especifically in relation to the legislation ( 98/24/CE + 2004/37/CE) foreseen to set occupational exposure limits (OELs) Identification of available scientific data Evaluation of the relationship exposure/effects Recommendation of "OELs" : 8-h TWA, 15-min STEL, BLVs and “notations” (eg. skin absorption, sensitisation, carcinogen category) based on own methodology Published recommendations (Aug. 2014) : 172 Aug. 24, 2014

Procedures Methodology Evaluations on a “case by case“ basis Recommendations with clear justifications (published on the EU website) Critical effects and mechanisms of action, described as detailed as necessary NOAEL and/or LOAEL, extrapolation model used, quantitative considerations in detail Systematic update of key scientific factors and of criteria (e.g. carcinogenicity) Aug. 25, 2014

Procedures Methodology Developed by the Committee parallel to its work (started 1990 as SEG) Published in 1999 and continuously updated since then Includes criteria on: General principles Uncertainty factors Time-weighted (8-hours) average values (TWA) Short term exposure (generally 15min) levels (STEL) Absorption through the skin Toxicity to reproduction Respiratory sensitisers BLVs (Biological Limit Values) / BGVs (Biological Guidance Values) Carcinogenic and mutagenic substances / risk assessment Aug. 25, 2014

Dose-Effect Relations in the Low Dose Range and Risk Evaluation (Concept adopted by SCOEL – published in Archives of Toxicology 82: 61-64, 2008) Chemical carcinogen, causing tumours in humans and/or experimental animals Genotoxic Non-genotoxic DNA reactive, causing mutations Genotoxicity only on chromosome level (e.g. spindle, topoisomerase) Clearly DNA-reactive & initiating Weak genotoxin, secondary mecha- nisms important Borderline cases A: No threshold, LNT model to apply B: Situation not clear  LNT as default C: Practical/apparent threshold likely D: Perfect/statistical threshold likely Numerical risk assessment,  risk management procedures NOAEL  health-based exposure limits

Groups of Carcinogens and Examples No threshold, LNT (Linear Non-Threshold) model to apply: A 12 vinyl chloride / vinyl bromide (risk assessment) MDA dimethyl / diethyl sulfate 1,3-butadiene (risk assessment) LNT as „default assumption“: B 11 acrylonitrile benzene (provisional assignment) arsenic naphthalene hexavalent chromium o-anisidine 2,6-dimethylaniline (insuff. data) naphthalene Practical/apparent threshold: C 10 formaldehyde vinyl acetate nitrobenzene pyridine silica lead (provisional OEL); lead chromate TRI DCM Ni glyceryl trinitrate Perfect/statistical threshold: D 4  carbon tetrachloride chloroform 1,4-dichlorobenzene Important distinction between B and C!

Example for „C“: Vinyl acetate (SCOEL 2005/2006): Local metabolism: Local tumours at the point of entry into the organsim No systemic bioavailability upon inhalation

Reasoning: Vinyl acetate, B or C ? Local tumours in animals upon inhalation and oral dosing Local hydrolysis to acetaldehyde and acetic acid Local genotoxicity of acetaldehyde plus cytotoxicity by cell acidification (M. Bogdanffy, EUROTOX Budapest 2002) Argumentation by von SCOEL (2005) Cell proliferation / irritation necessary for tumour developmpent No evidence of systemic effects Group C: OEL = 5 ppm

Example for „B“: Acrylonitrile Carcinogenic in rats (oral and inhalation dosing) Weak mutagen, but mutagenic epoxide metabolite Argumentation concerning brain tumours: No DNA adducts in brain Oxidative DNA damage in astrocytes in vitro Reversible „gap junctions“ damage in exposed astrocytes Dose-effect-curve sublinear Genotoxicity in vivo not clear But: multi-organ carcinogen! Acute toxicity through cyanide metabolite ! Gruppe B; no health-based OEL

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.

Special SCOEL Topics (with support of JRC, Ispra) Further development of biological monitoring Sensitising compounds (diisocyanates and others) PSLT = Poorly Soluble Low Toxicity („inert“) dusts Nanomaterials and carbon nanotubes Asbestos Bitumen Rubber industry and related compounds Diesel exhaust Aviation-related questions: aviation fuels, exhaust, oils and hydraulic fluids

Biological Monitoring: 13 Compounds with BLVs / BGVs (Feb. 2014) Acrylamide (BGV), aniline, benzene, Be, Cd, carbon disulphide, N,N-dimethylformamide, 4,6-dinitro-o-cresol, 2-ethoxyethanol (and acetate), hexachlorobenzene, hydrogen fluoride / fluorides, lead compounds, including lead chromate

Debate on Nanomaterials EU definition: particles sized 1 - 100 nm (Off J Eur Union L 275: 38-40) Scientific discussion: increasing numbers of publications, conferences, congresses (see Foth et al. Arch Toxicol 86:983-984, 2012) Present SCOEL discussion points: Toxicokinetics different from those of larger materials. Accumulation in cells / organs? Cardiovascular effects? Effect thresholds? Aug. 25, 2014

Nanomaterials Recent MAK Commission Report (DFG 2013) Open questions concerning measurement: aggregation, agglomeration, - relation to mass (mg/m3) not optimal! In principle similar effects of nanoparticles and microparticles, but quantitative differences (e.g. inflammation, oxidative stress, genotoxicity). Special problems in case of metal-based nanoparticles! Local / systemic effects? Definition of research needs Aug. 25, 2014

Nanoparticles may have local and systemic effects Systemic effects not well investigated In discussion (SCOEL): Transport via olfactoric nerve into CNS Cardiovascular effects Persistence in organs

Experimental Rodent Studies with Carbon Nanotubes Local inflammation effects in the lung N(L)OAEL: 0.1 mg/m3 Agglomerates! Aug. 24, 2014

Carbon Nanotubes: Summary for SCOEL State of discussion: Low local skin and eye toxicity CNT not sensitising themselves, but amplifying effect possible Low experimental toxicity, but chronic effects not well investigated Effects on foetus only after i.v. dosing Carcinogenicity and genotoxicity ? Aug. 25, 2014

Summary: Exposure Limits in Europe Since 1990 SCOEL has developed a methodology to derive OELs. SCOEL closely cooperates with national scientific OEL panels (especially MAK, DECOS, ANSES, Nordic Exports). Continuous review of chemicals of key interest Further development of biological monitoring Establishment of a new procedure for carcinogens Development of broader topics of key interest, partly on request by European official bodies (Commission, Parliament) Current discourse with ECHA on coherence with REACH procedures, especially the derivation of „DNELs“ vs. OELs