Seminário Nacional do Benzeno ( 5 e 6 dez/12) - Derivação de Limites de Exposição Ocupacional para Substâncias Carcinogênicas e Mutagênicas - Experiências Internacionais e Nacional

1. 1st day HM Bolt

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/Germany
Leibniz-Institut für Arbeitsforschung an der TU Dortmund
Leibniz Research Centre for Working Environment and Human Factors
WHO Collaborating Centre
for Occupational Health

3. 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

4. Chemical desasters with long-term influence on policy
and 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 deaths
http://www.sust-chem.ethz.ch/teaching/courses/MaterialCuG/Unfaelle.pdf (modified)

5. OELs and BLVs: Development of the SCOEL Mandate
2013: New mandate
1980 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

6. 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.“ [Nota bene: no explicit reference to carcinogens!]
Review: European aspects of standard setting in
occupational 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)
8

9. 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 dust
Lead D 98/24/CE
Asbestos D2003/18/CE
10

11. Binding Limit Values in the EU and in Germany
(binding)
(in Germany)

12. 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.“

13. 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 important
A: No threshold, B: Situation not clear C: Practical/apparent D: Perfect/statistical
LNT model to apply LNT as default threshold likely threshold likely
Numerical risk assessment, NOAEL
risk management procedures health-based exposure limits

14. 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.

15. Results of SCOEL Discussions (Examples)
No threshold, LNT (Linear Non-Threshold) model to apply:
A vinyl chloride / vinyl bromide (risk assessment) MDA
dimethyl / diethyl sulfate 1,3-butadiene (risk assessment)
LNT as default assumption:
B acrylonitrile benzene (provisional assignment) arsenic
naphthalene hexavalent chromium o-anisidine
 2,6-dimethylaniline (insuff. Data)
Practical/apparent threshold:
vinyl acetate nitrobenzene pyridine
C
lead (provisional OEL); lead chromate TRI DCM
glyceryl trinitrate
Perfect/statistical threshold:
D  carbon tetrachloride  chloroform

16. 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

17. 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

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

19. 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!

20. 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

21. 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

22. 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 relevant
carcinogens.
However: SCOEL/SEG discussions on benzene
dated prior to the introduction of the SCOEL
system for carcinogens!

23. SCOEL recommendation on benzene (I)
(1991, with addendum on biomonitoring 2006)
Benzene induces myelogenous leukemia
Growing evidence for lymphomas and multiple myelomas
Clastogenic in humans and animals,
with growig evidence for mutagenicity in vitro
Covalent 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

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

25. 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.“

26. Biological monitoring parameters (addendum 2006)
Benzene metabolism considered
t,t-Muconic acid
in urine
Benzene
in blood
S-Phenyl mercapturic acid
in urine

27. 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 0.6 1.0 2 4 6
t,t,-Muconic acid (mg/L): 0.8 1.6 2 3 5 7

28. Present Binding Limit Values: Discussion goes on!
(binding)
(in Germany)

29. 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!

30. 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