The document summarizes the position paper of the German AGS on establishing exposure-risk relationships for benzene. The AGS proposes risk-based occupational exposure limits (OELs) for benzene based on epidemiological data. It evaluates benzene's carcinogenicity and mode of action, as well as potential non-cancer effects. While linear extrapolation from high doses is proposed, the document acknowledges uncertainties in the mode of action and potential non-linearity at low doses. An OEL of 0.02 mg/m3, corresponding to a cancer risk of 1 in 100,000, is recommended as an acceptable risk level after 2013. Non-cancer effects are also possible at the tolerance risk level of 0.

1. EXPOSURE-RISK RELATIONSHIP FOR
BENZENE
Position Paper of the German AGS
Gisela H. Degen
Leibniz Research Centre for Working Environment and Human Factors
at the TU Dortmund (IfADo);
Chairperson of ’AK CM’ of Subcommittee III in the AGS
Brasilian Benzene Seminar, 6th December 2012 www.ifado.de

2. 0 OVERVIEW - CONTENT
Position Paper of the AGS - Exposure Risk Relationships for Benzene
1 INTRODUCTION - Cornerstones
2 RISK-BASED OEL‘s for Benzene
3 DATA EVALUATION - Epidemiology
4 EXTRAPOLATION – MoA Arguments
5 OTHER (non-cancer) EFFECTS ?
6 SUMMARY - other OELs
Brasilian Benzene Seminar, 6th December 2012 www.ifado.de

3. 1 CORNERSTONES
Position Paper of the AGS - Exposure Risk Relationships
for Benzene Upper risk level
 The ‘Traffic
light‘ Concept of Lower risk level
AGS with Risk
Bands ...
 The Guide for
Quantifying
cancer risks for
workplace
exposures
http://www.baua.de/de/Themen-von-A-Z/Gefahrstoffe/TRGS/Bekanntmachung-910.html
http://www.baua.de/en/Publications/Expert-Papers/Gd34.html
Brasilian Benzene Seminar, 6th December 2012

4. 2 RISK BASED OEL‘s – BENZENE
Position Paper of the AGS - Exposure Risk Relationships for Benzene
Risk Concentration
“Point of Departure”: ED10 (based on 47 mg/m3 ; 15 ppm
average of epidemiological studies)
4:1,000 (tolerable risk) 1.9 mg/m3; 0.6 ppm
4:10,000 (acceptable risk until 2013) 0.2 mg/m3; 0.06 ppm
4:100,000 (acceptable risk after 2013, 0.02 mg/m3; 0.006 ppm
latest by 2018)
• Carcinogenicity: Leukemia, numerous epidemiological studies,
additional risk (mean): 47 mg/m³ (10%), “point of departure“
• Genotoxicity as an important (partial) mechanism
• Non-cancer effects (Haematotoxicity, Immunotoxicity): no clear
non effect level identifiable, possibly already at tolerance risk
Brasilian Benzene Seminar, 6th December 2012

5. 3-1 DATA - Epidemiological Studies - Leukemia
Position Paper of the AGS - Exposure Risk Relationships for Benzene
Author Risk at Workplace
ED10 ED10 (ppm at 40 ED10 (mg/m3)
(ppm-years) Years occupational
exposure)
“Pliofilm-Cohort”, USA
Crump (1996) 912 22.8 74.1
Paxton (1996), with exposure estimates by:
Rinsky 430 10.8 35.1
Crump 604 15.1 49.1
Paustenbach 1436 35.9 116.7
Rinsky et al., (1987) 416 10.4 33.8
Rinsky et al., 2002 574 14.4 46.8
Brasilian Benzene Seminar, 6th December 2012

6. 3-2 DATA - Epidemiological Studies - Leukemia b
Position Paper of the AGS - Exposure Risk Relationships for Benzene
ED10 ED10 (ppm at 40 ED10 (mg/m3)
(ppm-Years) Years occupational
exposure )
Shoe factory, Italy
Seniori Constantini e al. (2003) 641 16.0 52.0
Chemiearbeiter, China
Hayes et al. (1997) 662 16.6 54.0
Chemiearbeiter, USA
Bloemen et al. (2004) 910 22.8 74.1
Wong et al. (1987a,b) 800 20 65.0
EDF-GDF, France
Guénel et al. (2002) 117 2.9 9.4
Oil Industry, Australia
Glass et al. (2003) 22 0.6 2.0
Glass et al. (2005) 50.3 1.3 4.1
Mean 582 15 47
Brasilian Benzene Seminar, 6th December 2012

7. 4-1 MODE OF ACTION
Position Paper of the AGS - Exposure Risk Relationships for Benzene
1) Metabolites: Catechol, Hydroquinone, 1,2- und 1,4-Benzoquinone,
1,2,4-Trihydroxybenzene --> Mutations, DNA-adducts and
secondary genotoxicity (clastogenic)
2) 1,4-Benzoquinone binding to DNA
3) Ring opening: trans,trans-Muconaldehyde --> mutagen and
clastogen.
4) oxidative DNA-damage
5) 1,4-Benzoquinone and Hydroquinone inhibit Topoisomerase II;
(DNA replication and Transcription)
6) Poor and error prone repair of DNA-double strang breaks in bone
marrow progenitor cells
(Hartwig, 2010)
Brasilian Benzene Seminar, 6th December 2012

8. 4-2 MODE OF ACTION
Position Paper of the AGS - Exposure Risk Relationships for Benzene
7) Myelotoxicity and haemogram changes
8) Immunotoxicity (Smith et al., 2007)
9) DNA-Methylation pattern similar to the pattern of AML-patients
(Bollati et al., 2007).
Conclusion: the decisive mechanism(s) leading to
AGS
leukemia after benzene exposure are not yet known.
MAK
Several reactive metabolites could cause a wide spectrum
of DNA-damage, including oxidative lesions, DNA-adducts
and apurinic sites. In addition, other effects which could
contribute to carcinogenic action have to be considered,
such as overexpression of transcription faktors, oncogene
activation and changes in signalling cascasdes.
Brasilian Benzene Seminar, 6th December 2012

9. 4-3 MoA & EXTRAPOLATION to LOW DOSES: LINEAR ?
Position Paper of the AGS - Exposure Risk Relationships for Benzene
Pro (Linear) Kontra (non-linear)
No single causal mechanism for Mechanistic ground: multiple
which a threshold or enhancer mechanisms for which a
effect can be quantified with threshold can be assumed;
sufficient certainty ... low impact of primary
genotoxicity
The range of non-linearity may Multicausality in carcinogenesis
be at or below the commonly argues against a linear
encountered environmental exposure-risk-relationship (ERR)
exposure to benzene
Brasilian Benzene Seminar, 6th December 2012

10. 4-4 MoA & EXTRAPOLATION to LOW DOSES: LINEAR ?
Position Paper of the AGS - Exposure Risk Relationships for Benzene
Pro Kontra
In vivo MN-assay in mice (Zhang et al., 2010) In vitro MN-assays with human
showed induction of micronuclei still at very and murine bone marrow cells
low concentrations (extrapolated NOAEL showed non linear dose-
around 60 ppb). response relationships.
Aneuploidy induction for other chromoso- The induction of aneuploidy
mes (e.g., 7) found at low concentrations for chromosome 9 was non-
and effects on hyperploidy of chromoso- linear and only significant at
mes 7,8,9 showed a linear trend. high benzene concentrations
Indication of aneuploidy already at very low (>31 ppm)
concentrations (≤1 ppm benzene in air, (Zhang et al., 1996).
Xing et al., 2010; ca. 0.5 ppm, Kim et al.,
2010; >0 bis <30 ppm-years and more; Qu
et al., 2003). Aneuploidy is not the only
relevant mechanisms.
Brasilian Benzene Seminar, 6th December 2012

11. 4-5 MoA & EXTRAPOLATION to LOW DOSES: LINEAR ?
Position Paper of the AGS - Exposure Risk Relationships for Benzene
Pro Kontra
DNA-adducts in bone marrow of mice at DNA-adducts in P32-Post-
low concentrations with a linear dose-effect labelling were only seen at
relationship. high doses.
Errors/Mistakes in DNA-repair can lead to
point mutations. Indications for impaired Oxidative DNA-lesions
and erroneous DNA-repair in particular for probably contribute to the
double strang-breaks (Hogswood et al., 2009; effects; these are efficiently
Bi et al., 2010; Lan et al., 2009; Hartwig, 2010). repaired.
Oxidative lesions seem to occur at very low
benzene exposure (Uzma et al., 2010; Manini
et al., 2010)
Brasilian Benzene Seminar, 6th December 2012

12. 5-1 OTHER ADVERSE EFFECTS
Position Paper of the AGS - Exposure Risk Relationships for Benzene
Pro Kontra
Haematotoxicity with its NOAEC Haematotoxicity is a prerequisite
not clearly delineated from the for leukemia and this non-cancer
carcinogenic effect. H. seems not endpoint has a threshold.
a prerequisite for carcinogenicity
(Hirabayashi & Inoue, 2010).
Gene expression - significant In several epidemiological
changes indicative of leukemia, studies no significant findings for
immuntoxicity and oxidative leukemia at < 40 ppm-years
effects already seen clearly
below 1 ppm (McHale et al., 2011)
Brasilian Benzene Seminar, 6th December 2012

13. 5-2 NON-CANCER EFFECTS – UNCERTAINTY
Position Paper of the AGS - Exposure Risk Relationships for Benzene
• LOAEL of ≈0.4 ppm for haematotoxic effects is
controversial (Lan et al., Qu et al., // Schnatter et al.,
Lammet et al., Swaen et al.)
• But: Indications for immunotoxic effects at the same
level (Lan et al., Uzma et al.)
• But: Animal experiment (mouse, several endpoints)
leads to an extrapolated threshold at this level
Overall: no ‘solid‘ threshold value deducible;
a non-cancer risk cannot be excluded entirely
at the level of the tolerance risk (0.6 ppm)
Brasilian Benzene Seminar, 6th December 2012

14. 6-1 SUMMARY : RISK BASED OEL‘s – BENZENE
Position Paper of the AGS - Exposure Risk Relationships for Benzene
Risk Concentration
“Point of Departure”: ED10 (based on 47 mg/m3 ; 15 ppm
average of epidemiological studies)
4:1,000 (tolerable risk) 1.9 mg/m3; 0.6 ppm
4:10,000 (acceptable risk until 2013) 0.2 mg/m3; 0.06 ppm
4:100,000 (acceptable risk after 2013, 0.02 mg/m3; 0.006 ppm
latest by 2018)
• Carcinogenicity: Leukemia, numerous epidemiological studies,
additional risk (mean): 47 mg/m³ (10%), „point of departure“
• Genotoxicity as an important (partial) mechanism (linear extrapolation)
• Non-cancer effects (Haematotoxicity, Immunotoxicity): no clear
non-effect level identifiable, possibly already at tolerance risk
Brasilian Benzene Seminar, 6th December 2012

15. 6-2 CANCER RISKS – META-ANALYSIS
Position Paper of the AGS - Exposure Risk Relationships for Benzene
Metaanalysis of Khalade et al., 2010
Aggregated Leukemia forms - on basis of 15 studies:
mean relative risk 1.4 (95%-CI: 1.23-1.57);
very heterogenous results ...
For the lowest cumulated exposure group of up to
40 ppm-years the analysis yielded a relative risk of
1.64 (95%-CI: 1.13-2.39) with an increasing risk for
higher ppm-years (significant trend: p=0.015).
ED10 = 15.6 ppm
(AGS: 15 ppm)
Brasilian Benzene Seminar, 6th December 2012

16. 6-3 PUBLISHED CANCER RISK ESTIMATES FOR BENZENE
Position Paper of the AGS - Exposure Risk Relationships for Benzene
Author unit risk (per ED10 ED10
µg/m3, general (ppm, (mg/m3,
population) workplace) workplace)
EPA (2009, as of 1998) 2.2-7.8 • 10-6 24-84 77-273
WHO (2000) 6 • 10-6 30.8 100
Wahrendorf & Becher 9.2 • 10-6 18 58
(1990), LAI (1993, 2004)
for comparison:
AGS paper (2012) 10 • 10-6 15 47
Brasilian Benzene Seminar, 6th December 2012

17. 6-4 SUMMARY – BENZENE EXPOSURE: RISK / LIMITS
Position Paper of the AGS - Exposure Risk Relationships for Benzene
Candidate Comments
OEL [mg/m³]
3.2 SCOEL BOELV
1.6 ACGIH TLV
0.12 - 3.56 Air concentration linked to a 10-5 Risk (40 years
exposure, work place conditions) after Crump (1994)
0.016 Air concentration linked to a 10-5-Risk (40 years
exposure, work place conditions) after WHO (2000)
0.017 DMEL based on an „apparent threshold“ for cancer,
after Glass (2006) with an extra safety factor of 5
1.9 4:1000 risk; AGS 2012, workplace
0.2 4:10000 risk; AGS 2012, workplace
0.02 4:100000 risk; AGS 2012, workplace
Brasilian Benzene Seminar, 6th December 2012

18. THANK YOU FOR THE INTEREST !
The most valuable contributions of the
rapporteur (Fritz Kalberlag, FOBIG) and all
members of AKCM / UA III are gratefully
acknowledged ..........
Benzene: full paper (in German) available at:
http://www.baua.de/de/Themen-von-A-Z/Gefahrstoffe/TRGS/Begruendungen-910.html
Brasilian Benzene Seminar, 6th December 2012 www.ifado.de