07 gisela degen

www.ifado.deBrasilian Benzene Seminar, 6th December 2012

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

www.ifado.de

0 OVERVIEW - CONTENTPosition Paper of the AGS - Exposure Risk Relationships for Benzene

Brasilian Benzene Seminar, 6th December 2012

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

1 CORNERSTONES Position Paper of the AGS - Exposure Risk Relationships for Benzene


The ‘Traffic light‘ Concept of 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

Upper risk level

Lower risk level

2 RISK BASED OEL‘s – BENZENE Position Paper of the AGS - Exposure Risk Relationships for Benzene


Risk Concentration

“Point of Departure”: ED10 (based on average of epidemiological studies)

47 mg/m3 ; 15 ppm

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,

latest by 2018)

0.02 mg/m3; 0.006 ppm

• 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

3-1 DATA - Epidemiological Studies - Leukemia Position Paper of the AGS - Exposure Risk Relationships for Benzene


Author Risk at Workplace

ED10 (ppm-years)

ED10 (ppm at 40 Years occupational exposure)

ED10 (mg/m3)

“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

3-2 DATA - Epidemiological Studies - Leukemia bPosition Paper of the AGS - Exposure Risk Relationships for Benzene


ED10 (ppm-Years)

ED10 (ppm at 40 Years occupational exposure )

ED10 (mg/m3)

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

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)

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).

AGSMAK

Conclusion: the decisive mechanism(s) leading to leukemia after benzene exposure are not yet known. 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.

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 which a threshold or enhancer effect can be quantified with sufficient certainty ...

Mechanistic ground: multiple mechanisms for which a threshold can be assumed;

low impact of primary genotoxicity

The range of non-linearity may be at or below the commonly encountered environmental exposure to benzene

Multicausality in carcinogenesis argues against a linear exposure-risk-relationship (ERR)



Pro KontraIn vivo MN-assay in mice (Zhang et al., 2010) showed induction of micronuclei still at very low concentrations (extrapolated NOAEL around 60 ppb).

In vitro MN-assays with human and murine bone marrow cells showed non linear dose-response relationships.

Aneuploidy induction for other chromoso-mes (e.g., 7) found at low concentrations and effects on hyperploidy of chromoso-mes 7,8,9 showed a linear trend. Indication of aneuploidy already at very low concentrations (≤1 ppm benzene in air, 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.

The induction of aneuploidy for chromosome 9 was non-linear and only significant at high benzene concentrations (>31 ppm)(Zhang et al., 1996).



Pro KontraDNA-adducts in bone marrow of mice at low concentrations with a linear dose-effect relationship.

DNA-adducts in P32-Post-labelling were only seen at high doses.

Errors/Mistakes in DNA-repair can lead to point mutations. Indications for impaired and erroneous DNA-repair in particular for double strang breaks (Hogswood et al., 2009; Bi et al., 2010; Lan et al., 2009; Hartwig, 2010). Oxidative lesions seem to occur at very low benzene exposure (Uzma et al., 2010; Manini et al., 2010)

Oxidative DNA-lesions probably contribute to the effects; these are efficiently repaired.

5-1 OTHER ADVERSE EFFECTS Position Paper of the AGS - Exposure Risk Relationships for Benzene


Pro KontraHaematotoxicity with its NOAEC not clearly delineated from the carcinogenic effect. H. seems not a prerequisite for carcinogenicity (Hirabayashi & Inoue, 2010).

Haematotoxicity is a prerequisite for leukemia and this non-cancer endpoint has a threshold.

Gene expression - significant changes indicative of leukemia, immuntoxicity and oxidative effects already seen clearly below 1 ppm (McHale et al., 2011)

In several epidemiological studies no significant findings for leukemia at < 40 ppm-years

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)

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 average of epidemiological studies)

47 mg/m3 ; 15 ppm

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,

latest by 2018)

0.02 mg/m3; 0.006 ppm

• 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

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)

6-3 PUBLISHED CANCER RISK ESTIMATES FOR BENZENE Position Paper of the AGS - Exposure Risk Relationships for Benzene


Author unit risk (per µg/m3, general

population)

ED10 (ppm,

workplace)

ED10 (mg/m3,

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 (1990), LAI (1993, 2004)

9.2 • 10-6 18 58

for comparison:

AGS paper (2012) 10 • 10-6 15 47

6-4 SUMMARY – BENZENE EXPOSURE: RISK / LIMITS Position Paper of the AGS - Exposure Risk Relationships for Benzene


Candidate OEL [mg/m³]

Comments

3.2 SCOEL BOELV1.6 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

www.ifado.de

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

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