Benzene Exposure and Cancer

Transcription

1 Benzene Exposure and Cancer Deborah Glass PhD, Dip.Occ.Hyg, FAIOH Monash Centre for Occupational and Environmental Health, School of Epidemiology and Preventive Medicine, Monash University

2 IARC Vol 100 F (on website 2012) Class 1 Carcinogen Benzene causes AML/ANLL There is limited evidence in humans for a causal association of benzene with ALL, CLL, MM, NHL There is sufficient evidence of carcinogenicity in experimental animals. 2

3 Benzene metabolites increase risk of leukaemia SCH 2 CH COOH NHCOCH 3 S-phenylmercapturic acid via GSH conjugate nonenzymatic rearrangenment OH benzene CYP 2E1 O H O OH O CYP O benzene oxide oxepin H O HO O epoxide hydrolase E,E-muconaldehyde E,E-muconic acid OH OH phenol CYP 2E1 OH OH hydroquinone benzene dihydrodiol CYP dihydrodiol dehydragenase OH OH OH OH O catechol benzene diolepoxide Simplified Benzene Metabolism CYP 2E1 OH OH O O O Slide courtesy Stephen Rappaport OH O 1,2-benzoquinone 1,2,4-trihydroxybenzene 1,4-benzoquinone 3

4 Leukaemia - not a single disease Myeloid vs Lymphoid AML, ALL, 8FAB/REAL 10 th th Rev, ICD CML, coded adds CLL MDS CLL L WHO reclassifies Categories change Categories change 8 th Rev, ICD coded CLL FAB/REAL 10 th Rev, ICD adds MDS WHO reclassifies 4

5 Are benzene-induced leukaemias different? Biomarkers of exposure benzene, tt-ma or S-PMA in urine protein adducts BO-Alb Chromosomal damage reported in chromosomes 1-22 and X loss part or all of 5, 6, 7, 10 trisomy 8, 9, 17, 18, 22 translocation 21;22 Disease progression different? 5

6 Is there a threshold? For an individual or a population? Effects seen after <1ppm for short period Reduced blood cell production Genetic damage Possibly supra linear response at low exposures 6

7 Benzene TLV over the years ppm ppm ppm ppm Leather industry & leukaemia ppm A2 Pliofilm study published, debate about exposure ppm A1 2003/4 Lan study x sectional survey 1ppm 2012 Schnatter et al MDS <1ppm max 7

8 Risk estimation and the Pliofilm study 1,165 men exposed to benzene 1940s USA Cumulative Benzene Exposure ppm-years SMR < > Rinsky et al

9 Accuracy of exposure estimates and models Exposure assumptions Additional lifetime leukaemia deaths per 1000 workers at 45 ppm-years (95% CI) Rinsky 5.1 ( ) Crump and Allen ( ) Crump and Allen ( ) Brett et al (1989) 1 hit linear model, per 1000 working 10ppm White (1982) 9

10 Measuring exposure to benzene Then: Colourimetric tubes Imprecise Spot measurements Often mixed exposures Now: 8 hour TWA personal monitoring Precise analysis Repeated samples 10

11 Health Watch case-control study Odds ratio (log scale) Leukaemia NHL/MM 0.1 < > 16 Cumulative Lifetime Benzene Exposure midpoint (ppm-years) 98 11

12 Combining two lowest exposure groups Exposure (ppm-years) Cases OR (95% CI) < ( ) ( ) ( ) > ( ) 12

13 Evidence for peaks Odds Ratio (log scale) With CB/BTX cases Without CB/BTX cases Cumulative Exposure (ppm-years)

14 Pooling Three Nested Case Control Studies of Benzene Exposure in Petroleum Workers Refs: 1. Schnatter et al : Rushton et al : Glass et al : Canada 1 no consistent dose response, but small study U.K. 2 inconsistent dose response based on 31 LH cancers based on 90 leukemias based on 79 LH cancers 60 LH cancers Incl. 5 MDS before pooling data à update studies 193 LH cancers Incl. 11 MDS 370 LH cancers Pool data from three previous studies Australia 3 strong dose response, especially for AML 117 LH cancers Incl. 13 MDS 14

15 Disease groups in analyses Disease Groups Number of cases Number of controls Acute myeloid leukaemia (AML) Chronic myeloid leukaemia (CML) Chronic lymphocytic leukaemia (CLL) Myelodysplastic syndrome (MDS) Myeloproliferative disease (MPD)

16 Benzene exposure was low Meta-analysis of AML and benzene <40ppm-years lowest exposure group (Khalade et al. 2010) 90% of participants accumulated <20 ppm-years Mean duration 22 years Mean cumulative exposure 5.15 ppm-years Mean exposure intensity 0.2 ppm 46% allocated peak exposure (prob >3ppm at least weekly) 40% had high probability of dermal exposure at least weekly 16 16

17 % Cases & Controls allocated Peak & Dermal Exposure by Disease Group Exposure metric AML MDS CLL CML MPD Cases Control Cases Control Cases Control Cases Control Cases Control Peak No Yes Dermal None Low Medium High

18 Average Benzene Exposure by Case/Control Status & Disease Group (log-scale) Average Benzene Exposure (ppm) Cases Controls Cases Controls Cases Controls Cases Controls Cases Controls AML MDS CLL CML MPD 18 18

19 MDS Risk & Cumulative Benzene Exposure 100 Odds ratios for MDS by tertiles of exposure (ppm-years) Odds Ratios All Subjects More Certain Diagnoses 0.1 >0.348 and <2.93 >2.93 >0.348 and <2.93 Cumulative Exposure (ppm-years) >

20 Pooled Analysis MDS Cases / Controls Current day exposure zone Suggests MDS cases over-represented at ppm 20 20

21 Conclusions: LH Subtypes Suggests relationship between Bz exposure & MDS MDS: Possibly more sensitive outcome than AML AML: Several ORs were >1, few statistically significant Higher benzene exposures needed for significant risks of AML? Some cases formerly classified as AML were MDS CML: Several ORs >1, no clear exposure response MPD: No dose response patterns,? 2-20 year window. CLL: There was no suggestion of a strong relationship 21 21

22 What we still need to know: Which diseases? Which exposure metric? What exposure-risk relationship at low exposures? Does genotype matter? Can benzene-induced leukaemias be identified? 22

23 Adding possible high exposures (PHEs) Cumulative Exposure with PHEs added log scale (ppm/ years) Cumulative Exposure log scale (ppm/years) 23

24 Odds ratios reduced Benzene exposure (ppm-years) 2 >2-4 >4-8 >8-16 >16 Number of cases Cumulative exposure & PHEs OR (95% CI) ( ) 1.2 ( ) 2.7 ( ) 7.8 ( ) 24

25 Checked equivalence of study exposure estimates Empirical cumulative distribution function Revised exposure assessment Original exposure assessment Little change from original estimates ppm-years 25

26 Cumulative Exposure for MDS Cases & Controls Empirical cumulative distribution function MDS by the Pooled-Analysis Classification Controls ppm-years 26 26