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1.1 Talaska
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Biomarkers of Polycyclic Aromatic Hydrocarbon Exposure in European Coke Oven Workers: relationship
between PAH internal dose markers and target organ DNA adduct levels
Glenn Talaska, Jeff Thoroman, Brenda Schuman, Tobias Weiß
and Heiko Kafferlein
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1HP Conversions
• 1 umol/mol creatinine = 1.93 ug/l • 1 ug/l = 0.49 umol/mol creatinine
– Essentially multiply or divide by 2
• 1ug/l ~= 0.8ug/g creatinine
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Some Issues in PAH Biomonitoring
• 1HP used to estimate exposure to 4+ ring PAH– Similar physical properties, better signal than BAP metabolites
• 1HP reference values– ACGIH: 1ug/l Nq BEI– NOEL (based on indirect epi data): 2.7ug/l– Based on current Air standards (TLVs) : 4.4 ug/l – HSE Guidance Value: ~8ug/l (4 umol/mol creatinine)
• Only the estimated NOEL is Health Based
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0.00 0.25 0.50 0.75 1.00
urinary 1-HP (ug/l)
0.00
1.70
3.40
5.10
6.80
8.50nu
mbe
r of s
tudi
es
Distribution of estimates of median1-hydroxypyrene levels by smoking status
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Approaches to Relate Metabolite Levels to Health Effects
• Metabolite levels and subsequent disease• Metabolite levels and intermediate biomarkers
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Data to Date
• Schoket’s group reported (2008) that 22 of 37 studies relating DNA adduct levels to urinary metabolites were negative (Gyorffy et al, Mutagenesis, 23, 1‐18.
• Why?
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More issues
• Target versus surrogate tissues for effective dose biomarkers
• Temporal relationship between markers– What exposure window does the marker capture?– Relationship between metabolites and adducts
• Pre‐shift versus post‐shift 1HP levels– 1HP has multiple elimination half‐lives, can they be used to advantage ?
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DNA Adducts as a Health Effect
• Plausible biology: the pre‐mutagenic lesion• Associated with liver cancer prospectively in China (Groopman Group) and Veglia et al (2008) Adducts and Lung and bladder cancer risk in current smokers (meta analysis)
• Increases in adducts levels correlated with increased cancer risk in smokers, benzidine workers and others.
• Can they be used as an endpoint to determine a level of metabolite that can considered “safe” ?
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Coke Oven Workers and Urinary Bladder Cancer (UBC)
• Manz saw an increase in UBC in coke oven workers using PMR
• Doll reported increases in UBC in coal gasification workers
• IARC (1984) reports increases in lung and kidney cancers (not UBC)
• Armstrong et al (2003) reported a URR of 1.33 for UBC and PAH exposure, but mostly for aluminum plant workers
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Coke oven work and genotoxicity
• Coke oven workers have elevated levels of mutagens in their urine (8X over controls)
• Urinary mutagenicity related to BOTH GST and NAT2 activities suggesting both PAH and aromatic amines may be involved
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Methods
• Pre‐shift urine samples obtained from 32 coke oven workers–3 supervisors–10 side area workers–10 side oven workers–2 top and side oven workers–7 top oven workers
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Methods (cont.)
• Urine samples frozen with glycerin and shipped to Cincinnati
• Thawed, filtered to collect the exfoliated urothelial cells; DNA isolation and adduct analysis by 32P‐postlabeling
• Supernatants: metabolites concentrated on C‐18 Sep‐paks, eluted and analyzed on HPLC with fluorescence detection(ex:242nm; em:387nm)
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Results
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Correlation Tableadduct 1 adduct 2 adduct 3 adduct 4
1HP ‐0.17 ‐0.14 0.110.69*P<0.01
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Cigarettes per Day All Workers Side area and Supers
Oven Workers
1HP 0.21 0.16 0.29
Adduct 4 0.12 0.32 0.14
Months Working
1HP ‐0.22 0.05 ‐0.49*
Adduct 4 ‐0.43* 0 ‐0.63*
Correlations with Smoking and Tenure
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Discussion
• Adduct 4 was not positively identified as a PAH Adduct…..may be an aromatic amine (AA).
• But, not related to smoking and Weiß saw that there was no increase in AA metabolites in a cokery.
• 1HP levels <1 ug/l NOT associated with increased adduct levels
• 1HP levels >1 ARE associated with increased DNA adduct levels. (consistent with previous SCE data)
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Discussion Question
• Are adduct levels sufficient warning‐viz. the precautionary principle‐ for occupational cancer when there are limited data showing statistically significant increases in UBC in this group of workers?
• If so, then a 1HP level greater than 1ug/l indicate an increase in risk and effect
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Thank You
• The University of Cincinnati College of Medicine, Department of Environmental Health, Cincinnati, OH USA
• Institute for Prevention and Occupational Medicine, Ruhr University Bochum, Germany
• Coke Oven Workers participating in the studies
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Acute (short term) Exposure
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Chronic Exposure
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