An organizational approach for the assessment of DNA adduct data in risk assessment: case studies for aflatoxin B1, tamoxifen and vinyl chloride.
The framework analysis previously presented for using DNA adduct information in the risk assessment of chemical carcinogens was applied in a series of case studies which place the adduct information into context with the key events in carcinogenesis to determine whether they could be used to support a mutagenic mode of action (MOA) for the examined chemicals. Three data-rich chemicals, aflatoxin B1 (AFB1), tamoxifen (Tam) and vinyl chloride (VCl) were selected for this exercise. These chemicals were selected because they are known human carcinogens and have different characteristics: AFB1 forms a unique adduct and human exposure is through contaminated foods; Tam is a pharmaceutical given to women so that the dose and duration of exposure are known, forms unique adducts in rodents, and has both estrogenic and genotoxic properties; and VCl, to which there is industrial exposure, forms a number of adducts that are identical to endogenous adducts found in unexposed people. All three chemicals produce liver tumors in rats. AFB1 and VCl also produce liver tumors in humans, but Tam induces human uterine tumors, only. To support a mutagenic MOA, the chemical-induced adducts must be characterized, shown to be pro-mutagenic, be present in the tumor target tissue, and produce mutations of the class found in the tumor. The adducts formed by AFB1 and VCl support a mutagenic MOA for their carcinogenicity. However, the data available for Tam shows a mutagenic MOA for liver tumors in rats, but its carcinogenicity in humans is most likely via a different MOA.
The Dow Chemical Company , Midland, MI , USA .
Lynn H
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Pottenger
Larry S
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Andrews
Ammie N
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Bachman
Peter J
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Boogaard
Jean
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Cadet
Michelle R
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Embry
Peter B
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Farmer
Matthew W
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Himmelstein
Annie M
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Jarabek
Elizabeth A
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Martin
Robert J
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Mauthe
Rudranath
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Persaud
R Julian
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Preston
Rita
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Schoeny
Julie
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Skare
James A
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Swenberg
Gary M
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Williams
Errol
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Zeiger
Fagen
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Zhang
James H
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Kim
D016604:Aflatoxin B1 / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D018736:DNA Adducts / Q000032:analysis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation; D051381:Rats; D018570:Risk Assessment / Q000379:methods*; D013629:Tamoxifen / Q000493:pharmacokinetics / Q000633:toxicity*; D014018:Tissue Distribution; D014752:Vinyl Chloride / Q000493:pharmacokinetics / Q000633:toxicity*
D002273:Carcinogens; D018736:DNA Adducts; D009153:Mutagens; D013629:Tamoxifen; D016604:Aflatoxin B1; D014752:Vinyl Chloride