Synergy between components of mixtures is a difficult problem for risk assessment, particularly when one or more of the components is not itself active. We have found that when certain mixtures of carcinogens and non-carcinogens are applied topically, the DNA binding of the carcinogens is increased significantly in the lung. Enhancement of dermal absorption and saturation of dermal metabolism are two possible mechanisms where non-carcinogens can cause increased internal organ dose of carcinogens. We will explore the potential for these interactions in acute, sub-chronic and chronic exposures studies with a model carcinogen, benzo(a)pyrene and two non-carcinogens, pyrene and kerosene. The focus of the research will be to determine whether and how non-carcinogens can alter the target organ effects of a model carcinogen and to develop a risk assessment model for mixtures based on the interaction between carcinogenic and non-carcinogenic components in the whole animal. This work is an attempt to deal this potential problem in a systematic way. Since millions of persons in occupations are exposed to carcinogenic complex mixtures, these data should be very useful in decreasing the uncertainties of risk assessment of these exposures.
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| Shertzer, Howard G; Dalton, Timothy P; Talaska, Glenn et al. (2002) Decrease in 4-aminobiphenyl-induced methemoglobinemia in Cyp1a2(-/-) knockout mice. Toxicol Appl Pharmacol 181:32-7 |
| Uno, S; Dalton, T P; Shertzer, H G et al. (2001) Benzo[a]pyrene-induced toxicity: paradoxical protection in Cyp1a1(-/-) knockout mice having increased hepatic BaP-DNA adduct levels. Biochem Biophys Res Commun 289:1049-56 |
