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Stephen Nesnow,¹ Marc J. Mass,¹ Jeffrey A. Ross,¹ Anthony J. Galati,² Guy R. Lambert,¹ Chris Gennings,³ Walter H. Carter Jr.,³ and Gary D. Stoner⁴

¹National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina;
²Department of Pathology, Medical College of Ohio, Toledo, Ohio;
³Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia;
⁴Division of Environmental Health Sciences, School of Public Health, Ohio State University, Columbus, Ohio

Abstract

The binary, ternary, quaternary, and quintary interactions of a five-component mixture of carcinogenic environmental polycyclic aromatic hydrocarbons (PAHs) using response surface analyses are described. Initially, lung tumor dose-response curves in strain A/J mice for each of the individual PAHs benzo[a]pyrene (B[a]P) , benzo[b]fluoranthene (B[b]F) , dibenz[a,h]anthracene (DBA) , 5-methylchrysene (5MC) , and cyclopenta[cd]pyrene (CPP) were obtained. From these data, doses were selected for the quintary mixture study based on toxicity, survival, range of response, and predicted tumor yields. The ratios of doses among PAHs were designed to simulate PAH ratios found in environmental air and combustion samples. Quintary mixtures of B[a]P, B[b]F, DBA, 5MC, and CPP were administered to male strain A/J mice in a 2⁵ factorial 32-dose group dosing scheme (combinations of five PAHs each at either high or low doses) and lung adenomas were scored. Comparison of observed lung adenoma formation with that expected from additivity identified both greater than additive and less than additive interactions that were dose related i.e., greater than additive at lower doses and less than additive at higher doses. To identify specific interactions, a response surface analysis using response addition was applied to the tumor data. This response surface model contained five dose, ten binary, ten ternary, five quaternary, and one quintary parameter. This analysis produced statistically significant values for 16 parameters. The model and model parameters were evaluated by estimating the dose-response relationships for each of the five PAHs. The predicted dose-response curves for all five PAHs indicated a good estimation. The binary interaction functions were dominated for the most part by DBA and were inhibitory. The response surface model predicted, to a significant degree, the observed lung tumorigenic responses of the quintary mixtures. These data suggest that although interactions between PAHs do occur, they are limited in extent. -- Environ Health Perspect 106(Suppl 6) :1337-1346 (1998) .

http://ehpnet1.niehs.nih.gov/docs/1998/Suppl-6/1337-1346nesnow/abstract.html

Key words: carcinogenesis, mixtures, polycyclic aromatic hydrocarbons, interactions, response surface modeling