Effect of a complex environmental mixture from coal tar containing polycyclic aromatic hydrocarbons (PAH) on the tumor initiation, PAH-DNA binding and metabolic activation of carcinogenic PAH in mouse epidermis

Human exposure to polycyclic aromatic hydrocarbons (PAH) occurs through com plex mixtures such as coal tar. The effect of complex PAH mixtures on the a ctivation of carcinogenic PAH to DNA-binding derivatives and carcinogenesis were investigated in mice treated topically with NIST (National Institute of Standards and Technology) Standard Reference Material 1597 (SRM), a comp lex mixture of PAH extracted from coal tar, and either additional benzo[a]p yrene (B[a]P) or dibenzo[a,l]pyrene (DB[a,l]P), In an initiation-promotion study using 12-O-tetradecanoylphorbol-13-acetate as the promoter for 25 wee ks, the SRM and B[a]P co-treated mice had a similar incidence of papillomas per mouse compared with the group exposed to B[a]P alone as the initiator. PAH-DNA adduct analysis of epidermal DNA by P-33-post-labeling and reverse d-phase high-performance liquid chromatography found the SRM co-treatment l ed to a significant decrease in the total level of DNA adducts and B[a]P-DN A adducts to less than that observed in mice treated with B[a]P alone at 6, 12 and 72 h exposure. After 24 and 48 h exposure, there was no significant difference in the levels of adducts between these groups. In the DB[a,l]P initiation-promotion study, the co-treated group had significantly fewer pa pillomas per mouse than mice treated with DB[a,l]P alone as initiator. Aver aging over the times of exposure gave strong evidence that mice co-treated with SRM and DB[a,l]P had a significantly lower level of PAH-DNA adducts th an mice treated with DB[a,l]P alone. Western immunoblots showed that both c ytochrome P450 (CYP) 1A1 and 1B1 were induced by the SRM, These results are consistent with the hypothesis that two major factors determining the carc inogenic activity of PAH within a complex mixture are (i) the persistence o f certain PAH-DNA adducts as well as total adduct levels, and (ii) the abil ity of the components present in the mixture to inhibit the activation of c arcinogenic PAH by the induced CYP enzymes.