DNA adduct measurements, cell proliferation and tumor mutation induction in relation to tumor formation in B6C3F1 mice fed coal tar or benzo[a]pyrene

Coal tar is a complex mixture containing hundreds of compounds, at least 30 of which are polycyclic aromatic hydrocarbons, including the carcinogen be nzo[a]pyrene (BaP), Although humans are exposed to complex mixtures on a da ily basis, the synergistic or individual effects of components within a mix ture on the carcinogenic process remain unclear, We have compared DNA adduc t formation and cell proliferation in mice fed coal tar or BaP for 4 weeks with tumor formation in a 2 year chronic feeding study. Additionally, we ha ve analyzed tumor DNA for mutations in the K-ras, H-ras and p53 genes, In t he forestomach of mice fed either coal tar or BaP an adduct indicative of B aP was detected, with adduct levels increasing in a dose-responsive manner, K-ms mutations were detected in the forestomach tumors, with the incidence being similar in mice fed coal tar or BaP, These results suggest that the BaP within coal tar is associated with forestomach tumor induction in coal tarfed mice. DNA adduct levels in the small intestine were not predictive o f tumor incidence in this tissue; instead, the tumors appeared to result fr om compound-induced cell proliferation at high doses of coal tar. K-rns mut ations were detected in lung tumors. Since lung tumors were not increased b y BaP, coal tar components other than BaP appear to be responsible for the tumors induced in this tissue. N-ras mutations, primarily occurring at codo n 61, were the most common mutation observed in liver tumors induced by coa l tar. Since this mutation profile is observed in spontaneous hepatic tumor s, components in the coal tar may be promoting the expansion of pre-existin g lesions.