Quantification of DNA adducts formed in liver, lungs, and isolated lung cells of rats and mice exposed to C-14-styrene by nose-only inhalation

Bronchiolo-alveolar tumors were observed in mice exposed chronically to 160 ppm styrene, whereas no tumors were seen in rats up to concentrations of 1 000 ppm. Clara cells, which are predominant in the bronchiolo-alveolar regi on in mouse lungs but less numerous in rat and human lung, contain various cytochrome P450s, which may oxidize styrene to the rodent carcinogen styren e-7,8-oxide (SO) and other reactive metabolites. Reactive metabolites may f orm specific DNA adducts and induce the tumors observed in mice. To determi ne DNA adducts in specific tissues and cell types, rats and mice were expos ed to 160 ppm [ring-U-C-14]styrene by nose-only inhalation for 6 h in a rec irculating exposure system. Liver and lungs were isolated 0 and 42 h after exposure. Fractions enriched in Type II cells and Clara cells were isolated from rat and mouse lung, respectively. DNA adduct profiles differed quanti tatively and qualitatively in liver, total lung, and enriched lung cell fra ctions, At 0 and 42 h after exposure, the two isomeric N7-guanine adducts o f SO (measured together, HPEG) were present in liver at 3.0 +/- 0.2 and 1.9 +/- 0.3 (rat) and 1.2 +/- 0.2 and 3.2 +/- 0.5 (mouse) per 10(8) bases. Sev eral other, unidentified adducts were present at two to three times higher concentrations in mouse, but not in rat liver. In both rat and mouse lung, HPEG was the major adduct at similar to 1 per Ins bases at 0 h, and these l evels halved at 42 h. In both rat Type II and non-Type II cells, HPEG was t he major adduct and was about three times higher in Type II cells than in t otal lung. For mice, DNA adduct levels in Clara cells and non-Clara cells w ere similar to total lung. The hepatic covalent binding index (CBI) at 0 an d 42 h was 0.19 +/- 0.06 and 0.14 +/- 0.03 (rat) and 0.25 +/- 0.11 and 0.44 +/- 0.23 (mouse), respectively. The pulmonary CBIs, based on tissues combi ned for 0 and 42 h, were 0.17 +/- 0.04 (rat) and 0.24 +/- 0.04 (mouse). Com pared with CBIs for other genotoxicants, these values indicate that styrene has only very weak adduct-forming potency. The overall results of this stu dy indicate that DNA adduct formation does not play an important role in st yrene tumorigenicity in chronically exposed mice.