Evaluation of potential modes of action of inhaled ethylbenzene in rats and mice.

Potential factors underlying the tumorigenic activity of ethylbenzene (EB) were examined in F344 rats and B6C3F1 mice inhaling 750 ppm EB vapor 6 h/day, 5 days/week, for one or four weeks. Target tissues (kidneys of rats and livers and lungs of mice) were evaluated for changes in organ weights, mixed function oxygenases (MFO), glucuronosyl transferase activities, S-phase DNA synthesis, apoptosis, alpha2u-globulin deposition, and histopathology. In male rats, kidney weight increases were accompanied by focal increases in hyaline droplets, alpha2u-globulin, degeneration, and S-phase synthesis in proximal tubules. In female rats, only decreased S-phase synthesis and MFO activities occurred. In mice, increased liver weights were accompanied by hepatocellular hypertrophy, mitotic figures, S-phase synthesis, and enzyme activities. S-phase synthesis rates in terminal bronchiolar epithelium were elevated and accompanied by loss of MFO activity. Exposure to a nontumorigenic level of 75 ppm for one week caused few changes. These data, considered with the general lack of EB genotoxicity, suggest a mode of tumorigenesis dependent upon increased cell proliferation and altered population dynamics in male rat kidney and mouse liver and lungs. A similar response in the kidneys of female rats appears to require a longer exposure period than was employed.