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Toxicological Sciences 71, 53-66 (2003)
Copyright © 2003 by the Society of Toxicology

CARCINOGENICITY

Evaluation of Potential Modes of Action of Inhaled Ethylbenzene in Rats and Mice

William T. Stott*,1, Keith A. Johnson*, Rainer Bahnemann{dagger}, Susan J. Day* and Randal J. McGuirk*

* Toxicology & Environmental Research and Consulting, Building 1803, The Dow Chemical Company, Midland, Michigan 48674; and {dagger} BASF AG, Carl Bosch Strasse 38, DUP/PC-Z 470, 67056 Ludwigshafen, Germany

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, {alpha}2u-globulin deposition, and histopathology. In male rats, kidney weight increases were accompanied by focal increases in hyaline droplets, {alpha}2u-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.

Key Words: ethylbenzene; inhalation exposure; tumorigenesis; mode of action; target tissues; S-phase DNA.


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