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

Abstract

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.

Disposition and Metabolism of Cumene in F344 Rats and B6C3F1 Mice

“…Furthermore, it has been demonstrated that for coumarin, naphthalene, and styrene, which are structurally related to cumene, inhibition of CYP2F2 results in inhibition of lung toxicity (Cruzan et al, 2009, and references therein). CYP2F4 is much less prevalent in rat Clara cells, and, moreover, human lungs contain much fewer Clara cells and the relevant CYP2F isoform (CYP2F1) than rats or mice (Stott et al, 2003). A cytotoxicity-driven mode of action pertaining to mouse specific lung tumors for this group of compounds by the CYP2F family recently has been proposed (Cruzan et al, 2009).…”

Toxicological Profile for Ethylbenzene

“…Slight, statistically significant increases in relative liver weights (≤7% compared to controls) were observed in male and female B6C3F1 mice exposed to 750 ppm, but not 75 ppm, ethylbenzene vapor for 1 or 4 weeks (Stott et al 2003). Histopathological assessment showed hepatocellular hypertrophy, mitotic figures, and S-phase DNA synthesis in mice exposed to 750 ppm ethylbenzene vapor for 1 or 4 weeks, but serum activities of hepatic enzymes (alanine transaminase, asparatate transpeptidase, alkaline phosphatase, and γ-glutamyl trnaspeptidase) were not elevated compared to controls.…”

“…Relative kidney weight was significantly increased (11-20%) in male rats exposed to 2,000 ppm for 2 days (Toftgard and Nilsen 1982) and 1,200 ppm ethylbenzene for 4 days (Ethylbenzene Producers Association 1986a), and in male and female rats exposed to 750 ppm ethylbenzene (6-7%), but not at 75 ppm, for 1 week (Stott et al 2003). Although no change in renal histopathology accompanied increased kidney weight in rats exposed to 1,200 ppm ethylbenzene for 4 days (Ethylbenzene Producers Association 1986a), increased accumulation of α 2µ -globulin and hyaline droplets were observed after 1 week in the kidneys of male rats exposed to 750 ppm ethylbenzene compared to controls (Stott et al 2003). Renal congestion was reported in rats and mice that died during exposure to 2,400 or 1,200 ppm ethylbenzene, respectively (Ethylbenzene Producers Association 1986a).…”

“…Several studies have shown that exposure of rats or mice to inhaled ethylbenzene for durations of 4 weeks -7 months increases relative kidney weight NIOSH 1981;NTP 1999;Stott et al 2003;Wolf et al 1956). Concentration-related increases in renal microsomal enzymes (7-ethoxycoumarin O-deethylase, UDP glucuronyl-transferase) and renal glutathione concentration were reported in rats following a 5-16-week exposure to ethylbenzene at concentrations ranging from 50 to 600 ppm .…”

“…Concentration-related increases in renal microsomal enzymes (7-ethoxycoumarin O-deethylase, UDP glucuronyl-transferase) and renal glutathione concentration were reported in rats following a 5-16-week exposure to ethylbenzene at concentrations ranging from 50 to 600 ppm . Histopathological changes in the kidney include α 2µ -globulin-associated changes (nuclear-size and staining variations and vacuolation or decreased amount of cytoplasm) in male rats exposed to 750 ppm for 4 weeks (Stott et al 2003) and swelling of the tubular epithelium in rats exposed to 600 ppm ethylbenzene for up to 7 months (Wolf et al 1956). …”