Subchronic hepatotoxicity evaluation of bromobenzene in Fischer 344 rats

• Published in: Journal of applied toxicology Vol. 33; no. 5; pp. 370 - 377
• Main Authors: Dodd, Darol E., Pluta, Linda J., Sochaski, Mark A., Banas, Deborah A., Thomas, Russell S.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-05-2013; Wiley Subscription Services, Inc
• Subjects: Administration, Oral; Alterations; Animals; Blood; Body weight; Body Weight - drug effects; bromobenzene; Bromobenzenes - toxicity; Corn Oil - chemistry; Dosage; dose-response; Dose-Response Relationship, Drug; Endpoint Determination; Hepatocytes - drug effects; hepatotoxicity; Hydrocarbons; Incidence; Liver; Liver - drug effects; Liver - metabolism; Male; Males; No-Observed-Adverse-Effect Level; Organ Size - drug effects; Rats; Rats, Inbred F344; Rodents; time course; Toxicity; Toxicity Tests, Subchronic
• DOI: 10.1002/jat.2732
• EISSN: 1099-1263
• ISSN: 0260-437X

ABSTRACT
Male Fischer 344 (F344) rats were exposed to bromobenzene (BB) for 5 days and 2, 4 and 13 weeks. BB was administered by gavage (corn oil vehicle) at doses of 0, 25, 100, 200, 300 and 400 mg kg−1 per day. Endpoints evaluated included clinical observations, body weights, liver weights, serum chemistry, blood BB, gross pathology and liver histopathology. There were no BB exposure‐related clinical signs of toxicity. Mean body weight decreased by 5–10% compared with control in the 400 mg kg−1 per day group. Liver weight increases were dose‐ and exposure time‐related and statistically significant at ≥25 mg kg−1 per day. Incidence and severity of centrilobular cytoplasmic alteration and hepatocyte hypertrophy were related to dose and exposure time. At early time points (5 days and 2 weeks), centrilobular inflammation, including granulomatous areas, and necrotic and anisokaryocytic hepatocytes were observed in rats of the two highest BB dose groups. Blood BB concentrations increased linearly with dose and at 13 weeks ranged from 8 to 136 µg ml−1 (25–400 mg kg−1 per day). In conclusion, rats administered BB doses up to 400 mg kg−1 per day for up to 13 weeks had mild liver effects. A NOAEL of 200 mg kg−1 per day was selected based on the statistically significant incidence of hepatocyte hypertrophy at doses ≥ 400 mg kg−1 per day. Copyright © 2012 John Wiley & Sons, Ltd.
Male Fischer 344 rats were administered bromobenzene by gavage at 0, 25, 100, 200, 300, or 400 mg kg−1 per day for 5 days and 2, 4 and 13 weeks. Mean body weight decreased 5‐10% at 400 mg kg−1 per day. Liver weight increases were dose‐ and exposure time‐related and significant at ≥25 mg kg−1 per day. Incidence and severity of centrilobular cytoplasmic alteration and hepatocyte hypertrophy were also related to dose and exposure time. A NOAEL of 200 mg kg−1 per day was selected based on a statistically significant increase in hypertrophy at ≥400 mg kg−1 per day.