Journal
REGULATORY TOXICOLOGY AND PHARMACOLOGY
Volume 59, Issue 3, Pages 430-436Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.yrtph.2011.01.007
Keywords
Renal tubule tumors; Alpha(2u)-globulin nephropathy; Chronic progressive nephropathy; Hazard assessment
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Funding
- Lyondell Chemical Company, a LyondellBasell company, Houston, TX
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An independent Pathology Working Group (PWG) re-evaluated the kidney changes in National Toxicology Program (NIP) toxicology/carcinogenicity studies of tert-butyl alcohol (TBA) in F344/N rats to determine possible mode(s) of action underlying renal tubule tumors in male rats at 2-years. In the 13-week study, the PWG confirmed that the normal pattern of round hyaline droplets in proximal convoluted tubules was replaced by angular droplet accumulation, and identified precursors of granular casts in the outer medulla, changes typical of alpha(2u)-globulin (alpha(2u)-g) nephropathy. In the 2-year study, the PWG confirmed the NIP observation of increased renal tubule tumors in treated male groups. Linear papillary mineralization, another hallmark of the alpha(2u)-g pathway was present only in treated male rats. Chronic progressive nephropathy (CPN) was exacerbated in high-dose males and females, with a relationship between advanced grades of CPN and renal tumor occurrence. Hyperplasia of the papilla lining was a component of CPN in both sexes, but there was no pelvic urothelial hyperplasia. High-dose females showed no TBA-related nephrotoxicity. The PWG concluded that both alpha(2u)-g nephropathy and exacerbated CPN modes of action were operative in TBA renal tumorigenicity in male rats, neither of which has relevance for human cancer risk. (C) 2011 Elsevier Inc. All rights reserved.
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