Histopathology re-examination of the NTP toxicity/carcinogenicity studies of tert-butyl alcohol to identify renal tumor and toxicity modes of action

• Published in: Regulatory toxicology and pharmacology Vol. 102; pp. 65 - 73
• Main Authors: Hard, Gordon C., Cohen, Samuel M., Ma, Jihyun, Yu, Fang, Arnold, Lora L., Banton, Marcy I.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01-03-2019
• Subjects: Alpha-Globulins - metabolism; alpha2u-globulin nephropathy; Animals; Carcinogenicity Tests; Chronic progressive nephropathy; Female; Hyperplasia - chemically induced; Hyperplasia - pathology; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Kidney Diseases - chemically induced; Kidney Diseases - metabolism; Kidney Diseases - pathology; Male; Modes-of-action; Rats, Inbred F344; Renal tubule tumors; Risk Assessment; tert-Butyl alcohol; tert-Butyl Alcohol - toxicity; Toxicity Tests, Subchronic; Renal tubule tumors; Modes-of-action; Chronic progressive nephropathy; tert-Butyl alcohol; alpha2u-globulin nephropathy
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1016/j.yrtph.2018.12.011

Tert-butyl alcohol (TBA) targets the rat kidney following repeated exposures, including renal tubule tumors. The mode of action (MOA) of these tumors, concluded by a pathology working group, involves both alpha2u-globulin nephropathy (α2u-gN) and exacerbated chronic progressive nephropathy (CPN), but has been disputed and an undefined MOA proposed. This study further reviews the histology slides of male and female rat kidneys from the NTP drinking water 13-week toxicity and 2-year carcinogenicity studies, including the 15-month interim sacrifice group. The papillary epithelial lining alteration formerly referred to as “transitional cell hyperplasia” develops as part of advanced CPN and does not represent a separate toxicity. No changes were observed in the kidney pelvis urothelium. The only alterations in subchronic male rats involved α2u-gN and CPN, without test article-related alterations in females. Focused examination of areas of parenchyma unaffected by CPN in TBA-treated male and female rats of the chronic studies revealed no renal tubule abnormalities other than from the effects of α2u-gN and CPN. Unrelated to toxicity were spontaneous amphophilic or vacuolar tubule proliferative lesions. All observed TBA-associated non-neoplastic and neoplastic histopathological changes in the kidney can be explained by α2u-gN or enhanced CPN, neither of which are relevant to humans.
•α2u-gN histopathological changes present in kidney sections from NTP drinking water rat studies on tert butyl alcohol (TBA).•Spontaneous chronic progressive nephropathy (CPN) was exacerbated by TBA, including to end-stage kidney.•Renal papilla lining vesicular change (“transitional cell hyperplasia”) and tubulitis were part of advanced CPN.•Renal tumors in the NTP study included 3 alveolar-vacuolar proliferative lesions, known to be of spontaneous origin.•CPN exacerbation and α2u-gN were the only forms of nephrotoxicity and modes of action for rat TBA-associated renal tumors.