The Role of alpha2u-Globulin and Chronic Progressive Nephropathy in the IRIS Toxicological Review of tert-Butanol
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The IRIS Toxicological Review of tert-Butanol (TBA) assessed the human relevance of kidney effects observed in male and female rats. EPA and IARC frameworks were used to evaluate whether TBA caused alpha 2u¿globulin¿associated nephropathy. While evidence implies that an alpha 2u¿globulin mode of action (MOA) is operative, it is relatively weak and is not solely responsible for the renal tubule nephropathy observed in male rats. The evidence shows that chronic progressive nephropathy (CPN) also plays a role in exacerbating TBA-induced nephropathy in male and female rats. While the etiology of CPN is unknown and it has no known analog in the aging human kidney, it cannot be ruled out that a chemical which exacerbates CPN in rats could also exacerbate disease processes in the human kidney. Several other effects in the kidney unrelated to alpha 2u¿globulin were observed in female rats, including suppurative inflammation, transitional epithelial hyperplasia, and increased kidney weights. Because these specific effects observed in TBA exposed female rats were not confounded by alpha 2u¿globulin¿related processes, and therefore, relevant to humans, a reference dose was derived. Concerning cancer, CPN and other effects induced by both alpha 2u¿globulin processes and TBA play a role in renal tubule nephropathy, and the evidence indicates that CPN augments the renal tubule tumor induction associated with TBA exposure in male rats. Poor dose¿response relationships between alpha 2u¿globulin processes and renal tumors in male rats and a lack of renal tumors in female rats despite increased CPN severity, however, suggest that other, unknown processes contribute to renal tumor development. Based on this analysis, these renal tumors are considered relevant to humans but were not considered suitable for quantitative analysis.
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