Key Issues and Uncertainties in Tert-Butanol (TBA) Induced Kidney Toxicity
This study discusses the key issues and uncertainties surrounding Tert-Butanol (TBA) induced kidney toxicity. It covers the role of alpha-2u globulin nephropathy, chronic progressive nephropathy (CPN), and the validity of concluding another unknown mode of action. Findings suggest TBA as a weak inducer of alpha-2u nephropathy in male rats, inconclusive evidence regarding CPN, and observations pointing to a different MOA. Various adverse effects on the kidneys are noted beyond alpha-2u and CPN, indicating the presence of another mechanism affecting both male and female rats.
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Lawrence H. Lash, Ph.D. PROFESSOR AND ASSOCIATE CHAIR DEPARTMENT OF PHARMACOLOGY WAYNE STATE UNIVERSITY SCHOOL OF MEDICINE DETROIT, MI 48201 L.H.LASH@WAYNE.EDU
tert tert- -Butanol (TBA) Butanol (TBA)- -Induced Kidney Toxicity: Key Issues and Uncertainties Toxicity: Key Issues and Uncertainties Induced Kidney 1) Role and importance of alpha-2u globulin nephropathy 2) Role and importance of chronic progressive nephropathy (CPN) 3) Validity of conclusion that besides alpha-2u and CPN, another unknown MOA 4) Relevance of renal tumors to humans 5) Use of data with ETBE and MTBE for TBA
tert tert- -Butanol (TBA) Butanol (TBA)- -Induced Kidney Toxicity: Key Issues and Uncertainties Toxicity: Key Issues and Uncertainties Induced Kidney 1) Role and importance of alpha-2u globulin nephropathy Findings are consistent with TBA being a weak inducer of a2u nephropathy in male rats; This MOA is not relevant to humans; Clear, thorough discussion of the well-established criteria for deciding whether a chemical is an inducer
tert tert- -Butanol (TBA) Butanol (TBA)- -Induced Kidney Toxicity: Key Issues and Uncertainties Toxicity: Key Issues and Uncertainties Induced Kidney 2) Role and importance of chronic progressive nephropathy (CPN) Evidence regarding the role of CPN said to inconclusive Problems with data include very high background rates and lack of clear dose response All key issues regarding time, dose, biological plausibility, and concordance/coherence are thoroughly discussed.
tert tert- -Butanol (TBA) Butanol (TBA)- -Induced Kidney Toxicity: Key Issues and Uncertainties Toxicity: Key Issues and Uncertainties Induced Kidney 3) Validity of conclusion that besides alpha-2u and CPN, another unknown MOA Several other adverse effects involving the kidneys have been observed that clearly cannot be attributed to alpha-2u or CPN, so it seems clear that another MOA is operative. Key observations include: Occurrence in both male and female rats; suppurative inflammation in female rats; transitional epithelial hyperplasia in male and female rats; TBA-associated increase in severity of nephropathy in male and female rats; mineralization in male rats; increased kidney weights in rats but not mice.
tert tert- -Butanol (TBA) Butanol (TBA)- -Induced Kidney Toxicity: Key Issues and Uncertainties Toxicity: Key Issues and Uncertainties Induced Kidney 4) Relevance of renal tumors to humans: Factors leading one to at least conclude that TBA is a suggestive or possible renal carcinogen in humans: Some dose-dependent effects in non-cancer endpoints in rats If one eliminates effects associated with the a2u response and CPN, there are still TBA-associated adverse effects on kidneys Designation as suggestive of causing renal cancer in human is appropriate
tert tert- -Butanol (TBA) Butanol (TBA)- -Induced Kidney Toxicity: Key Issues and Uncertainties Toxicity: Key Issues and Uncertainties Induced Kidney 5) Use of data with ETBE and MTBE for TBA: While TBA is a known metabolite of both ETBE and MTBE, some aspects are unclear, and this is not properly pointed out in document How much TBA is generated during exposure to ETBE or MTBE? How well do renal effects observed with ETBE/MTBE correspond to those observed with TBA?
tert tert- -Butanol (TBA) Butanol (TBA)- -Induced Kidney Toxicity: Key Issues and Uncertainties Toxicity: Key Issues and Uncertainties Induced Kidney Conclusions: 1) well-organized according to new format Draft IRIS document generally very clear, well-written, and 2) Discussion of uncertainties is well balanced in virtually all cases 3) Points for revision/reconsideration -- minor
