Disentangling Mechanisms of Kidney Toxicity and Carcinogenicity in t-Butanol Toxicological Review
This toxicological review delves into the mechanisms of kidney toxicity and carcinogenicity associated with t-Butanol exposure. Findings highlight nephropathy evidence, individual animal responses, and the role of advanced chronic progressive nephropathy in male rat renal tumors. Transitional cell hyperplasia and suppurative inflammation are also discussed in relation to nephrotoxicity.
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Presentation Transcript
Draft Toxicological Review of t-Butanol: Disentangling mechanisms of kidney toxicity and carcinogenicity: Public Comment: LyondellBasell Gordon C Hard - Independent Consultant DVSc, PhD, DSc DACVP, FRCPath, FRCVS, FAToxSci Tairua, New Zealand IRIS Public Science Meeting June 29-30, 2016 Arlington, VA
G C Hard Report on TBA to LyondellBasell, 2005 GC Hard, RH Bruner, SM Cohen, JM Pletcher, KS Regan Regulatory Toxicol Pharmacol, 2011 13 13- -week toxicity study week toxicity study male rats male rats Hyaline droplet accumulation Hyaline droplet accumulation - - angular droplets Granular cast precursors present at OSOM Granular cast precursors present at OSOM- -ISOM border Granular casts seen in specially Granular casts seen in specially- -stained kidneys Two Two- -year carcinogenicity year carcinogenicity s study tudy 15 15- -month interim sacrifice month interim sacrifice male rats male rats Linear papillary mineralization (LPM) present Linear papillary mineralization (LPM) present Two Two- -year terminal sacrifice year terminal sacrifice LPM in most tumor LPM in most tumor- -bearing male rats bearing male rats Most rats with tumors or ATH had advanced CPN Most rats with tumors or ATH had advanced CPN CPN severity in males linked to tumors 3.5 versus 2.9 angular droplets ISOM border stained kidneys Absence of chemical Absence of chemical- -related nephrotoxicity in both sexes related nephrotoxicity in both sexes Hyperplasia of papilla lining Hyperplasia of papilla lining a component of CPN a component of CPN
CONCLUSIONS The 2u-g nephropathy evidence is not limited but relatively robust Tubule cell exfoliation necessitates compensatory regeneration The only responses to TBA in rat kidneys are 2u-g nephropathy in males and exacerbated CPN Individual animal evidence is sufficient to support advanced CPN as contributing to the RTT response TBA male rat renal tumors are adequately explained by 2u-g nephropathy combined with advanced CPN Transitional cell hyperplasia in the TBA study is not a nephrotoxic response Suppurative inflammation is not a nephrotoxic response but caused by bacterial infection
TBA Female rat High dose Transitional cell hyperplasia of papilla
