Friday, March 13, 2009

Houdini Alert - Formerly "less" toxic ketone causes cancer and kidney damage

ToxicologyVolume 258, Issues 2-3, 28 April 2009, Pages 131-138

Methyl isobutyl ketone (MIBK) induction of α2u-globulin nephropathy in male, but not female rats
S.J. Borghoffa, , , G.C. Hardb, N.M. Berdascoc, R. Gingelld, S.M. Greene and W. Gulledgef
aIntegrated Laboratory Systems Inc., Division of Investigative Toxicology, P.O. Box 13501, Research Triangle Park, NC 27709, United States
bPrivate Consultant, Tairua 3508, New Zealand
cDow Chemical Company, Midland, MI 48640, United States
dShell Oil Company, Houston, TX 77210, United States
eThe Eastman Chemical Company, Kingsport, TN 37660, United States
fAmerican Chemistry Council, Arlington, VA 22209, United States
Male F-344 rats were administered corn oil (vehicle control), d-limonene (positive control, 300 mg/kg), or MIBK (1000 mg/kg) and female F-344 rats corn oil (vehicle control) or MIBK for 10 consecutive days by oral gavage. Approximately 24 h after the final dose the kidneys were excised and the left kidney prepared and evaluated for histological changes including protein (hyaline) droplet accumulation, immunohistochemical staining for α2u-globulin (α2u), and proliferating cell nuclear antigen (PCNA) to quantitate renal cell proliferation. The right kidney was prepared for quantitation of total protein and α2u using an ELISA. MIBK elicited an increase in protein droplets, accumulation of α2u, and renal cell proliferation in male, but not female rats, responses characteristic of α2u-mediated nephropathy. MIBK produced identical histopathological changes in the male rat kidney when compared to d-limonene, an acknowledged inducer of α2u-nephropathy except that the grade of severity tended to be slightly lower with MIBK. MIBK did not induce any effects in female rats. Therefore, renal histopathology, along with the other measures of α2u accumulation, provides additional weight of evidence to support the inclusion of MIBK in the category of chemicals exerting renal effects through a α2u-nephropathy-mediated mode-of-action.
BrooklynDodger(s) comments: The credit line for the lead author reminds us that the Houdini complex has set up shop in the Research Triangle, next door to NIEHS, NTP and EPA NCEA. That's also the site of the facility formerly known as the Chemical Industry Institute for Toxicology. The Houdini attack on hazard determination aims to knock out tumor sites, species and genders one-by-one until there's not enough left for classification. While NTP was running the bioassay of MIBK, Dow, Shell, Eastman and the organization formerly known at the Chemical Manufacturer's Association were at work on making the bioassay disappear.

Alpha-2 (male rat kidney) may be considered the "mother of all Houdini risk assessments," if size and impact is the criterion (gasoline), although it was not the ancestress in the way bladder stones were used against saccharine and melamine. In the bioassay, MIBK caused nephropathy in the female mice. Like gasoline, but unlike limonene, MIBK caused liver tumors in mice of both genders.

However, EPA has chosen to ignore the liver tumors from gasoline, so it can ignore the kidney tumors as well, so as to ignore the need to regulate gasoline as a carcinogen.

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