Interlaboratory Study Comparison of the 15-Day Intact Adult Male Rat Screening Assay: Evaluation of an Antithyroid Chemical and a Negative Control Chemical

Validation of the 15‐day intact adult male rat screening assay (IAMRSA), an endocrine activity screen, was extended beyond the 28 substances evaluated to date. Two independent laboratories evaluated specificity using allyl alcohol (AA), a putative negative control, and DE‐71 (technical grade pentabr...

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Published in:	Birth defects research. Part B. Developmental and reproductive toxicology Vol. 95; no. 1; pp. 63 - 78
Main Authors:	Becker, Richard A., Bergfelt, Don R., Borghoff, Susan, Davis, Jeffrey P., Hamby, Bonnie T., O'Connor, John C., Kaplan, A. Michael, Sloan, Carol S., Tyl, Rochelle W., Wade, Michael, Marty, Mary Sue
Format:	Journal Article
Language:	English
Published:	United States Blackwell Publishing Ltd 01-02-2012
Subjects:	Aging - drug effects allyl alcohol Animals Antithyroid Agents - toxicity Body Weight - drug effects Drug Evaluation, Preclinical endocrine disruption endocrine screening Feeding Behavior - drug effects Halogenated Diphenyl Ethers - toxicity Laboratories Male Organ Size - drug effects pentabromodiphenyl ether Propanols - toxicity Rats Rats, Sprague-Dawley pentabromodiphenyl ether endocrine screening allyl alcohol endocrine disruption
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Summary:	Validation of the 15‐day intact adult male rat screening assay (IAMRSA), an endocrine activity screen, was extended beyond the 28 substances evaluated to date. Two independent laboratories evaluated specificity using allyl alcohol (AA), a putative negative control, and DE‐71 (technical grade pentabromodiphenyl ether) for comparison with previous pubertal assays that demonstrated thyroid effects. Male rats (15/group) were gavaged daily with AA (0, 10, 30, or 40 mg/kg/day) or DE‐71 (0, 3, 30, or 60 mg/kg/day) for 15 days. Body and organ weights and serum hormone concentrations were measured, and a limited histopathological assessment was conducted. AA results were considered negative at doses that did not exceed the maximum tolerated dose (MTD); effects reported were dose‐related decreases in weight gain, increased liver weights and, although the pattern varied across studies, alterations in some androgen‐sensitive endpoints in the high‐dose where the maximum tolerated dose was exceeded. In the DE‐71 studies, dose‐dependent increases in liver weights (consistent with hepatic enzyme induction), decreases in tri‐iodothyronine and thyroxine, concomitant thyroid stimulating hormone increases were observed and one laboratory reported histopathological thyroid changes in mid‐ and high‐dose groups, and the other increased thyroid weights. For DE‐71, the IAMRSA was comparable in sensitivity to the pubertal assays. Overall, the specificity and sensitivity of the IAMRSA for deployment in an endocrine screening battery are supported. However, differentiating primary endocrine‐mediated effects from secondary effects caused by systemic toxicity will be challenging, emphasizing the need to utilize a battery of assays and a weight of evidence approach when evaluating the potential endocrine activity of chemicals.
Bibliography:	ArticleID:BDRB20343 ark:/67375/WNG-4FSLTSN6-9 istex:DA799DBB57472CAE2FF6C3D75D39D6D150BAC2FC American Chemistry Council's Long-Range Research Initiative American Chemistry Council's Long‐Range Research Initiative. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1542-9733 1542-9741
DOI:	10.1002/bdrb.20343