Mechanistic considerations for the relevance of animal data on thyroid neoplasia to human risk assessment

McClain, R.M.

doi:10.1016/0027-5107(95)00139-5

Cited by 88 publications

(62 citation statements)

References 47 publications

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“…Some mechanisms of toxicity, such as disruption of thyroid hormone homeostasis in rodents are probably shared by non-coplanar PCBs and the lower molecular weight PBDEs. However, this mode of action as mediated by PB-like enzyme inducers at relatively high doses is thought not to be relevant to humans (McClain 1995). Results presented here and from previous work conducted in our laboratory demonstrate that biotransformation pathways for BDE47 and BDE99 potentially produce reactive intermediates possibly associated with some toxic responses previously observed in rats.…”

Section: Discussionmentioning

confidence: 55%

Disposition of 2,2′,4,4′,5,5′-hexabromodiphenyl ether (BDE153) and its interaction with other polybrominated diphenyl ethers (PBDEs) in rodents

et al. 2006

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1.The disposition of the 14 C-labeled polybrominated diphenyl ether (PBDE), 2,2′,4,4′,5,5′-hexaBDE (BDE153) was investigated in rodents following single and multiple doses and in a mixture with radiolabeled 2,2′,4,4′-tetraBDE (BDE47) and 2,2′,4,4′,5-pentaBDE (BDE99). 2.In single exposure studies, there was little or no effect of dose on BDE153 disposition in male rats in the range of 1-100 µmol/kg. No major sex or species differences in the in vivo fate of BDE153 were detected. BDE153 was: 1) approximately 70% absorbed in rats or mice following gavage. 2) retained in tissues. 3) poorly metabolized and slowly excreted. 3.Mixture studies indicated that, relative to each other, more BDE47 was distributed to adipose tissue, more BDE153 accumulated in liver, and BDE99 was metabolized to the greatest extent. BDE153 was probably retained in liver due to minimal metabolism and elimination after "first pass" distribution to the tissue following gavage.

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Section: Discussionmentioning

confidence: 55%

Disposition of 2,2′,4,4′,5,5′-hexabromodiphenyl ether (BDE153) and its interaction with other polybrominated diphenyl ethers (PBDEs) in rodents

et al. 2006

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“…In fact, there are some data (described herein) to suggest that dogs as compared to humans are slightly more susceptible to such a mechanism given the right conditions. In any case, the historic weight of evidence strongly supports the conclusion that this mechanism is unlikely to translate to humans (McClain 1995).…”

Section: Introductionmentioning

confidence: 76%

Effects of Lersivirine on Canine and Rodent Thyroid Function

et al. 2013

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Lersivirine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) being developed for the treatment of HIV-1 infection. Like other NNRTIs, lersivirine is a potent enzyme inducer in rodents capable of inducing a number of hepatic enzymes including those involved in its own metabolism. Preclinically lersivirine has been associated with hepatocellular hypertrophy and thyroid gland follicular cell hypertrophy in rats, mice, and dogs. In rodents, we show that development of thyroid hypertrophy is related to the classic mechanism, namely increased thyroxine (T4) clearance secondary to induction of uridine-diphosphoglucuronosyltransferase (UDPGT) in the liver and a resulting increase in thyroidstimulating hormone. Similarly, lersivirine-exposed dogs exhibit a significant increase in hepatic UDPGT enzyme activity along with increased T4 clearance although clear effects on serum thyroid hormone levels were less apparent. These effects on thyroid hormonal clearance in the dog suggest that thyroid gland hypertrophy in this species is due to the same mechanism shown to occur in rodents although, as expected, dogs better adapt to these effects and therefore maintain relatively normal thyroid hormonal balance. It is also notable that the minimal thyroid follicular hypertrophy that occurs in dogs does not progress as is seen in rodents. As is the case with rodents, these adaptive changes in the dog are not considered indicative of a human health risk.

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“…In dogs given prednisone, increases in hepatic ALP and GGT, but not ALT, activities are seen, often along with increases in serum ALP, GGT, and ALT activities (Rutgers 1995;Solter et al 1994). Increased serum activity of the liver ALP isoenzyme (LALP) can occur following a single dose of prednisone in the dog (Wiedmeyer et al 2002a); however, significant increases in serum CIALP activity do not occur before seven to ten days of prednisone administration (Solter et al 1994;Wiedmeyer et al 2002b).…”

Section: Corticosteroid-mediated Induction Of Hepatobiliary Biomarkermentioning

confidence: 99%

Effects of Hepatic Drug-metabolizing Enzyme Induction on Clinical Pathology Parameters in Animals and Man

et al. 2010

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Hepatic drug-metabolizing enzyme (DME) induction is an adaptive response associated with changes in preclinical species; this response can include increases in liver weight, hepatocellular hyperplasia and hypertrophy, and upregulated tissue expression of DMEs. Effects of DME induction on clinical pathology markers of hepatobiliary injury and function in animals as well as humans are not well established. This component of a multipart review of the comparative pathology of xenobiotically mediated induction of hepatic metabolizing enzymes reviews pertinent data from retrospective and prospective preclinical and clinical studies. Particular attention is given to studies with confirmation of DME induction and concurrent evaluation of liver and/or serum hepatobiliary marker enzyme activities and histopathology. These results collectively indicate that in the rat, when histologic findings are limited to hepatocellular hypertrophy, DME induction is not expected to be associated with consistent or substantive changes in serum or plasma activity of hepatobiliary marker enzymes such as alanine aminotransferase, alkaline phosphatase, and gamma glutamyltransferase. In the dog and the monkey, published studies also do not demonstrate a consistent relationship across DME-inducing agents and changes in these clinical pathology parameters. However, increased liver alkaline phosphatase or gamma glutamyltransferase activity in dogs treated with phenobarbital or corticosteroids suggests that direct or indirect induction of select hepatobiliary injury markers can occur both in the absence of liver injury and independently of induction of DME activity. Although correlations between tissue and serum levels of these hepatobiliary markers are limited and inconsistent, increases in serum/plasma activities that are substantial or involve changes in other markers generally reflect hepatobiliary insult rather than DME induction. Extrahepatic effects, including disruption of the hypothalamic-pituitary-thyroid axis, can also occur as a direct outcome of hepatic DME induction in humans and animals. Importantly, hepatic DME induction and associated changes in preclinical species are not necessarily predictive of the occurrence, magnitude, or enzyme induction profile in humans.

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Mechanistic considerations for the relevance of animal data on thyroid neoplasia to human risk assessment

Cited by 88 publications

References 47 publications

Disposition of 2,2′,4,4′,5,5′-hexabromodiphenyl ether (BDE153) and its interaction with other polybrominated diphenyl ethers (PBDEs) in rodents

Disposition of 2,2′,4,4′,5,5′-hexabromodiphenyl ether (BDE153) and its interaction with other polybrominated diphenyl ethers (PBDEs) in rodents

Effects of Lersivirine on Canine and Rodent Thyroid Function

Effects of Hepatic Drug-metabolizing Enzyme Induction on Clinical Pathology Parameters in Animals and Man

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