2006
DOI: 10.1080/10408440600975242
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Thiazopyr and Thyroid Disruption: Case Study Within the Context of the 2006 IPCS Human Relevance Framework for Analysis of a Cancer Mode of Action

Abstract: Thiazopyr increases the incidence of male rat thyroid follicular-cell tumors; however, it is not carcinogenic in mice. Thiazopyr is not genotoxic. Thiazopyr exerts its carcinogenic effect on the rat thyroid gland secondary to enhanced metabolism of thyroxin leading to hormone imbalance. The relevance of these rat tumors to human health was assessed by using the 2006 IPCS Human Relevance Framework. The postulated rodent tumor mode of action was tested against the Bradford Hill criteria and was found to satisfy … Show more

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Cited by 62 publications
(26 citation statements)
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“…If all of the key events are possible in humans, then the mode of action is relevant to humans, and an appropriate assessment of risk can be made on the detailed qualitative and quantitative aspects of the metabolism, kinetics, and physiologic responses to the chemical, taking into account the dose response and human exposures. In the frameworks that have been developed by EPA and Health Canada 31 and by IPCS 32 , numerous case studies are provided illustrating the process 17,18,[33][34][35] . In all of these examples, the ultimate mode of action involves either DNA reactivity or increased cell proliferation.…”
Section: Human Relevancementioning
confidence: 99%
“…If all of the key events are possible in humans, then the mode of action is relevant to humans, and an appropriate assessment of risk can be made on the detailed qualitative and quantitative aspects of the metabolism, kinetics, and physiologic responses to the chemical, taking into account the dose response and human exposures. In the frameworks that have been developed by EPA and Health Canada 31 and by IPCS 32 , numerous case studies are provided illustrating the process 17,18,[33][34][35] . In all of these examples, the ultimate mode of action involves either DNA reactivity or increased cell proliferation.…”
Section: Human Relevancementioning
confidence: 99%
“…Sufficient evidence has been established from animal studies demonstrating the key events in development of thyroid tumors via perturbation of HPT axis that include hepatic enzyme induction, enhanced T4 metabolism (primarily glucuronidation) and clearance, and decreased serum T4 (Curran and DeGroot, 1991;Dellarco et al, 2006). The decrease in serum T4 stimulates the HPT axis to reestablish thyroid hormone homeostasis by increasing circulating levels of TSH, which induce thyroid follicular cells to produce and release more thyroid hormone (IARC, 1999(IARC, , 2001McClain, 1995;Hurley et al, 1998).…”
Section: Biological Plausibility and Coherencementioning
confidence: 96%
“…With respect to the thyroid, follicular cell tumors may present as adenomas or carcinomas, but only adenomas were increased in male and female rats with pronamide treatment in the rat chronic study. The hypothesized liver UGT-mediated secondary MoA for induction of thyroid follicular cell adenomas is well established and is considered not relevant to humans based on the species differences in the kinetics of thyroxine clearance and thyroid reserve capacity (Jahnke et al, 2004;Dellarco et al, 2006).…”
Section: Strength Consistency and Specificity Of Association Of Effementioning
confidence: 99%
“…Since the initial adverse finding in the thyroid occurred only after 12 months of exposure and consisted of a slight increase in TFC hyperplasia, it was anticipated that the elucidation of the underlying molecular basis for this chronically observed effect would be challenging. Furthermore, the MOAs responsible for thyroid tumors have been well described in the rat but much less information is published concerning the mouse (Dellarco et al, 2006;Hill et al, 1989).…”
Section: Fluopyrammentioning
confidence: 98%