Interspecies differences in susceptibility to perturbation of thyroid homeostasis: a case study with perchlorate

Lewandowski, Thomas A.; Seeley, Mara; Beck, Barbara D.

doi:10.1016/j.yrtph.2004.03.002

Cited by 43 publications

(28 citation statements)

References 64 publications

(80 reference statements)

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“…Moreover, as noted by a number of authors, the rat actually provides an exquisitely sensitive model for thyroid axis disruption due to some peculiarities of its thyroid physiology. High expression of sodium iodide symporter (NIS) in thyroid follicle cells, negligible TBG in pubertal animals (as used in most toxicity studies) with consequently low TH half-life in plasma, and low amounts of colloid stores in the thyroid mean that the rat has very limited ability to compensate for any exogenous influences on its thyroid economy (Lewandowski et al, 2004). Although this might render extrapolations from rat to humans overly sensitive for human health risk assessment, for hazard identification (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…These mean that serum half-life of thyroid hormones is low (due to a greater proportion of free TH) and intrathyroidal stores are very limited. Consequently the rat is significantly less able to compensate for perturbations in its thyroid axis than humans and other mammals generally (Lewandowski et al, 2004). This may at least in part explain why animal data on thyroid neoplasias secondary to hormonal imbalance are of limited relevance in human health risk assessment (Hard, 1998 1995).…”

Section: Mammalian Assaysmentioning

confidence: 99%

“…Thyroid cancers are commonly observed in rats exposed chronically to goitrogens, and seem to result from increased cell division (i.e., hyperplastic changes) in the thyroid that is driven by elevated TSH in response to the reduced ciculating thyroid hormone concentrations. This susceptibility to thyroid cancers in response to non-genotoxic goitrogens is regarded as a manifestation of the exceptional sensitivity of the rat thyroid axis and is generally not regarded as relevant in human health risk assessment (Lewandowski et al, 2004).…”

Section: Methimazole (Mmi)mentioning

confidence: 99%

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Screening chemicals for thyroid-disrupting activity: A critical comparison of mammalian and amphibian models

Pickford

2010

Critical Reviews in Toxicology

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In order to minimize risks to human and environmental health, chemical safety assessment programs are being reinforced with toxicity tests more specifically designed for detecting endocrine disrupters. This includes the necessity to detect thyroid-disrupting chemicals, which may operate through a variety of modes of action, and have potential to impair neurological development in humans, with resulting deficits of individual and social potential. Mindful of these concerns, the consensus favors in vivo models for both hazard characterization (testing) and hazard identification (screening) steps, in order to minimize false negatives. Owing to its obligate dependence on thyroid hormones, it has been proposed that amphibian metamorphosis be used as a generalized vertebrate model for thyroid function in screening batteries for detection of thyroid disrupters. However, it seems unlikely that such an assay would ever fully replace in vivo mammalian assays currently being validated for human health risk assessment: in its current form the amphibian metamorphosis screening assay would not provide capacity for reliably detecting other modes of endocrine-disrupting activity. Conversely, several candidate mammalian screening assays appear to offer robust capacity to detect a variety of modes of endocrine-disrupting activity, including thyroid activity. To assess whether omission of an amphibian metamorphosis assay from an in vivo screening battery would generate false negatives, the response of amphibian and mammalian assays to a variety known thyroid disrupters, as reported in peer-reviewed literature or government agency reports, was critically reviewed. Of the chemicals investigated from the literature selected (41), more had been tested in mammalian studies with thyroid-relevant endpoints (32) than in amphibian assays with appropriate windows of exposure and developmental endpoints (27). One chemical (methoxychlor) was reported to exhibit thyroid activity in an appropriate amphibian assay in the absence of corresponding activity in a suitable mammalian assay, whereas none of the chemicals surveyed were reported as thyroid active in mammalian assays but reported as negative in an appropriate amphibian assay. Given the need for one or more in vivo mammalian assays for screening chemicals for detecting (anti-)estrogenic/(anti-)androgenic activity and effects on steroidogenesis, inclusion of an in vivo amphibian assay specifically to detect thyroid disrupters would likely be as an addition to these mammalian assays. As there is little convincing evidence that an amphibian screening assay would detect significant numbers of thyroid-active chemicals not picked up by mammalian assays, the routine use of an amphibian metamorphosis assay at screening level could introduce unnecessary and unjustified redundancy into chemical safety assessment programs, when there is pressure to reduce animal use in toxicity testing.

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Section: Discussionmentioning

confidence: 99%

Section: Mammalian Assaysmentioning

confidence: 99%

Section: Methimazole (Mmi)mentioning

confidence: 99%

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Screening chemicals for thyroid-disrupting activity: A critical comparison of mammalian and amphibian models

Pickford

2010

Critical Reviews in Toxicology

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“…Thus, it is possible that a species-specific effect on thyroid hormone metabolism may exist, possibly involving changes in liver enzyme profile. Bearing in mind that the significance of rodent thyroid cancers to human risk assessment has also been widely questioned (Hill et al 1998;Poirier et al 1999;IARC 2001;Lewandowski et al 2004) and in this case the thyroid effect was observed in only one rodent species, the significance to humans is uncertain.…”

Section: Evidence Of Carcinogenicitymentioning

confidence: 99%

The Mutagenicity and Carcinogenicity of Inorganic Manganese Compounds: A Synthesis of The Evidence

Assem

Holmes

Levy

2011

Journal of Toxicology and Environmental Health, Part B

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Manganese (Mn), a naturally occurring element present in many foodstuffs, is an essential trace element with many biological functions. In industry, inorganic Mn compounds have a range of different applications, although the majority of Mn is used to make alloys and steel. For the general population, the major source of exposure to Mn is dietary, although drinking water may constitute an additional source in some regions. However, in occupationally exposed humans, inhalation of Mn is likely to be an important additional route. In general, Mn and its inorganic compounds are considered to possess low mutagenic or carcinogenic potential compared with some heavy metals. In this review, an up-to-date analysis of the available published studies on the carcinogenic and genotoxic potential of inorganic Mn is provided (organic Mn compounds are not considered). The current literature indicates that Mn may be weakly mutagenic in vitro and possibly clastogenic in vivo, with unknown genotoxic effects in humans; the possible mechanisms underlying these effects are discussed. The experimental evidence on carcinogenicity (quantitative increase in incidence of thyroid tumors in mice but not rats) does not provide any clear evidence, while the available occupational and environmental epidemiological evidence is equivocal as to whether exposure to inorganic Mn is associated with a significant cancer risk. Hence, it is concluded that there is insufficient evidence to indicate that inorganic Mn exposure produces cancer in animals or humans.

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“…However, rats and humans may be similarly sensitive to perchlorateÕs ability to reduce thyroid hormone synthesis-a seemingly important issue. Likewise, considering that a human neonate has a serum half-life of T 4 of around 3 days (Vulsma et al, 1989) and intrathyroidal stores of T 4 estimated to be less than one dayÕs worth (van den Hove et al, 1999), it is easily predictable that human neonates will exhibit a decrease in serum thyroid hormone levels within 14 days of exposure to doses of perchlorate that would clearly not affect serum T 4 in normal adults. Thus, if we assume that a human neonate is no more sensitive to perchlorateÕs ability to inhibit thyroid hormone synthesis than are adults, we can still predict that they will be more vulnerable to the adverse effects of perchlorate.…”

mentioning

confidence: 99%

Interspecies differences in susceptibility to perturbation of thyroid hormone homeostasis requires a definition of “sensitivity” that is informative for risk analysis

Zoeller

2004

Regulatory Toxicology and Pharmacology

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Interspecies differences in susceptibility to perturbation of thyroid homeostasis: a case study with perchlorate

Cited by 43 publications

References 64 publications

Screening chemicals for thyroid-disrupting activity: A critical comparison of mammalian and amphibian models

Screening chemicals for thyroid-disrupting activity: A critical comparison of mammalian and amphibian models

The Mutagenicity and Carcinogenicity of Inorganic Manganese Compounds: A Synthesis of The Evidence

Interspecies differences in susceptibility to perturbation of thyroid hormone homeostasis requires a definition of “sensitivity” that is informative for risk analysis

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