Ethyl acrylate (EA) exposure and thyroid carcinogenicity in rats and mice with relevance to human health.

Ethyl acrylate (EA) was classified by IARC as a Group-2B Carcinogen based, in part, on data suggesting increased incidence of thyroid neoplasia in rats and mice exposed chronically to EA vapors. We examined chronic exposure of rats and mice to EA vapors, evaluated the data on the incidence of thyroid follicular neoplasia, and determined the relevance of thyroid tumors to human health risk. The data revealed a small statistically significant increase in thyroid tumors in EA-exposed male rats and mice. The tumor incidences were within the range of historical controls and were not consistently dose-dependent. Most thyroid tumors in exposed animals were benign. Chronic exposure of EA to rats and mice (drinking water or gavage) and dogs (capsules) had no evidence of thyroid neoplasia. Results from chronic studies, in vivo and in vitro data, and ToxCastTM/Tox 21 HTPS did not support genotoxic/mutagenic potential for EA. This suggests that the associations between EA exposure and thyroid neoplasia represent chance or random observations rather than a compound-mediated effect. Due to species-specific physiological differences, the hypothalamic-pituitary-thyroid axis of rodents is more sensitive to endocrine disruptive chemicals than that of humans which further suggests that findings in rodents have questionable relevance to human health.

Does GLP enhance the quality of toxicological evidence for regulatory decisions?

There is debate over whether the requirements of GLP are appropriate standards for evaluating the quality of toxicological data used to formulate regulations. A group promoting the importance of non-monotonic dose responses for endocrine disruptors contend that scoring systems giving primacy to GLP are biased against non-GLP studies from the literature and are merely record-keeping exercises to prevent fraudulent reporting of data from non-published guideline toxicology studies. They argue that guideline studies often employ insensitive species and outdated methods, and ignore the perspectives of subject-matter experts in endocrine disruption, who should be the sole arbiters of data quality. We believe regulatory agencies should use both non-GLP and GLP studies, that GLP requirements assure fundamental tenets of study integrity not typically addressed by journal peer-review, and that use of standardized test guidelines and GLP promotes consistency, reliability, comparability, and harmonization of various types of studies used by regulatory agencies worldwide. This debate suffers two impediments to progress: a conflation of different phases of study interpretation and levels of data validity, and a misleading characterization of many essential components of GLP and regulatory toxicology. Herein we provide clarifications critical for removing those impediments.

Effects of elevated glucocorticoids on reproduction and development: relevance to endocrine disruptor screening.

This article reviews the influence of the hypothalamo-pituitary-adrenocortical (HPA) axis on mammalian male and female reproduction and development of offspring and its potential impact on the identification of endocrine disruptive chemicals by in vivo assays. In the adult male rat and baboon, stress suppresses testosterone secretion via a direct inhibitory effect of elevated glucocorticoids on Leydig cells. In adult female sheep, stress disrupts reproductive function via multi-stage mechanisms involving glucocorticoid-mediated suppression of LH secretion, LH action on the ovary and the action of estradiol on its target cells (e.g., uterus). While physiological concentrations of endogenous glucocorticoids are supportive of fetal development, excessive glucocorticoids in utero (i.e., maternal stress) adversely affect mammalian offspring by "programing" abnormalities that are primarily manifest postpartum. The influence of stress on reproduction and development can also be mediated by 11ß-hydroxysteroid dehydrogenase (HSD), a bi-directional oxidative:reductive pathway, which governs the balance between biologically active (reduced) endogenous glucocorticoid and inactive (oxidized) metabolites. This pathway is mediated primarily by two isozymes, 11ß - HSD1 (reductase) and 11ß-HSD2 (oxidase) which act both in an intracrine (intracellular) and endocrine (systemic) fashion. The 11ß-HSD pathway appears to play a variety of physiological roles in mammalian reproduction and development and is a target for selected xenobiotics. The effects of the HPA axis on mammalian reproduction and development are potential confounders for in vivo bioassays in rodents employed to identify endocrine disruptive chemicals. Accordingly, consideration of the impact of the HPA axis should be incorporated into the design of bioassays for evaluating endocrine disruptors.

Critical analysis of endocrine disruptive activity of triclosan and its relevance to human exposure through the use of personal care products.

This review examines the mammalian and human literature pertaining to the potential endocrine disruptive effects of triclosan (TCS). Dietary exposure to TCS consistently produces a dose-dependent decrease in serum thyroxine (T4) in rats without any consistent change in TSH or triiodothyronine (T3). Human studies reveal no evidence that the TCS exposure through personal care product use affects the thyroid system. TCS binds to both androgen and estrogen receptors in vitro with low affinity and evokes diverse responses (e.g., agonist, antagonist, or none) in steroid receptor transfected cell-based reporter assays. Two of three studies in rats have failed to show that TCS exposure suppresses male reproductive function in vivo. Three of four studies have failed to show that TCS possesses estrogenic (or uterotrophic) activity in rats. However, two studies reported that, while TCS lacks estrogenic activity, it can amplify the action of estrogen in vivo. The in vitro, in vivo, and epidemiologic studies reviewed herein show little evidence that TCS adversely affects gestation or postpartum development of offspring. Furthermore, previously reported toxicity testing in a variety of mammalian species shows little evidence that TCS adversely affects thyroid function, male and female reproductive function, gestation, or postpartum development of offspring. Finally, doses of TCS reported to produce hypothyroxinemia, and occasional effects on male and female reproduction, gestation, and offspring in animal studies are several orders of magnitude greater than the estimated exposure levels of TCS in humans. Overall, little evidence exists that TCS exposure through personal care product use presents a risk of endocrine disruptive adverse health effects in humans.

Personal care products and endocrine disruption: A critical review of the literature.

This article reviews laboratory and epidemiological research into the endocrine disruptive effects of components of personal care products, namely, phthalate esters, parabens, ultraviolet (UV) filters, polycyclic musks, and antimicrobials. High doses of phthalates in utero can produce “phthalate syndrome,” demasculinizing effects in male rat offspring due to impaired testosterone production by fetal testes. However, evidence linking phthalate exposure to similar effects in humans appears inconclusive. Furthermore, phthalate exposure derived from personal care products is within safe limits and its principal bioavailable phthalate, diethyl phthalate (DEP), does not produce “phthalate syndrome.” Parabens exhibit very weak estrogen activity in vitro and in vivo, but evidence of paraben-induced developmental and reproductive toxicity in vivo lacks consistency and physiological coherence. Evidence attempting to link paraben exposure with human breast cancer is nonexistent. Select UV filters at high doses produce estrogenic, antithyroid, and other effects in rats in vivo. Again, no evidence links UV filter exposure to endocrine disruptive effects in humans. Some polycyclic musks weakly bind to estrogen, androgen, or progestin receptors and exhibit primarily antagonistic activity in vitro, which for the most part, has yet to be confirmed in vivo in mammals. The antimicrobials triclocarban and triclosan evoke weak responses mediated by aryl hydrocarbon, estrogen, and androgen receptors in vitro, which require confirmation in vivo. Preliminary observations suggest a novel interaction between triclocarban and testosterone. In conclusion, although select constituents exhibit interactions with the endocrine system in the laboratory, the evidence linking personal care products to endocrine disruptive effects in humans is for the most part lacking.

Weight-of-evidence evaluation of reproductive and developmental effects of low doses of bisphenol A.

Recent public concern has focused on potential reproductive and developmental effects from exposure to low levels of bisphenol A (BPA, CAS number 80-05-7). Two previous published reviews (Gray et al., 2004a; Goodman et al., 2006) conducted weight-of-evidence evaluations of in vivo reproductive/developmental toxicity from BPA exposure < or = 5 mg/kg-d based on studies published through February 2006. Here, an update of those analyses presents additional relevant studies that were published through July 25, 2008, and a weight-of-evidence analysis of the studies evaluated in all three reviews. As with the earlier literature, positive findings: (1) are countered by null findings in more numerous studies; (2) have not been replicated; (3) do not exhibit coherence and plausibility; (4) do not show consistency across species, doses, and time points; and/or (5) were from studies using non-oral exposure routes. Owing to the lack of first-pass metabolism, results from non-oral studies are of limited relevance to human exposure. Exposure levels in most of the low-dose oral and non-oral animal studies are generally much higher than those experienced by even the most exposed people in the general population. The weight of evidence does not support the hypothesis that low oral doses of BPA adversely affect human reproductive and developmental health.

An updated weight of the evidence evaluation of reproductive and developmental effects of low doses of bisphenol A.

There is controversy over whether low doses of bisphenol A (BPA, CAS no. 80-05-7) cause reproductive and developmental effects in humans. We update the 2004 weight-of-evidence assessment of an expert panel convened by Harvard's Center for Risk Analysis by critically evaluating over 50 additional studies published between April 2002 and February 2006 that examine in vivo reproductive and developmental toxicity in mammals at doses

Thyroid hormone, glucocorticoids, and prolactin at the nexus of physiology, reproduction, and toxicology.

A symposium at the 2003 Annual Meeting of the Society of Toxicology brought together an expert group of endocrinologists to review how non-reproductive hormones can affect the endocrine system. This publication captures the essence of those presentations. Paul Cooke and Denise Holsberger recapitulate the evidence of how thyroid hormones affect male and female reproduction, and reproductive development. Ray Witorsch summarizes the many effects of glucocorticoids on the reproductive system. Finally, Paul Sylvester reviews the mechanism of action of prolactin, and reminds us that this ancient hormone has many functions beyond lactation.

A critical review of methods for comparing estrogenic activity of endogenous and exogenous chemicals in human milk and infant formula.

The two primary sources of nutrition for infants are human milk and infant formula. Both contain an array of endogenous and exogenous chemicals that may act through many separate hormonal mechanisms. The safety of infant nutrition sources has been questioned based on the possibility that exogenous chemicals may exert adverse effects on nursing or formula-fed infants through estrogen-mediated mechanisms. In response to these and other concerns, the National Research Council recommended assessing the estrogenic potency of natural and anthropogenic hormonally active agents. Furthermore, the Endocrine Disruptor Screening and Testing Advisory Committee of the U.S. Environmental Protection Agency specifically recommended testing chemicals present in human milk as a representative mixture to which large segments of the population are exposed. To date, no clinical or epidemiologic evidence demonstrates that levels of chemicals currently found in human milk or infant formulas cause adverse effects in infants. Nonetheless, the question is sufficiently important to warrant a consideration of how best to evaluate potential estrogenic risks. We reviewed the types of data available for measuring estrogenic potency as well as methods for estimating health risks from mixtures of chemicals in infant nutrition sources that act via estrogenic mechanisms. We conclude that the science is insufficiently developed at this time to allow a credible assessment of health risks to infants based on estimates of estrogenic potency or on an understanding of toxicologic effects mediated by estrogenic mechanisms. However, clinical and epidemiologic data for infant nutrition sources may provide insights about risks of such substances in human milk and infant formulas.

Endocrine disruptors: can biological effects and environmental risks be predicted?

A large number of diverse nonsteroidal chemicals, referred to as xenoestrogens, bind to the estrogen receptor (ER) and evoke biological responses. The activity of most xenoestrogens is weak (from about 1/1000 th to 1/1000000 th that of estradiol). These substances interact with the binding pocket of the ER because they have chemical similarities to estradiol (usually a phenolic A-ring). Reduced activity of xenoestrogens probably results from lack of fit of the remainder of the molecule within the binding pocket. ER binding per se has only limited influence on endocrine disruption. The nature (estrogenic or antiestrogenic) or magnitude of the response is a function of the substance itself, complexities within the various stages of the ER signaling pathway, as well as other factors (such as, plasma binding of xenoestrogens, cross-talk between ER and other signaling pathways, androgen antagonism, and alternate modes of estrogen action). Whereas there is general agreement that high doses of nonsteroidal chemicals can evoke endocrine disruptive effects, there is no consensus that such substances produce low-dose effects or that humans are at risk of endocrine disruption due to exposure to environmentally relevant levels of such chemicals. Furthermore, screening programs to identify hormonally active chemicals (such as the Endocrine Disruptor Screening Program) may be premature in view of the complexity of the mechanisms involved.