Estrogen modulation: Tiered testing for human hazard evaluation

Ew, Carney; Am, Hoberman; Dr, Farmer; Rw, Kapp; Ai, Nikiforov; Bernstein, Maurice H.; Me, Hurtt; Wj, Breslin; Sz, Cagen; Gp, Daston

doi:10.1016/s0890-6238(97)00072-5

Cited by 17 publications

(8 citation statements)

References 61 publications

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“…The repeat dose in vivo toxicology studies required by the U.S. EPA and other worldwide regulatory agencies detect modulation of endocrine system activity (Carney et al, 1997;Stevens et al, 1997Stevens et al, , 1998. These studies are more predictive than in vitro screening assays as they assess a variety of endocrine-sensitive endpoints in animals that are capable of metabolic activation and/or detoxification.…”

Section: ]~ Vivo Studiesmentioning

confidence: 99%

Safety Evaluation and Risk Assessment of the Herbicide Roundup and Its Active Ingredient, Glyphosate, for Humans

Williams

Kroes

Munro

2000

Regulatory Toxicology and Pharmacology

731

481

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Section: ]~ Vivo Studiesmentioning

confidence: 99%

Safety Evaluation and Risk Assessment of the Herbicide Roundup and Its Active Ingredient, Glyphosate, for Humans

Williams

Kroes

Munro

2000

Regulatory Toxicology and Pharmacology

731

481

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“…In previous workshops and deliberations, the consensus of expert opinion has envisioned the regulatory use of the uterotrophic bioassay within a hierarchical array or series of tiers (Carney et al, 1997;EDSTAC, 1998;EU, 1997;Gray et al, 1997;Kupfer, 1988;OECD, 1998a;Reel et al, 1997; SETAC-Europe, 1997).…”

Section: Summary: the Background Data Support The Utility And Rmentioning

confidence: 99%

“…The possibility of estrogen-mediated effects and how to address them have been discussed in almost every workshop or process addressing the endocrine disruptor issue (Carney et al, 1997;EU, 1997;EDSTAC, 1998;Gray et al, 1997;SETAC-Europe, 1997). An outcome of these workshops and processes is a proposed assessment framework for endocrine disruptors based on a hierarchical, tiered approach.…”

Section: Introductionmentioning

confidence: 99%

“…Positive chemicals from this lower tier would then be screened in vivo because the intact animal incorporates the pharmacokinetic complexities of absorption, distribution, metabolism, and excretion (ADME). Reproductive and developmental tests for adverse effects comprise the final tier to accomplish the substance's hazard characterization for risk assessment (Carney et al, 1997;EDSTAC, 1998;EU, 1997;OECD, 1998a).…”

Section: Introductionmentioning

confidence: 99%

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Critical Review and Evaluation of the Uterotrophic Bioassay for the Identification of Possible Estrogen Agonists and Antagonists: In Support of the Validation of the OECD Uterotrophic Protocols for the Laboratory Rodent

Owens

Ashby

2002

Critical Reviews in Toxicology

110

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A current issue for regulatory agencies is endocrine-related modes of action such as those mediated by the estrogen, androgen, and thyroid nuclear receptors. At the national and international levels, the consensus recommendation for the assessment of such modes of action is a tiered series of in vitro and in vivo protocols. The tiered framework begins with screens for structural alerts and then moves to rapid, mechanistic in vitro screening assays, and then to in vivo screening bioassays. The objective of these screens is to identify substances that may warrant testing for endocrine-mediated adverse effects. The final framework tier as needed is to test these substances in long-term bioassays for adverse endocrine-mediated reproductive and/or developmental effects. The subject of this review, the rodent uterotrophic bioassay, is intended to be a rapid in vivo screening bioassay for possible estrogen agonists and based on the response of the estrogen-sensitive uterus. The central metric of bioassay is a statistically significant increase in the weight of the uterus after 3 consecutive days of test substance administration. The extensive background literature is summarized in this review on the mode of action underlying the bioassay and the uterine response to estrogens. The review includes the bioassay's history of development and how its employment has changed and evolved over time. The review describes two major uterotrophic bioassay versions, the intact, immature female and the mature, ovariectomized female, and the protocol factors likely to influence relevance, reproducibility, and reliability of bioassay. The emphasis of the review is the ability of the uterotrophic bioassay to identify the substances of current interest: weak estrogen agonists with binding affinities relative to the natural 17beta-estradiol in the log 0 to log -3 range. Using selected model substances having RBAs in this target range, the bioassay's performance in a hierarchical, tiered approach is evaluated, including the predictive capability of the uterotrophic bioassay based on available reproductive and developmental testing data. The review concludes that the uterotrophic bioassay is reliable and can identify substances that may act via an estrogen-mode of action, supporting the validity of the uterotrophic bioassay and its regulatory use as an in vivo mechanistic screening bioassay for estrogen agonists and antagonists.

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“…In accord with the results of the Tier 1 in vitro assays, there were also no definitive findings in the glyphosate subchronic, chronic, developmental and reproductive toxicity studies conducted for global registrations that would indicate an endocrine-modulating effect (Williams et al 2000, Williams et al 2012Giesy et al 2000;WHO/FAO 2004). These repeat dose in vivo toxicology studies had extended exposure periods encompassing various stages of endocrine development and did not detect endocrinopathies with histopathological assessment and endocrine organ weight data (Carney et al, 1997;Stevens et al, 1997Stevens et al, , 1998Harvey and Johnson, 2002).…”

Section: Regulatory Safety Studies and Tier 1 Endocrine Screening Assmentioning

confidence: 99%

Endocrine disruption: where are we with hazard and risk assessment?

Coady

Matthiessen²,

Zahner

et al. 2016

Preprint

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Estrogen modulation: Tiered testing for human hazard evaluation

Cited by 17 publications

References 61 publications

Safety Evaluation and Risk Assessment of the Herbicide Roundup and Its Active Ingredient, Glyphosate, for Humans

Safety Evaluation and Risk Assessment of the Herbicide Roundup and Its Active Ingredient, Glyphosate, for Humans

Critical Review and Evaluation of the Uterotrophic Bioassay for the Identification of Possible Estrogen Agonists and Antagonists: In Support of the Validation of the OECD Uterotrophic Protocols for the Laboratory Rodent

Endocrine disruption: where are we with hazard and risk assessment?

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