Endocrine disruption: Where are we now: Tier 2 testing

The focus of this session was on the proposed USEPA Endocrine Disruption Screening Program (EDSP) Tier 2 testing protocols. Tier 2 tests have been developed to evaluate the potential impacts of endocrine disrupting chemicals (EDCs) over the life cycle across organisms representing vertebrate and invertebrate classes. Key aspects of these Tier 2 testing protocols rely on selecting appropriate measurement end points to reveal differential sensitivity and adverse impacts across an organism’s life stages. To this end, certain Tier 2 tests utilize a multigenerational protocol, which detect both short- and long-term effects. However, multigenerational testing protocols can be time consuming and costly. As such, other testing protocols have also been considered, including partial life-cycle and extended one-generation tests. Regardless of the specifics of the multigenerational protocol, it is critical to identify key measurement end points that are responsive, reliable, and repeatable indicators of exposure to endocrine disrupting chemicals; these measures should also provide information to enable initial assessments of risk translated from individual to potential population level effects across a variety of living organisms. Presentations in Session three of the Society of Environmental Toxicology and Chemistry (SETAC) North America Focused Topic Meeting: Endocrine Disruption (February 4 – 6, 2014) focused on the current state of the science for EPA EDSP Tier 2 testing. Presentations in this session considered the strengths and weaknesses of the Tier 2 assays across several classes of organisms, and provided an industry perspective on Tier 2 testing. The interactive panel discussion provided an interesting perspective that balanced regulatory needs for reliable testing protocols that are highly repeatable and utilize consistent indices of exposure and adverse effect.

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Endocrine-Disrupting Chemicals and Public Health Protection: A Statement of Principles from The Endocrine Society

Endocrinology ◽

10.1210/en.2012-1422 ◽

2012 ◽

Vol 153 (9) ◽

pp. 4097-4110 ◽

Cited By ~ 507

Author(s):

R. Thomas Zoeller ◽

T. R. Brown ◽

L. L. Doan ◽

A. C. Gore ◽

N. E. Skakkebaek ◽

...

Keyword(s):

Life Cycle ◽

Screening Program ◽

Life Stage ◽

Endocrine Disrupting Chemicals ◽

Tissue Cell ◽

Endocrine Society ◽

Endocrine Disrupting Chemical ◽

Hormone Synthesis ◽

Endocrine Disrupting ◽

Irreversible Effects

An endocrine-disrupting chemical (EDC) is an exogenous chemical, or mixture of chemicals, that can interfere with any aspect of hormone action. The potential for deleterious effects of EDC must be considered relative to the regulation of hormone synthesis, secretion, and actions and the variability in regulation of these events across the life cycle. The developmental age at which EDC exposures occur is a critical consideration in understanding their effects. Because endocrine systems exhibit tissue-, cell-, and receptor-specific actions during the life cycle, EDC can produce complex, mosaic effects. This complexity causes difficulty when a static approach to toxicity through endocrine mechanisms driven by rigid guidelines is used to identify EDC and manage risk to human and wildlife populations. We propose that principles taken from fundamental endocrinology be employed to identify EDC and manage their risk to exposed populations. We emphasize the importance of developmental stage and, in particular, the realization that exposure to a presumptive “safe” dose of chemical may impact a life stage when there is normally no endogenous hormone exposure, thereby underscoring the potential for very low-dose EDC exposures to have potent and irreversible effects. Finally, with regard to the current program designed to detect putative EDC, namely, the Endocrine Disruptor Screening Program, we offer recommendations for strengthening this program through the incorporation of basic endocrine principles to promote further understanding of complex EDC effects, especially due to developmental exposures.

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Introduction to the science and regulation concerning endocrine disrupting chemicals: the challenges ahead

10.7287/peerj.preprints.2583v1 ◽

2016 ◽

Author(s):

Annegaaike Leopold ◽

Glen Van Der Kraak ◽

Mary K. Manibusan ◽

Niklas Andersson ◽

James R. Wheeler

Keyword(s):

Endocrine Disruption ◽

Screening Program ◽

Endocrine Disrupting Chemicals ◽

Current Status ◽

The European Union ◽

Endocrine Disrupting Chemical ◽

Science And Policy ◽

Advisory Groups ◽

Endocrine Disrupting ◽

Multi Stakeholder

Presentations in session one of the Society of Environmental Toxicology and Chemistry (SETAC) North America Focused Topic Meeting: Endocrine Disruption (February 4 – 6, 2014) described where the science and the regulations have arrived and identified the key challenges that lie ahead. The first presentation gave an overview of where the endocrine disrupting chemical (EDC) issue currently stands in terms of science and policy. It introduced the significant debate about whether suspected EDCs should be evaluated using a hazard-based or a risk-based approach. Subsequent presentations provided a synopsis of the US-EPA Endocrine Disruption Screening Program (EDSP), including a description of the legislative origins of the program, its risk-based nature, its evolution and its future through the input of multi-stakeholder advisory groups. A presentation was given about the current status of potential regulatory activities in the European Union (EU) relative to EDCs and the fact that it is a highly political subject in Europe was highlighted. Finally an EU- industry perspective was given on the repercussions of hazard versus risk-based approaches for EDCs. Both European speakers noted that the regulatory situation in the EU is not set and that at present it is not possible to predict exactly how EDCs will be addressed.

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Introduction to the science and regulation concerning endocrine disrupting chemicals: the challenges ahead

10.7287/peerj.preprints.2583 ◽

2016 ◽

Author(s):

Annegaaike Leopold ◽

Glen Van Der Kraak ◽

Mary K. Manibusan ◽

Niklas Andersson ◽

James R. Wheeler

Keyword(s):

Endocrine Disruption ◽

Screening Program ◽

Endocrine Disrupting Chemicals ◽

Current Status ◽

The European Union ◽

Endocrine Disrupting Chemical ◽

Science And Policy ◽

Advisory Groups ◽

Endocrine Disrupting ◽

Multi Stakeholder

Presentations in session one of the Society of Environmental Toxicology and Chemistry (SETAC) North America Focused Topic Meeting: Endocrine Disruption (February 4 – 6, 2014) described where the science and the regulations have arrived and identified the key challenges that lie ahead. The first presentation gave an overview of where the endocrine disrupting chemical (EDC) issue currently stands in terms of science and policy. It introduced the significant debate about whether suspected EDCs should be evaluated using a hazard-based or a risk-based approach. Subsequent presentations provided a synopsis of the US-EPA Endocrine Disruption Screening Program (EDSP), including a description of the legislative origins of the program, its risk-based nature, its evolution and its future through the input of multi-stakeholder advisory groups. A presentation was given about the current status of potential regulatory activities in the European Union (EU) relative to EDCs and the fact that it is a highly political subject in Europe was highlighted. Finally an EU- industry perspective was given on the repercussions of hazard versus risk-based approaches for EDCs. Both European speakers noted that the regulatory situation in the EU is not set and that at present it is not possible to predict exactly how EDCs will be addressed.

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Epigenetics, Evolution, Endocrine Disruption, Health, and Disease

Endocrinology ◽

10.1210/en.2005-1122 ◽

2006 ◽

Vol 147 (6) ◽

pp. s4-s10 ◽

Cited By ~ 193

Author(s):

David Crews ◽

John A. McLachlan

Keyword(s):

Mental Health ◽

Recent Work ◽

Endocrine Disruption ◽

Endocrine Disrupting Chemicals ◽

Epigenetic Mechanisms ◽

Physical And Mental Health ◽

Risk Levels ◽

Endocrine Disrupting ◽

Increase Risk ◽

Health And Disease

Abstract Endocrine-disrupting chemicals (EDCs) in the environment have been linked to human health and disease. This is particularly evident in compounds that mimic the effects of estrogens. Exposure to EDCs early in life can increase risk levels of compromised physical and mental health. Epigenetic mechanisms have been implicated in this process. Transgenerational consequences of EDC exposure is also discussed in both a proximate (mechanism) and ultimate (evolution) context as well as recent work suggesting how such transmission might become incorporated into the genome and subject to selection. We suggest a perspective for exploring and ultimately coming to understand diseases that may have environmental or endocrine origins.

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Gestational Exposure to Common Endocrine Disrupting Chemicals and Their Impact on Neurodevelopment and Behavior

Annual Review of Physiology ◽

10.1146/annurev-physiol-021119-034555 ◽

2020 ◽

Vol 82 (1) ◽

pp. 177-202 ◽

Cited By ~ 1

Author(s):

Dinushan Nesan ◽

Deborah M. Kurrasch

Keyword(s):

Endocrine Disruption ◽

Polybrominated Diphenyl Ethers ◽

Animal Studies ◽

Endocrine Disrupting Chemicals ◽

Lactational Exposure ◽

Gestational Exposure ◽

Early Life Exposure ◽

Endocrine Disrupting ◽

Physiological Homeostasis ◽

Nervous System Function

Endocrine disrupting chemicals are common in our environment and act on hormone systems and signaling pathways to alter physiological homeostasis. Gestational exposure can disrupt developmental programs, permanently altering tissues with impacts lasting into adulthood. The brain is a critical target for developmental endocrine disruption, resulting in altered neuroendocrine control of hormonal signaling, altered neurotransmitter control of nervous system function, and fundamental changes in behaviors such as learning, memory, and social interactions. Human cohort studies reveal correlations between maternal/fetal exposure to endocrine disruptors and incidence of neurodevelopmental disorders. Here, we summarize the major literature findings of endocrine disruption of neurodevelopment and concomitant changes in behavior by four major endocrine disruptor classes:bisphenol A, polychlorinated biphenyls, organophosphates, and polybrominated diphenyl ethers. We specifically review studies of gestational and/or lactational exposure to understand the effects of early life exposure to these compounds and summarize animal studies that help explain human correlative data.

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Engaging Undergraduates in the Scientific Process: Exploring Invertebrate Endocrine Disruption

The American Biology Teacher ◽

10.1525/abt.2016.78.5.410 ◽

2016 ◽

Vol 78 (5) ◽

pp. 410-416 ◽

Cited By ~ 1

Author(s):

Scott Layton ◽

Jason Belden

Keyword(s):

Endocrine Disruption ◽

Endocrine Disrupting Chemicals ◽

Model Organism ◽

Female Offspring ◽

Reproduction Rate ◽

Interest In Science ◽

Endocrine Disrupting ◽

Set Up ◽

Reproductive Study ◽

Analyze Data

Engaging students in the process of science to increase learning and critical thinking has become a key emphasis in undergraduate education. Introducing environmental topics, such as the effects of endocrine-disrupting chemicals, into undergraduate courses offers a new means to increase student engagement. Daphnia magna can serve as a model organism for endocrine disruption, and its ease of handling, rapid reproduction rate, and clearly defined endpoints make it useful in short-term, student research projects. The concept of endocrine disruption can be tested through a 21-day reproductive study of D. magna exposed to varying concentrations of the pesticide fenoxycarb. Students will observe an altered reproduction rate and increased production of males under conditions that would typically result only in the production of female offspring. This research system allows students to formulate hypotheses, set up experiments, analyze data, and present results, leading to a greater appreciation of and interest in science.

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Hormone-Activated Estrogen Receptors in Annelid Invertebrates: Implications for Evolution and Endocrine Disruption

Endocrinology ◽

10.1210/en.2008-1338 ◽

2008 ◽

Vol 150 (4) ◽

pp. 1731-1738 ◽

Cited By ~ 74

Author(s):

June Keay ◽

Joseph W. Thornton

Keyword(s):

Estrogen Receptors ◽

Endocrine Disruption ◽

Endocrine Disrupting Chemicals ◽

Estrogen Signaling ◽

Estrogen Sensitivity ◽

Endocrine Disrupting ◽

Platynereis Dumerilii ◽

Bilaterian Animal ◽

Capitella Capitata ◽

And Behavior

As the primary mediators of estrogen signaling in vertebrates, estrogen receptors (ERs) play crucial roles in reproduction, development, and behavior. They are also the major mediators of endocrine disruption by xenobiotic pollutants that mimic or block estrogen action. ERs that are sensitive to estrogen and endocrine disrupters have long been thought to be restricted to vertebrates: although there is evidence for estrogen signaling in invertebrates, the only ERs studied to date, from mollusks and cephalochordates, have been insensitive to estrogen and therefore incapable of mediating estrogen signaling or disruption. To determine whether estrogen sensitivity is ancestral or a unique characteristic of vertebrate ERs, we isolated and characterized ERs from two annelids, Platynereis dumerilii and Capitella capitata, because annelids are the sister phylum to mollusks and have been shown to produce and respond to estrogens. Functional assays show that annelid ERs specifically activate transcription in response to low estrogen concentrations and bind estrogen with high affinity. Furthermore, numerous known endocrine-disrupting chemicals activate or antagonize the annelid ER. This is the first report of a hormone-activated invertebrate ER. Our results indicate that estrogen signaling via the ER is as ancient as the ancestral bilaterian animal and corroborate the estrogen sensitivity of the ancestral steroid receptor. They suggest that the taxonomic scope of endocrine disruption by xenoestrogens may be very broad and reveal how functional diversity evolved in a gene family central to animal endocrinology.

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Developing a Laboratory Animal Model for Perinatal Endocrine Disruption: The Hamster Chronicles

Experimental Biology and Medicine ◽

10.1177/153537020222700904 ◽

2002 ◽

Vol 227 (9) ◽

pp. 709-723 ◽

Cited By ~ 18

Author(s):

William J. Hendry ◽

Daniel M. Sheehan ◽

Shafiq A. Khan ◽

Jeffrey V. May

Keyword(s):

Endocrine Disruption ◽

Reproductive Tract ◽

Developmental Toxicity ◽

Endocrine Disrupting Chemicals ◽

Experimental System ◽

Endocrine Disrupting ◽

Considerable Concern ◽

Insight Into ◽

Future Plans

At the biomedical, regulatory, and public level, considerable concern surrounds the concept that inappropriate exposure to endocrine-disrupting chemicals, especially during the prenatal and/or neonatal period, may disrupt normal reproductive tract development and adult function. The intent of this review was to 1. Describe some unique advantages of the hamster for perinatal endocrine disruptor (ED) studies, 2. Summarize the morphological and molecular consequences of exposure to the established perinatal ED, diethylstilbestrol, in the female and male hamster, 3. Present some new, histomorphological insight into the process of neonatal diethylstilbestrol-induced disruption in the hamster uterus, and 4. Introduce recent efforts and future plans to evaluate the potency and mechanism of action of other putative EDs in the hamster experimental system. Taken together, the findings indicate that the hamster represents a unique and sensitive in vivo system to probe the phenomenon of endocrine disruption. The spectrum of candidate endpoints includes developmental toxicity, neoplasia, and more subtle endpoints of reproductive dysfunction.

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Hormonal Confusion

Getting Risk Right ◽

10.7312/columbia/9780231166461.003.0005 ◽

2016 ◽

Author(s):

Geoffrey C. Kabat

Keyword(s):

European Union ◽

Hormone Therapy ◽

Human Health ◽

Endocrine Disruption ◽

Endocrine Disrupting Chemicals ◽

Environmental Exposures ◽

Environmental Estrogens ◽

The European Union ◽

Endocrine Disrupting

In the early 1990s concern emerged that hormonal compounds present in small amounts in food and water – “environmental estrogens” -- could be having subtle effects on human health and wildlife. This concern led to the formulation of the “endocrine-disruption hypothesis,” which has received widespread attention. Over twenty years of research have shown that environmental exposures to these substances is generally minute and are dwarfed by hormonal (phytoestrogenic) compounds in food, as well as by hormone therapy used by some women. Nevertheless, the issue of “endocrine-disrupting chemicals in the environment” is currently under debate within the European Union and elsewhere.

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