Available online at www.sciencedirect.com
ScienceDirect Editorial overview: Endocrine and metabolic diseases: Conversations on endocrine disruptors — rising above the din Scott M Belcher Current Opinion in Pharmacology 2014, 19:vi–vii For a complete overview see the Issue http://dx.doi.org/10.1016/j.coph.2014.10.003 1471-4892/# 2014 Elsevier Ltd. All right reserved.
Scott M Belcher Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH, USA e-mail: [email protected] Scott Belcher is professor of Pharmacology and Cell Biophysics in the College of Medicine at the University of Cincinnati. His research interests center around understanding the molecular, cellular, and physiological mechanisms that regulate the developmental actions of endogenous estrogens and endocrine disruptors in the heart and brain. Current research is primarily focused on mechanisms involving estrogen receptor beta action that influence cardiac pathology and estrogen-responsive growth of childhood brain tumors.
Endocrine disruptors are defined as compounds that alter the endocrine system and result in adverse or harmful effects. Ongoing attempts to address whether or not unintended exposures to specific environmental endocrine activity compounds are harmful have been an area of great interest across many traditional disciplines of biomedical research. The translation of this research into improved public health practices has been a topic of controversy that has been most intensely focused at a crossroads between the disciplines of endocrinology and toxicology [1,2]. The foundations of this section of Current Opinion in Pharmacology were set from conversations held at the International Workshop on Low Dose Effects and Non-monotonic Dose Responses for Endocrine Active Chemicals: Science to Practice [3], where it became apparent that there where discipline-specific gaps in fundamental understanding that hindered efficient interactions between basic and clinical scientists who are assessing the physiological and pharmacological basis of environmental endocrine action, and those translating this knowledge into improved public health. Most surprising was the fact that major impediments existed because of failures to communicate foundational principles across disciplines. Concepts such as mechanism, dose response, harm, or adaptation, for example, when used by a pharmacologist, toxicologist, evolutionary ecologist, or risk assessor, simply do not have the same meaning. The collection of reviews presented here are intended to provide crosscutting overviews and updates on some key concepts related to endocrine active compounds to which humans and non-human species are exposed, the sources of exposure, and the mechanistic basis of their actions. One of the key areas of cross-disciplinary controversy related to endocrine disruptors revolves around non-monotonic concentration response relationships and the nature of the contributing molecular mechanisms. The review by Cookman and Belcher (handled by Editor David G. Trist), ‘Classical nuclear hormone receptor activity as a mediator of complex concentration response relationships for endocrine active compounds’, highlights fundamental concepts of nuclear receptor mechanisms of action, and how multiple ligand binding sites influence nuclear receptor activities contribute to the complex dose response relationships of EDCs. The review by Kortenkamp, ‘Low dose mixture effects of endocrine disrupters and their implications for regulatory thresholds in chemical risk assessment’, looks more deeply into complex dose response relationships, by tackling the real-world complexity of how mixtures of multiple endocrine disruptive chemicals can interact to
Current Opinion in Pharmacology 2014, 19:vi–vii
www.sciencedirect.com
Editorial overview Belcher vii
have harmful effects. These interactions emphase clearly that better understanding of risks from exposures require better assessment of even very low levels of exposure that in isolation would not be expected to cause harmful outcomes. Concepts surrounding the intimate relationship between exposure and mechanism are expanded further in the review by Dishaw et al., ‘Exposures, mechanisms, and impacts of endocrine-active flame retardants’. This review highlights the important contribution of exposure science in identifying new chemicals that may be acting as endocrine disruptors. Focusing on flame retardants replacements of the persistent organic pollutant polybrominated diphenyl ethers (PBDEs), Dishaw et al. discuss the current understanding of how the use of replacement additive flame retardants has resulted in widespread human exposure and highlights new evidence indicating that these replacements may also act as endocrine disruptors. Focusing on the diverse nature of the effects of EDCs outside of traditional impacts on reproductive tissues, the review by Bell, ‘Endocrine-disrupting actions of PCBs on brain development and social and reproductive behaviors’, brings the developmental neuroscience perspective to the fore. Here the critical links between early developmental exposures to environmental compounds and their impacts of the structure and function of the nervous system and modification of complex behaviors is discussed. Human population based studies have also increasingly contributed to the discussion on potential harm related to EDC exposures. In the review ‘Endocrine Disruptive compounds and cardio-metabolic risk factors in children’, Khalil et al. take a closer look at evidence for chemical exposures that might be contributing to obesity and associated morbidities. Chamorro-Garcı´a and Blumberg address the emerging understanding related to how environmental exposures may influence physiology for multiple generations after exposure occurred in transgenerational effects of obesogens and the obesity epidemic. Shifting toward new approaches for hazards characterization and the increasing importance of computational approaches for toxicity testing, Thayer and colleagues
www.sciencedirect.com
take us on a ride into the future of 21st century approaches for toxicity testing in ‘Test driving ToxCast: endocrine profiling for 1858 chemicals included in phase II’. This brief review serves as an introduction into one approach geared toward utilizing publically available information resulting from the EPA’s high through put chemical screening and computational programs. ‘Bridging the gap between academic research and regulatory health risk assessment of Endocrine Disrupting Chemicals’ by Beronius et al., serves as a conduit between the academic researcher, the process of regulatory health risk assessment, and the translation of academic science into policy. Through better understanding of the current regulatory process, and with guidance on how to design and present basic hypothesis driven studies, findings of academic research will more efficiently integrate into the regulator decision-making process. While obstacles will remain, it is with hope that this volume serves to enhance communication across the diverse parties representing multiple disciplines of basic and applied science, as well as government and public stakeholders. I am especially grateful for the diligent effort of the many colleagues that contributed, either as authors, or as reviewers, and would like to extend special thanks to Editor Dr. David G. Trist for his valuable assistance.
References 1.
Gore AC, Balthazart J, Bikle D, Carpenter DO, Crews D, Czernichow P, Diamanti-Kandarakis E, Dores RM, Grattan D, Hof PR, Hollenberg AN, Lange C, Lee AV, Levine JE, Millar RP, Nelson RJ, Porta M, Poth M, Power DM, Prins GS, Ridgway EC, Rissman EF, Romijn JA, Sawchenko PE, Sly PD, So¨der O, Taylor HS, Tena-Sempere M, Vaudry H, Wallen K, Wang Z, Wartofsky L, Watson CS: Policy decisions on endocrine disruptors should be based on science across disciplines: a response to Dietrich et al.. Endocrinology 2013, 154:3957-3960.
2.
Dietrich DR, Aulock Sv, Marquardt H, Blaauboer B, Dekant W, Kehrer J, Hengstler J, Collier A, Gori GB, Pelkonen O, Lang F, Barile FA, Nijkamp FP, Stemmer K, Li A, Savolainen K, Hayes AW, Gooderham N, Harvey A: Scientifically unfounded precaution drives European Commission’s recommendations on EDC regulation, while defying common sense, well-established science and risk assessment principles. Chemico-Biol Interact 2013, 205:A1-A5.
3.
Beausoleil C, Ormsby J-N, Gies A, Hass U, Heindel JJ, Holmer ML, Nielsen PJ, Munn S, Schoenfelder G: Low dose effects and nonmonotonic dose responses for endocrine active chemicals: science to practice workshop: workshop summary. Chemosphere 2013, 93:847-856.
Current Opinion in Pharmacology 2014, 19:vi–vii
ScienceDirect Editorial overview: Endocrine and metabolic diseases: Conversations on endocrine disruptors — rising above the din Scott M Belcher Current Opinion in Pharmacology 2014, 19:vi–vii For a complete overview see the Issue http://dx.doi.org/10.1016/j.coph.2014.10.003 1471-4892/# 2014 Elsevier Ltd. All right reserved.
Scott M Belcher Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH, USA e-mail: [email protected] Scott Belcher is professor of Pharmacology and Cell Biophysics in the College of Medicine at the University of Cincinnati. His research interests center around understanding the molecular, cellular, and physiological mechanisms that regulate the developmental actions of endogenous estrogens and endocrine disruptors in the heart and brain. Current research is primarily focused on mechanisms involving estrogen receptor beta action that influence cardiac pathology and estrogen-responsive growth of childhood brain tumors.
Endocrine disruptors are defined as compounds that alter the endocrine system and result in adverse or harmful effects. Ongoing attempts to address whether or not unintended exposures to specific environmental endocrine activity compounds are harmful have been an area of great interest across many traditional disciplines of biomedical research. The translation of this research into improved public health practices has been a topic of controversy that has been most intensely focused at a crossroads between the disciplines of endocrinology and toxicology [1,2]. The foundations of this section of Current Opinion in Pharmacology were set from conversations held at the International Workshop on Low Dose Effects and Non-monotonic Dose Responses for Endocrine Active Chemicals: Science to Practice [3], where it became apparent that there where discipline-specific gaps in fundamental understanding that hindered efficient interactions between basic and clinical scientists who are assessing the physiological and pharmacological basis of environmental endocrine action, and those translating this knowledge into improved public health. Most surprising was the fact that major impediments existed because of failures to communicate foundational principles across disciplines. Concepts such as mechanism, dose response, harm, or adaptation, for example, when used by a pharmacologist, toxicologist, evolutionary ecologist, or risk assessor, simply do not have the same meaning. The collection of reviews presented here are intended to provide crosscutting overviews and updates on some key concepts related to endocrine active compounds to which humans and non-human species are exposed, the sources of exposure, and the mechanistic basis of their actions. One of the key areas of cross-disciplinary controversy related to endocrine disruptors revolves around non-monotonic concentration response relationships and the nature of the contributing molecular mechanisms. The review by Cookman and Belcher (handled by Editor David G. Trist), ‘Classical nuclear hormone receptor activity as a mediator of complex concentration response relationships for endocrine active compounds’, highlights fundamental concepts of nuclear receptor mechanisms of action, and how multiple ligand binding sites influence nuclear receptor activities contribute to the complex dose response relationships of EDCs. The review by Kortenkamp, ‘Low dose mixture effects of endocrine disrupters and their implications for regulatory thresholds in chemical risk assessment’, looks more deeply into complex dose response relationships, by tackling the real-world complexity of how mixtures of multiple endocrine disruptive chemicals can interact to
Current Opinion in Pharmacology 2014, 19:vi–vii
www.sciencedirect.com
Editorial overview Belcher vii
have harmful effects. These interactions emphase clearly that better understanding of risks from exposures require better assessment of even very low levels of exposure that in isolation would not be expected to cause harmful outcomes. Concepts surrounding the intimate relationship between exposure and mechanism are expanded further in the review by Dishaw et al., ‘Exposures, mechanisms, and impacts of endocrine-active flame retardants’. This review highlights the important contribution of exposure science in identifying new chemicals that may be acting as endocrine disruptors. Focusing on flame retardants replacements of the persistent organic pollutant polybrominated diphenyl ethers (PBDEs), Dishaw et al. discuss the current understanding of how the use of replacement additive flame retardants has resulted in widespread human exposure and highlights new evidence indicating that these replacements may also act as endocrine disruptors. Focusing on the diverse nature of the effects of EDCs outside of traditional impacts on reproductive tissues, the review by Bell, ‘Endocrine-disrupting actions of PCBs on brain development and social and reproductive behaviors’, brings the developmental neuroscience perspective to the fore. Here the critical links between early developmental exposures to environmental compounds and their impacts of the structure and function of the nervous system and modification of complex behaviors is discussed. Human population based studies have also increasingly contributed to the discussion on potential harm related to EDC exposures. In the review ‘Endocrine Disruptive compounds and cardio-metabolic risk factors in children’, Khalil et al. take a closer look at evidence for chemical exposures that might be contributing to obesity and associated morbidities. Chamorro-Garcı´a and Blumberg address the emerging understanding related to how environmental exposures may influence physiology for multiple generations after exposure occurred in transgenerational effects of obesogens and the obesity epidemic. Shifting toward new approaches for hazards characterization and the increasing importance of computational approaches for toxicity testing, Thayer and colleagues
www.sciencedirect.com
take us on a ride into the future of 21st century approaches for toxicity testing in ‘Test driving ToxCast: endocrine profiling for 1858 chemicals included in phase II’. This brief review serves as an introduction into one approach geared toward utilizing publically available information resulting from the EPA’s high through put chemical screening and computational programs. ‘Bridging the gap between academic research and regulatory health risk assessment of Endocrine Disrupting Chemicals’ by Beronius et al., serves as a conduit between the academic researcher, the process of regulatory health risk assessment, and the translation of academic science into policy. Through better understanding of the current regulatory process, and with guidance on how to design and present basic hypothesis driven studies, findings of academic research will more efficiently integrate into the regulator decision-making process. While obstacles will remain, it is with hope that this volume serves to enhance communication across the diverse parties representing multiple disciplines of basic and applied science, as well as government and public stakeholders. I am especially grateful for the diligent effort of the many colleagues that contributed, either as authors, or as reviewers, and would like to extend special thanks to Editor Dr. David G. Trist for his valuable assistance.
References 1.
Gore AC, Balthazart J, Bikle D, Carpenter DO, Crews D, Czernichow P, Diamanti-Kandarakis E, Dores RM, Grattan D, Hof PR, Hollenberg AN, Lange C, Lee AV, Levine JE, Millar RP, Nelson RJ, Porta M, Poth M, Power DM, Prins GS, Ridgway EC, Rissman EF, Romijn JA, Sawchenko PE, Sly PD, So¨der O, Taylor HS, Tena-Sempere M, Vaudry H, Wallen K, Wang Z, Wartofsky L, Watson CS: Policy decisions on endocrine disruptors should be based on science across disciplines: a response to Dietrich et al.. Endocrinology 2013, 154:3957-3960.
2.
Dietrich DR, Aulock Sv, Marquardt H, Blaauboer B, Dekant W, Kehrer J, Hengstler J, Collier A, Gori GB, Pelkonen O, Lang F, Barile FA, Nijkamp FP, Stemmer K, Li A, Savolainen K, Hayes AW, Gooderham N, Harvey A: Scientifically unfounded precaution drives European Commission’s recommendations on EDC regulation, while defying common sense, well-established science and risk assessment principles. Chemico-Biol Interact 2013, 205:A1-A5.
3.
Beausoleil C, Ormsby J-N, Gies A, Hass U, Heindel JJ, Holmer ML, Nielsen PJ, Munn S, Schoenfelder G: Low dose effects and nonmonotonic dose responses for endocrine active chemicals: science to practice workshop: workshop summary. Chemosphere 2013, 93:847-856.
Current Opinion in Pharmacology 2014, 19:vi–vii
