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Assessing the risk of exposures to endocrine disrupting chemicals
Chemosphere 93 (2013) 845–846
Contents lists available at SciVerse ScienceDirect
Chemosphere journal homepage: www.elsevier.com/locate/chemosphere
Editorial
Assessing the risk of exposures to endocrine disrupting chemicals q
The risk assessment process has been guided by principles of toxicology since it was developed some 50 years ago. These principles posit that toxicity decreases with decreasing doses. Thus, toxicity studies typically test chemicals starting at high doses and proceeding to progressively lower doses aiming to identify a dose at which no adverse effects are observed and extrapolating to predicted safe doses using additional factors to account for uncertainties in the accuracy of the animal model and test conditions. Thus the predicted safe dose is calculated but not tested. Over the last twenty years or so scientists have developed data showing that certain chemicals that disrupt endocrine signaling, e.g. endocrine disrupting Chemicals (EDCs), can act at low doses (in the range of low level environmentally relevant human exposures) in animal studies, and may show dose responses where the slope of the response changes direction i.e. non-monotonic dose responses (NMDR). If this scenario is true, the assumption that lower levels are safer may not be always correct. Recently a comprehensive review of the evidence for ‘‘low dose responses’’ and NMDR for EDCs was published (Vandenberg et al., 2012), which concluded that ‘‘nonmonotonic responses and low dose effects are remarkably common in studies of natural hormones and EDCs’’ and therefore ‘‘fundamental changes in chemical testing and safety determination are needed to protect human health’’. To further consider the data and conclusions of Vandenberg’s review, a workshop, ‘‘Low Dose Effects and Non-monotonic Dose Responses for Endocrine Active Chemicals: Science to Practice’’ was held in Berlin, September 11–13, 2012. A report from this workshop is included in this issue. The goal of the workshop was to bring scientists/risk assessors from regulatory agencies, academia and industry together for an open discussion of the issues and possible solutions. Workshop attendees examined the data supporting the ‘‘low dose paradigm’’ for endocrine active substances focusing separately on data supporting low dose effects from evidence for NMDR and the further research needs required to move closer to scientific agreement. Changes which might be required to incorporate ‘‘low dose response’’ and NMDR considerations into toxicity testing and risk assessment also formed a major part of the discussions. This workshop was successful in many aspects including bringing about 200 scientists together for three days of lectures and open discussion. While no consensus was expected nor reached, there were many signs of progress including a commitment to continue to foster interdisciplinary discussions
q JH is an employee of the NIEHS/NIH, any statements, opinions or conclusions contained herein do not necessarily represent the opinions, statements or conclusions of NIEHS, NIH or the US Government.
0045-6535/$ - see front matter Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.chemosphere.2013.07.007
among toxicologists, endocrinologists and epidemiologists from regulatory agencies, academia and industry. Although the strength of evidence supporting ‘‘low dose responses’’ and NMDRs varied across the attendees from ‘‘strong’’ to ‘‘it is only a hypothesis’’, as indicated from polling results at the workshop, over 90% of the attendees, accepted (based on polling results) that NMDR is different from ‘‘low dose responses’’, and could generally agree that NMDRs may exist at some range. There were also many practical proposals for further work over the next five years and beyond to move forward the debate including: To make practical assessments of what fits the definition of adverse effects since it was clear that there is a lack of agreement on the type of effects considered adverse. To investigate to what extent current study protocols identify NMDR and to what extent evaluations may overlook NMDRs because of default assumptions of monotonicity. To consider additional endpoints for guideline studies to better assess types of disruption of the endocrine system leading to disease and dysfunction, including identification of windows of sensitivity to endocrine disruption. To develop a consensus on the definition of low dose and how and when to include ‘‘low doses’’ in the design of toxicology studies. To develop guidance for academic researchers on minimum information requirements needed for publication in the open literature so their data would be more useful for risk assessors. It was suggested that such activities could be facilitated by a knowledge base of findings showing NMDR and low dose effects which may include raw data for analysis including guidance on appropriate statistical analysis to identify NMDRs. The mechanism for delivering on these proposals could be via a series of workshops, literature reviews and/or by setting up a number of task forces of academic, regulatory and industry scientists to develop consensus recommendations and guidance documents. We are now at a critical junction. The Berlin workshop showed that there can be open and frank discussion of the issues, it also indicated that there are still many aspects to be clarified. The long term legacy of this workshop is now in the hands of all the stakeholders including risk assessors from regulatory agencies as well as researchers from industry and academia. Can the momentum be maintained by implementation of the recommendations for further workshops and reviews over the next few years? Can all stakeholders work together to develop the needed data as well as agree on the consequent changes to toxicity testing and risk assessment
846
Editorial / Chemosphere 93 (2013) 845–846
methodology which may emerge? The Berlin workshop has provided the basis for a path forward. It is up to all stakeholders to continue working together to resolve and gain agreement on the fundamental issues. Reference Vandenberg, L.N., Colborn, T., Hayes, T.B., Heindel, J.J., Jacobs Jr., D.R., Lee, D.H., Shioda, T., Soto, A.M., vom Saal, F.S., Welshons, W.V., Zoeller, R.T., Myers, J.P., 2012. Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. Endocr. Rev. 33, 378–455.
Sharon Munn Joint Research Centre, European Commission, Ispra, Italy E-mail address: [email protected] Jerrold Heindel National Institute of Environmental Health Sciences/NIH, Research Triangle Park, NC, USA E-mail address: [email protected] Available online 1 August 2013
Contents lists available at SciVerse ScienceDirect
Chemosphere journal homepage: www.elsevier.com/locate/chemosphere
Editorial
Assessing the risk of exposures to endocrine disrupting chemicals q
The risk assessment process has been guided by principles of toxicology since it was developed some 50 years ago. These principles posit that toxicity decreases with decreasing doses. Thus, toxicity studies typically test chemicals starting at high doses and proceeding to progressively lower doses aiming to identify a dose at which no adverse effects are observed and extrapolating to predicted safe doses using additional factors to account for uncertainties in the accuracy of the animal model and test conditions. Thus the predicted safe dose is calculated but not tested. Over the last twenty years or so scientists have developed data showing that certain chemicals that disrupt endocrine signaling, e.g. endocrine disrupting Chemicals (EDCs), can act at low doses (in the range of low level environmentally relevant human exposures) in animal studies, and may show dose responses where the slope of the response changes direction i.e. non-monotonic dose responses (NMDR). If this scenario is true, the assumption that lower levels are safer may not be always correct. Recently a comprehensive review of the evidence for ‘‘low dose responses’’ and NMDR for EDCs was published (Vandenberg et al., 2012), which concluded that ‘‘nonmonotonic responses and low dose effects are remarkably common in studies of natural hormones and EDCs’’ and therefore ‘‘fundamental changes in chemical testing and safety determination are needed to protect human health’’. To further consider the data and conclusions of Vandenberg’s review, a workshop, ‘‘Low Dose Effects and Non-monotonic Dose Responses for Endocrine Active Chemicals: Science to Practice’’ was held in Berlin, September 11–13, 2012. A report from this workshop is included in this issue. The goal of the workshop was to bring scientists/risk assessors from regulatory agencies, academia and industry together for an open discussion of the issues and possible solutions. Workshop attendees examined the data supporting the ‘‘low dose paradigm’’ for endocrine active substances focusing separately on data supporting low dose effects from evidence for NMDR and the further research needs required to move closer to scientific agreement. Changes which might be required to incorporate ‘‘low dose response’’ and NMDR considerations into toxicity testing and risk assessment also formed a major part of the discussions. This workshop was successful in many aspects including bringing about 200 scientists together for three days of lectures and open discussion. While no consensus was expected nor reached, there were many signs of progress including a commitment to continue to foster interdisciplinary discussions
q JH is an employee of the NIEHS/NIH, any statements, opinions or conclusions contained herein do not necessarily represent the opinions, statements or conclusions of NIEHS, NIH or the US Government.
0045-6535/$ - see front matter Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.chemosphere.2013.07.007
among toxicologists, endocrinologists and epidemiologists from regulatory agencies, academia and industry. Although the strength of evidence supporting ‘‘low dose responses’’ and NMDRs varied across the attendees from ‘‘strong’’ to ‘‘it is only a hypothesis’’, as indicated from polling results at the workshop, over 90% of the attendees, accepted (based on polling results) that NMDR is different from ‘‘low dose responses’’, and could generally agree that NMDRs may exist at some range. There were also many practical proposals for further work over the next five years and beyond to move forward the debate including: To make practical assessments of what fits the definition of adverse effects since it was clear that there is a lack of agreement on the type of effects considered adverse. To investigate to what extent current study protocols identify NMDR and to what extent evaluations may overlook NMDRs because of default assumptions of monotonicity. To consider additional endpoints for guideline studies to better assess types of disruption of the endocrine system leading to disease and dysfunction, including identification of windows of sensitivity to endocrine disruption. To develop a consensus on the definition of low dose and how and when to include ‘‘low doses’’ in the design of toxicology studies. To develop guidance for academic researchers on minimum information requirements needed for publication in the open literature so their data would be more useful for risk assessors. It was suggested that such activities could be facilitated by a knowledge base of findings showing NMDR and low dose effects which may include raw data for analysis including guidance on appropriate statistical analysis to identify NMDRs. The mechanism for delivering on these proposals could be via a series of workshops, literature reviews and/or by setting up a number of task forces of academic, regulatory and industry scientists to develop consensus recommendations and guidance documents. We are now at a critical junction. The Berlin workshop showed that there can be open and frank discussion of the issues, it also indicated that there are still many aspects to be clarified. The long term legacy of this workshop is now in the hands of all the stakeholders including risk assessors from regulatory agencies as well as researchers from industry and academia. Can the momentum be maintained by implementation of the recommendations for further workshops and reviews over the next few years? Can all stakeholders work together to develop the needed data as well as agree on the consequent changes to toxicity testing and risk assessment
846
Editorial / Chemosphere 93 (2013) 845–846
methodology which may emerge? The Berlin workshop has provided the basis for a path forward. It is up to all stakeholders to continue working together to resolve and gain agreement on the fundamental issues. Reference Vandenberg, L.N., Colborn, T., Hayes, T.B., Heindel, J.J., Jacobs Jr., D.R., Lee, D.H., Shioda, T., Soto, A.M., vom Saal, F.S., Welshons, W.V., Zoeller, R.T., Myers, J.P., 2012. Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. Endocr. Rev. 33, 378–455.
Sharon Munn Joint Research Centre, European Commission, Ispra, Italy E-mail address: [email protected] Jerrold Heindel National Institute of Environmental Health Sciences/NIH, Research Triangle Park, NC, USA E-mail address: [email protected] Available online 1 August 2013