Behavioral toxicology in the 21st century: Challenges and opportunities for behavioral scientists: Summary of a symposium presented at the annual meeting of the Neurobehavioral Teratology Society, June, 2009
Introduction
Growing awareness of the disparity between the rate of deployment of new anthropogenic chemicals and assessment of their potential risks to public health prompted the EPA and NIEHS to request advice from the National Research Council on how to address this issue. In response, the NRC convened a Committee on Toxicity Testing and Assessment of Environmental Agents, which reported in January 2007 a “vision and strategy” for “toxicity testing in the 21st century” [67] (http://www.nap.edu/openbook.php?record_id=11970&w=1). In this new paradigm, the current practice of extensive animal-based characterization of chemical hazard, dose–response relationships, and extrapolation to human health is replaced by high-throughput in vitro tests, in silico models and evaluations of efficacy at the human population level.
The new paradigm raises substantial questions regarding the role of toxicologists concerned about the effects of chemicals on the behavior of intact animals. These questions are particularly acute given that one specified goal of the vision is to eliminate the use of whole animals in assessing chemical risk. Certain questions naturally arise about this vision, including:
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What are the implications of this proposed paradigm shift for behavioral toxicology?
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What roles can behavioral toxicology play in this new paradigm?
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What challenges do behavioral toxicologists face in applying their skills and expertise to this paradigm?
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What opportunities are presented by this paradigm shift?
A key component of this vision involves the concept of the “toxicity pathway”, which may be thought of as a biologic process perturbed beyond homeostasis by exposure to a chemical. That is, normal “signaling motifs, genetic circuits, and cellular-response networks” that make up the fundamental biochemical processes of life are presumed to function within a homeostatic range of operating characteristics. In this view, exposure to toxic chemicals perturbs these pathways and, with sufficient perturbation, produces toxicity in the whole organism. Theoretically, then, toxicity can be detected by changes in such pathways using in vitro tests and computational models, thus obviating the need for exposing test animals to substances of unknown biological activity.
This symposium was therefore convened to present these concepts to the community of behavioral toxicologists and teratologists at the annual meeting of the Neurobehavioral Teratology Society, and to encourage discussion of their implications for behavioral toxicology in the twenty-first century. Because of the central role of the toxicity pathway in the testing strategy of the NRC vision, it became the focus of the presentations in this symposium. The concept was introduced by Robert Kavlock, in the context of current efforts in the EPA to identify pathways useful for implementing the NRC vision. Kevin Crofton then described a developmental toxicity pathway based on disruption of thyroid hormone status, and Philip Bushnell followed with a description of potential pathways based on disruption of ion channels in the CNS. Bernard Weiss then raised cautionary flags with a description of the developmental toxicity of phthalate esters, and Deborah Rice discussed concerns about the NRC vision within the current regulatory framework. Finally, after discussion of the pros and cons of the vision, some possible constructive roles for behavioral toxicologists were suggested. The following sections of this report summarize the presentations of each of the speakers in the symposium.
Section snippets
Robert Kavlock: the NRC framework and EPA's ToxCast program
The NRC vision proposes an approach to toxicity testing based upon the idea that exposure to a toxic chemical activates one or more toxicity pathways in the organism (Fig. 1). A toxicity pathway may be considered to arise from perturbation of a sequence of inherent biological processes that generate normal biological functions. In this concept, exposure to a toxicant causes early cellular changes that induce a deviation from normal output of the pathway. Of course, exposure leads to an internal
Kevin Crofton: a thyroid hormone-mediated developmental neurotoxicity pathway
The toxicity pathway approach to toxicity testing is derived from the concept of mode of action, which can be defined as the sequence of key cellular and biochemical events initiated by the chemical that result in an adverse health outcome [10], [74]. The toxicity pathway concept [67] is a subset of the mode of action that consists of the alterations in the normal biological signaling pathway that is perturbed by the action of the chemical at the key initiating event. In either case, the events
Philip Bushnell: an ion channel-mediated toxicity pathway for acute neurotoxicity
The nervous system comprises a vast and highly complex network of signaling pathways that control the physiology and behavior of multi-cellular animals, and ion channels make up a major functional component of these pathways. Ion channels control the electrical polarity of neural membranes, propagation of signals along axons, release of neurotransmitters at presynaptic junctions, and mediaton of important aspects of the response of the postsynaptic membrane to neurotransmitter release.
Bernard Weiss: developmental toxicity of phthalates: a flaw in the vision
The 2007 NRC report, Toxicity Testing in the 21st Century: A Vision and a Strategy [22] envisions a future for toxicology in which the predominant mode of assessing potential toxicity rests on a massive number of in vitro assays surveying hundreds of metabolic pathways, on pharmacokinetic modeling, and on computational toxicology. It proposes such a scheme as a response to the difficulties of practicing toxicology as it is currently practiced while confronted by tens of thousands of
Deborah Rice: risk assessment implications of the NRC vision
The NRC strategy involves a series of actions that are logical scientifically, including (a) identifying pathways leading to toxic responses and associated biomarkers, (b) determining in vitro concentrations of chemicals that produce adverse effects, and (c) linking these in vitro concentrations to concentrations in humans determined through biomonitoring studies. Conceptually at least, once a pathway has been validated – that is, when effects at molecular targets are causally linked to adverse
Discussion
Two points should be clear from these presentations: 1) traditional toxicology cannot address the potential hazard of the overwhelming number of new anthropogenic chemicals in the environment, and 2) there is at present no other way to proceed. Therefore, the NRC proposed a drastically new approach, designed to address the fundamental problem posed by the daunting array of potential toxicants that, if successful, will require years of effort to bring to fruition.
Implementing the NRC goal faces
Opportunities and challenges for behavioral toxicologists in the 21st century
Given these challenges to implementing the NRC vision, behavioral toxicologists will continue to make important contributions risk assessment for the foreseeable future in at least two ways. First, they can continue along the traditional path by implementing studies in animals designed to address basic risk assessment issues, including studies of dose–effect relationships, susceptibility and extrapolation. Second, they can play a number of crucial roles in implementing the NRC vision. These
Conflict of interest statement
The authors assert an absence of conflicts of interest regarding this research.
Disclaimer: This manuscript has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency and approved for publication. Approval does not indicate that the contents reflect the views of the Agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use.
Acknowledgements
The organizers thank the Behavioral Toxicology Society for generous travel support and the Neurobehavioral Teratology Society for the opportunity to present this symposium. We also thank Drs. Ed Levin and William Mundy for reviews of a draft of this report. Dr. Weiss was supported in part by NIEHS grants ES013247 and ES015509 to B. Weiss and Center grant ES01247.
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