Correspondence Comment on “Lessons from Endocrine Disruption and Their Application to Other Issues Concerning Trace Organics in the Aquatic Environment” In a highly stimulating review, Sumpter and Johnson (1) presented 10 lessons summarizing the major messages that have been learned in their opinion from the research on endocrine disruption (ED) in wildlife. Several of the points raised by the authors address surprises, such as unusual field observations, while other lessons address specific observations on the toxic action of endocrine-disrupting chemicals (EDCs), such as chronic and low dose activity, additive behavior in mixtures, or life stage-specific effects. The finding that structurally diverse chemicals display commonalities in their biological effects becomes understandable only when recognizing that they share common mechanisms, i.e., interaction with specific molecules (e.g., hormone receptors) or processes (e.g., hormone synthesis) of the endocrine system. Similarly, the fact that the “unusual field observations in wildlife populations” (1) are not isolated cases but examples of one and the same problem becomes understandable only when recognizing that the commonality in these cases is the disturbance of the endocrine system. Thus, it is the mechanism or mode of action (in the context of this comment, I use the two terms synonymously)sand not, e.g., chemistryswhich is key to the ED issue. Although several of the lessons by Sumpter and Johnson (1) refer to ED mechanisms, I feel that the importance of mechanistic knowledge in the ED issue asks for a lesson on its own:
Lesson 11: Ecotoxicological Effect and Risk Assessment Needs Information on Mechanisms and Toxicity Pathways ED illustrates how mechanism-related information supports understanding, diagnosis, classification, and prediction of chemical toxicity. For example, knowing that a chemical acts through an endocrine mechanism explains why it may result in a U-shaped concentration-response curve, since hormones can act differently at low and high doses. Knowing that a chemical acts through an endocrine mechanism explains why it may evoke life stage-specific effects, since hormones can induce irreversible organizational effects during development, and reversible activational effects at the differentiated stage (2). Knowing that a chemical acts through an endocrine mechanism identifies potential targets of chemical toxicity since hormones have pleiotropic effects in multiple organs and act in homeostatic feedback loops (e.g., 3). Knowing that a chemical acts through an endocrine mechanism enables assessment of its behavior in mixtures, as compounds acting through the same primary target, e.g., estrogen receptors, show additivity (4). Finally, mechanistic knowledge is the basis for the rational development of biomarkers to diagnose whether animals are impacted by EDCs. Mechanism-related information is not only relevant for diagnostic but also for predictive hazard and risk assessment. The crucial point in this context has been raised by Sumpter and Johnson (1) who pointed out that EDC effects on wildlife had been not predicted by conventional risk assessment. 1084
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This failure is at least partly due to the absence of mechanismrelated endpoints in the existing testing procedures. In regulatory hazard testing for ecotoxicological risk assessment, we rely on tiered strategies, starting with comparatively simple toxicological information and going to more in-depth information at higher tiers. The toxicological endpoints measured are apical parameters such as survival, growth, and reproduction, since they relate to vital rates and therefore are of potential ecological relevance. However, apical endpoints inform on only a part of a chemical’s toxicity, and inclusion of mechanism-related endpoints helps to reveal the multiple toxicity profile of a chemical, which may point to ecologically relevant functions at risk, particularly for environmentally relevant scenarios such as low-dose, chronic exposure. One may argue that, e.g., the chronic reproductive effect of an estrogenic chemical would be detected by life cycle tests even without knowing that this chemical acts through an endocrine-disrupting pathway. The argument, however, does not fully apply since chronic or life cycle toxicity tests are performed for a rather limited number of substances only. By including mechanism-related endpoints at an early stage of testing, priorities could be set for further hazard evaluation, and, instead of executing the standard testing routine, a knowledge-based testing scheme could be applied, in which decision criteria would be production volume (exposure information) plus mechanism-related test parameters on the experimentally or computationally determined ability of the compound to activate a specific toxicity pathway (hazard information) (6). The ED case indicated the value of mechanism-related information for two further areas of predictive risk assessment: interspecies extrapolation and predictive toxicity models. To extrapolate effect thresholds determined in selected laboratory species to wildlife communities, we use approaches such as application factors or species sensitivity distributions (5, 7). Sumpter and Johnson (1) already discussed, in their lesson 3, that when a chemical acts through the estrogen receptor, its endocrine activity can be well extrapolated across all vertebrates (since for them the presence and function of an estrogen-receptor is shown), but not necessarily to invertebrates for which presence and function of estrogen receptors is uncertain. Thus, the mechanistic knowledge helps to define animal groups for which effect extrapolation is applicable or not, and it may also help to predict how close or distant effect concentrations will be among species, so that application factors could be varied with the mode of action of a chemical (7). Mechanismrelated knowledge has the further potential to support the development of predictive models of toxicity. To date, quantitative structure-activity relationships (QSARs) are frequently employed to predict toxic effects of untested chemicals. QSARs describe relationships between structural and/or physicochemical properties of chemicals and toxic effects and these QSARs are assigned a posteriori an underlying “mode of toxic action” (8). In the case of EDCs, where we have a priori mechanistic information on the initial steps of their biological action, establishment of activityactivity relationships may become possible, e.g., the prediction of a reproductive effect of a chemical from its ability to bind to the estrogen receptor. ED highlighted the importance of mechanism-related knowledge in retrospective and causative diagnosis, prediction of biological and ecological functions at risk, and the related classification of chemicals. ED is not the first, only, 10.1021/es051791d CCC: $33.50
2006 American Chemical Society Published on Web 12/27/2005
and unique example but it provides a particularly clear case. Promisingly, current activities at the OECD aim to include mechanism-related endpoints into regulatory hazard evaluation.
Literature Cited (1) Sumpter, J. P.; Johnson, A. C. Lessons learned from endocrine disruption and their application to other issues concerning trace organics in the aquatic environment. Environ. Sci. Technol. 2005, 39, 4321-4332. (2) Guillette, J. L. J.; Crain, D. A.: Ronney, A. A.; Pickford, D. B. Organisation versus activation: The role of endocrinedisrupting contaminants (EDCs) during embryonic development in wildlife. Environ. Health Perspect. 1995, 103 (Suppl) 7, 157-164. (3) Khan, I. A.; Mathews, S.; Okuzawa, K.; Kagawa, H.; Thomas, P. Alterations in the GnRH-LH system in relation to gonadal stage after Aroclor 1254 exposure in Atlantic croker. Comp. Biochem. Physiol. 2001, 129B, 251-259. (4) Silva, E.; Rajapakse, N.; Kortenkamp, A. Something from “nothing” - eight weak estrogenic chemicals combined at concentrations below NOECs produce significant mixture effects. Environ. Sci. Technol. 2002, 36, 1751-1756.
(5) Bradbury, S. P.; Feijtel, T. C. J.; van Leeuwen, C. J. Meeting the scientific needs of ecological risk assessment in a regulatory context. Environ. Sci. Technol. 2004, 38, 463A-470A. (6) Hutchinson, T. H.; Ankley, G. T.; Segner, H.; Tyler, C. R. Screening and testing for endocrine disruption in fish biomarkers as signposts not traffic lights in risk assessment. Environ. Health Perspect. (in press) doi:10.1289/ehp.8062. (7) de Wolf, W.; Siebel-Sauer, A.; Lecloux, A.; Koch, V.; Holt, M.; Feijtel, T.; Comber, M.; Boeije, G. Mode of action and aquatic toxicity thresholds of no concern. Environ. Toxicol. Chem. 2005, 24, 479-485. (8) Escher, B. I.; Hermens, J. L. M. Modes of action in ecotoxicology: their role in body burdens, species sensitivity, QSARS, and mixture effects. Environ. Sci. Technol. 2002, 36, 42014217.
Helmut Segner Centre for Fish and Wildlife Health University of Bern P.O. Box 8466, CH-3001 Bern, Switzerland ES051791D
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