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Tracey J. Woodruff,¹ Lauren Zeise,² Daniel A. Axelrad,³ Kathryn Z. Guyton,⁴ Sarah Janssen,^5,6 Mark Miller,^2,7 Gregory G. Miller,³ Jackie M. Schwartz,¹ George Alexeeff,² Henry Anderson,⁸ Linda Birnbaum,⁹ Frederic Bois,¹⁰ Vincent James Cogliano,¹¹ Kevin Crofton,⁹ Susan Y. Euling,⁴ Paul M.D. Foster,¹² Dori R. Germolec,¹² Earl Gray,⁹ Dale B. Hattis,¹³ Amy D. Kyle,¹⁴ Robert W. Luebke,⁹ Michael I. Luster,¹⁵ Chris Portier,¹² Deborah C. Rice,¹⁶ Gina Solomon,⁵ John Vandenberg,⁴ and R. Thomas Zoeller¹⁷

¹Program on Reproductive Health and the Environment, Department of Obstetrics and Gynecology, University of California, San Francisco, San Francisco, California, USA; ²Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Oakland, California, USA; ³Office of Policy, Economics and Innovation, and ⁴National Center for Environmental Assessment, U.S. Environmental Protection Agency, Washington, DC, USA; ⁵Department of Medicine, University of California, San Francisco, San Francisco, California, USA; ⁶National Resource Defense Council, San Francisco, California, USA; ⁷Pediatric Environmental Health Specialty Unit, University of California, San Francisco, California, USA; ⁸Wisconsin Division of Public Health, Madison, Wisconsin, USA; ⁹National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA; ¹⁰Institut National de l'Environnement Industriel et des Risques, Verneuil-en-Halatte, France; ¹¹International Agency for Research on Cancer, Lyon, France; ¹²National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA; ¹³George Perkins Marsh Institute, Clark University, Worcester, Massachusetts, USA; ¹⁴School of Public Health, University of California, Berkeley, Berkeley, California; ¹⁵National Institute for Occupational Safety and Health, Atlanta, Georgia, USA; ¹⁶Environmental and Occupational Health Program, Maine Center for Disease Control and Prevention, Augusta, Maine, USA; ¹⁷Department of Biology, University of Massachusetts, Amherst, Amherst, Massachusetts, USA

Abstract
Background: Assessing adverse effects from environmental chemical exposure is integral to public health policies. Toxicology assays identifying early biological changes from chemical exposure are increasing our ability to evaluate links between early biological disturbances and subsequent overt downstream effects. A workshop was held to consider how the resulting data inform consideration of an "adverse effect" in the context of hazard identification and risk assessment.

Objectives: Our objective here is to review what is known about the relationships between chemical exposure, early biological effects (upstream events) , and later overt effects (downstream events) through three case studies (thyroid hormone disruption, antiandrogen effects, immune system disruption) and to consider how to evaluate hazard and risk when early biological effect data are available.

Discussion: Each case study presents data on the toxicity pathways linking early biological perturbations with downstream overt effects. Case studies also emphasize several factors that can influence risk of overt disease as a result from early biological perturbations, including background chemical exposures, underlying individual biological processes, and disease susceptibility. Certain effects resulting from exposure during periods of sensitivity may be irreversible. A chemical can act through multiple modes of action, resulting in similar or different overt effects.

Conclusions: For certain classes of early perturbations, sufficient information on the disease process is known, so hazard and quantitative risk assessment can proceed using information on upstream biological perturbations. Upstream data will support improved approaches for considering developmental stage, background exposures, disease status, and other factors important to assessing hazard and risk for the whole population.

Key words: adverse health effects, androgen antagonists, hazard identification, immunotoxicants, risk assessment, science policy, thyroid hormone, toxicologic assessments. Environ Health Perspect 116:1568–1575 (2008) .  doi:10.1289/ehp.11516 available via http://dx.doi.org/ [Online 10 July 2008]

Address correspondence to T.J. Woodruff, University of California-San Francisco, Suite 1100, 1330 Broadway St., Oakland, CA 94612, USA. Telephone: (510) 986-8942 ; fax: (510) 986-8960. E-mail: woodrufft@obgyn.ucsf.edu

This work was supported by California Environmental Protection Agency, Office of Environmental and Health Hazard Assessment, contract OEHHA-06-S34 ; the U.S. Environmental Protection Agency, Office of Policy, Economics, and Innovation, National Center for Environmental Economics and National Center for Environmental Assessment, contract EP07H001060 ; the Intramural Research Program of the National Institute of Environmental Health Sciences (NIEHS) , National Institutes of Health (NIH) ; University of California, Berkeley, NIEHS Superfund Program at Berkeley, NIH grant P42 ES04705 ; and University of California, San Francisco.

This report has been reviewed by the National Institute of Occupational Safety and Health and the U.S. Environmental Protection Agency's Office of Research and Development, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the agency. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of institutions affiliated with the authors.

The authors declare they have no competing financial interests.

Received 27 March 2008 ; accepted 9 July 2008.