In 1999, the National Research Council’s Committee on Hormonally Active Agents in the Environment concluded that “in human populations suspected of being affected by hormonally active agents, prospective and cross-sectional studies using cohorts tracked from conception through adulthood are par- ticularly needed” (National Research Council 1999). Subsequently, as part of the conference “Endocrine Disruptors and Children’s Health: A Workshop to Examine the Effects of Endocrine Disruptors on Child Development for a National Longitudinal Study,” held 16–17 March 2000 (New York, NY), the authors jointly presented material for a session titled “Epidemiology and Assessment of Outcomes.” The objective of the session was to develop recommendations on how to design and execute a national longitudinal study of childhood development that incorpo- rates the latest information on the potential impact of endocrine disruptors on human development. The longitudinal study referred to in the workshop has since been named the National Children’s Study (NCS). We assume that the NCS will be a multi- center study of at least 100,000 children followed from before birth. Because the pri- mary hypotheses motivating the study (core hypotheses) are still under discussion, the pre- cise design of the study has not yet been speci- fied. Nonetheless, a comprehensive study of the determinants of health and development is envisioned. As the NCS is still being designed, the role that investigation of endocrine disrup- tors might play in the rationale and design is very much a salient issue. A more complete description of the proposed study appears else- where (Branum et al. 2003). In this paper we consider the importance of assessing endocrine disruption in the NCS. First, we briefly review the evidence that alter- ations of the early, normal endocrine environ- ment has adverse effects and the evidence that endocrine disruption is a potentially important hypothesis for human studies. We then weigh the need for assessment of endocrine disrup- tion in the NCS. Next, we note the salient fea- tures of earlier, similar cohort studies that serve as reference points for the design of the NCS. Finally, we discuss features of the NCS that would allow assessment of endocrine disrup- tion, even if endocrine disruption were not a primary hypothesis motivating the study. Long-term Effects of the Endocrine Environment during Pregnancy and Early Life In this section, we consider primarily exoge- nous effects of the endocrine environment, apart from those associated with normal differ- entiation and function. In humans, major alterations in the endocrine environment dur- ing pregnancy are known to have adverse con- sequences in offspring. The classic example is maternal diethylstilbestrol use causing adeno- carcinoma of the vagina in daughters (National Research Council 1999). Other examples are type 1 diabetes in pregnancy causing birth defects in offspring (Becerra et al. 1990) and hypothyroidism during pregnancy causing mental retardation in offspring (Haddow et al. 1999). Lesser degrees of maternal hypothy- roidism may also adversely affect the cognitive function of offspring (Haddow et al. 1999). That very small differences in hormone exposures during a critical period can affect an animal’s development is demonstrated by the intrauterine position phenomenon. Female mice adjacent to two male mice in utero, com- pared with those adjacent to two females, differ in terms of anogenital distance, activity level, body weight, estrous cycle length, age at sexual maturity, and other factors (vom Saal 1989). Similarly, among human females some evi- dence suggests that modestly higher in utero androgen exposure has detectable effects. A female dizygotic twin with a twin brother, compared with a female dizygotic twin with a twin sister, has fewer spontaneous otoacoustic emissions (clicking sounds generated by the ear) (McFadden 1993) and less craniofacial symmetry (Boklage 1985), and exhibits more risk-taking behavior (Resnick et al. 1993). The association with risk-taking behavior was found in a twin study designed to compare males with females; thus, biased observations depending on the sex of the co-twin seem unlikely, although other reasons besides an in utero androgen effect accounting for the associ- ation cannot be excluded. In another type of study, stored maternal pregnancy serum was analyzed for sex hormone–binding globulin and total testosterone, and the female off- spring, as adults, completed questionnaires about masculine and feminine behavior before their blood was analyzed (Udry et al. 1995). Lower sex hormone–binding globulin levels (implying higher free testosterone) were associ- ated with less femininity. Nonetheless, whether This article is part of the mini-monograph “Endocrine Disruptors and Children's Health.” Address correspondence to Matthew P. Longnecker, NIEHS, Epidemiology Branch, P.O. Box 12233, Research Triangle Park, NC 27709 USA. Telephone: (919) 541-5118. Fax: (919) 541-2511. E-mail: longnecker@niehs.nih.gov The opinions expressed herein are those of the individual authors and do not necessarily reflect the views of their respective organization, sponsoring institution, or the National Children’s Study Interagency Coordinating Committee. The authors declare they have no conflict of interest. Received 30 May 2002; accepted 16 December 2002. In this article we consider the importance of assessing endocrine disruption in a large new cohort that has been proposed, the National Children’s Study (NCS). We briefly review evidence that endocrine disruption is a potentially important hypothesis for human studies and weigh the need to assess endocrine disruption in the NCS. We note the salient features of earlier, similar cohort stud- ies that serve as reference points for the design of the NCS. Finally, we discuss features of the NCS that would allow or enhance assessment of endocrine disruption, even if endocrine disruption were not a primary hypothesis motivating the study. At this time, the evidence supporting endocrine dis- ruption in humans with background-level exposures is not strong. Thus, a compelling rationale for the NCS will probably need to be based on core hypotheses that focus on other issues. Nonetheless, if properly designed, the NCS could serve as an excellent resource for investigating future hypothe- ses regarding endocrine disruption. Key words: chemical actions, child, cohort studies, endocrine disruption, environment, epidemiology, health. Environ Health Perspect 111:1691–1697 (2003). doi:10.1289/ehp.5800 available via http://dx.doi.org/ [Online 18 March 2003] Endocrine Disruptors | Mini-Monograph Environmental Health Perspectives • VOLUME 111 | NUMBER 13 | October 2003 1691 An Approach to Assessment of Endocrine Disruption in the National Children’s Study Matthew P. Longnecker, 1 David C. Bellinger, 2 David Crews, 3 Brenda Eskenazi, 4 Ellen K. Silbergeld, 5 Tracey J. Woodruff, 6 and Ezra S. Susser 7 1 Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA; 2 Children’s Hospital Boston/Harvard Medical School, Boston, Massachusetts, USA; 3 University of Texas at Austin, Austin, Texas, USA; 4 Center for Children’s Environmental Health Research, University of California, Berkeley, School of Public Health, Berkeley, California, USA; 5 Department of Environmental Health Sciences, Johns Hopkins University, Baltimore, Maryland, USA; 6 U.S. Environmental Protection Agency, San Francisco, California, USA; 7 Division of Epidemiology, Joseph L. Mailman School of Public Health, Columbia University, New York, New York, USA