Research | Children’s Health Prenatal Exposure to Lead, δ-Aminolevulinic Acid, and Schizophrenia: Further Evidence Mark G.A. Opler,1 Stephen L. Buka,2 Justina Groeger,3 Ian McKeague,4 Catherine Wei,3 Pam Factor-Litvak,3 Michaeline Bresnahan,3,5 Joseph Graziano,6 Jill M. Goldstein,7 Larry J. Seidman,8 Alan S. Brown,1,5 and Ezra S. Susser 1,3,5 1Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York, USA; 2Department of Epidemiology, Brown University, Providence, Rhode Island, USA; 3Department of Epidemiology, and 4Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York, USA; 5New York State Psychiatric Institute, New York, New York, USA; 6Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York, USA; 7Department of Psychiatry at Massachusetts Mental Health Center, Harvard Medical School, and Harvard Institute of Psychiatric Epidemiology and Genetics, Department of Medicine, Harvard Medical School, Boston, Massachusetts, and the Department of Women’s Health, Brigham and Women’s Hospital, Boston, Massachusetts, USA; 8Public Psychiatry Division at Massachusetts Mental Health Center, and Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA BACKGROUND: A previously conducted study of prenatal lead exposure and schizophrenia using δ-aminolevulinic acid, a biologic marker of Pb exposure, in archived maternal serum samples col- lected from subjects enrolled in the Childhood Health and Development Study (1959–1966) based in Oakland, California, suggested a possible association between prenatal Pb exposure and the development of schizophrenia in later life. OBJECTIVES: In the present study we extend these ﬁndings using samples collected from the New England cohort of the National Collaborative Perinatal Project (1959–1966). Using similar meth- ods, in this study we found results that suggest a comparable association in this cohort. METHODS: We pooled matched sets of cases and controls from both the California and New England sites using a multilevel random-intercept logistic regression model, accounting for match- ing and site structure as well as adjusting for maternal age at delivery and maternal education. RESULTS: The estimated odds ratio for schizophrenia associated with exposure corresponding to 15 µg/dL of blood Pb was 1.92 (95% conﬁdence interval, 1.05–3.87; p = 0.03). CONCLUSION: Although several limitations constrain generalizability, these results are consistent with previous ﬁndings and provide further evidence for the role of early environmental exposures in the development of adult-onset psychiatric disorders. KEY WORDS: δ-aminolevulinic acid, developmental, lead, Pb, prenatal, prospective, psychosis, schiz- ophrenia. Environ Health Perspect 116:1586–1590 (2008). doi:10.1289/ehp.10464 available via http://dx.doi.org/ [Online 30 July 2008] A growing body of evidence supports the hypothesis that exposures that damage or disrupt the developing central nervous system are associated with schizophrenia and related disorders (McGrath and Murray 2003). Associations for some prenatal exposures have now been replicated—for example, nutritional deprivation (St. Clair et al. 2005; Susser et al. 1996). Exposure to potentially neurotoxic metals has not been carefully examined to date. In an earlier study, we measured a marker of second-trimester exposure to lead in prospectively collected serum samples from a birth cohort (Opler et al. 2004). The risk for schizophrenia spectrum disorders in adult- hood was shown to be approximately doubled in subjects with maternal blood Pb levels (BPb) > 15 µg/dL [indicated by elevated levels of δ-aminolevulinic acid (δ-ALA)] during the second trimester, although the sample was too small to draw definitive conclusions and the results failed to reach statistical signiﬁcance. There are reasons to suspect that chemical agents in general, and particularly those associ- ated with industrialization, may increase the risk of schizophrenia. Pb is a widely recognized developmental toxicant, leading to cognitive, 1586 behavioral, and physical impairments. Prospective birth cohorts in various parts of the world are consistent in ﬁnding that increased Pb exposure during development is associated with decrements in intellectual function up to 10 years of age [for a review, see Lanphear et al. (2005)]. There is also some suggestion that effects may persist into early adulthood; for example, Dietrich et al. (2001) found associa- tions between elevated prenatal and childhood BPb concentrations and increased rates of delinquency during adolescence. We designed the present study to expand our previous work with the Prenatal Determinants of Schizophrenia (PDS) study. As in our previous work, we capitalized on a large birth cohort in which pregnant women were recruited between 1959 and 1966. In this report, we used the New England sites of the National Collaborative Perinatal Project (NE-NCPP) (McGrath et al. 2003), whose data and design are similar to those of the PDS study. Many of the now adult offspring have been followed for neuropsychiatric out- comes. In this study, we independently ana- lyzed these data, which we then pooled with data from our original work to test the hypothesis that prenatal Pb exposure is associ- ated with risk of schizophrenia. Materials and Methods Description of cohorts. We obtained data and serum from two cohorts based in the United States. a) We included 81 subjects from the NE-NCPP. The NE-NCPP was part of a larger, multicenter cohort study initiated by the National Institute of Neurological and Communicative Disorders and Stroke, origi- nally designed to identify associations between prenatal factors and adverse infant and child development. The New England cohorts comprise 17,741 pregnancies collected prospectively from 1959 to 1966 at the Child Study Center, Brown University, Providence, Rhode Island, and the Boston Hospital for Women and Children, Hospital Medical Center, Boston (McGrath et al. 2003). b) The PDS study is based on a cohort of live births collected prospectively from 1959 through 1967 at the Kaiser Foundation Health Plan clinics in Alameda County, California, as part of the Child Health and Development Study. The PDS study includes the 12,094 live-born individuals remaining in the health plan until 1981, when it became possible to use comput- erized records to identify potential cases of schizophrenia (Susser et al. 2000). Address correspondence to M. Opler, Dept. of Epidemiology, Columbia University, 722 W. 168th St., New York, NY 10032 USA. Telephone: (646) 234-3607. Fax: (646) 758-8169. E-mail: mgo4@ columbia.edu Work for this article was supported in part by National Institutes of Health training grant 5 T32 MH 13043, National Alliance for Research on Schizophrenia and Depression Young Investigator Award, and National Institute of Environmental Health Sciences Center grant P30 ES 09089. The Child Health and Development Study has been supported by National Institute of Child Health and Human Development contracts NO1-HD-1-3334 and NO1-HD-6-3258 and is administered by the Public Health Institute, Berkeley, California (B. Cohn, principal investigator). The authors declare they have no competing ﬁnancial interests. Received 14 May 2007; accepted 30 July 2008. VOLUME 116 | NUMBER 11 | November 2008 • Environmental Health Perspectives