Studies of the effects of environmental agents on human health are a vital part of the mission of the institute. As such studies are almost always observational rather than experimental, interpretation of the data is complex. Good statistical collaboration in all phases, including conception, design, analysis, and interpretation, is essential to the success of this work. During the current year, we were active collaborators on many projects. These included studies of prenatal and childhood exposures and their later impacts on the health of children, studies of associations of adult disease with environmental exposures, and studies aimed at better understanding of the biology of certain reproductive conditions. We examined socio-economic predictors of lead concentrations in Polish children; it is vital to understand sources of exposure in order to prevent future exposure. We also examined possible consequences of early-life exposures to various compounds on later health outcomes in children. We used two populations, one of American children born in the 1960s, and one of Ukrainian children born in the 1990s in a region where pollution problems have been reported, to look at the association of prenatal exposure to organochlorines with birth weight and preterm delivery. The American cohort was also used to examine whether prenatal exposure to the anti-androgenic compound DDE was related to male genital birth defects. It was also used to examine whether prenatal exposure to polychlorinated biphenyls was related to subsequent mental and motor development of children. Pregnancy complications, as assessed by hospital admissions, were assessed in the Ukrainian cohort. We also used data from a recent large American survey to examine whether breast-feeding is protective against the development of asthma. Associations of a number of adult diseases with environmental exposures were examined. We used a large study of farmers, the Agricultural Health Study, to examine possible relationships of pesticides and other agricultural exposures to wheezing. In a case-control study of non-Hodgkin's lymphoma, both agricultural and lifestyle factors were examined as possible predictors. Associations of lung cancer with both air pollution and radon were examined. Possible relationships of diabetes and polychlorinated biphenyls were also examined. A number of reproductive conditions and disorders were studied. A base of basic knowledge is needed in order to understand possible environmental influences on these disorders. The etiology of uterine fibroids (leiomyomas) is poorly understood. Even incidence is not well established; we examined incidence rates and the role of parity as a risk factor. Pre-eclampsia is another understudied condition; we examined several risk factors for this disease. In addition, we studied a number of facets of pregnancy, including several examinations of both normal events and complications in the early stages of pregnancy, the role of human chorionic gonadotropin in successful pregnancy, associations of certain polymorphisms with intrauterine growth retardation, and the usefulness of placental weight as a measure of birth size. A number of the studies mentioned above are ongoing work that will continue. In addition, new projects for which no results are currently available are underway. Brief descriptions of some of these projects follows. We will examine the relationship between adolescent body size and prenatal exposure to DDT/DDE in a cohort of 300 boys born in the 1960s. Anthropometric measurements and stored maternal blood samples exist, and DDT/DDE concentrations in the blood are currrently being measured. This is an attempt to replicate a finding seen in a previous NIEHS study, where boys with higher prenatal exposure to DDE were taller and heavier than other boys. We will examine the relationship between prenatal exposure to the anti-androgenic compound DDE and anogenital distance at birth in a population in Mexico with relatively high exposure to DDT. We are in the planning and protocol development stages for a study of the effects of DDE on early menopause. The study will be done in mothers of children who were studied previously by NIEHS. DDE measurements during pregnancy are available, and questionnaires about menopausal status will be administered. We are collaborating on a study of fibroid growth dynamics. 300 women with uterine leiomyomas will be followed with MRI to determine the growth patterns of the fibroids; for women who undergo surgery, tissue will be obtained. Predictors and clinical consequences of fibroids will also be studied. Predictors include both biological ones, such as pathology, and lifestyle factors. Design work was done this year and data collection is underway. We are working on the design of a clinical study to determine whether, when resecting lung tumors, ligation first of an artery or a vein influences distant metastasis development. The study is currently moving through the approval process. We are working on the development of a large cohort study of unaffected sisters of women with breast cancer. Approximately 50000 sisters will be followed for at least 5 years. The study is designed to clarify the joint effects of environmental and genetic factors, and will allow examination of endogenous hormones, exogenous hormone disruptors, growth factors such as vitamin D and IGF, and environmental contaminants of general public concern such as pesticides and solvents.