The goal of this core is to characterize exposure-related health effects in human populations, define gene-environment interactions, and develop methods to reduce health risks. Much of the focus of this core has been on the areas of occupational and molecular epidemiology. To that end major efforts have been directed to development and application of biochemical and molecular markers for human population studies. The work of this core is inherently interdisciplinary. Close collaborations have been established with the Radiobiology and Environmental Carcinogenesis Core in the development of genetic markers that can be applied in epidemiologic studies. The focus is to apply molecular and biochemical markers of exposure, effect, and susceptibility. Other collaborations are established with the Environmental Science and Engineering Core and the new Exposure Facility Core to improve exposure evaluation in occupational and environmental epidemiology studies. Current research includes genetic susceptibility to lung cancer, biomarkers of occupational exposure to petrochemicals, markers of exposure and response to fuel fly-ash, bioaerosols and heavy metals. Additional studies of reproductive effects are ongoing for the textile, petrochemical and agricultural industries. International collaborations are ongoing in China, Taiwan, Japan, Africa, and Latin America. A recent initiative is the Program in Population Genetics which attempts to identify genes associated with chronic diseases. Once a candidate gene is identified the plan is to use it in molecular epidemiologic studies of exposed populations. The extramural support for this core is substantial with support coming from NIH (P01 to Drs. Christiani and Monson; and R01 grants to Drs. Christiani, Kelsey, Hu, Milton, Smith, and Xu). Additional support has come from CDC (NIOSH), the March of Dimes, American Cancer Society, ATSDR, and GM-UAW Research Committee. The Superfund Chemical Basic Research Program is directed by Dr. Monson and funded by NIEHS. This program has had a focus on metals and PCB and addresses environmental exposure, biologic pathogenesis, and epidemiologic studies. The specific focus is on exposure, response, and mechanism of metals, particularly lead, arsenic, and vanadium. What has been learned with the metals is currently being applied to PCBs. This program has a total of nine projects: 1) Community exposure to lead (Drs. Ryan and Hu). This study uses K-XRF bone-lead measurement techniques in high school students with detailed geographic and environmental information. 2) Genetic susceptibility to environmental intoxication (Dr. Kelsey with Dr. Xu). This project is looking at lead battery workers in Korea and explores the association with a known polymorphism in gene coding for the aminolevulenic and dehydratase (ALA-D) enzyme. 3) Lead exposure, bone accumulation, and reproductive toxicity among adults in Mexico (Dr. Hu). An inverse relationship was observed between birth weight and bone-lead in approximately 300 post-partum mothers. Future studies will include evaluation of psychomotor development and bone-lead. 4) Lead exposure, bone accumulation and cognitive performance in the elderly (Dr. Hu with Drs. Ryan and Spengler). This study previously investigated the relation between bone-lead and hypertension and kidney function. 5) Vanadium and human health (Dr. Christiani with Drs. Smith and Ryan) This study investigates the acute and chronic respiratory health of fuel-oil ash. 6) Pathogenesis and toxicity of vanadium compounds (Drs. Godleski and Paulauskis with Drs. Christiani and Hauser). This project is designed to investigate the mechanisms of vanadium toxicity. 7) Newborn health and environment (Drs. Korrick and Monson). Multiple measures have been taken for almost 600 mother-infant pairs with a final goal of 900 pairs. The relation between intra-uterine PCB and birth weight have been investigated. The results indicate a threshold for PCB-related changes in fetal growth. Intra-uterine lead exposure was associated with decreased birth weight 8) Assessment of metal contamination and ecological implications (Dr. Ford). The New Bedford Harbor was evaluated for benthic oxygen demand and the sediment-water flux of the heavy metals Co,Ni,Cu,Zn,Cd, and Pb and 9) Arsenic and bladder and skin cancers (Drs. Hunter and Christiani). This study is to conduct a nested case-control study of squamous cell cancer of the skin and bladder in the Nurses Health Study. Another collaboration is being conducted in Taiwan. Data collection is underway. Another research initiative is in the area of environmental and molecular epidemiology. This is a collaborative effort with the Radiobiology and Environmental Carcinogenesis Core. The program is designed to examine the relation between human cancer and genetic susceptibility, gene-environment interactions, and genetic damage. The program is led by Dr. Christiani with Drs. Liber and Kelsey collaborating. The study was started in late 1992 and to date has recruited 900 subjects. Studies are case-control in design and entail the evaluation of several genetic polymorphisms for lung cancer in relation to environmental agents including tobacco and PAH compounds. Other factors considered include dietary antioxidants and asbestos exposure. An odds ratio of approximately two has been identified for the CYP1A1 MspI polymorphism following adjustment for confounders. A protective benefit of carrot consumption was identified for the GSTM1 deletion polymorphism. These results suggest a possible intervention for current and previous smokers. There is insufficient statistical power, however, in the current subject pool to explore the main effects of less common polymorphisms. Future efforts will increase sample size to 1,500 cases in order to explore these relations. In addition to genetic polymorphism, other biomarkers have been considered including DNA adducts such as PAH-DNA adducts in blood mononuclear cells and lung tissue adducts. The lung tissue adducts were found to correlate well with the peripheral blood mononuclear cell adducts. PAH-DNA adducts were found to be inversely related to dietary intake of antioxidants. The antioxidants (vitamin A and selenium) were also found to be inversely related to sister chromotid exchange levels in Iymphocytes. Additional polymorphisms are being investigated in relation to 1,3 butadiene and arsenic exposures as well as brain cancer. The program in occupational and environmental airway diseases includes Drs. Milton, Christiani,Smith, Burge, Paulauskis, Godleski and Monson. The focus of this program is nonmalignant lung damage from exposure to cotton dust, gram-negative bacterial endotoxins, fuel-oil fly ash, endotoxin and beta-glucans of fungal origin, synthetic fibers, and machining fluids. Spirometry, including FEV, FVC, and PEF are principal outcomes along with respiratory symptoms. Additional studies are underway on heavy metals beyond those being conducted for the Superfund Basic Research Program. K-XRF is being used with collaborators in Mexico to explore the relation between lead exposure and male reproductive outcomes including sperm motility. Analysis of the exposure data indicates that mean bone lead concentrations are at least twice what would be expected for age-matched men. Other reproductive studies are directed at maternal and paternal reproductive health outcomes related to exposure to petrochemicals, organophosphate pesticides, lead, PCB, and dioxin. Outcomes include birth weight, early fetal loss, spontaneous abortion, sperm measures, and reproductive hormones. Several of these studies are being conducted in mainland China were population exposures are high. Another research area is the prospective evaluation of HAZMAT incidents in the Boston area. In addition to evaluating the incidents and clinical outcomes of exposed workers, these studies will evaluate the cost-effectiveness and clinical utility of medical tests commonly administered during HAZMAT responses. Preliminary results suggest that baseline audiometry and pulmonary function is indicated for response personnel. Several modeling studies are underway with collaboration from the Environmental Science and Engineering Core. These include development of a urinary biomarker (1 -hydroxypyrene) for coke-oven PAH exposures, and models for exposure to particles, gases, synthetic fibers, and metallic combustion particles. A recent initiative is the Program in Population Genetics. This program is designed to identify genes involved in common diseases. The studies that have been started are investigating hypertension, obesity, and asthma and are also being conducted in mainland China. The program is designed to add capability in gene mapping, candidate-gene assessment, and mutation and allele frequency.
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