Center for Children's Environmental Health and Disease Prevention at the Harvard School of Public Health, Boston Research Projects

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Project 1: Metals, Nutrition and Stress in Child Development
Community-Based Participatory Research Project
Project Leader: Robert O. Wright

Tar Creek Superfund Site Toxic waste sites typically contain multiple chemicals, yet the vast majority of epidemiologic studies focus only on the health effects of a single chemical, rather than joint exposures. The role of chronic stress in modifying the toxicity of metal exposure is another issue which may be relevant to community health, as the presence of a Superfund site has been demonstrated to be associated with increased chronic stress. The problem of environmental exposure on contaminated lands is also particularly acute for Native Americans whose traditional way of life has close ties to the environment. Because the land and what’s grown on it is central to individual and community life, not only are tribal populations disproportionately exposed to environmental toxicants, but the usual preventive measures, such as recommendations to reduce consumption of game or fish threaten to diminish their culture. Such a situation mandates a different approach to exposure assessment, education and health care intervention for communities in which subsistence lifestyles predispose them to exposure to environmental contaminants.

In this community-based participatory research project, the Harvard School of Public Health, L.E.A.D. (Local Environmental Action Demanded, a community advocacy group), and Integris Baptist Regional Health Center are partnering to utilize the culture-based exposure assessment conducted in Project 2 to develop a multi-component intervention program to reduce toxic metal exposures among children living on or near the Tar Creek Superfund site in northeast Oklahoma. The project comprises both observational specific aims on metal mixtures and psychological stress in predicting child development, as measured by the Bayley Scale Assessment, as well as nutritional interventions to promote increased dietary iron and calcium intake to reduce toxic metal absorption, home visits to develop social supports, and community-level interventions to promote targeted remediation of compliance and reduce exposure to toxic metals among children, as well as to determine the modifying influence of joint exposures to metals and stress on neurologic outcomes as measured by the Bayley Scales of Child Development.

Project 2: Exposure Assessment of Children and Metals in Mining Waste: Composition, Environmental Transport and Exposure Patterns
Exposure Assessment Research Project
Project Leader: James P. Shine

Project 2 explores the transport and fate of metals from mining wastes (“chat”) that could potentially lead to adverse exposure in children in communities surrounding the Tar Creek Superfund Site. Although metals in mining waste have been thought by some to be relatively unavailable for geochemical mobilization or biological uptake (due to interactions with reactive sulfides), researchers at the Harvard Children’s Center hypothesize that reactions releasing metals to which children are exposed may make metals from mining waste more bioavailable than suspected. Hey may also favor the release of some metals (such as zinc and cadmium) over others (such as copper and lead). Thus, the mixture of metals to which children are exposed may be very different from the mixture of metals present in the parent chat. In addition, metals that have mobilized off the chat piles into other exposure media such as soil, water, airborne particulates and indoor dust, may have a higher relative bioavailability when compared to parent waste material.

The Harvard Center is testing this hypothesis, and is determining whether the types and bioavailability of metals to which children are exposed can be better understood through a more sophisticated consideration of the underlying geochemistry of metals in mine wastes. Specifically, Harvard Center researchers are studying which metals are enriched in down-gradient exposure media relative to metals in chat waste, and are using sequential extraction techniques and X-ray absorption spectroscopy to demonstrate that metals in these down-gradient media have a higher relative bioavailability.

In conjunction with Project 1, researchers are using these data to conduct a nested case-control study to examine the extent that environmental and behavioral factors, including diet and activity patterns, may explain differences in blood levels of lead (Pb) and manganese (Mn) in children from the Tar Creek area with high and low levels of Pb and Mn in their blood. The researchers will use the samples collected in this project to supply the animal studies (Projects 3 and 4) with well-characterized exposure material with respect to the concentrations and potential bioavailability of metals within each media. Finally, in parallel with the exposure assessment, researchers are conducting micro-array experiments and assess their utility as part of an overall exposure/adverse health outcome assessment.

Project 3: Manganese, Iron, Cadmium and Lead Transport from the Environment to Critical Organs during Gestation and Early Development in a Rat Model
Laboratory-Based Mechanistic Study
Project Director: Joseph D. Brain

Project 3 explores the transport of iron (Fe), manganese (Mn), cadmium (Cd) and lead (Pb) from environments experienced by children to the blood and critical organs such as the brain, heart, liver and kidney. Researchers at the Harvard Children’s Center seek to better understand metal exposures of children and their mothers in settings like Tar Creek, Oklahoma by (1) utilizing exposures during and after pregnancy; (2) using metal ions as well as complex environmental samples from Tar Creek; and (3) comparing different routes of entry from the environment into the body.

Project 3 is also exploring the role of toxic metals and iron status as they interact to influence metal absorption. In animal models, the researchers are simultaneously studying both the molecular mechanisms of metal transport as well as the corresponding pharmacokinetics of metals from the nose, lung and gut to the blood, central nervous system and other organs. These data will be correlated with outcomes in both animal (Project 4) and human studies (Project 1). When data from Project 3 are combined with data from the exposure assessment in Project 2, researchers will be able to better identify which routes of exposure result in the most significant body burdens of toxic metals. From this knowledge, researchers at the Harvard Children’s Center should be able to craft optimal strategies in Tar Creek to reduce the dose of toxic metals to mothers and children and thus better respond to the environmental concerns of the citizens of Tar Creek.

Project 4: Metals Neurotoxicity Research Project
Laboratory-Based Mechanistic Study
Project Leader: Tim Maher

With the exception of research on lead, alterations in cognitive and behavioral function as a result of exposure to metals has to date received little systematic attention. Even less attention has been placed on the effects of exposures to combinations of metals or such exposures on a background of external environmental stressors – scenarios that are unfortunately all too common. The use of animal models to study the neurotoxic effects of such exposures allows for more tightly controlled experimental design than is possible in human studies and allows for a more in-depth examination of the effects of the exposures on the nervous system and the mechanisms that underlie those effects. The enhanced understanding of the sites and mechanisms of the toxic action of these exposures that animal models can provide may result in development of more effective interventions.

Development in the nervous system is marked by tremendous cellular plasticity as the highly intricate and specific connections within and between brain regions are established. Two important mechanisms by which such contaminants can adversely affect the proper establishment of neuronal structure are disruption of normal synaptic transmission, which can have dramatic effects on cellular plasticity, and the induction of cell death. Such effects at the cellular level could lead, at the behavioral level, to deficits in a variety of functions including intellectual and social behaviors.

In Project 4, researchers are examining neurotoxic effects in juvenile rates of in utero and postnatal exposure to individual metals found in mining waste (“chat”) from the Tar Creek Superfund Site, specific mixtures of those metals, and actual chat from the site. In addition, researchers are exploring how stress may modify the effects of metal exposures, as the psychological stresses that accompany life at a Superfund site have been raised as an issue of concern in the Tar Creek community.

The aim of these animal studies is to complement the research being conducted in Project 1. To accomplish this, researchers are looking at both the cellular and behavioral levels in rat models, and are taking advantage of experiments being conducted as part of Project 2 and Project 3, so that the exposures in the experiments reflect the actual exposures experienced by the Tar Creek community. When data from Project 4 are combined with the exposure assessment in Project 2 and body burden data from Project 3, researchers will better be able to identify which routes of exposure result in the most significant neurological effects and the contribution of manganese and lead in chat to the neurological impacts of exposure to the chat. Thus, the Harvard Children’s Center research will improve our understanding of the neurological effects of exposure to mixtures of metals, and in so doing, support the Center’s overall goal of crafting optimal strategies in Tar Creek to reduce the neurological effects of toxic metals in humans.

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Center for Children's Environmental Health and Disease Prevention at the Harvard School of Public Health, Boston Research Projects

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