Chemical mixtures released from hazardous waste sites: implications for health risk assessment.

Uncontrolled hazardous waste sites (HWS) and exposure to hazardous substances continue to pose complex public health problems. This paper presents an overview of chemicals, including chemical mixtures, that have been released into environmental media in the vicinity of HWS. We describe how this type of information is being used to assess the public health implications of exposures to chemical mixtures and to develop an integrated program of applied research to more accurately characterize the potential health effects of chemical mixtures. A narrative, weight-of-evidence approach, incorporating mechanistic insights on chemical interactions is described. The utility of this information in the context of risk analysis and public health practice is discussed.

Decision support methodologies for human health assessment of toxic substances: Agency for Toxic Substances and Disease Registry's perspectives on collaboration and infrastructure development among government, academia, and industry.

ATSDR's mission is to prevent or mitigate adverse human effects and diminished quality of life that result from exposure to hazardous substances from hazardous waste sites, unplanned releases, and other sources of pollution present in the environment. As part of this charge, human health assessments are performed through the use of data from animal studies environmental monitoring data and human epidemiological studies. Often sufficient data are not available to perform such assessments. Hence, modeling approaches are often used to estimate the likelihood of exposure to environmental chemicals and adverse health effects to human populations. In the last two decades, several computational techniques have been recognized as having potential to improve the accuracy of this process. As part of the assessment process, (1) chemicals of potential concern must be identified, (2) available data on their toxicity evaluated, (3) quantitative measures of their potential adverse health effects developed, and (4) exposure assessments made. The human health risk must then be characterized in a useful and understandable manner.

Assessment of effect levels of chemicals from quantitative structure-activity relationship (QSAR) models. I. Chronic lowest-observed-adverse-effect level (LOAEL).

With the multitude of new chemicals being synthesized and the paucity of long-term test data on chemicals that could be introduced into the environment, innovative approaches must be developed to determine the health and environmental effects of chemicals. Research was conducted to employ quantitative structure-activity relationship (QSAR) techniques to study the feasibility of developing models to estimate the noncarcinogenic toxicity of chemicals that are not addressed in the literature by relevant studies. A database of lowest-observed-adverse effect level (LOAEL) was assembled by extracting toxicity information from 104 U.S. EPA documents, 124 National Cancer Institute/National Toxicology Program (NCI/NTP) reports, and 6 current reports from the literature. A regression model, based on 234 chemicals of diverse structures and chemical classes including both alicyclic and aromatic compounds, was developed to assess the chronic oral LOAELs in rats. The model was incorporated into an automated computer package. Initial testing of this model indicates it has application to a wide range of chemicals. For about 55% of the compounds in the data set, the estimated LOAELs are within a factor of 2 of the observed LOAELs. For over 93%, they are within a factor of 5. Because of the paucity or absence of long-term toxicity data, the public health and risk assessment community could utilize such QSAR models to determine initial estimates of toxicity for the ever-increasing numbers of chemicals that lack complete pertinent data. However, this and other such models should be used only by expert toxicologists who must objectively look at the estimates thus generated in light of the overall weight of evidence of the available toxicologic information of the subject chemical(s).

An integrated framework to identify significant human exposures (SHELs).

Typically, health risk assessment methodologies have been designed to assess risks associated with exposure to individual chemicals through one specific medium, such as air, water, or food. This is partly because classical experimental methodology is used to study pure chemicals, and partly because a majority of early promulgated environmental laws (e.g., Clean Air Act, Clean Water Act) regulated chemicals in a given matrix via a specific route. Often, however, exposures in the ambient environment are through multiple routes, multiple media and to multiple chemicals. Presented here is a multimedia framework that health risk assessors can use to identify significant human exposure levels (SHELs) on a site-specific basis. This framework is presented in the context of a decision tree that links health guidance values such as minimal risk levels (MRLs) with site-specific data, using a range of decision-support models. It includes a provision to estimate a level of concern by comparing the estimated total dose (exposures) with guidance values established by the Agency, by other federal organizations, and by basket-survey results. If a SHEL has been identified, a range of follow-up public health actions may be indicated (i.e., surveillance, health education, or other preventive interventions). This framework serves to (1) integrate the overall health assessment process, (2) evaluate the need for public health interventions, (3) incorporate innovative decision-support methods/models, and (4) demonstrate utility of such methods in public health practice and the pursuit of the Agency's mission.

Effects of Sevin on the reproductive biology of the Coturnix.

Adult Coturnix quail (Coturnix coturnix japonica) were subjected to three levels of carbaryl pesticide treatment (Sevin-20 p.p.m., 40 p.p.m., and 400 p.p.m) and monitored to observe any modifications in either their reproductive biology or behavior. There was an increase in the amount of pesticide excreted with increasing treatment levels during the first 48 hours following intubation, after which pesticide levels in the fecal material for all groups approached zero. Addditionally, significant amounts of the pesticide were detected in the egg yolks after pesticide ingestion (treatment levels, 20, 40, and 400 p.p.m. resulted in pesticide residues of 1.58, 2.03, and 3.15 p.p.m., respectively). Egg production was significantly reduced (p less than or equal to 0.05), although egg viability was not affected by the pesticide stress. Agonistic behavior decreased in males while it increased in the females following pesticide ingestion.

Strategic elements of ATSDR's Great Lakes Human Health Effects Research Program.

The goal of the Agency for Toxic Substances and Disease Registry's (ATSDR) Great Lakes Human Health Effects Research Program is to identify at-risk populations and to prevent potential human health effects associated with exposure to chemical contaminants in the Great Lakes basin. While this research effort is mandated by the Great Lakes Critical Programs Act of 1990, it also represents a significant opportunity to define a broader model or strategy for other regional or systems-level studies of potential health effects in at-risk populations. This article describes the strategy developed by ATSDR for this purpose in the Great Lakes Basin, as well as the program's specific research objectives and current status. It also outlines the projected implications of this research effort for greater comprehension of the potential health effects of exposure to contaminants in the Great Lakes Basin.

An integrated exposure/pharmacokinetic based approach to the assessment of complex exposures. Lead: a case study.

A problem in evaluating the hazard represented by an environmental toxicant is that exposures can occur via multiple media such as water, land, and air. Lead is one of the toxicants of concern that has been associated with adverse effects on heme metabolism, serum vitamin D levels, and the mental and physical development of infants and children exposed at very low environmental levels. Effects of lead on development are particularly disturbing in that the consequences of early delays or deficits in physical or mental development may have long-term consequences over the lifetime of affected individuals. Experimental and epidemiologic studies have indicated that blood lead levels in the range of 10-15 micrograms/dl, or possibly lower, are likely to produce subclinical toxicity. Since a discernible threshold has not been demonstrated, it is prudent to preclude development of a Reference Dose (RfD) for lead. As an alternate, the U.S. Environmental Protection Agency (U.S. EPA) has developed the uptake/biokinetic lead model that provides a means for evaluating the relative contribution of various media to establishing blood lead levels in children. This approach will allow for the identification of site- and situation-specific abatement strategies based on projected blood lead levels in vulnerable human populations exposed to lead in air, diet, water, soil/dust, and paint; thus making it possible to evaluate regulatory decisions concerning each medium on blood levels and potential health effects.

Cancer policy framework for: public health assessment of carcinogens in the environment.

Cancer remains at the forefront of public health concerns in the United States and throughout the world. Over the past 20 years a wide range of federal agencies and other organizations have been involved in developing policy statements, classification strategies, and assessment methods to address carcinogenesis and health risks. Each of these documents was developed in response to issues confronted by those organizations in pursuing their mission, often as a direct function of legislative mandates. In pursuing its mandated responsibilities, the Agency for Toxic Substances and Disease Registry (ATSDR) must address public health concerns associated with exposure to carcinogens in the context of all available relevant information. This information includes both technical data as well as science policy positions adopted by the range of organizations with programs germane to the assessment and/or regulation of carcinogens. Because of distinct differences in perspective, practice, and policy dictated by the mandated activities of these organizations and the rapidly evolving understanding of carcinogenesis, apparently divergent positions may be reflected in their conclusions. The differences outlined above, coupled with requests from the public, other agencies, and the private sector for a statement reflecting the Agency's position on science and science policy issues related to cancer, prompted the development of this policy. This document is intended to serve as a framework to guide the Agency in its programs and actions regarding carcinogens and to harmonize such efforts with those of other federal agencies and relevant organizations. This framework reflects an assessment of current practice within the Agency and defines the appropriate roles of conclusions derived by other groups, professional judgment, and emerging scientific principles in ATSDR's public health assessments of exposures to carcinogens. This Cancer Policy Framework is not intended to encompass the development of operational guidelines per se, although the Agency recognizes the utility of such efforts. A central theme of this Cancer Policy Framework is the use of risk analysis as an organizing construct based on sound biomedical and other scientific judgment to define plausible exposure ranges of concern rather than single numerical conclusions that may convey an artificial sense of precision. The development and use of innovative tools for exposure and dose response assessment (with particular emphasis on molecular epidemiology) are also endorsed.

Risk assessment initiatives for noncancer endpoints: implications for risk characterization of chemical mixtures.

Current methods employed in risk assessment for noncarcinogens are associated with the estimation of reference doses (RfDs). These strategies reflect (appropriately) a protective philosophy in both theory and practice. The approaches are limited, however, in terms of the ability to project the likelihood of specific hazard above the reference dose and to integrate the health hazards of exposure to chemical mixtures (including both cancer and noncancer endpoints). Ongoing efforts that address guidelines for risk assessment of non-carcinogens, both singly and as components of mixtures, are presented. Included is a description of the range of potential biological response categories and associated parallel issues of adversity and severity. For example, the progression of histopathological change, organ system dysfunction and organismal disability is examined as it may affect risk characterization of mixtures. Mechanistic principles are suggested as an appropriate focus to systematically evaluate this progression. Once established, these principles may provide a reasonable framework in which to more accurately characterize risks associated with chemical mixtures.

Hazardous wastes, hazardous materials and environmental health inequity.

This paper reviews issues associated with the equity of locating hazardous waste sites and hazardous materials. Reports and case studies indicate that hazardous waste sites and the locations of hazardous materials are disproportionately situated near minority communities, especially African-American communities. This inequitable placement of hazardous waste sites is of concern, since exposure to toxic waste can adversely affect human health. Proximity to these sites may place these minority communities at higher risk of developing cancers and respiratory, cardiovascular, and neurological diseases, and of incurring increased levels of individual and family stress. The health of persons in minority communities near hazardous waste sites is further compromised by their lack of access to adequate health care. The potential health risks borne by racial and ethnic minorities and by low income communities as a consequence of exposure to toxic waste constitutes environmental inequity. In order to decrease the burden of these risks, we recommend developing environmental policies that address environmental inequity; conducting detailed demographic and health studies that assess the impact of exposure to toxic waste on minority populations; and devising educational programs to sensitize professional service providers and prevent exposure by community residents. This paper identifies research needs and opportunities.

ATSDR evaluation of health effects of chemicals. IV. Polycyclic aromatic hydrocarbons (PAHs): understanding a complex problem.

Polycyclic Aromatic Hydrocarbons (PAHs) are a group of chemicals that are formed during the incomplete burning of coal, oil, gas, wood, garbage, or other organic substances, such as tobacco and charbroiled meat. There are more than 100 PAHs. PAHs generally occur as complex mixtures (for example, as part of products such as soot), not as single compounds. PAHs are found throughout the environment in the air, water, and soil. As part of its mandate, the Agency for Toxic Substances and Disease Registry (ATSDR) prepares toxicological profiles on hazardous chemicals, including PAHs (ATSDR, 1995), found at facilities on the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) National Priorities List (NPL) and which pose the most significant potential threat to human health, as determined by ATSDR and the Environmental Protection Agency (EPA). These profiles include information on health effects of chemicals from different routes and durations of exposure, their potential for exposure, regulations and advisories, and the adequacy of the existing database. Assessing the health effects of PAHs is a major challenge because environmental exposures to these chemicals are usually to complex mixtures of PAHs with other chemicals. The biological consequences of human exposure to mixtures of PAHs depend on the toxicity, carcinogenic and noncarcinogenic, of the individual components of the mixture, the types of interactions among them, and confounding factors that are not thoroughly understood. Also identified are components of exposure and health effects research needed on PAHs that will allow estimation of realistic human health risks posed by exposures to PAHs. The exposure assessment component of research should focus on (1) development of reliable analytical methods for the determination of bioavailable PAHs following ingestion, (2) estimation of bioavailable PAHs from environmental media, particularly the determination of particle-bound PAHs, (3) data on ambient levels of PAHs metabolites in tissues/fluids of control populations, and (4) the need for a critical evaluation of current levels of PAHs found in environmental media including data from hazardous waste sites. The health effects component should focus on obtaining information on (1) the health effects of mixtures of PAHs particularly their noncarcinogenic effects in humans, and (2) their toxicokinetics. This report provides excerpts from the toxicological profile of PAHs (ATSDR, 1995) that contains more detailed information.

The Agency for Toxic Substances and Disease Registry's role in development and application of biomarkers in public health practice.

An overview of the Agency for Toxic Substances and Disease Registry's (ATSDR) biomarker program is presented in the context of the paradigm for biomarkers developed by the National Research Council (NRC, 1987, 1991). The status and projected utility of four biomarker studies conducted by NRC and sponsored by ATSDR, the Environmental Protection Agency (EPA), and the National Institute of Environmental Health Sciences (NIEHS) are discussed. These studies include a review of relevant research on biomarkers for specific toxicologic end points, including reproductive toxicology, pulmonary toxicology, neurotoxicology, and immunotoxicology. Also, the scope of related research on exposure characterization being conducted by the ATSDR-sponsored research program at Rutgers University is reviewed. The potential impact of biomarkers on public health assessments and on the range of ATSDR programs is described. Specifically, the role of biomarkers in dose reconstruction, in ATSDR's health studies program, and in the emerging field of molecular epidemiology is reviewed. In addition, future directions and research needs are addressed.