Chemical exposures at hazardous waste sites: Experiences from the United States and Poland.

The U.S. Agency for Toxic Substances and Disease Registry (ATSDR) and the Polish Nofer Institute of Occupational Health collaborate on issues related to hazardous chemical exposure at or near hazardous waste sites. This paper outlines the scope of hazardous chemical exposure in the United States and in Poland and identifies priority chemicals and chemical mixtures. Special attention is paid to exposures to metals and to evaluation of the health risks associated with those exposures. Studies in the United States indicate that exposure to hazardous waste site chemicals may be associated with an increased risk of adverse developmental - specifically cardiovascular and neurodevelopmental - effects.

Computational toxicology methods in public health practice.

ABSTRACT Hazard identification and health risk assessment traditionally rely on results of experimental testing in laboratory animals. It is a lengthy and expensive process, which at the end still involves large uncertainty because the sensitivity of animals is unequal to the sensitivity of humans. The Agency for Toxic Substances and Disease Registry (ATSDR) Computational Toxicology and Method Development Laboratory develops and applies advanced computational models that augment the traditional toxicological approach with multilevel cross-extrapolation techniques. On the one hand, these techniques help to reduce the uncertainty associated with experimental testing, and on the other, they encompass yet untested chemicals, which otherwise would be left out of public health assessment. Computational models also improve understanding of the mode of action of toxic agents, and fundamental mechanisms by which they may cause injury to the people. The improved knowledge is incorporated in scientific health guidance documents of the Agency, including the Toxicological Profiles, which are used as the basis for scientifically defensible public health assessments.

Inorganic: the other mercury.

There is a broad array of mercury species to which humans may be exposed. While exposure to methylmercury through fish consumption is widely recognized, the public is less aware of the sources and potential toxicity of inorganic forms of mercury. Some oral and laboratory thermometers, barometers, small batteries, thermostats, gas pressure regulators, light switches, dental amalgam fillings, cosmetic products, medications, cultural/religious practices, and gold mining all represent potential sources of exposure to inorganic forms of mercury. The route of exposure, the extent of absorption, the pharmacokinetics, and the effects all vary with the specific form of mercury and the magnitude and duration of exposure. If exposure is suspected, a number of tissue analyses can be conducted to confirm exposure or to determine whether an exposure might reasonably be expected to be biologically significant. By contrast with determination of exposure to methylmercury, for which hair and blood are credible indicators, urine is the preferred biological medium for the determination of exposure to inorganic mercury, including elemental mercury, with blood normally being of value only if exposure is ongoing. Although treatments are available to help rid the body of mercury in cases of extreme exposure, prevention of exposure will make such treatments unnecessary. Knowing the sources of mercury and avoiding unnecessary exposure are the prudent ways of preventing mercury intoxication. When exposure occurs, it should be kept in mind that not all unwanted exposures will result in adverse health consequences. In all cases, elimination of the source of exposure should be the first priority of public health officials.

The role of exposure versus body burden data in deriving health guidance values.

The Agency for Toxic Substances and Disease Registry (ATSDR) derives health-based guidance values to estimate daily human exposure to hazardous substances that are likely to be without appreciable risk of adverse noncancer effects for specific routes and durations of exposure. Most of these guidance values are derived from data showing external dose/health effect relationships. However, for chemicals that persist in the body, information on body burdens may provide more accurate understanding of their toxicity. This article evaluates the exposure versus body burden approaches using 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and lead as examples.

A statistical model for assessing genetic susceptibility as a risk factor in multifactorial diseases: lessons from occupational asthma.

BACKGROUND: Incorporating the influence of genetic variation in the risk assessment process is often considered, but no generalized approach exists. Many common human diseases such as asthma, cancer, and cardiovascular disease are complex in nature, as they are influenced variably by environmental, physiologic, and genetic factors. The genetic components most responsible for differences in individual disease risk are thought to be DNA variants (polymorphisms) that influence the expression or function of mediators involved in the pathological processes. OBJECTIVE: The purpose of this study was to estimate the combinatorial contribution of multiple genetic variants to disease risk. METHODS: We used a logistic regression model to help estimate the joint contribution that multiple genetic variants would have on disease risk. This model was developed using data collected from molecular epidemiology studies of allergic asthma that examined variants in 16 susceptibility genes. RESULTS: Based on the product of single gene variant odds ratios, the risk of developing asthma was assigned to genotype profiles, and the frequency of each profile was estimated for the general population. Our model predicts that multiple disease variants broaden the risk distribution, facilitating the identification of susceptible populations. This model also allows for incorporation of exposure information as an independent variable, which will be important for risk variants associated with specific exposures. CONCLUSION: The present model provided an opportunity to estimate the relative change in risk associated with multiple genetic variants. This will facilitate identification of susceptible populations and help provide a framework to model the genetic contribution in probabilistic risk assessment.

ATSDR evaluation of potential for human exposure to zinc.

As part of its mandate, the Agency for Toxic Substances and Disease Registry (ATSDR) prepares toxicological profiles on hazardous chemicals found at Comprehensive Environmental Response, Compensation and Liability Act (CERCLA) National Priorities List (NPL) sites that have the greatest public health impact. These profiles comprehensively summarize toxicological and environmental information. This article constitutes the release of portions of the toxicological profile for zinc. The primary purpose of this article is to provide interested individuals with environmental information on zinc that includes production data, environmental fate, potential for human exposure, analytical methods and a listing of regulations and advisories.

A regional approach to assess the impact of living in a chemical world.

In the United States, some 80,000 commercial and industrial chemicals are now in use of which over 30,000 are produced or used in the Great Lakes region. Thus, the environmental quality within the Great Lakes basin has been compromised particularly with respect to persistent toxic substances (PTS). Information derived from wildlife studies, prospective epidemiological and toxicological studies, databases, demographics, and Geographical Information Systems (GIS) demonstrate significant public health implications. Studies of human populations indicate: (a) elevated body burden levels of PTSs, (b) decrease in gestational age, (c) low birth weight (LBW), (d) greater risk of male children with birth defects (OR = 3.01), (e) developmental and neurological deficits, (f) increased risk of infertility, (g) changes in sex ratio, and (h) fluctuations in thyroid hormones. These findings have been identified in vulnerable populations, such as the developing fetus, children, minorities, and men and women of reproductive age who are more susceptible because of their physiologic sensitivity and/or elevated exposure to toxic chemicals. Typically such health effects are assessed on a chemical specific basis; however, most human populations are exposed to hazardous chemicals as mixtures in air, water, soil, and biota. In this article we present an assessment of the potential for joint toxic action of these substances in combinations in which they are typically found. These evaluations represent an integration of all available scientific evidence in accordance with the "NAS paradigm" for risk assessment. In aggregate, our evaluations have demonstrated a need for community-based frameworks and computational techniques to track patterns of environmentally related exposures and associated health effects.

ATSDR evaluation of the health effects of zinc and relevance to public health.

As part of its mandate, the Agency for Toxic Substances and Disease Registry (ATSDR) prepares toxicological profiles on hazardous chemicals found at Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) National Priorities List (NPL) sites, which have the greatest public health impact. These profiles comprehensively summarise toxicological and environmental information. This article constitutes the release of portions of the Toxicological Profile for Zinc. The primary purpose of this article is to provide public health officials, physicians, toxicologists, and other interested individuals and groups with an overall perspective on the toxicology of zinc. It contains descriptions and evaluations of toxicological studies and epidemiological investigations, and provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health.

Human health research and policy development: experience in the Great Lakes region.

As a direct outgrowth of industrial and agricultural activities, the quality of the Great Lakes ecosystem has declined significantly because of toxic substances in the water, eutrophication, overfishing, and invasive species that have been introduced into the waterways. Although measures have been adopted to restore the health of the ecosystem, contamination of Great Lakes sport fish continues arising from conditions that still prevail, but on a more limited scale. As a consequence, the Great Lakes states have issued guidelines for the public in the form of health advisories for fish consumption to encourage practices that will minimize exposure to contaminants found in Great Lakes sport fish. Scientific research has strongly influenced many policy decisions, including the development of laws, rules, and guidelines applicable to public health not only in regard to fish advisories but also other issues impacting human health. This paper proposes to outline how policy has been influenced by scientific findings and the far-reaching effect that these decisions have had on the health status of the public in the Great Lakes area and its potential for influencing the nation as a whole and our global neighbors. Within the Great Lakes basin, polychlorinated biphenyls (PCB) and mercury are the subject of the greatest number of fish advisories. Great Lakes-based researchers have studied populations residing in the Great Lakes basin to determine their level of awareness concerning fish consumption health advisories. They found that almost 50% of the residents who consumed Great Lakes sport fish were aware of sport fish consumption advisories. Of those with awareness, almost 60% were males and only about 40% were females. The researchers attributed the greater awareness among males to the health advisory materials that males receive with their fishing licenses and to their contact with fishing-related groups. The lower level of awareness among women regarding fish consumption advisories subsequently prompted the researchers to recommend targeting risk communication programs for female consumers of Great Lakes sport fish, particularly women of reproductive age. The Wisconsin Department of Health and Family Services subsequently followed the recommendation and developed uniform outreach materials for women, minorities, and the general public to be used by the Great Lakes states. The policy change directing educational materials to at-risk groups (e.g., women of reproductive age and minorities) is a direct outgrowth of the finding of low awareness about fish advisories among women who were interviewed.

The health impact of environmental pollutants: a special focus on lead exposure in South Africa.

Studies have shown blood lead levels of some children in South Africa at levels of health concern. New studies show even relatively low lead levels to have detrimental effects on cognitive function in young children. Large numbers of South African inner-city and other children have been shown to have unacceptably high blood lead levels. Studies indicate that blood lead levels of children living in South Africa's urban areas are higher than those of children in most developed countries, including Great Britain, Europe, and the United States. Although data and reported studies are very sparse, mean blood lead levels of approximately 15 microg/dl have been reported in children. Elevated blood lead levels were associated with socioeconomic status and housing conditions. Key environmental risk factors for elevated blood levels were contaminated soil and dust in the urban environment, and the still large number of automobiles using leaded gasoline. In view of emerging evidence linking lead at increasingly lower levels to adverse effects in children, the South African government is taking actions to reduce lead exposure among vulnerable groups. Currently, South Africa has no national lead surveillance program. The government, therefore, has developed international and regional partnerships to prevent and address the problem of lead exposure.

Case studies--arsenic.

Arsenic is found naturally in the environment. People may be exposed to arsenic by eating food, drinking water, breathing air, or by skin contact with soil or water that contains arsenic. In the U.S., the diet is a predominant source of exposure for the general population with smaller amounts coming from drinking water and air. Children may also be exposed to arsenic because of hand to mouth contact or eating dirt. In addition to the normal levels of arsenic in air, water, soil, and food, people could by exposed to higher levels in several ways such as in areas containing unusually high natural levels of arsenic in rocks which can lead to unusually high levels of arsenic in soil or water. People living in an area like this could take in elevated amounts of arsenic in drinking water. Workers in an occupation that involves arsenic production or use (for example, copper or lead smelting, wood treatment, pesticide application) could be exposed to elevated levels of arsenic at work. People who saw or sand arsenic-treated wood could inhale/ingest some of the sawdust which contains high levels of arsenic. Similarly, when pressure-treated wood is burned, high levels of arsenic could be released in the smoke. In agricultural areas where arsenic pesticides were used on crops the soil could contain high levels of arsenic. Some hazardous waste sites contain large quantities of arsenic. Arsenic ranks #1 on the ATSDR/EPA priority list of hazardous substances. Arsenic has been found in at least 1,014 current or former NPL sites. At the hazardous waster sites evaluated by ATSDR, exposure to arsenic in soil predominated over exposure to water, and no exposure to air had been recorded. However, there is no information on morbidity or mortality from exposure to arsenic in soil at hazardous waste sites. Exposure assessment, community and tribal involvement, and evaluation and surveillance of health effects are among the ATSDR future Superfund research program priority focus areas. Examples of exposures to arsenic in drinking water, diet and pesticide are given.

Six interaction profiles for simple mixtures.

The Agency for Toxic Substances and Disease Registry (ATSDR) has a program for chemical mixtures that encompasses research on chemical mixtures toxicity, health risk assessment, and development of innovative computational methods. ATSDR prepared a guidance document that instructs users on how to conduct health risk assessment on chemical mixtures (Guidance Manual for the Assessment of Joint Toxic Action of Chemical Mixtures). ATSDR also developed six interaction profiles for chemical mixtures. Two profiles were developed for persistent environmental chemicals that are often found in contaminated fish and also can be detected in human breast milk. The mixture included chlorinated dibenzo-p-dioxins, hexachlorobenzene, dichlorodiphenyl dichloroethane, methyl mercury, and polychlorinated biphenyls. Two profiles each were developed for mixtures of metals and mixtures of volatile organic chemicals (VOCs) that are frequently found at hazardous waste sites. The two metal profiles dealt with (a) lead, manganese, zinc, and copper; and (b) arsenic, cadmium, chromium, and lead; the two VOCs mixtures dealt with (a) 1,1,1-trichloroethane, 1,1-dichloroethane, trichloroethylene, and tetrachloroethylene; and (b) benzene, ethylbenzene, toluene, and xylenes (BTEX). Weight-of-evidence methodology was used to assess the joint toxic action for most of the mixtures. Physiologically based pharmacokinetic modeling was used for BTEX. In most cases, a target-organ toxicity dose modification of the hazard index approach is recommended for conducting exposure-based assessments of noncancer health hazards.

The impact of toxicology on public health policy and service: an update.

The Division of Toxicology, Agency for Toxic Substances and Disease Registry (ATSDR) has a Congressional mandate to develop toxicological profiles for chemicals of greatest concern at hazardous waste sites. These chemical profiles provide a comprehensive evaluation and interpretation of the health effects, chemical and physical properties, production and use, potential for human exposure, analytical methodologies, and regulations and advisories for those chemicals. In addition, these profiles identify critical gaps in the knowledge base for these chemicals and identify levels of significant human exposure. Health assessors and other public health officials use this information to make critical decisions regarding the potential for adverse health effects at hazardous waste sites and other chemical-release events through such activities as public health assessments, chemical-specific and health-specific consultations, health-guidance-value derivations, database development, and emergency response actions. In a previous paper, we provided an overview of six specific public-health activities conducted by the ATSDR Division of Toxicology and examined how these activities have made unique impacts on public health policy and service. In this paper, we follow up on two of these, ATSDR polychlorinated biphenyls (PCBs) activities and ATSDR mercury activities, and examine their long-term, continually evolving impacts on public health policy and service.

Sentinel human health indicators: to evaluate the health status of vulnerable communities.

The presence of toxic substances in the Great Lakes (GL) basin continues to be a significant concern. In the United States, some 70,000 commercial and industrial compounds are now in use. More than 30,000 are produced or used in the Great Lakes ecosystem. These substances include organochlorines (e.g., polychlorinated biphenyls (PCBs), dioxins, furans, dieldrin, etc.), heavy metals such as methylmercury, and alkylated lead, and polycyclic aromatic hydrocarbons (e.g., benzo[a]pyrene). The IJC has identified 42 locations in the GL basin of the United States and Canada as Areas of Concern (AOCs) because of high concentrations of these toxic substances. In 1990 the U.S. Congress amended the Great Lakes Critical Programs Act to create The Agency for Toxic Substances and Disease Registry (ATSDR) Great Lakes Human Health Effects Research Program (GLHHERP) to begin to address these issues. This program characterizes exposures to contaminants via consumption of GL fish and investigates the potential for short- and long-term adverse health effects. This paper reviews the GLHHERP program and indicators established to monitor and address the risks posed by these substances to vulnerable populations in the Great Lakes ecosystem.

Findings and accomplishments of ATSDR's Superfund-mandated Substance-Specific Applied Research Program.

Priority research needs determined by the Agency for Toxic Substances and Disease Registry (ATSDR) for the agencies top-ranked hazardous substances are being filled via regulatory mechanisms, private sector voluntarism, and university-based research. To date, 17 studies have been completed, 12 are ongoing, and 12 are currently planned. Under the direction of the Substance-Specific Applied Research Program (SSARP), ATSDR-supported research has filled research needs that significantly improved the information base available for making appropriate public health decisions. With the knowledge and understanding gained from this research, health professionals are better able to identify and interdict significant exposure and mitigate toxicity when exposure occurs. Thus, the SSARP has played, and continues to play, a vital role in contributing towards improving ATSDR's efforts to meet its mission and goals in environmental public health. In addition to addressing research needs of interest to ATSDR, findings from the program have contributed to the overall scientific knowledge about the effects of toxic substances in the environment.

Great lakes research--important human health findings and their impact on ATSDR's Superfund research program.

The Agency for Toxic Substances and Disease Registry (ATSDR) was created by the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) of 1980, commonly known as Superfund. ATSDR is the principal United States federal public health agency involved with issues of public health and applied science concerning the human health impact of living in the vicinity of a hazardous waste site, or emergencies resulting from unplanned releases of hazardous substances into community environments. In pursuing these mandates, ATSDR's mission is to prevent exposure and adverse human health effects and diminished quality of life associated with exposure to hazardous substances from waste sites, unplanned releases, and other sources of pollution present in the environment. There are more than 2,000 toxic substances found at hazardous waste sites in the United States. ATSDR has developed a prioritized list of 275 substances that pose the greatest hazard to human health. In conducting its work ATSDR has identified data gaps in knowledge about the toxicity of various hazardous substances as well as gaps in human exposure characterization. As part of its mandate, ATSDR initiated a Substance-Specific Applied Research Program (SSARP) to address these data gaps. The ATSDR Great Lakes Human Health Effects Research Program (GLHHERP) is a congressionally-mandated research program that characterizes exposure to persistent toxic substances and investigates the potential for adverse health outcome in at-risk populations. The research findings from this program in the areas of exposure, sociodemographic data, and health effects have significant public health implications for ATSDR's Superfund research activities.

Applications of computational toxicology methods at the Agency for Toxic Substances and Disease Registry.

In its efforts to provide consultations to state and local health departments, other federal agencies, health professionals, and the public on the health effects of environmental pollutants, the Agency for Toxic Substances and Disease Registry relies on the latest advances in computational toxicology. The computational toxicology laboratory at the agency is continually engaged in developing and applying models for decision-support tools such as physiologically based pharmacokinetic (PBPK) models, benchmark dose (BMD) models, and quantitative structure-activity relationship (QSAR) models. PBPK models are suitable for connecting exposure scenarios to biological indicators such as tissue dose or end point response. The models are used by the agency to identify the significance of exposure routes in producing tissue levels of possible contaminants for people living near hazardous waste sites. Additionally, PBPK models provide a credible scientific methodology for route-to-route extrapolations of health guidance values, which are usually determined from a very specific set of experiments. Also, scientists at the computational toxicology laboratory are using PBPK models for advancing toxicology research in such areas as joint toxicity assessment and child-based toxicity assessments. With BMD modeling, all the information embedded in an experimentally determined dose-response relationship is used to estimate, with minimum extrapolations, human health guidance values for environmental substances. Scientists in the laboratory also rely on QSAR models in the many cases where consultations from the agency are reported for chemicals that lack adequate experimental documentation.

Evaluating toxicologic end points to derive minimal risk levels for hazardous substances.

The Agency for Toxic Substances and Disease Registry (ATSDR) uses chemical-specific minimal risk levels (MRLs) to assist in evaluating public health risks associated with exposure to hazardous substances. MRLs are estimates of daily human exposure to a chemical that are likely to be without an appreciable risk of adverse noncancer health effects over a specified duration of exposure. MRLs serve as screening levels for health assessors to identify contaminants and potential health effects that may be of concern for populations living near hazardous waste sites and chemical releases. MRLs are derived from toxicologic data complied from a comprehensive literature search and are presented in ATSDR's toxicological profile for that substance. They are based on the most sensitive substance-induced end point considered to be of relevance to humans. MRLs for each substance are derived for acute (1-14 days), intermediate (15-364 days), and chronic (365 days and longer) exposure durations, and for the oral and inhalation routes of exposure. In this paper, we present an overview of the approach used for evaluating the toxicologic end points in deriving the MRLs. Examples are given to illustrate the agency's efforts to achieve increased understanding, reduced uncertainty and improved public health guidance.