Windows of sensitivity to toxic chemicals in the development of the endocrine system: an analysis of ATSDR's toxicological profile database.

This review utilizes the robust database of literature contained in toxicological profiles developed by the Agency for Toxic Substances and Disease Registry. The aim was to use this database to identify developmental toxicity studies reporting alterations in hormone levels in the developing fetus and offspring and identify windows of sensitivity. We identified 74 oral exposure studies in rats that provided relevant information on 30 chemicals from 21 profiles. Most studies located provided information on thyroid hormones, with fewer studies on anterior pituitary, adrenal medulla, ovaries, and testes. No studies pertaining to hormones of the posterior pituitary, pancreas, or adrenal cortex were located. The results demonstrate that development of the endocrine system may be affected by exposure to environmental contaminants at many different points, including gestational and/or lactational exposure. Moreover, this review demonstrates the need for more developmental toxicity studies focused on the endocrine system and specifically alterations in hormone levels.

Chemical mixtures: evaluation of risk for child-specific exposures in a multi-stressor environment.

Evaluating the health impact from exposure to chemical mixtures is multifaceted. One component is exposure. Exposure, and consequently risk assessment for mixtures and chemicals in general, are often viewed in terms of a given exposure to a given population at a given location over a given time period. However, environmental exposures are present throughout human lifetime. As a result, an evaluation of risk must include the distinctive characteristics related to chemical exposures which will impact risk depending upon the particular life stage where exposure occurs. Risks to offspring may be associated with unique exposures in utero, during infancy, childhood, or adolescent periods. For example, exposure of infants to anthropogenic chemicals via breast milk may be of concern. The Agency for Toxic Substances and Disease Registry's (ATSDR's) approach to evaluating risks associated with exposure to mixtures of chemicals is presented. In addition to the breast milk issues, indoor exposure to combined air pollutants, drinking water contaminants, and soil and dust contaminants are discussed. The difference between a mixture's risk evaluation for children and adults is in the distinct exposure scenarios resulting from variations in behavior, physiology, and/or pharmacokinetics between adults and children rather than in the method for the specific mixtures evaluation per se.

Health effects classification and its role in the derivation of minimal risk levels: immunological effects.

The Agency for Toxic Substances and Disease Registry (ATSDR) derives health-based guidance values known as minimal risk levels (MRLs). By definition, an MRL is a substance-specific estimate of the daily human exposure to a substance that is likely to be without an appreciable risk of adverse, noncancer effects over a specified duration of exposure. MRLs are preferentially derived from human studies, if available, or from the most sensitive animal species and the endpoint that is most relevant for humans. To date, the agency has derived 346 MRLs. Fifteen MRLs were derived for 11 different chemicals where the database has identified the immune system as the most sensitive target of toxicity. The chemicals include benzene, chlorfenvinphos, endosulfan, heptachlor, gamma-hexachlorocyclohexane, dibutyl tin, tributyl tin, PCBs, 2,3,4,7,8-pentachlorodibenzofuran, 2,3,7,8-tetrachlorodibenzo-p-dioxin, and 2,4-dichlorophenol. The agency's rationale for classification of immunological endpoints is discussed and a brief description given of the critical studies selected for MRL development using immune system endpoints.

The use of hematological effects in the development of minimal risk levels.

The Agency for Toxic Substances and Disease Registry (ATSDR) derives minimal risk levels (MRLs) to assist in evaluating risk of adverse health effects in individuals exposed to hazardous substances. MRLs are derived from published values identifying no-observed-adverse-effect levels (NOAELs) or lowest-observed-adverse-effect levels (LOAELs) in animal or human studies. The most sensitive end points are used. To date, 4 inhalation MRLs and 13 oral MRLs have been derived from hematological end points for 12 substances. This paper provides a brief overview of the hematological system, examples of hematological end points, and the MRL for substances with hematological end points.

Breast-feeding exposure of infants to cadmium, lead, and mercury: a public health viewpoint.

The purpose of this report is to provide an overview of the public health implications of exposure via breast milk to cadmium, lead, and mercury for nursing infants and to provide health-based guidance. Daily intakes were calculated and compared with guidance values used for public health assessments at hazardous waste sites. Cadmium, lead, and mercury under normal conditions are found in breast milk at concentration ranges of < 1 microgram/L, 2-5 micrograms/L, and 1.4-1.7 micrograms/L, respectively. Women exposed environmentally or occupationally can have higher levels in their breast milk. Concentrations of about 5 micrograms/L (cadmium), 20 micrograms/L (lead), and 3.5 micrograms/L (mercury) appear to be adequate screening levels. Many factors affect both the distribution of cadmium, lead, and mercury in breast milk and the health consequences to an infant. It is not clear what additional impact low-level exposure via breast milk may have on an infant born with a body burden to one of these metals. There is sufficient evidence to make the case that contaminated breast milk is a source of potential risk to infants in certain populations. Prevention strategies that include behavior modification and proper nutrition should be communicated to women at risk. Identification and elimination of exposure pathways and a critical analysis of the benefits of breast feeding versus heavy metal exposure are needed on a site-specific or individual basis. Research is required to better understand the impact of low-level exposure to heavy metals via breast milk. Breastfeeding should be encouraged under most circumstances.

Utilizing uncertainty factors in minimal risk levels derivation.

The Agency for Toxic Substances and Disease Registry (ATSDR) utilizes chemical-specific minimal risk levels (MRLs) to assist in evaluating public health risks associated with exposure to hazardous substances. During MRL derivation, uncertainty factors (UF) are used. Under current ATSDR methodology, default UFs of 10 are applied to extrapolate from a lowest-observed-adverse-effect level (LOAEL) to a no-observed-adverse-effect level (NOAEL), for interspecies extrapolation and for intraspecies variability. However, chemical-specific toxicity information has sometimes made it necessary and appropriate to deviate from using the standard UF of 10. Since its inception in January 1993 until December 1994, ATSDR's Inter-agency MRL Workgroup has derived 46 inhalation and 67 oral MRLs. When the substance-specific data permitted, the workgroup departed from the default UFs of 10 in 30 specific cases. Specific examples and rationales are presented in this paper.