Chemical risk assessment and uncertainty associated with extrapolation across exposure duration.

The Agency for Toxic Substances and Disease Registry (ATSDR) prepares toxicological profiles on priority substances in which available epidemiologic and toxicologic data are reviewed, summarized, and interpreted. When adequate data are available, ATSDR derives health guidance values called minimal risk levels (MRLs) for acute, intermediate, and chronic durations of exposure for oral and inhalation routes of exposure. The MRLs are generally derived by use of the no-observed-adverse-effect level (NOAEL) or the lowest-observed-adverse-effect level/uncertainty factor (LOAEL/UF) approach. The UF usually employed are for LOAEL-to-NOAEL extrapolation, animal to -human extrapolation, and inter-human variability. These health guidance values are intended to serve as screening tools for health assessors and other responders to identify contaminants of concern and potential health effects in the community at hazardous waste sites and during unplanned releases. When guidance values are not available for a specific exposure scenario because of a lack of chronic data, extrapolation across exposure durations may be made. For example, chronic guidance values may be derived from subchronic data by applying an additional uncertainty factor of 10 for extrapolation to chronic exposure duration. In this paper, we analyzed the ratio of chemical-specific LOAELs from acute to intermediate and from intermediate to chronic durations for oral and inhalation exposure routes. In addition, we investigated the impact of chemical structure and chemical structure activity relationship on validation of predictions across exposure durations.

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.

Aluminum toxicokinetics regarding infant diet and vaccinations.

Some vaccines contain aluminum adjuvants to enhance the immunological response, and it has been postulated that this aluminum could contribute to adverse health effects, especially in children who receive a vaccination series starting at birth. The pharmacokinetic properties and end-point toxicities of aluminum are presented. In assessing the relevance of dietary and medical aluminum exposure to public health, we estimated infant body burdens during the first year of life for breast milk and formula diets and for a standard vaccination schedule. We then compared those body burdens with that expected for intake at a level considered safe for intermediate-duration exposure. The methodology blends intake values and uptake fractions with an aluminum retention function derived from a human injection study using radioactive 26Al. The calculated body burden of aluminum from vaccinations exceeds that from dietary sources, however, it is below the minimal risk level equivalent curve after the brief period following injection.