creator: Baldwin, Linda A.
description- – The use of an uncertainty factor (UF) to account for interspecies variation in risk assessment procedures for noncarcinogens is well known and implemented by regulatory agencies at the federal and state levels. The approach that has been widely adopted is to assume that humans may be 10- fold more sensitive than the animal model. This factor of 10 has become routinely adopted in essentially all risk assessment procedures involving animal model data for extrapolation. Despite the long-standing use of the interspecies UF of 10, only limited biological and/or toxicological justification for the interspecies UF has ever been put forth by any regulatory agency (1) or national advisory committee (e.g., National Academy of Sciences Safe Drinking Committee). The adoption of the 10-fold factor appears to have been based on a combination of public health protection philosophy, practical/ intuitive toxicological insights based on experience, and a sense that it achieves its goal of protecting human health. The present paper offers what the authors we believe to be a toxicological and statistically defensible foundation for deriving the interspecies UF, its database requirements, and statistical procedures for its derivation. In brief, the recommended interspecies UF is defined as the 95% of the population of 95% prediction intervals (PI) for binary interspecies comparisons based on phylogenetic relatedness. More specifically, the UF is derived by determining the minimum ratio of the estimated toxicity value and its 95% upper or lower PI after back-transformation from the logarithmic expression. This paper presents the toxicological and statistical basis for this proposal and its implications for judging the reliability of current regulatory interspecies UF procedures as well as offering a fundamentally novel approach to deriving an interspecies UF.
collectiondatepublishercreatorformat description- – A comprehensive effort was undertaken to identify articles demonstrating chemical hormesis. Nearly 4000 potentially relevant articles were retrieved from preliminary computer database searches by using various key word descriptors and extensive cross-referencing. A priori evaluation criteria were established including study design features (e.g., number of doses, dose range) , statistical analysis, and reproducibility of results. Evidence of chemical hormesis was judged to have occurred in approximately 350 of the 4000 studies evaluated. Chemical hormesis was observed in a wide range of taxonomic groups and involved agents representing highly diverse chemical classes, many of potential environmental relevance. Numerous biological end points were assessed ; growth responses were the most prevalent, followed by metabolic effects, longevity, reproductive responses, and survival. Hormetic responses were generally observed to be of limited magnitude. The average low-dose maximum stimulation was approximately 50% greater than controls. The hormetic dose-response range was generally limited to about one order of magnitude, with the upper end of the hormetic curve approaching the estimated no observable effect level for the particular end point. Based on the evaluation criteria, high to moderate evidence of hormesis was observed in studies comprised of>6 doses ; with>3 doses in the hormetic zone. The present analysis suggests that chemical hormesis is a reproducible and relatively common biological phenomenon. A quantitative scheme is presented for future application to the database.
subjectcollectiondatepublishercreatorformat description- – The occurrence of U-shaped dose-response relationships (often termed hormesis) has been documented in numerous biological, toxicological, and pharmacological investigations. Many of the endpoints studied are of considerable significance to public health (e.g. body weight, cholesterol levels, ethanol consumption, longevity, cancer incidence, etc). Despite the fact that U-shaped dose-responses are widely and independently observed, little attempt has been made to assess this phenomenon in an integrative manner. This review provides an overview of the historical foundations of hormesis and a discussion of its definition within a mechanistic framework. The occurrence, generalizability, and biological significance of U-shaped dose-response relationships along with the concept of biological optimality are addressed.
subjectcollectiondatepublishercreatorformat description- – Hormesis, a dose-response relationship phenomenon characterized by low-dose stimulation and high-dose inhibition, has been frequently observed in properly designed studies and is broadly generalizable as being independent of chemical/physical agent, biological model, and endpoint measured. This under-recognized and -appreciated concept has the potential to profoundly change toxicology and its related disciplines with respect to study design, animal model selection, endpoint selection, risk assessment methods, and numerous other aspects, including chemotherapeutics. This article indicates that as a result of hormesis, fundamental changes in the concept and conduct of toxicology and risk assessment should be made, including (a) the definition of toxicology, (b) the process of hazard (e.g., including study design, selection of biological model, dose number and distribution, endpoint measured, and temporal sequence) and risk assessment [e.g., concept ofNOAEL (no observed adverse effect level), lowdose modeling, recognition of beneficial as well as harmful responses] for all agents, and (c) the harmonization of cancer and noncancer risk assessment.
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