creator: Calabrese, Edward J.
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A Toxicological Basis to Derive a Generic Interspecies Uncertainty Factor
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.
- – 1994-01-01
- – application/pdf
Daily Estimates of Soil Ingestion in Children
description- – Soil ingestion estimates play an important role in risk assessment of contaminated sites, and estimates of soil ingestion in children are of special interest. Current estimates of soil ingestion are trace-element specific and vary widely among elements. Although expressed as daily estimates, the actual estimates have been constructed by averaging soil ingestion over a study period of several days. The wide variability has resulted in uncertainty as to which method of estimation of soil ingestion is best. We developed a methodology for calculating a single estimate of soil ingestion for each subject for each day. Because the daily soil ingestion estimate represents the median estimate of eligible daily trace-element-specific soil ingestion estimates for each child, this median estimate is not trace-element specific. Summary estimates for individuals and weeks are calculated using these daily estimates. Using this methodology, the median daily soil ingestion estimate for 64 children participating in the 1989 Amherst soil ingestion study is 13 mg/day or less for 50% of the children and 138 mg/day or less for 95% of the children. Mean soil ingestion estimates (for up to an 8-day period) were 45 mg/day or less for 50% of the children, whereas 95% of the children reported a mean soil ingestion of 208 mg/day or less. Daily soil ingestion estimates were used subsequently to estimate the mean and variance in soil ingestion for each child and to extrapolate a soil ingestion distribution over a year, assuming that soil ingestion followed a log-normal distribution.
- – 1995-03-01
- – application/pdf
Soil Ingestion: A Concern for Acute Toxicity in Children
description- – Several soil ingestion studies have indicated that some children ingest substantial amounts of soil on given days. Although the EPA has assumed that 95% of children ingest 200 mg soil/day or less for exposure assessment purposes, some children have been observed to ingest up to 25-60 g soil during a single day. In light of the potential for children to ingest such large amounts of soil, an assessment was made of the possibility for soil pica episodes to result in acute intoxication from contaminant concentrations the EPA regards as representing conservative screening values (i.e., EPA soil screening levels and EPA Region III risk-based concentrations for residential soils) . For a set of 13 chemicals included in the analysis, contaminant doses resulting from a one-time soil pica episode (5-50 g of soil ingested) were compared with acute dosages shown to produce toxicity in humans in clinical studies or case reports. For four of these chemicals, a soil pica episode was found to result in a contaminant dose approximating or exceeding the acute human lethal dose. For five of the remaining chemicals, the contaminant dose from a soil pica episode was well within the reported dose range in humans for toxicity other than lethality. Because both the exposure episodes and the toxicological response information are derived from observations in humans, these findings are regarded as particularly relevant for human health risk assessment. They suggest that, for some chemicals, ostensibly conservative soil criteria based on chronic exposure using current EPA methodology may not be protective of children during acute soil pica episodes.
- – 1997-12-01
- – application/pdf
Hormesis as a Biological Hypothesis
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.
- – U-shaped
- – 1998-02-01
- – application/pdf
U-Shaped Dose-Responses in Biology, Toxicology, and Public Health
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.
- – 2001-01-01
- – application/pdf
Hormesis: The Dose-response Revolution
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.
- – 2003-01-01
- – application/pdf
The Importance of Hormesis to Public Health
description- – Background: Hormesis is a specific type of nonmonotonic dose response whose occurrence has been documented across a broad range of biological models, diverse types of exposure, and a variety of outcomes. The effects that occur at various points along this curve can be interpreted as beneficial or detrimental, depending on the biological or ecologic context in which they occur. Objective: Because hormesis appears to be a relatively common phenomenon that has not yet been incorporated into regulatory practice, the objective of this commentary is to explore some of its more obvious public health and risk assessment implications, with particular reference to issues raised recently within this journal by other authors. Discussion: Hormesis appears to be more common than dose-response curves that are currently used in the risk assessment process [e.g., linear no-threshold (LNT) ]. Although a number of mechanisms have been identified that explain many hormetic dose-response relationships, better understanding of this phenomenon will likely lead to different strategies not only for the prevention and treatment of disease but also for the promotion of improved public health as it relates to both specific and more holistic health outcomes. Conclusions: We believe that ignoring hormesis is poor policy because it ignores knowledge that could be used to improve public health.
- – U-shaped
- – 2006-11-01
- – application/pdf
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