An evaluation of benchmark dose methodology for non-cancer continuous-data health effects in animals due to exposures to dioxin (TCDD)

Gaylor, David W. and Aylward, Lesa L. (2004) An evaluation of benchmark dose methodology for non-cancer continuous-data health effects in animals due to exposures to dioxin (TCDD). Regulatory Toxicology and Pharmacology, 40 1: 9-17. doi:10.1016/j.yrtph.2004.04.002

Author Gaylor, David W.
Aylward, Lesa L.
Title An evaluation of benchmark dose methodology for non-cancer continuous-data health effects in animals due to exposures to dioxin (TCDD)
Journal name Regulatory Toxicology and Pharmacology   Check publisher's open access policy
ISSN 0273-2300
Publication date 2004-08
Sub-type Critical review of research, literature review, critical commentary
DOI 10.1016/j.yrtph.2004.04.002
Open Access Status Not yet assessed
Volume 40
Issue 1
Start page 9
End page 17
Total pages 9
Place of publication Maryland Heights, MO, United States
Publisher Academic Press
Language eng
Subject 3005 Toxicology
Formatted abstract
The U.S. Environmental Protection Agency (EPA) has conducted extensive reviews and analyses of health effects associated with exposures to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. Because the carcinogenicity of TCDD has received considerable attention from EPA and others, this paper focuses on animal data for non-cancer health effects that sometimes appear to be almost as sensitive as cancer to TCDD exposures. Benchmark dose (BMD) methodology can be used to identify point-of-departure (POD) estimates for use in derivation of reference doses or evaluation of margins of exposure. However, selection of an appropriate BMD methodology for assessment of non-cancer data, which are usually continuous (non-quantal), needs to be considered. One option available for a benchmark dose is to use a small percentage change in the mean response relative to the estimated maximum effect of TCDD at large doses. The benchmark based on a change estimated to equal 1% of the estimated maximum change from background to the asymptotic response at large doses (denoted as the relative ED01) was used by EPA in a reassessment of TCDD health risks. A lower confidence limit (LED01) could serve as a point of departure for setting a reference dose (RfD). This is a somewhat arbitrary effect level, generally within the background range of variation among unexposed animals, with an unknown risk. An alternative approach is recommended in which the risk of abnormal levels can be estimated. For continuous-data effects, a low and/or high percentile (e.g., 1st and/or 99th) in unexposed control animals can be used to define abnormal (not necessarily adverse) levels. From a dose-response curve and the standard deviation, it is possible to estimate the excess risk (proportion) of animals with abnormal levels as a function of dose for normally distributed levels. With this approach, the risk-based benchmark dose (BMD01) represents the dose with an estimated excess risk of 1% of the animals in the abnormal range rather than an arbitrary change in the value of the measured endpoint. Values for the relative and risk-based benchmark doses are computed from published data for a variety of non-cancer health effects associated with exposure to TCDD. For the 30 cases investigated, the BMD01 tended to vary around the lowest experimental dose tested, whereas the relative ED01 tended to be about a factor of three below the lowest dose, and the BMD01 was more precisely estimated than the ED01 as reflected by narrower confidence intervals. The BMDL01 values were on average more than fivefold higher than the corresponding LED01 values. However, these values still provide a conservative assessment for POD assessment, because the BMDL01 tends to be about an order of magnitude lower (more conservative) than the no-observed-adverse-effect level. This analysis demonstrates the potential impact of alternative choices in benchmark dose methodology. In combination with selection of appropriate adverse health effect endpoint(s) and studies, use of the risk-based BMD results in identification of more valid and meaningful POD estimates for non-cancer effects compared to the use of the relative ED approach.
Keyword Benchmark dose
Continuous data
Non-cancer health effects
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Critical review of research, literature review, critical commentary
Collection: National Research Centre for Environmental Toxicology Publications
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Citation counts: TR Web of Science Citation Count  Cited 20 times in Thomson Reuters Web of Science Article | Citations
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