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An empirical comparison of low-dose extrapolation from points of departure (PoD) compared to extrapolations based upon methods that account for model uncertainty.

Authors
Wheeler-MW; Bailer-AJ
Source
Regul Toxicol Pharmacol 2013 Oct; 67(1):75-82
NIOSHTIC No.
20042926
Abstract
Experiments with relatively high doses are often used to predict risks at appreciably lower doses. A point of departure (PoD) can be calculated as the dose associated with a specified moderate response level that is often in the range of experimental doses considered. A linear extrapolation to lower doses often follows. An alternative to the PoD method is to develop a model that accounts for the model uncertainty in the dose-response relationship and to use this model to estimate the risk at low doses. Two such approaches that account for model uncertainty are model averaging (MA) and semi-parametric methods. We use these methods, along with the PoD approach in the context of a large animal (40,000+ animal) bioassay that exhibited sub-linearity. When models are fit to high dose data and risks at low doses are predicted, the methods that account for model uncertainty produce dose estimates associated with an excess risk that are closer to the observed risk than the PoD linearization. This comparison provides empirical support to accompany previous simulation studies that suggest methods that incorporate model uncertainty provide viable, and arguably preferred, alternatives to linear extrapolation from a PoD.
Keywords
Risk-analysis; Risk-factors; Exposure-assessment; Statistical-analysis; Mathematical-models; Dose-response; Analytical-instruments; Analytical-models; Analytical-processes; Animals; Laboratory-animals; Bioassays; Simulation-methods; Models; Data-processing; Quantitative-analysis; Author Keywords: Benchmark doses; Cancer risk estimation; Dose-response data; Linear extrapolation; Model averaging; Semi parametric methods
Contact
Matthew W. Wheeler, Risk Evaluation Branch, National Institute for Occupational Safety and Health, 4626 Columbia Parkway, Cincinnati, OH 45226, USA
CODEN
RTOPDW
Publication Date
20131001
Document Type
Journal Article
Email Address
mwheeler@cdc.gov
Fiscal Year
2014
NTIS Accession No.
NTIS Price
Identifying No.
B20130805
Issue of Publication
1
ISSN
0273-2300
NIOSH Division
EID
Source Name
Regulatory Toxicology and Pharmacology : RTP
State
OH
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