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DOI10.3109/10408444.2013.853726
Shape and steepness of toxicological dose-response relationships of continuous endpoints
Slob, Wout1; Setzer, R. Woodrow2
发表日期2014-03-01
ISSN1040-8444
卷号44期号:3页码:270-297
英文摘要

A re-analysis of a large number of historical dose-response data for continuous endpoints indicates that an exponential or a Hill model with four parameters adequately describes toxicological dose-responses. No exceptions were found for the datasets considered, which related to a wide variety of endpoints and to both in vivo and in vitro studies of various types. For a given endpoint/study type dose-response shapes were found to be homogenous among chemicals in the in vitro studies considered, while a mild among-chemical variation in the steepness parameter seemed to be present in the in vivo studies. Our findings have various practical consequences. For continuous endpoints, model selection in the BMD approach is not a crucial issue. The often applied approach of using constraints on the model parameters to prevent "infinite" slopes at dose zero in fitting a model is not in line with our findings, and appears to be unjustified. Instead, more realistic ranges of parameter values could be derived from re-analyses of large numbers of historical dose-response datasets in the same endpoint and study type, which could be used as parameter constraints in future individual datasets. This approach will be particularly useful for weak datasets (e.g. few doses, much scatter). In addition, this approach may open the way to use fewer animals in future studies. In the discussion, we argue that distinctions between linear, sub/supralinear or thresholded dose-response shapes, based on visual inspection of plots, are not biologically meaningful nor useful for risk assessment.


英文关键词BMD;dose-response shape;historical data;linearity;model uncertainty;parameter constraints;sublinearity;threshold
语种英语
WOS记录号WOS:000331848100003
来源期刊CRITICAL REVIEWS IN TOXICOLOGY
来源机构美国环保署
文献类型期刊论文
条目标识符http://gcip.llas.ac.cn/handle/2XKMVOVA/58531
作者单位1.Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands;
2.US EPA, Natl Ctr Computat Toxicol, Res Triangle Pk, NC 27711 USA
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Slob, Wout,Setzer, R. Woodrow. Shape and steepness of toxicological dose-response relationships of continuous endpoints[J]. 美国环保署,2014,44(3):270-297.
APA Slob, Wout,&Setzer, R. Woodrow.(2014).Shape and steepness of toxicological dose-response relationships of continuous endpoints.CRITICAL REVIEWS IN TOXICOLOGY,44(3),270-297.
MLA Slob, Wout,et al."Shape and steepness of toxicological dose-response relationships of continuous endpoints".CRITICAL REVIEWS IN TOXICOLOGY 44.3(2014):270-297.
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