Uncertainties in biologically-based modeling of formaldehyde-induced respiratory cancer risk: identification of key issues.
Uncertainties in biologically-based modeling of formaldehyde-induced respiratory cancer risk: identification of key issues.
复制标题
甲醛诱发呼吸道癌风险的生物学模型的不确定性：关键问题的确定。
DOI：
10.1111/j.1539-6924.2008.01083.x
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
White,Paul
中科院分区：
文献类型：
--
作者：
Subramaniam,RaviP;Chen,Chao;Crump,KennyS;Devoney,Danielle;Fox,JohnF;Portier,ChristopherJ;Schlosser,PaulM;Thompson,ChadM;White,Paul
In a series of articles and a health‐risk assessment report, scientists at the CIIT Hamner Institutes developed a model (CIIT model) for estimating respiratory cancer risk due to inhaled formaldehyde within a conceptual framework incorporating extensive mechanistic information and advanced computational methods at the toxicokinetic and toxicodynamic levels. Several regulatory bodies have utilized predictions from this model; on the other hand, upon detailed evaluation the California EPA has decided against doing so. In this article, we study the CIIT model to identify key biological and statistical uncertainties that need careful evaluation if such two‐stage clonal expansion models are to be used for extrapolation of cancer risk from animal bioassays to human exposure. Broadly, these issues pertain to the use and interpretation of experimental labeling index and tumor data, the evaluation and biological interpretation of estimated parameters, and uncertainties in model specification, in particular that of initiated cells. We also identify key uncertainties in the scale‐up of the CIIT model to humans, focusing on assumptions underlying model parameters for cell replication rates and formaldehyde‐induced mutation. We discuss uncertainties in identifying parameter values in the model used to estimate and extrapolate DNA protein cross‐link levels. The authors of the CIIT modeling endeavor characterized their human risk estimates as “conservative in the face of modeling uncertainties.” The uncertainties discussed in this article indicate that such a claim is premature.
