Bogdanffy M S, Mathison B H, Kuykendall J R, Harman A E
Haskell Laboratory for Toxicology and Industrial Medicine, E.I. du Pont de Nemours and Co., Inc., Newark, DE 19714, USA.
Mutat Res. 1997 Oct 31;380(1-2):125-41.
Anatomical, physiological, biochemical and molecular factors that contribute to chemical-induced nasal carcinogenesis are either largely divergent between test species and humans, or we know very little of them. These factors, let alone the uncertainty associated with our knowledge gap, present a risk assessor with the formidable task of making judgments about risks to human health from exposure to chemicals that have been identified in rodent studies to be nasal carcinogens. This paper summarizes some of the critical attributes of the hazard identification and dose-response aspects of risk assessments for nasal carcinogens that must be accounted for by risk assessors in order to make informed decisions. Data on two example compounds, dimethyl sulfate and hexamethylphosphoramide, are discussed to illustrate the diversity of information that can be used to develop informed hypotheses about mode of action and decisions on appropriate dosimeters for interspecies extrapolation. Default approaches to interspecies dosimetry extrapolation are described briefly and are followed by a discussion of a generalized physiologically based pharmacokinetic model that, unlike default approaches, is flexible and capable of incorporating many of the critical species-specific factors. Recent advancements in interspecies nasal dosimetry modeling are remarkable. However, it is concluded that without the development of research programs aimed at understanding carcinogenic susceptibility factors in human and rodent nasal tissues, development of plausible modes of action will lag behind the advancements made in dosimetry modeling.
导致化学物质诱发鼻腔癌的解剖学、生理学、生物化学和分子因素，在实验物种和人类之间要么存在很大差异，要么我们对此知之甚少。这些因素，更不用说与我们的知识差距相关的不确定性了，给风险评估者带来了一项艰巨的任务，即判断接触在啮齿动物研究中已被确定为鼻腔致癌物的化学物质对人类健康的风险。本文总结了鼻腔致癌物风险评估中危害识别和剂量反应方面的一些关键属性，风险评估者在做出明智决策时必须考虑这些属性。讨论了两种示例化合物硫酸二甲酯和六甲基磷酰胺的数据，以说明可用于形成关于作用模式的明智假设以及关于种间外推合适剂量计的决策的信息多样性。简要描述了种间剂量学外推的默认方法，随后讨论了一种基于生理学的广义药代动力学模型，该模型与默认方法不同，具有灵活性，能够纳入许多关键的物种特异性因素。种间鼻腔剂量学建模的最新进展显著。然而，得出的结论是，如果不开展旨在了解人类和啮齿动物鼻腔组织致癌易感性因素的研究项目，合理作用模式的发展将落后于剂量学建模的进展。
