Calabrese E J
Toxicology Program, University of Massachusetts, Amherst 01003.
Environ Health Perspect. 1988 Apr;77:55-62. doi: 10.1289/ehp.887755.
This paper assesses the capacity of animal models to predict human response to carcinogenic agents with consideration for the heterogeneity of humans. It is widely accepted that human susceptibility to toxic substances, including carcinogens, is highly variable. Conventional rodent models are usually highly inbred and valued for their ability to display characteristic homogeneity. Current practice assumes that the homogeneity of response to toxic agents, including carcinogens, in the rodent model will be representative of humans. The issue then becomes, To which of the broad spectrum of human responses are specific animal models likely to be related? This paper examines the extent of human heterogeneity over a broad range of biochemical characteristics (e.g., aryl hydrocarbon hydroxylase activity, epoxide hydrase activity, beta-glucuronidase activity, debrisoquine hydroxylation, DNA-adduct formation) with emphasis on those biochemical characteristics that affect responses to carcinogens. Examples are presented to compare the heterogeneity of selected animal models for these biochemical characteristics as they relate to the spectrum of human responses noted above. The paper presents a theoretical perspective for determining to which part of the human population response spectrum common animal models are most likely to be extrapolated.
本文评估了动物模型在考虑人类异质性的情况下预测人类对致癌剂反应的能力。人们普遍认为，人类对包括致癌物在内的有毒物质的易感性差异很大。传统的啮齿动物模型通常是高度近亲繁殖的，并因其显示出特征性同质性的能力而受到重视。目前的做法是假设啮齿动物模型中对包括致癌物在内的有毒物质的反应同质性将代表人类。那么问题就变成了，特定的动物模型可能与人类广泛的反应中的哪一种相关？本文研究了人类在广泛的生化特征（如芳烃羟化酶活性、环氧化物水解酶活性、β-葡萄糖醛酸酶活性、异喹胍羟化、DNA加合物形成）方面的异质性程度，重点关注那些影响对致癌物反应的生化特征。文中给出了一些例子，比较了所选动物模型在这些生化特征方面的异质性，以及它们与上述人类反应谱的关系。本文提出了一个理论观点，以确定常见动物模型最有可能外推到人类反应谱的哪一部分。
