Legator M S, Ward J B
University of Texas Medical Branch, Department of Preventive Medicine and Community Health, Galveston 77550.
Mutat Res. 1991 Sep-Oct;250(1-2):457-65. doi: 10.1016/0027-5107(91)90202-y.
Mutagenicity studies have been used to identify specific agents as potential carcinogens or other human health hazards; however, they have been used minimally for risk assessment or in determining permissible levels of human exposure. The poor predictive value of in vitro mutagenesis tests for carcinogenic activity and a lack of mechanistic understanding of the roles of mutagens in the induction of specific cancers have made these tests unattractive for the purpose of risk assessment. However, the limited resources available for carcinogen testing and large number of chemicals which need to be evaluated necessitate the incorporation of more efficient methods into the evaluation process. In vivo genetic toxicity testing can be recommended for this purpose because in vivo assays incorporate the metabolic activation pathways that are relevant to humans. We propose the use of a multiple end-point in vivo comprehensive testing protocol (CTP) using rodents. Studies using sub-acute exposure to low levels of test agents by routes consistent with human exposure can be a useful adjunct to methods currently used to provide data for risk assessment. Evaluations can include metabolic and pharmacokinetic endpoints, in addition to genetic toxicity studies, in order to provide a comprehensive examination of the mechanism of toxicity of the agent. A parallelogram approach can be used to estimate effects in non-accessible human tissues by using data from accessible human tissues and analogous tissues in animals. A categorical risk assessment procedure can be used which would consider, in order of priority, genetic damage in man, genetic damage in animals that is highly relevant to disease outcome (mutation, chromosome damage), and data from animals that is of less certain relevance to disease. Action levels of environmental exposure would be determined based on the lowest observed effect levels or the highest observed no effect levels, using sub-acute low level exposure studies in rodents. As an example, the known genotoxic effects of benzene exposure at low levels in man and animals are discussed. The lowest observed genotoxic effects were observed at about 1-10 parts per million for man and 0.04-0.1 parts per million in subacute animal studies. If genetic toxicity is to achieve a prominent role in evaluating carcinogens and in characterizing germ-cell mutagens, minimal testing requirements must be established to ascertain the risks associated with environmental mutagen exposure. The use of the in vivo approach described here should provide the information needed to meet this goal.(ABSTRACT TRUNCATED AT 400 WORDS)
致突变性研究已被用于识别特定物质是否为潜在致癌物或其他人类健康危害；然而，它们在风险评估或确定人类可接触的允许水平方面的应用却非常有限。体外诱变试验对致癌活性的预测价值不佳，且对诱变剂在特定癌症诱发过程中所起作用缺乏机制上的理解，这使得这些试验对于风险评估而言并不具有吸引力。然而，用于致癌物检测的资源有限，而需要评估的化学物质数量众多，因此有必要将更有效的方法纳入评估过程。为此，可推荐进行体内遗传毒性检测，因为体内试验纳入了与人类相关的代谢活化途径。我们建议使用一种针对啮齿动物的多终点体内综合检测方案（CTP）。通过与人类接触途径一致的方式对低水平受试物进行亚急性暴露的研究，可作为目前用于提供风险评估数据的方法的有益补充。评估可包括代谢和药代动力学终点，以及遗传毒性研究，以便全面考察受试物的毒性机制。可采用平行四边形方法，利用来自可获取的人体组织和动物类似组织的数据，来估计难以获取的人体组织中的效应。可采用一种分类风险评估程序，该程序将按优先顺序考虑人类的遗传损伤、与疾病结果高度相关的动物遗传损伤（突变、染色体损伤），以及与疾病相关性不太确定的动物数据。环境暴露的行动水平将根据在啮齿动物中进行的亚急性低水平暴露研究中观察到的最低效应水平或最高无效应水平来确定。例如，文中讨论了已知的人类和动物低水平接触苯的遗传毒性效应。在人类中，约百万分之一至百万分之十时观察到最低的遗传毒性效应，在亚急性动物研究中为百万分之零点零四至百万分之零点一。如果遗传毒性要在评估致癌物和表征生殖细胞诱变剂方面发挥重要作用，就必须确定最低检测要求，以确定与环境诱变剂暴露相关的风险。使用本文所述的体内方法应能提供实现这一目标所需的信息。（摘要截选至400字）
