Butterworth B E, Conolly R B, Morgan K T
Chemical Industry Institute of Toxicology, (CIIT), Research Triangle Park, NC 27709, USA.
Cancer Lett. 1995 Jun 29;93(1):129-46. doi: 10.1016/0304-3835(95)03794-W.
The current standard approach for assessing carcinogenic potential is to conduct a near lifetime rodent pathology study with the high dose set to the maximum tolerated dose (MTD) of the test chemical. The linearized multistage model is then used as the default approach to estimate the potential human cancer risk at environmental elvels of the chemical. There is an increasing appreciation in the scientific and regulatory communities that chemical carcinogens differ dramatically in potency, exhibit a high degree of tissue and species specificity, and act through different modes of action. This paper advocates a decision tree strategy for classifying carcinogens that are acting primarily through genotoxic, cytotoxic, or mitogenic pathways. A primary concern is whether the chemical has direct genotoxic potential resulting from DNA reactivity or clastogenicity of the compound or its metabolite(s). Knowledge of the exposure-response curve for cytotoxicity is important because initiation and promotion events may occur secondary to a variety of associated activities such as regenerative cell proliferation. Mitogens indice direct stimulation of growth and may provide a selective growth advantage to spontaneously initiated precancerous cells. Of particular concern is the situation where pathological changes induced during the course of the treatment at high doses near the MTD are absent at lower, environmentally relevant, doses. If the tumor response is coincident with the preceding toxic response, it may not be justified to use the high-dose data in extrapolating to expected responses at low environmental exposures where no induced tissue abnormalities occur. Suggestions are presented for appropriate risk assessment approaches for different modes of action. Examples discussed are formaldehyde, a weakly genotoxic rodent nasal carcinogen; chloroform, a nongenotoxic-cytotoxic rodent liver and kidney carcinogen; and phenobarbital, a nongenotoxic-mitogenic rodent liver carcinogen.
当前评估致癌潜力的标准方法是进行一项近终生的啮齿动物病理学研究，将高剂量设定为受试化学品的最大耐受剂量（MTD）。然后，线性化多阶段模型被用作默认方法，以估计该化学品在环境水平下对人类的潜在癌症风险。科学界和监管界越来越认识到，化学致癌物在效力上有很大差异，表现出高度的组织和物种特异性，并通过不同的作用方式起作用。本文提倡采用决策树策略对主要通过遗传毒性、细胞毒性或促有丝分裂途径起作用的致癌物进行分类。一个主要关注点是该化学品是否因化合物或其代谢物的DNA反应性或致断裂性而具有直接遗传毒性潜力。了解细胞毒性的暴露-反应曲线很重要，因为引发和促进事件可能继发于各种相关活动，如再生细胞增殖。促有丝分裂原可直接刺激生长，并可能为自发引发的癌前细胞提供选择性生长优势。特别令人担忧的是，在接近MTD的高剂量治疗过程中诱导的病理变化在较低的、与环境相关的剂量下不存在的情况。如果肿瘤反应与先前的毒性反应一致，那么在推断低环境暴露下预期反应（此时未发生诱导的组织异常）时使用高剂量数据可能不合理。针对不同作用方式提出了适当的风险评估方法建议。讨论的例子包括甲醛，一种弱遗传毒性的啮齿动物鼻腔致癌物；氯仿，一种非遗传毒性-细胞毒性的啮齿动物肝脏和肾脏致癌物；以及苯巴比妥，一种非遗传毒性-促有丝分裂的啮齿动物肝脏致癌物。
