Pariza M W
Department of Food Microbiology and Toxicology, University of Wisconsin, Madison 53706.
Proc Natl Acad Sci U S A. 1992 Feb 1;89(3):860-1. doi: 10.1073/pnas.89.3.860.
Carcinogenic risk assessments are based on extrapolating from high-dose chronic rodent-feeding studies to human-exposure levels. A serious problem is that about half of all substances tested at their respective maximum tolerated dose (MTD) are found to induce cancer. The MTD as currently defined has been criticized because it may stimulate cell proliferation in susceptible tissues. Such chemically induced mitogenesis is postulated to increase the probability that neoplasia will develop at the affected site. It is proposed that, in the development of an MTD for a given substance, chemically induced mitogenesis be considered an undesirable toxic manifestation. Hence, mitogenesis should not be induced by a substance fed at its true MTD. Since MTDs determined in this fashion are likely to be lower than those developed using current criteria, an added level of protection is introduced by employing a safety factor similar to that used now in determining acceptable daily intakes for noncarcinogenic food additives. In calculating acceptable daily intakes, the usual safety factor is 100; i.e., the acceptable daily intake is set at 1% of the no-observed-effect level. Hence it is proposed that the acceptable daily level of exposure to a substance that does not induce cancer at its MTD as defined herein be set at 1% of that MTD. On the other hand, a chemical that induces cancer at its MTD as defined herein would continue to be regulated as is customary now.
致癌风险评估是基于从高剂量慢性啮齿动物喂养研究推断至人体暴露水平。一个严重的问题是，在各自最大耐受剂量（MTD）下进行测试的所有物质中，约有一半被发现会诱发癌症。目前定义的MTD受到了批评，因为它可能会刺激易感组织中的细胞增殖。这种化学诱导的有丝分裂被认为会增加受影响部位发生肿瘤的概率。有人提出，在确定给定物质的MTD时，化学诱导的有丝分裂应被视为一种不良的毒性表现。因此，以其真实MTD喂食的物质不应诱导有丝分裂。由于以这种方式确定的MTD可能低于使用当前标准制定的MTD，通过采用与目前用于确定非致癌食品添加剂可接受每日摄入量时使用的安全系数类似的安全系数，引入了额外的保护水平。在计算可接受每日摄入量时，通常的安全系数是100；即，可接受每日摄入量设定为未观察到效应水平的1%。因此，有人提议，对于在此定义的MTD下不诱发癌症的物质，其可接受每日暴露水平应设定为该MTD的1%。另一方面，在此定义的MTD下诱发癌症的化学物质将继续按照目前的惯例进行监管。
