Ashby J, Tennant R W, Zeiger E, Stasiewicz S
ICI Central Toxicology Laboratory, Alderley Park, Cheshire, Great Britain.
Mutat Res. 1989 Jun;223(2):73-103. doi: 10.1016/0165-1218(89)90037-2.
This paper is an extension and update of an earlier review published in this journal (Ashby and Tennant, 1988). A summary of the rodent carcinogenicity bioassay data on a further 42 chemicals tested by the U.S. National Toxicology Program (NTP) is presented. An evaluation of each chemical for structural alerts to DNA-reactivity is also provided, together with a summary of its mutagenicity to Salmonella. The 42 chemicals were numbered and evaluated as an extension of the earlier analysis of 222 NTP chemicals. The activity patterns and conclusions derived from the earlier study remain unchanged for the larger group of 264 chemicals. Based on the extended database of 264 NTP chemicals, the sensitivity of the Salmonella assay for rodent carcinogens is 58% and the specificity for the non-carcinogens is 73%. A total of 32 chemicals were defined as equivocal for carcinogenicity and, of these, 11 (34%) are mutagenic to Salmonella. An evaluation is made of instances where predictions of carcinogenicity, based on structural alerts, disagree with the Salmonella mutagenicity result (12% of the database). The majority of the disagreements are for structural alerts on non-mutagens, and that places these alerts as a sensitive primary screen with a specificity lower than that of the Salmonella assay. That analysis indicates some need for assays complementary to the Salmonella test when screening for potential genotoxic carcinogens. It also reveals that the correlation between structural alerts and mutagenicity to Salmonella is probably greater than 90%. Chemicals predicted to show Michael-type alkylating activity (i.e., CH2 = CHX; where X = an electron-withdrawing group, e.g. acrylamide) have been confirmed as a structural alert, and the halomethanes (624 are possible) have been classified as structurally-alerting. To this end an extended carcinogen-alert model structure is presented. Among the 138 NTP carcinogens now reviewed, 45 (33%) are non-mutagenic to Salmonella and possess a chemical structure that does not alert to DNA-reactivity. These carcinogens therefore either illustrate the need for complementary genetic screening tests to the Salmonella assay, or they represent the group of non-genotoxic carcinogens referred to most specifically by Weisburger and Williams (1981); the latter concept is favoured.
本文是对发表于本期刊的一篇早期综述（阿什比和坦南特，1988年）的扩展与更新。文中呈现了美国国家毒理学计划（NTP）对另外42种化学品进行啮齿动物致癌性生物测定的数据总结。还对每种化学品进行了DNA反应性结构警示评估，并总结了其对沙门氏菌的致突变性。这42种化学品被编号，并作为对早期222种NTP化学品分析的扩展进行评估。对于这264种化学品组成的更大群体而言，早期研究得出的活性模式和结论保持不变。基于264种NTP化学品的扩展数据库，沙门氏菌试验对啮齿动物致癌物的敏感性为58%，对非致癌物的特异性为73%。共有32种化学品被定义为致癌性不明确，其中11种（34%）对沙门氏菌有致突变性。对基于结构警示预测致癌性与沙门氏菌致突变性结果不一致的情况进行了评估（占数据库的12%）。大多数不一致情况是关于非诱变剂的结构警示，这使得这些警示成为一种敏感的初步筛选方法，但其特异性低于沙门氏菌试验。该分析表明，在筛选潜在的遗传毒性致癌物时，需要一些与沙门氏菌试验互补的检测方法。分析还表明，结构警示与对沙门氏菌的致突变性之间的相关性可能大于90%。预测显示迈克尔型烷基化活性的化学品（即CH2 = CHX；其中X = 吸电子基团，如丙烯酰胺）已被确认为一种结构警示，卤代甲烷（共624种可能）已被归类为具有结构警示性。为此，提出了一个扩展的致癌物警示模型结构。在目前审查的138种NTP致癌物中，45种（33%）对沙门氏菌无致突变性，且其化学结构不显示DNA反应性警示。因此，这些致癌物要么表明需要对沙门氏菌试验进行互补的遗传筛选检测，要么代表了魏斯伯格和威廉姆斯（1981年）最明确提及的非遗传毒性致癌物群体；后一种观点更受青睐。
