Ashby J, Tennant R W
ICI Central Toxicology Laboratory, Cheshire, Great Britain.
Mutat Res. 1991 May;257(3):229-306. doi: 10.1016/0165-1110(91)90003-e.
An analysis is presented in which are evaluated correlations among chemical structure, mutagenicity to Salmonella, and carcinogenicity to rats and mice among 301 chemicals tested by the U.S. NTP. Overall, there was a high correlation between structural alerts to DNA reactivity and mutagenicity, but the correlation of either property with carcinogenicity was low. If rodent carcinogenicity is regarded as a singular property of chemicals, then neither structural alerts nor mutagenicity to Salmonella are effective in its prediction. Given this, the database was fragmented and new correlations sought between the derived sub-groups. First, the 301 chemicals were segregated into six broad chemical groupings. Second, the rodent cancer data were partially segregated by target tissue. Using the previously assigned structural alerts to DNA reactivity (electrophilicity), the chemicals were split into 154 alerting chemicals and 147 non-alerting chemicals. The alerting chemicals were split into three chemical groups; aromatic amino/nitro-types, alkylating agents and miscellaneous structurally-alerting groups. The non-alerting chemicals were subjectively split into three broad categories; non-alerting, non-alerting containing a non-reactive halogen group, and non-alerting chemical with minor concerns about a possible structural alert. The tumor data for all 301 chemicals are re-presented according to these six chemical groupings. The most significant findings to emerge from comparisons among these six groups of chemicals were as follows: (a) Most of the rodent carcinogens, including most of the 2-species and/or multiple site carcinogens, were among the structurally alerting chemicals. (b) Most of the structurally alerting chemicals were mutagenic; 84% of the carcinogens and 66% of the non-carcinogens. 100% of the 33 aromatic amino/nitro-type 2-species carcinogens were mutagenic. Thus, for structurally alerting chemicals, the Salmonella assay showed high sensitivity and low specificity (0.84 and 0.33, respectively). (c) Among the 147 non-alerting chemicals less than 5% were mutagenic, whether they were carcinogens or non-carcinogens (sensitivity 0.04).
本文呈现了一项分析，该分析评估了美国国家毒理学计划（NTP）测试的301种化学物质的化学结构、对沙门氏菌的致突变性以及对大鼠和小鼠的致癌性之间的相关性。总体而言，对DNA反应性的结构警示与致突变性之间存在高度相关性，但这两种特性与致癌性的相关性都较低。如果将啮齿动物致癌性视为化学物质的单一特性，那么无论是结构警示还是对沙门氏菌的致突变性都无法有效地预测它。鉴于此，数据库被拆分，并在派生的子组之间寻找新的相关性。首先，将301种化学物质分为六大类化学分组。其次，啮齿动物癌症数据按靶组织进行了部分分类。利用先前指定的对DNA反应性（亲电性）的结构警示，将这些化学物质分为154种有警示作用的化学物质和147种无警示作用的化学物质。有警示作用的化学物质又分为三个化学组：芳香族氨基/硝基类、烷基化剂和其他结构有警示作用的组。无警示作用的化学物质主观上分为三大类：无警示作用、含有非反应性卤素基团的无警示作用物质以及对可能的结构警示略有担忧的无警示作用化学物质。根据这六种化学分组重新呈现了所有301种化学物质的肿瘤数据。在这六组化学物质的比较中出现的最显著发现如下：（a）大多数啮齿动物致癌物，包括大多数两种物种和/或多个部位的致癌物，都在有结构警示作用的化学物质中。（b）大多数有结构警示作用的化学物质具有致突变性；致癌物中的84%和非致癌物中的66%。33种芳香族氨基/硝基类两种物种致癌物中有100%具有致突变性。因此，对于有结构警示作用的化学物质，沙门氏菌试验显示出高敏感性和低特异性（分别为0.84和0.33）。（c）在147种无警示作用的化学物质中，无论它们是致癌物还是非致癌物，致突变性低于5%（敏感性为0.04）。
