Ashby J, Basketter D A, Paton D, Kimber I
Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, UK.
Toxicology. 1995 Dec 10;103(3):177-94. doi: 10.1016/0300-483x(95)03132-y.
Murine local lymph assay node data for 106 chemicals are listed. Among these, 73 are active in the assay indicating their potential as skin sensitizing agents. Broad structure activity relationships (SAR) are suggested based on the electrophilic theory of skin sensitization suggested by Landsteiner and Jacobs in 1936, and elaborated by Dupuis and Benezra in 1982. Eight classes of agent are discerned; electrophiles, potential electrophiles after metabolism, Michael-reactive agents, benzoylating agents, ionic chemicals and miscellaneous agents. The electrophilic theory cannot at present fully explain the activity of agents in the last two classes. That fact will hopefully focus research into their mode of action. Some chemicals fit equally into more than one class, and such agents are entered into the several classes in order not to bias the analysis. Attention is given to why not all chemicals of a class are active in the assay. It is concluded that a combination of inappropriate lipophilicity, molecular size and metabolic detoxification are responsible for these inactivities. Given a sufficient number of analogues tested within each class it should be possible eventually to predict with accuracy the skin sensitizing potential of new members of the class. However, the present analysis is qualitative, not quantitative. Finally, the parallelism between sensitizing potential and mutagenic potential for chemicals is explored further.
