The Center for Alternatives to Animal Testing is an academic center affiliated with the Division of Toxicological Sciences in the Department of Environmental Health Sciences of the Johns Hopkins University Bloomberg School of Public Health.

 

Johns Hopkins School of Public Health

Commemorative Booklet for CAAT 20th Anniversary Symposium

Modeling Chemically Induced Allergic Contact Dermititis

Philip S. Magee
University of California at San Francisco, San Francisco

Allergic contact dermatitis begins when the immune system reacts to a chemical absorbed by the epidermis. The initial reaction leads to a complex response familiar to anyone exposed to poison oak or related plant allergens.

In order to predict the allergic potential of new chemicals reaching the market, we must understand their potential for immune system reactivity. Animal testing of new commercial and medicinal compounds requires the use of at least 25 animals per test. While not fatal, these tests can be accurately described as animal cruelty and should be minimized whenever possible.

As greater than 90% of chemical allergens are electrophiles, a logical alternative approach would be to model the heat of reaction of both known and inactive chemicals. As a point of reactivity, reduced models of the protein nucleophile were selected as highly probable sites of reaction. It also was assumed that the rate-determining step is the initial nucleophilic reaction of the protein with the allergen. As these reactions are all exothermic, we expected a low activation energy with reactivity accurately related to the heat of reaction.

For practical purposes, semi-empirical quantum mechanics (AM1) was selected to model the heats of reaction of both known allergic chemicals and those of the same chemical types that do not cause allergic reactions. Both reactants and products were modeled for their thermodynamic heat of formation.

We were fortunate to discover a narrow breakpoint between reactivity and non-reactivity of a potential allergen. The situation is not as clear for more reactive chemicals, which may react before reaching the viable epidermis. Other complications include rapid metabolic destruction and rapid transport that clears the reactant before allergic reaction occurs.

More than 160 examples of known allergic reactive chemicals were studied, as well as many examples of clinically untested compounds showing similar levels of reactivity. Compounds showing higher than 30 kcal/mol of reactivity by computation are early warning signs of future problems.