EXAGGERATED EXPOSURE IN PREDICTIVE TESTING 183 widespread use of the human tolerance test, however, is its time-consuming nature and the difficulty of recruiting volunteers. SENSITIZING POTENTIAL Sensitization is an important type of possible adverse reaction to toiletties and cosmetics it usually involves the risk of causing an allergic contact dermatitis and needs to be considered separately from irritancy. Allergens may sensitize occasional individuals at concentrations which are without any significant effect on the majority of the population this feature of allergenicity causes great difficulty in predictive testing. Some dermato- logists nevertheless take the view that exposing a group of randomly-chosen subjects under test conditions to an exaggerated concentration of a sus- pected allergen increases the chance of recognizing its sensitizing potential. If so, what degree of exaggeration is appropriate? Marzulli and Maibach (15) recently reported a detailed investigation of sensitizing properties using exaggerated concentrations of test materials. For example, with sorbic acid tested at 20•o concentration, one of the 33 subjects they tested gave a positive reaction. The crucial question is what proportion of users, if any, would be sensitized at a typical use-concentra- tion of about 0.1-0.2•o. Clearly this is unanswerable without knowing the shape of the dose-response curve for an allergen of the same or a similar type, extending right down to normal use-level concentrations of the test substance. These authors did, in fact, conduct tests at several concentration levels with a number of compounds but the proportion of subjects with positive responses did not show a dose-response pattern justifying any broad conclusions a graded dose-response relationship may perhaps be inferred on theoretical grounds but even the extensive work carried out by Marzulli and Maibach (15) was evidently insufficient to demonstrate it clearly. Some toxicologists concerned with toiletties and cosmetics prefer to conduct tests for sensitizing potential at normal use-concentration of the test materials, using human volunteers. If such tests involve multiple ex- posures under occlusive patches, the resulting minor degree of skin damage should marginally increase the likelihood of a positive response. However, since it is well known that toiletties and cosmetics in general sensitize less than, say, 1 in 10 000 users, the predictive value of any use-concentration test carried out with only a few hundred volunteers must be exceedingly

184 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS small. Selection of atopic subjects for test panels is sometimes considered to improve predictive value but the evidence to indicate that atopics show enhanced susceptibility to topical allergens in general is questionable (16). Bearing in mind the objections to grossly exaggerated exposure testing and recognizing that sensitization testing at normal use-concentration often yields negative results that cannot be interpreted or which may be un- reliable, there are certain attractions in devising a test procedure to enhance responses to use-concentrations and to ensure that positive results are obtained even with moderate or mild sensitizers. Kligman (17) in proposing his 'maximization' test, offered a procedure giving 24/24 positive responses to p-phenylenediamine even though he was still unable to detect some known mild sensitizers such as lanolin. The value of this type of test for cosmetic evaluation does not therefore yet seem to have been established. At the present time, despite the energetic attempts by a number of highly-skilled investigators, there is clearly no satisfactory way of predicting the sensitizing potential of cosmetics and toiletries by means of human volunteer studies nevertheless, such studies carry a definite risk of sensitiz- ing volunteers, possibly for some years (18), and their justification is there- fore doubtful. As an alternative, a reliable test for sensitizing potential using laboratory animals would obviously be helpful. Whereas the response of some other mammals closely resembles the human response to irritants, there are marked interspecies differences in allergic responses. Suitability of the guinea-pig for sensitization testing has been validated to some extent (19) but it would be unwise to expect guinea- pig studies to eliminate any but the most potent sensitizers. Thus, although it is reasonably practical to test for the sensitizing potential of raw materials by conducting challenge tests at elevated concentrations using animals or man, no comparable procedure is yet available for studying complete formulations likely to display no more than mild sensitizing ability. Rather than applying maximizing procedures of dubious predictive value, it is probably better to allow a product to be used normally by gradually increas- ing numbers of individuals. This view takes for granted a prior scrutiny of the raw materials to eliminate any potent known sensitizers and an adequate scheme for monitoring adverse reactions if they are reported by users of the product.