For new chemicals introduced into the workplace or marketplace, and which come into contact with the skin, it is necessary, to conduct a thorough skin safety testing and risk assessment program to be certain that the exposures will be well tolerated. One vital risk assessment process involves the determination of allergic skin reactions, referred to as skin sensitization, the clinical manifestation of which is allergic contact dermatitis (ACD). Essential elements for conducting a sound risk assessment involve the development of an understanding of the sensitization potential of the contact allergen and the likely dose, nature, extent and duration of exposure. The critical exposure determinant for evaluating skin sensitization risk is dose per unit area of skin exposed. One area of difficulty in the development of a quantitative risk assessment for a contact allergen is objective information regarding its relative potency compared with other skin sensitizers.

It has been well known for years that chemical allergens display dose-response characteristics regardless of whether the sensitization is induced in an experimental system or in humans. The development of a novel predictive assay in the mouse, the Local Lymph Node Assay (LLNA), provides new opportunities for the objective and quantitative estimation of skin sensitization potency. For the purposes of hazard identification, the LLNA measures sensitization potential as a function of lymphocyte proliferative responses induced in draining lymph nodes by test chemicals; those chemicals that at one or more test concentration provoke a 3-fold or greater increase in LNC proliferation compared with vehicle controls are classified as potential contact allergens. This method has been applied more recently to determination of relative potency, with comparisons between chemicals based on the mathematical derivation of an EC3 value, this being the estimated concentration of chemical necessary to cause a 3-fold increase in lymph node cell proliferative activity. Experience to date with this approach has been very encouraging; clear differences between skin sensitizing chemicals can be discerned and such differences appear to correlate with the ability to induce contact allergy in experimental models and with what is known of their sensitizing activity among humans. It is this latter correlation that is of greatest significance in evaluating the accuracy of relative potency determinations made using the LLNA and the utility of these in the risk assessment process.

We have shown that derivation of the EC3 for a chemical provides an objective and quantitative measure of potency when compared with chemicals that had been assigned to classes based on their human sensitizing potency. In one study, 20 chemicals were assigned to 1 of 5 human potency classes (strong, moderate, weak, extremely weak and non-sensitizing) based solely on the expert clinical judgment of the authors. These classifications correlated well with the calculated EC3 values from LLNA studies. In a second study, we have determined the potency rankings for 21 chemicals based upon quantitative data from human repeat patch test studies reported in the literature, together with our clinical experience, and compared these with the rankings derived from LLNA EC3 values. The results show clearly that LLNA EC3 values are very comparable with the NOELs calculated from the literature. Moreover, the potency rankings based upon LLNA EC3 data support their human classification.

In summary, it is clear that the LLNA can be used to provide quantitative estimates of relative skin sensitizing potency (EC3 values) that correlate closely with what is known of the ability of chemicals to cause skin sensitization in humans. Such information, in combination with an understanding of the exposure, will be of considerable utility in the development of sound risk assessments for skin sensitizing chemicals.

References
Basketter, D.A., P. Evans, G.F. Gerberick, and I. Kimber. 1999. Chemical allergy: Estimation of potency, thresholds and risk assessment. Comments on Toxicology, 7:79-89.

Kimber, I., G.F. Gerberick, and D.A. Basketter. 1999. Thresholds in contact sensitization: Theoretical and practical consideration. Food & Chemical Toxicology, 37:553-560.

Robinson, M.K., G.F. Gerberick, C.A. Ryan, P. McNamee, I. White and D.A.Basketter. 2000. The importance of exposure assessment of skin sensitization risk. Contact Dermatitis, 42:251-259.

Basketter, D.A., L. Blaikie, R.J. Dearman, I. Kimber, C.A. Ryan, G.F. Gerberick, P. Harvey, P. Evans, I.R. White and R.J.G. Rycroft. 2000. Use of the local lymph node assay for the estimation of relative contact allergenic potency. Contact Dermatitis 42:344-348.

Gerberick, G.F., M.K. Robinson. 2000. A skin sensitization risk assessment process for evaluation of new ingredients and products. American Journal of Contact Dermatitis 11:65-73.

Gerberick, G.F., M.K. Robinson, C.A. Ryan, R.J.Dearman, I. Kimber, D.A. Basketter, Z. Wright and J.G. Marks. 2001. Contact allergenic potency: correlation of human and local lymph node assay data. American Journal of Contact Dermatitis 12:156-161.

Gerberick, G.F., M.K. Robinson, S. P. Felter, I.R. White and D.A. Basketter. 2001. Understanding fragrance allergy using an exposure-based risk assessment approach. Contact Dermatitis 45:333-340.