AN INTEGRATED APPROACH TO PHOTOTOXICITY TESTING: THE IN VITRO 3T3 NRU PHOTOIRRITANCY ASSAY AND THE ALBINO HAIRLESS MOUSE MODEL (CRL:SKH1-HR) WITH INTRACUTANEOUS ADMINISTRATION AND A HIGH DOSE OF ULTRAVIOLET A RADIATION

In assessing the potential phototoxicity of drugs and chemicals, the in vitro 3T3 NRU Photoirritancy assay and other in vitro phototoxicity models tend to produce results indicative of phototoxic potential for a relatively large number of compounds. Surveys from laboratories that conduct the 3T3 assay indicate that 35% to 60% of tested compounds result in findings suggestive of phototoxic potential. Once a compound has been found to be positive in this in vitro assay, a reasonable approach is to conduct an in vivo phototoxicity test. However, certain compounds that are considered phototoxic in man are not readily phototoxic in standard animal tests (e.g., chlorpromazine and tetracyclines), but do show activity in the 3T3 assay. To address the apparent lack of sensitivity of the animal models and correlation with clinical experience, we modified the albino hairless mouse model to maximize sensitivity for cutaneous phototoxicity by the use of intracutaneous administration of formulations and exposure to a relatively high dose of ultraviolet A (315 – 400 nm) radiation. This approach enabled us to readily detect phototoxicity in mice for compounds that are considered phototoxic clinically, but not easily demonstrated to be phototoxic in more standard animal models. This maximized test reveals excellent concordance for compounds that are positive in the 3T3 assay and are considered phototoxic clinically. Additionally, some compounds that elicit positive findings in the 3T3 assay do not elicit phototoxicity in the maximized mouse test. Use of this integrated in vitro and in vivo approach should help address some difficulties associated with preclinical phototoxicity testing. Further work is needed to define the underlying mechanisms that account for these findings.