J Pharmacol Toxicol 42 (1999) 1–9 1056-8719/99/$–see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S1056-8719(99)00037-4 Reviews Strategies for the assessment of acute skin irritation potential Michael K. Robinson,* Rosemarie Osborne, and Mary A. Perkins The Procter & Gamble Company, Miami Valley Laboratories, P.O. Box 538707, Cincinnati, Ohio 45253-8707 Received August 10, 1999; revised and accepted August 17, 1999 1. Introduction The manufacture, transport, and marketing of chemicals and finished products requires the prior toxicologic evalua- tion and assessment of skin reactivity (corrosion and irrita- tion) that may result from intended or accidental skin expo- sure. Procedures for the skin testing of new chemicals and finished products is rapidly evolving in the face of techno- logic advancements and political pressures. Traditionally, testing for skin corrosion and skin irritation has been con- ducted in animals (Organization for Economic Cooperation and Development, OECD, 1993). In the mid 1940s, Draize published his method for assessing skin irritation hazard in rabbits (Draize et al., 1944). This method gradually became the world standard, although it has been modified to varying degrees by regulatory authorities in different parts of the world (Patil et al., 1998). In essence, the method calls for the occluded application of test chemicals to rabbit skin for a duration up to 24 h. To this day, different variations of this procedure form the basis for classification of skin corrosion and irritation hazard to man (European Community, 1992). Depending on the severity of the skin reactions (e.g., erythema, edema, necrotic changes), their speed of onset, and their persistence and reversibility, classifications of skin corrosion and irritation hazard are assigned. The labeling or transport restrictions imposed on chemicals or finished products are based on the length of time required to develop a proscribed level of skin response (Code of Federal Regu- lations, 1991). In recent years, the Draize skin corrosion/irritation test has become a major focus for the elimination of animal test- ing and the development of alternative test methods. Pres- sure from animal rights organizations has led to legislation to restrict marketing of products, the ingredients of which have been tested on animals (European Economic Commu- nity, EEC, 1993). The need to protect worker and consumer safety, comply with regulatory requirements, and also re- duce or eliminate the reliance on animal test methods has led to a major effort to develop alternative methods for as- sessing the skin corrosion and irritation potential of chemi- cals. In addition to the animal rights concerns, there are data suggesting that the rabbit skin irritation test methods are not always reliable in predicting the true irritation potential of chemicals in man (Phillips et al., 1972; Nixon et al., 1975; Campbell and Bruce, 1981). In the area of in vitro skin corrosion testing, several test methods have been described over the past few years (Gor- don et al., 1994; Basketter et al., 1994a; Perkins et al., 1996) and some have been granted regulatory exemptions (Gor- don et al., 1994; Perkins et al., 1996). A recently completed validation study identified two in vitro methods, transcuta- neous electrical resistance and cytotoxicity in the skin equiva- lent construct, Episkin™ (Episkin, Chaponost, France), as valid alternative methods for skin corrosion (Fentem et al., 1998). In vitro skin irritation test methods are not as far de- veloped in terms of the validation process (Botham et al., 1998), although a number of individual research reports have been published (Osborne and Perkins, 1994; Boelsma et al., 1996; Augustin et al., 1997; Augustin et al., 1998; Perkins et al., 1999). Efforts are underway to identify poten- tial in vitro skin irritation test methods and evaluate them through rigorous prevalidation and validation studies. In addition to in vitro test methods, there is increasing ef- fort to directly assess the skin irritation potential of chemi- cals in human subjects. A protocol developed and published in 1994 (Basketter et al., 1994b) has undergone extensive testing in laboratories around the world (Basketter et al., 1996; Griffiths et al., 1997; Robinson et al., 1999). Compar- isons to existing data sets suggest that this method is supe- rior to animal testing for the classification of skin irritation potential (York et al., 1996). The method has also been used to investigate various parameters of the human skin irrita- tion response (Basketter et al., 1996; Basketter et al., 1996; Robinson et al., 1998; McFadden et al., 1998). Although this method has not yet been applied to the testing of fin- ished products, other recommendations for the human test- ing of product formulations have been described (Walker et al., 1997). The purpose of this review is to examine the current de- velopment and validation status of in vitro and human skin testing methods. It will include a brief update on the devel- opment and validation status of various in vitro skin corro- sion tests. It then summarizes ongoing efforts to develop in * Corresponding author. Michael K. Robinson. Tel.: 513-627-2192.