STRATEGIES FOR THE ASSESSMENT OF ACUTE SKIN IRRITATION POTENTIAL.
The manufacture, transport, and marketing of chemicals and finished products requires the prior toxicologic evaluation and assessment of skin reactivity (corrosion and irritation) that may result from intended or accidental skin exposure. Procedures for the skin testing of new chemicals and finished products is rapidly evolving in the face of technologic advancements and political pressures. Traditionally, testing for skin corrosion and skin irritation has been conducted 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 Regulations, 1991). In recent years, the Draize skin corrosion/irritation test has become a major focus for the elimination of animal testing and the development of alternative test methods. Pressure from animal rights organizations has led to legislation to restrict marketing of products, the ingredients of which have been tested on animals (European Economic Community, EEC, 1993). The need to protect worker and consumer safety, comply with regulatory requirements, and also reduce or eliminate the reliance on animal test methods has led to a major effort to develop alternative methods for assessing the skin corrosion and irritation potential of chemicals. 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 (Gordon et al, 1994; Basketter et al., 1994a; Perkins et al, 1996) and some have been granted regulatory exemptions (Gordon et al, 1994; Perkins et al, 1996). A recently completed validation study identified two in vitro methods, transcutaneous electrical resistance and cytotoxicity in the skin equivalent 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 developed 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 potential 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 effort to directly assess the skin irritation potential of chemicals 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). Comparisons to existing data sets suggest that this method is superior 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 irritation 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 finished products, other recommendations for the human testing of product formulations have been described (Walker et al, 1997). The purpose of this review is to examine the current development and validation status of in vitro and human skin testing methods. It will include a brief update on the development and validation status of various in vitro skin corrosion tests. It then summarizes ongoing efforts to develop in vitro and human skin irritation test methods, both for the assessment of acute skin irritation potential as well as the much milder irritation responses of both chemicals and finished products.
Acute skin irritation potential, Corrosion, Corrosivity, Corrosivity testing, Cutaneous irritancy, Cutaneous irritation, Cutaneous toxicity, Dermal corrosion, Dermal irritancy, Dermal irritancy testing, Dermal irritation, Draize, Draize skin corrosion/irritation test, ECVAM, EpiDerm, EpiSkin, ICCVAM, IL-1a, MTT, MTT ET-50 tissue viability assay, MTT assay, Skin corrosion, Skin corrosivity, Skin irritancy, Skin irritation, Skin irritation potential
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