Application of in vitro human skin models to dermal irritancy: a brief overview and future prospects

The assessment of skin irritation potential represents an important component of the overall safety evaluation programme for new and existing chemicals, which is predominantly performed in laboratory animal studies. These in vivo skin irritancy tests have been subjected to much scientific condemnation with respect to their relevance to human risk assessment. The application of in vitro models in the initial assessment of skin irritation potential is regarded as desirable by the scientific community, but the development of such tests on a mechanistic basis is an important requirement with respect to validation of in vitro tests. The approach adopted in this paper is based on the hypothesis that a cellular insult and subsequent release of inflammatory mediators from the epidermal keratinocyte is a key initiating event in the development of an epidermal inflammatory response following exposure to an irritant. This reversible inflammatory response is mechanistically distinct from a corrosive lesion resulting from the direct physicochemical interaction of a chemical with the stratum corneum. The potential of a chemical to elicit a corrosive response can be successfully predicted by in vitro systems using appropriate endpoints. The stratum corneum (dead cell layer) is also an important selective permeability barrier and a major factor in the severity of a subsequent biological response following topical exposure, which must be taken into account in in vitro systems to assess less severe irritant responses. This paper emphasizes an in vitro mechanistic approach to human skin irritancy testing that is anticipated to facilitate safety assessment. The use of in vitro human skin models, incorporating aspects of barrier function and inflammatory mediator release, will contribute to an improved understanding of mechanisms underlying initiation of an epidermal inflammatory reaction and enable a critical assessment of the value of this approach for human risk assessment purposes. It is not anticipated that in vitro human skin models per se will provide a definitive answer for dermal irritancy, but they appear promising as an initial assessment in the safety evaluation process.