Dermal risk assessment

U S Environmental Protection Agency. Risk Assessment Guidance for Superfund (RAGS), Vol. I Human Health Evaluation Manual (Part E, Supplemental Guidancefor Dermal Risk Assessment) Interim, 2004 http //www.epa.gov/oswer/ riskassessment/ragse/index.htm (last accessed 12 July 2010). 

This present chapter focuses on some critical aspects influencing dermal absorption. This is followed by an overview of existing dermal absorption methodologies, including a discussion regarding the validation of these model systems. Some toxicokinetic considerations regarding the use of percentage of absorption in present risk assessment are presented. Finally, some considerations for improvement of dermal risk assessment, with special attention to dermal kinetic aspects, are provided. 

An overview of a tiered approach for the use of dermal absorption data in dermal risk assessments is provided. Initial tiers utilize default assumptions, while higher tiers require results from in vivo and in vitro dermal absorption studies. For dermal absorption studies, challenges in data analysis, as well as in application of the data to risk assessment, are identified. 

Although not of importance for the assessment of the dermal uptake as such, information on the metabolites formed after dermal and oral exposure is of the utmost importance for dermal risk assessment. This information, as well as information on the rate of dermal (and oral) uptake, will aid in the decision as to... 

These linear kinetic models and diffusion models of skin absorption kinetics have a number of features in common they are subject to similar constraints and have a similar theoretical basis. The kinetic models, however, are more versatile and are potentially powerful predictive tools used to simulate various aspects of percutaneous absorption. Techniques for simulating multiple-dose behavior evaporation, cutaneous metabolism, microbial degradation, and other surface-loss processes dermal risk assessment transdermal drug delivery and vehicle effects have all been described. Recently, more sophisticated approaches involving physiologically relevant perfusion-limited models for simulating skin absorption pharmacokinetics have been described. These advanced models provide the conceptual framework from which experiments may be designed to simultaneously assess the role of the cutaneous vasculature and cutaneous metabolism in percutaneous absorption. 

Because risk is principally a function of usage or exposure, any form of assessment should only be based on experimental protocols that reproduce demographic use of the product in question. In dermal risk assessment, it is important that any estimation of skin absorption take into consideration the likely amount, extent, and duration of exposure that would occur in use (see, for example, Barlow et al., 2001). These parameters are readily controlled during in vitro experiments, and certainly the amount of product applied has been the subject of considerable guidance. There are several published recommendations on both the expression of dose levels and the specific quantities involved. The FDA/AAPS guidelines (Skelly etal., 1987)... 

These equivocal data suggest that no universal rule can presently be established regarding the total absorbed dose for use in calculating safety margins in dermal risk assessment. Data must be generated for each compound, and the results should be carefully analyzed before assessing risk. 

EXAMPLES OF THE USE OF IN VITRO SKIN PENETRATION DATA IN DERMAL RISK ASSESSMENT... 

Figure 8.4 Competing processes that can significantly modify the degree to which materials present in the stratum corneum are subsequently absorbed. (From Howes, D., Watkinson, A.C., and Brain, K.R. (1997). A more complete approach to the modeling of dermal risk assessment, in K.R. Brain, V.J. James, and K.A. Walters (eds.). Perspectives in Percutaneous Penetration, Vol. 5b, Cardiff, U.K. STS Publishing, pp. 68-69. (Used with permission.)...

Examples of the complexity of dermal risk assessments for enviromnental contaminants and cosmetic ingredients and the use of parameters derived from in vitro skin permeation experiments are given next. 

The updated guidance document (EPA, 2001) includes refinements to the above equation to accoimt for the potential bioavailability of contaminants in the stratum comeum when exposure has ended and variable exposure times. Furthermore, the newer document discusses, in depth, the use of mathematical predictions of the permeability coeffident in dermal risk assessment. It is important to appreciate that the permeability coefficient should be determined experimentally using, ideally, a donor phase that mimics as closely as possible the existing environmental conditions. The use of permeability coeffidents predicted from theoretically derived equations adds a further imcertainty to the overall risk calculation. Although it has been suggested that the dermal permeability estimates are the most uncertain of the parameters in the dermal dose computation (EPA, 1992), it could be argued, given the refinement of in vitro techniques and the correlation between in vitro and in vivo measurements of human skin (Franz, 1978 Wester et al., 1992 van de Sandt et al., 2000 Cnubben et al., 2002 Zobrist et al., 2003 Colombo et al., 2003), that these measurements are the least assumptive and the most accurate of all the parameters used. 

Soil contamination presents further complexities in dermal risk assessment (see Chapter 11, this volume). Briefly, additional factors involved in the estimation of risk include soil type (and particle size) and loading rate skin-soil adherence (Holmes etal., 1999), which can vary according to body site area of exposure (fraction of body area exposed is limited by clothing) and climate. The equation used to determine the dermally absorbed dose from soil contact is the same as that... 

Oppl, R., Kalberlah, F, Evans, RG., and Hemmen, J.J. (2003). A toolkit for dermal risk assessment and management an overview. Annals of Occupational Hygiene, 47, 629-640. 

Compared to permethrin, the molecular weight and lipophilicty of DEEP suggest that it should be more readily absorbed across skin. This repellent is more readily absorbed across rodent skin than either porcine or human skin. About 6% of a topical dose of commercially formulated DEET (15% in ethanol) was absorbed across human skin within 8 h (Selim et al., 1995). Our laboratory also reported about 3% dose absorption in poreine skin within this same time period however, absorption in mice skin ranged from 10 to 21% of the dose (Baynes et al., 1997). These data highlight the potential problem of overestimating the risk of DEET in humans if rodent data are used in dermal risk assessment. 

Robinson, P.J., Prediction simple risk models and overview of dermal risk assessment, in Dermal Absorption and Toxicity Assessment (M.S. Roberts and K.A. Walters, eds.). New York Dekker, pp. 203-229, 1998. 

While data from animal skin are abundant, some studies suggest that animal skin is more permeable than that of humans [93,94]. To date, there is no consensus on the circumstances producing equivalent permeability in animal and human skin, and animal data must await further validation of employed models. Human in vivo models are currently considered a gold standard for studying human dermal risk assessment. Human in vitro studies, compared to in vivo studies, may be advantageous in that multiple replicate experiments are more easily performed and toxic compounds may be safely studied. 

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