Dermal absorption/toxicity models

Menon, G.K., and S.H. Lee. 1998. Ultrastructural effects of some solvents and vehicles on the stratum corneum and other skin components Evidence for an extended mosaic-partitioning model of the skin barrier. In Dermal absorption and toxicity assessment, eds. M.S. Roberts and K.A. Walters. New York Marcel Dekker, chap. 29. 

This model has a straightforward structure and is simple to use. It is based on studies carried out in part for the specific purpose of model development. However, not all of the required information is publicly available. The databases are not described at the study level the exposure data are only available in classes, although more detailed information is available on request. The choice of the statistics is not discussed. In the risk-assessment approach, some steps are not clearly presented. Sub-chronic toxicity studies, and not chronic toxicity studies, are used in the risk assessment. Exposure duration and frequency considerations are not discussed. Route-to-route extrapolation is considered acceptable implicitly, without further evaluation of the various issues involved. The rationale for using a dermal absorption default of 10 %, in the absence of data, is not discussed. 

Absorption of uranium through the skin has not been characterized in humans. Dermal absorption in animal models can be inferred from the appearance of toxicity in mice, rats, rabbits, and guinea pigs after dermal exposure to uranium compounds (Orcutt 1949). Absorption was also shown to occur through the conjunctival sac of the eye. 

There are two major types of studies that comprise the field of dermato-toxicology chemical absorption and irritation/sensitization. By far, computational approaches in this field have been focused on the former due to the ability to generate quantitative data suitable for a computational approach. This is also logical since a chemical must traverse the protective outer layer of the skin in order to gain access to its viable cells and exert a toxicological effect. Thus computational approaches to predict toxicity are confounded by chemical properties that allow absorption to occur, with the best work at this point on models to predict dermal absorption. This will be the focus of the present chapter. 

The Corley model (Corley et al. 1994) is an expansion of the model of human inhalation exposure by Johanson (1986). In the Corley model, disposition of 2-butoxyacetic acid was included, and the model was expanded to include data on rats, the most commonly used species in experimental toxicity tests of 2-butoxyethanol. This model was further modified on the basis of data on human metabolites and dermal absorption of 2-butoxyethanol vapor (Corley et al. 1997). Other routes of exposure, including oral, dermal, and intravenous infusion, were included (Figure 2-11). This is a new model, however, and has not yet been subjected to extensive testing. 

Purpose The dermal absorption data enable EPA to make risk assessments when the oral or inhalation route determined the toxic effects in defined faboratory animal models yet the exposure to humans is expected by the dermal route. A complete kinetic analysis is essential to convert oral or inhalation low-effect and no-effect doses into dermal low-effect and no-effect doses. This affows for the calculation of margin of exposure or risk to predict systemic toxic effects that otherwise may not be tested practicalfy by the dermaf route. The rat is the preferred model because a large toxicology database exists in this species. The rat absorption... 

A second aspect of risk assessment for fragranced products concans systemic levels achieved by a combination of dermal absorption and inhalation. The hazards associated with each ingredient are earefuUy evaluated and eontroUed by a combination of exposure assessment plus intrinsic toxicity assessment (Gerberick and Robinson, 2000). Because most absorption occurs via the dermal route (caused by high dilution of the vapor into room air), skin absorption provides the link between these two areas. Absorption models should therefore attempt to answer the questions. What fraction of a topically applied dose will be absorbed and How rapidly will this occur ... 

Drug and chemical dermal absorption typically involves experiments conducted using single chemicals, making the mechanisms of absorption of individual chemicals extensively studied (the subject of most chapters in this volume). Similarly, most risk assessment profiles and mathematical models are based on the behavior of single chemicals. A primary route of occupational and environmental exposure to toxic chemicals is through the skin however, such exposures are often to complex chemical mixtures. In fact, the effects of coadministered chemicals on the rate and extent of absorption of a topically applied systemic toxicant may determine whether... 

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. 

Reentry intervals are now established on the basis of (1) data on dermal absorption or dermal dose response (2) inhalation, dermal, and oral acute toxicity studies in animal models (3) foliar and soil residue dissipation data and, (4) available human exposure data. CDFA recommends several sources as useful guides for determining residues of pesticides on soil and leaf surfaces (dislodgeable residue) and conducting field reentry studies involving human volunteers (1-5). Human exposure studies may not be required if adequate animal data from (1) through (3) above are... 

Absorption across biological membranes is often necessary for a chemical to manifest toxicity. In many cases several membranes need to be crossed and the structure of both the chemical and the membrane need to be evaluated in the process. The major routes of absorption are ingestion, inhalation, dermal and, in the case of exposures in aquatic systems, gills. Factors that influence absorption have been reviewed recently. Methods to assess absorption include in vivo, in vitro, various cellular cultures as well as modelling approaches. Solubility and permeability are barriers to absorption and guidelines have been developed to estimate the likelihood of candidate molecules being absorbed after oral administration. ... 

Absorption, Distribution, Metabolism, and Excretion. There is an obvious data need to determine the pharmacokinetic and toxicokinetic behavior of HDl in both humans and laboratory animals. Determination of blood levels of inhaled, ingested and dermally absorbed HDl would be difficult, given the very short half-life in biological matrices (Berode et al. 1991) and the rate at which HDl binds to proteins in the blood. Although some information is known about the metabolism of HDl in humans inhaling a known quantity of HDl (Brorson et al. 1990), the rate at which absorption occurs, where the majority of the metabolism of HDl occurs (in the water in the mucous layer of the bronchi as opposed to the blood or the kidney), and the distribution patterns and toxic effects of the metabolite (if any) are not well described. Information in these areas of toxicokinetics and toxicodynamics could also be useful in developing a PBPK/PD model for HDl. Research should focus on the respiratory and dermal routes of exposure. 

Blancato, J. N., and Bischoff, K. B. (1993). The application of pharmacokinetic models to predict target dose. In Health Risk Assessment Dermal Inhalation Exposure and Absorption [Pg.610]

On the other hand, in vivo methods are expensive and time-consuming. However, these tests not only provide rich information on the carcinogenicity, dermal, pulmonary, and gastrointestinal toxicides induced by NIR NMs, but also can evaluate the immunological, reproductive, and developmental toxicity to determine the ehronie systemic toxicity and related mechanism of NIR NMs. In addition, animal models are particularly useful to study absorption, distribution, metabolism, and elimination of NIR NMs in the body. Thus, in vivo test results are often suitable for use as a prognostic of long-term physiological effects. 

Wester RC, Maibach HI (1993) Animal models for percutaneous absorption. In Wang RGM, Knaak JB, Maibach HI (eds) Health risk assessment dermal and inhalation exposure and absorption of toxicants. CRC, Boca Raton, EL... 

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