Short-Term dermal absorption and penetration of chemicals from aqueous solutions: theory and experiment.

Dermal penetration of organic chemical-contaminated water from showering and bathing scenarios is a concern of regulatory agencies that have been tasked with determining safe exposure levels. During household showering and bathing, nearly the entire surface area of the body is exposed for short periods of time (5-15 minutes). The primary means of predicting body burden during brief exposures is to estimate total chemical penetrated from the steady-state penetration rate using a skin permeability coefficient. A variety of approaches has been recommended to estimate "body burden." The purpose of this investigation was to collect experimental data from short-term exposures to an organic chemical (dibromomethane [DBM]) in aqueous solution so that methods for estimating body burden could be compared. Rat skins were exposed in vitro to saturated aqueous solutions of DBM for 20 minutes and the amount of chemical in the receptor solution and the skin was analyzed. The total DBM mass in the receptor solution and the skin was taken to represent an in vivo body burden. These results were compared with the estimates of penetration from steady-state calculations, square root of time calculations, and a biologically based mathematical model. Results indicated that the amount of chemical in the skin and its fate during short exposures is important. The square root of time approach predicted total amount of chemical absorbed and penetrated better than did the steady-state approach. The biologically based mathematical model accurately predicted total body burden and could be used to distinguish between the amount of chemical in the skin and the amount of chemical that penetrated through the skin, which would be useful for understanding local toxicity.

Detection of oxidative species and low-molecular-weight DNA in skin following dermal exposure with JP-8 jet fuel.

Dermal absorption of JP-8 jet fuel can lead to skin irritation within hours after exposure. This study detected the formation of oxidative species and low-molecular-weight DNA in rat skin as potential indicators of JP-8-induced skin injury. At 0, 1, 2, 4 and 6 h after the beginning of a 1-h exposure, skin samples were removed and analyzed for oxidative species formation and low-molecular-weight DNA analysis. At 1, 2 and 4 h, mean oxidative species levels increased significantly (P < 0.05) above unexposed samples. Significantly higher (P < 0.05) low-molecular-weight DNA values were observed at 4 and 6 h compared with unexposed controls. These results demonstrate significant increases in oxidative species and low-molecular-weight DNA levels in the skin following dermal exposure to JP-8. These responses may serve as indicators of skin injury following exposure to JP-8 jet fuel and other volatile chemicals or mixtures.

Dermal exposure to m-xylene leads to increasing oxidative species and low molecular weight DNA levels in rat skin.

Dermal absorption of organic solvents, such as m-xylene, can lead to skin inflammation and pathological changes within hours after exposure. This study detected oxidative species formation and low molecular weight (LMW) DNA in rat skin as potential indicators of m-xylene-induced skin injury. At 0, 1, 2, 4, and 6 h after the beginning of a 1-h exposure, skin samples were removed and analyzed for oxidative species formation and LMW DNA analysis. At 2 h, mean oxidative species levels increased significantly (P < 0.05) above unexposed samples. Significantly higher (P < 0.05) LMW DNA values were observed at 2, 4, and 6 h compared to unexposed controls. These results show that oxidative species formation and LMW DNA levels in the skin may serve as indicators for predicting safe exposure levels to m-xylene and other volatile organic solvents.

Effect of JP-8 jet fuel on molecular and histological parameters related to acute skin irritation.

Organic chemicals such as jet fuels and solvents can cause skin irritation after dermal exposure. The molecular responses to these chemicals resulting in acute irritation are not understood well enough to establish safe exposure limits. Male F-344 rats were dermally exposed to JP-8 jet fuel for 1 h using Hill Top Chambers. Whole skin samples were collected at 0, 1, 2, 4, and 6 h after the beginning of the exposures, homogenized, and analyzed for interleukin (IL)-1alpha and inducible nitric oxide synthase (iNOS) protein and nitrite levels. IL-1alpha levels (determined by ELISA) ranged from approximately 11 to 34% above the 0-h samples over the observed time period. At 1 and 2 h, significantly higher (p < 0.05) levels of IL-1alpha were detected when compared to the 0-h samples. Western blot analysis revealed significantly higher (p < 0.05) levels of iNOS at 4 and 6 h compared to 0-h samples. Increases in IL-1alpha and iNOS expression were also observed in the skin immunohistochemically. Nitrite concentrations in skin samples were measured to estimate nitric oxide production. Although nitrite concentrations in the skin increased approximately 6-27% above the 0-h samples over the observed time period, no significant changes in nitrite levels were detected. Pathological changes in the skin following JP-8 exposure were evaluated histologically. Increased numbers of granulocytes were observed infiltrating the skin at 2 h and were more prominent by 6 h. These data show that a 1-h exposure to JP-8 results in a local inflammatory response, which can be detected by changes in molecular and histological parameters.

Assessment of skin absorption and penetration of JP-8 jet fuel and its components.

Dermal penetration and absorption of jet fuels in general, and JP-8 in particular, is not well understood, even though government and industry, worldwide, use over 4.5 billion gallons of JP-8 per year. Exposures to JP-8 can occur from vapor, liquid, or aerosol. Inhalation and dermal exposure are the most prevalent routes. JP-8 may cause irritation during repeated or prolonged exposures, but it is unknown whether systemic toxicity can occur from dermal penetration of fuels. The purpose of this investigation was to measure the penetration and absorption of JP-8 and its major constituents with rat skin, so that the potential for effects with human exposures can be assessed. We used static diffusion cells to measure both the flux of JP-8 and components across the skin and the kinetics of absorption into the skin. Total flux of the hydrocarbon components was 20.3 micrograms/cm(2)/h. Thirteen individual components of JP-8 penetrated into the receptor solution. The fluxes ranged from a high of 51.5 micrograms/cm(2)/h (an additive, diethylene glycol monomethyl ether) to a low of 0.334 micrograms/cm(2)/h (tridecane). Aromatic components penetrated most rapidly. Six components (all aliphatic) were identified in the skin. Concentrations absorbed into the skin at 3.5 h ranged from 0.055 micrograms per gram skin (tetradecane) to 0.266 micrograms per gram skin (undecane). These results suggest: (1) that JP-8 penetration will not cause systemic toxicity because of low fluxes of all the components; and (2) the absorption of aliphatic components into the skin may be a cause of skin irritation.

Systemic uptake and clearance of chloroform by hairless rats following dermal exposure: II. Absorption of the neat solvent.

Blood concentrations of chloroform were monitored after exposing small areas (approximately 5.5 cm2) of the backs of hairless rats to liberal excesses of the solvent for either 1, 3, or 8 min. The amounts absorbed were quantified by comparing areas-under-the-curves (AUCs) of blood concentration versus time plots to the AUC obtained on infusing an aqueous chloroform solution of known concentration for 30 min (positive control). Chloroform penetrated the dermal barrier rapidly, the skin's horny layer and the deeper skin tissues acting as reservoirs for chloroform only for short durations. Evaporative and physiological clearance from these reservoirs was rapid once the chloroform was removed from the surface. Pressure of the template used to confine the exposure affected uptake. For blood levels, the time to reach the maximum blood concentration increased with increased exposure duration. Amounts absorbed also depended on exposure duration. Blood level profiles indicated systemic uptake of chloroform following a 3-min exposure was about 1.3-fold higher than for a 1-min exposure (not significant), while the 8-min exposure produced an AUC roughly 3.8-fold higher than found at 3 min (p = 0.026). Chloroform is rapidly cleared from rat blood (terminal elimination rate constant = 0.009/min). Calculations indicated that its absorption from these area-limited exposures far exceeds that which would be absorbed had the chloroform been presented to the skin as a saturated aqueous solution.

Predicting vehicle effects on the dermal absorption of halogenated methanes using physiologically based modeling.

Occupational and environmental settings present opportunities for humans to come into contact with a variety of chemicals via the dermal route. The chemicals contacting the skin are likely to be diluted with a vehicle or present as a component of a mixture. In order to support risk assessment activities, we evaluated the vehicle effects on dermal penetration of two halogenated hydrocarbons, dibromomethane (DBM) and bromochloromethane (BCM). In vivo exposures to 15 combinations of of these in water, mineral oil, and corn oil vehicles were conducted, and blood was sampled for dibromomethane and bromochloromethane during the exposure at 0.5, 1, 2, 4, 8, 12, and 24 h. A physiologically based pharmacokinetic (PBPK) model was used to estimate the total amounts of dibromomethane or bromochloromethane that were absorbed during the exposure, and the dermal permeability coefficients were determined. While the permeability coefficients for dibromomethane and bromochloromethane were approximately 73- and 40-fold higher, respectively, in the water vehicle than in the corn oil, the permeability coefficient, when normalized for the skin:vehicle matrix partition coefficient, varied by less than a factor of 2. The permeability in an aqueous vehicle was then successfully used to predict the permeability coefficient for dibromomethane in a nonpolar vehicle, peanut oil.

Uptake of chloroform by skin on brief exposures to the neat liquid.

The uptake of chloroform into hairless rat's stratum corneum after application of the neat solvent directly to the skin has been studied. Tape stripping was used to determine amounts deposited within the stratum corneum and also the clearance of the compound from the skin following varied levels of exposure. Three minutes exposure to neat chloroform was adequate to achieve a limiting accumulation in the stratum corneum and thus it appears to take this long for the gradient of chloroform to be established fully across this structure. There was indication of progressively deeper penetration of chloroform as the exposure time was increased from 1 to 8 minutes. Local irritation and a loosening of the superficial layers of stratum corneum were apparent with as little as 2 minutes of exposure to the solvent and were exacerbated with further increases in exposure duration. Following exposure, clearance of the solvent from the skin surface was rapid. Interestingly, the rate of clearance, as followed by stripping, was comparable on live and freshly euthanized rats. This implies that once the exposure is terminated evaporation from the surface, and not systemic uptake by way of the local vasculature, is the predominant means of clearance at an open surface.

Physiologically based modeling of nonsteady state dermal absorption of halogenated methanes from an aqueous solution.

Dermal absorption of organic chemicals from aqueous solutions are a concern in both the workplace and the home. Organic chemicals are generally not very soluble in water and the exposure may never reach steady state because the concentration of chemical decreases during the exposure. In vivo animal studies which mimic human exposures, but are carefully controlled, are one way to measure absorption. Whole animal studies are superior to excised skin measurements, because the physiological responses including blood flow, metabolism, and biological defenses are present. In this study, we develop a physiologically based model for nonsteady state exposures to organic chemicals in aqueous solutions. A key feature of this model is a compartment which describes loss of chemical in the exposure solution due to absorption into the skin. We exposed rats to a range of aqueous concentrations of dibromomethane (2.4 to 9.4 mg/ml) and bromochloromethane (3.6 to 12.8 mg/ml) and measured blood concentrations during 24-hr exposures. The blood concentrations peaked at about 1-2 hr and diminished to nearly nothing at 24 hr. Physiologically based models were used to estimate permeability coefficients for each of the exposures, although none of the exposures reached steady state due to the decreasing concentration of chemical on the surface of the skin. A constant permeability coefficient adequately described the blood concentrations during the prolonged exposure. Physiologically based models can be used to estimate permeability coefficients when the concentration of chemical on the skin is not constant. These permeability parameters can subsequently be used for assessing the risks in human exposure situations.

Inflammatory damage to skin by prolonged contact with 1,2-dichlorobenzene and chloropentafluorobenzene.

Skin samples from Fischer-344 rats and Hartley guinea pigs exposed dermally to 1,2-dichlorobenzene (DCB) and chloropentafluorobenzene (CPFB) for up to 4 h were examined for chemical-induced damage. Samples were stained with hematoxylin and eosin and scored for polymorphonuclear cell (PMN) margination, dermal inflammation, and epidermal necrosis by light microscopy. Ultrastructural evaluation of samples fixed with 2% glutaraldehyde and postfixed with 1% osmium tetroxide was used to visualize margination of PMNs. Guinea pigs exhibited postexposure inflammatory changes following an exposure of about an hour-and-a-half shorter duration than rats. DCB-induced inflammation and PMN margination occurred following an exposure about a half hour shorter in both species compared to CPFB. In contrast, epidermal necrosis was more severe with CPFB than with DCB. These changes may account for decreases in chemical penetration rates which have been observed in previous studies with DCB and CPFB in rats and guinea pigs.

Parallel dermal subcompartments for modeling chemical absorption.

Understanding the absorption of chemicals through the skin is of importance to many fields of study. Biologically-based models can be used to simulate the absorption process and predict the rate of absorption and the amount of the chemical in various parts of the body and skin. When these models consist of physiological and biochemical parameters that can be measured, they can be extremely useful. When a model is appropriately validated, the results can be extrapolated across species to predict the effect of human exposure. In this paper we develop two new physiologically-based pharmacokinetic (PBPK) models which predict the concentration of Dibromomethane in the blood of rats after dermal vapor exposure. These two new models expand a previously developed homogeneous skin model by adding parallel skin subcompartments to represent skin appendages and layered subcompartments to represent the distinct layers of the skin. The predictions of these new models match the experimental data better than the original homogeneous model, as well as being more physiologically descriptive. Sensitivity analysis showed us which parameters were the most sensitive to change and thus revealing the parameters we should be most concerned with measuring. After being properly validated, these models could be a great improvement over previous models in the ability to extrapolate results for different species, doses, and durations.

Systemic uptake and clearance of chloroform by hairless rats following dermal exposure. I. Brief exposure to aqueous solutions.

The systemic uptake of chloroform from dilute aqueous solutions into live hairless rats under conditions simulating dermal environmental exposure was studied. Whole blood was sampled during a 30-min immersion of an animal within water containing a known concentration of chloroform and then for 5.5 h following its removal from the bath. The amount of chloroform systemically absorbed was determined by comparing the AUCs of the blood concentration vs. time plots from dermal exposure to that obtained after i.v. infusion (for a period of 30 min) of an aqueous solution containing a known amount of chloroform (positive control). Although dermal data implied two-compartment disposition characteristics, i.v. infusion data fit best to a three-compartment disposition. Linear pharmacokinetics was observed both by i.v. administration and percutaneous absorption at the dose levels studied. Chloroform was detected in the rat blood as early as 4 min following exposure. Our findings suggest that about 10.2 mg of chloroform was systemically absorbed after dermal exposure of a rat to an aqueous solution of 0.44 mg/ml. This amount is substantially higher than the predictions of mathematical risk-models put forth by some investigators. However, when expressed as the "effective" permeability coefficient (Kpeff), close agreement was noticed between our value and those estimated by others using physiologically based pharmacokinetic (PBPK) models. Also, in terms of Kpeff, reasonable agreement existed between our and another investigator's past estimates of uptake based on depletion of bath level of chloroform and the actual uptake measured in our current experiments. The estimated onset of systemic entry seen here is entirely consistent with our estimate of how long it takes to establish the diffusion gradient across the stratum corneum based on tape stripping.

Rat to human extrapolation of HCFC-123 kinetics deduced from halothane kinetics: a corollary approach to physiologically based pharmacokinetic modeling.

The goal of this study was to develop a human physiologically based pharmacokinetic (PBPK) model for the chemical HCFC-123 (2,2-dichloro-1,1,1-trifluoroethane) and its major metabolite, trifluoroacetic acid (TFA). No human kinetic data for HCFC-123 are available, thus a corollary approach was developed. HCFC-123 is a structural analog of the common anesthetic agent halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) and follows a common pathway of oxidative biotransformation, resulting in the formation of the same metabolite, TFA. In this study, halothane models for rats and humans were developed and validated. Then the corollary approach was used to develop a human HCFC-123 model from a rat HCFC-123 model. This strategy was implemented by using a previously validated PBPK model for HCFC-123/TFA in the Fisher 344 rat as a template model for halothane in rats. Model predictions were then compared to, and were in good agreement with, measured values for the concentration of halothane in rat blood and fat tissue. A human PBPK model for halothane was developed. The identical mode structure (with the exception of the description for the fat compartment) that was used to describe halothane and TFA in the rat was used for describing halothane and TFA in the human. Human physiological parameters for tissue volumes and flows were taken from the literature, and human tissue partition coefficients for halothane were measured in the laboratory. Based on reported similarity in metabolism of halothane by humans and rats, metabolic constants for halothane in the rat were used in the human model, and specific parameters describing the kinetics of TFA were estimated by optimization. The model was validated against human exposure data for halothane from six published studies (expired breath concentrations of halothane and serum/urine data for TFA). A similar approach was then used to derive a human HCFC-123 model for humans from the HCFC-123 rat model. The corollary approach described here illustrates the innovative use of template model structures to aid in the development and validation of models for structural analogs with similar metabolism and activity in biologic systems. Furthermore, given that the PBPK model adequately describes the kinetics of halothane in rats and humans and of HCFC-123 in rats, use of the human PBPK model is proposed for deriving dose-response estimates of human health risks in the absence of human kinetic data.

Multilayered dermal subcompartments for modeling chemical absorption.

Dermal penetration of chemicals and drugs is of concern to both toxicologists and pharmacologists. Environmental professionals try to limit exposure to chemicals using protective clothing and gloves or barrier creams to trap chemicals. Drug developers try to enhance penetration of chemicals through the skin for medical purposes. Both can use predictive biologically-based mathematical models to assist in understanding the processes involved. These models are especially useful when they are based on physiological and biochemical parameters which can be measured in the laboratory. Appropriately validated models based on conservation of mass, diffusion and chemical transport by flow can be predictive of human exposures. In this paper we develop two new physiologically-based pharmacokinetic (PBPK) skin models to predict blood concentrations of dibromomethane in rats after skin-only vapor exposures. These new models improve the predictions of the blood concentrations especially at the beginning of the exposures. Sensitivity analysis shows that the permeability constants followed by partition coefficients have the most impact on blood concentration predictions. With proper validation the new models could be used to improve species, dose, and duration extrapolations of chemical or drug penetration. They could also be used to investigate and predict concentrations of drugs or chemicals in the skin.

Uptake of chloroform by skin during short exposures to contaminated water.

Uptake of chloroform into hairless rat stratum corneum from dilute aqueous solutions was studied using tape-stripping to determine amounts deposited in the skin under various environmental exposure scenarios. The length of exposure of sedated animals to the chloroform-containing medium, the frequency and duration of tape-stripping, and the number of tape-strips per location were varied to map the stratum corneum substantivity of chloroform. Eight minutes immersion of the rat within a well-stirred solution at 36 degrees C was found to be adequate time for the gradient to be established fully across the stratum corneum. Penetration was progressively deeper as the exposure time increased. Substantial evaporative loss of chloroform from the aqueous medium of application seem to be responsible for lower cumulative amounts taken up when the same solution was held on the rat's skin within a stainless steel template of fixed area. Of the total uptake (29 mg) from a dilute stirred solution of chloroform (0.44 mg/ml) at 36 degrees C, about 95% was systematically absorbed after a 30 min exposure as determined by residuals (measurement of bath concentrations).

Dose-dependent metabolism of 2,2-dichloro-1,1,1-trifluoroethane: a physiologically based pharmacokinetic model in the male Fischer 344 rat.

2,2-Dichloro-1,1,1-trifluorethane (HCFC-123) is used industrially as a refrigerant, as a foam blowing agent, and as a solvent. It is also being considered as a replacement for halons and chlorinated fluorocarbons which have been banned by the Montreal Protocol because they deplete atmospheric ozone. Male Fischer 344 rats were exposed to 1.0, 0.1, and 0.01% HCFC-123 by inhalation. Parent compound was measured in blood, fat, and exhaled breath and trifluoroacetic acid (TFA) was measured in blood and urine. A physiologically based pharmacokinetic (PBPK) model was developed which included a gut compartment and a variable size fat compartment in addition to the standard flow-limited compartments. Compartment volumes and flows were chosen from the literature, partition coefficients were measured in the laboratory, and metabolic parameters were optimized from experimental data using model simulations. Laboratory experiments showed that the TFA blood concentration during the 1.0% exposure was more than 50% less than the TFA blood concentration during the 0.1% exposure. After cessation of the 4-hr exposure, TFA blood concentrations from the 1.0% exposure rebounded and peaked between 12 and 26 hr after the exposure at about the same concentration as the 0.1% peak. This rebound phenomenon suggested that it was not killing of the metabolic enzymes but substrate inhibition that made the TFA blood concentrations lower than expected. Substrate inhibition by halothane, a structural analog of HCFC-123, has been described in the literature. Only by including a term for substrate inhibition in the PBPK model could pharmacokinetic data for TFA in blood be simulated adequately. This combination of laboratory experimentation and PBPK modeling can be applied to relate the levels of parent and metabolite to toxic effects with some hope of elucidating the toxic species. This work is the first step toward developing models that can be used to predict the toxicokinetics of HCFC-123 in humans throughout various potential use scenarios.

Mechanistic insights aid the search for CFC substitutes: risk assessment of HCFC-123 as an example.

An international consensus on the need to reduce the use of chlorofluorocarbons (CFCs) and other ozone-depleting gases such as the halons led to the adoptions of the 1987 Montreal Protocol and Title VI of the 1990 Clean Air Act Amendments, "Protecting Stratospheric Ozone." These agreements included major provisions for reducing and eventually phasing out production and use of CFCs and halons as well as advancing the development of replacement chemicals. Because of the ubiquitous use and benefits of CFCs and halons, an expeditious search for safe replacements to meet the legislative deadlines is of critical importance. Toxicity testing and health risk assessment programs were established to evaluate the health and environmental impact of these replacement chemicals. Development and implementation of these programs as well as the structural-activity relationships significant for the development of the replacement chemicals are described below. A dose-response evaluation for the health risk assessment of the replacement chemical HCFC-123 (2,2-dichloro-1,1,1-trifluoroethane) is also presented to show an innovative use of physiologically based pharmacokinetic (PBPK) modeling. This is based on a parallelogram approach using data on the anesthetic gas halothane, a structural analog to HCFC-123. Halothane and HCFC-123 both form the same metabolite, trifluoroacetic acid (TFA), indicative of the same metabolic oxidative pathway attributed to hepatotoxicity. The parallelogram approach demonstrates the application of template model structures and shows how PBPK modeling, together with judicious experimental design, can be used to improve the accuracy of health risk assessment and to decrease the need for extensive laboratory animal testing.

Significance of the dermal route of exposure to risk assessment.

The skin is a route of exposure that needs to be considered when conducting a risk assessment. It is necessary to identify the potential for dermal penetration by a chemical as well as to determine the overall importance of the dermal route of exposure as compared with inhalation or oral routes of exposure. The physical state of the chemical, vapor or liquid, the concentration, neat or dilute, and the vehicle, lipid or aqueous, is also important. Dermal risk is related to the product of the amounts of penetration and toxicity. Toxicity involves local effects on the skin itself and the potential for systemic effects. Dermal penetration is described in large part by the permeability constant. When permeability constants are not known, partition coefficients can be used to estimate a chemical's potential to permeate the skin. With these concepts in mind, a tiered approach is proposed for dermal risk assessment. A key first step is the determination of a skin-to-air or skin-to-medium partition coefficient to estimate a potential for dermal absorption. Building a physiologically-based pharmacokinetic (PBPK) model is another step in the tiered approach and is useful prior to classical in vivo toxicity tests. A PBPK model can be used to determine a permeability constant for a chemical as well as to show the distribution of the chemical systemically. A detailed understanding of species differences in the structure and function of the skin and how they relate to differences in penetration rates is necessary in order to extrapolate animal data from PBPK models to the human. A study is in progress to examine anatomical differences for four species.

Kinetics of water vapor sorption in porcine stratum corneum.

The kinetics of water vapor absorption-desorption was studied in the porcine stratum corneum (sc) at 25 degrees C. Dry sc samples were exposed to several relative humidities followed by exposure to dry air, and the change in weight was monitored over time by use of a thermal gravimetric analysis technique. Diffusion coefficients were estimated by simulation and data fit optimization to modifications of the non-steady-state solution of Fick's law. Very good fits of experimental data to theoretical equations were obtained. The stratum corneum-water absorption isotherm was characterized by a linear increase from the origin, extending to about 55% relative humidity (10% water gain), followed by an upward curve where water gain increased further by increasing relative humidity. Water absorption and water desorption in the porcine sc were asymmetrical processes, desorption being the slower one. Water diffusivity for the absorption process was related to sc water content in two phases. In the first (water gain < 9%) diffusion coefficients increased as water concentration increased. In the second (water gain > 9%) diffusion coefficients were independent of water concentration, equal to 1.17 x 10(-10) cm2/s. Water diffusivity in the desorption phase was shown to decrease linearly as sc water content decreased. Analysis of the absorption isotherm and of the derived diffusion coefficients suggested at least two forms of water associated with the sc. The first, termed "firmly bound water" and characterized by low diffusion coefficients, was most apparent with dry sc and with a sc water gain of up to 10%.(ABSTRACT TRUNCATED AT 250 WORDS)

Water diffusivity in porcine stratum corneum measured by a thermal gravimetric analysis technique.

Water is a natural constituent of the stratum corneum (sc) affecting its plasticity and modulating its barrier function. Diffusion coefficients (D) were calculated by measuring the desorption rates of water from porcine sc and dermis samples by a thermal gravimetric analysis (TGA) technique at isothermal conditions in the range 30-80 degrees C. Water-loaded samples were exposed to a flow of dry air, and the change of weight and of temperature were monitored with time. Distinct abrupt decreases in rate of desorption marked three different phases of water in the sc, designated as free, bulk, and bound water. Concomitant with the sharp change in evaporation rate, an increase in temperature was observed, in accordance with the absorption of heat accompanied with the water desorption process. Desorption curves were plotted against time and optimized. Values of D were estimated from the ratio of the evaporated water to the initial sc water content, as a function of the square root of time. The "initial slope" and the t1/2 (time for which Mt/Mo = 0.5, where Mo is the equilibrium amount of water absorbed in the membrane and Mt is the amount of water released by the membrane in a time t) methods gave similar results. The water D values of sc at 30 degrees C calculated by the two methods were 3.3 +/- 0.6 x 10(-10) and 2.7 +/- 0.8 x 10(-10) cm2/s, respectively. These values were about two orders of magnitude lower than the calculated D value for water in the dermis.(ABSTRACT TRUNCATED AT 250 WORDS)