A Physiologically-Based Pharmacokinetic Model Assessment of Methyl t-Butyl Ether in Groundwater for a Bathing and Showering Determination

Methyl t -butyl ether (MTBE) is a gasoline additive that has appeared in private wells as a result of leaking underground storage tanks. Neurological symptoms (headache, dizziness) have been reported from household use of MTBE-affected water, consistent with animal studies showing acute CNS depression from MTBE exposure. The current research evaluates acute CNS effects during bathing/showering by application of physiologically-based pharmacokinetic (PBPK) techniques to compare internal doses in animal toxicity studies to human exposure scenarios. An additional reference point was the delivered dose associated with the acute Minimum Risk Level (MRL) for MTBE established by the Agency for Toxic Substances and Disease Registry. A PBPK model for MTBE and its principal metabolite, t -butyl alcohol (TBA) was developed and validated against published data in rats and humans. PBPK analysis of animal studies showed that acute CNS toxicity after MTBE exposure can be attributed principally to the parent compound since the metabolite (TBA) internal dose was below that needed for CNS effects. The PBPK model was combined with an exposure model for bathing and showering which integrates inhalation and dermal exposures. This modeling indicated that bathing or showering in water containing MTBE at 1 mg/L would produce brain concentrations ˜1000-fold below the animal effects level and twofold below brain concentrations associated with the acute MRL. These findings indicate that MTBE water concentrations of 1 mg/L or below are unlikely to trigger acute CNS effects during bathing and showering. However, MTBE's strong odor may be a secondary but deciding factor regarding the suitability of such water for domestic uses.     

Water Adherence Factors for Human Skin

On incidental dermal exposure to chemicals in water, a key exposure factor is the amount of water adhering to skin. Although soil adherence factors have been developed for risk assessment, measurements of water adherence on human skin have not been described. In the Environmental Protection Agency's (EPA's) dermal risk assessment guidance, dermal dose from environmental exposures is based upon the flux rate across the skin, which assumes that an unlimited amount of chemical is available for absorption. This assumption is applicable to certain exposure scenarios such as swimming and bathing. However, exposures to contaminated water frequently involve scenarios where the available chemical is limited by the amount of water adhering to the skin, for example, during accidental splashes. We conducted studies in human volunteers to investigate water adherence per unit area of skin after brief contact with water. In two sets of experiments, either water was applied with a micropipette to 10‐cm² areas of the lower leg, foot, and hand, or the foot and hand were briefly immersed in water. In males, using a micropipette, water adherence ranged from 1.93 (foot) to 7.13 μL/cm² (lower leg). In females, it ranged from 1.10 (lower leg) to 4.83 μL/cm² (hand). Hand and foot immersion resulted in relatively higher values of 6.89 and 5.17 μL/cm², respectively, in males, and 5.40 and 6.39 μL/cm² in females. Water adherence was affected by amount of body hair and type of exposure. Water adherence factors can be used to calculate the applied dose per unit area for exposures involving intermittent water contact.     

A Physiologically Based Pharmacokinetic Assessment of Tetrachloroethylene in Groundwater for a Bathing and Showering Determination

A two-step methodology is described to make a health-based determination for the bathing and showering use of the water from a private well contaminated with volatile organic chemicals. The chemical perchloroethylene (PERC) is utilized to illustrate the approach. First, a chemical-specific exposure model is used to predict the concentration of PERC in the shower air, shower water, and in the air above the bathtub. Second, a physiologically based pharmacokinetic (PBPK) model is used to predict the concentration of PERC delivered to the target tissue, the brain, since the focus is on neurological endpoints. The simulation exercise includes concurrent dermal and inhalation routes of exposure. A reference target tissue level (RTTL) in the brain is estimated using the PBPK model. A hazard index based on this benchmark guideline is used to make a regulatory determination for bathing and showering use of the contaminated water.     

Exposure to Chlorination By-Products from Hot Water Uses

Exposures to chlorination by-products (CBP) within public water supplies are multiroute in water. Cold water is primarily used for ingestion while a mixture of cold water and hot water is used for showering, bathing others, dish washing, etc. These latter two activities result in inhalation and dermal exposure. Heating water was observed to change the concentration of various CBP. An increase in the trihalomethanes (THM) concentrations and a decrease in the haloacetonitriles and halopropanones concentration, though an initial rise in the concentration of dichloropropanone, were observed. The extent of the increase in the THM is dependent on the chlorine residual present. Therefore, estimates of total exposure to CBP from public water supplies need to consider any changes in their concentration with different water uses. The overall THM exposures calculated using the THM concentration in heated water were 50% higher than those calculated using the THM concentration present in cold water. The estimated lifetime cancer risk associated with exposure to THM in water during the shower is therefore underestimated by 50% if the concentration of THM in cold water is used in the risk assessment.     

Assessment of Airborne Exposure to Trihalomethanes from Tap Water in Residential Showers and Baths

This study evaluates airborne concentrations of common trihalomethane (THM) compounds in bathrooms during showering and bathing in homes supplied with chlorinated tap water. Three homes in an urban area were selected, each having three bedrooms, a full bath, and approximately 1,000 square feet of living area. THMs were concurrently measured in tap water and air in the shower/bath enclosure and the bathroom vanity area using Summa canisters. Chloroform (TCM), bromodichloromethane (BDCM), and chlorodibromomethane (CDBM) were quantified using U.S. Environmental Protection Agency (EPA) Method TO-14. Air samples were collected prior to, during, and after the water-use event for 16 shower and 7 bath events. Flow rate and temperature were measured, but not controlled. The increase in average airborne concentration (+/- standard error) during showers (expressed as microg/m3 in shower enclosure or bathroom air per microg/L in water) was 3.3+/-0.4 for TCM, 1.8+/-0.3 for BDCM, and 0.5+/-0.1 for CDBM (n = 12), and during baths was 1.2+/-0.4 for TCM, 0.59+/-0.21 for BDCM, and 0.15+/-0.05 for CDBM (n = 4). The relative contribution of each chemical to the airborne concentrations was consistent for all shower and bath events, with apparent release of TCM > BDCM > CDBM. The results are therefore consistent with their relative concentration in tap water and their vapor pressures. When the shower findings for TCM are normalized for water concentration, flow rate, shower volume, and duration, the average exposure concentrations in these urban residences are about 30% lower than those reported by other investigators using EPA analytical methods. This difference is likely attributable primarily to greater air exchange rates in residential shower/bath stalls compared to more "airtight" laboratory shower chambers. This appears to be the first field study to thoroughly evaluate THM exposures from residential showers and baths, and can be used to validate previously published models of tap water volatile chemical transfer to indoor air.     

A Compartmental Model for the Prediction of Breath Concentration and Absorbed Dose of Chloroform After Exposure While Showering

In order to predict the exhaled breath concentration of chloroform in individuals exposed to chloroform while showering, an existing physiologically based pharmacokinetic (PB-PK) model was modified to include a multicompartment, PB-PK model for the skin and a completely mixed shower exposure model. The PB-PK model of the skin included the stratum corneum as the principal resistance to absorption and a viable epidermis which is in dynamic equilibrium with the skin microcirculation. This model was calibrated with measured exhaled breath concentrations of chloroform in individuals exposed while showering with and without dermal absorption. The calibration effort indicated that the expected value of skin-blood partitioning coefficient would be 1.2 when the degree of transfer of chloroform from shower water into shower air was 61%. The stratum corneum permeability coefficient for chloroform was estimated to be within the range of 0.16-0.36 cm/hr and the expected value was 0.2 cm/hr. The estimated ratio of the dermally and inhaled absorbed doses ranged between 0.6 and 2.2 and the expected value was 0.75. These results indicate that for the purposes of risk assessment for dermal exposure to chloroform, a simple steady-state model can be used to predict the degree of dermal absorption and that a reasonable value of skin permeability coefficient for chloroform used in this model would be 0.2 cm/hr. Further research should be conducted to compare the elimination of chloroform via exhaled breath when different exposure routes are being compared. The model results from this study suggest that multiple measurements of exhaled breath concentrations after exposure may be necessary when making comparisons of breath concentrations that involve different exposure routes.     

A Time‐Dependent Risk Assessment for Broken Compact Fluorescent Lamps

Environmental Protection Agency (EPA) ambient air quality guidelines are meant to limit long‐term exposures of toxins to safe levels. Unfortunately, there is little guidance for what constitutes a safe level from a one‐time (or very infrequent) short exposure(s). In the case of mercury, a review of the derivation of the EPA ambient air quality standard shows that it implicitly assumes a tissue burden model. The time dependence of the tissue burden is commonly described in terms of a half‐life, a modeling assumption that presumes that the decline in the tissue burden after a single exposure can be approximately described as an exponential decay. In this article, we use a simple exponential tissue burden model to derive a time‐dependent no observable adverse effect level (NOAEL) for mercury concentrations in air. The model predicts that tissue body burden will asymptotically approach the EPA air quality level for long exposure times, and reach workplace standard levels for exposures of a few hours. The model was used along with data on mercury levels from experimental work done by the Maine Department of Environmental Protection to evaluate the risks from a broken compact fluorescent lamp in a residential setting. Mercury levels approached the NOAEL only when the debris was left in an almost sealed room. Normal common‐sense cleaning measures: removal of debris to an outside area, and ventilation of the room for several minutes, reduced exposures to less than 1% of the NOAEL.     

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°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°C, about 95% was systematically absorbed after a 30 min exposure as determined by residuals (measurement of bath concentrations).     

A random walk model of skin permeation.

A new mathematical model for permeability of chemicals in aqueous vehicle through skin is presented. The rationale for this model is to represent diffusion by its fundamental molecular mechanism, i.e., random thermal motion. Diffusion is modeled as a two-dimensional random walk through the biphasic (lipid and corneocyte) stratum corneum (SC). This approach permits calculations of diffusion phenomena in a morphologically realistic SC structure. Two concepts are key in the application of the model to the prediction of steady-state skin permeability coefficients: "effective diffusivity" and "effective path length," meaning the diffusivity and thickness of a homogeneous membrane having identical permeation properties as the stratum corneum. Algebraic expressions for these two variables are developed as functions of the molecular weight and octanol-water partition coefficient of the diffusing substance. Combining these with expressions for membrane-vehicle partition coefficient and permeability of the aqueous epidermis enables the calculation of steady-state skin permeability coefficients. The resulting four-parameter algebraic model was regressed against the "Flynn data base" with excellent results (R2 = 0.84: SE = 0.0076; F = 154; N = 94). The model provides insight into the contributions of stratum corneum diffusivity and effective path lengths to overall skin permeability and may prove useful in the prediction of non-steady-state diffusion phenomena.     

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.     

A Comparative Pharmacokinetic Estimate of Mercury in U.S. Infants Following Yearly Exposures to Inactivated Influenza Vaccines Containing Thimerosal

The use of thimerosal preservative in childhood vaccines has been largely eliminated over the past decade in the United States because vaccines have been reformulated in single‐dose vials that do not require preservative. An exception is the inactivated influenza vaccines, which are formulated in both multidose vials requiring preservative and preservative‐free single‐dose vials. As part of an ongoing evaluation by USFDA of the safety of biologics throughout their lifecycle, the infant body burden of mercury following scheduled exposures to thimerosal preservative in inactivated influenza vaccines in the United States was estimated and compared to the infant body burden of mercury following daily exposures to dietary methylmercury at the reference dose established by the USEPA. Body burdens were estimated using kinetic parameters derived from experiments conducted in infant monkeys that were exposed episodically to thimerosal or MeHg at identical doses. We found that the body burden of mercury (AUC) in infants (including low birth weight) over the first 4.5 years of life following yearly exposures to thimerosal was two orders of magnitude lower than that estimated for exposures to the lowest regulatory threshold for MeHg over the same time period. In addition, peak body burdens of mercury following episodic exposures to thimerosal in this worst‐case analysis did not exceed the corresponding safe body burden of mercury from methylmercury at any time, even for low‐birth‐weight infants. Our pharmacokinetic analysis supports the acknowledged safety of thimerosal when used as a preservative at current levels in certain multidose infant vaccines in the United States.     

Use of Monte Carlo Simulation for Human Exposure Assessment at a Superfund Site

This work presents a comparison of probabilistic and deterministic health risk estimates based on data from an industrial site in the northeastern United States. The risk assessment considered exposures to volatile solvents by drinking water ingestion and showering. Probability densities used as inputs included concentrations, contact rates, and exposure frequencies; dose-response inputs were single values. Deterministic risk estimates were calculated by the "reasonable maximum exposure" (RME) approach recommended by the EPA Superfund program. The RME non-carcinogenic risk fell between the 90th and the 95th percentile of the probability density; the RME cancer risk fell between the 95th percentile and the maximum. These results suggest that in this case (1) EPA's deterministic RME risk was reasonably protective, (2) results of probabilistic and deterministic calculations were consistent, and (3) commercially available software Monte Carlo software effectively provided multiple risk estimates recommended by recent EPA guidance.     

Chlorine Truck Attack Consequences and Mitigation

We develop and apply an integrated modeling system to estimate fatalities from intentional release of 17 tons of chlorine from a tank truck in a generic urban area. A public response model specifies locations and actions of the populace. A chemical source term model predicts initial characteristics of the chlorine vapor and aerosol cloud. An atmospheric dispersion model predicts cloud spreading and movement. A building air exchange model simulates movement of chlorine from outdoors into buildings at each location. A dose‐response model translates chlorine exposures into predicted fatalities. Important parameters outside defender control include wind speed, atmospheric stability class, amount of chlorine released, and dose‐response model parameters. Without fast and effective defense response, with 2.5 m/sec wind and stability class F, we estimate approximately 4,000 (half within ～10 minutes) to 30,000 fatalities (half within ～20 minutes), depending on dose‐response model. Although we assume 7% of the population was outdoors, they represent 60–90% of fatalities. Changing weather conditions result in approximately 50–90% lower total fatalities. Measures such as sheltering in place, evacuation, and use of security barriers and cryogenic storage can reduce fatalities, sometimes by 50% or more, depending on response speed and other factors.     

Field Measurement of Dermal Soil Loading Attributable to Various Activities: Implications for Exposure Assessment

Estimates of soil adherence to skin are required for assessment of dermal exposures to contaminants in soils. Previously available estimates depend heavily on indirect measurements and/or artificial activities and reflect sampling of hands only. Results are presented here from direct measurement of soil loading on skin surfaces of volunteers before and after normal occupational and recreational activities that might reasonably be expected to lead to soil contact. Skin surfaces assayed included hands, forearms, lower legs, faces and/or feet. Observed hand loadings vary over five orders of magnitude (roughly from 10^–3 to 10² mg/cm²) and are dependent upon type of activity. Hand loadings within the current default range of 0.2 to 1.0 mg/cm² were produced by activities providing opportunity for relatively vigorous soil contact (rugby, farming). Loadings less than 0.2 mg/cm² were found on hands following activities presenting less opportunity for direct soil contact (soccer, professional grounds maintenance) and on other body parts under many conditions. The default range does not, however, represent a worst case. Children playing in mud on the shore of a lake generated geometric mean loadings well in excess of 1 mg/cm² on hands, arms, legs, and feet. Post-activity average loadings on hands were typically higher than average loadings on other body parts resulting from the same activity. Hand data from limited activities cannot, however, be used to conservatively predict loadings that might occur on other body surfaces without regard to activity since non-hand loadings attributable to higher contact activities exceeded hand loadings resulting from lower contact activities. Differences between pre- and post-activity loadings also demonstrate that dermal contact with soil is episodic. Typical background (pre-activity) geometric mean loadings appear to be on the order of 10^-2 mg/cm² or less. Because exposures are activity dependent, quantification of dermal exposure to soil will remain inadequate until data describing relevant human behavior (type of activity, frequency, duration including interval before bathing, clothing worn, etc.) are generated.     

Steady-State Solutions to PBPK Models and Their Applications to Risk Assessment I: Route-to-Route Extrapolation of Volatile Chemicals

Although analysis of in vivo pharmacokinetic data necessitates use of time-dependent physiologically-based pharmacokinetic (PBPK) models, risk assessment applications are often driven primarily by steady-state and/or integrated (e.g., AUC) dosimetry. To that end, we present an analysis of steady-state solutions to a PBPK model for a generic volatile chemical metabolized in the liver. We derive an equivalent model that is much simpler and contains many fewer parameters than the full PBPK model. The state of the system can be specified by two state variables-the rate of metabolism and the rate of clearance by exhalation. For a given oral dose rate or inhalation exposure concentration, the system state only depends on the blood-air partition coefficient, metabolic constants, and the rates of blood flow to the liver and of alveolar ventilation. At exposures where metabolism is close to linear, only the effective first-order metabolic rate is needed. Furthermore, in this case, the relationship between cumulative exposure and average internal dose (e.g., AUCs) remains the same for time-varying exposures. We apply our analysis to oral-inhalation route extrapolation, showing that for any dose metric, route equivalence only depends on the parameters that determine the system state. Even if the appropriate dose metric is unknown, bounds can be placed on the route-to-route equivalence with very limited data. We illustrate this analysis by showing that it reproduces exactly the PBPK-model-based route-to-route extrapolation in EPA's 2000 risk assessment for vinyl chloride. Overall, we find that in many cases, steady-state solutions exactly reproduce or closely approximate the solutions using the full PBPK model, while being substantially more transparent. Subsequent work will examine the utility of steady-state solutions for analyzing cross-species extrapolation and intraspecies variability.     

Quantitative Risk Estimation for a Legionella pneumophila Infection Due to Whirlpool Use

Quantitative microbiological risk assessment was used to quantify the risk associated with the exposure to Legionella pneumophila in a whirlpool. Conceptually, air bubbles ascend to the surface, intercepting Legionella from the traversed water. At the surface the bubble bursts into dominantly noninhalable jet drops and inhalable film drops. Assuming that film drops carry half of the intercepted Legionella, a total of four (95% interval: 1–9) and 4.5×10⁴ (4.4×10⁴ – 4.7×10⁴) cfu/min were estimated to be aerosolized for concentrations of 1 and 1,000 legionellas per liter, respectively. Using a dose‐response model for guinea pigs to represent humans, infection risks for active whirlpool use with 100 cfu/L water for 15 minutes were 0.29 (～0.11–0.48) for susceptible males and 0.22 (～0.06–0.42) for susceptible females. A L. pneumophila concentration of ≥1,000 cfu/L water was estimated to nearly always cause an infection (mean: 0.95; 95% interval: 0.9–～1). Estimated infection risks were time‐dependent, ranging from 0.02 (0–0.11) for 1‐minute exposures to 0.93 (0.86–0.97) for 2‐hour exposures when the L. pneumophila concentration was 100 cfu/L water. Pool water in Dutch bathing establishments should contain <100 cfu Legionella/L water. This study suggests that stricter provisions might be required to assure adequate public health protection.     

Annual Burden of Occupationally‐Acquired Influenza Infections in Hospitals and Emergency Departments in the United States

Infections among health‐care personnel (HCP) occur as a result of providing care to patients with infectious diseases, but surveillance is limited to a few diseases. The objective of this study is to determine the annual number of influenza infections acquired by HCP as a result of occupational exposures to influenza patients in hospitals and emergency departments (EDs) in the United States. A risk analysis approach was taken. A compartmental model was used to estimate the influenza dose received in a single exposure, and a dose–response function applied to calculate the probability of infection. A three‐step algorithm tabulated the total number of influenza infections based on: the total number of occupational exposures (tabulated in previous work), the total number of HCP with occupational exposures, and the probability of infection in an occupational exposure. Estimated influenza infections were highly dependent upon the dose–response function. Given current compliance with infection control precautions, we estimated 151,300 and 34,150 influenza infections annually with two dose–response functions (annual incidence proportions of 9.3% and 2.1%, respectively). Greater reductions in infectious were achieved by full compliance with vaccination and IC precautions than with patient isolation. The burden of occupationally‐acquired influenza among HCP in hospitals and EDs in the United States is not trivial, and can be reduced through improved compliance with vaccination and preventive measures, including engineering and administrative controls.     

A Distributed Parameter Physiologically-Based Pharmacokinetic Model for Dermal and Inhalation Exposure to Volatile Organic Compounds

Estimates of dermal dose from exposures to toxic chemicals are typically derived using models that assume instantaneous establishment of steady-state dermal mass flux. However, dermal absorption theory indicates that this assumption is invalid for short-term exposures to volatile organic chemicals (VOCs). A generalized distributed parameter physiologically-based pharmacokinetic model (DP-PBPK), which describes unsteady state dermal mass flux via a partial differential equation (Fickian diffusion), has been developed for inhalation and dermal absorption of VOCs. In the present study, the DP-PBPK model has been parameterized for chloroform, and compared with two simpler PBPK models of chloroform. The latter are lumped parameter models, employing ordinary differential equations, that do not account for the dermal absorption time lag associated with the accumulation of permeant chemical in tissue represented by permeability coefficients. All three models were evaluated by comparing simulated post-exposure exhaled breath concentration profiles with measured concentrations following environmental chloroform exposures. The DP-PBPK model predicted a time-lag in the exhaled breath concentration profile, consistent with the experimental data. The DP-PBPK model also predicted significant volatilization of chloroform, for a simulated dermal exposure scenario. The end-exposure dermal dose predicted by the DP-PBPK model is similar to that predicted by the EPA recommended method for short-term exposures, and is significantly greater than the end-exposure dose predicted by the lumped parameter models. However, the net dermal dose predicted by the DP-PBPK model is substantially less than that predicted by the EPA method, due to the post-exposure volatilization predicted by the DP-PBPK model. Moreover, the net dermal dose of chloroform predicted by all three models was nearly the same, even though the lumped parameter models did not predict substantial volatilization.     

Chloroform Exposure and the Health Risk Associated with Multiple Uses of Chlorinated Tap Water

Recently, showers have been suspected to be an important source of indoor exposure to volatile organic compounds (VOC). The chloroform dose to an individual from showering was determined based on exhaled breath analysis. The postexposure chloroform breath concentration ranged from 6.0-21 micrograms/m3, while all corresponding background breath concentrations were less than 0.86 micrograms/m3. The internal dose from showering (inhalation plus dermal) was comparable to estimates of the dose from daily water ingestion. The risk associated with a single, 10-min shower was estimated to be 1.22 x 10(-4), while the estimated risk from daily ingestion of tap water ranged from 0.130 x 10(-4) to 1.80 x 10(-4) for 0.15 and 2.0 L, respectively. Since the estimates of chloroform risk from domestic water use for the three exposure routes--ingestion, inhalation, and dermal--are similar, all routes must be used to calculate the total risk when making policy decisions regarding the quality of the municipal water supply.     

Estimating Dermal Uptake of Nonionic Organic Chemicals from Water and Soil: I. Unified Fugacity-Based Models for Risk Assessments

Contamination of water and soil that might eventually contact human skin makes it imperative to include the dermal uptake route in efforts to assess potential environmental health risks. Direct measurements of dermal uptake from either water or soil are only available for a small number of the thousands of chemicals likely to be found in the environment. We propose here a mass-transfer model for estimating skin permeability and dermal uptake for organic chemicals that contaminate soil and water. Statistical relationships between measured permeabilities and chemical properties reveal that permeability varies primarily with the octanol-water partition coefficient (Kow) and secondarily with the molecular weight. From these results, we derive a fugacity-based model for skin permeability that addresses the inherent permeability of the skin, the interaction of the skin with the environmental medium on skin (water or soil), and retains a relatively simple algebraic form. Model predictions are compared to measured human skin permeabilities for some 50 compounds in water and four compounds in soil. The model is adjusted to account for dermal uptake during both short-term (10-20 min) and long-term (several hour) exposures. This model is recommended for compounds with molecular weight less than or equal to 280 g.