PBTK modeling demonstrates contribution of dermal and inhalation exposure components to end-exhaled breath concentrations of naphthalene

BACKGROUND: Dermal and inhalation exposure to jet propulsion fuel 8 (JP-8) have been measured in a few occupational exposure studies. However, a quantitative understanding of the relationship between external exposures and end-exhaled air concentrations has not been described for occupational and environmental exposure scenarios. OBJECTIVE: Our goal was to construct a physiologically based toxicokinetic (PBTK) model that quantitatively describes the relative contribution of dermal and inhalation exposures to the end-exhaled air concentrations of naphthalene among U.S. Air Force personnel. METHODS: The PBTK model comprised five compartments representing the stratum corneum, viable epidermis, blood, fat, and other tissues. The parameters were optimized using exclusively human exposure and biological monitoring data. RESULTS: The optimized values of parameters for naphthalene were a) permeability coefficient for the stratum corneum 6.8 x 10(-5) cm/hr, b) permeability coefficient for the viable epidermis 3.0 x 10(-3) cm/hr, c) fat:blood partition coefficient 25.6, and d) other tissue:blood partition coefficient 5.2. The skin permeability coefficient was comparable to the values estimated from in vitro studies. Based on simulations of workers' exposures to JP-8 during aircraft fuel-cell maintenance operations, the median relative contribution of dermal exposure to the end-exhaled breath concentration of naphthalene was 4% (10th percentile 1% and 90th percentile 11%). CONCLUSIONS: PBTK modeling allowed contributions of the end-exhaled air concentration of naphthalene to be partitioned between dermal and inhalation routes of exposure. Further study of inter- and intraindividual variations in exposure assessment is required to better characterize the toxicokinetic behavior of JP-8 components after occupational and/or environmental exposures.     

Benzene percutaneous absorption: dermal exposure relative to other benzene sources

Skin is one of several exposure routes whereby benzene, a widely distributed environmental contaminant that causes leukemia, enters the body, so accurate predictions of its percutaneous absorption are important for risk assessment. Determining benzene's skin-exposure dose and subsequent absorption is difficult because it has a low boiling point and exists as both liquid and vapor. Industrial and environmental benzene is present as a contaminant in other vehicles/solvents, and its percutaneous absorption is in part dependent upon co-solvent volatility. Co-solvents such as benzene in toluene rapidly evaporate from skin, whereas benzene contaminant in water is retained on skin longer due to water's lower volatility. Co-solvents can also affect benzene-skin partition coefficients; thus, permeability coefficients and percentage doses absorbed can vary many-fold. The exposure situation will determine percutaneous absorption, which, if low, can be overwhelmed by benzene intake from the food we eat and the air we breathe.     

Glyceryl trioleate-water partition coefficients for three simple organic compounds

Conclusions The partition coefficients of n-hexane, benzene and carbon tetrachloride between glyceryl trioleate and water have been derived from vapour pressure measurements. Within the accuracy of about ±50%, they are independent of temperature from 20°–37°C, and are all about two or three times larger than literature values for octanol and water. This lends support to the proposition that octanol-water partition coefficients, for which there are extensive literature tabulations,are a useful substitute for lipid-water partition coefficients needed in bioaccumulation studies.It is appropriate to add here a note of caution regarding the practice of equating the partition coefficient to a ratio of solubilities. These quantities are indeed equal if both the lipid and water are saturated with the solute in question. At solute concentrations below saturation, however, they are equal only if the solute activity coefficient is independent of its concentration in each solvent. This seems to be the case for simple solutes dissolved in water, but is not true for these same solutes in octanol or in lipid (PLATFORD 1976, 19 77). A distinction should therefore be made between partition coefficients for solutes present at saturation, and for those present in trace amounts.     

Human blood concentrations of cotinine, a biomonitoring marker for tobacco smoke, extrapolated from nicotine metabolism in rats and humans and physiologically based pharmacokinetic modeling

The present study defined a simplified physiologically based pharmacokinetic (PBPK) model for nicotine and its primary metabolite cotinine in humans, based on metabolic parameters determined in vitro using relevant liver microsomes, coefficients derived in silico, physiological parameters derived from the literature, and an established rat PBPK model. The model consists of an absorption compartment, a metabolizing compartment, and a central compartment for nicotine and three equivalent compartments for cotinine. Evaluation of a rat model was performed by making comparisons with predicted concentrations in blood and in vivo experimental pharmacokinetic values obtained from rats after oral treatment with nicotine (1.0 mg/kg, a no-observed-adverseeffect level) for 14 days. Elimination rates of nicotine in vitro were established from data from rat liver microsomes and from human pooled liver microsomes. Human biomonitoring data (17 ng nicotine and 150 ng cotinine per mL plasma 1 h after smoking) from pooled five male Japanese smokers (daily intake of 43 mg nicotine by smoking) revealed that these blood concentrations could be calculated using a human PBPK model. These results indicate that a simplified PBPK model for nicotine/cotinine is useful for a forward dosimetry approach in humans and for estimating blood concentrations of other related compounds resulting from exposure to low chemical doses.     

A real-time in-vivo method for studying the percutaneous absorption of volatile chemicals

Realistic estimates of percutaneous absorption following exposures to solvents in the workplace, or through contaminated soil and water, are critical to understanding human health risks. A method was developed to determine dermal uptake of solvents under non-steady-state conditions using real-time breath analysis in rats, monkeys, and humans. The exhaled breath was analyzed using an ion-trap mass spectrometer, which can quantitate chemicals in the exhaled breath stream in the 1-5 ppb range. The resulting data were evaluated using physiologically-based pharmacokinetic (PBPK) models to estimate dermal permeability constants (Kp) under various exposure conditions. The effects of exposure matrix (soil versus water), occlusion versus non-occlusion, and species differences on the absorption of methyl chloroform, trichloroethylene, and benzene were compared. Exposure concentrations were analyzed before and at 0.5-hour intervals throughout the exposures. The percentage of each chemical absorbed and the corresponding Kp were estimated by optimization of the PBPK model to the medium concentration and the exhaled-breath data. The method was found to be sufficiently sensitive for animal and human dermal studies at low exposure concentrations over small body surface areas, for short periods, using non-steady-state exposure conditions.     

Potential of physiologically based pharmacokinetics to amalgamate kinetic data of trichloroethylene and tetrachloroethylene obtained in rats and man

A physiologically based pharmacokinetic model was used to amalgamate information obtained in rats and man by various routes of exposure to trichloroethylene (TRI) and tetrachloroethylene (TETRA). Since there have been no pharmacokinetic data on drinking water exposure, drinking water exposure to TRI was conducted in rats using 14C-TRI. Several partition coefficients of TRI and TETRA were also determined in the present study. Simulations of the kinetics of TRI and TETRA were made with the unified physiologically based pharmacokinetic model to determine whether reported pharmacokinetic data from different routes of exposure to TRI and TETRA (inhalation, intravenous, drinking water in rats, and inhalation in man) could be simulated. The results indicated that the unified model used in this study successfully simulates the pharmacokinetics of TRI and TETRA irrespective of the routes and exposure intensities. Subsequently, sensitivity analyses were performed. Since both TRI and TETRA require bioactivation to produce their toxicity, the amounts metabolised in the body were used as indicators of toxicity. Vmax (maximum velocity of metabolism in the liver), alveolar ventilation, and the blood/air partition coefficient had a more profound effect than other factors on the amounts of these chemicals metabolised when parameter values were altered. The model was applied to simulate the biologically permissible values of exhaled air concentration and blood concentration of these compounds for monitoring exposure intensities in occupational settings. The simulated maximum permissible values showed good agreement with those obtained by field studies. Finally, the model was applied to the risk assessment of drinking water exposures to TRI and TETRA, assuming that a man weighing 70 kg drinks 2 l of the most contaminated drinking water ever reported in the US; 32 ppb for TRI and 5 ppb for TETRA. The simulated metabolised amounts of TRI and TETRA under steady state condition in man were a fifth of an order of magnitude lower than non-cancer causing metabolised amounts of TRI and TETRA in rats through inhalation.     

Potential of physiologically based pharmacokinetics to amalgamate kinetic data of trichloroethylene and tetrachloroethylene obtained in rats and man.

A physiologically based pharmacokinetic model was used to amalgamate information obtained in rats and man by various routes of exposure to trichloroethylene (TRI) and tetrachloroethylene (TETRA). Since there have been no pharmacokinetic data on drinking water exposure, drinking water exposure to TRI was conducted in rats using 14C-TRI. Several partition coefficients of TRI and TETRA were also determined in the present study. Simulations of the kinetics of TRI and TETRA were made with the unified physiologically based pharmacokinetic model to determine whether reported pharmacokinetic data from different routes of exposure to TRI and TETRA (inhalation, intravenous, drinking water in rats, and inhalation in man) could be simulated. The results indicated that the unified model used in this study successfully simulates the pharmacokinetics of TRI and TETRA irrespective of the routes and exposure intensities. Subsequently, sensitivity analyses were performed. Since both TRI and TETRA require bioactivation to produce their toxicity, the amounts metabolised in the body were used as indicators of toxicity. Vmax (maximum velocity of metabolism in the liver), alveolar ventilation, and the blood/air partition coefficient had a more profound effect than other factors on the amounts of these chemicals metabolised when parameter values were altered. The model was applied to simulate the biologically permissible values of exhaled air concentration and blood concentration of these compounds for monitoring exposure intensities in occupational settings. The simulated maximum permissible values showed good agreement with those obtained by field studies. Finally, the model was applied to the risk assessment of drinking water exposures to TRI and TETRA, assuming that a man weighing 70 kg drinks 2 l of the most contaminated drinking water ever reported in the US; 32 ppb for TRI and 5 ppb for TETRA. The simulated metabolised amounts of TRI and TETRA under steady state condition in man were a fifth of an order of magnitude lower than non-cancer causing metabolised amounts of TRI and TETRA in rats through inhalation.     

Biological monitoring of tetrahydrofuran: contribution of a physiologically based pharmacokinetic model

A seven-compartment physiologically based pharmacokinetic (PBPK) model was developed to predict biological levels of tetrahydrofuran under various exposure scenarios. Affinities for the tissue were estimated from measurements of liquid-gas partition coefficients for water, olive oil, and blood. Metabolism was assumed to follow a rapid first order reaction. urinary excretion was simulated considering passive reabsorption of tetrahydrofuran in the tubules. The validity of the model was tested by comparison with available experimental and field data. Agreement was satisfactory with all studies available except one, which showed much higher results than expected. The source of this difference could not be identified, but cannot be explained by different exposure conditions, such as duration, concentration, or physical work load. However, it is recommended that this particular study not be used in the establishment of a biological exposure index. Simulation of repeated occupational exposure with the PBPK model allowed the prediction of biological levels that would be reached after repeated exposure at the American Conference of Governmental Industrial Hygienists' threshold limit value, time-weighted average of 200 ppm. For samples taken at the end of the shift, the PBPK model predicts 5.1 ppm for breath, 57 mumol/L (4.1 mg/L) for venous blood, and 100 mumol/L (7.2 mg/L) for urine.     

超声辐照兔外阴皮肤的病理学转归

目的:探讨超声治疗外阴白色病变的机制。方法:实验兔随机分成辐照组4组(每组10只)及对照组(10只)。辐照组以CZF-1超声治疗仪样机对兔外阴皮肤真皮层进行连续直线辐照,功率4W,4组分别于辐照后1、4、7和14天取材,对照组不辐照立即取材。作光镜、电镜检查。结果:超声辐照后第1天外阴充血水肿,皮肤完整,稍硬,增厚感,皮温升高。第4天外阴充血水肿消失,仍然稍硬,皮温正常。第7天后外阴外观正常,皮肤色泽及质地同辐照前。组织学变化:超声辐照后第1天,表皮完好,真皮乳头层水肿,轻度充血。第4天充血水肿消退,可有慢性炎性细胞浸润。第7天后可见新生毛细血管增生。第14天与正常外阴皮肤一致。超微结构变化:第1、4、7天可见血管内皮细胞线粒体肿胀、微吞饮小泡数量多,成纤维细胞线粒体肿胀、粗面内质网扩张,神经纤维内线粒体肿胀。结论:提示超声有利于微血管、胶原纤维和神经末梢的增生与修复。推测超声用于外阴白色病变临床治疗是有效和安全的。     

Skin physiology

This review article offers a brief overview of skin physiology, including the epidermis, dermis, basement membrane zone and the role of psychological stress. Skin is the largest organ; it is complex and multifunctional, containing many specialized cells that are adapted to different functions. Skin consists of a superficial layer (epidermis) that adheres closely to the deeper layer (dermis) via the basement membrane. Loose connective tissue and fat underlie the dermis. The epidermis is composed of stratified squamous epithelium, comprising layers of closely packed cells produced by cell division of the ‘basal’ cell layer (a single sheet of columnar cells at the lowest level of the epidermis). The dermis lies below the epidermis and supports it structurally and nutritionally. The basement membrane zone forms an adhesion complex between the dermis and epidermis, providing support for the basal cells to allow growth, multiplication and migration, and allowing nutrients and cells to cross from the dermis. Psychological stress may precipitate or aggravate chronic disorders of the skin.     

Unexpected cause of raised benzene absorption in coke oven by-product workers

BACKGROUND: Urinary biological monitoring for benzene (by measuring benzene metabolites) in coke oven by-product workers produced the unexpected result that 2 out of 10 employees had significantly raised urinary S-phenylmercapturic acid (S-PMA). However, simultaneous personal air sampling showed no excessive airborne exposure. METHODS: Possible causes for this finding were investigated having excluded inhalation as the route of uptake. It was suspected that skin absorption via contaminated overalls was the possible mechanism and a standard frequency for overall change was introduced. RESULTS: Changing overalls after every four shifts reduced uptake levels to less than the equivalent of 1 ppm inhaled dose for all employees. CONCLUSION: Skin absorption of benzene in coke oven by-product workers from contaminated overalls can be significant and therefore overalls should be changed on a regular and frequent basis.     

Measurements of exposure concentrations of benzene, toluene and xylene, and amounts of respiratory uptake

With respect to benzene, toluene, and o-, m- and p-xylene contained in indoor air, this study determined the amounts of their uptake through the human respiratory system using the difference between concentrations in inhalation and exhalation, and examined their relationship to concentrations in blood and urine measured before and after exposure. At relatively high concentrations, respiratory absorption of these compounds tended to increase rapidly in the early stage of exposure but decrease after several hours. It was also confirmed that concentrations of these compounds in both blood and urine increased during the first 3 hours of exposure. These results suggested that measurements of concentrations in inhalation and exhalation may provide a simple method for estimating the extent of respiratory exposure to these substances.     

Percutaneous penetration of benzene in hairless mice: an estimate of dermal absorption during tire-building operations

Repeated skin contact with solvents containing as much as 0.5% benzene is common in workers building regular bias passenger tires. To estimate the amount of benzene absorbed through the skin of these workers, a series of in vivo studies was conducted in hairless mice. Percutaneous absorption, following single dermal applications of 14C-benzene contained in rubber solvent at a concentration of 0.5% (v/v), was calculated directly from the sums of radioactivity found in excreta, expired breath, and the carcass. Data from the study, together with observations made during tire-building operations, suggest that a worker could absorb 4-8 mg of benzene daily through the skin. This compares to 14 mg per day via inhalation at the NIOSH recommended standard of 1 ppm. Thus dermal absorption could contribute from 20-40% of the total benzene dose of these workers.     

Computational toxicology of chloroform: reverse dosimetry using Bayesian inference, Markov chain Monte Carlo simulation, and human biomonitoring data

BACKGROUND: One problem of interpreting population-based biomonitoring data is the reconstruction of corresponding external exposure in cases where no such data are available. OBJECTIVES: We demonstrate the use of a computational framework that integrates physiologically based pharmacokinetic (PBPK) modeling, Bayesian inference, and Markov chain Monte Carlo simulation to obtain a population estimate of environmental chloroform source concentrations consistent with human biomonitoring data. The biomonitoring data consist of chloroform blood concentrations measured as part of the Third National Health and Nutrition Examination Survey (NHANES III), and for which no corresponding exposure data were collected. METHODS: We used a combined PBPK and shower exposure model to consider several routes and sources of exposure: ingestion of tap water, inhalation of ambient household air, and inhalation and dermal absorption while showering. We determined posterior distributions for chloroform concentration in tap water and ambient household air using U.S. Environmental Protection Agency Total Exposure Assessment Methodology (TEAM) data as prior distributions for the Bayesian analysis. RESULTS: Posterior distributions for exposure indicate that 95% of the population represented by the NHANES III data had likely chloroform exposures < or = 67 microg/L [corrected] in tap water and < or = 0.02 microg/L in ambient household air. CONCLUSIONS: Our results demonstrate the application of computer simulation to aid in the interpretation of human biomonitoring data in the context of the exposure-health evaluation-risk assessment continuum. These results should be considered as a demonstration of the method and can be improved with the addition of more detailed data.     

PBPK modeling/Monte Carlo simulation of methylene chloride kinetic changes in mice in relation to age and acute, subchronic, and chronic inhalation exposure.

During a 2-year chronic inhalation study on methylene chloride (2000 or 0 ppm; 6 hr/day, 5 days/week), gas-uptake pharmacokinetic studies and tissue partition coefficient determinations were conducted on female B6C3F1, mice after 1 day, 1 month, 1 year, and 2 years of exposure. Using physiologically based pharmacokinetic (PBPK) modeling coupled with Monte Carlo simulation and bootstrap resampling for data analyses, a significant induction in the mixed function oxidase (MFO) rate constant (Vmaxc) was observed at the 1-day and 1-month exposure points when compared to concurrent control mice while decreases in glutathione S-transferase (GST) rate constant (Kfc) were observed in the 1-day and 1-month exposed mice. Within exposure groups, the apparent Vmaxc maintained significant increases in the 1-month and 2-year control groups. Although the same initial increase exists in the exposed group, the 2-year Vmaxc is significantly smaller than the 1-month group (p < 0.001). Within group differences in median Kfc values show a significant decrease in both 1-month and 2-year groups among control and exposed mice (p < 0.001). Although no changes in methylene chloride solubility as a result of prior exposure were observed in blood, muscle, liver, or lung, a marginal decrease in the fat:air partition coefficient was found in the exposed mice at p = 0.053. Age related solubility differences were found in muscle:air, liver:air, lung:air, and fat:air partition coefficients at p < 0.001, while the solubility of methylene chloride in blood was not affected by age (p = 0.461). As a result of this study, we conclude that age and prior exposure to methylene chloride can produce notable changes in disposition and metabolism and may represent important factors in the interpretation for toxicologic data and its application to risk assessment.     

Levels of retinyl palmitate and retinol in stratum corneum, epidermis and dermis of SKH-1 mice

Vitamin A (retinol) regulates many biological functions, including epidermal cell growth. Retinyl palmitate (RP) is the major esterified form of retinol and the predominant component of retinoids in the skin; however, how endogenous levels of RP and retinol in the skin are affected by the age of the animal remains unknown. Furthermore, the levels of retinol and RP in the various skin layers - the stratum corneum, epidermis and dermis of skin - have not been reported. In this paper, we report the development of a convenient method for separation of the skin from SKH-1 female mice into the stratum corneum, epidermis, and dermis and the determination of the levels of RP and retinol in the three fractions by HPLC analysis. The total quantities of RP and retinol from the stratum corneum, epidermis, and dermis are comparable to those extracted from the same amount of intact skin from the same mouse. There was an age-related effect on the levels of RP and retinol in the skin and liver of female mice. An age-related effect was also observed in the stratum corneum, epidermis, and dermis. The levels of RP and retinol were highest in the epidermis of 20-week-old mice, and decreased when the age increased to 60- and 68-weeks. The total amount of RP at 20 weeks of age was found to be 1.52 ng/mg skin, and decreased about 4-fold at 60- and 68-weeks of age. A similar trend was found for the effects of age on the levels of retinol.     

Evaluation of dermal absorption and protective effectiveness of respirators for xylene in spray painters

Objectives To determine the contribution of dermal absorption on the total exposure dose and the performance of respirators in the field for xylene in spray painters. Methods Eighteen male spray painters worked at shipyard were recruited for this study. The subjects were monitored during a 3-day-work period using a repeated-measures study design. Personal exposure to xylene outside and inside mask were collected using two 3 M model 3500 organic vapor monitors, respectively. Urine was collected before and after the work shift and urinary methyl hippuric acid (MHA) was determined. Total 98 of air and urine samples were obtained, respectively. Results Air sampling results showed that workers were primarily exposed to xylene and ethyl benzene. Xylene and ethyl benzene concentrations outside the mask were 52.6 ± 63.7 (mean ± SD) and 33.2 ± 32.4 ppm, and concentrations inside the mask were 2.09 ± 2.74 and 1.79 ± 2.16 ppm, respectively. The median workplace protection factors of respirators for xylene and ethyl benzene were 25.0 and 17.4, respectively. On average, workers could reduce xylene inhalation by 96% and ethyl benzene inhalation by 94% for wearing respirators. A significant correlation (R ² = 0.935; P < 0.001) was found between the WPFs for xylene and ethyl benzene. Total urinary MHA concentration was 240.2 ± 42.3 (mean ± SE) mg/g creatinine, whereas urinary MHA via skin absorption was estimated to be 202.1 ± 40.1 mg/g creatinine. The contribution of dermal absorption to the total exposure dose of xylene was 64 ± 4.3%. Conclusion The present study showed that inhalation of solvent vapors in workers decreased as a result of wearing respirators and dermal exposure became the main contributor to the total body burden of solvents. Because workers had different attitude and behavior to wear respirators, the measured workplace protection factors varied. It is therefore equally important to prevent from being exposed to solvents through skin for shipyard spray painters.     

Bioavailability of octamethylcyclotetrasiloxane (D(4)) after exposure to silicones by inhalation and implantation.

We developed a physiologically based pharmacokinetic (PBPK) model to predict the target organ doses of octamethylcyclotetrasiloxane (D(4)) after intravenous (IV), inhalation, or implantation exposures. The model used (14)C-D(4) IV disposition data in rats to estimate tissue distribution coefficients, metabolism, and excretion parameters. We validated the model by comparing the predicted blood and tissues concentrations of D(4) after inhalation to experimental results in both rats and humans. We then used the model to simulate D(4) kinetics after single and/or repeated D(4) exposures in rats and humans. The model predicted bioaccumulation of D(4) in fatty tissues (e.g., breast), especially in women. Because of its high lipid solubility (Log P(oct/water) = 5.1), D(4) persisted in fat with a half life of 11.1 days after inhalation and 18.2 days after breast implant exposure. Metabolism and excretion remained constant with repeated exposures, larger doses, and/or different routes of exposure. The accumulation of D(4) in fatty tissues should play an important role in the risk assessment of D(4) especially in women exposed daily to multiple personal care products and silicone breast implants.     

Levels of benzene and other volatile aromatic compounds in the blood of non-smokers and smokers

The concentrations of benzene, toluene, ethylbenzene, and o-, m-and p-xylene were measured in venous blood samples collected from 13 non-smokers and 14 cigarette smokers. The blood samples were analysed by a purge and trap technique followed by gas chromatography/mass spectrometry/computer analysis. The above-mentioned volatile organic compounds (VOC) could be detected in measurable amounts in all blood samples. This finding seems to reflect the ubiquitous exposure of humans to these agents in the urban environment, in non-smokers as well as in smokers. Smokers were found to have significantly higher blood concentrations of benzene (median 547 ng/l) and toluene (median 2201 ng/l) than non-smokers (median 190 ng/l and 1141 ng/l, respectively). The concentrations of ethylbenzene and xylenes also tended to be higher in smokers when compared to non-smokers. The different concentrations of these compounds in the blood of non-smokers appear to reflect the common concentration pattern found in outdoor urban air as well as in indoor air and also seem to be influenced by the different blood/air partition coefficients of these compounds. The results indicate that smoking is associated with a significant additional exposure to VOC, in particular to benzene and toluene.     

Skin absorption of some vaporous solvents in volunteers

Objectives: To determine the dermal absorption rates of vaporous 1,1,1-trichloroethane (111TRI), trichloroethene (TRI), tetrachloroethene (TETRA), hexane (HEX), toluene (TOL) and m-xylene (XYL) in humans. The determined absorption data were used for the validation of two published models for prediction of non-steady-state skin absorption. Methods: Five volunteers were dermally exposed on an area of about 1,000 cm² (forearm and hand) for 20 or 30 min. An inhalation exposure with a known dose rate served as a reference. Using the solvent concentrations in exhaled air, measured after both inhalation and dermal exposure, we calculated the maximum absorption rate into the blood, and the average absorption rates into the skin throughout the exposure, using the linear system dynamics method. Results: The absorption rates into the skin, normalised for exposure concentration, amounted to 0.021 cm/h (111TRI), 0.049 cm/h (TRI), 0.054 cm/h (TETRA), 0.013 cm/h (HEX), 0.14 cm/h (TOL), and 0.12 cm/h (XYL). The maximum absorption rates into the blood ranged from 0.005 nmol/h for 111TRI and HEX to 0.050 nmol/hr for TOL. The ratios between the predicted and experimental values of the absorption rates into the skin ranged, for the model of Cleek and Bunge [4], from 0.3 (HEX) to 1.1 (TRI and TETRA), and for the model of Wilschut and Ten Berge [22], from 1.1 (HEX) to 4.7 (XYL). Conclusion: The linear system dynamics method allowed us to calculate not only the total amount absorbed by the skin but also the maximum absorption rate into the blood. The steady-state absorption rate, usually described by a permeability constant, will be below the absorption rate into the skin and above the maximum absorption rate into the blood. The skin absorption rates predicted by the models showed a good agreement with the experimental values. A comparison of the estimated whole-body skin uptake with the inhalatory uptake from the same atmosphere, revealed that the dermal uptake contributed from 0.1% (HEX) to 1% (TOL and XYL) to the total uptake. Received: 27 September 1999 / Accepted: 25 March 2000