PBPK modeling of the percutaneous absorption of perchloroethylene from a soil matrix in rats and humans.

Perchloroethylene (PCE) is a widely used volatile organic chemical. Exposures to PCE are primarily through inhalation and dermal contact. The dermal absorption of PCE from a soil matrix was compared in rats and humans using real-time MS/MS exhaled breath technology and physiologically based pharmacokinetic (PBPK) modeling. Studies with rats were performed to compare the effects of loading volume, concentration, and occlusion. In rats, the percutaneous permeability coefficient (K(P)) for PCE was 0.102 +/- 0.017, and was independent of loading volume, concentration, or occlusion. Exhaled breath concentrations peaked within 1 h in nonoccluded exposures, but were maintained over the 5 h exposure period when the system was occluded. Three human volunteers submerged a hand in a container of PCE-laden soil for 2 h and their exhaled breath was continually monitored during and for 2.5 h following exposure. The absorption and elimination kinetics of PCE were slower in these subjects than initially predicted based upon the PBPK model developed from rat dermal kinetic data. The resulting K(P) for humans was over 100-fold lower than for the rat utilizing a single, well-stirred dermal compartment. Therefore, two additional PBPK skin compartment models were evaluated: a parallel model to simulate follicular uptake and a layered model to portray a stratum corneum barrier. The parallel dual dermal compartment model was not capable of describing the exhaled breath kinetics, whereas the layered model substantially improved the fit of the model to the complex kinetics of dermal absorption through the hand. In real-world situations, percutaneous absorption of PCE is likely to be minimal.     

In vitro and in vivo percutaneous absorption of 14C-octamethylcyclotetrasiloxane (14C-D4) and 14C-decamethylcyclopentasiloxane (14C-D5)

Octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5) are cyclic siloxanes used as chemical intermediates with some applications in consumer products. The in vitro percutaneous absorption of 14C-D4 and 14C-D5 was studied in flow-through diffusion cells. Single doses were applied neat and in antiperspirant formulations to dermatomed human skin for 24h. The majority of applied D4 and D5 ( approximately 90%) volatilized before being absorbed. Only 0.5% of applied D4 was absorbed while the absorption of D5 (0.04%) was one order of magnitude lower. The largest percentage (>90%) of the absorbed D4 and D5 was found in the skin. The fate of D4 and D5 absorbed in the skin was studied in rat in vivo. A single dose of 14C-D4 (10, 4.8 and 2mg/cm2) and 14C-D5 (10mg/cm2) was topically applied inside a dosing chamber attached to the dorsal area. Rats were housed in metabolism cages up to 24h to enable collection of urine, feces, expired/escaped volatiles. The majority of applied D4 or D5 had volatilized from the skin surface. Less than 1.0% of the applied D4 and only 0.2% of applied D5 was absorbed with approximately 60% of absorbed D4 and 30% of absorbed D5 reaching systemic compartments. The amount absorbed into the skin decreased with time showing that residual D4 and D5 diffused back to the skin surface and continued to evaporate. Overall, a low tendency to pass through the skin into systemic compartments was demonstrated for both D4 (< or = 0.5% of applied dose) and D5 (<0.1% of applied dose).     

Physiological modeling of inhalation kinetics of octamethylcyclotetrasiloxane in humans during rest and exercise.

In a recent pharmacokinetic study, six human volunteers were exposed by inhalation to 10 ppm (14)C-D(4) for 1 h during alternating periods of rest and exercise. Octamethylcyclotetrasiloxane (D(4)) concentrations were determined in exhaled breath and blood. Total metabolite concentrations were estimated in blood, while the amounts of individual metabolites were measured in urine. Here, we use these data to develop a physiologically based pharmacokinetic (PBPK) model for D(4) in humans. Consistent with PBPK modeling efforts for D(4) in the rat, a conventional inhalation PBPK model assuming flow-limited tissue uptake failed to adequately describe these data. A refined model with sequestered D(4) in blood, diffusion-limited tissue uptake, and an explicit pathway for D(4) metabolism to short-chain linear siloxanes successfully described all data. Hepatic extraction in these volunteers, calculated from model parameters, was 0.65 to 0.8, i.e., hepatic clearance was nearly flow-limited. The decreased retention of inhaled D(4) seen in humans during periods of exercise was explained by altered ventilation/perfusion characteristics during exercise and a rapid approach to steady-state conditions. The urinary time course excretion of metabolites was consistent with a metabolic scheme in which sequential hydrolysis of linear siloxanes followed oxidative demethylation and ring opening. The unusual properties of D(4) (high lipophilicity coupled with high hepatic and exhalation clearance) lead to rapid decreases in free D(4) in blood. The success of D(4) PBPK models with a similar physiological structure in both humans and rats increases confidence in the utility of the model for predicting human tissue concentrations of D(4) and metabolites during inhalation exposures.     

Comparison of the human skin grafted onto nude mouse model with in vivo and in vitro models in the prediction of percutaneous penetration of three lipophilic pesticides

The evaluation of the degree of percutaneous penetration of agrochemicals is a key part of risk assessment for operators. The availability of suitable and predictive experimental models is crucial, in particular in the case of lipophilic compounds which persist in the stratum corneum (SC). Regulatory models (rat in vivo, human and rat in vitro) and the innovative human skin grafted onto nude mice (HuSki) model were compared for their ability to predict the human skin absorption. Radiolabelled malathion, lindane and cypermethrin (4microg/cm(2)) were topically applied to each model. The % of applied dose absorbed and that present in skin and SC were evaluated at 24h. Additionally, the absorption profile of cypermethrin was evaluated in the in vivo rat and HuSki models for up to 11 days. We found that the human in vitro and HuSki models closely predicted the human skin absorption at 24h, while rat models overestimated the human skin absorption. Furthermore, our experiments with cypermethrin indicated that evaluation of % percutaneous absorption over extended periods of time was feasible with the HuSki model. In our studies the HuSki model overcame the limitations of the regulatory models and is promising to realistically refine the dermal absorption assessment of topically applied chemicals.     

Mixture component effects on the in vitro dermal absorption of pentachlorophenol

Interactions between chemicals in a mixture and interactions of mixture components with the skin can significantly alter the rate and extent of percutaneous absorption, as well as the cutaneous disposition of a topically applied chemical. The predictive ability of dermal absorption models, and consequently the dermal risk assessment process, would be greatly improved by the elucidation and characterization of these interactions. Pentachlorophenol (PCP), a compound known to penetrate the skin readily, was used as a marker compound to examine mixture component effects using in vitro porcine skin models. PCP was administered in ethanol or in a 40% ethanol/60% water mixture or a 40% ethanol/60% water mixture containing either the rubefacient methyl nicotinate (MNA) or the surfactant sodium lauryl sulfate (SLS), or both MNA and SLS. Experiments were also conducted with 14C-labelled 3,3',4,4'-tetrachlorobiphenyl (TCB) and 3,3',4,4',5-pentachlorobiphenyl (PCB). Maximal PCP absorption was 14.12% of the applied dose from the mixture containing SLS, MNA, ethanol and water. However, when PCP was administered in ethanol only, absorption was only 1.12% of the applied dose. There were also qualitative differences among the absorption profiles for the different PCP mixtures. In contrast with the PCP results, absorption of TCB or PCB was negligible in perfused porcine skin, with only 0.14% of the applied TCB dose and 0.05% of the applied PCB dose being maximally absorbed. The low absorption levels for the PCB congeners precluded the identification of mixture component effects. These results suggest that dermal absorption estimates from a single chemical exposure may not reflect absorption seen after exposure as a chemical mixture and that absorption of both TCB and PCB are minimal in this model system.     

Pharmacokinetics of fluazifop-butyl in human volunteers. II: Dermal dosing.

1. The absorption of the herbicide fluazifop-butyl (f-b), has been determined from plasma and urine measurements in groups of six male volunteers following dermal administration of 2.5, 25 and 250 micrograms cm-2 from standardized formulations containing 0.05, 0.5 and 5.0% (w/v) fluazifop-butyl to a skin area of 800 cm2. 2. Urinary excretion rate of the principal metabolite fluazifop, following dosing with the 5% formulation, was described by a two-compartment pharmacokinetic model; the average elimination half-lives of initial and terminal phases were 18 h and approximately 70 h, respectively. For the other dose levels the elimination half-life was estimated to be 17 h; urine concentrations at later time points were too low to characterize a second compartment. 3. The estimated total fluazifop-butyl absorbed was 8.0, 3.4 and 1.6% of the applied dose for the 0.05, 0.5 and 5.0% formulations, respectively. 4. Up to 50% of the applied fluazifop-butyl was readily removed by skin washing and the majority of the remainder was transferred to clothing during the 24 h following application. 5. When six volunteers were given a daily dermal dose of the 0.5% formulation for five consecutive days, the plasma and urinary excretion kinetics of fluazifop could be accurately predicted by simple mathematical extrapolation of the kinetic data from the single exposure study at the equivalent daily dose. 6. It is concluded that fluazifop-butyl is only slowly and poorly absorbed through human skin and has a low potential to accumulate in man.     

Dermal penetration of [14C]captan in young and adult rats.

Age dependence in dermal absorption has been a major concern in risk assessment. Captan, a chloroalkyl thio heterocyclic fungicide, was selected for study of age dependence as representative of this class of pesticides. Dermal penetration of [14C]captan applied at 0.286 mumol/cm2 was determined in young (33-d-old) and adult (82-d-old) female Fischer 344 rats in vivo and by two in vitro methods. Dermal penetration in vivo at 72 h was about 9% of the recovered dose in both young and adult rats. The percentage penetration was found to increase as dosage (0.1, 0.5, 2.7 mumol/cm2) decreased. Two in vitro methods gave variable dermal penetration values compared with in vivo results. A static system yielded twofold higher dermal penetration values compared with in vivo results for both young and adult rats. A flow system yielded higher dermal penetration values in young rats and lower penetration values in adults compared with in vivo results. Concentration in body, kidney, and liver was less in young than in adult rats given the same absorbed dosage. A physiological pharmacokinetic model was developed having a dual compartment for the treated skin and appeared to describe dermal absorption and disposition well. From this model, tissue/blood ratios of captan-derived radioactivity for organs were found to range from 0.35 to 3.4, indicating no large uptake or binding preferences by any organ. This preliminary pharmacokinetic model summarizes the experimental findings and could provide impetus for more complex and realistic models.     

Are highly lipophilic volatile compounds expected to bioaccumulate with repeated exposures?

With non-volatile compounds, high lipophilicity (i.e., fat:blood partition coefficients, Pf, in the range of several hundred to a thousand or higher) typically leads to concerns for bioaccumulation. To evaluate the extent to which highly cleared, lipophilic vapors are expected to accumulate in blood and tissues, we conducted pharmacokinetic (PK) analysis, using both a generic physiologically based (PBPK) model for inhalation of volatile compounds (VCs) and a more detailed PBPK model specifically developed for a highly lipophilic volatile (decamethylcyclopentasiloxane, D(5)). The generic PBPK model for inhalation of VCs in humans showed that highly metabolized, lipophilic compounds, with a low blood:air partition coefficient (Pb), do not accumulate in blood or systemic tissues with repeat exposures although a period of days to weeks may be required for fat to reach periodic steady state. VCs with higher Pb (in the hundreds) and lower hepatic extraction accumulate in blood on repeat exposures. The more detailed PBPK model for D(5) also showed that this lipophilc VC does not accumulate in blood and predictions of the increases in D(5) in fat with repeat exposures in rats agreed with experiments. In general, the major characteristic favoring accumulation of VCs in blood and systemic tissues is poor whole-body clearance, not lipophilicty. The term bioaccumulation should be used to refer to cases where repeat exposures lead to increases in VC blood (or central compartment) concentration. Based on this definition, highly cleared VCs, such as D(5), would not be considered to bioaccumulate on repeat exposures.     

Kinetics of finite dose absorption through skin 1. Vanillylnonanamide

Despite the considerable success in predicting the steady-state dermal absorption rates of chemical compounds from large reservoirs applied to skin, correspondingly little progress has been made in predicting the absorption rate and extent for small doses of topically applied compounds. In the latter case, steady-state absorption rates are generally not obtained, and rapid evaporation or penetration of the dose solvent makes application of permeability coefficient models problematic. This report presents a new analysis of the finite dose problem in terms of a diffusion model with three parameters-a characteristic time for diffusion, h2/D; a skin solubility factor, S(m)h; and a capacity factor for absorption of the dose during the dry down period, M*. These parameters can be related to the molecular weight and oil and water solubilities of the permeant in a manner similar to models describing steady-state absorption from saturated solutions. Some variation of the parameter values based on the chemical nature and volume of the dose solvent is anticipated. The applicability of the model is demonstrated by analyzing the in vitro absorption rates of varying doses of vanillylnonamide (VN, synthetic capsaicin) applied to excised human skin from propylene glycol. The analysis shows that a three-parameter model that assigns all of the resistance to transport to diffusion through the stratum corneum is able to explain most of the significant features of VN absorption through skin.     

Utility of real time breath analysis and physiologically based pharmacokinetic modeling to determine the percutaneous absorption of methyl chloroform in rats and humans.

Due to the large surface area of the skin, percutaneous absorption has the potential to contribute significantly to the total bioavailability of some compounds. Breath elimination data, acquired in real-time using a novel MS/MS system, was assessed using a PBPK model with a dermal compartment to determine the percutaneous absorption of methyl chloroform (MC) in rats and humans from exposures to MC in non-occluded soil or occluded water matrices. Rats were exposed to MC using a dermal exposure cell attached to a clipper-shaved area on their back. The soil exposure cell was covered with a charcoal patch to capture volatilized MC and prevent contamination of exhaled breath. This technique allowed the determination of MC dermal absorption kinetics under realistic, non-occluded conditions. Human exposures were conducted by immersing one hand in 0.1% MC in water, or 0.75% MC in soil. The dermal PBPK model was used to estimate skin permeability (Kp) based on the fit of the exhaled breath data. Rat skin K(p)s were estimated to be 0.25 and 0.15 cm/h for MC in water and soil matrices, respectively. In comparison, human permeability coefficients for water matrix exposures were 40-fold lower at 0.006 cm/h. Due to evaporation and differences in apparent Kp, nearly twice as much MC was absorbed from the occluded water (61.3%) compared to the non-occluded soil (32.5%) system in the rat. The PBPK model was used to simulate dermal exposures to MC-contaminated water and soil in children and adults using worst-case EPA default assumptions. The simulations indicate that neither children nor adults will absorb significant amounts of MC from non-occluded exposures, independent of the length of exposure. The results from these simulations reiterate the importance of conducting dermal exposures under realistic conditions.     

Route-specific differences in distribution characteristics of octamethylcyclotetrasiloxane in rats: analysis using PBPK models.

Octamethylcyclotetrasiloxane (D(4)) is used in selected consumer products and has a potential for human exposure from multiple routes. Here we develop a physiologically based pharmacokinetic (PBPK) model to describe the tissue dosimetry, plasma concentration, and clearance in the rat following inhalation and dermal, oral, and iv exposure. An initial multiroute PBPK model, based on a previously published inhalation PBPK model for D(4), provided excellent fits to the observed concentration time course of D(4) metabolites in urine and D(4) exhalation rate following dermal exposures. However, the pharmacokinetics of D(4), following oral and iv exposure, were sensitive to the mode of entry into the blood compartment. A refined model, describing delivery of D(4) from the GI tract to the nonexchangeable/deep blood compartment, provided the best fits to observed plasma D(4), exhaled D(4), and D(4) metabolites excreted in the urine following oral exposure. Pharmacokinetics following iv administration was best described by delivery of D(4) directly into the deep blood compartment, possibly reflecting a kinetically identifiable characteristic of the administration of D(4) as an emulsion for the intravenous route of exposure. This model-based analysis indicates that the pharmacokinetics of D(4) delivered by the inhalation or dermal routes is similar, and is different from the iv or oral delivery routes.     

Percutaneous penetration and distribution of VX using in vitro pig or human excised skin validation of demeton-S-methyl as adequate simulant for VX skin permeation investigations

The organophosphorus (OP) chemical warfare V agent O-ethyl-S-[2(di-isopropylamino)ethyl] methyl phosphonothioate (VX), is a highly toxic compound which mainly penetrates the body via percutaneous pathways. Hence, the following prerequisite: to ascertain compound absorption and percutaneous profile distribution with a view to further assessing the efficacy of topical skin protectants. We first selected the most appropriate receptor fluid to carry out in vitro VX absorption experiments, namely: Hanks's Balanced Salt Solution (HBSS). After a 24-h topical exposure time lapse, we measured altogether the percentage of applied dose unabsorbed and absorbed, penetration rate, lag time, permeability coefficient (K(p)), and dose of VXeq present in skin. To such an end, we used full-thickness and split-thickness pig-ear or human abdominal skin membranes. Further, we scrutinised the potential use of two specific molecules as suitable surrogates for VX percutaneous penetration analyses: thus, we compared the present VX toxicokinetic parameters to earlier findings from our research unit, with respect to OP insecticides demethon-S-methyl (DSM) and paraoxon (POX). Within the framework of our study, we wish to highlight the following evidence: (a) pig-ear skin proves a relevant model to predict in vitro human abdominal skin, taking into account a 2-fold higher skin permeability to VXeq; (b) both full or split-thickness skin membranes may be used indiscriminately to gauge penetration rate and absorbed dose; (c) DSM applied on full-thickness pig-ear skin is the most relevant model to mimic the in vitro VX absorption through full-thickness skin model.     

Metabolism of butoxyethanol in excised human skin in vitro

Glycol ethers are widely used in industrial and household applications because their chemical and physical properties make them versatile solvents, miscible with both water and organic media. Due to the ease with which the glycol ethers are absorbed through the skin and the potential for development of adverse health effects it is important to understand the extent to which local metabolism can contribute to local and systemic toxicity. Sections of previously frozen, full thickness excised human skin samples were placed on transwell supports and placed with the underside of the skin in contact with receptor fluid. The skin surface was dosed with 115.2 mg of neat butoxyethanol and the absorption and metabolism of butoxyethanol to butoxyacetic acid monitored over time. In total 64.94+/-0.04 mg of butoxyethanol or its metabolites were removed from the surface of the skin at 24h, representing the equivalent of 56% of the applied dose, the equivalent of 17.5% of the applied dose was recovered from the receiver fluid, 3% from within the skin and the remaining 23.5% of the dose was lost to the atmosphere through evaporation. After 24h a total of 31.5 microg of butoxyacetic acid had been produced representing approximately 0.03% of the applied dose. Therefore approximately 0.16% (31.5 microg as a percentage of the total amount of butoxyethanol reaching the receiver fluid (20.17 mg) of the absorbed butoxyethanol was metabolised to butoxyacetic acid during its passage through the skin. This suggested that, although enzyme activities capable of converting butoxyethanol to butoxyacetic acid are present in skin, metabolic conversion during percutaneous absorption was small and systemic exposure to the parent compound rather than the metabolite would occur following dermal exposure to butoxyethanol. This experiment demonstrates that it is possible to maintain metabolic activity in skin samples in an in vitro setup for short, but experimentally useful, periods.     

Pharmacokinetic models of dermal absorption.

Many studies have used pharmacokinetic (compartment) models for skin to predict or analyze dermal absorption of chemicals. Comparing these models is difficult because the relationships between rate constants and the physicochemical parameters were not always defined clearly, simplifying assumptions built into models sometimes were not stated, and which skin layers were included often were not specified. In this paper we review and compare published one- and two-compartment models for which rate constants were expressed in terms of the physicochemical and physical properties of the skin (i.e., diffusion coefficients, partition coefficients and thickness). Nine one-compartment and two two-compartment models are presented with a consistent nomenclature and clearly defined assumptions. In addition, methods used for estimating the physicochemical parameters required by the various are summarized. These eleven compartment models are compared with calculations from a two-membrane skin model that corresponds better with skin function. Many of the compartment models do not predict key characteristics of the two-membrane skin model, especially the effect of blood flow on skin concentration and penetration rates, even when the same input parameters were used. The compartment models developed by Kubota and by McCarley are better predictors of the two-membrane model results, because these models were developed to match characteristics of the membrane model.     

Penetration of β-naphthylamine and o-toluidine through human skin in vitro

Several aromatic amines (AAs) are known to be carcinogens for humans. AAs are considered to be substantially absorbed through the skin. However, the database for dermal absorption of AAs in general is limited and no specific studies on dermal absorption of β-naphthylamine (BNA) and o-toluidine (OT) have been published. In the present study using diffusion cells, we investigated dermal penetration of BNA and OT through human skin. We have demonstrated that both AAs penetrate through human skin fast (lag time: ∼1.2 vs. 0.8 h) and in high percentages (54 vs. 50%, respectively, of the applied dose within 24 h). A skin notation is therefore justified for these substances.     

Polychlorinated biphenyls (PCBs): dermal absorption, systemic elimination, and dermal wash efficiency

The objectives of this study were to determine the dermal absorption, systemic elimination, and dermal wash efficiency for polychlorinated biphenyls (PCBs). 14C-Labeled 42% PCB and 14C-labeled 54% PCB were topically and parenterally administered to rhesus monkeys and guinea pigs. Dermal absorption, determined by 14C urinary excretion, was extensive. In guinea pigs, 33% of the applied 14C-labeled 42% PCB dose and 56% of the 14C-labeled 54% PCB dose were absorbed. In rhesus monkeys, 15-34% of the labeled 42% PCB was dermally absorbed, depending on the magnitude of the applied dose. 14C-labeled 42% PCB applied to guinea pig skin was immediately washed with water and acetone. Only 59% of the applied dose was removed from the skin. A post-24-h washing removed only 1% of applied labeled 42% PCB and 20% of applied labeled 54% PCB. Postcontamination washing cannot be assumed to remove all contaminated PCB from skin. The body elimination of 14C was continuous and slow, with elimination half-lives on the order of 2-3 d in the guinea pig and 4-7 d in the monkey. Only 50-65% of an intramuscular dose could be accounted for in urine and feces for up to 28 d excretion. The elimination half-lives following topical administration were not much greater than that following intramuscular administration. This suggests that PCBs are rapidly and extensively absorbed through the skin, and that they are then probably generally distributed throughout the body, and then slowly eliminated.     

Effect of dose on the percutaneous absorption of 2- and 4-chloronitrobenzene in rats.

The effect of dose on the dermal absorption of 2- and 4-chloronitrobenzene (2- and 4-CNB) has been investigated in rats following nonocclusive protective dermal application on an area of 4 cm2 per animal at approximately 0.0325, 0.325, and 3.25 mg/cm2 (0.65, 6.5, and 65 mg/kg, respectively). At the three-dose levels, 33-40% and 51-62% of the dose of 2- and 4-CNB, respectively, was absorbed from the skin within 72 hr. The balance of the dose was recovered in the protective device and the organic trap (i.e. that portion unavailable for dermal absorption). The absorbed radioactivity was excreted in urine (21-28% of dose, 2-CNB; 43-45%, 4-CNB) and feces (11-15%, 2-CNB; 5-12%, 4-CNB). The extent and rate of dermal absorption and urinary and fecal excretion of 2-CNB were linear over the 0.65-65 mg/kg dose range; for 4-CNB they were linear over the 0.65-6.5 mg/kg dose, and nonlinear at the 65 mg/kg dose.     

Absorption and metabolism of 5-(4-nitrophenyl)-2,4-pentadienal (Spydust)

5-(4-Nitrophenyl)-2,4-pentadienal (NPPD) was recently alleged to have been used as a tracking agent to monitor the activities of U.S. citizens in the Soviet Union. In order to better assess human risk from possible exposure to this compound the absorption and metabolism of [14C]NPPD has been investigated in male F344 rats. These studies have revealed that NPPD was readily and quantitatively absorbed from the gastrointestinal tract, distributed throughout the tissues, metabolized, and rapidly excreted primarily in urine. NPPD was sparingly absorbed following dermal administration of 0.01, 0.1, and 1.0 mg/cm2. The amount absorbed increased as the dose increased but the percentage of the dose absorbed decreased as the dose increased, e.g., 50% (5 of 10 micrograms applied) of the low dose was absorbed but only 5% (50 of 100 micrograms applied) of the high dose was absorbed. The material absorbed after dermal administration was rapidly excreted and the distribution and metabolism of the dermally administered compound was no different from oral administration. A total of five metabolites, 4-nitrocinnamic acid, 4-acetamidobenzoic acid, 4-nitrohippuric acid, 4-acetamidocinnamic acid, and 4-nitrobenzoic acid, were identified by cochromatography with authentic standards and comparison of UV spectra. These metabolites are formed by oxidative metabolism of the pentadienal side chain, reduction of the nitro group, and/or conjugation of the resulting amino group with acetate or carboxylic acid with glycine.     

Estimation of the dermal absorption of m-xylene vapor in humans using breath sampling and physiologically based pharmacokinetic analysis.

A physiologically-based pharmacokinetic model, containing a skin compartment, was derived and used to simulate experimentally determined exposure to m-xylene, using human volunteers exposed under controlled conditions. Biological monitoring was conducted by sampling, in exhaled alveolar air and blood, m-xylene and urinary methyl hippuric acid concentrations. The dermal absorption of m-xylene vapor was successfully and conveniently studied using a breath sampling technique, and the contribution to m-xylene body burden from the dermal route of exposure was estimated to be 1.8%. The model was used to investigate the protection afforded by an air-fed, half-face mask. By iteratively changing the dermal exposure concentration, it was possible to predict the ambient concentration that was required to deliver the observed urinary excretion of methylhippuric acid, during and following inhalation exposure to 50 ppm m-xylene vapor. This latter extrapolation demonstrates how physiologically-based pharmacokinetic modeling can be applied in a practical and occupationally relevant way, and permitted a further step not possible with biological monitoring alone. The ability of the model to extrapolate an ambient exposure concentration was dependent upon human metabolism data, thereby demonstrating the mechanistic toxicological basis of model output. The methyl hydroxylation of m-xylene is catalyzed by the hepatic mixed function oxidase enzyme, cytochrome P450 2E1 and is active in the occupationally relevant, (<100 ppm) exposure range of m-xylene. The use of a scaled-up in vitro maximum rate of metabolism (Vmaxc) in the model also demonstrates the increasingly valuable potential utility of biokinetic data determined using alternative, non-animal methods in human chemical-risk assessment.