Reflections on the OECD guidelines for in vitro skin absorption studies.

At the 8th conference of Occupational and Environmental Exposure of the Skin to Chemicals (OEESC) (16-18 September 2019) in Dublin, Ireland, several researchers performing skin permeation assays convened to discuss in vitro skin permeability experiments. We, along with other colleagues, all of us hands-on skin permeation researchers, present here the results from our discussions on the available OECD guidelines. The discussions were especially focused on three OECD skin absorption documents, including a recent revision of one: i) OECD Guidance Document 28 (GD28) for the conduct of skin absorption studies (OECD, 2004), ii) Test Guideline 428 (TGD428) for measuring skin absorption of chemical in vitro (OECD, 2004), and iii) OECD Guidance Notes 156 (GN156) on dermal absorption issued in 2011 (OECD, 2011). GN156 (OECD, 2019) is currently under review but not finalized. A mutual concern was that these guidance documents do not comprehensively address methodological issues or the performance of the test, which might be partially due to the years needed to finalize and update OECD documents with new skin research evidence. Here, we summarize the numerous factors that can influence skin permeation and its measurement, and where guidance on several of these are omitted and often not discussed in published articles. We propose several improvements of these guidelines, which would contribute in harmonizing future in vitro skin permeation experiments.

Stratum Corneum Sampling to Assess Bioequivalence between Topical Acyclovir Products.

PURPOSE: To examine the potential of stratum corneum (SC) sampling via tape-stripping in humans to assess bioequivalence of topical acyclovir drug products, and to explore the potential value of alternative metrics of local skin bioavailability calculable from SC sampling experiments. METHODS: Three acyclovir creams were considered in two separate studies in which drug amounts in the SC after uptake and clearance periods were measured and used to assess bioequivalence. In each study, a "reference" formulation (evaluated twice) was compared to the "test" in 10 subjects. Each application site was replicated to achieve greater statistical power with fewer volunteers. RESULTS: SC sampling revealed similarities and differences between products consistent with results from other surrogate bioequivalence measures, including dermal open-flow microperfusion experiments. Further analysis of the tape-stripping data permitted acyclovir flux into the viable skin to be deduced and drug concentration in that 'compartment' to be estimated. CONCLUSIONS: Acyclovir quantities determined in the SC, following a single-time point uptake and clearance protocol, can be judiciously used both to objectively compare product performance in vivo and to assess delivery of the active into skin tissue below the barrier, thereby permitting local concentrations at or near to the site of action to be determined.

A compartment model to predict in vitro finite dose absorption of chemicals by human skin.

Dermal uptake is an important and complex exposure route for a wide range of chemicals. Dermal exposure can occur due to occupational settings, pharmaceutical applications, environmental contamination, or consumer product use. The large range of both chemicals and scenarios of interest makes it difficult to perform generalizable experiments, creating a need for a generic model to simulate various scenarios. In this study, a model consisting of a series of four well-mixed compartments, representing the source solution (vehicle), stratum corneum, viable tissue, and receptor fluid, was developed for predicting dermal absorption. The model considers experimental conditions including small applied doses as well as evaporation of the vehicle and chemical. To evaluate the model assumptions, we compare model predictions for a set of 26 chemicals to finite dose in-vitro experiments from a single laboratory using steady-state permeability coefficient and equilibrium partition coefficient data derived from in-vitro experiments of infinite dose exposures to these same chemicals from a different laboratory. We find that the model accurately predicts, to within an order of magnitude, total absorption after 24 h for 19 of these chemicals. In combination with key information on experimental conditions, the model is generalizable and can advance efficient assessment of dermal exposure for chemical risk assessment.

A systematic scoping review of the sustainability of vertical farming, plant-based alternatives, food delivery services and blockchain in food systems.

Food system technologies (FSTs) are being developed to accelerate the transformation towards sustainable food systems. Here we conducted a systematic scoping review that accounts for multiple dimensions of sustainability to describe the extent, range and nature of peer-reviewed literature that assesses the sustainability performance of four FSTs: plant-based alternatives, vertical farming, food deliveries and blockchain technology. Included literature had a dominant focus on environmental sustainability and less on public health and socio-economic sustainability. Gaps in the literature include empirical assessments on the sustainability of blockchain technology, plant-based seafood alternatives, public health consequences of food deliveries and socio-economic consequences of vertical farming. The development of a holistic sustainability assessment framework that demonstrates the impact of deploying FSTs is needed to guide investments in and the development of sustainable food innovation.

Assessment of Drug Delivery Kinetics to Epidermal Targets In Vivo.

It has proven challenging to quantify 'drug input' from a formulation to the viable skin because the epidermal and dermal targets of topically applied drugs are difficult, if not impossible, to access in vivo. Defining the drug input function to the viable skin with a straightforward and practical experimental approach would enable a key component of dermal pharmacokinetics to be characterised. It has been hypothesised that measuring drug uptake into and clearance from the stratum corneum (SC) by tape-stripping allows estimation of a topical drug's input function into the viable tissue. This study aimed to test this idea by determining the input of nicotine and lidocaine into the viable skin, following the application of commercialised transdermal patches to healthy human volunteers. The known input rates of these delivery systems were used to validate and assess the results from the tape-stripping protocol. The drug input rates from in vivo tape-stripping agreed well with the claimed delivery rates of the patches. The experimental approach was then used to determine the input of lidocaine from a marketed cream, a typical topical product for which the amount of drug absorbed has not been well-characterised. A significantly higher delivery of lidocaine from the cream than from the patch was found. The different input rates between drugs and formulations in vivo were confirmed qualitatively and quantitatively in vitro in conventional diffusion cells using dermatomed abdominal pig skin.

Topical bioavailability of diclofenac from locally-acting, dermatological formulations.

Assessment of the bioavailability of topically applied drugs designed to act within or beneath the skin is a challenging objective. A number of different, but potentially complementary, techniques are under evaluation. The objective of this work was to evaluate in vitro skin penetration and stratum corneum tape-stripping in vivo as tools with which to measure topical diclofenac bioavailability from three approved and commercialized products (two gels and one solution). Drug uptake into, and its subsequent clearance from, the stratum corneum of human volunteers was used to estimate the input rate of diclofenac into the viable skin layers. This flux was compared to that measured across excised porcine skin in conventional diffusion cells. Both techniques clearly demonstrated (a) the superiority in terms of drug delivery from the solution, and (b) that the two gels performed similarly. There was qualitative and, importantly, quantitative agreement between the in vitro and in vivo measurements of drug flux into and beyond the viable skin. Evidence is therefore presented to support an in vivo - in vitro correlation between methods to assess topical drug bioavailability. The potential value of the stratum corneum tape-stripping technique to quantify drug delivery into (epi)dermal and subcutaneous tissue beneath the barrier is demonstrated.

Anticancer drug sensitivity and expression of multidrug resistance markers in early passage human sarcomas.

We have established new human sarcoma lines and examined their sensitivity to common antitumor drugs and expression of putative multidrug resistance (MDR) proteins. Eighty-two sarcoma samples were transplanted in nude mice. Fourteen of these sarcomas were established as tumor cell lines. We determined a chemosensitivity profile to antitumor drugs (MDR drugs = doxorubicin, mitoxantrone, and vincristine; non-MDR drugs = cisplatin, ifosfamide, and bleomycin) for each tumor line in vivo. Response to chemotherapy with doxorubicin and ifosfamide was observed in 30-50% of these tumor lines. Our results obtained with xenotransplants are similar to the results documented in clinical trials in which doxorubicin and ifosfamide are effective in 30-50% of the patients. Furthermore, we examined expression of MDR-relevant markers like P-glycoprotein, MDR-associated protein, lung resistance protein, and mdr1 mRNA in these xenotransplants. A relationship between mdr1 mRNA expression and response to doxorubicin was demonstrated in >90% of our tumor lines. In six sarcomas with mdr1 mRNA expression, five were resistant against doxorubicin and cross-resistant against several other drugs, whereas from eight sarcomas, which lacked detectable mdr1 mRNA, seven were sensitive to doxorubicin and other drugs. We found lung resistance protein or MDR-associated protein expressed in three resistant and mdr1 mRNA-positive sarcomas. These results demonstrate that mdr1 mRNA expression is a putative marker for drug resistance in our sarcoma lines. We conclude, therefore, that inherent P-glycoprotein expression might be also responsible for drug resistance occurring in treatment of patients with sarcomas. The established tumor lines are useful for additional investigations on mechanisms of drug resistance in sarcomas and as models for preclinical screening of new antitumor drugs.

Inter- and intralaboratory variation of in vitro diffusion cell measurements: an international multicenter study using quasi-standardized methods and materials.

In vitro measurements of skin absorption are an increasingly important aspect of regulatory studies, product support claims, and formulation screening. However, such measurements are significantly affected by skin variability. The purpose of this study was to determine inter- and intralaboratory variation in diffusion cell measurements caused by factors other than skin. This was attained through the use of an artificial (silicone rubber) rate-limiting membrane and the provision of materials including a standard penetrant, methyl paraben (MP), and a minimally prescriptive protocol to each of the 18 participating laboratories. "Standardized" calculations of MP flux were determined from the data submitted by each laboratory by applying a predefined mathematical model. This was deemed necessary to eliminate any interlaboratory variation caused by different methods of flux calculations. Average fluxes of MP calculated and reported by each laboratory (60 +/- 27 microg cm(-2) h(-1), n = 25, range 27-101) were in agreement with the standardized calculations of MP flux (60 +/- 21 microg cm(-2) h(-1), range 19-120). The coefficient of variation between laboratories was approximately 35% and was manifest as a fourfold difference between the lowest and highest average flux values and a sixfold difference between the lowest and highest individual flux values. Intralaboratory variation was lower, averaging 10% for five individuals using the same equipment within a single laboratory. Further studies should be performed to clarify the exact components responsible for nonskin-related variability in diffusion cell measurements. It is clear that further developments of in vitro methodologies for measuring skin absorption are required.

Secondary combined resistance to the multidrug-resistance-reversing activity of cyclosporin A in the cell line F4-6RADR-CsA.

Multidrug-resistant tumor cells can be resensitized by combined application of the selecting cytostatic drug and a chemosensitizer, such as cyclosporin A (CsA) or a calcium channel blocker. Since clinical trials on the circumvention of multidrug resistance (MDR) with chemosensitizers report disparate results, we investigated whether tumor cells of the MDR phenotype can develop additional resistance to the cytostatic chemosensitizer combination. Thus, the Adriamycin(ADR)-selected, P-glycoprotein-positive MDR Friend leukemia cell line F4-6RADR was exposed to stepwise increased concentrations of CsA at a constant level of 0.05 microgram/ml ADR. The initial CsA concentration (plus 0.05 microgram/ml ADR) to inhibit cell growth of F4-6RADR cells by 50% (IC50) was 0.04 microgram/ml. By continuous incubation for more than 6 months, the IC50 for CsA (at constant ADR) was elevated to 3.6 micrograms/ml (90-fold), thus generating the variant F4-6RADR-CsA. The F4-6RADR-CsA cells were cross-resistant for cyclosporin H (CsH), a non-immunosuppressive derivative of CsA. As shown by immunocytochemistry as well as by the polymerase chain reaction and by Western blotting including densitometry, P-glycoprotein was preserved in the F4-6RADR-CsA variant and was expressed at a 4-fold higher level than in F4-6RADR cells. Sodium dodecyl sulfate/polyacrylamide gel electrophoresis analysis could detect no new proteins in F4-6RADR-CsA as compared to F4-6RADR. Interestingly, resistance of F4-6RADR-CsA cells remained reversible for the calcium antagonists verapamil and dihydropyridine B859-35 (dexniguldipine-HCl), indicating that CsA and these compounds interfere with the P glycoprotein function by different pharmacodynamic mechanisms. Transport studies with [14C]ADR, performed in the presence and absence of chemosensitizers, confirmed the good correlation of P-glycoprotein function with the pattern of resistance found in proliferation assays. Cellular accumulation of [3H]cyclosporin was reduced to 71% of that of the F4-6 controls in F4-6RADR-CsA cells, but remained at the level of controls in F4-6RADR cells. Results indicate that increased amounts of the P-glycoprotein--besides other, perhaps more important mechanisms that are as yet unknown--partially mediate CsA resistance in F4-6RADR-CsA cells. We have designated this new form of resistance "secondary combined resistance" (SCR). The results suggest that at least some clinical cases of insensitivity to chemosensitizers or of relapse after reversing therapy could be explained by SCR, and that resensitizing treatment of tumor patients should be based on the consideration of several chemosensitizers of different pharmacodynamics.

Intracellular localization, vesicular accumulation and kinetics of daunorubicin in sensitive and multidrug-resistant gastric carcinoma EPG85-257 cells.

In the human gastric carcinoma cell line EPG85-257P (parent) induction of resistance to daunorubicin (DAU) was achieved by selection with stepwise increased concentrations of the drug. The new variant was named EPG85-257DAU and was shown to overexpress the mdr1 gene product 170 kDa P-glycoprotein (P-Gp) as demonstrated by immunocytochemistry and mdr1-specific RT-PCR. To investigate the intracellular pathway of DAU the subcellular distribution of this autofluorescent drug was studied in the resistant cells and compared to its chemosensitive counterpart EPG85-257P. When sensitive cells were exposed to DAU the drug rapidly accumulated in the nucleus until cell death. No redistribution of DAU to the cytoplasm was observed. In resistant cells exposed to the drug DAU also accumulated in the nucleus but to a lesser extent than in parent cells. Following exposure, nuclear fluorescence was observed to decrease over a time period of up to 48 h. Six hours after DAU exposure formation of fluorescent vesicle formation started in the perinuclear region and increased continuously. After 48 h nuclear fluorescence was no longer detectable and DAU was located exclusively in vesicles. During this period the vesicles moved from the region of origin to the cell periphery. A pulse chase experiment showed, that vesicles may contain DAU derived from the nucleus. Treatment of EPG85-257DAU cells with DAU in conjunction with the chemosensitizer cyclosporin A (CsA) increased nuclear fluorescence without impairing vesicle formation. Disruption of microtubules by nocodazole led to an accumulation of vesicles in the perinuclear region indicating that microtubules are involved in vesicular transport. Treatment of EPG85-257DAU cells with the actin disruptor cytochalasin B led to accumulation of vesicles in the cell periphery indicating that actin may be involved in exocytosis. Uptake and efflux of DAU and rhodamin (RH) were determined in sensitive and resistant cells using a fluorescence activated cell sorter. Uptake of both compounds was distinctly lower in resistant than in sensitive cells. When resistant cells preloaded for 2 h with RH subsequently were incubated in drug free medium the substance was rapidly released indicating transmembrane transport by P-Gp. In contrast, despite expression of P-Gp in resistant cells no considerable release of DAU was observed for up to 2 h under the same experimental protocol. This indicates that in resistant cells intracellular DAU at least in part may be inaccessible for P-Gp and that vesicular drug transport appears to contribute to DAU resistance by removing intracellular DAU via exocytosis.

Release rates from topical formulations containing drugs in suspension.

Expressions describing release rates from topical formulations of drug suspensions are proposed and compared to the exact solution of the governing differential material balances. These expressions are also compared to the approximate solution proposed by Higuchi more than 35 years ago. For the first time, the quality and limitations of the Higuchi solution are evaluated in detail. Despite its simple form, Higuchi's equation reasonably represents the rate of drug release for most drug concentrations, although it strictly predicts the exact result only when the initial drug concentration is much larger than its solubility limit. A modification of the Higuchi equation is proposed which improves the prediction of the cumulative mass released to within 0.5% for all suspended drug concentrations. We also present simple algebraic expressions for calculating the time required for all of the drug to dissolve, and the fraction of mass released when dissolution is complete.

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.

Physiologically relevant one-compartment pharmacokinetic models for skin. 1. Development of models.

Many studies have used pharmacokinetic (compartment) models for skin to predict or analyze absorption of chemicals through skin. In these studies, several different definitions of the rate constants were used. The purpose of this study was to develop a general procedure for relating compartment model rate constants to dermal absorption parameters, such as permeability and partition coefficients, and to assess whether different definitions of the rate constants produce different results. Rate constant expressions were developed by requiring a one-compartment model to match a one-membrane model at specific conditions. Because a membrane model contains more information than a compartment model, a compartment model cannot match the membrane model in all respects. Consequently, many compartment models (i.e., different definitions of the rate constants) can be developed which match the membrane model for different conditions. Using this procedure, 11 different compartment models were developed and compared to the membrane model for four different dermal absorption scenarios. The compartment model that most closely matches the membrane model depends on the specific exposure scenario and what is to be predicted. One of the new compartment models agrees reasonably well with the membrane model, for the cases considered.

Physiologically relevant two-compartment pharmacokinetic models for skin.

Pharmacokinetic (compartment) models for skin have been used to predict or analyze absorption of chemical into and through skin. For highly lipophilic chemicals, the stratum corneum (sc) and the viable epidermis (v.e.) both contribute a significant resistance to chemical penetration and thus, both should be included in the model. This paper describes two-compartment models that represent the sc and the ve separately by extending the procedures previously developed for one-compartment models. The two-compartment models described here were developed by matching characteristics of a two-membrane model of skin. These compartment models were compared with membrane representations of the s.c. and v.e. for several different dermal exposure scenarios. When valid, which it is for many chemical exposure scenarios, the two-compartment model developed using characteristic times of the membrane model (model B2) more closely represents the two-membrane model than the model developed with equilibrium conditions of the membrane model (model B1). When model B2 is invalid, then model B1 is recommended. Criteria are provided for choosing from the various one- or two-compartment model options.

Chemical release from topical formulations across synthetic membranes: infinite dose.

Drug release rates from topical preparations are sometimes measured by monitoring the cumulative mass of drug appearing in a receptor solution (MR). If the topical formulation and receptor solution are in direct contact, then MR increases linearly with square root of t. When a synthetic membrane is placed between the topical formulation and receptor solution, drug appearance in the receptor solution is delayed and MR is not immediately linear in square root of t. As a result, linear regressions of MR with square root of t produce positive values for the square root of t-intercept. Here, we mathematically model chemical release from an infinite-dose, topical formulation across synthetic membrane to quanitiatively determine the physical meaning of the square root of t-intercept. To correctly determine drug diffusivity in the topical formulation, the experiment must be conducted long enough that MR is linear in square root of t. Theoretically based procedures are presented for testing which data should not be used in linear regression of MR with square root of t. Theoretical predictions are compared with previously published experimental results for ethyl salicylate across a poly(dimethylsiloxane) (Silastic) membrane and for hydrocortisone across several different synthetic membranes.

Physiologically relevant one-compartment pharmacokinetic models for skin. 2. Comparison of models when combined with a systemic pharmacokinetic model.

Transport of chemicals through skin is best modeled as passive diffusion through a membrane, but mathematical solutions for realistic conditions are cumbersome. Compartment models, representing skin as a stirred tank, are mathematically simpler but less physiologically relevant. In a previous paper, several different compartment models were developed assuming constant blood and vehicle concentrations. Here, five skin models (four of the previously described compartment models and one membrane model) are combined with a one-compartment systemic pharmacokinetic (PK) model to examine the effects of changing vehicle and blood concentrations and to clarify how differences between skin models affect the predicted systemic response. The skin-PK models were solved with the same input parameters (i.e., permeability coefficients, partition coefficients, skin thickness, and cutaneous blood flow rates) and compared for five different exposure scenarios. Because the models have different underlying assumptions, they do predict different results. For many exposure situations compartment models give acceptable results, with the most pronounced differences from the membrane model during short exposure times. Generally, the compartment model that most closely represents the membrane model was developed by forcing it to match the membrane model for conditions similar to those of the given exposure scenario.

Antagonistic effects of caffeine and alcohol on mental performance parameters.

Scientific experiments done so far allow no clear conclusions about the popular belief that freshly brewed coffee can offset the debilitating effects of alcoholic intoxication. This question was addressed using a computer-controlled and subject-paced rapid information processing task (RIP) which was shown earlier to be sensitive to psychoactive substances. Nine male students were tested in a Latin square design before and after the intake of 3.3 mg/kg caffeine (or placebo) followed by 0.7 g/kg alcohol (or placebo). Whereas the mean RIP-task processing rate and the mean reaction time were impaired by alcohol and improved by caffeine, no changes were observed after the combination of alcohol and caffeine. Thus, it was concluded that under the tested conditions, caffeine was able to offset the debilitating effects of alcohol.

The determination of a diffusional pathlength through the stratum corneum.

The stratum corneum possesses a very heterogenous structure. As such a diffusing molecule can access a number of different pathways. It is probable that the excellent barrier properties of the stratum corneum result from a tortuous diffusional pathway around the dead cells. However, there are considerable problems in designing diffusion experiments and analysing the data to prove, without doubt, which is the predominant pathway. The mathematical problems posed are discussed in this article.

[Morphological and functional features of cytostatic drug resistance and the effects of MDR modulators]. / Morphologische und funktionelle Befunde zur Zytostatika-Resistenz und der Wirksamkeit von MDR-Modulatoren.

Manifold mechanisms of resistance can be expressed by malignancies. Profound information on this aspect is a prerequisite for comprehensive individual chemotherapy. Based on both morphological and functional findings, the diagnosis of P-Glycoprotein (P-Gp) mediated Multidrug Resistance (MDR) can be verified. In order to describe minimum criteria for conclusive diagnosis, morphological and biochemical findings (Immunocytochemistry, RT-PCR, ultrastructural and Laser-Scan microscopy) and functional data (cytostatic drug transport, proliferation) were correlated in tumor cell lines of the MDR phenotype as opposed to cells with atypical resistance. Frequently, single features of MDR are found in atypical, P-Gp negative resistance. Accumulation deficits for mitoxantrone based on vesicular drug transport were found in P-Gp negative gastric carcinoma cell line EPG85-257RNOV. Nocodazole blocked microtubule formation which is essential for vesicle transfer from perinuclear regions to the periphery of the cytosol. Cytochalasin blocked exocytosis of drug containing vesicles. MDR modulators were ineffective. Alternatively, P-Gp mediated drug extrusion and exocytosis of drug containing vesicles may constitute complementary mechanisms of resistance. In gastric carcinoma cells EPG85-257DAU, MDR modulators do increase cytosolic daunorubicin load, but drug binding to nuclear target sites is still inhibited due to drug containment within vesicles. To complicate matters, MDR modulators may be functional even in MDR negative cells, as shown in a panel of melanoma cell lines. Data show that conclusive diagnosis of P-Gp-mediated MDR should be based on more than one experimental approach including immunocytochemistry, a sensitive assay such as RT-PCR and--whenever feasible--a functional test.

Percutaneous absorption of 4-cyanophenol from freshly contaminated soil in vitro: effects of soil loading and contamination concentration.

Despite the skin's excellent barrier function, dermal exposure to soil contaminated with toxic chemicals can represent a significant health hazard (e.g., via multiple work related contacts in the farming and waste disposal industries). The development of environmental standards or limits for chemical levels in soil has been impeded because quantification of percutaneous uptake from this medium has not been well-defined. The objective of the research described here, therefore, was to better characterize the rate and extent of dermal penetration as a function of soil loading and degree of soil contamination. The absorption of a model compound (4-cyanophenol, CP) across hairless mouse skin in vitro has been determined at four different soil loadings (5, 11, 38 and 148 mg cm-2) and at six levels of soil contamination (concentrations ranging from 0.19 to 38 mg/g soil). Following 8 h of exposure, the amount of CP absorbed was independent of soil loading when CP concentration was constant, implying that the quantity of soil presentwas always sufficientto provide atleast a single layer of tightly packed particles. At the lowest loadings, however, with increasing times of exposure, the CP transport rate fell off due to depletion of chemical from the soil. At constant soil loading (38 mg cm(-2)), CP flux (Jss) across the skin was linearly proportional to the level of contamination (C(o)soil) over the range 0.19 to 23.5 mg of CP per gram of soil: Jss (micorg cm(-2) h(-1)) = (1.1 x 10(-5) g cm(-2) h(-1)) x Csoil (microg/g soil). At the highest CP contamination concentration, however, the transport rate was about an order of magnitude higher than expected, possibly due to the presence of pure CP crystals. In conclusion, these results provide new quantifications of the characteristics of dermal uptake from chemically contaminated soils and important information with which to develop and verify predictive models of dermal absorption.