Document 3J3kq9Myzj2M5v4Vdzj6BmmNO

Risk Analysis, Vol. 14, No. 3, 1994 Significance of the Dermal Route of Exposure to Risk Assessment David R. Mattie,'**John H. Grabau,' and James N. McDougal' Receiwd December 9, 1993 The skin is a route of exposure that needs to be consideredwhen conducting a risk assessment. It is necessary to identify the potential for dermal penetration by a chemical as well as to determine the overall importance of the dermal route of exposure as compared with inhalation or oral routes of exposure. The physical state of the chemical, vapor or liquid, the concentration, neat or dilute, and the vehicle, lipid or aqueous, is also important. Dermal risk is related to the product of the amounts of penetration and toxicity. Toxicity involves local effects on the skin itself and the potential for systemic effects. Dermal penetration is described in large part by the permeability constant. When permeability constantsare not known, partition coefficients can be used to estimate a chemical's potential to permeate the skin. With these concepts in mind, a tiered approach is proposed for dermal risk assessment. A key first step is the determination of a skin-to-airor skinto-medium partition coefficient to estimate a potential for dermal absorption. Building a physioIogically-based pharmacokinetic (PBPK) model is another step in the tiered approach and is useful prior to classical in vivo toxicity tests. A PBPK model can be used to determine a permeability constant for a chemical as well as to show the distribution of the chemical systemically. A detailed understanding of species differences in the structure and function of the skin and how they relate to differences in penetration rates is necessary in order to extrapolate animal data from PBPK models to the human. A study is in progress to examine anatomical differences for four species. KEY WORDS: Skin; partition coefficients; permeability constants. 1. INTRODUCTION 1.1. Background cals (both of which may penetrate the barriers of the skin) requires an experiment-based understanding of chemical absorption through the skin to adequately determine risks of such exposures. if I The skin, constituting about 10% of total human body weight, acts as the major interface between the homeostatic internal environment of the body and the comparatively unregulated and potentially hostile external environment. The skin primarily functions as a protective barrier that restrains entry of chemical substances into the body. The potential for occupational or accidental skin exposure to nonvolatile and volatile chemi- Personnel working in an occupational environment are often exposed to a variety of chemicals. Maintenance, repair and fueling operations expose workers to engine oils, lubricants, fuels, hydraulic fluids, paints and solvents. All of these types of compounds present a potential for dermal exposure. Up to 40% of all occupational illness may involve the skin.(') For some substances, cutaneous absorption is a major contributor to overall exposure.(z) The absorbed total uptake of xylene from * Toxicology Division, Armstrong Laboratory, Wright-Patterson Air Force Base, Ohio 45433-7400. * To whom all correspondence should be addressed. hand skin contact with solvent mixtures for 15 min was greater than that from inhalation over a full 8-hr shift in auto body repair shops.(3)The dermal route was found 277 0272-433~106006?77107.00/1C 1994 Society for Risk Analysis i i 278 Mattie et al. to be the major contributor to total polychlorinated biphenyls body burden of transformer maintenance and repair per~onnel.'~G) loves are of limited protection, as permeation of chemicals through glove material is known to occur.(s) Absorption of chemicals through the skin now appears to be of greater significance than previously suggested by industry or epidemiological experience.@) The dermal route of exposure may not always be the most important route, but it may often contribute significantly to total exposure. For a highly fat soluble chemical such as dibromomethane, the body burden from dermal penetration compared with inhalation was approximately 6% in one rat study.(') If respiratory protection were worn but the skin was exposed, absorption of this chemical vapor would still occur. A method to compare dermal vapor exposure to inhalation exposure at the same concentration has been described as a ratio of input functions for the contribution of each route of exposure, provided that the permeability constant, surface area of skin exposed, and alveolar ventilation rate are known or can be determined.@) Chemicals in the liquid state must also be considered because many exposure chemicals exist as a neat liquid or dissolved in a liquid medium such as water. Concentrations of pure liquid are much greater than in their vapor form. This results in greater total penetration through the skin. Even though the concentration on the skin is different between a vapor and the liquid form of a chemical, the solubility of a chemical in the skin should not be affected once the chemical enters the skin unless the liquid form of the chemical alters the skin barrier. T~uruta(a~n)d others have reported on the percutaneous absorption of organic solvents. Morgan et al.(l0) demonstrated that significant amounts of volatile organic chemicals (VOCs) can be absorbed through the skin during dermal exposure of rats to Icw levels of this class of chemical in aqueous solutions. Absorption to neat chemical did not appear to result in the same absorption rate as chemical in aqueous solution. Permeability constants were not determined by Morgan er aI.,('O) but peak blood levels after neat chemical exposure were approximately an order of magnitude greater than after chemical in aqueous solution. Estimation of the significance of dermal absorption of VOCs from aqueous solutions based on data for pure liquids may not provide an accurate assessment of actual exposure levels. Additional studies in this area have looked at chloroform, a VOC that contaminates chlorine-treated municipal tap water.(") Individuals are, therefore, exposed to chloroform while showering with chlorine-treated tap water. In situationswhere water should not be consumed due to contamination with VOCs, individuals should also consider avoiding bathing with the water. Dermal risk is a function of exposure penetration and toxicity. A toxic chemical that cannot penetrate the skin may be limited to local toxic effects on the skin. A chemical with a relatively low toxicity potential that readily penetrates the skin and enters circulation may have sys- temic effects or produce target organ toxicity. Therefore, it is necessary to know the capacity of a chemical for percutaneous absorption in order to assess its overall potential risk. 2. ESTIMATES OF DERMAL PENETRATION Various methods have been used to measure the potential of a chemical to penetrate the skin. The perme- ability constant (K,,)of a chemical is a quantitative expression of the capacity of a chemical to enter and diffuse through the skin. Permeability constants are used to predict the absorption rate or flux, which is the mass of chemical absorbed per unit area of skin per unit time. The solubility of a chemical in skin (partition coefficient [PC]) is an important parameter for determining the permeability constant when the diffusion coefficient for skin is known. Flux, or rate of penetration of a chemical across the skin, is determined by concentration at the skin surface, the surface area exposed, and solubility of chemical in the skin.(12J3)Skin-to-air PC values for a chemical are a measure of the solubility of the chemical in skin and should correlate with the permeability constant as shown in the following equation for flux: Flux = Dk C 1 = kpC where Flux is mg/cm2/hr,D is the diffusion constant of the chemical in the skin (cm2/hr), k,,,is the solubility or PC of the chemical in skin (unitless), C is the concentration of chemical on the surface of the skin (mg/cm3), 1 is the skin thickness (an),and kp is the permeability constant (cm/hr). Physical and chemical properties of chemicals such as solubility are important descriptors of skin penetrat i ~ n . ( ~ J ~T*h'e~P)C for skin, a measure of the affinity of a chemical for skin tissue, is the ratio of concentrations at equilibrium between the tissue and an adjacent medium, such as air, water or other environmental vehicle. Various experimental methods have been reported in the literature for determining PC values for skin. One i l r c Dermal Route of Exposure 279 method uses the octanol/water PC as a surrogate for par- titioning between the skin (octanol phase) and the en- vironment or vehicle (water Octanol/water PC values are typically determined by shaking the test compound in a mixture containing equal parts of water and octanol. After sufficient time for equilibration to occur, the ratio of the amount of test compound in each solvent is determined.(16) Hawkins and Reifenrath(18) compared octanoVwater PC values to the percent of ap- plied dose of pesticides and steroid hormones after ex- posure in vitro through pig and human skin. Kasting et uZ.Q7) used octanol/water PC values in a mathematical model to estimate the flux of chemicals across the skin. Berner et ut. (I9) used octanouwater PC values to confirm skin permeation rates for a series of chemicals prior to examining the relationship between the pKa of these chemicals and acute skin irritation. Octanolhater PC values have been used to estimate dermal flux for setting a skin notation guideline for a threshold limit value-time weighted average.(") Although the octanolhater PC has been used extensively in estimating dermal penetration, it is an oversimplification of the process of chemical interaction with the skin. The octanol/water PC assumes that skin is homogenous with respect to octanol and that water is the environmental medium. Surber et aZ.(") measured stratum corneum (SC)/ water and SC/isopropyl myristate PC values. In their study, PCs were determined as a function of equil- ibration time, initial concentration of drug in the vehicle, delipidization of stratum corneum, and source and prep- aration of stratum comeurn. The PCs were considered as predictors of percutaneous penetration for the purpose of conducting dermal risk assessment^.('^) 3. TIERED APPROACH A tiered approach is proposed for determining the potential hazard of a chemical for dermal risk assessment as shown in Fig. 1.This approach employs toxicity tests in an orderly sequence that can be stopped at various levels depending on the application and potential for exposure of the chemical, potential for full-scale development of the system of intended use, initial toxicity results, etc. The first phase is conducted completely with in vitro tests and structure-activitycomparisons. Dermal PCs are proposed as an important first step at this level. A procedure for determining skin:air PC values was developed in this laboratory and will be summarized in this oaoer. ExDosure assessment is also an imDortant earlv component of the tiered approach. Knowing the physical form of the chemical, the expected concentration, and possible environmental medium are essential in planning the appropriate tests to conduct initially as well as throughout the tiered approach. The second phase involves acute in vivo toxicity studies such as a dermal limit test. The Phase I screen is used to eliminate as many chemicals as possible in order to decrease the number of animal studies. Another relatively early step in the tiered approach is the development of a physiologically-based pharmacokinetic (PBPK) model with a skin compartment. The use of PBPK models will also be discussed, and an example of their use is presented in this paper. Physiologically-based pharmacokinetic model development spans two levels of the tiered approach because development of a model involves in vivo procedures. A PBPK model could still be developed without completing all of the endpoints for a Phase I1 screen. Completion of a PBPK model and short-term dermal exposure studies represents the Phase I11 screen. Phase IV is the screening phase for genotoxicity and carcinogenicity. Completion of this phase would provide a comprehensive hazard assessment of potential dermal risk. It is possible that in vitro genotoxicity testing will need to be conducted prior to the completion of earlier phases. 4. SKIN:AIR PARTITION COEFFICIENTS The headspace method for PC determination, developed by Sat0 and Nakajimac21)and modified by Gargas et al.,(=)has been used extensively in this laboratory for determining PCs of a variety of biological tissues. However, the methodology was not adequate for measuring the skin:air PC. A modification in the preparation of skin for the headspace method was developed in order to measure skin:air PC values. Dibromomethane was used as a prototype for skin:air PCs. Male Fischer 344 (F-344) rats (Charles River Laboratories) were between 8 and 16 weeks old at the time the skin was collected for PC determination. Clipped dorsal skin was collected and cut into 1 x 0.5 cm strips. The pieces of skin were placed on the walls of scintillation vials (24.65 ml volume) without saline. Sample vials containing skin and the corresponding empty reference vials were injected with an equal concentration of chemical vapor. At equilibrium, vapor from the headspace of the sample and reference vials were measured on a gas chromatograph with a flame ionization detector. i 1 \ - 280 iSESSMENT Mattie et d. 3UAL KPOSURE SSESSMENT DERMAL RISK ASSESSMENT I INHALATION RISK ASSESSMENT Fig. 1. Tiered approach to dermal risk assessment. iHAZARD ASSESSMENT +, After measuring the amount of chemical as area counts from all of the reference and sample vials in a set, sample vials were compared with corresponding reference vials using the following equation modified from Gargas et al. (22): -(referencevial area counts) (vial volume) (skin sample area counts) (vial volume - sample volume) PC = (skin sample area counts) (sample volume) After developing the technique for determining a skin:air PC value using dibromomethane, the procedure was used for other VOCs of interest (Table I). The skin:air partition coefficient for dibromome- thane and selected VOCs is shown in Table I. Approximately 19 samples were analyzed for each chemical. The most common equilibration time for this group of volatile chemicals was 4 hr. The skin:air PCvalues ranged from 1.9 for hexane to 91.9 for styrene. The octanoV water PC values(=) were compared with the corresponding skin:air PC values for 11 of the above chemicals. There was no correlation (9=0.09) between the octanoV water PC values and skin:air PC values (Fig. 2).Perme- ability constants were available for nine of the chemicals for which skin:air PC values were measured in this st~dy.('*'~*T~he~r)e was good correlation (? =0.93) be- tween permeability constants and skin:air PC values (Fig. Dermal Route of Exposure Table I. Rat Skin:Air Partition Coefficients for Selected Volatile Organic Chemicals Chemical ~~ Dibrornomethane Perchloroethylene Trichloroethylene Benzene Hexane Toluene Xylene Styrene Methylene chloride Carbon tetrachloride Methyl chloroform Halothane lsoflurane Skin:air PC ( 2 SE) ~~ 68.3 2 3.1 41.5 2 1.2 31.8 1.5 34.5 2 1.9 1.9 2 0.1 43.0 2 1.8 50.4 2 1.7 91.9 2 6.8 13.6 2 0.5 12.4 t 0.6 10.8 t 0.6 10.6 I0.7 4.5 I0.3 N 10 16 19 19 18 16 24 20 17 24 18 17 16 Equilibration time (hr) 4 4 4 4 4 4 2 3 2 4 4 3 6 281 -17 -16 Partition coefficients Fig. 3. Comparison of rat skin:air partition coefficients with rat permeability constants. 300- 200- MmyIch&dmn OT- 100- e8wene wromomshan, ' ''UehyleneCNoride 0 I-' I' ' ''I' "" 0 5 1015202!5S35404550!SW65M75W85SJ% Partitioncoeffidents Fig. 2. Comparison of skin:air partition coefficients with octanoV water PC values. 3). When octanol/water PC values were compared directly to eight of the permeability constants (minus the octanolhater PC for isoflurane), the correlation was also poor (9=0.04). If a sa1ine:air or water:air PC value is determined for a chemical, a skin:saline or skin:water PC value can be calculated for the chemical by dividing the skin:air PC value by the sa1ine:air or water:air PC value. Comparison of octanol/water PC values with skin:saline PC values still resulted in a poor correlation (12= 0.20). The skin:air PC values were compared to both octanol/water PC values and permeability constants. Octanol/water PC values have been used as a qualitative measure of skin permeability.(1"18.25,26) Skin:air PC val- ues for the chemicals tested showed a correlation with permeability constants but did not show as good a correlation with octanolhater PC values. Octanolhater PC values for the VOCs examined in this study appeared to be poor indicators of the solubility of these chemicals in skin. No single bulk solvent, such as octanol, precisely mimics the solvent properties of the stratum corneum transport barrier.(=) In addition, the skin:air PC values were determined for chemicals with poor water solubility. The predictive ability of octanol/water PC values is most likely lower for these volatile chemicals because octanolhvater PC values are based on water representing the vehicle or environmental medium. The data in this study suggest that skin:air PC values are a better indicator of the relative skin permeability for the volatile chemicals examined in this study. Skin:saline PC values would be representative of permeability into skin from an aqueous environmentalmedium. Determining a skin:air PC or skin:saline PC is proposed as an initial screen to identify the potential for skin absorption of volatile chemicals with unknown permeability constants. 5. PBPK MODELING In addition to indicating potential permeability, skin PCs are necessary or developing the dermal compartment in a PBPK model. PBPK models mathematically describe the dynamics of chemicals in the body, including permeability of membranes and partitioningof chemicals into tissues. A PBPK model is developed by grouping various tissue types together based on similar blood flows and PCs. Each compartment has a measured physiological blood flow. Model parameters are determined from , 282 Mattie et al. laboratory studies or literature values and can be changed to extrapolate across species. Absorption, distribution, metabolism and elimination of a chemical are then math- ematically described for each compartment which has such a process. The skin:air PC is essential for the rate equation in the dermal compartment describing the up- take of chemical from air into the skin. A skin:saline PC value is calculated, as described above, for the rate equation for uptake into skin from an aqueous medium. A PBPK model with a dermal compartment can then be utilized to determine the permeability constant for a chemical. The difference in concentration, surface area and exposure duration between the laboratory and an actual occupational situation can also be described using a PBPK model. In addition, metabolism of the chemical, which may be quantitatively or qualitatively different between experimental species and humans, can be esti- mated with existing methods and their impact on pene- tration described using a PBPK model. PBPK modeling provides the means to relate laboratory animal exposures to the human situation by extrapolating across exposure concentrations, routes of exposure and species.@)Ac- curate extrapolation from animal exposures to personnel in the workplace will provide the means to more quickly and efficiently set safe, but not overly restrictive, dermal exposure standards. For a PBPK model to accurately estimate a perme- ability constant for a chemical in skin, a number of con- ditions are important. A PBPK model with a dermal compartment must be validated based on exposure for a second route of exposure, such as the inhalation route. Skin PC data should be experimentally determined for the dermal compartment. Actual dermal exposures should be conducted in order to measure the uptake of chemical into the blood. The concentration of chemical in blood after dermal exposure is then used in model simulations to estimate the permeability constant for that chemical. Previous work with PBPK models in this laboratory has demonstrated their usefulness in extrapolation and the risk assessment PBPK models were developed based on the work of McDougal et al. ,(7J3*24) which described each of three different in vivo dermal exposures in rats: whole body dermal exposure to ben- zene vapor,(13)exposure to neat benzene from a closed cell on the dorsal skin (unpublished data and Ref. lo), and exposure to saturated solutions of benzene in water also from a closed cell.('O) The models were used to estimate the permeability constants of benzene fiom blood concentrations achieved during exposure to each form of the chemical. The estimated permeability constant for dermal vapor was 0.152 cmhr, for neat benzene 0.0025 cm/hr, and for aqueous solutions 0.05 cm/hr. The phys- ical form of the chemical and the presence of water resulted in different rates of absorption. The permeability constant for rat skin from aqueous solutionswas one half the human permeability constant value used for dermal risk assessment, 0.111 ~ m / h r . (R~a~t )skin has been reported to be more permeable than human skin by a factor of two to four,@)so the rat permeability constant was expected to be at least twice as high as the human value for benzene. 6. SPECIES DIFFERENCES IN SKIN PENETRATION In an attempt to better understand factors affecting dermal penetration and to be able to better extrapolate between animal species and humans, a study was initiated to quantitate selected anatomical differences in skin from a number of animal species. Anatomical differences that may affect permeability include density and size of hair follicles, density of sebaceous and apocrine glands, capillav density and distance from the surface, as well as thickness of the various layers of the epidermis and dermis. Anatomical differences in skin between species will be compared to permeability constants for three model chemicals to determine possible correlations between structure and permeability. Permeability constants will be determined using PBPK models for chloropentafluorobenzene, perfluoroheptane and dichlorobenzene. Sections of dorsal skin were collected from IAF/ HA hairless and Hartley guinea pigs, fuzzy and F-344 rats, B6C3F1 and Cr1:SKHl hairless mice, and farm pigs. Pieces of skin were processed at the same time and under identical conditions for standard histopathology sections in paraffin. One set of sections was stained with hematoxylin and eosin and another set with Massons trichrome. Image analysis was conducted on sections from each strain using an image analysis system. Parameters measured were thickness (stratum Corneum, stratum granulosum, viable epidermis and total epidermis); average depth and distribution of capillaries, venules and arterioles; surface area of each type of blood vessel relative to basement membrane of the epidermis; and depth and surface area of hair follicles and sebaceous glands relative to the basement membrane of the epidermis. Exploratory data (Table 11) showed that the hairless guinea pig and farm pig have the thickest epidermal layers and the F-344 rat and the mouse the thinnest epidermal layers. There was a wide range for average depth of capillaries, venules and arterioles with the hairless guinea pig and mouse having capillaries and venules closer to the epidermis and the F-344 rat having all ves- ! I b Dermal Route of Exposure Table 11. Anatomical Parameters in Skin from Four Animal Species (N= 3) Mouse Guinea Pig Rat `r Swine j SKHl B7C3F1 Hartley Hairless Fuzzy F-344 farm Folliclevolume" ( X Gland volume' ( x 26.4 2 1.7 299 t 39 389 t 19 479 t 20 1.7 ? 0.4 1.4 t 0.2 13.2 t 1.5 421 5 55 536 t 20 410 t 109 1.2 t 0.6 1.0 t 0.3 26.8 t 0.7 446 t 149 903 f 218 602 t 275 1.5 t 0.1 0.3 t 0.1 59.6 t 3.9 333 t 48 610 t 59 743 t 298 2.5 f 0.1 1.1 T 0.2 47.0 t 3.0 519 t 138 723 t 188 715 f 89 2.0 t 0.5 2.4 2 0.3 20.9 t 2.2 803 t 83 970 t 57 1340 t 63 0.5 -C 0.1 1.0 t 0.2 52.2 t 7.2 511 2 13 623 t 87 792 t 123 6.4 ? 2.0 5.1 t 2.5 Ratio of follicle or sebaceous gland area to total area. sels farther away from the epidermis. The farm pig had REFERENCES the greatest volume of hair follicles and sebaceous glands; F-344 rat the least follicular volume and Hartley guinea pig the least gland volume. 1. K. F. Wheeler, "Barrier Lotions, Along With Gloves, Can Help Deter Occupational Dermatitis," Occupational Health und Sufery Jan., 60-61 (1992). Additional skin samples will be analyzed to confirm 2. G. Scansetti, G. Piolatto, and G. F. Rubino, "Skin Notation in 4 i these preliminary data. A PBPK model will be built for each of the three strains showing the widest variation in the Context of Workplace Exposure Standards," Amer. J. Indust. Med 14, 725-732 (1988). 3. W. Daniell, A. Stebbins, D. Kalman, J. F. O'Donnell, and S. anatomical parameters. Exploratory information sug- W. Horstxnan, "The Contributions to Solvent Uptake by Skin and gests the use of E344 rats and Hartley and hairless guinea InhalationExposure,"Am Ind f$g.h o c . 1. 53,124129 (1992). c pigs. A better understanding of the anatomical differ- 4. P. S. J. Lees, M. Corn, and P. Breysse, "Evidence for Dermal Absorption as the Major Route of Body Entry During Exposure ences of skin in animal species may lead to a better extrapolation of animal skin data to human skin. m.of Transformer Maintenance and Repairmen to PCBs," Am I d ASSOC.J. 48,257-264 (1987). 5. J. L. Perkins and V. B. Knight, "Risk Assessment of Dermal Exposure to Polychlorinated Biphenyls Permeating a Polyvinyl chloride Glwe,"Am Ind Hyg.Assoc. J. 50, A-171-172(1989). 6. P. Grandjean, A. Berlin, M. Gilbert, and W. Penning, "Pre- 7. SUMMARY The dermal route is an important potential route of exposure. There is still much research to be conducted to understand the skin and its significance in risk assessment. venting Percutaneous Absorption of Industrial Chemicals: The `Skin' Denotation," Amer. J. Indurt. Med. 14, 97-107 (1988). 7. J. N. McDougal, G. W. Jepson, H. J. Clewell 111, and M. E. Andersen, "Dermal Absorption of Dihalomethane Vapors," Tar- UoL AppL PhurmacoL 19, 150-158 (1985). 8. 1. N. McDougal and H. J. Clewell 111, "Dermal to Inhalation Extrapolation for Organic Chemicals,''in T. R. Gcrrity and C. J. Henry (eds.), principlrc of Route-to-Route Earapolatwn for R i s k A s s m e n t (Elswier Science Publishing, New York, 1990). pp. 313-317. 9. H. Tsumta, "Percutaneous Absorption of Organic Solvents. 1. ACKNOWLEDGMENTS Comparative Study of the In Mvo Percutaneous Absorption of Chlorinated Solvents in Mice," Indurt.Health 13,227-236 (1975). 10. D. L. Morgan, S. W. Cooper, D. L. Carlock, J. J. Sykora, B. Sutton, D. R. Mattie, and J. N. McDougal, "Dermal Absorption We would like to thank George Bates, Jill Solscheid, Peggy Parish, Jerry Nicholson and GaIy Jepson for their technical assistance. The animals used in this study were handled in accordance with the principles in the Guide for the Care and Use of Laboratory AnimaLr, prepared by the Committee on Care and Use of Laboratory Animals of the Institute of Laboratory Animals Resources, National Research Council, DHHS, National Institute of Health Publication no.#86-23, 1985, and the Animal Welfare Act of 1966, as amended. of Neat and Aqueous Volatile Organic Chemicals in the Fischer 344 Rat," Envimn. Res. 55, 51-63 (1991). 11. W. K. Jo, C. P. Weisel, and P. J. Lioy, "Chloroform Exposure and the Health Risk Associated with Multiple Uses of Chlorinated Tap Water," Risk Analysis 10, 581-585 (1990). 12. G. L. Flynn. S.H. Yakowsky. and T. J. Roseman, "Mass Transport Phenomena and Models: Theoretical Concepis," 1.P h a n Sci. 63, 479-510 (1974). 13. J. N. McDougal. G. W.'Jepson, H. J. Clewell 111, M. L. Gargas, and M. E. Andersen, "Dermal Absorption of Organic Chemical Vapors in Rats and Humans," Fundam. Appl. Taricol. 14, 299- 308 (1990). 14. L. K. Penhing, L. D. Lambert, and K. Knutson, "Partition Coefficient and Solubilities of Estradiol in a Variety of Vehicles Predict the In Mw Flux Across the Human Skin Sandwich Flap," Clin. Res. 37, 727A (1989). I 284 15. C. Surber, K.-P. Wilhelm, H. I. Maibach, L. L. Hall, and R. H. Guy, "Partitioning of Chemicals into Human Stratum Corneum: Implications for Risk Assessment Following Dermal Exposure," Fund. Appl. TOX.15, 99-107 (1990). 16. R. L. Bronaugh and E. R. Congdon, "Percutaneous Absorption of Hair Dyes: Correlation with Partition Coefficients," J. Invest. Dematol. 83, 124-127 (1984). 17. G. B. Kasting, R. L. Smith, and E. R. Cooper, "Effect of Lipid Solubility and Molecular Size on Percutaneous Absorption," Phamacol. Skin 1, 138-153 (1987). 18. G. S. Hawkins and W. G. Reifenrath, "Influence of Skin Source, Penetration Cell Fluid, and Partition Coefficient on In vitro Skin Penetration," J. Pharmaceutical Sci. 75, 378-381 (1986). 19. B. Berner, D. R. Wilson, R. H. Guy, G. C. Mauenga, F. H. Clark, and H. I. Maibach, "The Relationship of pK, and Acute Skin Irritation in Man," Pharmaceutical Res. 5, 660463 (1988). 20. V. Fiserova-Bergerova, J. T. Pierce, and P. 0. Droz, "Dermal Absorption Potential of Industrial Chemicals: Criteria for Skin Notation," Amer. J. Indusr. Med. 17, 617635 (1990). 21. A. Sato and T. Nakajima, "Partition Coefficients of Some Aro- matic Hydrocarbons and Ketones in Water, Blood, and Oil," Brit. J. Indust. Med. 36, 231-234 (1979). 22. M. L. Gargas, R. J. Burgess, D. E. Voisard, G. H. Cason, and M. E. Andersen, "Partition Coefficients of Low-Molecular-Weight Volatile Chemicals in Various Liquids and Tissues," TadcoL Appl. Phamacol. 98, 87-99 (1989). 23. A. Leo, C. Hansch, and D. Elkins, "Partithn Coefficients and Their Uses," Chem Rev. 71, 525-616 (1971). 24. J. N. McDougal, G. W. Jepson, H. J. Clewell 111, M. G. MacNaughton, and M. E. Andersen. "A Physiological Pharmacokinetic Model for Dermal Absorption of Vapors in the Rat," Tm'col.AppL Phamacol. 85, 286-294 (1986). 25. B. D. Anderson and P. V. Raykar, "Solute Structure-Permeability Relationships in Human Stratum Corneum," J. Invest. DemaroL 93, -286 (1989). Mattie et al. 26. N. E. Tayar, R.4. Tsai, B. Testa, P.-A. Canupt, C. Hansch, and A. Leo, "Percutaneous Penetration of Drugs: A Quantitative Structure-Permeability Relationship Study," J. Pharmaceutical Sci. 80, 744-749 (1991). 21. M. E. Andersen, H. J. Clewell 111, M. L. Gargas, F. A. Smith, and R. H. Reitz, "Physiologically Based Pharmacokinetics and the Risk Assessment Process for Methylene Chloride," Taricol. Appl. Phannacol. 87, 185-205 (1987). 28. H. J. Clewell 111 and M. E. Andersen, "Risk Assessment Extrapolations and Physiological Modeling," Taricol. Ind. Health. 1, 111-131 (1985). 29. H. J. Clewell I11 and M. E. Andersen, ``Improving Toxicology Testing Protocols Using Computer Simulations," Taricol. k r r . 49, 139-158 (1989). 30. R. A. Corky, A. L. Mendrala, F. A. Smith, D. A. Staats, M. L. Gargas, R. B. Conolly, M. E. Andersen, and R. H. Rietz, "Development of a Physiologically Based Pharmacokinetic Model for Chloroform," T a r Appl. P h a n 103, 512-527 (1990). 31. J. W. Fisher, T. A. Whittaker, D. H. Taylor, H. J. Clewell 111, and M. E. Andersen, "Physiologically Based Pharmacokinetic Modeling of the Pregnant Rat: A Multiroute Exposure Model for Trichloroethylene and Its Metabolite, Trichloroacetic Acid," TmicoL AppL PhannacoL 99. 395-414 (1989). 32. M. L. Gargas,M. E. Andersen, and H. J. Clewell 111, "A Phys- iologically Based Simulation Approach for Determining Metabolic Constants from Gas Uptake Data," T&L AppL PhamacoL 86.341-352 (1986). 33. H. R. Reitz, J. N. McDougal, M.W. Himmelstein, R. J. Nolan, and A. M. Schumann, "Physiologically-Bad Pharmacokinetic Modeling with Methylchloroform: Implications for Interspecies, High DoselLOw Dose,and Dose Route Extrapolations," TaaicoL Appl. P~OIVUZC9O5,L185-199 (1988). 34. I. H. Blank and D. J. McAuIXfe, "Penetration of Benzene Through Human Skin," J. Invet. DemaroL 85, 522-526 (1985).