Document YrL5o1GNq49bD3KdGd2Q6j3DN

ENVIRONMENTAL RESEARCH 56,%108 (1991) Pharmacokinetics of the Dermal Route of Exposure to Volatile I. P,?' Organic Chemicals in Water: A Computer Simulation Model iJO ANNE SHATKIN* AND HALINA SZUNWALD BROWN?'' L 1 ;*Environment. Technology and Society Program, Clark University, Worcester, Massachusera r: 01610; and tCenter for Technology, Environment and Development (CENTED), Clark Universe# re IE. Worcester, Massachusetts 01610 in I Received November 8, 1990 f sa A kinetic model of dermal absorption of nonpolar organic nonelectrolytes in dilute aqueous solutions is described. The model uses systems dynamics STELLA software and is designed for a Macintosh computer. The model assumes the outer stratum corneum layer skin to be the rate-determining barrier to dermal absorption and assumes that both stratcorneum and viable epidermal layers have storage capacity for lipophilic solutes. The modd predicts between 30 and 94% of experimental results with humans under the same tions. The degree of departure between experimental and theoretical results is inversely related to the solutes's octanoVwater partition coefficient,which is consistent with recently hypothesized mechanisms of transport of molecules across the dermal The model has potentially useful applications for risk assessment if used within its htIlitS. 0 1991 Academc Ress, Inc. INTRODUCTION T r Skin absorption may be a significant pathway of entry into the human body \ volatile organic contaminants (VOCs) in tap water, in addition to the inhalatim contaminated indoor air and the direct ingestion pathways. In this paper we describe a kinetic model of transdermal absorpti organic nonelectrolytes in dilute aqueous solutions. The model is used on a Macintosh computer and represents a further elaboration on an model proposed in an earlier paper (Brown and Hattis, 1989). We use the ma to follow the course of absorption and distribution of several VOCs under se k exposure scenarios and suggest a range of its possible applications. f. THEORETICAL BASIS Stratum corneum represents the major bamer to percutaneous abs (Scheuplein and Blank, 1973; Elias, 1981; Yardley, 1985). Once believed properties of a homogeneous barrier to physiological water uptake and 10s stratum corneum has been shown to consist of two distinct layers of v properties: stratum disjunctum and stratum compactum. It appears junctum region acts as a barrier to solute uptake, as demonstrated (1963) and Bettley (1970), whereas the compactum region forms a barrier (Bettley, 1970; Bowser and White, 1985). ' To whom requests for reprints should be addressed. 0013-9351/91 $3.00 Copyright Q 1991 by Academic Res, lnc. M riphts of revroduction in anv form reserved. 90 ic; # SKIN ABS0RF"ION MODEL um behaves as a relatively uniform, if not homogeneous, diffuplein et al. (1%9) questioned the first assumption over 2 dewing significant binding of radiolabeled steroids in aqueous sohuman stratum corneum, the importance of the storage and its showed that the extent of stratum corneum binding is proportional to of nonpolar solutes across stratum corneum on the grounds that it rogeneous membrane. Raykar et al. (1988), for example, suggested ce of two distinct pathways for transport of solutes across stratum compounds. A combination of the two pathways would apply to h intermediate properties. Only transport via the lipid pathway is the premise of Fick's Law. Anderson et al. (1988) further hypoth- dings suggest that the assumption of passive diffusion across stratum ,the lipid content of stratum corneum and its potential for storage of n and Hattis, 1989). In that work, we treated the stratum corneum ne and disregarded its storage properties. In this paper, we describe 1 of dermal absorption which incorporates the most recent findings e two regions, Marzulli (1963) and Bettley (1970) have shown that e been reported in the literature for total stratum corneum, not its two s. Furthermore, the very small thickness of the stratum compactum (5-7 ydrated) makes its contribution to total storage in stratum corneum insignif- SHATKIN AND BROWN METHODS Description of the Model The pharmacokinetic model is shown schematically in Fig. 1. Both a t r d i compartmental representation and a scheme designed to represent the phys ical significance of the model are shown. We identify three body compart stratum corneum, viable epidermis, and blood. Molecules diffuse thro hydrated stratum corneum and viable epidermis in a dissolved state passive means, with the passage through stratum corneum being the ra step. We assume a uniform thickness of 40 pm for stratum corneum, adjustments for different parts of the body are also made, as shown late scenario assumed is either hand or full-body immersion into a vessel contaminated water of a known volume. The viable epidermis is 200 pm thick between stratum corneum and dermal capillary b testing the sensitivity of the model we vary that thickness up to assumption that solute can be stored beyond the capillaries in the epid papillary dermal layers. is made between a chemical in the dermal blood vessels and a chem circulation. The rate of transfer of a chemical from the epidermis proportional to the instantaneous amount in the epidermis, the e flow rate, and the relative solubilities of the agent in the two dermishlood partition coefficient, Keb).The blood and epide outer reservoir stratum corneum viable epidermis blood metabolism FIG. 1 . Schematic representation of the model of dermal absorption. ; th as onal ikg?:nts: full! Ire]) jting wh *The Ute. )be i in the and jpints .he of ~ he I'he ! t 1 i it' elimination rate includes excretion via exhalation, urinary filtration, nd deposition in other body compartments. It represents the net rate of a chemical in blood and accounts for reentry into the venous circutemporary storage in various organs. Exploration of elimination of om blood using a full pharmacokinetic model shows that the latter is most important process in short exposures such as bathing (Hattis et al., ume first-order kinetic behavior of the chemical between all compartall directions, whereby the instantaneous rate of change in the is proportional to the concentration in that compartment and to the specific to that compartment. In the feedback loops, we assume the tance the solute had to travel to exit the compartment is half the of the compartment. We also assume that solute travels only within the skin area and only in a direction perpendicular to the skin. Solute in the rneum reservoir at the end of exposure is assumed to be absorbed into eventually. Other pathways for transdermal solute uptake, such as the of transport via hair follicles, or cuts in the skin, are assumed to be el was developed using STELLA systems dynamic software from High Systems of New Hampshire. System dynamics is helpful in explorx behavior of any dynamic system governed by feedback mechaELLA model, all components of the dynamic system can be rep- terms of stocks and flows: stocks represent net accumulation through represent the movement of stock per unit time, or the rate of A allows one to construct a model on a terminal screen as an ructural diagram, element by element. The conceptual relationships the elements are entered visually by arrows, while the mathematical hips between the independent variables (such as skin surface, membrane solute concentration) are entered explicitly. These are shown in The compartments and their mutual relationships shown in Fig. 2 o those shown in Fig. 1 but the variables that determine the rates of r between the compartments are shown as well. For example, the rate of across stratum corneum depends on the surface area of the skin, S,the of stratum corneum, H,, the stratum corneudwater partition coeffi- the solute's diffusion coefficient in stratum corneum, D,,, and the of chemical in the bathtub, as indicated by the arrow pointing from o the rate regulator. Total absorbed in Fig. 2 represents the amount entering the body over time without regard to its fate and includes erial removed from the blood by any of the mechanisms discussed above, as that stored in the blood and skin. It thus represents the total amount hrough the flow regulator termed "bath to SC rate" minus the amount ough "SC to bath rate" flow regulator. A more detailed description of pplications to pharmacokinetics has been published previously (BoHattis et al., 1986). uired parameters and validation with experimental data are discussed in ' i$I 1 f ?i ' i is 95 +gfRUCrURAL EQUATIONS m m b = bathtub dr * (-bath to SC rate + SC to bath rate) +corneum = Stratum corneum + dr * ( -SC to epidermis rate bath to SC rate + epidermis to SC rate - SC to bath rate) + +ermis = epidermis dr (SC to epidermis rate blood to epidermis rate - epidermis to blood rate - epideris to SC rate) + += blood dr * (-elimination rate - blood to epidermis rate epidermis to blood rate) tion = elimination + dt * (elimination rate) to bath = SC to bath + dr * (SC to bath rate) mAL ABSORBED = total absorbed + dr * (bath to SC rate - SC to bath rate) BATE EQUATIONS B.th to SC rate = (0, * K, * S * bathtub)/H, * V,) - Stratum corneum * S * DJ(H,, * 0.5 * VsJ te = (De * S * Stratum corneum)/(K,, * V, rate = (epidermis * F,dKeb* VJ qpidermis to SC = (S * De * epidermis)/(V, * He * 0.5) * He) t tion rate = K, * blood i* equations of the model. Symbols used: Hw, Stratum corneum thickness {cm}; m diffusion coefficient {cm2/min};K,, Stratum corneudwater partition coeffi- kin surface {cm?; De, Epidermis diffusion coefficient {crn2/min};He,Epidermis b, Epidermisblood partition coefficient {unitless}; Fcb.Epidermal blood flow {mY !! II um corneudepidermis partition coefficient {unitless}; V,, Blood volume {cm3}; Ve, m3}; V,, SC volume {cm3};K,,Elimination rate constant {rnin-I}. and DknZare diffusion coefficients in stratum corneum. The diffusion of benzene in stratum comeum was experimentally estimated by Blank {I liffe (1985) to be 4.1 x lov9cm2/sec. surface (S). Experimental values of 320 cm2for adult hands and forearms sed to validate the model (Dutkiewicz and Tyras, 1967, I=), except for enol data where 347 cm2was used (Baranowska-Dutkiewicz, 1981). Other- 3 data of Guy and Maibach (1977) were used. We also assume that the is stored only in the surface area of the skin that is immersed in the i OK and that no diffusion into nonimmersed skin occurs. \ e skin area of a 9-kg infant was calculated from the published data for a 3-kg . -~ t, 1900 cm2 (Guy and Maibach, 1977), assuming that the surface-to-volume mtio increases to a V3 power with increasing volume. Thus, the surface of a 9-kg 1 900 x (3)"3 = 3800 cm2.In the bathtub scenarios we assumed that 91 and 1 e body is immersed for adult and infant, respectively, which includes the gs, arms, and, for adults only, the upper chest region. 4 diflusion coeficient (De). As estimated by Scheuplein (1959, 1976) 3.6 x cm2/minwas used for all solutes. Stratum corneum thickness (HsJ. An average of 0.004 cm for fully hydrated j stratum corneum was used (Blank and Scheul Epidermis thickness (He). Blank and McAulBe (1985), Blank and Scheuplein , (19691, and Guy et af. (1982) used a value of 0.02 cm for transport of molecules arrOss viable epidermisbetween stratum corneum and blood vessels. Values rang& from 0.02 to 0.1 cm were used in the model to account for the possibility of ' Storage in lower dermal layers. [ later time. The rate of decline in the concentration of the chemical in the blood I &ng the postexposure period was therefore slower in these experiments than it d d have been in the absence of substantial earlier exposure. To account for the derestimation, values ranging from 0.05 to 1 min-' were therefore used in the 1 d e l . As shown later, the value of K,has little effect on the results of the model. 1 In the case of trichloroethylene and tetrachloroethylene, a full pharmacokinetic 'f @l (Hattis et al., 1986) was used to estimate time-dependent elimination constants under the conditions of the first 20 min of bathing. These are: 1 Tetrachloroethylene 5 (1-0.03 * Time) t Trichloroethylene 6 (1-0.035 * Time). 1 Ocrunol/waterpartition coefficient (Kow).The following published values were e used: \ Ethylbenzene Styrene Toluene i I Tetrachloroethylene Trichloroethylene Chloroform 2230 932 669 339 263 93 29 RESULTS AND DISCUSSION model prediction of the time course of absorption and distribution of eth- ne from aqueous solution is shown in Fig. 4. The skin compartments b steady state much before the blood compartment. Storage capacity of I corneum compared to epidermis is small due to the size of the reservoir, 1 as expected, the blood is the main reservoir among the three compart.Increasing the epidermal thickness (not shown here) significantly increases I rage capacity of that compartment, resulting in a smaller proportion of absorbed in the blood compartment. These changes affect primarily the lag b achieving steady state by the skin compartments, because with either I al thickness the total absorbed is almost identical. it 60 min the amount of solute taken up from solution (total absorbed) is than can be accounted for by storage in the three compartments. elimination of the penetrant, because the elimination rates of the 1 under consideration were very high. The significanceof this cannot be in a quantitative way. Since our definition of elimination is simply re- the solute from the blood, without regard to its subsequent fate, a s cant fraction of "eliminated" material may be stored in other body comments rather than be removed from the body. If so, "total absorbed" is a amre appropriate parameter for describing the toxicologically significant dose. On the other hand, if little storage in the body takes place then the total amount in Mood and the skin compartments is of toxicological significance. Short of study- & a full-body pharmacokinetic model, and due to the fact that we studied li- 1 J 3- ! e ! 8 ! i! r i! c 1)rrCCted . dore' I litbtareb r 12:;$account ficantly $nnking y = 0.2 5, Jo el dermal experi- mg. n d This is i f ferent pain. , = 93) & s.Wilkinson. F. J. G. Ebling, R. H. Ebling, and J. L. Burton,Eds.), 4th ed. Vol. 1. Blackwell, IUY un,loglcd !-I>port. t INSTRUCTIONS TO AUTHORS Manuscripts. Environmental Research publishes original reports describing studies of the toxic effects of environmental agents in humans and animals. The principal aims of the journal are to define the etiology of environmentally induced illness. and to increase understanding of the mechanisms by which environmental agents cause disease. The study of environmental health is inherently multidisciplinary. 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