© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Indoor Air 2014; 24: 292–306 wileyonlinelibrary.com/journal/ina Printed in Singapore. All rights reserved
INDOOR AIR doi:10.1111/ina.12079
Predicting dermal absorption of gas-phase chemicals: transient model development, evaluation, and application Abstract A transient model is developed to predict dermal absorption of gasphase chemicals via direct air-to-skin-to-blood transport under non-steady-state conditions. It differs from published models in that it considers convective masstransfer resistance in the boundary layer of air adjacent to the skin. Results calculated with this transient model are in good agreement with the limited experimental results that are available for comparison. The sensitivity of the modeled estimates to key parameters is examined. The model is then used to estimate air-to-skin-to-blood absorption of six phthalate esters for scenarios in which (A) a previously unexposed occupant encounters gas-phase phthalates in three different environments over a single 24-h period; (B) the same as ‘A’, but the pattern is repeated for seven consecutive days. In the 24-h scenario, the transient model predicts more phthalate absorbed into skin and less absorbed into blood than would a steady-state model. In the 7-day scenario, results calculated by the transient and steady-state models converge over a time period that varies between 3 and 4 days for all but the largest phthalate (DEHP). Dermal intake is comparable to or larger than inhalation intake for DEP, DiBP, DnBP, and BBzP in Scenario ‘A’ and for all six phthalates in Scenario ‘B’.
M. Gong1, Y. Zhang1, C. J. Weschler1,2,3 1 Department of Building Science, Tsinghua University, Beijing, China, 2Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ, USA, 3International Center for Indoor Environment and Energy, Technical University of Denmark, Lyngby, Copenhagen, Denmark
Key words: Dermal permeability; Percutaneous transport; Phthalates; Skin absorption; Stratum corneum; Vapor absorption. C. J. Weschler Environmental and Occupational Health Sciences Institute Rutgers University 170 Frelinghuysen Rd., Piscataway, NJ 08854 USA Tel.: +848-445-2073 Fax: +732-445-0116 e-mail:
[email protected] Received for review 14 June 2013. Accepted for publication 13 November 2013.
Practical Implications
Dermal absorption from air has often been overlooked in exposure assessments. However, our transient model suggests that dermal intake of certain gas-phase phthalate esters is comparable to, or larger than, inhalation intake under commonly occurring indoor conditions. This may also be the case for other organic chemicals that have physicochemical properties that favor dermal absorption directly from air. Consequently, this pathway should be included in aggregate exposure and risk assessments. Furthermore, under conditions where the exposure concentrations are changing or there is insufficient time to achieve steady-state, the transient model presented in this study is more appropriate for estimating dermal absorption than is a steady-state model.
Nomenclature
A BBzP Cgi Cg(t) Cs0 (x) Cv0 (x)
292
area of exposure (m2) butylbenzyl phthalate gas-phase chemical concentration at the air-skin interface (lg/m3) gas-phase chemical concentration in the air (lg/m3) initial chemical concentration in stratum corneum (SC) (lg/m3) initial chemical concentration in viable epidermis (VE) (lg/m3)
Csc Cve Dg Dsc Dve DMP DEP
chemical concentration in stratum corneum (SC) (lg/m3) chemical concentration in viable epidermis (VE) (lg/m3) molecular diffusion coefficient in the gasphase (m2/s) effective diffusion coefficient in stratum corneum (SC) (m2/s) effective diffusion coefficient in viable epidermis (VE) (m2/s) dimethyl phthalate diethyl phthalate
Transient model of dermal absorption from air DiBP DnBP DEHP Hcp hc hm Js kp_g Kow Ksc_g Ksc_w Kve_g Kve_w Kwg Lsc Lve Ms _s M Mb _b M Mbs _ bs M MW R Ras T ta texp tl tsk ts v x q cp a
di(isobutyl) phthalate di(n-butyl) phthalate di(2-ethylhexyl) phthalate Henry’s law constant (mol/l/atm) convective heat-transfer coefficient around human surface (m/h) convective mass-transfer coefficient around human surface (m/h) steady-state absorption flux into blood (lg/ m2 per h) overall skin permeability coefficient from gas-phase to the blood (m/h) partition coefficient between octanol and water partition coefficient between stratum corneum (SC) and air partition coefficient between stratum corneum (SC) and water partition coefficient between viable epidermis (VE) and air partition coefficient between viable epidermis and water partition coefficient between water and gasphase thickness of stratum corneum (SC) (m) thickness of viable epidermis (VE) (m) amount absorbed into skin (lg) dermal absorption flux into skin (lg/m2 per h) amount absorbed into blood (lg) dermal absorption flux into blood (lg/m2 per h) amount absorbed into blood at steady-state (lg) dermal absorption flux into blood at steady-state (lg/m2 per h) molecular weight (g/mol) gas constant (0.0821 atm l/mol per K) ratio of resistance across the air boundary layer to the sum of the resistances across the stratum corneum and viable epidermis absolute temperature (K) ambient air temperature (°C) time of exposure (h) absorption lag time (h) human surface temperature (°C) time to reach steady-state (h) air velocity around human surface (m/s) distance in the epidermis from the inner skin surface (m) air density (kg/m3) air specific heat (kJ/K per kg) air thermal diffusivity (m2/s)
Introduction
Dermal absorption of gas-phase chemicals is a somewhat overlooked exposure pathway. However,
experimental data demonstrate that this pathway can make a significant contribution to the total intake of an airborne pollutant (Rauma et al., 2013; Rehal and Maibach, 2011). Piotrowski (1967, 1971) measured direct dermal absorption from the air that was 30% of total intake (dermal plus inhalation) for nitrobenzene and 38% of total intake for phenol. Studies have found that dermal absorption of gas-phase glycol ethers contributes 10–75% to the summed dermal and inhalation intake (Brooke et al., 1998; Johanson and Boman, 1991; Jones et al., 2003). More recently, Bader et al. (2008) have shown that dermal absorption of gas-phase N-methyl-2-pyrrolidone contributes 33–42% to summed intake. Dermal absorption of gas-phase chemicals is not only potentially significant for volatile organic compounds (VOCs); recent analyses suggest that dermal absorption of some gas-phase semivolatile organic compounds (SVOCs) may be significant compared with inhalation intake (Bek€ o et al., 2013; Little et al., 2012; Weschler and Nazaroff, 2008, 2012). Human and animal studies of dermal absorption are costly and often limited by ethical considerations; mathematical models to predict dermal absorption of gas-phase chemicals are practical screening tools that can be used to target subsequent experimental efforts on the chemicals of greatest concern. A US EPA document outlines an equation that can be used to estimate dermal absorption from the gas-phase if the permeability coefficient from an aqueous solution in contact with skin is known (USEPA, 1992). Wilschut and Ten Berge (1996) presented two models for estimating the skin permeation rate of vapors. The first was a regression analysis, based on limited experimental data, with the octanol–water partition coefficient, the vapor pressure and the molecular weight as independent variables. The second adapted a skin permeation model for organics from aqueous solutions by considering partitioning between air and water as well as the layer of air adjacent to the skin. A similar mass-transfer resistance approach has been used more recently by Weschler and Nazaroff (2012) and Xu et al. (2009). However, these models can only be used to estimate dermal absorption of gas-phase chemicals under steady-state conditions. Several PBPK models have been developed to predict transient dermal absorption of gas-phase chemicals (Loizou et al., 1999; Poet et al., 2000). However, the application of these PBPK models is limited because of the parameters that must be determined to use the model. In the software ‘IH Skinperm’ (Tibaldi et al., 2014) the authors have constructed a semi-empirical model to predict transient dermal absorption of gas-phase chemicals based on mass balance considerations. Numerous models based on Fick’s Law have been constructed to predict the dynamics of dermal absorption from aqueous solutions in contact with the skin surface (Cleek and Bunge, 1993; Reddy et al., 2000) and from intermittent contact with contaminated 293
Gong et al. surfaces (Riley et al., 2004). Such models can be used not only to predict transient state exposure, but also tend to be more universal and accurate than PBPK models. The Cleek and Bunge model can be used to estimate dermal absorption of gas-phase chemicals if the vehicle in contact with the skin is air (Bunge and Cleek, 1995; Bunge et al., 1995; Cleek and Bunge, 1993), but it does not consider convective mass-transfer resistance through the air boundary layer adjacent to the skin. This may reduce the accuracy of the predictions, especially when resistance across the boundary layer adjacent to skin is large relative to resistance across the stratum corneum and viable epidermis. Additionally, it is difficult to apply the model in situations where the gas-phase concentration of the absorbing species is changing (e.g. sequential exposures in different microenvironments). The purpose of this study is to develop a ‘transient’ mass-transfer model for dermal absorption of gasphase chemicals that considers convective mass-transfer resistance in the boundary layer of air adjacent to the skin as well as potential changes in the airborne concentration of the chemical that is being absorbed. This model enables estimates, under non-steady-state conditions, of dermal absorption of gas-phase chemicals. For two hypothetical exposure scenarios, predictions from the present transient model are compared with those from a steady-state model for the absorption of different phthalate esters into skin and blood.
Methods Transient model development
To construct the transient model for dermal absorption of gas-phase chemicals, several assumptions have been made: skin is considered as two pseudo-homogenous layers, the stratum corneum (SC) and the viable epidermis (VE); the transport process is considered to be onedimensional given that the skin’s surface area is much larger than its thickness; metabolism, desquamation, and ionization of chemicals within the skin, and the contribution of the skin appendage pathways, have not been included in the model. A schematic representation of the dermal absorption process is shown in Figure 1. These governing equations describe the transient mass diffusion through skin: @Csc @ 2 Csc ¼ Dsc @t @x2 @Cve @ 2 Cve ¼ Dve @t @x2
for Lve \x\Lsc þ Lve
for 0\x\Lve
ð1Þ
ð2Þ
where Csc and Cve are the chemical concentrations in the stratum corneum and viable epidermis (lg/m3), Dsc and Dve are the effective diffusion coefficients in the 294
Fig. 1 Schematic illustrating processes and parameters involved in dermal absorption of gas-phase chemicals. The parameters are defined in the text. The open red and blue circles represent arterial and venous dermal capillaries
stratum corneum and viable epidermis (m2/s), Lsc and Lve are the thicknesses of the stratum corneum and viable epidermis (m), respectively, and x is the distance in the epidermis from the boundary between the viable epidermis and the dermis (m). The skin initially contains an arbitrary amount of the chemical in question and is exposed to gas-phase chemicals at a concentration that may be changing with time. The concentration in blood or at the viable epidermis–dermis interface is considered to be zero for fast blood flow. In addition, equilibrium is assumed at the air–skin interface and the stratum corneum–viable epidermis interface, and the flux is conserved at the stratum corneum–viable epidermis interface. Mathematically, the initial and boundary conditions are these: Cve ¼ Cv0 ðxÞ; Csc ¼ Cs0 ðxÞ for 0\x\Lsc þLve ; t ¼ 0 ð3Þ Cve ¼ 0
for x ¼ 0; t [ 0
ð4Þ
Csc Cve ¼ Ksc g Kve g
for x ¼ Lve ; t [ 0
ð5Þ
@Csc @Cve ¼ Dve for x ¼ Lve ; t [ 0 @x @x @Csc Csc ¼ hm Cg ðtÞ Dsc @x Ksc g
Dsc
for x ¼ Lsc þ Lve ; t [ 0
ð6Þ
ð7Þ
where Cs0 (x) and Cv0 (x) are the initial concentrations in the stratum corneum and viable epidermis (lg/m3), hm is the convective mass-transfer coefficient around the human surface (m/h), Ksc_g is the partition coefficient between the stratum corneum and air, Kve_g is the partition coefficient between the viable epidermis and
Transient model of dermal absorption from air air, and Cg (t) is the gas-phase concentration in the air where exposure occurs (lg/m3). The analytical solutions to equations (1–7) have been manually derived using the generalized orthogonal function expansion method with reference to an analogous heat-transfer solution (Ozisik, 1983). The analytical solutions for concentrations in the stratum corneum and viable epidermis (Csc, Cve), absorption _ s, M _ b ), and the amount flux into skin and blood (M absorbed into skin and blood (Ms, Mb) are shown in Eqs S1–S12 of Appendix S1. Steady-state model
When the dermal absorption process is at steady-state, the dermal absorption flux into blood and the amount absorbed into blood can be calculated using the following simple equations: _ bs ¼ kp M Z
g
Cg ðtÞ
texp
Mbs ¼
kp
g
ð8Þ
Cg ðtÞ t Adt
ð9Þ
0
where texp is the time of exposure (h), A is the area of exposure (m2), and kp_g is the overall skin permeability coefficient from gas-phase to blood (m/h). The latter can be calculated using the following equation: kp
g
¼
1 1 hm
þ DscLKscsc
þ DveLKveve g
ð10Þ g
Parameter estimation
To calculate dermal absorption of gas-phase chemicals using either the transient or the steady-state models, the relevant parameters need to be determined or estimated. These include Lsc, Lve, hm, Ksc_g, Kve_g, Dsc, and Dve. The stratum corneum (SC) thickness (Lsc) varies with age, gender, location on the body and water content (Cleek and Bunge, 1993; Egawa et al., 2007). Although the stratum corneum is thicker on the palms and soles of the feet, over most of the body the stratum corneum thickness is roughly 10–50 lm (Rushmer et al., 1966). In our analyses, we use 25 lm as a reasonable average value for Lsc based on an experimental study (Egawa et al., 2007) in which the researchers measured the thickness of forearm (22.6 lm), back of hand (29.3 lm), and palm (173 lm). The viable epidermis (VE) thickness (Lve) is in the range 50–200 lm (Reddy et al., 2000; USEPA, 1992); other studies have used 100 lm as an average value for Lve (Bunge and Cleek, 1995; Cleek and Bunge, 1993), and this is the value we will use. Direct measurements of Ksc_g are very limited. To our knowledge, only Mattie et al. (1994) have measured Ksc_g for a number of organic compounds. How-
ever, the skin used in their experiment was from rats, and there are differences between rat skin and human skin (McDougal et al., 1990; Poet et al., 2000). So in this study, Ksc_g is obtained by multiplying the partition coefficient between the stratum corneum (SC) and water (Ksc_w) and the partition coefficient between water and air (Kwg), that is Ksc
g
¼ Ksc
w
Kwg
ð11Þ
The partition coefficient between the SC and water (Ksc_w) is influenced by the hydration state of the SC. Under typical in vivo conditions (Nitsche et al., 2006; Wang et al., 2007), it is partially hydrated, with water content of approximately 30% by weight. This is the SC hydration state that we will use when considering transport from air through skin. Nitsche et al. (2006) have derived equations for estimating partition coefficients between the stratum corneum and water that consider both the lipid and corneocyte phases in the SC. Based on equations 3, B8, 10, and 11, as well as the parameters in Table 1 and Appendix A of Nitsche et al., we obtain equations for estimating Ksc_w when the stratum corneum is partially hydrated (0.43 g water/1 g dry SC): Ksc
w
0:27 ¼ 0:040K0:81 ow þ 4:06Kow þ 0:359
ð12Þ
The above equation is the same as that derived by Wang et al. (2007) for partially hydrated stratum corneum and will be used in what follows. The parameter Kwg can be estimated using the following equation (Weschler and Nazaroff, 2008): Kwg ¼ Hcp RT
ð13Þ
where Hcp is Henry’s law constant (note that we use units of mol/L/atm, consistent with the definition in Weschler and Nazaroff), R is the gas constant (0.0821 atm L/mol/K), and T is the absolute temperature (K). Substituting equations (12) and (13) into equation (11), we can calculate Ksc_g for partially hydrated conditions as follows: 0:27 Ksc g ¼ð0:040K0:81 ow þ4:06Kow þ0:359ÞHcp RT
ð14Þ
The effective diffusion coefficient in the stratum corneum (Dsc) can be calculated from Fick’s first law using the permeability of an organic compound from an aqueous solution (kp_w) and the calculated Ksc_w: Dsc ¼
kp w Lsc Ksc w
ð15Þ
Numerous models have been derived to estimate the permeability of an organic compound from an aqueous 295
Gong et al. solution (kp_w) (Abraham et al., 1999; Barratt, 1995; Mitragotri, 2002; Potts and Guy, 1992). However, the predicted permeabilities calculated with these models are for fully hydrated stratum corneum and are not appropriate for our analysis. Wang et al. (2007) derived equations for the permeability of partially hydrated stratum corneum based on fundamental transport theory. We have used the equations in Table 4 of Wang et al., substituting throughout these equations ‘25 lm’ for ‘13.365 lm’ for the thickness of the stratum corneum (Lsc), to estimate the effective diffusion coefficient in partially hydrated stratum corneum (Dsc). To obtain the partition coefficient between the viable epidermis (VE) and air, Kve_g, we multiply the partition coefficient between the viable epidermis and water (Kve_w) and the partition coefficient between the water and air (Kwg), that is Kve
g
¼ Kve
w
Kwg
ð16Þ
Recently, considerable progress has been made estimating solute transport in the viable epidermis and dermis by considering the VE’s multiple phases and the composition of these phases (Dancik et al., 2013; Kretsos et al., 2008; Nitsche and Kasting, 2013). Using equation (D.1), (D.2), (D.5), (D.7), (D.8), and (D.9) in Appendix D of Dancik et al. (2013), Kve_w (Ked/non in Dancik’s paper) and Dve (Dve/non in Dancik’s paper) can be calculated. To estimate hm, we use the Chilton–Colburn Analogy for heat and mass transfer, shown in equation (17). Numerous studies have measured and derived empirical correlations for the convective heat-transfer coefficient around the human surface (hc) (De Dear et al., 1997; Fanger, 1970; Kurazumi et al., 2008; Sørensen and Voigt, 2003). hc ¼ qcp ða=Dg Þ2=3 hm
ð17Þ
where, q is the air density (kg/m3), cp is the specific heat of air (kJ/K per kg), a is the thermal diffusivity (m2/s), and Dg is the molecular diffusion coefficient in the gasphase (m2/s). The convective heat-transfer coefficent (hc) for the human body is influenced by the ambient environment. Convection from human surfaces can be classified into three distinct modes: free convection, where the air velocity is
