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

Abstract

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.

Keywords: Compartment modeling; Dermal absorption; Fick's law of diffusion; Human dermal permeability; In vitro model.

Figure 1.

A: General schematic of the compartment model. Each of the four compartments is assumed to be well mixed with bidirectional chemical transfer as indicated by the blue arrows. Evaporation of chemical and vehicle from the source compartment is allowed. (Left) Source thickness decreases from its initial value until the vehicle has fully evaporated. (Middle) Skin absorption after the vehicle evaporates. Scenario 1 is used when the chemical remaining on the skin surface is a liquid; chemical transfer and evaporation proceed as if the chemical is in a saturated vehicle. Scenario 2 is used when the remaining chemical is solid; chemical transfer from the source to the SC stops but evaporation continues. (Right) After chemical on the skin surface is gone, it can evaporate from the SC. B: Definitions of the forward and reverse rate constants, $k_{i,j}$ (cm³ s⁻¹), describing mass transfer between adjacent compartments $i$ and $j$, and the permeability coefficients in the SC and VT compartments. In these equations, $A_{sk}$ is the exposed skin area (cm²),$L_j$ is the thickness (cm) of compartment j, ${\mathrm{D}}_{\mathrm{j}}$ is the effective diffusivity (cm² s⁻¹) of the absorbing chemical in compartment j, $K_{j/S}$ is the partition coefficient of the absorbing chemical between compartment j and the source solution (j is either the SC, VT, or RF), and $k_p^j$ is the permeability coefficient (cm s⁻¹) for compartment j (j is either the SC or VT). $B=k_p^{SC}/k_p^{VT}$. Because the mass transfer rate from the RF to the VT is the product of $k_{RF,VT}$ and the concentration in the RF, $k_{RF,VT}$ does not need to be calculated if sink conditions are maintained in the RF (i.e., concentration in the RF is zero), even though $k_{RF,VT}$ is not zero (see Eqs. (2) and (3)).

Figure 2:

A: Ratio of model predictions to experimental observations from Hewitt et al. (2020) of the cumulative mass of chemical in the RF at 24 h for the 26 chemicals listed in Table S5 by number. Model results were calculated at the default air velocity of 10 cm s⁻¹. Horizontal lines represent perfect model predictions (solid) and over or underestimates by factors of five (dotted) and ten (dashed). Circles denote chemicals that are solids at skin temperature and triangles those that are liquids. The four chemicals selected as case studies are denoted with red symbols. Chemicals used in the case study, chemicals that were over or underestimated by a factor larger than ten, and propylparaben, which was measured twice by Hewitt et al., have been labeled. B: Predicted fraction of the applied mass in each compartment, and air, during the first hour of exposure to example chemicals. Vertical dotted lines identify the time at which the vehicle has fully evaporated. Compartments are labeled and designated by color: Source (blue; solid), SC (green; dashed), VT (orange; dashed), RF (black; solid), and evaporated (purple; solid).