Dermal absorption of chemicals: estimation by IH SkinPerm.

This article describes the IH SkinPerm mathematical tool for estimating dermal absorption. The first part provides the scientific background of the IH SkinPerm model, including the QSARs and the developed differential equations. Then the practical value of the tool is demonstrated through example dermal absorption assessments for substances with skin notations. IH SkinPerm simulates three types of dermal absorption scenarios relevant to occupational environments. The first is dermal absorption from instantaneous splash type exposures onto bare skin for pure liquids. The second estimates dermal absorption from the deposition of pure liquids over time. The third enables estimation of dermal uptake from an airborne vapor concentration. A simulation with IH SkinPerm was made using vapor absorption data published from volunteer exposure studies. Comparison of measured and estimated dermal absorbed dose showed IH SkinPerm estimated dermal absorbed dose was within a factor of 3 compared to the reported study values. IH SkinPerm accounts for substance volatility and evaporated mass and provides real-time description of dermal absorption with graphical displays and numerical outputs. To assess absorption resulting from dermal exposure scenarios, the mass of the substance loaded onto the skin, substance physical chemical properties, exposure duration, and the skin surface area affected are the only required input parameters.

Simulation of urinary excretion of 1-hydroxypyrene in various scenarios of exposure to polycyclic aromatic hydrocarbons with a generic, cross-chemical predictive PBTK-model.

INTRODUCTION: A physiologically based toxicokinetic (PBTK) model can predict blood and urine concentrations, given a certain exposure scenario of inhalation, dermal and/or oral exposure. The recently developed PBTK-model IndusChemFate is a unified model that mimics the uptake, distribution, metabolism and elimination of a chemical in a reference human of 70 kg. Prediction of the uptake by inhalation is governed by pulmonary exchange to blood. Oral uptake is simulated as a bolus dose that is taken up at a first-order rate. Dermal uptake is estimated by the use of a novel dermal physiologically based module that considers dermal deposition rate and duration of deposition. Moreover, evaporation during skin contact is fully accounted for and related to the volatility of the substance. Partitioning of the chemical and metabolite(s) over blood and tissues is estimated by a Quantitative Structure-Property Relationship (QSPR) algorithm. The aim of this study was to test the generic PBTK-model by comparing measured urinary levels of 1-hydroxypyrene in various inhalation and dermal exposure scenarios with the result of model simulations. EXPERIMENTAL: In the last three decades, numerous biomonitoring studies of PAH-exposed humans were published that used the bioindicator 1-hydroxypyrene (1-OH-pyrene) in urine. Longitudinal studies that encompass both dosimetry and biomonitoring with repeated sampling in time were selected to test the accuracy of the PBTK-model by comparing the reported concentrations of 1-OHP in urine with the model-predicted values. Two controlled human volunteer studies and three field studies of workers exposed to polycyclic aromatic hydrocarbons (PAH) were included. RESULTS: The urinary pyrene-metabolite levels of a controlled human inhalation study, a transdermal uptake study of bitumen fume, efficacy of respirator use in electrode paste workers, cokery workers in shale oil industry and a longitudinal study of five coke liquefaction workers were compared to the PBTK-predicted values. The simulations showed that the model-predicted concentrations of urinary pyrene and metabolites over time, as well as peak-concentrations and total excreted amount in different exposure scenarios of inhalation and transdermal exposure were in all comparisons within an order of magnitude. The model predicts that only a very small fraction is excreted in urine as parent pyrene and as free 1-OH-pyrene. The predominant urinary metabolite is 1-OH-pyrene-glucuronide. Enterohepatic circulation of 1-OH-pyrene-glucuronide seems the reason of the delayed release from the body. CONCLUSIONS: It appeared that urinary excretion of pyrene and pyrene-metabolites in humans is predictable with the PBTK-model. The model outcomes have a satisfying accuracy for early testing, in so-called 1st tier simulations and in range finding. This newly developed generic PBTK-model IndusChemFate is a tool that can be used to do early explorations of the significance of uptake of pyrene in the human body following industrial or environmental exposure scenarios. And it can be used to optimize the sampling time and urine sampling frequency of a biomonitoring program.

Dermal penetration of propylene glycols: measured absorption across human abdominal skin in vitro and comparison with a QSAR model.

The dermal penetration of undiluted monopropylene glycol (MPG) and dipropylene glycol (DPG) has been measured in vitro using human abdominal skin under conditions of infinite dose application, and the results compared with predictions from the SKINPERM QSAR model (ten Berge, 2009). The measured steady-state penetration rates (Jss) for MPG and DPG were 97.6 and 39.3 µg/cm2/h, respectively, and the permeability coefficients (Kp) were 9.48×10(-5) cm/h for MPG and 3.85×10(-5) cm/h for DPG. In comparison, the SKINPERM model slightly over-predicted Jss and Kp for MPG and DPG by between 2.6- and 5.1-fold, respectively. The model predictions of 254 µg/cm2/h and 24.6×10(-5) cm/h for MPG, and 202 µg/cm2/h and 19.8×10(-5) cm/h for DPG were in fairly good agreement with the measured values. Further, the model predicted a Jss of 101 µg/cm2/h and a Kp of 9.9×10(-5) cm/h for the homologue tripropylene glycol. Assuming that the measured Jss was the same under conditions of finite dose application (taken to be 10 µL/ cm2) and was maintained over a 24-h period (both conservative assumptions), the relative dermal absorption of the applied dose was estimated to be 23% (0.96%/h) for MPG and 9% (0.39%/h) for DPG. However, the extrapolation for MPG may be further overestimated due to possible residence in the stratum corneum under infinite conditions of exposure that would not be applicable to a finite loading dose.

A simple dermal absorption model: derivation and application.

This paper deals with the derivation of a QSAR for the estimation of: the skin permeation coefficient from aqueous solutions in cm h(-1), the stratum corneum/water partition coefficient. These QSARs enable the estimation of: the aqueous permeation coefficient in cm h(-1), the maximum dermal absorption in mg cm(-2) h(-1) from a saturated aqueous solution at steady state, the lag time in hours (h), the diffusivity of a substance in the stratum corneum in cm2 h(-1). By using the independent variables: the log(octanol/water partition coefficient), the molecular weight,the water solubility. The estimated maximum dermal absorption and the lag time were compared with some recent measured data of substances, which were not used for developing the QSARs. The estimates were generally in the same order of magnitude as the measured absorption and lag time. These QSARs are recommended for risk assessment of chemicals in the scope of the European REACH legislation.

Mortality update of workers exposed to acrylonitrile in The Netherlands.

To study the possible carcinogenic effects of acrylonitrile, we updated the follow up of a cohort of 2842 acrylonitrile workers. The comparison group consisted of 3961 workers from a nitrogen fixation plant. Industrial hygiene assessments quantified past exposure to acrylonitrile, 8-hour averages as well as peak exposure, the use of personal protective equipment, and exposure to other potential carcinogenic agents. Standardized mortality ratios were calculated to adjust for the effect of age distribution, length of follow up, and temporal changes in background mortality rates. Cumulative dose-effect relations were determined for 3 exposure categories and 3 latency periods. The results show that no cancer excess seems related to exposure to acrylonitrile. This additional follow up of a cohort of 2842 workers exposed to acrylonitrile further supports the notion that occupational exposures to acrylonitrile that have occurred in the past have not noticeably increased workers' cancer mortality rates.

Quantitative structure-activity relationships (QSARs) for the prediction of skin permeation of exogenous chemicals.

Quantitative structure-activity relationships (QSARs) for the skin permeability coefficients of 158 compounds through excised human skin in vitro have been developed. A number of compounds, including hydrocortisone derivatives, were removed from the dataset as reported permeability data for these compounds was considered to be in error. QSARs developed for the dataset with the outliers removed included terms for hydrophobicity, molecular size, and hydrogen bonding. These descriptors provided an excellent fit to the data (r2 = 0.90), are easily calculated from molecular structure, and are mechanistically interpretable. Further analyses of the dataset indicated that good QSARs could be developed utilising hydrophobicity and molecular size alone, with molecular volume and molecular weight providing good quantification of molecular size.