Comparison of dermal and inhalation routes of entry for organic chemicals

The quantitative comparison of the chemical concentration inside the body as the result of a dermal exposure versus an inhalation exposure is useful for assessing human health risks and deciding on an appropriate protective posture. In order to describe the relationship between dermal and inhalation routes of exposure, a variety of organic chemicals were evaluated. The types of chemicals chosen for the study were halogenated hydrocarbons, aromatic compounds, non-polar hydrocarbons and inhalation anesthetics. Both dermal and inhalation exposures were conducted in rats and the chemicals were in the form of vapors. Prior to the dermal exposure, rat fur was closely clipped and during the exposure rats were provided fresh breathing air through latex masks. Blood samples were taken during 4-hour exposures and analyzed for the chemical of interest. A physiologically based pharmacokinetic model was used to predict permeability constants (cm/hr) consistent with the observed blood concentrations of the chemical. The ratio of dermal exposure to inhalation exposure required to achieve the same internal dose of chemical was calculated for each test chemical. The calculated ratio in humans ranged from 18 for styrene to 1180 for isoflurane. This methodology can be used to estimate the dermal exposure required to reach the internal dose achieved by a specific inhalation exposure. Such extrapolation is important since allowable exposure standards are often set for inhalation exposures, but occupational exposures may be dermal

PBPK modelling of inter-individual variability in the pharmacokinetics of environmental chemicals

International audienceGeneric PBPK models, applicable to a large number of substances, coupled to parameter databases and QSAR modules, are now available for predictive modelling of inter-individual variability in the absorption, distribution, metabolism and excretion of environmental chemicals. When needed, Markov chain Monte Carlo methods and multilevel population models can be jointly used for a Bayesian calibration of a PBPK model, to improve our understanding of the determinants of population heterogeneity and differential susceptibility. This article reviews those developments and illustrates them with recent applications to environmentally relevant questions

Development of an integrated multi-species and multi-dose route PBPK model for volatile methyl siloxanes – D4 and D5

AbstractThere are currently seven published physiologically based pharmacokinetic (PBPK) models describing aspects of the pharmacokinetics of octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5) for various exposure routes in rat and human. Each model addressed the biological and physico-chemical properties of D4 and D5 (highly lipophilic coupled with low blood: air partition coefficient and high liver clearance) that result in unique kinetic behaviors as well differences between D4 and D5. However, the proliferation of these models resulted in challenges for various risk assessment applications when needing to determine the optimum model for estimating dose metrics. To enhance the utility of these PBPK models for risk assessment, we integrated the suite of structures into one coherent model capable of simulating the entire set of existing data equally well as older more limited scope models. In this paper, we describe the steps required to develop this integrated model, the choice of physiological, partitioning and biochemical parameters for the model, and the concordance of the model behavior across key data sets. This integrated model is sufficiently robust to derive relevant dose metrics following individual or combined dermal and inhalation exposures of workers, consumer or the general population to D4 and D5 for route-to-route, interspecies and high to low dose extrapolations for risk assessment

Is the Relationship between Prenatal Exposure to PCB-153 and Decreased Birth Weight Attributable to Pharmacokinetics?

Background: A recent meta-analysis based on data from > 7,000 pregnancies reported an association between prenatal polychlorinated biphenyl (PCB)–153 exposure and reduced birth weight. Gestational weight gain, which is associated negatively with PCB levels in maternal and cord blood, and positively with birth weight, could substantially confound this association. Objective: We sought to estimate the influence of gestational weight gain on the association between PCB-153 exposure and birth weight using a pharmacokinetic model. Methods: We modified a recently published pharmacokinetic model and ran Monte Carlo simulations accounting for variability in physiologic parameters and their correlations. We evaluated the pharmacokinetic model by comparing simulated plasma PCB-153 levels during pregnancy to serial measurements in 10 pregnant women from another study population. We estimated the association between simulated plasma PCB-153 levels and birth weight using linear regression models. Results: The plasma PCB-153 level profiles generated with the pharmacokinetic model were comparable to measured levels in 10 pregnant women. We estimated a 118-g decrease in birth weight (95% CI: –129, –106 g) for each 1-μg/L increase in simulated cord plasma PCB-153, compared with the 150-g decrease estimated based on the previous meta-analysis. The estimated decrease in birth weight was reduced to –6 g (95% CI: –18, 6 g) when adjusted for simulated gestational weight gain. Conclusion: Our findings suggest that associations previously noted between PCB levels and birth weight may be attributable to confounding by maternal weight gain during pregnancy. Citation: Verner MA, McDougall R, Glynn A, Andersen ME, Clewell HJ III, Longnecker MP. 2013. Is the relationship between prenatal exposure to PCB-153 and decreased birth weight attributable to pharmacokinetics? Environ Health Perspect 121:1219–1224; http://dx.doi.org/10.1289/ehp.120645

Update on a Pharmacokinetic-Centric Alternative Tier II Program for MMT—Part II: Physiologically Based Pharmacokinetic Modeling and Manganese Risk Assessment

Recently, a variety of physiologically based pharmacokinetic (PBPK) models have been developed for the essential element manganese. This paper reviews the development of PBPK models (e.g., adult, pregnant, lactating, and neonatal rats, nonhuman primates, and adult, pregnant, lactating, and neonatal humans) and relevant risk assessment applications. Each PBPK model incorporates critical features including dose-dependent saturable tissue capacities and asymmetrical diffusional flux of manganese into brain and other tissues. Varied influx and efflux diffusion rate and binding constants for different brain regions account for the differential increases in regional brain manganese concentrations observed experimentally. We also present novel PBPK simulations to predict manganese tissue concentrations in fetal, neonatal, pregnant, or aged individuals, as well as individuals with liver disease or chronic manganese inhalation. The results of these simulations could help guide risk assessors in the application of uncertainty factors as they establish exposure guidelines for the general public or workers

Physiologically Based Pharmacokinetic (PBPK) Modeling of Interstrain Variability in Trichloroethylene Metabolism in the Mouse

Background: Quantitative estimation of toxicokinetic variability in the human population is a persistent challenge in risk assessment of environmental chemicals. Traditionally, interindividual differences in the population are accounted for by default assumptions or, in rare cases, are based on human toxicokinetic data