A database of chemical absorption in human skin with mechanistic modeling applications.

Whether from environmental and occupational hazards or from topical pharmaceuticals, the human skin comes into contact with various chemicals every day. In vivo experiments not only require large investments of both time and money, but in vivo experiments can also be unethical due to the need to intentionally or incidentally expose humans or animals to toxic chemicals. Comparatively, in vitro experiments offer ethical and financial advantages when combined with the opportunity to selectively choose chemicals for experimentation.

A regression analysis using simple descriptors for multiple dermal datasets: Going from individual membranes to the full skin.

In silico methods to estimate and/or quantify skin absorption of chemicals as a function of chemistry are needed to realistically predict pharmacological, occupational, and environmental exposures. The Potts-Guy equation is a well-established approach, using multi-linear regression analysis describing skin permeability (Kp) in terms of the octanol/water partition coefficient (logP) and molecular weight (MW). In this work, we obtained regression equations for different human datasets relevant to environmental and cosmetic chemicals.

Global optimization of the Michaelis-Menten parameters using physiologically-based pharmacokinetic (PBPK) modeling and chloroform vapor uptake data in F344 rats.

To quantify metabolism, a physiologically based pharmacokinetic (PBPK) model for a volatile compound can be calibrated with the closed chamber (i.e. vapor uptake) inhalation data.

A physiologically based pharmacokinetic model of vitamin D.

Despite the plethora of studies discussing the benefits of vitamin D on physiological functioning, few mathematical models of vitamin D predict the response of the body on low-concentration supplementation of vitamin D under sunlight-restricted conditions. This study developed a physiologically based pharmacokinetic (PBPK) model utilizing published human data on the metabolic cascade of orally derived, low-concentration (placebo, 5 μg and 10 μg) supplementation of vitamin D over the course of 28 days in the absence of sunlight. Vitamin D and its metabolites are highly lipophilic and binding assays of these compounds in serum may not account for binding by lipids and additional proteins.

Development of a human physiologically based pharmacokinetic (PBPK) model for dermal permeability for lindane.

Lindane is a neurotoxicant used for the treatment of lice and scabies present on human skin. Due to its pharmaceutical application, an extensive pharmacokinetic database exists in humans. Mathematical diffusion models allow for calculation of lindane skin permeability coefficients using human kinetic data obtained from in vitro and in vivo experimentation as well as a default compound-specific calculation based on physicochemical characteristics used in the absence of kinetic data.

Improving in vitro to in vivo extrapolation by incorporating toxicokinetic measurements: a case study of lindane-induced neurotoxicity.

Approaches for extrapolating in vitro toxicity testing results for prediction of human in vivo outcomes are needed. The purpose of this case study was to employ in vitro toxicokinetics and PBPK modeling to perform in vitro to in vivo extrapolation (IVIVE) of lindane neurotoxicity. Lindane cell and media concentrations in vitro, together with in vitro concentration-response data for lindane effects on neuronal network firing rates, were compared to in vivo data and model simulations as an exercise in extrapolation for chemical-induced neurotoxicity in rodents and humans.

Scientific considerations for evaluating cancer bioassays conducted by the Ramazzini Institute.

Background: The Ramazzini Institute (RI) has completed nearly 400 cancer bioassays on > 200 compounds. The European Food Safety Authority (EFSA) and others have suggested that study design and protocol differences between the RI and other laboratories by may contribute to controversy regarding cancer hazard findings, principally findings on lymphoma/leukemia diagnoses.

Objective: We aimed to evaluate RI study design, protocol differences, and accuracy of tumor diagnoses for their impact on carcinogenic hazard characterization.

Human health effects of trichloroethylene: key findings and scientific issues.

Background: In support of the Integrated Risk Information System (IRIS), the U.S. Environmental Protection Agency (EPA) completed a toxicological review of trichloroethylene (TCE) in September 2011, which was the result of an effort spanning > 20 years.

Cutting Edge PBPK Models and Analyses: Providing the Basis for Future Modeling Efforts and Bridges to Emerging Toxicology Paradigms.

Physiologically based Pharmacokinetic (PBPK) models are used for predictions of internal or target dose from environmental and pharmacologic chemical exposures. Their use in human risk assessment is dependent on the nature of databases (animal or human) used to develop and test them, and includes extrapolations across species, experimental paradigms, and determination of variability of response within human populations. Integration of state-of-the science PBPK modeling with emerging computational toxicology models is critical for extrapolation between in vitro exposures, in vivo physiologic exposure, whole organism responses, and long-term health outcomes.

Characterizing uncertainty and population variability in the toxicokinetics of trichloroethylene and metabolites in mice, rats, and humans using an updated database, physiologically based pharmacokinetic (PBPK) model, and Bayesian approach.

We have developed a comprehensive, Bayesian, PBPK model-based analysis of the population toxicokinetics of trichloroethylene (TCE) and its metabolites in mice, rats, and humans, considering a wider range of physiological, chemical, in vitro, and in vivo data than any previously published analysis of TCE. The toxicokinetics of the "population average," its population variability, and their uncertainties are characterized in an approach that strives to be maximally transparent and objective. Estimates of experimental variability and uncertainty were also included in this analysis.

A physiologically based pharmacokinetic model for intravenous and ingested dimethylarsinic acid in mice.

A physiologically based pharmacokinetic (PBPK) model for the organoarsenical dimethylarsinic acid (DMA(V)) was developed in mice. The model was calibrated using tissue time course data from multiple tissues in mice administered DMA(V) intravenously. The final model structure was based on diffusion limitation kinetics.

Difficulty of mode of action determination for trichloroethylene: An example of complex interactions of metabolites and other chemical exposures.

The mode(s) of action (MOA) of a pollutant for adverse health effects may be dependent on the mixture of metabolites resulting from exposure to a single agent and may also be affected by coexposure to pollutants that have similar targets or affected pathways. Trichloroethylene (TCE) can be an useful example for illustration of the complexity coexposure can present to elucidation of the MOA of an agent. TCE exposure has been associated with increased risk of liver and kidney cancer in both laboratory animal and epidemiologic studies.

An example of model structure differences using sensitivity analyses in physiologically based pharmacokinetic models of trichloroethylene in humans.

Trichloroethylene (TCE) is an industrial chemical and an environmental contaminant. TCE and its metabolites may be carcinogenic and affect human health. Physiologically based pharmacokinetic (PBPK) models that differ in compartmentalization are developed for TCE metabolism in humans, and the focus of this investigation is to evaluate alternative models.

Issues in the pharmacokinetics of trichloroethylene and its metabolites.

Much progress has been made in understanding the complex pharmacokinetics of trichloroethylene (TCE) . Qualitatively, it is clear that TCE is metabolized to multiple metabolites either locally or into systemic circulation. Many of these metabolites are thought to have toxicologic importance.

Comments on article "Applying mode-of-action and pharmacokinetic considerations in contemporary cancer risk assessments: an example with trichloroethylene" by Clewell and Andersen.

In their 2004 article, Clewell and Andersen provide their perspective on the application of mode-of-action (MOA) and pharmacokinetic considerations in contemporary cancer risk assessment using trichloroethylene (TCE) as a case example. TCE is a complex chemical toxicologically, with multiple metabolites, multiple sites of observed toxicity, and multiple potential MOAs. As scientists who are responsible for revising the U.

Duration adjustment of acute exposure guideline level values for trichloroethylene using a physiologically-based pharmacokinetic model.

Acute Exposure Guideline Level (AEGL) recommendations are developed for 10-minute, 30-minute, 1-hour, 4-hours, and 8-hours exposure durations and are designated for three levels of severity: AEGL-1 represents concentrations above which acute exposures may cause noticeable discomfort including irritation; AEGL-2 represents concentrations above which acute exposure may cause irreversible health effects or impaired ability to escape; and AEGL-3 represents concentrations above which exposure may cause life-threatening health effects or death. The default procedure for setting AEGL values across durations when applicable data are unavailable involves estimation based on Haber's rule, which has an underlying assumption that cumulative exposure is the determinant of toxicity. For acute exposure to trichloroethylene (TCE), however, experimental data indicate that momentary tissue concentration, and not the cumulative amount of exposure, is important.

Moving from external exposure concentration to internal dose: duration extrapolation based on physiologically based pharmacokinetic derived estimates of internal dose.

The potential human health risk(s) from chemical exposure must frequently be assessed under conditions for which adequate human or animal data are not available. The default method for exposure-duration adjustment, based on Haber's rule, C (external exposure concentration) or C(n) (the ten Berge modification) x t (exposure duration) = K (a constant toxic effect), has been criticized for prediction errors. A promising alternative approach to duration adjustment is based on equivalence of internal dose, that is, target-tissue dose levels, across different exposure durations.

Genotoxicity and metabolism of the source-water contaminant 1,1-dichloropropene: activation by GSTT1-1 and structure-activity considerations.

1,1-Dichloropropene (1,1-DCPe) is a contaminant of some source waters used to make drinking water. Because of this and the fact that no toxicological data were available for this compound, which is structurally similar to the rodent carcinogen 1,3-dichloropropene (1,3-DCPe), 1,1-DCPe was placed on the Contaminant Candidate List of the US Environmental Protection Agency. Consequently, we have performed a hazard characterization of 1,1-DCPe by evaluating its mutagenicity in the Salmonella assay and its DNA damaging (comet assay) and apoptotic (caspase assay) activities in human lymphoblastoid cells.

Visualization-based analysis for a mixed-inhibition binary PBPK model: determination of inhibition mechanism.

A physiologically based pharmacokinetic (PBPK) model incorporating mixed enzyme inhibition was used to determine the mechanism of metabolic interactions occurring during simultaneous exposures to the organic solvents chloroform and trichloroethylene (TCE). Visualization-based sensitivity and identifiability analyses of the model were performed to determine the conditions under which four inhibitory parameters describing inhibitor binding could be estimated. The sensitivity methods were used to reduce the 4-parameter estimation problem into two distinct 2-parameter problems.

The metabolic rate constants and specific activity of human and rat hepatic cytochrome P-450 2E1 toward toluene and chloroform.

Chloroform (CHCl3) is a near-ubiquitous environmental contaminant, a by-product of the disinfection of drinking water sources and a commercially important compound. Standards for safe exposure have been established based on information defining its toxicity, which is mediated by metabolites. The metabolism of CHCl3 is via cytochrome P-450 2E1 (CYP2E1)-mediated oxidation to phosgene, which is known to obey a saturable mechanism.

Kinetic modeling of beta-chloroprene metabolism: II. The application of physiologically based modeling for cancer dose response analysis.

beta-Chloroprene (2-chloro-1,3-butadiene; CD), which is used in the synthesis of polychloroprene, caused significant incidences of several tumor types in B6C3F1 mice and Fischer rats, but not in Wistar rats or Syrian hamsters. This project investigates the relevance of the bioassay lung tumor findings to human health risk by developing a physiologically based toxicokinetic (PBTK) model and exploring a tissue specific exposure-dose-response relationship. Key steps included identification of the plausible genotoxic mode of action, experimental quantification of tissue-to-air partition coefficients, scaling of in vitro parameters of CD metabolism for input into the PBTK model, comparing the model with in vivo experimental gas uptake data, selecting an appropriate tissue dosimetric, and predicting a corresponding human exposure concentration.

Metabolism and mutagenicity of source water contaminants 1,3-dichloropropane and 2,2-dichloropropane.

Cytochrome P450-dependent oxidation and glutathione (GSH)-dependent conjugation are the primary routes of metabolism of haloalkanes. Using rat liver microsomes and cytosol, we investigated the metabolism of two halopropanes found on the U.S.

Pharmacokinetic modeling of arsenite uptake and metabolism in hepatocytes--mechanistic insights and implications for further experiments.

Arsenic (iAs) is a known human carcinogen and widespread contaminant in drinking water. To provide a quantitative framework for experimental design and hypothesis testing, we developed a pharmacokinetic model describing the uptake and methylation of arsenite (AsIII) in primary rat hepatocytes. Measured metabolites were inorganic As (iAs), mono-methylated As (MMA), and di-methylated As (DMA) concentration in cells and media.