Evaluating the impact of anatomical and physiological variability on human equivalent doses using PBPK models.

Addressing human anatomical and physiological variability is a crucial component of human health risk assessment of chemicals. Experts have recommended probabilistic chemical risk assessment paradigms in which distributional adjustment factors are used to account for various sources of uncertainty and variability, including variability in the pharmacokinetic behavior of a given substance in different humans. In practice, convenient assumptions about the distribution forms of adjustment factors and human equivalent doses (HEDs) are often used.

A Model Template Approach for Rapid Evaluation and Application of Physiologically Based Pharmacokinetic Models: Extension to Volatile Organic Compounds.

Chemical risk assessors use physiologically based pharmacokinetic (PBPK) models to perform dosimetric calculations, including extrapolations between exposure scenarios, species, and populations of interest. Assessors should complete a thorough quality assurance (QA) review to ensure biological accuracy and correct implementation prior to using these models. This process can be time-consuming, and we developed a PBPK model template that allows for faster, more efficient QA review.

Evaluation of a rapid, generic human gestational dose model.

Chemical risk assessment considers potentially susceptible populations including pregnant women and developing fetuses. Humans encounter thousands of chemicals in their environments, few of which have been fully characterized. Toxicokinetic (TK) information is needed to relate chemical exposure to potentially bioactive tissue concentrations.

A Generic Pharmacokinetic Model for Quantifying Mother-to-Offspring Transfer of Lipophilic Persistent Environmental Chemicals.

Lipophilic persistent environmental chemicals (LPECs) can accumulate in a woman's body and transfer to her developing child across the placenta and via breast milk. To assess health risks associated with developmental exposures to LPECs, we developed a pharmacokinetic (PK) model that quantifies mother-to-offspring transfer of LPECs during pregnancy and lactation and facilitates internal dosimetry calculations for offspring. We parameterized the model for mice, rats, and humans using time-varying functions for body mass and milk consumption rates.

Uncertainty estimation strategies for quantitative non-targeted analysis.

Non-targeted analysis (NTA) methods are widely used for chemical discovery but seldom employed for quantitation due to a lack of robust methods to estimate chemical concentrations with confidence limits. Herein, we present and evaluate new statistical methods for quantitative NTA (qNTA) using high-resolution mass spectrometry (HRMS) data from EPA's Non-Targeted Analysis Collaborative Trial (ENTACT). Experimental intensities of ENTACT analytes were observed at multiple concentrations using a semi-automated NTA workflow.

Health Effects of Naphthalene Exposure: A Systematic Evidence Map and Analysis of Potential Considerations for Dose-Response Evaluation.

Background: Naphthalene is a polycyclic aromatic hydrocarbon that has been associated with health effects, including cancer. As the state of the science on naphthalene toxicity continues to evolve, updated toxicity reference value(s) may be required to support human health risk assessment.

Objectives: We present a systematic evidence map of studies that could be used to derive toxicity reference value(s) for naphthalene.

A Model Template Approach for Rapid Evaluation and Application of Physiologically Based Pharmacokinetic Models for Use in Human Health Risk Assessments: A Case Study on Per- and Polyfluoroalkyl Substances.

Physiologically based pharmacokinetic (PBPK) models are commonly used in risk assessments to perform inter- and intraspecies extrapolations as well as to extrapolate between different dosing scenarios; however, they must first undergo quality assurance review, which can be a time-consuming process, especially when model code is not readily available. We developed and implemented (using R and MCSim) a PBPK model template capable of replicating published model results for several chemical-specific PBPK models. This model template allows for faster quality assurance review because the general model equations only need to be reviewed once, and application to a specific chemical then only requires reviewing input parameters.

Pharmacokinetics of bisphenol A in humans following dermal administration.

Background: Human exposures to bisphenol A (BPA) are widespread. The current study addresses uncertainties regarding human pharmacokinetics of BPA following dermal exposure.

Objective: To examine the absorption, distribution, metabolism and excretion of BPA in humans following dermal administration.

A Physiologically Based Pharmacokinetic Model for Naphthalene With Inhalation and Skin Routes of Exposure.

Naphthalene, a volatile organic compound present in moth repellants and petroleum-based fuels, has been shown to induce toxicity in mice and rats during chronic inhalation exposures. Although simpler default methods exist for extrapolating toxicity points of departure from animals to humans, using a physiologically based pharmacokinetic (PBPK) model to perform such extrapolations is generally preferred. Confidence in PBPK models increases when they have been validated using both animal and human in vivo pharmacokinetic (PK) data.

Empirical models for anatomical and physiological changes in a human mother and fetus during pregnancy and gestation.

Many parameters treated as constants in traditional physiologically based pharmacokinetic models must be formulated as time-varying quantities when modeling pregnancy and gestation due to the dramatic physiological and anatomical changes that occur during this period. While several collections of empirical models for such parameters have been published, each has shortcomings. We sought to create a repository of empirical models for tissue volumes, blood flow rates, and other quantities that undergo substantial changes in a human mother and her fetus during the time between conception and birth, and to address deficiencies with similar, previously published repositories.

Simulating exposure-related behaviors using agent-based models embedded with needs-based artificial intelligence.

Exposure to a chemical is a critical consideration in the assessment of risk, as it adds real-world context to toxicological information. Descriptions of where and how individuals spend their time are important for characterizing exposures to chemicals in consumer products and in indoor environments. Herein we create an agent-based model (ABM) that simulates longitudinal patterns in human behavior.

A Method for Identifying Prevalent Chemical Combinations in the U.S. Population.

Background: Through the food and water they ingest, the air they breathe, and the consumer products with which they interact at home and at work, humans are exposed to tens of thousands of chemicals, many of which have not been evaluated to determine their potential toxicities. Furthermore, while current chemical testing tends to focus on individual chemicals, the exposures that people actually experience involve mixtures of chemicals. Unfortunately, the number of mixtures that can be formed from the thousands of environmental chemicals is enormous, and testing all of them would be impossible.