A physiologically based pharmacokinetic (PBPK) model describing the kinetics of a commercial mixture α-, β-, and γ-hexabromocyclododecane exposure in mice.

Hexabromocyclododecane (HBCD) is a brominated flame retardant, that is added, but not chemically bonded, to consumer products. HBCD is sold as a commercial-grade HBCD mixture containing three major stereoisomers: alpha (α), beta (β), and gamma (γ), with relative amounts of 12% for α-HBCD, 6% for β-HBCD, and 82% for γ-HBCD. HBCDs are widely measured in the environment and in biological matrices.

A new approach methodology to identify tumorigenic chemicals using short-term exposures and transcript profiling.

Current methods for cancer risk assessment are resource-intensive and not feasible for most of the thousands of untested chemicals. In earlier studies, we developed a new approach methodology (NAM) to identify liver tumorigens using gene expression biomarkers and associated tumorigenic activation levels (TALs) after short-term exposures in rats. The biomarkers are used to predict the six most common rodent liver cancer molecular initiating events.

In Vitro Hepatic Clearance Evaluations of Per- and Polyfluoroalkyl Substances (PFAS) across Multiple Structural Categories.

Toxicokinetic (TK) assays and in vitro-in vivo extrapolation (IVIVE) models are New Approach Methods (NAMs) used to translate in vitro points of departure to exposure estimates required to reach equivalent blood concentrations. Per- and polyfluoroalkyl substances (PFAS) are a large chemical class with wide-ranging industrial applications for which only limited toxicity data are available for human health evaluation. To address the lack of TK data, a pooled primary human hepatocyte suspension model was used with targeted liquid chromatography-mass spectrometry to investigate substrate depletion for 54 PFAS.

A Comparison of In Vitro Points of Departure with Human Blood Levels for Per- and Polyfluoroalkyl Substances (PFAS).

Per- and polyfluoroalkyl substances (PFAS) are widely used, and their fluorinated state contributes to unique uses and stability but also long half-lives in the environment and humans. PFAS have been shown to be toxic, leading to immunosuppression, cancer, and other adverse health outcomes. Only a small fraction of the PFAS in commerce have been evaluated for toxicity using in vivo tests, which leads to a need to prioritize which compounds to examine further.

Dose Response, Dosimetric, and Metabolic Evaluations of Replacement PFAS Perfluoro-(2,5,8-trimethyl-3,6,9-trioxadodecanoic) Acid (HFPO-TeA).

Few studies are available on the environmental and toxicological effects of perfluoroalkyl ether carboxylic acids (PFECAs), such as GenX, which are replacing legacy PFAS in manufacturing processes. To collect initial data on the toxicity and toxicokinetics of a longer-chain PFECA, male and female Sprague Dawley rats were exposed to perfluoro-(2,5,8-trimethyl-3,6,9-trioxadodecanoic) acid (HFPO-TeA) by oral gavage for five days over multiple dose levels (0.3-335.

Development and application of a systematic and quantitative weighting framework to evaluate the quality and relevance of relative potency estimates for dioxin-like compounds (DLCs) for human health risk assessment.

The toxic equivalency factors (TEFs) approach for dioxin-like chemicals (DLCs) is currently based on a qualitative assessment of a heterogeneous data set of relative estimates of potency (REPs) spanning several orders of magnitude with highly variable study quality and relevance. An effort was undertaken to develop a weighting framework to systematically evaluate and quantitatively integrate the quality and relevance for development of more robust TEFs. Six main-study characteristics were identified as most important in characterizing the quality and relevance of an individual REP for human health risk assessment: study type, study model, pharmacokinetics, REP derivation method, REP derivation quality, and endpoint.

A multi-tiered hierarchical Bayesian approach to derive toxic equivalency factors for dioxin-like compounds.

In 2005, the World Health Organization (WHO) re-evaluated Toxic Equivalency factors (TEFs) developed for dioxin-like compounds believed to act through the Ah receptor based on an updated database of relative estimated potency (REP)(REP database). This re-evalution identified the need to develop a consistent approach for dose-response modeling. Further, the WHO Panel discussed the significant heterogeneity of experimental datasets and dataset quality underlying the REPs in the database.

Determinants of gene expression in the human liver: Impact of aging and sex on xenobiotic metabolism.

There is a need to characterize the potential susceptibility of older adults to toxicity from environmental chemical exposures. Liver xenobiotic metabolizing enzymes (XMEs) play important roles in detoxifying and eliminating xenobiotics. We examined global gene expression in the livers of young (21-45 years) and old (69+ years) men and women.

A PBPK model describing the pharmacokinetics of γ-HBCD exposure in mice.

The brominated flame retardant, hexabromocyclododecane (HBCD), is added-but not bound-to consumer products and is eventually found in the environment and human tissues. Commercial-grade HBCD mixtures contain three major stereoisomers, alpha (α), beta (β), and gamma (γ), that are typically at a ratio of 12%:6%:82%, respectively. Although HBCD is widely used, the toxicological effects from its exposure in humans are not clearly understood.

Benchmark Concentrations for Untargeted Metabolomics Versus Transcriptomics for Liver Injury Compounds in In Vitro Liver Models.

Interpretation of untargeted metabolomics data from both in vivo and physiologically relevant in vitro model systems continues to be a significant challenge for toxicology research. Potency-based modeling of toxicological responses has served as a pillar of interpretive context and translation of testing data. In this study, we leverage the resolving power of concentration-response modeling through benchmark concentration (BMC) analysis to interpret untargeted metabolomics data from differentiated cultures of HepaRG cells exposed to a panel of reference compounds and integrate data in a potency-aligned framework with matched transcriptomic data.

Exploration of xenobiotic metabolism within cell lines used for Tox21 chemical screening.

The Tox21 Program has investigated thousands of chemicals with high-throughput screening assays using cell-based assays to link thousands of chemicals to individual molecular targets/pathways. However, these systems have been widely criticized for their suspected lack of 'metabolic competence' to bioactivate or detoxify chemical exposures. In this study, 9 cell line backgrounds used in Tox21 assays (i.

Evaluation of 5-day In Vivo Rat Liver and Kidney With High-throughput Transcriptomics for Estimating Benchmark Doses of Apical Outcomes.

A 5-day in vivo rat model was evaluated as an approach to estimate chemical exposures that may pose minimal risk by comparing benchmark dose (BMD) values for transcriptional changes in the liver and kidney to BMD values for toxicological endpoints from traditional toxicity studies. Eighteen chemicals, most having been tested by the National Toxicology Program in 2-year bioassays, were evaluated. Some of these chemicals are potent hepatotoxicants (eg, DE71, PFOA, and furan) in rodents, some exhibit toxicity but have minimal hepatic effects (eg, acrylamide and α,β-thujone), and some exhibit little overt toxicity (eg, ginseng and milk thistle extract) based on traditional toxicological evaluations.

KRAS-retroviral fusion transcripts and gene amplification in arsenic-transformed, human prostate CAsE-PE cancer cells.

CAsE-PE cells are an arsenic-transformed, human prostate epithelial line containing oncogenic mutations in KRAS compared to immortalized, normal KRAS parent cells, RWPE-1. We previously reported increased copy number of mutated KRAS in CAsE-PE cells, suggesting gene amplification. Here, KRAS flanking genomic and transcriptomic regions were sequenced in CAsE-PE cells for insight into KRAS amplification.

Mixed organic and inorganic tapwater exposures and potential effects in greater Chicago area, USA.

Safe drinking water at the point of use (tapwater, TW) is a public-health priority. TW exposures and potential human-health concerns of 540 organics and 35 inorganics were assessed in 45 Chicago-area United States (US) homes in 2017. No US Environmental Protection Agency (EPA) enforceable Maximum Contaminant Level(s) (MCL) were exceeded in any residential or water treatment plant (WTP) pre-distribution TW sample.

Elevated Arsenic and Lead Concentrations in Natural Healing Clay Applied Topically as a Treatment for Ulcerative Dermatitis in Mice.

Ulcerative dermatitis in laboratory mice remains an ongoing clinical problem and animal welfare issue. Many products have been used to treat dermatitis in mice, with varying success. Recently, the topical administration of healing clays, such as bentonite and green clays, has been explored as a viable, natural treatment.

Toxicokinetics of perfluorohexanoic acid (PFHxA), perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA) in male and female Hsd:Sprague dawley SD rats following intravenous or gavage administration.

Poly- and perfluorinated alkyl substances (PFAS) are environmentally persistent chemicals associated with many adverse health outcomes. The National Toxicology Program evaluated the toxicokinetics (TK) of several PFAS to provide context for toxicologic findings.Plasma TK parameters and tissue (liver, kidney, brain) concentrations are reported for perfluorohexanoic acid (PFHxA), perfluorooctanoic acid (PFOA) or perfluorodecanoic acid (PFDA) after single-dose administration in male and female Hsd:Sprague-Dawley (SD) rats.

Evaluating Sufficient Similarity of Botanical Dietary Supplements: Combining Chemical and In Vitro Biological Data.

Botanical dietary supplements are complex mixtures with numerous potential sources of variation along the supply chain from raw plant material to the market. Approaches for determining sufficient similarity (ie, complex mixture read-across) may be required to extrapolate efficacy or safety data from a tested sample to other products containing the botanical ingredient(s) of interest. In this work, screening-level approaches for generating both chemical and biological-response profiles were used to evaluate the similarity of black cohosh (Actaea racemosa) and Echinacea purpurea samples to well-characterized National Toxicology Program (NTP) test articles.

Methods for evaluating variability in human health dose-response characterization.

The Reference Dose (RfD) and Reference Concentration (RfC) are human health reference values (RfVs) representing exposure concentrations at or below which there is presumed to be little risk of adverse effects in the general human population. The 2009 National Research Council report recommended redefining RfVs as "a risk-specific dose (for example, the dose associated with a 1 in 100,000 risk of a particular end point)." Distributions representing variability in human response to environmental contaminant exposures are critical for deriving risk-specific doses.

Arsenite malignantly transforms human prostate epithelial cells in vitro by gene amplification of mutated KRAS.

Inorganic arsenic is an environmental human carcinogen of several organs including the urinary tract. RWPE-1 cells are immortalized, non-tumorigenic, human prostate epithelia that become malignantly transformed into the CAsE-PE line after continuous in vitro exposure to 5μM arsenite over a period of months. For insight into in vitro arsenite transformation, we performed RNA-seq for differential gene expression and targeted sequencing of KRAS.

Using Tox21 High-Throughput Screening Assays for the Evaluation of Botanical and Dietary Supplements.

Recent nationwide surveys found that natural products, including botanical dietary supplements, are used by ∼18% of adults. In many cases, there is a paucity of toxicological data available for these substances to allow for confident evaluations of product safety. The National Toxicology Program (NTP) has received numerous nominations from the public and federal agencies to study the toxicological effects of botanical dietary supplements.

The Power of Resolution: Contextualized Understanding of Biological Responses to Liver Injury Chemicals Using High-throughput Transcriptomics and Benchmark Concentration Modeling.

Prediction of human response to chemical exposures is a major challenge in both pharmaceutical and toxicological research. Transcriptomics has been a powerful tool to explore chemical-biological interactions, however, limited throughput, high-costs, and complexity of transcriptomic interpretations have yielded numerous studies lacking sufficient experimental context for predictive application. To address these challenges, we have utilized a novel high-throughput transcriptomics (HTT) platform, TempO-Seq, to apply the interpretive power of concentration-response modeling with exposures to 24 reference compounds in both differentiated and non-differentiated human HepaRG cell cultures.

A Chemical Category-Based Prioritization Approach for Selecting 75 Per- and Polyfluoroalkyl Substances (PFAS) for Tiered Toxicity and Toxicokinetic Testing.

Per- and polyfluoroalkyl substances (PFASs) are a group of fluorinated substances of interest to researchers, regulators, and the public due to their widespread presence in the environment. A few PFASs have comparatively extensive amounts of human epidemiological, exposure, and experimental animal toxicity data (e.g.

Mutational analysis of pentabrominated diphenyl-induced hepatocellular tumors in rats and mice, tissue levels of PBDE congeners in rats and mice, and AhR genotyping of Wistar Han rats.

This article describes data related to the research article entitled "Carcinogenic activity of pentabrominated diphenyl ether mixture (DE-71) in rats and mice" (Dunnick et al., 2018). PBDE-induced hepatocellular tumors harbored and mutations and the methods for these studies are provided.

Evaluation and Optimization of Pharmacokinetic Models for to Extrapolation of Estrogenic Activity for Environmental Chemicals.

Background: To effectively incorporate data into regulatory use, confidence must be established in the quantitative extrapolation of activity to relevant end points in animals or humans.

Objective: Our goal was to evaluate and optimize to extrapolation (IVIVE) approaches using in vitro estrogen receptor (ER) activity to predict estrogenic effects measured in rodent uterotrophic studies.

Methods: We evaluated three pharmacokinetic (PK) models with varying complexities to extrapolate to dosimetry for a group of 29 ER agonists, using data from validated [U.