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. Here, we demonstrate a prioritization approach that combines human biomonitoring data (blood concentrations) with bioactivity data (concentrations at which bioactivity is observed in vitro) for 31 PFAS. The in vitro data are taken from a battery of cell-based assays, mostly run on human cells. The result is a Bioactive Concentration to Blood Concentration Ratio (BCBCR), similar to a margin of exposure (MoE). Chemicals with low BCBCR values could then be prioritized for further risk assessment. Using this method, two of the PFAS, PFOA (Perfluorooctanoic Acid) and PFOS (Perfluorooctane Sulfonic Acid), have BCBCR values < 1 for some populations. An additional 9 PFAS have BCBCR values < 100 for some populations. This study shows a promising approach to screening level risk assessments of compounds such as PFAS that are long-lived in humans and other species.

Aggregating data for computational toxicology applications: The U.S. Environmental Protection Agency (EPA) Aggregated Computational Toxicology Resource (ACToR) System.

Computational toxicology combines data from high-throughput test methods, chemical structure analyses and other biological domains (e.g., genes, proteins, cells, tissues) with the goals of predicting and understanding the underlying mechanistic causes of chemical toxicity and for predicting toxicity of new chemicals and products. A key feature of such approaches is their reliance on knowledge extracted from large collections of data and data sets in computable formats. The U.S. Environmental Protection Agency (EPA) has developed a large data resource called ACToR (Aggregated Computational Toxicology Resource) to support these data-intensive efforts. ACToR comprises four main repositories: core ACToR (chemical identifiers and structures, and summary data on hazard, exposure, use, and other domains), ToxRefDB (Toxicity Reference Database, a compilation of detailed in vivo toxicity data from guideline studies), ExpoCastDB (detailed human exposure data from observational studies of selected chemicals), and ToxCastDB (data from high-throughput screening programs, including links to underlying biological information related to genes and pathways). The EPA DSSTox (Distributed Structure-Searchable Toxicity) program provides expert-reviewed chemical structures and associated information for these and other high-interest public inventories. Overall, the ACToR system contains information on about 400,000 chemicals from 1100 different sources. The entire system is built using open source tools and is freely available to download. This review describes the organization of the data repository and provides selected examples of use cases.

Editor's Highlight: Analysis of the Effects of Cell Stress and Cytotoxicity on In Vitro Assay Activity Across a Diverse Chemical and Assay Space.

Chemical toxicity can arise from disruption of specific biomolecular functions or through more generalized cell stress and cytotoxicity-mediated processes. Here, responses of 1060 chemicals including pharmaceuticals, natural products, pesticidals, consumer, and industrial chemicals across a battery of 815 in vitro assay endpoints from 7 high-throughput assay technology platforms were analyzed in order to distinguish between these types of activities. Both cell-based and cell-free assays showed a rapid increase in the frequency of responses at concentrations where cell stress/cytotoxicity responses were observed in cell-based assays. Chemicals that were positive on at least 2 viability/cytotoxicity assays within the concentration range tested (typically up to 100 µM) activated a median of 12% of assay endpoints whereas those that were not cytotoxic in this concentration range activated 1.3% of the assays endpoints. The results suggest that activity can be broadly divided into: (1) specific biomolecular interactions against one or more targets (eg, receptors or enzymes) at concentrations below which overt cytotoxicity-associated activity is observed; and (2) activity associated with cell stress or cytotoxicity, which may result from triggering specific cell stress pathways, chemical reactivity, physico-chemical disruption of proteins or membranes, or broad low-affinity non-covalent interactions. Chemicals showing a greater number of specific biomolecular interactions are generally designed to be bioactive (pharmaceuticals or pesticidal active ingredients), whereas intentional food-use chemicals tended to show the fewest specific interactions. The analyses presented here provide context for use of these data in ongoing studies to predict in vivo toxicity from chemicals lacking extensive hazard assessment.

Exploring consumer exposure pathways and patterns of use for chemicals in the environment.

Humans are exposed to thousands of chemicals in the workplace, home, and via air, water, food, and soil. A major challenge in estimating chemical exposures is to understand which chemicals are present in these media and microenvironments. Here we describe the Chemical/Product Categories Database (CPCat), a new, publically available (http://actor.epa.gov/cpcat) database of information on chemicals mapped to "use categories" describing the usage or function of the chemical. CPCat was created by combining multiple and diverse sources of data on consumer- and industrial-process based chemical uses from regulatory agencies, manufacturers, and retailers in various countries. The database uses a controlled vocabulary of 833 terms and a novel nomenclature to capture and streamline descriptors of chemical use for 43,596 chemicals from the various sources. Examples of potential applications of CPCat are provided, including identifying chemicals to which children may be exposed and to support prioritization of chemicals for toxicity screening. CPCat is expected to be a valuable resource for regulators, risk assessors, and exposure scientists to identify potential sources of human exposures and exposure pathways, particularly for use in high-throughput chemical exposure assessment.

Assessment of data quality for the NHEXAS--Part II: Minnesota children's pesticide exposure study (MNCPES).

The Minnesota Children's Pesticide Exposure Study (MNCPES) of the National Human Exposure Assessment Survey (NHEXAS) was conducted in Minnesota to evaluate children's pesticide exposure. This study complements and extends the populations and chemicals included in the NHEXAS Region V study. One of the goals of the study was to test protocols for acquiring exposure measurements and developing databases for use in exposure models and assessments. Analysis of the data quality is one element in assessing the performance of the collection and analysis protocols used in this study. Data quality information must also be available to investigators to guide analysis of the study data. During the planning phase of MNCPES, quality assurance (QA) goals were established for precision, accuracy, and quantification limits. The data quality was assessed against these goals. The assessment is complex. First, data are not available for all analytes and media sampled. In addition, several laboratories were responsible for the analysis of the collected samples. Each laboratory provided data according to their standard operating procedures (SOPs) and protocols. Detection limits were authenticated for each analyte in each sample type. The approach used to calculate detection limits varied across the different analytical methods. The analytical methods for pesticides in air, food, hand rinses, dust wipe and urine were sufficiently sensitive and met the QA goals, with very few exceptions. This was also true for polynuclear aromatic hydrocarbons (PAHs) in air and food. The analytical methods for drinking water and beverages had very low detection limits; however, there were very little measurable data for these samples. The collection and analysis methods for pesticides in surface press samples and soil, and for PAHs in dust wipes were not sufficiently sensitive. Accuracy was assessed primarily as recovery from field controls. The results were good for pesticides and PAHs in air (75-125% recovery). Recovery was lower (<75%) for pesticides in drinking water and beverages. The recovery of pesticides from hand rinses met QA goals (75-100%), but surface press samples showed lower recovery (50-70%). Analysis by gas chromatography-mass spectrometry (GC-MS) did not confirm the presence of atrazine and other pesticides in hand rinse and surface press samples that had been detected by GC-ECD, but instead GC-MS confirmed background interferences. Assessment of the precision of sample collection and analysis is based on the percent relative standard deviation (%RSD) between the results for duplicate samples. Data are available only for pesticides and PAHs in air. Precision was good (<20% RSD) for analytes with measurable data. There were a few analytes with %RSD >20%, but the number of data pairs was very small in these cases. Precision for instrumental analysis of food sample extracts was excellent, with the median %RSD < 20 for all measurable pesticides. The median %RSD for the analysis of replicate aliquots of food from the same sample composite was considerably higher, indicating the potential for inhomogeneity of food homogenates.

The exposure data landscape for manufactured chemicals.

The U.S. Environmental Protection Agency is developing chemical screening and prioritization programs to evaluate environmental chemicals for potential risk to human health in a rapid and efficient manner. As part of these efforts, it is important to catalog available information on chemical toxicity and exposure from widely dispersed sources. The main objective of this analysis is to define important aspects of the exposure space and to catalog the available exposure information for chemicals being considered for analysis as part of the U.S. EPA ToxCast™ screening and prioritization program. Publicly available exposure data have been extracted into ACToR (Aggregated Computational Toxicology Resource), which combines information for hundreds of thousands of chemicals from >600 public sources. We use data from ACToR to assess the exposure data landscape for environmental chemicals. Of the roughly 100,000 chemicals that have at least limited toxicity information available, less than one-fifth also have exposure information - and for most of these the information is of limited utility (e.g., production volume). Readily accessible data on concentrations in exposure-related media are only available for a much smaller fraction. Among these, the largest number of chemicals is measured in water with over 1150 unique compounds, followed by 788 substances measured in soil, and 670 in air. These small numbers clearly reflect a focus of resources on those substances previously identified as possibly posing a hazard to human health. Exposure to a much broader number of chemicals will need to be measured in order to fully realize the envisioned goal of using exposure information to guide toxicity testing.

The Appalachian Tri-State Node Experiences with the National Institute on Drug Abuse Clinical Trials Network.

The National Institute on Drug Abuse (NIDA)-sponsored Clinical Trial Network (CTN) recently celebrated 10 years of conducting "real world" research into the treatment of addiction. This article reviews the history and results of the most recent CTN studies and describes the experiences of one of the 13 participating research affiliates, the Appalachian Tri-State (ATS) Node. We discuss our "bidirectional" collaboration with multiple community treatment programs (CTPs) on research and dissemination activities and include their experiences as a member of our ATS Node.Results of CTN clinical trials have found unexpectedly that treatment as usual (TAU) is often almost as good as evidence-based interventions such as Motivational Interviewing (MI), possibly due to the difficulty in implementing evidence-based practices most effectively among divergent treatment sites and heterogeneous clinical populations. Some expected findings from the reviewed research are that severity of addiction and comorbidity moderate treatment outcomes and must be accounted for in future CTN-sponsored studies. Notwithstanding these results, much has been learned and recommendations are suggested for changes in CTN research designs that will address methodological limitations and increase treatment effectiveness in future CTN studies.