Expanded Systematic Evidence Map for Hundreds of Per- and Polyfluoroalkyl Substances (PFAS) and Comprehensive PFAS Human Health Dashboard.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) encompass a class of chemically and structurally diverse compounds that are extensively used in industry and detected in the environment. The US Environmental Protection Agency (US EPA) 2021 PFAS Strategic Roadmap describes national research plans to address the challenge of PFAS. OBJECTIVES: Systematic Evidence Map (SEM) methods were used to survey and summarize available epidemiological and mammalian bioassay evidence that could inform human health hazard identification for a set of 345 PFAS that were identified by the US EPA's Center for Computational Toxicology and Exposure (CCTE) for in vitro toxicity and toxicokinetic assay testing and through interagency discussions on PFAS of interest. This work builds from the 2022 evidence map that collated evidence on a separate set of ∼150 PFAS. Like our previous work, this SEM does not include PFAS that are the subject of ongoing or completed assessments at the US EPA. METHODS: SEM methods were used to search, screen, and inventory mammalian bioassay and epidemiological literature from peer-reviewed and gray literature sources using manual review and machine-learning software. For each included study, study design details and health end points examined were summarized in interactive web-based literature inventories. Some included studies also underwent study evaluation and detailed extraction of health end point data. All underlying data is publicly available online as interactive visuals with downloadable metadata. RESULTS: More than 13,000 studies were identified from scientific databases. Screening processes identified 121 mammalian bioassay and 111 epidemiological studies that met screening criteria. Epidemiological evidence (available for 12 PFAS) mostly assessed the reproductive, endocrine, developmental, metabolic, cardiovascular, and immune systems. Mammalian bioassay evidence (available for 30 PFAS) commonly assessed effects in the reproductive, whole-body, nervous, and hepatic systems. Overall, 41 PFAS had evidence across mammalian bioassay and epidemiology data streams (roughly 11% of searched chemicals). DISCUSSION: No epidemiological and/or mammalian bioassay evidence were identified for most of the PFAS included in our search. Results from this SEM, our 2022 SEM on ∼150 PFAS, and other PFAS assessment products from the US EPA are compiled into a comprehensive PFAS dashboard that provides researchers and regulators an overview of the current PFAS human health landscape including data gaps and can serve as a scoping tool to facilitate prioritization of PFAS-related research and/or risk assessment activities. https://doi.org/10.1289/EHP13423.

Systematic evidence map (SEM) template: Report format and methods used for the US EPA Integrated Risk Information System (IRIS) program, Provisional Peer Reviewed Toxicity Value (PPRTV) program, and other "fit for purpose" literature-based human health analyses.

BACKGROUND: Systematic evidence maps (SEMs) are gaining visibility in environmental health for their utility to serve as problem formulation tools and assist in decision-making, especially for priority setting. SEMs are now routinely prepared as part of the assessment development process for the US Environmental Protection Agency (EPA) Integrated Risk Information System (IRIS) and Provisional Peer Reviewed Toxicity Value (PPRTV) assessments. SEMs can also be prepared to explore the available literature for an individual chemical or groups of chemicals of emerging interest. OBJECTIVES: This document describes the typical methods used to produce SEMs for the IRIS and PPRTV Programs, as well as "fit for purpose" applications using a variety of examples drawn from existing analyses. It is intended to serve as an example base template that can be adapted as needed for the specific SEM. The presented methods include workflows intended to facilitate rapid production. The Populations, Exposures, Comparators and Outcomes (PECO) criteria are typically kept broad to identify mammalian animal bioassay and epidemiological studies that could be informative for human hazard identification. In addition, a variety of supplemental content is tracked, e.g., studies presenting information on in vitro model systems, non-mammalian model systems, exposure-level-only studies in humans, pharmacokinetic models, and absorption, distribution, metabolism, and excretion (ADME). The availability of New Approach Methods (NAMs) evidence is also tracked (e.g., high throughput, transcriptomic, in silico, etc.). Genotoxicity studies may be considered as PECO relevant or supplemental material, depending on the topic and context of the review. Standard systematic review practices (e.g., two independent reviewers per record) and specialized software applications are used to search and screen the literature and may include the use of machine learning software. Mammalian bioassay and epidemiological studies that meet the PECO criteria after full-text review are briefly summarized using structured web-based extraction forms with respect to study design and health system(s) assessed. Extracted data is available in interactive visual formats and can be downloaded in open access formats. Methods for conducting study evaluation are also presented which is conducted on a case-by-case basis, depending on the usage of the SEM.

Use of systematic evidence maps within the US environmental protection agency (EPA) integrated risk information system (IRIS) program: Advancements to date and looking ahead.

Systematic evidence maps (SEMs) are increasingly used to inform decision-making and risk management priority-setting and to serve as problem formulation tools to refine the focus of questions that get addressed in full systematic reviews. Within the U.S. Environmental Protection Agency (EPA) Office of Research and Development (ORD) Integrated Risk Information System (IRIS), SEMs have been used to inform data gaps, determine the need for updated assessments, inform assessment priorities, and inform development of study evaluation considerations, among other uses. Increased utilization of SEMs across the environmental health field has the potential to increase transparency and efficiency for data gathering, problem formulation, read-across, and evidence surveillance. Use of the SEM templates published in the companion text (Thayer et al.) can promote harmonization in the environmental health community and create more opportunities for sharing extracted content.

Systematic Evidence Map for Over One Hundred and Fifty Per- and Polyfluoroalkyl Substances (PFAS).

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are a large class of synthetic (man-made) chemicals widely used in consumer products and industrial processes. Thousands of distinct PFAS exist in commerce. The 2019 U.S. Environmental Protection Agency (U.S. EPA) Per- and Polyfluoroalkyl Substances (PFAS) Action Plan outlines a multiprogram national research plan to address the challenge of PFAS. One component of this strategy involves the use of systematic evidence map (SEM) approaches to characterize the evidence base for hundreds of PFAS. OBJECTIVE: SEM methods were used to summarize available epidemiological and animal bioassay evidence for a set of ∼150 PFAS that were prioritized in 2019 by the U.S. EPA's Center for Computational Toxicology and Exposure (CCTE) for in vitro toxicity and toxicokinetic assay testing. METHODS: Systematic review methods were used to identify and screen literature using manual review and machine-learning software. The Populations, Exposures, Comparators, and Outcomes (PECO) criteria were kept broad to identify mammalian animal bioassay and epidemiological studies that could inform human hazard identification. A variety of supplemental content was also tracked, including information on in vitro model systems; exposure measurement-only studies in humans; and absorption, distribution, metabolism, and excretion (ADME). Animal bioassay and epidemiology studies meeting PECO criteria were summarized with respect to study design, and health system(s) were assessed. Because animal bioassay studies with ≥21-d exposure duration (or reproductive/developmental study design) were most useful to CCTE analyses, these studies underwent study evaluation and detailed data extraction. All data extraction is publicly available online as interactive visuals with downloadable metadata. RESULTS: More than 40,000 studies were identified from scientific databases. Screening processes identified 44 animal and 148 epidemiology studies from the peer-reviewed literature and 95 animal and 50 epidemiology studies from gray literature that met PECO criteria. Epidemiological evidence (available for 15 PFAS) mostly assessed the reproductive, endocrine, developmental, metabolic, cardiovascular, and immune systems. Animal evidence (available for 40 PFAS) commonly assessed effects in the reproductive, developmental, urinary, immunological, and hepatic systems. Overall, 45 PFAS had evidence across animal and epidemiology data streams. DISCUSSION: Many of the ∼150 PFAS were data poor. Epidemiological and animal evidence were lacking for most of the PFAS included in our search. By disseminating this information, we hope to facilitate additional assessment work by providing the initial scoping literature survey and identifying key research needs. Future research on data-poor PFAS will help support a more complete understanding of the potential health effects from PFAS exposures. https://doi.org/10.1289/EHP10343.

Evaluating reliability and risk of bias of in vivo animal data for risk assessment of chemicals - Exploring the use of the SciRAP tool in a systematic review context.

Within the field of health risk assessment, it is essential that evaluations of reliability or validity of toxicity data are conducted with structure and transparency. To this end, different tools for evaluating toxicity studies have been developed by different groups and organizations, for different specific purposes. The Science in Risk Assessment and Policy (SciRAP) tool was developed for use in the regulatory health risk assessment of chemicals and to promote structured and transparent evaluation of study reliability within European regulatory frameworks. As such, the SciRAP tool is not specifically tailored for use in a systematic review context. However, in light of the current movement towards applying systematic review in the field of environmental health and chemical assessments and European chemicals regulation, we were interested in exploring how SciRAP could be applied in such a context. To achieve this, the scope of the SciRAP tool was first compared to two tools developed based on systematic review principles at the US Environmental Protection Agency's IRIS program and the National Toxicology Program's Office of Health Assessment and Translation (OHAT). Next, the SciRAP and IRIS tools were both applied in a case study to evaluate the same nine in vivo animal studies and the resulting evaluations were compared. The SciRAP tool was found to address the majority of the elements included for study evaluation in the OHAT and IRIS tools. In the case study, no major differences were found in the conclusions drawn when using SciRAP or IRIS tools. However, future developments to bring the SciRAP tool more in line with systematic review principles were identified and are discussed. Overall, this work illustrates the advantages of applying structured and pre-defined methods for study evaluation and provides a unique case study comparing the impact of using different tools for evaluating animal toxicity studies.

A novel study evaluation strategy in the systematic review of animal toxicology studies for human health assessments of environmental chemicals.

A key aspect of the systematic review process is study evaluation to understand the strengths and weaknesses of individual studies included in the review. The present manuscript describes the process currently being used by the Environmental Protection Agency's (EPA) Integrated Risk Information System (IRIS) Program to evaluate animal toxicity studies, illustrated by application to the recent systematic reviews of two phthalates: diisobutyl phthalate (DIBP) and diethyl phthalate (DEP). The IRIS Program uses a domain-based approach that was developed after careful consideration of tools used by others to evaluate experimental animal studies in toxicology and pre-clinical research. Standard practice is to have studies evaluated by at least two independent reviewers for aspects related to reporting quality, risk of bias/internal validity (e.g., randomization, blinding at outcome assessment, methods used to expose animals and assess outcomes, etc.), and sensitivity to identify factors that may limit the ability of a study to detect a true effect. To promote consistency across raters, prompting considerations and example responses are provided to reviewers, and a pilot phase is conducted. The evaluation process is performed separately for each outcome reported in a study, as the utility of a study may vary for different outcomes. Input from subject matter experts is used to identify chemical- and outcome-specific considerations (e.g., lifestage of exposure and outcome assessment when considering reproductive effects) to guide judgments within particular evaluation domains. For each evaluation domain, reviewers reach a consensus on a rating of Good, Adequate, Deficient, or Critically Deficient. These individual domain ratings are then used to determine the overall confidence in the study (High Confidence, Medium Confidence, Low Confidence, or Deficient). Study evaluation results, including the justifications for reviewer judgements, are documented and made publicly available in EPA's version of Health Assessment Workspace Collaborative (HAWC), a free and open source web-based software application. (The views expressed are those of the authors and do not necessarily represent the views or policies of the US EPA).

Potential frameworks to support evaluation of mechanistic data for developmental neurotoxicity outcomes: A symposium report.

A key challenge in systematically incorporating mechanistic data into human health assessments is that, compared to studies of apical health endpoints, these data are both more abundant (mechanistic studies routinely outnumber other studies by several orders of magnitude) and more heterogeneous (e.g. different species, test system, tissue, cell type, exposure paradigm, or specific assays performed). A structured decision-making process for organizing, integrating, and weighing mechanistic DNT data for use in human health risk assessments will improve the consistency and efficiency of such evaluations. At the Developmental Neurotoxicology Society (DNTS) 2016 annual meeting, a symposium was held to address the application of existing organizing principles and frameworks for evaluation of mechanistic data relevant to interpreting neurotoxicology data. Speakers identified considerations with potential to advance the use of mechanistic DNT data in risk assessment, including considering the context of each exposure, since epigenetics, tissue type, sex, stress, nutrition and other factors can modify toxicity responses in organisms. It was also suggested that, because behavior is a manifestation of complex nervous system function, the presence and absence of behavioral change itself could be used to organize the interpretation of multiple complex simultaneous mechanistic changes. Several challenges were identified with frameworks and their implementation, and ongoing research to develop these approaches represents an early step toward full evaluation of mechanistic DNT data for assessments.

A systematic review of the health effects associated with the inhalation of particle-filtered and whole diesel exhaust.

Background: Diesel exhaust is a complex mixture comprised of gases and particulate matter and is a contributor to ambient air pollution. To reduce health risks, recent changes in diesel engine technology have significantly altered the composition of diesel exhaust, primarily by lowering emissions of particulate matter. However, animal toxicological studies continue to report health effects following exposure to diesel exhaust from engines employing particulate filters. The cause of these effects remains unclear.Objective and methods: To gain an understanding of the role of both particle-filtered and whole diesel exhaust on specific health outcomes, we conducted a systematic review in which we examined animal toxicological and controlled human exposure studies that included a comparison between inhalation of particle-filtered and whole diesel exhaust on any health endpoint.Results: We identified 26 studies that met both the inclusion and study evaluation criteria. For most health outcomes, the particle filtration methods employed in the included studies did not appreciably attenuate the health effects associated with exposure to whole diesel exhaust. There were also several health endpoints for which significant effects were associated with exposure to either particle-filtered or whole diesel exhaust, but not to both.Conclusions: Overall, the results from this systematic review demonstrate that exposure to different components in diesel exhaust can have distinct and independent health effects. Thus, to better inform human health risk assessments, future studies aimed at elucidating the health effects from diesel exhaust should include exposure to both particle-filtered and whole diesel exhaust.

Hazards of diisobutyl phthalate (DIBP) exposure: A systematic review of animal toxicology studies.

BACKGROUND: Biomonitoring studies indicate a trend towards increased human exposure to diisobutyl phthalate (DIBP), a replacement for dibutyl phthalate (DBP). Recent reviews have found DIBP to be a male reproductive toxicant, but have not evaluated other hazards of DIBP exposure. OBJECTIVE: To inform chemical risk assessment, we performed a systematic review to identify and characterize outcomes within six broad hazard categories (male reproductive, female reproductive, developmental, liver, kidney, and cancer) following exposure of nonhuman mammalian animals to DIBP or the primary metabolite, monoisobutyl phthalate (MIBP). METHODS: A literature search was conducted in four online scientific databases [PubMed, Web of Science, Toxline, and Toxic Substances Control Act Test Submissions 2.0 (TSCATS2)], and augmented by review of regulatory sources as well as forward and backward searches. Studies were identified for inclusion based on defined PECO (Population, Exposure, Comparator, Outcome) criteria. Studies were evaluated using criteria defined a priori for reporting quality, risk of bias, and sensitivity using a domain-based approach. Evidence was synthesized by outcome and life stage of exposure, and strength of evidence was summarized into categories of robust, moderate, slight, indeterminate, or compelling evidence of no effect, using a structured framework. RESULTS: Nineteen toxicological studies in rats or mice met the inclusion criteria. There was robust evidence that DIBP causes male reproductive toxicity. Male rats and mice exposed to DIBP during gestation had decreased testosterone and adverse effects on sperm or testicular histology, with additional phthalate syndrome effects observed in male rats. There was also evidence of androgen-dependent and -independent male reproductive effects in rats and mice following peripubertal or young adult exposure to DIBP or MIBP, but confidence was reduced because of concerns over risk of bias and sensitivity in the available studies. There was also robust evidence that DIBP causes developmental toxicity; specifically, increased post-implantation loss and decreased pre- and postnatal growth. For other hazards, evidence was limited by the small number of studies, experimental designs that were suboptimal for evaluating outcomes, and study evaluation concerns such as incomplete reporting of methods and results. There was slight evidence for female reproductive toxicity and effects on liver, and indeterminate evidence for effects on kidney and cancer. CONCLUSION: Results support DIBP as a children's health concern and indicate that male reproductive and developmental toxicities are hazards of DIBP exposure, with some evidence for female reproductive and liver toxicity. Data gaps include the need for more studies on male reproductive effects following postnatal and adult exposure, and studies to characterize potential hormonal mechanisms in females.

Developmental toxicity of the PBDE metabolite 6-OH-BDE-47 in zebrafish and the potential role of thyroid receptor ß.

6-hydroxy-2,2',4,4'-tetrabromodiphenyl ether (6-OH-BDE-47) is both a polybrominated diphenyl ether (PBDE) flame retardant metabolite and a marine natural product. It has been identified both as a neurotoxicant in cell-based studies and as a developmental toxicant in zebrafish. However, hydroxylated PBDE metabolites are also considered thyroid hormone disruptors due to their structural similarity to endogenous thyroid hormones. The purpose of this study was to evaluate the effects of 6-OH-BDE-47 on a developmental pathway regulated by thyroid hormones in zebrafish. Morphological measurements of development (head trunk angle, otic vesicle length, and eye pigmentation) were recorded in embryos at 30h post fertilization (hpf) and detailed craniofacial morphology was examined in 4 day old larvae using cartilage staining. Exposure to 6-OH-BDE-47 resulted in severe developmental delays. A 100nM concentration resulted in a 26% decrease in head trunk angle, a 54% increase in otic vesicle length, and a 42% decrease in eye pigmentation. Similarly, altered developmental morphology was observed following thyroid receptor ß morpholino knockdown, exposure to the thyroid hormone triiodothyronine (T3) or to thyroid disrupting chemicals (TDC; iopanoic acid and propylthiouracil). The threshold for lower jaw deformities and craniofacial cartilage malformations was at doses greater than 50nM. Of interest, these developmental delays and effects were rescued by microinjection of TRß mRNA during the 1-2 cell stage. These data indicate that OH-BDEs can adversely affect early life development of zebrafish and suggest they may be impacting thyroid hormone regulation in vivo through downregulation of the thyroid hormone receptor.

Exposures, mechanisms, and impacts of endocrine-active flame retardants.

This review summarizes the endocrine and neurodevelopmental effects of two current-use additive flame retardants (FRs), tris (1,3-dichloro-isopropyl) phosphate (TDCPP) and Firemaster(®) 550 (FM 550), and the recently phased-out polybrominated diphenyl ethers (PBDEs), all of which were historically or are currently used in polyurethane foam applications. Use of these chemicals in consumer products has led to widespread exposure in indoor environments. PBDEs and their hydroxylated metabolites appear to primarily target the thyroid system, likely due to their structural similarity to endogenous thyroid hormones. In contrast, much less is known about the toxicity of TDCPP and FM 550. However, recent in vitro and in vivo studies suggest that both should be considered endocrine disruptors as studies have linked TDCPP exposure with changes in circulating hormone levels, and FM 550 exposure with changes in adipogenic and osteogenic pathways.

Developmental exposure to organophosphate flame retardants elicits overt toxicity and alters behavior in early life stage zebrafish (Danio rerio).

Organophosphate flame retardants (OPFRs) are common replacements for the phased-out polybrominated diphenyl ethers (PBDEs) and have been detected at high concentrations in environmental samples. OPFRs are structurally similar to organophosphate pesticides and may adversely affect the developing nervous system. This study evaluated the overt toxicity, uptake, and neurobehavioral effects of tris (1,3-dichloro-2-propyl) phosphate (TDCPP), tris (2-chloroethyl) phosphate (TCEP), tris (1-chloro-2-propyl) phosphate (TCPP), and tris (2,3-dibromopropyl) phosphate (TDBPP) in early life stage zebrafish. Chlorpyrifos was used as a positive control. For overt toxicity and neurobehavioral assessments, zebrafish were exposed from 0 to 5 days postfertilization (dpf). Hatching, death, or malformations were evaluated daily. Teratogenic effects were scored by visual examination on 6 dpf. To evaluate uptake and metabolism, zebrafish were exposed to 1 µM of each organophosphate (OP) flame retardant and collected on 1 and 5 dpf to monitor accumulation. Larval swimming activity was measured in 6 dpf larvae to evaluate neurobehavioral effects of exposures below the acute toxicity threshold. TDBPP elicited the greatest toxicity at >1 µM. TDCPP and chlorpyrifos were overtly toxic at concentrations ≥10 µM, TCEP, and TCPP were not overtly toxic at the doses tested. Tissue concentrations increased with increasing hydrophobicity of the parent chemical after 24 h exposures. TDCPP and TDBPP and their respective metabolites were detected in embryos on 5 dpf. For all chemicals tested, developmental exposures that were not overtly toxic significantly altered larval swimming activity. These data indicate that OPFRs adversely affect development of early life stage zebrafish.

Critical duration of exposure for developmental chlorpyrifos-induced neurobehavioral toxicity.

Developmental exposure of rats to the pesticide chlorpyrifos (CPF) causes persistent neurobehavioral impairment. In a parallel series of studies with zebrafish, we have also found persisting behavioral dysfunction after developmental CPF exposure. We have developed a battery of measures of zebrafish behavior, which are reliable and sensitive to toxicant-induced damage. This study determined the critical duration of developmental CPF exposure for causing persisting neurobehavioral effects. Tests of sensorimotor response (tap startle response and habituation), stress response (novel tank diving test) and learning (3-chamber tank spatial discrimination) were conducted with adult zebrafish after early developmental CPF exposure. The CPF exposure level was 100 ng/ml with durations of 0-1, 0-2, 0-3, 0-4 and 0-5 days after fertilization. Developmental CPF exposure had persisting behavioral effects in zebrafish tested as adults. In the tactile startle test, CPF exposed fish showed decreased habituation to startle and a trend toward increased overall startle response. In the novel tank exploration test, exposed fish showed decreased escape diving response and increased swimming activity. In the 3-chamber learning test, the 0-5 day CPF exposure group had a significantly lower learning rate. There was evidence for persisting declines in brain dopamine and norepinepherine levels after developmental CPF exposure. In all of the measures the clearest persistent effects were seen in fish exposed for the full duration of five days after fertilization. In a follow-up experiment there were some indications for persisting behavioral effects after exposure during only the later phase of this developmental window. This study demonstrated the selective long-term neurobehavioral alterations caused by exposure to CPF in zebrafish. The zebrafish model can facilitate the determination of the molecular mechanisms underlying long-term neurobehavioral impairment after developmental toxicant exposure.

Is the PentaBDE replacement, tris (1,3-dichloro-2-propyl) phosphate (TDCPP), a developmental neurotoxicant? Studies in PC12 cells.

Organophosphate flame retardants (OPFRs) are used as replacements for the commercial PentaBDE mixture that was phased out in 2004. OPFRs are ubiquitous in the environment and detected at high concentrations in residential dust, suggesting widespread human exposure. OPFRs are structurally similar to neurotoxic organophosphate pesticides, raising concerns about exposure and toxicity to humans. This study evaluated the neurotoxicity of tris (1,3-dichloro-2-propyl) phosphate (TDCPP) compared to the organophosphate pesticide, chlorpyrifos (CPF), a known developmental neurotoxicant. We also tested the neurotoxicity of three structurally similar OPFRs, tris (2-chloroethyl) phosphate (TCEP), tris (1-chloropropyl) phosphate (TCPP), and tris (2,3-dibromopropyl) phosphate (TDBPP), and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), a major component of PentaBDE. Using undifferentiated and differentiating PC12 cells, changes in DNA synthesis, oxidative stress, differentiation into dopaminergic or cholinergic neurophenotypes, cell number, cell growth and neurite growth were assessed. TDCPP displayed concentration-dependent neurotoxicity, often with effects equivalent to or greater than equimolar concentrations of CPF. TDCPP inhibited DNA synthesis, and all OPFRs decreased cell number and altered neurodifferentiation. Although TDCPP elevated oxidative stress, there was no adverse effect on cell viability or growth. TDCPP and TDBPP promoted differentiation into both neuronal phenotypes, while TCEP and TCPP promoted only the cholinergic phenotype. BDE-47 had no effect on cell number, cell growth or neurite growth. Our results demonstrate that different OPFRs show divergent effects on neurodifferentiation, suggesting the participation of multiple mechanisms of toxicity. Additionally, these data suggest that OPFRs may affect neurodevelopment with similar or greater potency compared to known and suspected neurotoxicants.

A novel hydrogel-coated polyester mesh prevents postsurgical adhesions in a rat model.

BACKGROUND: The specific aim of this study was to determine the whether a novel, hydrogel-coated polyester mesh (Scout) can be used to reduce the incidence and severity of adhesion formation in vivo. METHODS: An established rat model of post-surgical adhesion formation was used in which adhesions are generated through surgical trauma to the surfaces of the cecum and the adjacent abdominal wall. Thirty-seven rats were randomly allocated either to a control group (no intervention; n=14 rats) or to one of two treatment groups in which the abraded surfaces were separated with either the Scout material (n=11 rats) or an FDA-approved form of expanded polytetrafluorethylene (PTFE) (PRECLUDE Vessel Guard; n=12 rats). Animals were euthanized 7 d after surgery and gross necropsy examinations were performed. Mechanical testing was used to measure the strength of any adhesions that were identified, and histology was used to characterize within the adhesion tissue and on the surface(s) of the barrier materials. RESULTS: Five animals were excluded because of surgical failure (1 control; 2 PRECLUDE Vessel Guard; 2 Scout). Adhesions were seen in 10 of 13 control animals (77%). There were no adhesions in any of the animals treated with either PRECLUDE Vessel Guard or Scout material. Histology demonstrated mild cellular adhesion to both the PRECLUDE Vessel Guard and the Scout material. Although there was a sub-acute to chronic inflammatory response to the surgical trauma, there was no evidence of delamination, shearing, or degradation of either the Scout material or PRECLUDE Vessel Guard. CONCLUSIONS: The hydrogel-coated Scout material was as effective as the approved predicate material in this model. Both materials were well tolerated. Further testing of the Scout material is now warranted.

The relationship between PROP and ethanol preferences: an evaluation of 4 inbred mouse strains.

Ethanol's taste attributes undoubtedly contribute to the development of drug preference. Ethanol's taste is both sweet and bitter. Taster status for bitter 6-n-propylthiouracil (PROP) has been proposed as a genetic marker for alcoholism; however, human results are conflicting. We collected preference scores for both tastants in 4 mouse strains selected on the basis of previously reported taste preference, with the generally accepted idea that inbred mice show minimal within-strain variation. Eighty-eight male mice (22 per strain) participated. The strains were as follows: C57BL/6J, ethanol preferring; BALB/cJ, ethanol avoiding; SWR/J, PROP avoiding; and C3HeB/FeJ, PROP neutral. Using a brief-access (1-min trials) 2-bottle preference test, we assessed the taste response of each strain to PROP and ethanol on separate days. Although PROP avoiding versus neutral mice could be segregated into significantly different populations, this was not the case for ethanol avoiding versus preferring mice, and all strains showed high variability. On average, only BALB/cJ, SWR/J, and C3HeB/FeJ mice conformed to their literature-reported preferences; nonetheless, there were a substantial number of discordant animals. C57BL/6J did not conform to previous results, indicating that they are ethanol preferring. Finally, we did not observe a significant relationship between PROP and ethanol preferences across strains. The high variability per strain and the number of animals in disagreement with their respective literature-reported preference raise concerns regarding their utility for investigations underlying mechanisms of taste-mediated ingestive responses. Absent postingestive consequences, the brief-access results suggest a possible degree of previously masked polymorphisms in taste preferences or a more recent drift in underlying genetic factors. The absence of a relationship between PROP and ethanol indicates that the bitter quality in ethanol may be more highly related to other bitter compounds that are mediated by different genetic influences.