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Abstract Background The variable region-containing chitin-binding proteins (VCBPs) are found in protochordates and consist of two tandem immunoglobulin variable (V)-type domains and a chitin-binding domain. We previously have shown that these polymorphic genes, which primarily are expressed in the gut, exhibit characteristics of immune genes. In this report, we describe VCBP genomic organization and characterize adjacent and intervening genetic features which may influence both their polymorphism and complex transcriptional repertoire. Results VCBP genes 1, 2, 4, and 5 are encoded in a single contiguous gene-rich chromosomal region and VCBP3 is encoded in a separate locus. The VCBPs exhibit extensive haplotype variation, including copy number variation (CNV), indel polymorphism and a markedly elevated variation in repeat type and density. In at least one haplotype, inverted repeats occur more frequently than elsewhere in the genome. Multi-animal cDNA screening, as well as transcriptional profilingusing a novel transfection system, suggests that haplotype-specific transcriptional variants may contribute to VCBP genetic diversity. Conclusion The availability of the Branchiostoma floridae genome (Joint Genome Institute, Brafl1), along with BAC and PAC screening and sequencing described here, reveal that the relatively limited number of VCBP genes present in the amphioxus genome exhibit exceptionally high haplotype variation. These VCBP haplotypes contribute a diverse pool of allelic variants, which includes gene copy number variation, pseudogenes, and other polymorphisms, while contributing secondary effects on gene transcription as well.

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

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., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: To examine a) whether there are significant differences in the severity of symptoms of fatigue, sleep disturbance, or depression between patients with rectal cancer who develop co-occurring symptoms and those with no symptoms before and at the end of chemotherapy and radiation therapy (CRT); b) differences in gut microbial diversity between those with co-occurring symptoms and those with no symptoms; and c) whether before-treatment diversity measurements and taxa abundances can predict co-occurrence of symptoms., Methods: Stool samples and symptom ratings were collected from 31 patients with rectal cancer prior to and at the end of (24-28 treatments) CRT. Descriptive statistics were computed and the Mann-Whitney U test was performed for symptoms. Gut microbiome data were analyzed using R's vegan package software., Results: Participants with co-occurring symptoms reported greater severity of fatigue at the end of CRT than those with no symptoms. Bacteroides and Blautia2 abundances differed between participants with co-occurring symptoms and those with no symptoms. Our random forest classification (unsupervised learning algorithm) predicted participants who developed co-occurring symptoms with 74% accuracy, using specific phylum, family, and genera abundances as predictors., Conclusion: Our preliminary results point to an association between the gut microbiota and co-occurring symptoms in rectal cancer patients and serves as a first step in potential identification of a microbiota-based classifier.

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)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Ltd.)

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., Competing Interests: Declaration of competing interest None of the authors have any financial or other conflicts of interest to declare., (Published by Elsevier Inc.)

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.

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., (Published by Elsevier Ltd.)

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., (Copyright © 2011 Elsevier Inc. All rights reserved.)

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., (Copyright © 2011 Elsevier Inc. All rights reserved.)