Assessing author willingness to enter study information into structured data templates as part of the manuscript submission process: A pilot study.

Background: Environmental health and other researchers can benefit from automated or semi-automated summaries of data within published studies as summarizing study methods and results is time and resource intensive. Automated summaries can be designed to identify and extract details of interest pertaining to the study design, population, testing agent/intervention, or outcome (etc.). Much of the data reported across existing publications lack unified structure, standardization and machine-readable formats or may be presented in complex tables which serve as barriers that impede the development of automated data extraction methodologies.As full automation of data extraction seems unlikely soon, encouraging investigators to submit structured summaries of methods and results in standardized formats with meta-data tagging of content may be of value during the publication process. This would produce machine-readable content to facilitate automated data extraction, establish sharable data repositories, help make research data FAIR, and could improve reporting quality. Objectives: A pilot study was conducted to assess the feasibility of asking participants to summarize study methods and results using a structured, web-based data extraction model as a potential workflow that could be implemented during the manuscript submission process. Methods: Eight participants entered study details and data into the Health Assessment Workplace Collaborative (HAWC). Participants were surveyed after the extraction exercise to ascertain 1) whether this extraction exercise will impact their conducting and reporting of future research, 2) the ease of data extraction, including which fields were easiest and relatively more problematic to extract and 3) the amount of time taken to perform data extractions and other related tasks. Investigators then presented participants the potential benefits of providing structured data in the format they were extracting. After this, participants were surveyed about 1) their willingness to provide structured data during the publication process and 2) whether they felt the potential application of structured data entry approaches and their implementation during the journal submission process should continue to be further explored. Conclusions: Routine provision of structured data that summarizes key information from research studies could reduce the amount of effort required for reusing that data in the future, such as in systematic reviews or agency scientific assessments. Our pilot study suggests that directly asking authors to provide that data, via structured templates, may be a viable approach to achieving this: participants were willing to do so, and the overall process was not prohibitively arduous. We also found some support for the hypothesis that use of study templates may have halo benefits in improving the conduct and completeness of reporting of future research. While limitations in the generalizability of our findings mean that the conditions of success of templates cannot be assumed, further research into how such templates might be designed and implemented does seem to have enough chance of success that it ought to be undertaken.

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. METHODS: Human and animal health effect studies and physiologically based pharmacokinetic (PBPK) models were identified from a literature search based on populations, exposures, comparators, and outcomes (PECO) criteria. Human and animal studies meeting PECO criteria were refined to a smaller subset considered most informative for deriving chronic reference value(s), which are preferred for assessing risk to the general public. This subset was evaluated for risk of bias and sensitivity, and the suitability of each study for dose-response analysis was qualitatively assessed. Lowest observed adverse effect levels (LOAELs) were extracted and summarized. Other potentially relevant studies (e.g., mechanistic and toxicokinetic studies) were tracked as supplemental information but not evaluated further. Existing reference values for naphthalene are also summarized. RESULTS: We identified 26 epidemiology studies and 16 animal studies that were considered most informative for further analysis. Eleven PBPK models were identified. The available epidemiology studies generally had significant risk of bias and/or sensitivity concerns and were mostly found to have low suitability for dose-response analysis due to the nature of the exposure measurements. The animal studies had fewer risk of bias and sensitivity concerns and were mostly found to be suitable for dose-response analysis. CONCLUSION: Although both epidemiological and animal studies of naphthalene provide weight of evidence for hazard identification, the available animal studies appear more suitable for reference value derivation. PBPK models and mechanistic and toxicokinetic data can be applied to extrapolate these animal data to humans, considering mode of action and interspecies metabolic differences. https://doi.org/10.1289/EHP7381.

Application of systematic evidence mapping to assess the impact of new research when updating health reference values: A case example using acrolein.

BACKGROUND: The environmental health community needs transparent, methodologically rigorous, and rapid approaches for updating human health risk assessments. These assessments often contain reference values for cancer and/or noncancer effects. Increasingly, the use of systematic review methods are preferred when developing these assessments. Systematic evidence maps are a type of analysis that has the potential to be very helpful in the update process, especially when combined with machine-learning software advances designed to expedite the process of conducting a review. OBJECTIVES: To evaluate the applicability of evidence mapping to determine whether new evidence is likely to result in a change to an existing health reference value, using inhalation exposure to the air pollutant acrolein as a case example. METHODS: New literature published since the 2008 California Environmental Protection Agency's Office of Environmental Health Hazard Assessment (OEHHA) Reference Exposure Level (REL) for acrolein was assessed. Systematic review methods were used to search the literature and screening included the use of machine-learning software. The Populations, Exposures, Comparators and Outcomes (PECO) criteria were kept broad to identify studies that characterized acute and chronic exposure and could be informative for hazard characterization. Studies that met the PECO criteria after full-text review were briefly summarized before their suitability for chronic point of departure (POD) derivation and calculation of a reference value was considered. Studies considered potentially suitable underwent a targeted evaluation to determine their suitability for use in dose-response analysis. RESULTS: Over 15,000 studies were identified from scientific databases. Both machine-learning and manual screening processes were used to identify 60 studies considered PECO-relevant after full-text review. Most of these PECO-relevant studies were short-term exposure animal studies (acute or less than 1 month of exposure) and considered less suitable for deriving a chronic reference value when compared to the subchronic study in rats used in the 2008 OEHHA assessment. Thirteen epidemiological studies were identified but had limitations in the exposure assessment that made them less suitable for dose-response compared to the subchronic rat study. Among the 13 studies, there were four controlled trial studies that have the potential to be informative for future acute reference value derivation. Thus, the 2008 subchronic rat study used by OEHHA appears to still be the most appropriate study for chronic reference value derivation. In addition, advances in dosimetric modeling for gases, including new evidence pertinent to acrolein, could be considered when updating existing acrolein toxicity values. CONCLUSIONS: Evidence mapping is a very useful tool to assess the need for updating an assessment based on understanding the potential impact of new studies on revising an existing health reference value. In this case example, the focus was to identify studies suitable for chronic exposure dose-response analysis, while also identifying studies that may be important to consider for acute exposure scenarios, hazard identification, or for future research. This allows the evidence map to be a useful resource for a range of decision-making contexts. Specialized systematic review software increased the efficiency of the process in terms of human resources and time to conduct the analysis.

Assessment of Health Effects of Exogenous Urea: Summary and Key Findings.

PURPOSE OF REVIEW: Urea has been utilized as a reductant in diesel fuels to lower emission of nitrogen oxides, igniting interest in probable human health hazards associated with exposure to exogenous urea. Here, we summarize and update key findings on potential health effects of exogenous urea, including carcinogenicity. RECENT FINDINGS: No definitive target organs for oral exposure were identified; however, results in animal studies suggest that the liver and kidney could be potential target organs of urea toxicity. The available human-subject literature suggests that the impact on lung function is minimal. Based on the literature on exogenous urea, we concluded that there was inadequate information to assess the carcinogenic potential of urea, or perform a quantitative assessment to derive reference values. Given the limited information on exogenous urea, additional research to address gaps for exogenous urea should include long-term cancer bioassays, two-generation reproductive toxicity studies, and mode-of-action investigations.

Use of epidemiologic data in Integrated Risk Information System (IRIS) assessments.

In human health risk assessment, information from epidemiologic studies is typically utilized in the hazard identification step of the risk assessment paradigm. However, in the assessment of many chemicals by the Integrated Risk Information System (IRIS), epidemiologic data, both observational and experimental, have also been used in the derivation of toxicological risk estimates (i.e., reference doses [RfD], reference concentrations [RfC], oral cancer slope factors [CSF] and inhalation unit risks [IUR]). Of the 545 health assessments posted on the IRIS database as of June 2007, 44 assessments derived non-cancer or cancer risk estimates based on human data. RfD and RfC calculations were based on a spectrum of endpoints from changes in enzyme activity to specific neurological or dermal effects. There are 12 assessments with IURs based on human data, two assessments that extrapolated human inhalation data to derive CSFs and one that used human data to directly derive a CSF. Lung or respiratory cancer is the most common endpoint for cancer assessments based on human data. To date, only one chemical, benzene, has utilized human data for derivation of all three quantitative risk estimates (i.e., RfC, RfD, and dose-response modeling for cancer assessment). Through examples from the IRIS database, this paper will demonstrate how epidemiologic data have been used in IRIS assessments for both adding to the body of evidence in the hazard identification process and in the quantification of risk estimates in the dose-response component of the risk assessment paradigm.

Arginine to cysteine mutation (R499C) found in a Japanese patient with complete myeloperoxidase deficiency.

Animal models suggest that a deficiency in myeloperoxidase (MPO; EC 1.11.1.7), a lysosomal hemoprotein involved in host defense, may be associated with a decreased level of immunity. A nonsynonymous mutation, resulting in an arginine to cysteine substitution (Arg499Cys or R499C), has been identified in the exon 9 genetic coding region of a Japanese patient with complete MPO deficiency. Genetic analysis revealed that the mRNA of the patient could be correctly transcribed then further translated into a peptide sequence. However, the Western blot analysis confirmed the absence of MPO peptides. An initial screening assay of the patient's blood exhibited an abnormal hematograph, and no MPO activity was detected. To determine if this mutation might be associated with MPO deficiency, DNA samples for 387 controls were examined. Genetic analysis was performed using standard PCR techniques for amplification and sequencing. None of the control samples possessed the R499C substitution. This mutation is in close proximity to a different mutation (G501S) previously found in another Japanese MPO-deficient patient, and the amino acid, H502, which is strongly involved in heme binding, leading to the speculation that heme binding may play a role in complete MPO deficiency.

Susceptibility loci to coronary arteritis in animal model of Kawasaki disease induced with Candida albicans -derived substances.

We have established an animal model of coronary arteritis which is histopathologically similar to that observed in cases of Kawasaki disease (KD), is a well-known childhood vasculitis syndrome. Coronary arteritis in this mouse model has been induced by intraperitoneal injection of Candida albicans -derived substances (CADS). Arteritis varied by mouse strain with the highest incidence by 71.1% (27/38) found in C3H/HeN mice, but absent in CBA/JN mice (0%, 0/27), suggesting association of genomic background to develop the disease. The present study aims to elucidate the susceptibility loci associated with coronary arteritis by using this animal model. The association of the onset of arteritis with polymorphic microsatellite markers between the two strains was examined using one hundred and fifteen of N1 backcross progeny [(CBAxC3H)F1xC3H]. Based on our analysis, arteritis-susceptibility loci with suggestive linkage were mapped on D1Mit171 and D1Mit245(map position 20.2 cM) on chromosome 1 (P=0.0019). These loci include several kinds of inflammatory cytokine receptors, such as interleukin 1 receptor and tumor necrosis factor receptor. We also found the cytokine response against CADS, levels of inflammatory cytokines interleukin-1 beta, tumor necrosis factor-alpha, and interleukin-6 in sera increased within 24 hr after CADS injection. Our results may indicate based on genomics that ligand-receptor interaction between these inflammatory cytokines and the receptors of these cytokines may affect the onset of arteritis.

The effects of organic solvents on poly(ADP-ribose) polymerase-1 activity: implications for neurotoxicity.

Poly(ADP-ribose) polymerase-1 (PARP-1; EC 2.4.2.30), also termed as poly(ADP-ribose) synthetase, is a key enzyme in the recognition and repair of damaged DNA. Several conditions (e.g., ischemia-reperfusion or chemical-induced injury) have been shown to overactivate PARP-1, causing neurodegeneration and necrotic or apoptotic cell death from NAD+ and ATP depletion. In contrast, inhibitors of PARP-1 have been shown to have a neuroprotective effect by ameliorating this response. The purpose of this study was to determine the effects of three routinely used organic solvents (ethanol, methanol, and dimethyl sulfoxide (DMSO)) on the activity of purified PARP-1. A dose-response was examined with each of these solvents. A 112% and 82% increase in PARP-1 activity was observed with 15% ethanol and 20% methanol, respectively. In contrast, a near 20% decrease in the activity was observed with 4% DMSO. Kinetic analysis revealed that the maximal velocity remained unchanged with increasing concentrations of DMSO up to 20%, indicating that DMSO is a competitive inhibitor of PARP-1. Thus, PARP-1 inhibition by DMSO depends on NAD+ concentration and in some pathological processes might be significant even at low DMSO concentrations. Our findings suggest that the interpretation of data from dose-response studies obtained when using common organic solvents may be dramatically skewed, either exaggerating the inherent toxicity of the compound or masking its potential for damage.

Genomic variations in myeloperoxidase gene in the Japanese population.

Myeloperoxidase (MPO; EC 1.11.1.7) is a lysosomal hemeprotein that plays an important role in the host defense mechanism against microbial diseases. This neutrophil disorder, characterized by the lack of MPO, may result in a weakened defense activity. Complete MPO deficiency has been postulated to be to originate from genomic mutation. Recently, two Japanese patients were reported with MPO deficiency. Both had base substitutions in the exon 9 region of the MPO gene; a region in close proximity functionally important residue, His502. Genomic DNA from 387 Japanese individuals was examined to determine the prevalence of these recently discovered base substitutions. None of these DNA samples possessed the mutations found in the MPO deficient cases, though two synonymous and one non-synonymous mutation were found. The frequency of mutation in the exon 9 coding region was estimated to be one heterozygote in 129, thus the homozygote of such mutations would be revealed one in 16,000 in the Japanese population.

Septin 3 gene polymorphism in Alzheimer's disease.

Septin 3 is a novel member of the septin subfamily of GTPase domain proteins that was recently identified in human neuronal cells. These proteins are involved in vesicle trafficking, neurite outgrowth, and neurofibrillary tangle formation; however, the expression and functional role of septin 3 in normal neuronal tissues and as an etiological agent in neurological disorders is currently unclear. To further characterize these parameters, the present study analyzed the expression of three isoforms of septin 3 (A, B, and C) in fetal and adult human brains and polymorphism of the septin 3 exon 11 microsatellite in control, pure Alzheimer's disease (AD), Lewy body variant (LBV) of AD, and Parkinson's disease. Septin 3 mRNAs for isoforms A and B, but not C, were detected in the frontal cortex of fetus and adult human samples, as measured by reverse transcription-coupled polymerase chain reaction. Genotype analyses indicated that polymorphic septin 3 alleles were distributed in two peaks of frequency in both control and disease groups. Categorization of the alleles into short (S) and long (L) types revealed a significant difference between AD patients and controls (p = 0.034 by chi-square test). Furthermore, the S-allele homozygosity was significantly underrepresented in AD compared with control (p = 0.015 by chi-square test). These results suggest that polymorphism in exon 11 of septin 3 may have a determinative role in the pathogenesis of AD.

Novel missense mutation found in a Japanese patient with myeloperoxidase deficiency.

Myeloperoxidase (MPO; EC 1.11.1.7) plays an important role in the host defense mechanism against microbial diseases. The neutrophil disorder characterized by the lack of MPO activity, is speculated to be associated with a decreased level of immunity. A Japanese patient was identified with complete MPO deficiency through automated hematography. Neutrophil function analysis revealed that MPO activity was significantly diminished with slightly elevated superoxide production. Mutational analysis of the patient revealed a glycine to serine substitution (G501S) in the exon 9 region. This mutation was not detected in the 96 healthy controls analyzed. The amino acid substitution found may be responsible for the failure of mature MPO production in the patient. This is the first case of MPO deficiency of G501S missense mutation identified in a Japanese patient.

Parkinson's disease and CYP2D6 polymorphism in Asian populations: A meta-analysis.

Polymorphism of CYP2D6 and its relationship with the development of Parkinson's disease (PD) has been controversial. The distribution of the B-mutation of CYP2D6, a mutation that results in the absence of a functional protein, differs by ethnicity and accounts for less than 1% of the 'poor metabolizer' phenotype in Asians. Thus, a meta-analysis was conducted to determine if polymorphism, other than the B-mutation, within the CYP2D6 gene confers a greater susceptibility to PD outcome among Asian populations. Eleven studies were identified, two of which were excluded due to unavailability in the English language or availability of the same original data in more detail in another publication. None of the studies showed a statistically significant association between CYP2D6 polymorphism and PD (p<0.05). The overall odds ratio was 0.84 (95% confidence interval 0.66-1.08). We conclude that among Asian populations, there is no convincing evidence of an association between CYP2D6 polymorphism and the risk of developing PD.

Selective inhibition of acetylcholinesterase in the cerebellum and hippocampus of mice following an acute treatment with malathion.

Adult male ICR mice were treated by intraperitoneal injection with 250 mg/kg of bodyweight of commercial malathion (a dose corresponding to 1/12 the LD50). After 6 h, acetylcholinesterase (AChE) activity in blood, liver, and six brain regions was determined. A statistically significant inhibition was observed in whole blood (23%), liver (21%), and, in particular, the central nervous system; the greatest degree of AChE inhibition was observed in the cerebellum (45%), followed by the hippocampus (29%). There was no significant change in AChE activity in the caudate putamen, frontal cortex, midbrain, or pons medulla. These results demonstrate that the magnitude of AChE inhibition in peripheral tissues does not accurately reflect the central-inhibitory effects of malathion on AChE activity in specific brain regions.