Human Exposure Data Research Articles

Integrated Approach for Testing and Assessment for Developmental Neurotoxicity (DNT) to Prioritize Aromatic Organophosphorus Flame Retardants.

Organophosphorus flame retardants (OPFRs) are abundant and persistent in the environment but have limited toxicity information. Their similarity in structure to organophosphate pesticides presents great concern for developmental neurotoxicity (DNT). However, current in vivo testing is not suitable to provide DNT information on the amount of OPFRs that lack data. Over the past decade, an in vitro battery was developed to enhance DNT assessment, consisting of assays that evaluate cellular processes in neurodevelopment and function. In this study, behavioral data of small model organisms were also included. To assess if these assays provide sufficient mechanistic coverage to prioritize chemicals for further testing and/or identify hazards, an integrated approach to testing and assessment (IATA) was developed with additional information from the Integrated Chemical Environment (ICE) and the literature. Human biomonitoring and exposure data were identified and physiologically-based toxicokinetic models were applied to relate in vitro toxicity data to human exposure based on maximum plasma concentration. Eight OPFRs were evaluated, including aromatic OPFRs (triphenyl phosphate (TPHP), isopropylated phenyl phosphate (IPP), 2-ethylhexyl diphenyl phosphate (EHDP), tricresyl phosphate (TMPP), isodecyl diphenyl phosphate (IDDP), tert-butylphenyl diphenyl phosphate (BPDP)) and halogenated FRs ((Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), tris(2-chloroethyl) phosphate (TCEP)). Two representative brominated flame retardants (BFRs) (2,2'4,4'-tetrabromodiphenyl ether (BDE-47) and 3,3',5,5'-tetrabromobisphenol A (TBBPA)) with known DNT potential were selected for toxicity benchmarking. Data from the DNT battery indicate that the aromatic OPFRs have activity at similar concentrations as the BFRs and should therefore be evaluated further. However, these assays provide limited information on the mechanism of the compounds. By integrating information from ICE and the literature, endocrine disruption was identified as a potential mechanism. This IATA case study indicates that human exposure to some OPFRs could lead to a plasma concentration similar to those exerting in vitro activities, indicating potential concern for human health.

Impact of dioxins on reproductive health in female mammals.

Extensive research has been conducted to investigate the toxicological impact of dioxins on mammals, revealing profound effects on the female reproductive system in both humans and animals. Dioxin exposure significantly disrupts the intricate functions of the ovary, a pivotal organ responsible for reproductive and endocrine processes. This disruption manifests as infertility, premature ovarian failure, and disturbances in sex steroid hormone levels. Comprehensive studies, encompassing accidental human exposure and experimental animal data, have raised a wealth of information with consistent yet varied conclusion influenced by experimental factors. This review begins by providing an overarching background on the ovary, emphasizing its fundamental role in reproductive health, particularly in ovarian steroidogenesis and hormone receptor regulation. Subsequently, a detailed examination of the Aryl hydrocarbon Receptor (AhR) and its role in governing ovarian function is presented. The review then outlines the sources and toxicity of dioxins, with a specific focus on AhR involvement in mediating reproductive toxicity in mammals. Within this context, the impact of dioxins, notably 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), on Folliculogenesis and Preimplantation embryos is discussed. Furthermore, the review delves into the disruptions of the female hormonal system caused by TCDD and their ramifications in endometriosis. Notably, variations in the effects of TCDD on the female reproductive and hormonal system are highlighted in relation to TCDD dose, animal species, and age. As a forward-looking perspective, questions arise regarding the potential involvement of molecular mechanisms beyond AhR in mediating the female reproductive toxicity of dioxins.

Mechanisms of Immune Dysregulation Induced by Pesticide Exposure and their Implications for Cancer: A Systematic Review

The inappropriate use of pesticides contaminates natural resources and has consequences for human health. Evidence of immune dysregulation caused by pesticides has been presented, but studies linking exposure to these substances with immune dysregulation and its relationship to cancer are scarce. This study systematically reviews the published literature that addresses the topic of immune dysregulation and cancer and its relationship to pesticide exposure. Studies developed in vitro cell culture and in vivo experimental animals and human exposure data were included. The results show that pesticide exposure has a relevant impact on immune dysfunction, negatively affecting immune system cells and cytokine production in innate and adaptive responses. The main consequences reported were suppression of the Th1 response, induction of the Th2 response, cellular balance dysregulation, and cytokine production changes. All reported events are related to the occurrence of immunosuppression. This dysregulation is paramount for cancer progression and may lead to a worse prognosis in chronically exposed populations. These findings also point to the need for further studies, primarily focused on human exposure.

Recommendations for a Military Health System Auditory Blast Injury Prevention Standard.

Although existing auditory injury prevention standards benefit warfighters, the Department of Defense could do more to understand and address auditory injuries (e.g., hearing loss, tinnitus, and central processing deficits) among service members. The Blast Injury Prevention Standards Recommendation (BIPSR) Process is designed to address the needs of all the Military Services for biomedically valid Military Health System (MHS) Blast Injury Prevention Standards. Through the BIPSR Process, stakeholders provided their intended uses and requested functionalities for an MHS Blast Injury Prevention Standard. The BIPSR Process established a broad-based, non-advocacy panel of auditory injury Subject Matter Expert (SME) Panel with members drawn from industry, academia, and government. The SME Panel selected evaluation factors, weighted priorities, and then evaluated the resulting candidate MHS Auditory Blast Injury Prevention Standards against the evaluation criteria. The SME Panel members provided rationales for their decisions, documented discussions, and used iterative rounds of feedback to promote consensus building among members. The BIPSR Process used multi-attribute utility theory to combine members' evaluations and compare the candidate standards. The SME Panel identified and collated information about existing auditory injury datasets to identify gaps and promote data sharing and comprehensive evaluations of standards for preventing auditory blast injury. The panel evaluated the candidate standards and developed recommendations for an MHS Blast Injury Prevention Standard. The BIPSR Process illuminated important characteristics, capabilities, and limitations of candidate standards and existing datasets (e.g., limited human exposure data to evaluate the validity of injury prediction) for auditory blast injury prevention. The evaluation resulted in the recommendation to use the 8-hour Equivalent Level (LAeq8hr) as the interim MHS Auditory Blast Injury Prevention Standard while the community performs additional research to fill critical knowledge gaps.

SAT433 Improving The Risk Assessment Procedures For Endocrine Disrupting Chemicals Affecting Thyroid Homeostasis: A Scoping Study

Abstract Disclosure: C. La Motta: None. This project aims at improving the risk assessment procedure currently adopted for the endocrine disrupting chemicals (EDCs), focusing in particular on those contained in food contact materials and articles and affecting thyroid homeostasis. EDCs generally display a complex toxicity profile, thus making toxicological evaluation and health risk assessment difficult to achieve. The current standardized methods are rather insufficient to identify and test their complex toxicity, and the application of traditional risk assessment principles may be problematic for this kind of substances. This issue is even more crucial when ECDs are part of food contact materials and articles, which are commonly used by the whole population. The increasingly wider distribution of these products on the global market raised the exposure of consumers to chemical agents on constant and cumulative basis, even for persistent compounds, highlighting the urgency of governing the matter. A number of lists including chemicals exploited for the manufacture of food contact materials and articles have been drawn up by international regulators and public and private bodies. However, besides far from being harmonized, they do not provide systematic information regarding thyroid disrupting properties. Actually, the awareness of science on the thyroid safety profile of compounds intentionally used in the food planet is still limited and fragmented, thus requiring an intensive research activity to fill the existing knowledge gap. We carried out a thoroughly survey of the available databases of chemicals for food contact materials and articles, selecting sixteen EDCs characterized by a high level of uncertainty concerning the toxicological profile and/or dearth of information on human exposure data. The selected compounds should be now investigated by making use of both computational tools and in vitro and in vivo studies, to ascertain their adverse thyroid effects. The resulting outcomes will allow to achieve a reliable risk assessment for the benefit of entire population. Presentation: Saturday, June 17, 2023

Time Patterns in Internal Human Exposure Data to Bisphenols, Phthalates, DINCH, Organophosphate Flame Retardants, Cadmium and Polyaromatic Hydrocarbons in Europe.

Human biomonitoring (HBM) data in Europe are often fragmented and collected in different EU countries and sampling periods. Exposure levels for children and adult women in Europe were evaluated over time. For the period 2000-2010, literature and aggregated data were collected in a harmonized way across studies. Between 2011-2012, biobanked samples from the DEMOCOPHES project were used. For 2014-2021, HBM data were generated within the HBM4EU Aligned Studies. Time patterns on internal exposure were evaluated visually and statistically using the 50th and 90th percentiles (P50/P90) for phthalates/DINCH and organophosphorus flame retardants (OPFRs) in children (5-12 years), and cadmium, bisphenols and polycyclic aromatic hydrocarbons (PAHs) in women (24-52 years). Restricted phthalate metabolites show decreasing patterns for children. Phthalate substitute, DINCH, shows a non-significant increasing pattern. For OPFRs, no trends were statistically significant. For women, BPA shows a clear decreasing pattern, while substitutes BPF and BPS show an increasing pattern coinciding with the BPA restrictions introduced. No clear patterns are observed for PAHs or cadmium. Although the causal relations were not studied as such, exposure levels to chemicals restricted at EU level visually decreased, while the levels for some of their substitutes increased. The results support policy efficacy monitoring and the policy-supportive role played by HBM.

Systemic inflammatory effects of zinc oxide particles: is a re-evaluation of exposure limits needed?

Exposure to airborne substances such as gases, vapours, and particles remains a relevant health risk in many workplaces. A current topic and cause for discussion is the investigation of the health effects of particles containing zinc oxide (ZnO). Among other data, those collected from our study on human exposure data of ZnO in 2018 prompted the National Research Centre for the Working Environment 2021 to formulate a new, sharply lowered proposed occupational exposure limit (OEL) for zinc in workplaces. Since the publication of the Danish report, further studies have been conducted with ZnO. In the following text, all arguments for deriving this new limit value for zinc from the report are discussed, extended with the more recent data since 2018. It should be noted that especially the application of time extrapolation factors needs further discussion and harmonization between regulatory authorities. From our point of view, the data situation can justify a higher OEL for zinc than that proposed by the Danish National Research Centre for the Working Environment.

Linking Transthyretin-Binding Chemicals and Free Thyroid Hormones: In Vitro to In Vivo Extrapolation Based on a Competitive Binding Model.

Large numbers of pollutants competitively inhibit the binding between thyroid hormones and transthyretin (TTR) in vitro. However, the impact of this unintended binding on free thyroid hormones in vivo has not yet been characterized. Herein, we established a quantitative in vitro to in vivo extrapolation (QIVIVE) method based on a competitive binding model to quantify the effect of TTR-binding chemicals on free thyroid hormones in human blood. Twenty-five TTR-binding chemicals including 6 hydroxyl polybromodiphenyl ethers (OH-PDBEs), 6 hydroxyl polychlorobiphenyls (OH-PCBs), 4 halogenphenols, 5 per- and polyfluorinated substances (PFASs), and 4 phenols were selected for investigation. Incorporating the in vitro binding parameters and human exposure data, the QIVIVE model could well predict the in vivo effect on free thyroid hormones. Co-exposure to twenty-five typical TTR-binding chemicals resulted in median increases of 0.080 and 0.060% in circulating levels of free thyroxine (FT4) and free triiodothyronine (FT3) in the general population. Individuals with occupational exposure to TTR-binding chemicals suffered 1.88-32.2% increases in free thyroid hormone levels. This study provides a quantitative tool to evaluate the thyroid-disrupting risks of TTR-binding chemicals and proposes a new framework for assessing the in vivo effects of chemical exposures on endogenous molecules.

Human risk associated with exposure to mixtures of antiandrogenic chemicals evaluated using in vitro hazard and human biomonitoring data

BackgroundScientific evidence for underestimated toxicity from unintentional exposure to chemical mixtures is mounting. Yet, harmonized approaches on how to assess the actual risk of mixtures is lacking. As part of the European Joint programme ‘Human Biomonitoring for Europe’ we explored a novel methodology for mixture risk assessment of chemicals affecting male reproductive function. MethodologyWe explored a methodology for chemical mixture risk assessment based on human in vitro data combined with human exposure data, thereby circumventing the drawbacks of using hazard data from rodents and estimated exposure intake levels. Human androgen receptor (hAR) antagonism was selected as the most important molecular initiating event linked to adverse outcomes on male reproductive health. ResultsOur work identified 231 chemicals able to interfere with hAR activity. Among these were 61 finally identified as having both reliable hAR antagonist and human biomonitoring data. Calculation of risk quotients indicated that PCBs (118, 138, 157), phthalates (BBP, DBP, DIBP), benzophenone-3, PFOS, methylparaben, triclosan, some pesticides (i.e cypermethrin, β-endosulfan, methylparathion, p,p-DDE), and a PAH metabolite (1-hydroxypyrene) contributed to the mixture effect. The major chemical mixture drivers were PCB 118, BBP, PFOS, DBP, and the UV filter benzophenone-3, together contributing with 75% of the total mixture effect that was primarily driven by high exposure values. ConclusionsThis viable way forward for mixture risk assessment of chemicals has the advantages of (1) being a more comprehensive mixture risk assessment also covering data-poor chemicals, and (2) including human data only. However, the approach is subjected to uncertainties in terms of in vitro to in vivo extrapolation, it is not ready for decision making, and needs further development. Still, the results indicate a concern for adverse effects on reproductive function in highly exposed boys, especially when considering additional exposure to data-poor chemicals and chemicals acting by other mechanisms of action.

Microplastics Scoping Review of Environmental and Human Exposure Data

Scientific studies of microplastics have expanded since 2015, propelling the topic to the forefront of scientific inquiry. Microplastics are ubiquitous in the environment and pose a potential risk to human health. The purpose of this review is to organize microplastics literature into areas of scientific research, summarize the state of the literature and identify the current data gaps in knowledge to promote a better understanding of human exposure to microplastics and their potential health effects. We searched for published literature from eight databases. Our search focused on three categories: (1) microplastics in the environment, (2) adsorption and absorption of chemicals to microplastics, and (3) human exposure to microplastics in the environment. We screened all abstracts to select articles that focused on microplastics. We then screened the remaining articles using criteria outlined in a questionnaire to identify and assign articles to the three scoping review categories. After screening abstracts, we selected 1186 articles (19%) to thoroughly assess their appropriateness for inclusion in the final review. Of the 1186 articles, 903 (76.1%) belonged to the environmental category, 268 (22.6%) to the adsorption and absorption category, and 16 (1.3%) to the human exposure category. Water was the most frequently studied environmental medium (440 articles). Our assessment resulted in 572 articles selected for the final review. Of the 572 publications, 268 (48.2%) included a geographic component and 110 (19.2%) were the product of literature reviews. We also show that relatively few publications have investigated human health effects associated with exposures to microplastics.

Establishing a Quantitative Framework for Regulatory Interpretation of Genetic Toxicity Dose-Response Data: MOE (Margin of Exposure) Case Study of 48 Compounds with both in vivo Mutagenicity and Carcinogenicity Dose-Response Data.

Quantitative relationships between carcinogenic potency and mutagenic potency have been previously examined using a benchmark dose (BMD)-based approach. We extended those analyses by using human exposure data for 48 compounds to calculate carcinogenicity- and genotoxicity-derived margin of exposure values (MOEs) that can be used to prioritize substances for risk management. MOEs for 16 of the 48 compounds were below 10,000, and consequently highlighted for regulatory concern. Of these, 15 were highlighted using genotoxicity-derived (micronucleus (MN) dose-response data) MOEs. Thirteen compounds were highlighted using carcinogenicity-derived MOEs; 12 compounds were overlapping. MOEs were also calculated using transgenic rodent (TGR) mutagenicity data. For 10 of the 12 compounds examined using TGR data, the results similarly revealed that mutagenicity-derived MOEs yield regulatory decisions that correspond with those based on carcinogenicity-derived MOEs. The effect of benchmark response (BMR) on MOE determination was also examined. Reinterpretation of the analyses using a BMR of 50% indicated that four out of 15 compounds prioritized using MN-derived MOEs based on a default BMR of 5% would have been missed. The results indicate that regulatory decisions based on in vivo genotoxicity dose-response data would be consistent with those based on carcinogenicity dose-response data; in some cases, genotoxicity-based decisions would be more conservative. Going forward, and in the absence of carcinogenicity data, in vivo genotoxicity assays (MN and TGR) can be used to effectively prioritise substances for regulatory action. Routine use of the MOE approach necessitates the availability of reliable human exposure estimates, and consensus regarding appropriate BMRs for genotoxicity endpoints. This article is protected by copyright. All rights reserved.

Potential harm to the skin from unfiltered krypton chloride ‘far-ultraviolet-C’ lamps, even below an occupational exposure limit

Ultraviolet-C (UVC) radiation can effectively inactivate pathogens on surfaces and in the air. Due to the potential for harm to skin and eyes, human exposure to UVC should be limited within the guideline exposure limits produced by the International Commission on Non-Ionising Radiation Protection (ICNIRP) or the American Conference of Governmental Industrial Hygienists (ACGIHs). Both organisations state an effective spectrally weighted limit of 3 mJ cm−2, although the spectral weighting factors of the two organisations diverged following a revision of the ACGIH guidelines in 2022. Using existing published human exposure data, the effective spectrally weighted radiant exposure was calculated for both unfiltered and filtered (to reduce UV emissions above 230 nm) krypton chloride (KrCl*) excimer lamps. The effective radiant exposure of the filtered KrCl* lamp was greater than 3 mJ cm−2 when applying ICNIRP or either of the revised ACGIH spectral weightings. This indicates that both guidelines are appropriately conservative for this specific lamp. However, the effective radiant exposure of the unfiltered KrCl* lamp was as low as 1 mJ cm−2 with the revised ACGIH weighting function that can be applied to the skin if the eyes are protected. Erythema has therefore been directly observed in a clinical study at an exposure within the revised ACGIH guideline limits. Extrapolating this information means that a mild sunburn could be induced in Fitzpatrick skin types I and II if that particular ACGIH weighting function were applied and an individual received an effective exposure of 3 mJ cm−2. Whilst it is improbable that such an effect would be seen in current deployment of KrCl* lamp technology, it does highlight the need for further research into skin sensitivity and irradiance–time reciprocity for UVC wavelengths.

Theme (concept) paper ‐ Advancing Aggregate Exposure to Chemicals in EU (ExpoAdvance)

Theme (concept) paper ‐ Advancing Aggregate Exposure to Chemicals in EU (ExpoAdvance)

Size characteristics of asbestiform fibers in lung tissue of animals that grazed in areas rich in ophiolitic outcrops in Central Calabria (Southern Italy)

In Calabria (Southern Italy) naturally occurring asbestos (NOA) mainly occurs in the ophiolitic sequences cropping in the Mount Reventino area. The most common type of asbestos detected was the amphibole tremolite; fibrous antigorite and minor chrysotile were also found. The development of asbestos-related diseases depends on, among other things, the morphological characteristics of fibers, length and width, affecting the durability of asbestos fibers in the lung.In this work fifteen lung samples of sheep, goats and wild boars, grazing around the Mount Reventino area were collected and asbestos fibers analysed. Observed fibers (357), of which 97 % were tremolite and 3 % antigorite fibers, were grouped according to species, grazing area and age of the animals. The aim of this work was to highlight any differences among the groupings and to compare our size results with data in literature related to exposed populations.Principal Component Analysis (PCA) highlighted a positive correlation between tremolite fiber length and width and revealed groupings in terms of animal age. The Kruskal-Wallis test showed statistically significant differences between fiber mean widths in young and old animals. 63 % observed asbestiform fibers were longer than 5 μm and 7 % of the fibers were longer than 20 μm (critical fiber length connected to the frustrated phagocytosis by the macrophage). Fibers conforming to the Stanton Hypothesis size (predictor of the carcinogenic potency of fibers) were 1 %.Our size parameters of fibers detected in the animal lungs were in fairly good agreement with literature data for human asbestos exposure to tremolite.These results confirmed that an animal-sentinel system could be used to monitor the natural background of the airborne breathable fibers exposure. In addition, the size correlation of animal-human breathed fibers could be useful to study their potential toxicity.Additional data are necessary for improving the agreement with human exposure data.

Semi-automated harmonization and selection of chemical data for risk and impact assessment.

Chemical data for thousands of substances are available for safety, risk, life cycle and substitution assessments, as submitted for example under the European Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) Regulation. However, to widely disseminate reported physicochemical properties as well as human and ecological exposure and toxicological data for use in various science and policy fields, systematic methods for data harmonization and selection are necessary. In response to this need, we developed a semi-automated method for deriving appropriate substance property values as input for various assessment frameworks with different requirements for resolution and data quality. Starting with data reported for a given substance and property, we propose a set of aligned data selection and harmonization criteria to obtain a representative mean value and related confidence intervals per chemical-property combination. The proposed method was tested on a set of octanol-water partition coefficients (Kow) for an illustrative set of 20 substances, reported under the REACH regulation as example data source. Our method is generally applicable to any set of substances, and can assess specific distributions in quality and variability across reported data. Further research can likely extend our method for mining information from text fields and adapt it to available data reported or collected from other sources and other substance properties to improve the reliability of input data for risk and impact assessments.

Allometric scaling – A useful tool for the extrapolation of toxicokinetic parameters of new psychoactive substances from animals to humans?

Extrapolation of toxicokinetic (TK) parameters of new psychoactive substances (NPS) from pigs to humans using allometric scaling. Isoflurane anaesthetized pigs received a dose of 200 μg/kg body weight (BW) of the (synthetic) cannabinoids (SC) JWH-210, RCS-4, 5F-MDMB-P7AICA or THC via pulmonary administration or an intravenous dose of the new synthetic opioid (NSO) U-47700 (100 μg/kg BW) or tramadol (1 mg/kg BW). Blood samples were taken up to 8 h. Analytes were quantified after liquid-liquid or solid-phase extraction using a LC-MS/MS method. Based on these data concentration-time profiles were generated and TK models were developed using allometric scaling (AS). Furthermore, a validation of the AS technique was performed for THC and tramadol comparing observed animal data with human data published in literature. AS of TK data from different species to humans represents a well-established tool for prediction of human exposure. This technique assumes that distribution and elimination processes are predominantly weight-dependent and thus differences between species based on weight can be explained. Using a power function, various TK parameters, including clearance and volume of distribution, can be estimated implementing an allometric exponent. An empirical allometric exponent for the majority of the small-molecule drugs lay between 0.4 and 1.5, dependent on the elimination pathway (renal, hepatic, or mixed) and characteristic of the drug. Regarding JWH-210, RCS-4, THC and U-47700 a three-compartment TK model described best the TK data obtained in the pig model. Concerning 5F-MDMB-P7AICA a four-compartment model was considered to be more appropriate. Model parameters in pig serum were precisely estimated with reasonable residual standard errors. AS exponents of 0.75 or 1.0 were found to fit best for the studied drugs. Upscaling the developed THC and tramadol pig TK model to humans applying AS revealed adequate prediction of observed human data published in literature. The AS approach has successfully been applied for the elucidation of TK parameters of several SC and the NSO U-47700 using the well-established pig model following intravenous or pulmonary administration. As for THC and tramadol, TK parameters were mostly analogous to literature values following administration of the drugs to humans. Regarding the NPS, human exposure data are lacking. Consequently, human exposure had to be predicted without a comparison to observed human data. The allometric scaling technique has proven to be a useful tool for the extrapolation of TK parameters of NPS from animals to humans. More details will be presented during the Young Scientist Symposium.

Genomic Diversity, Antimicrobial Resistance, and Virulence Gene Profiles of Salmonella Serovar Kentucky Isolated from Humans, Food, and Animal Ceca Content Sources in the United States.

Salmonella serovar Kentucky is frequently isolated from chickens and dairy cattle, but recovery from humans is comparatively low based on the U.S. National Antimicrobial Resistance Monitoring System (NARMS) reports. We aimed to better describe the genetic diversity, antimicrobial resistance, and virulence determinants of Salmonella Kentucky isolates from humans, food animal ceca, retail meat and poultry products, imported foods and food products, and other samples. We analyzed the genomes of 774 Salmonella Kentucky isolates and found that 63% (54/86) of human isolates were sequence type (ST)198, 33% (29/86) were ST152, and 3.5% (3/86) were ST314. Ninety-one percent (570/629) of cecal isolates and retail meat and poultry isolates were ST152 or ST152-like (one allele difference), and 9.2% (58/629) were ST198. Isolates from imported food were mostly ST198 (60%, 22/37) and ST314 (29.7%, 11/37). ST198 isolates clustered into two main lineages. Clade ST198.2 comprised almost entirely isolates from humans and imported foods, all containing triple mutations in the quinolone resistance-determining region (QRDR) that confer resistance to fluoroquinolones. Clade ST198.1 contained isolates from humans, ceca, retail meat and poultry products, and imported foods that largely lacked QRDR mutations. ST152 isolates from cattle had a lineage (Clade 2) distinct from ST152 isolates from chicken (Clade 4), and half of ST152 human isolates clustered within two other clades (Clades 1 and 3), largely distinct from Clades 2 and 4. Although clinical illness associated with Salmonella Kentucky is low, ST198 appears to account for most human infections in the Unites States but is uncommon among ceca of domestic food animals and retail meat and poultry products. These findings, combined with human exposure data, suggest that fluoroquinolone-resistant ST198 infections may be linked to the consumption of food products that are imported or consumed while traveling. We also found unique differences in the composition of virulence genes and antimicrobial resistance genes among the clades, which may provide clues to the host specificity and pathogenicity of Salmonella Kentucky lineages.

Environmental monitoring and potential health risk assessment from Pymetrozine exposure among communities in typical rice-growing areas of China.

Pymetrozine is one of the most commonly used insecticides in China. This study was conducted to analyse Pymetrozine's potential exposures through various environmental routes beyond the treatment areas. The aim was to estimate the potential health risk for communities due to non-dietary exposures to Pymetrozine in soil and paddy water. Data on registration of pesticides in China, government reports, questionnaires, interviews and literature reviews as well as toxicological health investigations were evaluated to determine the hazard and dose-response characteristics of Pymetrozine. These were based on the US EPA exposure and human health risk assessment methods and exposure data from soil and paddy water samples collected between 10 and 20m around the resident's location. The exposure doses from dermal contact through soil and paddy water were estimated. The potential cancer risk from the following exposure routes was evaluated: ingestion through soil; dermal contact exposure through soil; dermal contact exposure through paddy water. The potential total cancer risk for residents was estimated to be less than 1 × 10-6. These were relatively low and within the acceptable risk levels. The potential hazard quotient (HQ) from acute and lifetime exposure by dermal contact through paddy water and soil and acute and lifetime exposure by soil ingestion for residents was less than 1, indicating an acceptable risk level. This study suggested that there were negligible cancer risk and non-cancer risks based on ingestion and dermal contact routes of exposure to residents.

ToxCast chemical library Wnt screen identifies diethanolamine as an activator of neural progenitor proliferation.

Numerous autism spectrum disorder (ASD) risk genes are associated with Wnt signaling, suggesting that brain development may be especially sensitive to genetic perturbation of this pathway. Additionally, valproic acid, which modulates Wnt signaling, increases risk for ASD when taken during pregnancy. We previously found that an autism‐linked gain‐of‐function UBE3A T485A mutant construct hyperactivated canonical Wnt signaling, providing a genetic means to elevate Wnt signaling above baseline levels. To identify environmental use chemicals that enhance or suppress Wnt signaling, we screened the ToxCast Phase I and II libraries in cells expressing this autism‐linked UBE3A T485A gain‐of‐function mutant construct. Using structural comparisons, we identify classes of chemicals that stimulated Wnt signaling, including ethanolamines, as well as chemicals that inhibited Wnt signaling, such as agricultural pesticides, and synthetic hormone analogs. To prioritize chemicals for follow‐up, we leveraged predicted human exposure data, and identified diethanolamine (DEA) as a chemical that stimulates Wnt signaling in UBE3A T485A –transfected cells, and has a high potential for prenatal exposure in humans. DEA enhanced proliferation in primary human neural progenitor cell lines (phNPC), but did not affect expression of canonical Wnt target genes in NPCs or primary mouse neuron cultures. Instead, we found DEA increased expression of the H3K9 methylation sensitive gene CALB1, consistent with competitive inhibition of the methyl donor enzymatic pathways.

Development of a predictive model for individual susceptibility to hearing loss using human genetic, exposure and epidemiological data

Development of a predictive model for individual susceptibility to hearing loss using human genetic, exposure and epidemiological data