Frontiers in toxicology最新文献

{"title":"A systematic review and meta-analysis of the impact of triclosan exposure on human semen quality.","authors":"Cecilia Adedeji Adegbola, Tunmise Maryanne Akhigbe, Adetomiwa Ezekiel Adeogun, Eva Tvrdá, Alica Pizent, Roland Eghoghosoa Akhigbe","doi":"10.3389/ftox.2024.1469340","DOIUrl":"10.3389/ftox.2024.1469340","url":null,"abstract":"<p><strong>Introduction: </strong>Triclosan is an antibacterial and antifungal compound that is frequently found in personal care and consumer products, and its its impact on male reproductive health is a growing concern. Despite existing experimental studies demonstrating its potential threats to male fertility, reports on its effects on human semen quality remains limited and inconsistent. Therefore, this study presents a systematic review and meta-analysis assessing the relationship between triclosan exposure and semen quality.</p><p><strong>Methods: </strong>This study was registered with PROSPERO (CRD42024524192) and adhered to PRISMA guidelines.</p><p><strong>Results: </strong>The study analyzed 562 screened studies, out of which five articles including 1,312 male subjects were finally included in the study. The eligible studies were geographically diverse, with three from China, one from Belgium, and one from Poland. More so, the eligible studies were both case-control and cross-sectional. The meta-analysis revealed that triclosan exposure significantly reduced sperm concentration (Standard Mean Difference (SMD) -0.42 [95% CI: -0.75, -0.10], P = 0.01) and sperm total motility (SMD -1.30 [95% CI: -2.26, -0.34], P = 0.008). Mechanistic insights from animal and <i>in vitro</i> studies showed that oxidative stress may mediate the adverse effects of triclosan on semen quality.</p><p><strong>Discussion: </strong>This meta-analysis is the first comprehensive evaluation of the impact of triclosan on human semen quality, highlighting its potential to impair male fertility through reductions in sperm concentration and motility. However, the high heterogeneity among the included studies underscores the need for further high-quality research to establish more definitive conclusions regarding the effects of triclosan exposure on human reproductive health.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11525012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A new approach methodology to identify tumorigenic chemicals using short-term exposures and transcript profiling.","authors":"Victoria Ledbetter, Scott Auerbach, Logan J Everett, Beena Vallanat, Anna Lowit, Gregory Akerman, William Gwinn, Leah C Wehmas, Michael F Hughes, Michael Devito, J Christopher Corton","doi":"10.3389/ftox.2024.1422325","DOIUrl":"10.3389/ftox.2024.1422325","url":null,"abstract":"<p><p>Current methods for cancer risk assessment are resource-intensive and not feasible for most of the thousands of untested chemicals. In earlier studies, we developed a new approach methodology (NAM) to identify liver tumorigens using gene expression biomarkers and associated tumorigenic activation levels (TALs) after short-term exposures in rats. The biomarkers are used to predict the six most common rodent liver cancer molecular initiating events. In the present study, we wished to confirm that our approach could be used to identify liver tumorigens at only one time point/dose and if the approach could be applied to (targeted) RNA-Seq analyses. Male rats were exposed for 4 days by daily gavage to 15 chemicals at doses with known chronic outcomes and liver transcript profiles were generated using Affymetrix arrays. Our approach had 75% or 85% predictive accuracy using TALs derived from the TG-GATES or DrugMatrix studies, respectively. In a dataset generated from the livers of male rats exposed to 16 chemicals at up to 10 doses for 5 days, we found that our NAM coupled with targeted RNA-Seq (TempO-Seq) could be used to identify tumorigenic chemicals with predictive accuracies of up to 91%. Overall, these results demonstrate that our NAM can be applied to both microarray and (targeted) RNA-Seq data generated from short-term rat exposures to identify chemicals, their doses, and mode of action that would induce liver tumors, one of the most common endpoints in rodent bioassays.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11526388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reproductive toxicology: keeping up with our changing world.","authors":"Laura B Miller, Morgan B Feuz, Ralph G Meyer, Mirella L Meyer-Ficca","doi":"10.3389/ftox.2024.1456687","DOIUrl":"10.3389/ftox.2024.1456687","url":null,"abstract":"<p><p>Reproductive toxicology testing is essential to safeguard public health of current and future generations. Traditional toxicological testing of male reproduction has focused on evaluating substances for acute toxicity to the reproductive system, with fertility assessment as a main endpoint and infertility a main adverse outcome. Newer studies in the last few decades have significantly widened our understanding of what represents an adverse event in reproductive toxicology, and thus changed our perspective of what constitutes a reproductive toxicant, such as endocrine disrupting chemicals that affect fertility and offspring health in an intergenerational manner. Besides infertility or congenital abnormalities, adverse outcomes can present as increased likelihood for various health problems in offspring, including metabolic syndrome, neurodevelopmental problems like autism and increased cancer predisposition, among others. To enable toxicologic studies to accurately represent the population, toxicologic testing designs need to model changing population characteristics and exposure circumstances. Current trends of increasing importance in human reproduction include increased paternal age, with an associated decline of nicotinamide adenine dinucleotide (NAD), and a higher prevalence of obesity, both of which are factors that toxicological testing study design should account for. In this perspective article, we highlighted some limitations of standard testing protocols, the need for expanding the assessed reproductive endpoint by including genetic and epigenetic sperm parameters, and the potential of recent developments, including mixture testing, novel animal models, <i>in vitro</i> systems like organoids, multigenerational testing protocols, as well as <i>in silico</i> modelling, machine learning and artificial intelligence.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11502475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142514141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microplastics and nanoplastics in cardiovascular disease-a narrative review with worrying links.","authors":"Haixiang Zheng, Gianpaolo Vidili, Gavino Casu, Eliano Pio Navarese, Leonardo A Sechi, Youren Chen","doi":"10.3389/ftox.2024.1479292","DOIUrl":"https://doi.org/10.3389/ftox.2024.1479292","url":null,"abstract":"<p><p>With the widespread use of plastic products and the increase in waste, microplastics and nanoplastics (MNPs) have become an important issue in global environmental pollution. In recent years, an increasing number of studies have shown that MNPs may have negative impacts on human health. This review aimed to explore the association between MNPs and cardiovascular disease and provide an outlook for future research. Research has shown that there may be a link between MNPs exposure and cardiovascular disease. Laboratory studies have shown that animals exposed to MNPs often exhibit abnormalities in the cardiovascular system, such as increased blood pressure, vascular inflammation, and myocardial damage. Epidemiological surveys have also revealed that people exposed to MNPs are more likely to suffer from cardiovascular diseases, such as hypertension and myocardial infarction. Although the specific impact mechanism is not fully understood, there are several possible pathways of action, including the effects of toxic substances on MNPs and interference with the endocrine system. In summary, MNPs exposure may have a negative impact on cardiovascular health, but further research is needed to confirm its specific mechanism and extent of impact to guide relevant public health and environmental policies.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11499192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142514139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New approach methodologies (NAMs) for the <i>in vitro</i> assessment of cleaning products for respiratory irritation: workshop report.","authors":"Lynne T Haber, Mark A Bradley, Amanda N Buerger, Holger Behrsing, Sabina Burla, Phillip W Clapp, Scott Dotson, Casey Fisher, Keith R Genco, Francis H Kruszewski, Shaun D McCullough, Kathryn E Page, Vivek Patel, Nathan Pechacek, Clive Roper, Monita Sharma, Annie M Jarabek","doi":"10.3389/ftox.2024.1431790","DOIUrl":"https://doi.org/10.3389/ftox.2024.1431790","url":null,"abstract":"<p><p>The use of <i>in vitro</i> new approach methodologies (NAMs) to assess respiratory irritation depends on several factors, including the specifics of exposure methods and cell/tissue-based test systems. This topic was examined in the context of human health risk assessment for cleaning products at a 1-day public workshop held on 2 March 2023, organized by the American Cleaning Institute^® (ACI). The goals of this workshop were to (1) review <i>in vitro</i> NAMs for evaluation of respiratory irritation, (2) examine different perspectives on current challenges and suggested solutions, and (3) publish a manuscript of the proceedings. Targeted sessions focused on exposure methods, <i>in vitro</i> cell/tissue test systems, and application to human health risk assessment. The importance of characterization of assays and development of reporting standards was noted throughout the workshop. The exposure methods session emphasized that the appropriate exposure system design depends on the purpose of the assessment. This is particularly important given the many dosimetry and technical considerations affecting relevance and translation of results to human exposure scenarios. Discussion in the <i>in vitro</i> cell/tissue test systems session focused on the wide variety of cell systems with varying suitability for evaluating key mechanistic steps, such as molecular initiating events (MIEs) and key events (KEs) likely present in any putative respiratory irritation adverse outcome pathway (AOP). This suggests the opportunity to further develop guidance around <i>in vitro</i> cell/tissue test system endpoint selection, assay design, characterization and validation, and analytics that provide information about a given assay's utility. The session on applications for human health protection emphasized using mechanistic understanding to inform the choice of test systems and integration of NAMs-derived data with other data sources (e.g., physicochemical properties, exposure information, and existing <i>in vivo</i> data) as the basis for <i>in vitro</i> to <i>in vivo</i> extrapolation. In addition, this group noted a need to develop procedures to align NAMs-based points of departure (PODs) and uncertainty factor selection with current human health risk assessment methods, together with consideration of elements unique to <i>in vitro</i> data. Current approaches are described and priorities for future characterization of <i>in vitro</i> NAMs to assess respiratory irritation are noted.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11493779/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142514140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ergot alkaloid control in biotechnological processes and pharmaceuticals (a mini review).","authors":"A Volnin, A Parshikov, N Tsybulko, P Mizina, N Sidelnikov","doi":"10.3389/ftox.2024.1463758","DOIUrl":"https://doi.org/10.3389/ftox.2024.1463758","url":null,"abstract":"<p><p>The control of ergot alkaloids in biotechnological processes is important in the context of obtaining new strain producers and studying the mechanisms of the biosynthesis, accumulation and secretion of alkaloids and the manufacturing of alkaloids. In pharmaceuticals, it is important to analyze the purity of raw materials, especially those capable of racemization, quality control of dosage forms and bulk drugs, stability during storage, etc. This review describes the methods used for qualitative and quantitative chemical analysis of ergot alkaloids in tablets and pharmaceutic forms, liquid cultural media and mycelia from submerged cultures of ergot and other organisms producing ergoalkaloid, sclerotias of industrial <i>Claviceps spp</i>. parasitic strains. We reviewed analytical approaches for the determination of ergopeptines (including their dihydro- and bromine derivatives) and semisynthetic ergot-derived medicines such as cabergoline, necergoline and pergolide, including precursors for their synthesis. Over the last few decades, strategies and approaches for the analysis of ergoalkaloids for medical use have changed, but the general principles and objectives have remained the same as before. These changes are related to the development of new genetically improved strains producing ergoalkaloids and the development of technologies for the online control of biotechnological processes and pharmaceutical manufacturing (\"process analytical technologies,\" PAT). Overall, the industry is moving toward \"smart manufacturing.\" The development of approaches to production cost estimation and product quality management, manufacturing management, increasing profitability and reducing the negative impact on personnel and the environment are integral components of sustainable development. Analytical approaches for the analysis of ergot alkaloids in pharmaceutical raw materials should have high enough specificity for the separation of dihydro derivatives, enantiomers and R-S epimers of alkaloids, but low values of the quantitative detection limit are less frequently needed. In terms of methodology, detection methods based on mass spectrometry have become more developed and widespread, but NMR analysis remains in demand because of its high accuracy and specificity. Both rapid methods and liquid chromatography remain in demand in routine practice, with rapid analysis evolving toward higher accuracy owing to improved analytical performance and new equipment. New composite electrochemical sensors (including disposable sensors) have demonstrated potential for real-time process control.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11493748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142514138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A systematic review of the toxic potential of parabens in fish.","authors":"Asok K Dasmahapatra, Joydeep Chatterjee, Paul B Tchounwou","doi":"10.3389/ftox.2024.1399467","DOIUrl":"10.3389/ftox.2024.1399467","url":null,"abstract":"<p><p>Parabens are the most prevalent ingredients in cosmetics and personal care products (PCPs). They are colorless and tasteless and exhibit good stability when combined with other components. Because of these unique physicochemical properties, they are extensively used as antimicrobial and antifungal agents. Their release into the aquatic ecosystem poses potential threats to aquatic organisms, including fish. We conducted an electronic search in PubMed (http://www.ncbi.nlm.nih.gov/pubmed) using the search term parabens and fish and sorted 93 articles consisting of methyl paraben (MTP), ethyl paraben (ETP), propyl paraben (PPP), butyl paraben (BTP), and benzyl paraben (BNP) in several fish species. Furthermore, we confined our search to six fish species (common carp, <i>Cyprinus carpio</i>; fathead minnows, <i>Pimephales promelas</i>; Japanese medaka, <i>Oryzias latipes</i>; rainbow trout, <i>Oncorhynchus mykiss</i>; Nile tilapia, <i>Oreochromis niloticus</i>; and zebrafish, <i>Danio rerio)</i> and four common parabens (MTP, ETP, PPP, and BTP) and sorted 48 articles for review. Our search indicates that among all six fish, zebrafish was the most studied fish and the MTP was the most tested paraben in fish. Moreover, depending on the alkyl chain length and linearity, long-chained parabens were more toxic than the parabens with short chains. Parabens can be considered endocrine disruptors (EDs), targeting estrogen-androgen-thyroid-steroidogenesis (EATS) pathways, blocking the development and growth of gametes, and causing intergenerational toxicity to impact the viability of offspring/larvae. Paraben exposure can also induce behavioral changes and nervous system disorders in fish. Although the USEPA and EU limit the use of parabens in cosmetics and pharmaceuticals, their prolonged persistence in the environment may pose an additional health risk to humans.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11491439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application and interpretation of immunophenotyping data in safety and risk assessment.","authors":"Victor J Johnson, Michael I Luster, Andrew Maier, Corey Boles, Eric W Miller, Daniel E Arrieta","doi":"10.3389/ftox.2024.1409365","DOIUrl":"10.3389/ftox.2024.1409365","url":null,"abstract":"<p><p>The use of immunophenotyping during immunotoxicity investigations was first popularized in the 1980 s and has since become more integrated into diagnostic and non-clinical assessments. The data provided from immunophenotyping can serve as an initial source of information to guide decisions for additional, more advanced, immunotoxicity testing as well as for human health safety and risk assessment of drugs and chemicals. However, comprehensive guidance describing applications of immunophenotyping data in immunotoxicity investigations is lacking, particularly among regulatory bodies. Therefore, a critical examination is needed for the appropriate interpretations and potential misinterpretations of such data during the assessment of drug safety and chemical risk. As such, the current uses and implications of immunophenotyping data in human health safety and risk assessments has been evaluated to provide additional context for the application of current methodologies and guidelines. In addition, case studies are presented to highlight the challenges of interpreting immunophenotyping results along with incorporating the findings into immunotoxicity investigations. Based on the analyses of current approaches and methodologies, a decision flow is presented for use of immunophenotyping data during risk informed decision making.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11486759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fulfilling the criteria for CLP classification: the implications for substances under the EU chemicals legislation.","authors":"Diana Kättström, Anna Beronius, Urban Boije Af Gennäs, Christina Rudén, Marlene Ågerstrand","doi":"10.3389/ftox.2024.1452065","DOIUrl":"https://doi.org/10.3389/ftox.2024.1452065","url":null,"abstract":"<p><p>The CLP mandates manufacturers and importers to classify substances and mixtures according to hazard criteria, with notifications submitted to the European Chemicals Agency (ECHA). Substances meeting hazard criteria must be appropriately labelled and packaged to communicate hazards effectively. The CLP establishes hazard classification criteria but does not independently prohibit or restrict the use of hazardous chemicals. Instead, it serves as a basis for regulatory obligations in other specific regulations. This study investigates the regulatory implications of meeting hazard criteria under the CLP across EU regulations and directives listed in EU Chemicals Legislation Finder (EUCLEF). The results show that fulfilling criteria for human health hazard classes trigger regulatory obligations in the highest number of regulations/directives, with carcinogenicity, mutagenicity, and reproductive toxicity (CMR) leading to obligations in 19 of 20 pieces of legislation linked to the CLP. Conversely, physical, environmental, and ozone layer hazards are associated with fewer regulations and directives, and lead to fewer prohibitions. The study underscores the pivotal role of the CLP in EU chemical legislation and the need for coherence and consistency across regulations. While regulatory obligations are primarily aimed at substances meeting hazard criteria, the variability in self-classification notifications and limitations in harmonized classification processes were observed. Moreover, the complexity of the regulatory structure poses challenges for stakeholders and policymakers, including inconsistencies, compliance difficulties, and the need for frequent revisions. Addressing these challenges is critical for enhancing regulatory effectiveness and ensuring a more coherent and harmonized approach to chemical management in the EU.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11484064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neonicotinoid pesticides: evidence of developmental neurotoxicity from regulatory rodent studies.","authors":"Jennifer Beth Sass, Nathan Donley, William Freese","doi":"10.3389/ftox.2024.1438890","DOIUrl":"https://doi.org/10.3389/ftox.2024.1438890","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Neonicotinoids are the most widely used class of insecticides in the United States (U.S.). and the world. Consistent with their high use and persistence, neonicotinoids are often found contaminating drinking water and food. They are also detected in human urine, breast milk, amniotic and cerebrospinal fluids, as well as the brains of treated rodents. Neonicotinoids were once thought to pose little neurotoxic risk to humans, but a growing body of research challenges that assumption. In this study we provide the first comprehensive assessment of unpublished rodent developmental neurotoxicity (DNT) studies on five neonicotinoids that were submitted to the U.S. Environmental Protection Agency (EPA) by neonicotinoid manufacturers. Groups of female rats were administered three different doses of a neonicotinoid during pregnancy and lactation, and their offspring subjected to various neurological tests and brain measurements. We identified nicotine-like effects such as reduced brain size, indicative of neuronal cell loss. Statistically significant shrinkage of brain tissue was observed in high-dose offspring for five neonicotinoids: acetamiprid, clothianidin, imidacloprid, thiacloprid, and thiamethoxam. Two brain regions reduced in the rodent studies-the corpus callosum and caudate-putamen-tend to be smaller in people diagnosed with attention-deficit hyperactivity disorder (ADHD), and in children of mothers who smoked during pregnancy, suggesting a possible link between perinatal neonicotinoid exposure and ADHD. A decreased auditory startle reflex was reported for acetamiprid at all doses and was statistically significant in the mid- and high-dose offspring, and for clothianidin in juvenile high-dose females. No mid- or low-dose brain morphometric data were submitted for acetamiprid, imidacloprid, or thiacloprid. Thiamethoxam mid- and low-dose brain morphometric data were provided to EPA upon request. Only partial mid-dose brain morphometry data were submitted for clothianidin, but no low-dose data. Yet despite this lack of data, EPA concluded that only the high-dose brain morphometric effects were treatment-related-setting the mid-dose as the study's No Observed Adverse Effect Level (NOAEL) or failing to find a definitive NOAEL for acetamiprid, clothianidin, imidacloprid, thiacloprid and thiamethoxam. We found numerous deficiencies in EPA's regulatory oversight and data analyses. EPA dismissed statistically significant adverse effects, accepted substandard DNT studies despite lack of valid positive control data, and allowed neonicotinoid registrants to unduly influence agency decision-making. We conclude that perinatal exposure to neonicotinoids and their metabolites induces adverse, nicotine-like neurotoxic effects in rodent bioassays, and that the exposure limits set by EPA for human exposure are either not protective or not supported by available neurotoxicity data. We propose regulatory changes to empower EPA to better protect public health f","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11480014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}