Critical Reviews in Toxicology最新文献

{"title":"Female reproductive toxicity after exposure to malathion or diazinon: a systematic review of rodent and human studies.","authors":"Indiamara Guesser Barbosa, Virgínia Meneghini Lazzari, Gabriel Adan Araújo Leite","doi":"10.1080/10408444.2025.2548581","DOIUrl":"10.1080/10408444.2025.2548581","url":null,"abstract":"<p><p>Malathion and diazinon are pesticides widely used in agriculture as well as for domestic and veterinary purposes to control pests, such as scale insects, aphids, and fleas. However, these compounds may have harmful effects on the female genital system in humans and animals. This study conducted a systematic review of the scientific literature on the female reproductive effects in humans and rodents exposed to malathion or diazinon. The search was conducted from March to September 2024 and was updated in July 2025. It was carried out in the Embase, LILACS, PubMed, SciELO, Scopus, and Web of Science databases by using different combinations of the terms \"diazinon\", \"malathion\", \"ovary\", \"uterus\", \"female reproduction\", \"humans\", \"rats\", and \"mice\" accompanied by the Boolean operators AND or OR. A total of 241 articles were found when the search was conducted using rats or mice as exposed organisms. After removing the duplicates and excluding the articles that showed administration routes not applicable to humans and the studies that were unavailable in full, only seven articles were included in this systematic review. These studies were assessed in relation to the risk of bias as recommended by the SYRCLE's risk of bias tool. For the search involving human studies, 291 articles were found; however, only four articles were deemed relevant for this review after removing the duplicates and the studies that did not meet the eligibility criteria. Then, the included studies were evaluated in relation to the risk of bias as recommended by the Newcastle-Ottawa Scale. Afterwards, the extraction of the results was performed, and the outcomes were organized in tables. When possible, a meta-analysis was carried out with all the studies that assessed the same sexual steroid and gonadotrophic hormones in females. In this review, the results demonstrated that malathion and diazinon impair female reproduction in rodents by reducing ovarian hormone production, increasing oxidative stress, diminishing oocyte quality, and inducing histopathological changes in the reproductive organs. In humans, the included studies demonstrated that exposure to these pesticides is associated with a higher risk for developing endometriosis and an increased risk of ovarian, uterine, and thyroid cancers. After assessing the effects of these organophosphates on hormonal levels by meta-analysis in this review, it was shown a reduction in progesterone concentrations (reduction of 37.43%; overall effect size: <i>Z</i> = 2.05, <i>p</i> = 0.04; mean difference and confidence interval: -9.33 [-18.23, -0.43]) but there were no effects in estradiol (overall effect size: <i>Z</i> = 0.31, <i>p</i> = 0.76; mean difference and confidence interval: 2.66 [-14.21, -19.54]), testosterone (overall effect size: <i>Z</i> = 0.91, <i>p</i> = 0.36; mean difference and confidence interval: 0.08 [-0.09, 0.24]), FSH (overall effect size: <i>Z</i> = 0.86, <i>p</i> = 0.39; mean difference and confidence inte","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"796-807"},"PeriodicalIF":4.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbial degradation mechanisms, degradation pathways, and genetic engineering for pyrethroids: current knowledge and future perspectives.","authors":"Jiahui Wu, Hui Peng, Peng Cheng, Hongmei Liu, Ye Zhang, Maoqing Gong","doi":"10.1080/10408444.2024.2433632","DOIUrl":"10.1080/10408444.2024.2433632","url":null,"abstract":"<p><p>Pyrethroids are synthetic products derived from natural pyrethroids present in flowers and are extensively used as pesticides for agriculture, animal husbandry, and household pest control. However, excessive and prolonged usage of pyrethroid insecticides can result in adverse effects on both non-target and target species. Therefore, effective technologies need to be developed to remove pyrethroid contamination and ensure environmental safety. Microbial remediation of various pesticide contaminants is highly practicable, low cost, and eco-friendly compared to physical and chemical methods. Different microbiota are screened to eliminate or degrade the contaminants. Microbial remediation technology utilizes the natural ability of microbiota to treat contaminated areas. Previous studies have mostly focused on the isolation and screening of microorganisms for pyrethroid biodegradation, as well as on the kinetics and pathways of pyrethroid biodegradation. In order to develop effective bioremediation strategies, further research based on molecular biology and bioengineering is required for a comprehensive exploration of pyrethroid-degrading microorganisms. To date, the microbial degradation of pyrethroid pesticides and the underlying mechanisms have been rarely reviewed. Therefore, this critical review encompasses the latest knowledge on synthetic pyrethroids from structural properties, bio-toxicity, and characterization of microbial degradation strains to degradation characteristics, intrinsic mechanisms, and microbial degradation pathways. The future of microbial remediation depends on combining advanced gene technology with traditional bioremediation methods to sustainably degrade pesticide contaminants. It also summarizes the factors affecting degradation efficiency and concludes with prospects, along with current challenges and limitations.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"80-104"},"PeriodicalIF":5.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comparative toxicological and epidemiological evaluation of dioxins and PFAS chemicals.","authors":"Dennis Paustenbach, Karmen Kissell, Aryatara Shakya","doi":"10.1080/10408444.2025.2560827","DOIUrl":"10.1080/10408444.2025.2560827","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Regulatory frameworks, informed by robust and transparent scientific evidence, can significantly benefit society when thoughtful and measured regulation is promulgated. However, regulations founded on incomplete or misinterpreted science often result in unintended consequences. As was the case with the polychlorinated dibenzodioxin and polychlorinated dibenzofuran (PCDD/PCDF) chemicals, for the past 50 years, there has been a lack of scientific consensus on the adverse health effects of per- and polyfluoroalkyl substances (PFAS) in humans at current blood concentrations (about 4 ppb TEQ) or even concentrations 10-300-fold higher (40-1200 ppb TEQ). Despite their distinctly different chemical structures, the dioxins, particularly 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and perfluorooctanoic acid (PFOA)/perfluorooctanesulfonic acid (PFOS), share notable similarities: environmental persistence, biological recalcitrance, slightly unpredictable acute toxicity, a lack of genotoxicity, and suggestive data on adverse health effects in humans; across a wide range of doses. Both substances display varying degrees of acute toxicity across species, and both have been associated with the onset of wasting syndrome in certain animals at fairly high doses, but wasting syndrome is not seen in humans. Although there is moderate to high acute toxicity in multiple animal species for both families of chemicals, there is low acute toxicity in humans. In humans, both compounds interact with fatty acid metabolism. The evidence indicates that both are either weakly genotoxic or non-genotoxic. The dioxins can cause cancer in a variety of animal species, but even in humans exposed to high doses, no increased cancer risk is apparent. PFAS chemicals are similar; weakly carcinogenic in animals and, perhaps, lacking carcinogenic potency in humans. However, unlike with dioxins, high human exposure to PFAS has only occurred in the workplace; thus, few data from highly exposed human populations are available to rigorously evaluate the human cancer risk or other potential effects at elevated doses. Similar to the widespread presence of dioxins reported in the 1970s-1980s, PFAS chemicals are now globally ubiquitous, with detectable concentrations in nearly every individual, fish, and wildlife species. As awareness has increased over time, pressure to prevent the release or manufacture of PFOA and PFOS has decreased the blood concentrations in Americans by 10-fold over the past 15 years, paralleling trends observed with the dioxins when global concerns surfaced. The dioxins were regulated in a heavy-handed manner despite scientific uncertainty regarding their human health risks over a range of exposure levels, as well as a lack of consensus on dose-response relationships, thresholds for adverse effects, and human relevance of high-dose animal studies. The regulatory actions that occurred with the dioxins ultimately resulted in substantial economic and societal costs, even i","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"809-866"},"PeriodicalIF":4.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145547582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Use and limitations of clinical data in the identification and classification of low molecular weight chemicals (LMWCs) as respiratory sensitizers: recommendations for improvement.","authors":"Julia Scheel, Nora L Krutz, Ramya Rajagopal, Nikaeta Sadekar, Stuart Hindle, Christina Hickey, Clive Campbell, Phil Botham","doi":"10.1080/10408444.2024.2433222","DOIUrl":"10.1080/10408444.2024.2433222","url":null,"abstract":"<p><p>While progress has been made in recent years, there are still no suitable and accepted <i>in silico</i>, <i>in vitro,</i> or <i>in vivo</i> models that can be used to accurately predict whether a chemical substance has the intrinsic property to cause immune-mediated chemical respiratory allergy, typically manifested as allergic asthma or allergic rhinitis which represents a severe health hazard. Regulatory authorities have relied primarily on clinical evidence (case reports, clinical databases, worker exposure studies) to classify substances as respiratory sensitizers, but this evidence can lack a proven immunological mechanism which is necessary to identify substances which can cause life-long sensitization and clinically relevant allergic symptoms in the respiratory tract in an exposed population (such respiratory allergens may be considered as \"true\" sensitizers, in analogy to the definition of skin sensitization, and in contrast to respiratory irritants). In light of this, the European Center for Ecotoxicology and Toxicology of Chemicals convened a Task Force to evaluate the types of clinical methods and data sources and the implications of relying on such data for regulatory decision making from a scientific perspective. Recognizing that there are benefits and important insights from using such data, significant shortcomings were identified. With clinical work being focused on treatment and diagnosis of individual patients, the approaches and methods used for clinical guidance, diagnostics and reporting have serious limitations in proving the respiratory sensitization potential of a specific chemical, definitely restricting their suitability in deriving legally binding hazard classifications for human health protection. Even within the current broader regulatory definition of respiratory sensitization, a robust assessment and sound evidence of causation by a specific chemical seems mandatory in order to avoid misclassifications. Application of a systematic weight-of-evidence approach is considered suitable to determine the level of confidence, including a thorough assessment of the specificity or non-specificity of observed bronchial hyperreactivity. Recommendations proposed in this publication may not only aid industry and regulators in their decision making but also facilitate a further exchange between stakeholders to improve the data used to (a) more precisely identify true respiratory sensitizers to effectively protect human health, (b) aid evaluation of potential predictive models, and (c) encourage regulators to clarify guidance and to consider a re-evaluation of the current regulatory definition of respiratory sensitizers.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"27-54"},"PeriodicalIF":5.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Letter to the Editor: Critical analysis of \"The use of canonical dose-response models for benchmark dose analysis of continuous toxicological data\" by Slob et al. (2025).","authors":"José Cortiñas Abrahantes, Efisio Solazzo, Marc Aerts, Peter Craig, Ursula Gundert-Remy, Thor Halldorsson, Laurentius Hoogenboom, Salomon Sand, Thomas Tietz","doi":"10.1080/10408444.2025.2581776","DOIUrl":"10.1080/10408444.2025.2581776","url":null,"abstract":"","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"1111-1115"},"PeriodicalIF":5.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Letter to the editor regarding the review article: Yamada T, Cohen SM, Lake BG. The modes of action for rodent liver tumor formation by activators of the constitutive androstane receptor (CAR) and the peroxisome proliferator-activated receptor alpha (PPARα) are not relevant to human cancer risk: an updated critical evaluation. Crit Rev Toxicol. 2025;55(5):549-586. doi: 10.1080/10408444.2025.2513332.","authors":"C Roland Wolf, Colin J Henderson, Michael Schwarz, Francesco Inesta-Vaquera, Richard R Meehan","doi":"10.1080/10408444.2025.2601199","DOIUrl":"10.1080/10408444.2025.2601199","url":null,"abstract":"","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"1123-1125"},"PeriodicalIF":5.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In search of certainty beyond the cholinergic system: a systematic review of developmental chlorpyrifos exposure and neurotransmitter systems disruption in preclinical models.","authors":"Cristian Perez-Fernandez, Diego Ruiz-Sobremazas, Mario Ruiz-Coca, Fernando Sánchez-Santed, Miguel Morales-Navas","doi":"10.1080/10408444.2025.2543405","DOIUrl":"10.1080/10408444.2025.2543405","url":null,"abstract":"<p><p>Chlorpyrifos (CPF) is one of the most widely used pesticides globally, despite being strictly regulated and banned in several developed countries. It remains in use across many developing and underdeveloped nations. While its primary mechanism of action is acetylcholinesterase inhibition, multiple preclinical and clinical studies have reported developmental and cognitive alterations at lower doses that do not trigger this mechanism. These effects are particularly concerning during early development, when the central nervous system is immature and more vulnerable. Although various alternative molecular targets have been proposed, growing attention has been given to neurotransmitter systems beyond the cholinergic pathway. However, empirical data is inconsistent, and no qualitative or quantitative reviews have provided a clear understanding of these mechanisms. This systematic review aims to address this gap, focusing on preclinical rodent studies. Using a rigorous methodology, 41 studies were included in the qualitative analysis, covering 126 outcomes related to the dopaminergic, serotonergic, GABAergic, glutamatergic, and endocannabinoid systems. Overall, the included studies showed a low level of methodological quality and a high risk of bias. Only a few molecular targets were systematically investigated. We introduce two new evaluative metrics-Weight of Evidence and Percentage of Convergence-to highlight five key findings. Notably, preweaning CPF exposure consistently reduced the activity of endocannabinoid-degrading enzymes (FAAH and MAGL), resulting in elevated endocannabinoid tone, particularly increased levels of AEA. Additionally, there is consistent support for CPF-induced serotonergic alterations, particularly upregulation of 5HT2 and 5HT1A receptors following neonatal exposure. Due to insufficient data convergence across laboratories, a meta-analysis was deemed inappropriate. In conclusion, while numerous molecules have been linked to low-dose developmental CPF exposure, only a limited number show consistent empirical support, and only under postnatal exposure conditions. Future research should investigate prenatal exposure effects more systematically and replicate postnatal findings across independent laboratories to strengthen the reliability of these promising results through robust, quantitative analyses.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"751-776"},"PeriodicalIF":4.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>In vitro</i> human brain barrier models for studying thyroid hormone transport.","authors":"Kim Heikamp, Timo Hamers, Ellen V S Hessel","doi":"10.1080/10408444.2025.2540446","DOIUrl":"10.1080/10408444.2025.2540446","url":null,"abstract":"<p><p>Early brain development is dependent on the supply of thyroid hormone (TH) to the fetal brain. Disruption of TH concentrations in early brain development is associated with lower IQ and delayed motor development in children. How TH system disruption may affect brain development has mainly been studied in animal models that are not always relevant to humans and do not reflect the TH system in the developing brain. Furthermore, using animal models for safety assessments also raises ethical concerns, is still low-throughput and associated with high costs. All these reasons stress the need to develop new approach methodologies (NAMs), including <i>in vitro</i> methods that help to improve human relevant risk assessment. Initiatives are taken to develop <i>in vitro</i> assays for important key events in the fetal brain, but before TH can enter the fetal brain, it has to pass the developing blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). During brain development, the composition of the barriers change over time, as well as the interplay between the two different barriers. Therefore, barrier models need to be included in testing strategies for TH system disruption in the developing brain and these models should take the timepoint of development into account. Barriers are crucial for the supply of TH in the brain. TH is actively transported through these barriers via TH transmembrane transporters (THTMTs) such as MCT8 and OATP1C1, but alternatively, other THTMTs may be involved too. Furthermore, transport of TH across the brain barriers can be disrupted by chemicals. Currently, the extent of THTMT inhibition and its subsequent adverse effects on brain development is largely undiscovered. To further investigate TH transport across the BBB and BCSFB, human cell-based NAMs are being developed that more closely resemble the human brain barriers. These models take the complex cellular composition of the brain barriers into account and in case of organ-on-chip models, the blood/cerebrospinal fluid flow as well. In this review, aspects of accurate <i>in vitro</i> models ranging from simple mono-cultures to extended 3D cultures of the brain barriers are discussed as well as how (a combination of) these <i>in vitro</i> models can be utilized to study TH transport and its disruption in the brain.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"645-661"},"PeriodicalIF":4.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"European Food Safety Authority database for <i>in vivo</i> developmental neurotoxicity studies of pesticides.","authors":"Iris Mangas, Eliana Spilioti, Andrea Terron, Martina Panzarea, Monica Nepal, Barbara Viviani, Marco Binaglia, Kevin M Crofton","doi":"10.1080/10408444.2025.2521280","DOIUrl":"10.1080/10408444.2025.2521280","url":null,"abstract":"<p><p>Current evidence on the prevalence of neurodevelopmental disorders has raised concerns over the environmental etiology for developmental neurotoxicity. As the use of standardized <i>in vivo</i> developmental neurotoxicity methods has been restricted due to high costs, limited testing capacity and extrapolation uncertainties, a shift to implementation of higher throughput technologies is urgently needed. A fit-for-purpose Developmental Neurotoxicity <i>In Vitro</i> Battery based on New Approach Methodologies has been recently developed to support the regulatory decision-making process. To increase confidence in its predictive performance and readiness, the authors, under the auspices of European Food Safety Authority, have created a curated database of <i>in vivo</i> study results from developmental neurotoxicity guideline or guideline-like <i>in vivo</i> studies. Methods, data and results from publicly available US Environmental Protection Agency Data Evaluation Records have been entered into a standardized data extraction model, developed to facilitate quantitative data collection and harmonization. The goal of the present work was to build a transparent and publicly available database of developmental neurotoxicity data from guideline studies, suitable for comparison with outputs from NAM assays such as the Developmental Neurotoxicity <i>In Vitro</i> battery. This effort represents a significant advancement for future analyses and will serve as a key stone for the development of transparent and publicly accessible databases of developmental neurotoxicity data.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"587-598"},"PeriodicalIF":4.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms of developmental neurotoxicity mediated by perturbed thyroid hormone homeostasis in the brain: an adverse outcome pathway network.","authors":"Nathalie T O M Dierichs, Aldert H Piersma, Robin P Peeters, W Edward Visser, Marcel E Meima, Ellen V S Hessel","doi":"10.1080/10408444.2025.2461076","DOIUrl":"10.1080/10408444.2025.2461076","url":null,"abstract":"<p><p>Thyroid hormone (TH) is crucial for proper neurodevelopment. Insufficient TH concentrations in early life are associated with lower IQ and delayed motor development in children. Intracellular levels of TH are modulated via the transmembrane transport of TH and intracellular deiodination, and can mediate gene transcription via binding to the nuclear TH receptor. Chemical exposure can disrupt TH homeostasis via modes of action targeting intracellular mechanisms, thereby potentially influencing TH transport, deiodination or signaling. Understanding the cause and effect relationships of chemical hazards interfering with TH homeostasis in the developing brain is necessary to identify how chemicals might disturb brain development and result in neurodevelopmental disorders. Adverse Outcome Pathways (AOPs) can provide a template for mapping these relationships, and so far multiple AOPs have been developed for TH homeostasis and adverse effects on cognition. The present review aims to expand current AOP networks by (1) summarizing the most important factors in the regulation of brain development under influence of TH, (2) integrating human-based mechanistic information of biological pathways which can be disturbed by TH disrupting chemicals, and (3) by incorporating brain-specific TH-mediated physiology, including barriers and cell specificity, as well as clinical knowledge. TH-specific pathways in the fetal brain are highlighted and supported by distinguishing cell type specific Molecular Initiating Events (MIEs) and downstream Key Events (KEs) for astrocytes, neurons and oligodendrocytes. Two main pathways leading to adverse outcomes (AOs) in the areas of 'cognition' and 'motor function' are decreased myelination due to oligodendrocyte dysfunction, and decreased synaptogenesis and network formation via the neurons. The proposed AOP framework can form a basis for selecting developmental neurotoxic <i>in vitro</i> and <i>in silico</i> test systems for an innovative human-focused hazard testing strategy and risk assessment of chemical exposure.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"304-320"},"PeriodicalIF":5.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}