Critical Reviews in Toxicology最新文献

{"title":"Mechanistic insights regarding neuropsychiatric and neuropathologic impacts of air pollution.","authors":"Katherine M Rentschler, Urmila P Kodavanti","doi":"10.1080/10408444.2024.2420972","DOIUrl":"10.1080/10408444.2024.2420972","url":null,"abstract":"<p><p>Air pollution is a significant environmental health risk for urban areas and developing countries. Air pollution may contribute to the incidence of cardiopulmonary and metabolic diseases. Evidence also points to the role of air pollution in worsening or developing neurological and neuropsychiatric conditions. Inhaled pollutants include compositionally differing mixtures of respirable gaseous and particulate components of varied sizes, solubilities, and chemistry. Inhalation of combustibles and volatile organic compounds (VOCs) or other irritant particulate matter (PM) may trigger lung sensory afferents which initiate a sympathetic stress response <i>via</i> activation of the hypothalamic-pituitary-adrenal (HPA) and sympathetic-adrenal-medullary (SAM) axes. Activation of SAM and HPA axes are associated with selective inhibition of hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-thyroid (HPT) axes following exposure. Regarding chronic exposure in susceptible hosts, these changes may become pathological by causing neuroinflammation, neurotransmitter, and neuroendocrine imbalances. Soluble PM, such as metals and nano-size particles may translocate across the olfactory, trigeminal, or vagal nerves through retrograde axonal transport, or through systemic circulation which may disrupt the blood-brain barrier (BBB) and deposit in neural tissue. Neuronal deposition of metallic components can have a negative impact through multiple molecular mechanisms. In addition to systemic translocation, the release of pituitary and stress hormones, altered metabolic hormonal status and resultant circulating metabolic milieu, and sympathetically and HPA-mediated changes in immune markers, may secondarily impact the brain through a variety of regulatory adrenal hormone-dependent mechanisms. Several reviews covering air pollution as a risk factor for neuropsychiatric disorders have been published, but no reviews discuss the in-depth intersection between molecular and stress-related neuroendocrine mechanisms, thereby addressing adaptation and susceptibility variations and link to peripheral tissue effects. The purpose of this review is to discuss evidence regarding neurochemical, neuroendocrine, and molecular mechanisms which may contribute to neuropathology from air pollution exposure. This review also covers bi-directional neural and systemic interactions which may raise the risk for air pollution-related systemic illness.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"953-980"},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12043015/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Objective causal predictions from observational data.","authors":"Louis Anthony Cox","doi":"10.1080/10408444.2024.2399856","DOIUrl":"10.1080/10408444.2024.2399856","url":null,"abstract":"<p><p>Many recent articles in public health risk assessment have stated that causal conclusions drawn from observational data must rely on inherently untestable assumptions. They claim that such assumptions ultimately can only be evaluated by informed human judgments. We call this the <i>subjective approach</i> to causal interpretation of observational results. Its theoretical and conceptual foundation is a potential outcomes model of causation in which counterfactual outcomes cannot be observed. It risks depriving decision-makers and the public of the key benefits of traditional objective science, which invites scrutiny and independent verification through testable causal models and interventional hypotheses. We introduce an alternative <i>objective approach</i> to causal analysis of exposure-response relationships in observational data. This is designed to be more objective in the specific sense that it is independently verifiable (or refutable) and data-driven, requiring no inherently untestable assumptions. This approach uses empirically testable interventional causal models, specifically causal Bayesian networks (CBNs), instead of untestable potential outcomes models. It enables empirical validation of causal claims through Invariant Causal Prediction (ICP) tests across multiple studies. We explain how to use CBNs and individual conditional expectation (ICE) plots to quantify the effects on health risks of changing exposures while taking into account realistic complexities such as imperfectly controlled confounding, missing data, and measurement error. By ensuring that all causal assumptions are explicit and empirically testable, our framework may help to improve the reliability and transparency of causal inferences in health risk assessments.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"895-924"},"PeriodicalIF":5.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460008","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":"Thank you to authors and reviewers of papers in Critical Reviews in Toxicology (CRT) volume 54, 2024.","authors":"Roger O McClellan","doi":"10.1080/10408444.2024.2440252","DOIUrl":"https://doi.org/10.1080/10408444.2024.2440252","url":null,"abstract":"","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":"54 10","pages":"695"},"PeriodicalIF":5.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876605","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":"Xylene: weight of evidence approach case study to determine the need for an extended one generation reproductive study with a developmental neurotoxicity animal cohort.","authors":"Frank Faulhammer, Martijn Rooseboom, Neslihan Aygun Kocabas, Josje H E Arts, Alexandra Cordova, Elaine Freeman, Larry G Higgins, Muna Nahar, Emily Richmond, Steffen Schneider, Keith Morris-Schaffer","doi":"10.1080/10408444.2024.2413073","DOIUrl":"10.1080/10408444.2024.2413073","url":null,"abstract":"<p><p>Xylene is a high production volume chemical that is widely used as a solvent and polymer precursor, and is currently undergoing substance evaluation under Registration, Evaluation, Authorization and Restriction of Chemicals (REACH). Xylenes recently received testing decisions on one-generation reproductive toxicity (EOGRT) studies with additional developmental neurotoxicity (DNT) cohorts for each of the three isomers. Xylene presents a unique opportunity to investigate the need for additional animal DNT toxicology testing because it is a legacy industrial chemical for which a significant amount of animal and human data already exists on its toxicity profile, including central nervous system effects. Therefore, to address the need for further vertebrate testing, a comprehensive weight of evidence (WOE) review of published and previously unpublished new studies of xylene substances was performed. Evidence topics included the pharmacokinetics, narcotic effects in humans and animals, narcotic mode of action (MOA), and strength of DNT signal for xylene. Pharmacokinetic data indicate minimal distribution of the unmetabolized parent compound to the fetus relative to parental brain tissue, and rapid metabolism of xylene to methyl hippuric acid (MHA), which is also rapidly excreted in both humans and animals. Xylene exposure has also resulted in transient, nonspecific neurological effects including delays in reaction time of human volunteers and reductions in motor activity of animals. This narcotic MOA for xylene occurs by the nonspecific perturbation of nervous cell membrane phospholipids, such that membrane-bound proteins and their respective functions are impaired. Furthermore, an in-depth review of the available DNT data indicates significant methodological deficiencies in several studies in the literature purported to provide evidence of a DNT concern following xylene exposure and no DNT concern reported in one reliable study. In conclusion, based on xylene's pharmacokinetics, narcotic effects on the central nervous system observed in animal and human studies, its narcotic MOA, and the lack of a robust signal from the published DNT studies, there is no trigger for the additional EOGRT study DNT cohort to be conducted for xylene. Further, the findings on narcotic effects and MOA underscore the difficulty in separating transient, acute intoxication effects <i>via</i> direct exposure of the offspring from investigating DNT effects (as investigated in a standard guideline (426) DNT study) in the EOGRT study, therefore producing unreliable data, which is ethically at odds with REACH and 3 R principles.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"925-952"},"PeriodicalIF":5.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616363","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":"Comprehensive analysis of the toxicity-related findings from repeated-dose subacute toxicity studies of industrial chemicals in male rats.","authors":"Jun-Ichi Takeshita, Yoshitaka Goto, Shinji Yamamoto, Takamitsu Sasaki, Kouichi Yoshinari","doi":"10.1080/10408444.2024.2427221","DOIUrl":"10.1080/10408444.2024.2427221","url":null,"abstract":"<p><p>The demand for alternatives to animal testing has increased, but there has been no significant progress in developing alternatives for repeated-dose toxicity tests despite their importance in chemical risk assessment. A comprehensive analysis of existing toxicity studies is the first step toward understanding toxicity and developing alternatives. However, such an analysis has yet to be performed for industrial chemicals. Therefore, we collected and organized publicly available repeated-dose subacute toxicity studies in male rats and constructed a database consisting of more than 2000 toxicity studies with about 500 toxicity-related findings. We then analyzed the no observed effect and lowest observed effect levels, toxicity-related findings, and organ categories in the database. The analyses revealed commonly and uncommonly observed toxicity-related findings and organ categories, as well as toxicity-related findings and organ categories with low and high median lowest observed effect levels. In addition, we extracted the toxicity studies registered in the Japanese and European chemical regulatory systems and conducted the same analysis for these datasets as the entire database. The results suggest that commonly observed toxicity-related findings were similar, but some toxicity-related findings differed in the frequency of observations between the two datasets.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"996-1010"},"PeriodicalIF":5.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784390","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 systematic review of herbicide safener toxicity.","authors":"Derek Simonsen, Vanessa Livania, David M Cwiertny, Riley J Samuelson, John D Sivey, Hans-Joachim Lehmler","doi":"10.1080/10408444.2024.2391431","DOIUrl":"10.1080/10408444.2024.2391431","url":null,"abstract":"<p><p>Herbicide safeners are agrochemicals added to herbicide formulations to protect crops from herbicide damage without reducing the effectiveness of the herbicide against weeds. While safeners are typically structurally similar to their co-formulated herbicides, they are classified as \"inert\" in the United States, meaning they are not held to the same regulatory standards as the herbicides. This review systematically examines the toxicity of safeners, which is important given their large-scale global use and potential for exposure to wildlife, livestock, and humans. A systematic review of peer-reviewed literature identified only seven studies examining safener toxicity. Regulatory toxicity data, compiled from the European Chemicals Agency (ECHA) database, included data for 9 of the 18 commercial safeners. Most safeners have low acute ecotoxicity and mammalian toxicity; however, chronic effects and the underlying mechanism are less clear. Benoxacor showed enantioselective metabolism and depletion by drug-metabolizing enzymes. In conclusion, despite the widespread use of safeners, significant knowledge gaps exist regarding their toxicity. More research is needed to fully characterize the potential risks of safeners to human health and the environment. Regulatory agencies should consider reclassifying safeners as active ingredients to ensure adequate toxicity testing and risk assessment.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"805-855"},"PeriodicalIF":5.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11666415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular similarity in chemical informatics and predictive toxicity modeling: from quantitative read-across (q-RA) to quantitative read-across structure-activity relationship (q-RASAR) with the application of machine learning.","authors":"Arkaprava Banerjee, Supratik Kar, Kunal Roy, Grace Patlewicz, Nathaniel Charest, Emilio Benfenati, Mark T D Cronin","doi":"10.1080/10408444.2024.2386260","DOIUrl":"10.1080/10408444.2024.2386260","url":null,"abstract":"<p><p>This article aims to provide a comprehensive critical, yet readable, review of general interest to the chemistry community on molecular similarity as applied to chemical informatics and predictive modeling with a special focus on read-across (RA) and read-across structure-activity relationships (RASAR). Molecular similarity-based computational tools, such as quantitative structure-activity relationships (QSARs) and RA, are routinely used to fill the data gaps for a wide range of properties including toxicity endpoints for regulatory purposes. This review will explore the background of RA starting from how structural information has been used through to how other similarity contexts such as physicochemical, absorption, distribution, metabolism, and elimination (ADME) properties, and biological aspects are being characterized. More recent developments of RA's integration with QSAR have resulted in the emergence of novel models such as ToxRead, generalized read-across (GenRA), and quantitative RASAR (q-RASAR). Conventional QSAR techniques have been excluded from this review except where necessary for context.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"659-684"},"PeriodicalIF":4.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12010357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mode of action of dieldrin-induced liver tumors: application to human risk assessment.","authors":"James E Klaunig, Samuel M Cohen","doi":"10.1080/10408444.2024.2377208","DOIUrl":"10.1080/10408444.2024.2377208","url":null,"abstract":"<p><p>Dieldrin is an organochlorine insecticide that was widely used until 1970 when its use was banned because of its liver carcinogenicity in mice. Several long-term rodent bioassays have reported dieldrin to induce liver tumors in in several strains of mice, but not in rats. This article reviews the available information on dieldrin liver effects and performs an analysis of mode of action (MOA) and human relevance of these liver findings. Scientific evidence strongly supports a MOA based on CAR activation, leading to alterations in gene expression, which result in increased hepatocellular proliferation, clonal expansion leading to altered hepatic foci, and ultimately the formation of hepatocellular adenomas and carcinomas. Associative events include increased liver weight, centrilobular hypertrophy, increased expression of Cyp2b10 and its resulting increased enzymatic activity. Other associative events include alterations of intercellular gap junction communication and oxidative stress. Alternative MOAs are evaluated and shown not to be related to dieldrin administration. Weight of evidence shows that dieldrin is not DNA reactive, it is not mutagenic, and it is not genotoxic in general. Furthermore, activation of other pertinent nuclear receptors, including PXR, PPARα, AhR, and estrogen are not related to dieldrin-induced liver tumors nor is there liver cytotoxicity. In previous studies, rats, dogs, and non-human primates did not show increased cell proliferation or production of pre-neoplastic or neoplastic lesions following dieldrin treatment. Thus, the evidence strongly indicates that dieldrin-induced mouse liver tumors are due to CAR activation and are specific to the mouse, which are qualitatively not relevant to human hepatocarcinogenesis. Thus, there is no carcinogenic risk to humans. This conclusion is also supported by a lack of positive epidemiologic findings for evidence of liver carcinogenicity. Based on current understanding of the mode of action of dieldrin-induced liver tumors in mice, the appropriate conclusion is that dieldrin is a mouse specific liver carcinogen and it does not pose a cancer risk to humans.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"634-658"},"PeriodicalIF":5.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792182","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":"Evaluation of rat and rabbit embryofetal development studies with pharmaceuticals: the added value of a second species.","authors":"Puck Roos, Caroline Anggasta, Aldert H Piersma, Peter J K van Meer, Peter T Theunissen","doi":"10.1080/10408444.2024.2374281","DOIUrl":"10.1080/10408444.2024.2374281","url":null,"abstract":"<p><p>Embryofetal development (EFD) studies are performed to characterize risk of drugs in pregnant women and on embryofetal development. In line with the ICH S5(R3) guideline, these studies are generally conducted in one rodent and one non-rodent species, commonly rats and rabbits. However, the added value of conducting EFD studies in two species to risk assessment is debatable. In this study, rat and rabbit EFD studies were evaluated to analyze the added value of a second species. Information on rat and rabbit EFD studies conducted for human pharmaceuticals submitted for marketing authorization to the European Medicines Agency between 2004 and 2022 was collected from the database of the Dutch Medicines Evaluation Board, along with EFD studies conducted for known human teratogens. In total, 369 compounds were included in the database. For 55.6% of the compounds similar effects were observed in rat and rabbit EFD studies. Discordance was observed for 44.6% of compounds. Discordance could often be explained based on occurrence of maternal toxicity or the compound's mechanism of action. For other compounds, discordance was considered of limited clinical relevance due to high exposure margins or less concerning EFD toxicity. For 6.2%, discordance could not be explained and was considered clinically relevant. Furthermore, for specific therapeutic classes, concordance between rat and rabbit could vary. In conclusion, in many cases the added value of conducting EFD studies in two species is limited. These data could help identify scenarios in which (additional) EFD studies could be waived or create a weight-of-evidence model to determine the need for (additional) EFD studies.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"619-633"},"PeriodicalIF":5.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874433","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":"Benzene metabolism and health risk evaluation: insights gained from biomonitoring.","authors":"Sean M Hays,Christopher R Kirman,Louis Anthony Cox,Satinder S Sarang","doi":"10.1080/10408444.2024.2379896","DOIUrl":"https://doi.org/10.1080/10408444.2024.2379896","url":null,"abstract":"Metabolic conversion of benzene (Bz) is thought to be required for the hematotoxic effects observed following Bz exposures. Most safe exposure limits set for Bz utilize epidemiology data on the hematotoxic effects of Bz for the dose-response assessments. These hematotoxic effects occurred among workers exposed to elevated Bz levels, thus dose extrapolation is required for assessing relevant risks for populations exposed orders of magnitude lower. Thus, understanding how Bz is metabolized over a wide range of air Bz levels is an important topic for risk assessments for Bz. Here, we analyze biomonitoring data for workers exposed to Bz to make evaluations of how the metabolism of Bz varies across a wide range of exposures. Our analysis indicates that the presence of metabolites derived from exposures to sources other than Bz (nonspecific metabolites of Bz) are significant confounders among biomonitoring studies and this precludes making any assessments of how Bz metabolism differs below approximately 3 ppm air Bz exposures using such nonspecific metabolites.","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":"20 1","pages":"1-9"},"PeriodicalIF":5.9,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253241","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}