Critical Reviews in Toxicology最新文献

{"title":"Genotoxic and epigenetic signatures of early-life pesticide exposure: a systematic review and meta-analysis.","authors":"Moustafa Sherif, Aya Darwish, Aya Samy, Shimaa Sami, Ádám Balázs","doi":"10.1080/10408444.2026.2623020","DOIUrl":"10.1080/10408444.2026.2623020","url":null,"abstract":"<p><p>Prenatal and early childhood exposure to pesticides is a global concern, yet the genotoxic mechanisms potentially linking these exposures to adverse health outcomes remain incompletely characterized. We conducted a systematic review and random-effects meta-analysis of studies reporting primary DNA damage, cytogenetic damage, DNA methylation, or gene expression outcomes associated with prenatal and early childhood pesticide exposure. We searched four databases following PRISMA guidelines and assessed using risk of bias using the Newcastle-Ottawa Scale. Twenty-eight studies met inclusion criteria. Meta-analysis revealed substantial DNA damage in pesticide-exposed groups (Cohen's <i>d</i> = 4.85, 95%CI = 3.31-6.39), with stronger effects in maternal and cord blood than in children's blood. Cytogenetic damage showed consistent increases in agricultural versus urban areas, though with significant heterogeneity in effect magnitude. Pathway-specific gene expression analysis revealed significant downregulation of DNA damage/repair genes (-1.08, 95%CI:-1.20,-0.96) and distinct biological responses across inflammatory, oxidative stress, and cell signaling pathways. DNA methylation responses varied by pesticide class, with o,p'-DDT consistently associated with hypermethylation. Pronounced sex-specific effects and genetic susceptibility emerged as important effect modifiers. The evidence supports substantial genotoxic and epigenetic alterations following early-life pesticide exposure, highlighting mechanistic pathways that may underlie adverse health outcomes and reinforcing the need for precautionary policies during critical developmental windows.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"57-75"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146200473","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 the effects of vanadium exposure on the health of human populations.","authors":"Thalía O Macías-Camacho, Martha A Sánchez-Rodríguez","doi":"10.1080/10408444.2026.2687720","DOIUrl":"10.1080/10408444.2026.2687720","url":null,"abstract":"<p><strong>Background: </strong>Vanadium is a metal naturally occurring in various ecosystems. Both natural and anthropogenic sources contribute to high concentrations in the air, soil, and water. Several experimental and epidemiological studies have linked this exposure to multiple adverse health effects.</p><p><strong>Objective: </strong>To analytically synthesize the available evidence to establish the effects of vanadium exposure on human health and to determine whether this metal is an epidemiological risk.</p><p><strong>Methods: </strong>The study protocol was registered in PROSPERO (ID CRD42023447293). A systematic review was conducted following the PRISMA 2020 methodology. A search for cross-sectional, case-control, and cohort studies was performed in six databases (PubMed, Scopus, ScienceDirect, LILACS, Web of Science, SciELO) up to May 5, 2025. The search terms used were: \"human, vanadium, pollution, exposure, diseases, damage\".</p><p><strong>Results: </strong>8,397 articles were identified, of which 27 were ultimately selected. The prevalent adverse effects reported were on pregnancy, fetal development, reproductive health, and the cardiovascular system, in addition to findings in different organs.</p><p><strong>Conclusions: </strong>Evidence regarding the effects of vanadium in human populations is limited; nevertheless, the available reports substantiate its potential harmful effects on fetal development and various human systems. The oxidation state and concentration of vanadium are determining factors in these effects, and controversy persists regarding its etiological role in certain pathologies.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"389-408"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148789309","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":"Inhalation exposure and health effects of copper particles in the context of occupational exposure limit derivation.","authors":"Craig A Poland, Adriana Oller, Len Levy, Sue Hubbard, Michelle Kelvin, Yamini Gopalapillai","doi":"10.1080/10408444.2026.2684936","DOIUrl":"10.1080/10408444.2026.2684936","url":null,"abstract":"<p><p>Copper is a naturally occurring element found in the Earth's crust, soil, water, and air. However, human activities such as smelting, refining, and producing copper-containing products pose a likelihood of occupational inhalation exposure. While copper is an essential element vital to human health, it is also a redox-active metal; thus, exposure beyond tolerable ranges could elicit a toxicological response. Previous occupational exposure limits (OELs) for copper and its compounds have been proposed, but most are based on limited datasets. More recent data available on the health effects of copper inhalation in exposed workforces, the characterization of copper forms in smelters during inhalation exposure, and inhalation effects in rodents have prompted a reevaluation of copper's inhalation toxicity in the context of deriving an up-to-date and more robust OEL. This review examines the toxicological impact of copper inhalation, from its toxicological mode of action to respiratory effects in animal models and humans, in the context of adversity, and identifies relevant points of departure (PoDs) for establishing an OEL. Coupled with data on the rapid clearance of copper from the lung, this information was used in a dosimetric model to quantitatively translate the PoD from the <i>in vivo</i> test model to a human equivalent concentration (HEC) for copper. To address areas of uncertainty and variability, the scientific rationale for chemical-specific versus default assessment factors is discussed.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"299-321"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148344081","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 framework for assessing the safety of degraded pharmaceuticals for long-duration space missions - Part 2: framework application in four case studies.","authors":"Andrey Massarsky, Veneese J B Evans, Ernest S Fung, Lisa G L Yang, Keegan L Rogers, Amanda N Buerger, Andrew Maier, John F Reichard","doi":"10.1080/10408444.2026.2633422","DOIUrl":"10.1080/10408444.2026.2633422","url":null,"abstract":"<p><p>Spaceflight environmental conditions can alter the rate of degradation for some drug products; however, only a limited number of drugs have been tested after prolonged exposure to spaceflight. Existing ground-based drug stability studies do not include key factors associated with spaceflight, such as levels of carbon dioxide (CO₂) and ionizing radiation that are significantly higher than on Earth. The National Aeronautics and Space Administration (NASA) has recognized the use of expired or degraded drugs as a risk for space crews because the loss of active pharmaceutical ingredient (API) decreases the therapeutic efficacy of the drug product and increases exposures to potentially hazardous degradation products. A risk assessment framework to systematically evaluate the toxicological risk of drug degradants was described in Part 1. The framework consists of five steps: (1) defining the use scenario of the drug, (2) identifying the API degradants, (3) assessing hazards and dose-response of the degradation products, (4) assessing the dose of degradation products, and (5) characterizing the risk for adverse health effects. Herein, four case studies are presented to illustrate the use of the framework for evaluating degradants for adverse health effects. Four representative medications that are candidates for the NASA's exploration drug formulary are evaluated: azithromycin 250 and 500 mg tablets, diclofenac 1% topical gel, gabapentin 300 mg capsule, and an oral contraceptive tablet consisting of a combination of ethinyl estradiol (0.035 mg tablet) and norethindrone (1 mg tablet). For the drug products evaluated herein, the results show that diclofenac, gabapentin, and ethinyl estradiol degradants are unlikely to present health risks within the range of degradant doses estimated under the framework. However, the results suggest that there may be risks for azithromycin and norethindrone degradants, which may need to be considered in NASA's risk management program. The case studies demonstrate that the framework can accommodate many use scenarios and enables risk classification for API degradants.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"127-155"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147688757","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":"Critical review and implications of the results of the National Toxicology Program's carcinogenicity study of tris(chloropropyl)phosphate.","authors":"Tracy Greene, Robinan Gentry","doi":"10.1080/10408444.2026.2620786","DOIUrl":"10.1080/10408444.2026.2620786","url":null,"abstract":"<p><p>The National Toxicology Program (NTP) conducted a 2-year carcinogenicity study on male and female Harlan Sprague-Dawley rats and B6C3F1 mice, which were given tris(2-chloroisopropyl)phosphate (TCPP) in their diet at concentrations up to 10,000-20,000 ppm. The study found significant trends in the incidence of hepatocellular adenomas or carcinomas in male rats and uterine adenomas and carcinomas in female rats. Female mice showed a significant increase in hepatocellular carcinomas and adenomas at 10,000 ppm, while male mice exhibited increased liver tumor incidences across all dosed groups (1250-5000 ppm). NTP concluded that TCPP shows some evidence of carcinogenic activity in male and female rats and male mice, with clear evidence in female mice. Significant increases in tumor incidences were typically noted at higher concentrations, while no significant increases in the incidence of most tumors were reported at the lowest exposures that were higher than exposures expected in humans. Without specific data to develop a TCPP-specific carcinogenic mode of action (MOA) in rats or mice, the lack of genotoxicity suggests a nonlinear MOA or one with a threshold. This investigation applied the Environmental Protection Agency's (USEPA) benchmark dose (BMD) modeling and the European Union's (EU) PROAST modeling to predict acceptable exposure levels using both linear and nonlinear methods.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"23-37"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147316746","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":"Blood lead levels (BLLs), exposure pathways and health impacts in South Asia: a comprehensive review.","authors":"Ritwika Roy, Reshmi Das","doi":"10.1080/10408444.2026.2692126","DOIUrl":"10.1080/10408444.2026.2692126","url":null,"abstract":"<p><p>Lead remains a pervasive toxicant in South Asia. We compiled published blood lead levels (BLLs), food, and environmental lead concentrations from South Asia (India, Bangladesh, Pakistan, Nepal and Sri Lanka) to identify the primary sources contributing to population exposure. Across all regions, reported BLLs frequently exceeded the current Centers for Disease Control and Prevention (CDC) reference value of 3.5 µg/dL. Elevated BLLs were consistently associated with adverse health outcomes, including neurocognitive impairment, anemia, hypertension, renal and hepatic dysfunction, and oxidative and genotoxic effects in both children and adults. Comparative assessment of lead concentrations across environmental media indicated significant contamination of dietary sources, with rice, vegetables and spices emerging as a major contributor to population exposure. However, airborne lead also played major role particularly in densely populated industrial settings. Correlation analysis demonstrated positive association between literature derived BLL and lead concentration in numerous environmental media, emphasizing the cumulative influence of multi pathway lead exposure. Despite heterogeneity in study designs and geographic coverage, the findings confirmed that non-fuel sources now dominate the lead exposure in South Asian regions. This review highlights the critical need for enhanced food safety regulations, reinforced environmental monitoring and targeted public health interventions in order to mitigate lead exposure and its related health impacts especially in vulnerable populations.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"425-445"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148720181","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 the modes of action for key noncancer effects of 1,3-Butadiene: input from an independent expert panel to support derivation of data-derived extrapolation factors.","authors":"Christopher R Kirman, John C Lipscomb, John Rogers, Rita S Schoeny, Jennifer G Seed, Babasaheb R Sonawane, Sean M Hays","doi":"10.1080/10408444.2026.2661191","DOIUrl":"10.1080/10408444.2026.2661191","url":null,"abstract":"<p><p>1,3-Butadiene (BD) is an important industrial chemical used in the production of plastics, rubbers, and polymers. This evaluation synthesizes mode of action (MOA) information to support interspecies extrapolations for key noncancer effects of BD (ovarian atrophy, lower fetal weight). Data-derived extrapolation factors (DDEFs) were calculated to account for substantial toxicokinetic differences between mice, rats, and humans. MOAs for the key noncancer effects were developed using the IPCS framework and modified Bradford-Hill considerations. An independent panel of six topic experts reviewed the weight of evidence, assessed human relevance, and provided recommendations on dosimetry approaches. DDEF values were calculated using newly published hemoglobin adduct data, including measurements from female workers, to quantify species differences in internal doses of BD's reactive epoxide metabolites. For ovarian atrophy, the MOA focuses on BD's metabolism to the diepoxide metabolite. The expert panel expressed high confidence (mean score: 8.2/10) in this MOA. For fetal weight effects, the proposed MOA involves metabolism to multiple epoxide metabolites, glutathione depletion, and subsequent toxicity. The panel expressed medium confidence (5.2/10) in this MOA, noting data gaps regarding mechanisms in pregnant animals. Based on hemoglobin adduct data from exposed workers and laboratory animals, preferred DDEFs for mouse-to-human extrapolation were 0.00064 for ovarian atrophy (based on BD's diepoxide metabolite) and 0.0070 for fetal body weight effects (based on all three epoxide metabolites of BD). Application of MOA-informed DDEFs has substantial impact on BD risk assessment. Using EPA's proposed occupational exposure value calculation as an example, incorporating species differences in BD metabolism and pharmacokinetics yields protective values of 24-260 ppm (compared to 0.17 ppm without quantitative pharmacokinetic adjustment), all well above the current OSHA permissible exposure limit of 1 ppm. These findings demonstrate that existing occupational standards are protective for BD's noncancer endpoints when best available science on species differences in toxicokinetics is appropriately considered. This work illustrates the critical importance of incorporating MOA evidence and quantitative dosimetry data to ensure risk assessments reflect scientific understanding and avoid potentially overestimating human health risks.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"252-278"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148204423","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":"Particles, fragments, fibers: what IARC missed in its assessment of talc mineralogy. (Authors' reply to Comment on [\"The IARC re-classification of talc carcinogenicity: a move in the wrong direction?\"]).","authors":"Andrey A Korchevskiy, Ann G Wylie","doi":"10.1080/10408444.2026.2641747","DOIUrl":"10.1080/10408444.2026.2641747","url":null,"abstract":"<p><p>This short communication is a response to the Letter to the Editor submitted by Alessandro Gualtieri (2026, forthcoming) entitled-Comments on the article \"The IARC re-classification of talc carcinogenicity: a move in the wrong direction?\" by A.A. Korchevskiy and A.G. Wylie (Crit Rev Toxicol. 55(9):867-889). The response argues that the definitions of the terms \"asbestos\", \"asbestiform\", and \"fibrous\" in the IARC Monograph, Volume 136 on talc do not consider recent advances in mineralogical science and may lead to contradictions in interpreting information for toxicological assessment.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"48-56"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147590739","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 framework for assessing the safety of degraded pharmaceuticals for long-duration space missions - Part 1: framework development.","authors":"Andrey Massarsky, Veneese J B Evans, Ernest S Fung, Lisa G L Yang, Keegan L Rogers, Amanda N Buerger, Andrew Maier, John F Reichard","doi":"10.1080/10408444.2025.2533943","DOIUrl":"10.1080/10408444.2025.2533943","url":null,"abstract":"<p><p>The National Aeronautics and Space Administration (NASA) is planning exploration space missions to Mars, which will require plans for a wide array of medical contingencies, most of which require treatment with medications. A major challenge is that medications cannot be resupplied beyond Earth orbit, and many medications will exceed their labeled expiration date over the duration of an exploration-class mission. Furthermore, the spaceflight environment may alter the rate or pathways involved in the degradation of active pharmaceutical ingredients (APIs). However, the stability of only a handful of drugs have ever been tested after prolonged exposure to spaceflight. Existing ground-based drug stability studies do not include key factors associated with spaceflight, such as levels of carbon dioxide (CO₂) and ionizing radiation that are significantly higher than on Earth. Therefore, there is a risk that some expired or degraded medications will accumulate hazardous impurities, that, at sufficiently high doses, could cause acute or long-term health effects in astronauts. To address this risk, an assessment framework is proposed based on the accepted principles of chemical risk assessment. This communication describes the five steps of the proposed risk assessment framework, which are: (1) defining the use scenario of the drug, (2) identifying the API degradants, (3) assessing hazards and dose-response of the degradation products, (4) assessing the dose of degradant products, and (5) characterizing the risk for adverse health effects. To predict and identify drug degradants, this framework leverages known chemical reaction pathways and API chemistry (i.e. susceptible moieties) and data from stability studies. The framework focuses on health effects of greatest concern: high acute toxicity, sensitization, and mutagenicity and carcinogenesis. Hazard analysis uses chemical hazard databases, <i>in silico</i> prediction tools, and available terrestrial and spaceflight drug degradation studies. Risk is characterized relative to established health-based exposure limits (HBELs) or threshold of toxicological concern values (TTCs). A companion article describes case studies that apply this framework to four different classes of APIs under consideration for use during exploration spaceflight: azithromycin, diclofenac, gabapentin, and oral contraceptive (combination of ethinyl estradiol and norethindrone).</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"93-126"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147638126","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":"Perspectives on aerosol inhalability: concepts and applications.","authors":"Robert F Phalen, Mark D Hoover, Roger O McClellan","doi":"10.1080/10408444.2025.2458276","DOIUrl":"10.1080/10408444.2025.2458276","url":null,"abstract":"<p><p>The original motivation for the aerosol inhalability convention was to account for the fact that the inhalation efficiency of particles can cause the composition of the particle-containing air that is inhaled into the mouth and nose to differ significantly from the composition of the ambient air. Therefore, without appropriate adjustments for the inhalation efficiency of particles, air samples could over- or underestimate the actual exposures of inhaled materials, possibly compromising some workplace air standards. Subsequently, the concepts and applications of inhalability and inhalability sampling have been expanded to inhalation exposures outside of the workplace, including general human populations, medical patients, cell cultures, and animal research subjects. As described in this commentary, some of these applications have occurred in ways that could misrepresent actual exposures. Scientific advances in the understanding and applications of inhalability-related concepts are needed. Such advances will best be achieved through multidisciplinary collaborations involving modeling, wind tunnel mannequin and human subject studies, and health effects studies involving input from aerosol scientists, engineers, physiologists, anatomists, physicians, veterinarians, mathematical modelers, and regulators.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"227-247"},"PeriodicalIF":5.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514973","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}