Critical Reviews in Toxicology最新文献

{"title":"The formaldehyde dispute - Part A: acute and chronic inhalation toxicity and the evolution of scientific knowledge.","authors":"Jacob Siracusa, Quincy Perry, Michael Stevens, Dennis J Paustenbach","doi":"10.1080/10408444.2026.2630665","DOIUrl":"https://doi.org/10.1080/10408444.2026.2630665","url":null,"abstract":"<p><p>Formaldehyde is a simple, highly reactive aldehyde whose inhalation toxicity has been characterized through more than five decades of human, animal, and mechanistic research. Across this literature, inhalation was illustrated to follow a concentration-dependent continuum of effects confined to the tissues of initial contact. Controlled human chamber studies reported no measurable pulmonary impairment below 0.3 ppm, the onset of mild ocular and nasal irritation at 0.3 to 0.5 ppm, and reversible sensory irritation observed at concentrations approaching 1 ppm. These findings were consistent with observations from community and occupational investigations. Chronic inhalation bioassays in rats and mice identified a sharp transition between adaptive epithelial responses and sustained cytotoxic injury within the nasal epithelium. Continuous exposure to concentrations ≤2 ppm produced minimal and reversible histopathologic changes, whereas exposures ≥6 ppm were associated with persistent epithelial necrosis, regenerative proliferation, and nasal squamous cell carcinomas localized to regions of highest vapor flux in the rat nasal cavity. In these studies, tumors were not observed at concentrations that did not overwhelm local tissue repair capacity. Computational dosimetry, DNA-protein crosslink kinetics, and biologically based dose-response (BBDR) modeling indicated that these outcomes arose from localized tissue injury rather than from cumulative systemic dose. Despite the extensive experimental database, disagreement has persisted for several decades regarding the appropriate approach for conducting a quantitative risk assessment of formaldehyde. Its non-linear, concentration-response, high endogenous background levels, and pronounced interspecies differences would indicate that the use of the Linear-No-Threshold (LNT) model is not appropriate for identifying acceptable levels of exposure. Nonetheless, EPA proposed an 8-hour occupational exposure value (OEV) of 0.11 ppm and 0.17 ppm for a 15-minute OEV. This review synthesizes the human, experimental, and mechanistic evidence underlying formaldehyde's acute and chronic inhalation toxicity. Using a classic approach to risk assessment, we propose that an OEV of 0.3 ppm (8 hr TWA) and a short-term limit (15 min) of 1.0 ppm are sufficiently low to protect the vast majority of workers from temporary irritation, as well as chronic effects (such as cancer). This recommendation is supported by three significant reviews of formaldehyde and at least seven rigorous human exposure studies conducted over the past 35 years.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"1-19"},"PeriodicalIF":4.1,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856186","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":"The formaldehyde dispute - Part B: scientific critique of EPA's formaldehyde occupational exposure values (OEVs) and proposed alternative occupational exposure limits (OELs).","authors":"Quincy Perry, Jacob Siracusa, Michael Stevens, Patricia Underwood, Dennis Paustenbach","doi":"10.1080/10408444.2026.2630662","DOIUrl":"https://doi.org/10.1080/10408444.2026.2630662","url":null,"abstract":"<p><p>In 2024, the U.S. Environmental Protection Agency (EPA) finalized its Integrated Risk Information System (IRIS) Toxicological Review and Toxic Substances Control Act (TSCA) Risk Evaluation for formaldehyde. After analyzing all the data that they deemed relevant, TSCA relied on IRIS's proposed inhalation reference values to establish an 8-hour occupational exposure value (OEV) of 0.11 ppm derived from epidemiological evidence of nasopharyngeal cancer. They also developed a 15-minute OEV of 0.17 ppm based on the goal of preventing sensory irritation. In an earlier draft of EPA's TSCA Risk Evaluation, they initially proposed an 8-hour OEV of 0.011 ppm derived from residential exposure studies of children, but this was withdrawn. This review examined EPA's methodology, the nearly 40 years of scientific literature underlying the EPA's conclusions, and the more than 300 public comments, which were submitted to the draft IRIS Toxicological Review (Docket ID: [EPA-HQ-ORD-2010-0396]) and draft TSCA Risk Evaluation (Docket ID: [EPA-HQ-OPPT-2023-0613]). A minimum of five significant flaws were identified and discussed: (1) heavy reliance on epidemiological studies which had serious confounding factors and design limitations; (2) application of default uncertainty factors which were too high given the robust human data; (3) use of exclusion criteria which dismissed high-quality studies from being considered; (4) the use of a linear no-threshold (LNT) model despite decades of substantial evidence for a threshold-driven mode of action (MOA); and (5) neglect for a validated biologically based dose-response (BBDR) model which may have been the most robust ever developed. Based on our weight-of-evidence evaluation of toxicological, mechanistic, and epidemiological data, we propose occupational exposure limits (OELs) of 0.3 ppm (8-hour TWA) and 1 ppm (15-min STEL). These values are grounded in controlled human exposure studies of asthmatics and non-asthmatics and supported by an internationally accepted BBDR model estimating an approximately 1 in 940,000 increased cancer risk for workers. As such, these OELs protect against sensory irritation, asthma, and other adverse effects, as well as carcinogenicity. They are also aligned with limits adopted by other domestic and international regulatory bodies. Immediately before this paper was accepted, EPA released their <i>Updated Draft Risk Calculation Memorandum: Formaldehyde</i> for public comment, which proposed to drop their promulgated OEVs (0.11 ppm and 0.17 ppm) and adopt an 8-hour OEV of 0.3 ppm to protect against sensory irritation and cancer, similarly to what was recommended in this paper.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"1-28"},"PeriodicalIF":4.1,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856189","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":"https://doi.org/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":"1-29"},"PeriodicalIF":4.1,"publicationDate":"2026-04-16","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":"Letter to the Editor: Comprehensive review of octocrylene toxicology data and human exposure assessment for personal care products.","authors":"Joseph C DiNardo","doi":"10.1080/10408444.2026.2640891","DOIUrl":"https://doi.org/10.1080/10408444.2026.2640891","url":null,"abstract":"","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"1-2"},"PeriodicalIF":4.1,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147670960","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":"Response to Mr. DiNardo's \"Letter to the Editor: Comprehensive review of octocrylene toxicology data and human exposure assessment for personal care products\".","authors":"Kimberly G Norman, Lewis E Kaufman, Peter Griem, Carl D'Ruiz, Linda Loretz, Alexandra Kowcz, Samuel M Cohen, Anthony R Scialli, Alan R Boobis, David Jacobson-Kram, Rita Schoeny, Thomas J Rosol, Gary M Williams, Norbert E Kaminski, F Peter Guengerich, J F Nash","doi":"10.1080/10408444.2026.2640896","DOIUrl":"https://doi.org/10.1080/10408444.2026.2640896","url":null,"abstract":"","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"1-3"},"PeriodicalIF":4.1,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147671051","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":"https://doi.org/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":"1-34"},"PeriodicalIF":4.1,"publicationDate":"2026-04-09","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":"Role of constitutive androstane receptor in developmental toxicology: linking chemical exposure, nutrition, and disease susceptibility.","authors":"Ryota Shizu, Kouichi Yoshinari","doi":"10.1080/10408444.2026.2623026","DOIUrl":"https://doi.org/10.1080/10408444.2026.2623026","url":null,"abstract":"<p><p>The constitutive androstane receptor (CAR) is a xenobiotic-sensing nuclear receptor that regulates gene transcription involved in drug metabolism, especially in the liver. CAR activation influences detoxification pathways and disrupts endocrine homeostasis, notably thyroid hormone (TH) signaling. THs are crucial for neurodevelopment, skeletal maturation, and metabolic regulation. When activated by antiseizure medications, such as phenobarbital, or environmental chemicals, such as perfluoroalkyl substances, CAR induces hepatic enzymes, including UDP-glucuronosyltransferases (UGTs), which increase the clearance of THs and raise thyroid-stimulating hormone levels. Developmental exposure to CAR activators in rodents has been linked to reduced circulating and brain TH levels, resulting in impaired neurodevelopmental outcomes. Given that CAR expression is very low in fetal and neonatal livers, maternal CAR activation may significantly disrupt fetal TH signaling. Additionally, CAR modulates host gene expression affecting microbial composition and bile acid homeostasis, with emerging evidence connecting it to early-life metabolic programming, including low birth weight. Epigenetic changes caused by CAR agonists during the neonatal period can persist into adulthood at least in rodents, suggesting a potential role of CAR in the developmental origins of health and disease, or DOHaD. While it is essential to consider species differences in ligand specificity and UGT isoform expression when extrapolating findings from rodents into humans, CAR is increasingly recognized as a mediator between environmental exposure and endocrine-metabolic disruption. This review integrates animal and human evidence to highlight the critical yet underappreciated functions of CAR in mediating developmental toxicity and long-term health outcomes.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"1-17"},"PeriodicalIF":4.1,"publicationDate":"2026-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147282884","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":"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":"https://doi.org/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":"1-19"},"PeriodicalIF":4.1,"publicationDate":"2026-02-16","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":"Wildfires in the Pan-Amazon: what is known about health impacts on affected populations?","authors":"Elizeu Chiodi Pereira, Dayane da Fonseca Barbosa, Fernando Viana Rodovalho, Thiago Nogueira, Kelly Polido Kaneshiro Olympio","doi":"10.1080/10408444.2025.2606263","DOIUrl":"10.1080/10408444.2025.2606263","url":null,"abstract":"<p><p>According to the World Health Organization, climate change is associated with detrimental health effects through air pollution, increased risk of infectious diseases, as well as extreme heat and drought. The rise in wildfires, exacerbated by climate change, plays a fundamental role in air pollution by emitting diverse pollutants responsible for adverse health effects, environmental and economic damage, directly impacting the health of populations, especially the most vulnerable. This study aimed to evaluate the effects on human health stemming from exposure to wildfire smoke in the Amazon region. For this purpose, a literature review following the PRISMA methodology was conducted in the Web of Science, PubMed, LILACS, and Scopus databases, with no restrictions for biological sex or time frame using descriptors such as \"Exposure\", \"Health effect*\", \"Wildfire*\", and \"Air pollution\". Articles in English, Spanish, and Portuguese were included. A total of 302 articles were identified, of which 30 met the inclusion and exclusion criteria. Studies were identified only in the Brazilian Amazon, and the groups most susceptible to smoke effects were children up to 5 years old and the elderly aged 60 and above, in addition to individuals with preexisting comorbidities. Only one article conducted a biomonitoring study in the region; the others worked with hospital admission data. Coordinated health actions are necessary to protect the health of exposed populations, especially those in conditions of social vulnerability, to ensure health protection and adequate environmental safety.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"1-22"},"PeriodicalIF":4.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146017372","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":"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 (2025).","authors":"Alessandro Francesco Gualtieri","doi":"10.1080/10408444.2026.2641755","DOIUrl":"10.1080/10408444.2026.2641755","url":null,"abstract":"","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"38-47"},"PeriodicalIF":4.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147590745","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}