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.
Microplastics (MPs) have been detected across multiple maternal and neonatal biological matrices, suggesting widespread exposure during critical developmental stages. However, the mechanisms shaping their distribution and accumulation within the maternal-fetal system remain poorly understood. This systematic review and quantitative synthesis provides a comprehensive quantitative profiling of MP burden across six maternal and neonatal biological matrices placenta, breast milk, endometrium, amniotic fluid, meconium, and feces. Our analysis reveals three critical insights: (1) Tissue‑specific MP signatures, with placental samples showing a 2.3‑fold higher fragment proportion and polypropylene (PP) dominance, suggesting selective barrier permeation; (2) A striking endometrial MP accumulation, implicating this tissue as a potential reservoir for intergenerational transfer; and (3) Distinct polymer clustering in perinatal matrices (polyamide/polyurethane (PA/PU) in breast milk vs. polyethylene terephthalate/polycarbonate (PET/PC) in amniotic fluid), indicating distinct exposure windows. Multivariate modeling confirms size‑dependent transport transplacental passage correlates strongly with <100 µm polymers. Crucially, we demonstrates that the majority of the variance in MP distribution stems from interactions between particle characteristics and developmental biology, thereby challenging conventional exposure paradigms based on environmental concentration alone. These findings establish a quantitative framework for understanding MP trafficking in perinatal systems and highlight the importance of integrating particle characteristics and biological context into future exposure and risk assessments.
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 in vivo 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.
The aim of this study was to identify the methodologies currently used by contract research organizations (CROs) for counting ovarian follicles and corpora lutea (CL) in the OECD Test Guideline (TG) 443 (Extended One-Generation Reproductive Toxicity, EOGRT) studies. The current study further sought to characterize variability and its sources in follicle and CL counts. A database of 73 EOGRT studies with information on methodology, reporting and numerical data of follicular and CL counts was assembled and analyzed, revealing that quantitative follicle enumeration was conducted in 97% of studies, while quantitative CL evaluation was performed in 59%. Only 27% of studies provided details on sampling procedures related to location within the ovary, section thickness, step length, number of steps as well as type of histological staining. The percentage coefficient of variation (%CV) for follicle counts in control females ranged from 7.7% to 78.5%, indicating high variability. The median study-specific %CVs for primordial follicles and for combined primordial and growing follicles were 36% and 33%, respectively, while the median %CV for CL was 29%. The intra‑laboratory %CV decreased, indicating improved precision of the follicle‑count method, when a greater number of sections were evaluated but was also influenced by the number of studies performed within the laboratory, based on the dataset included in this evaluation. While the ratios of primordial to growing follicles are not a requirement in the OECD TG 443, they can reveal differences in follicle identification if the variability in ratios between the studies is high. Accordingly, the high variability in the ratios across studies demonstrated that well-defined criteria for follicle identification and validation of antibodies are necessary. The overall conclusion is that the lack of information on follicle identification criteria, and inconsistencies in terminology and reporting practices further complicate the interpretation of results of follicle and CL counts in the EOGRT studies. Our results highlight that clarification of the ovarian follicle terminology and identification criteria at the OECD level as well as clarity on best practices for follicle and CL counting are essential to improve the consistency and reliability of ovarian toxicity testing in EOGRT studies.
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.
Antineoplastic agents exacerbate oxidative stress and trigger inflammatory responses in the testis. Numerous studies have proposed antioxidants as a therapeutic approach to ameliorate chemotherapy-induced damage and improve reproductive outcomes. This systematic review aims to evaluate the potential therapeutic value of antioxidants in mitigating chemotherapy-induced male reproductive damage and address knowledge gaps to guide future research efforts. A comprehensive literature search was conducted in accordance with the PRISMA guidelines using the Google Scholar and Web of Science databases to identify experimental studies published between 2012 and 2025. The search strategy employed the following keywords: "antioxidant" AND "oxidative stress" AND "spermatozoa" AND "testosterone" AND "histopathology" AND ("rat" OR "mice") AND ("chemotherapy" OR "chemotherapeutic" OR "antineoplastic"). The study design was guided by the PICO framework. Data extraction focused on reproductive histopathological changes, testosterone levels, and sperm parameters. A total of 28 studies were deemed eligible for inclusion. The methodological quality and risk of bias of the included studies were assessed using SYRCLE's Risk of Bias tool. The majority of findings suggest that antioxidant administration mitigated male reproductive toxicity by improving sperm parameters, testicular histopathology, and testosterone levels; however, a small number of studies reported no significant effects. Additionally, a number of the included studies also presented the beneficial effects of several antioxidants on other endocrine parameters and oxidative stress markers. Current preclinical evidence suggests that antioxidants may mitigate chemotherapy-induced reproductive toxicity; however, clinical studies are required to clarify their clinical applicability, optimal dosing, and long-term safety.
Propylene oxide (PO) is a high-production-volume chemical widely used as an industrial intermediate and classified as carcinogen and mutagen in humans. Despite its regulatory significance, a comprehensive evaluation of its endocrine-disrupting (ED) potential has not been previously conducted. This review applies a weight-of-evidence (WoE) approach, integrating data from regulatory dossiers, peer-reviewed literature, publicly accessible databases, and in silico predictions to assess whether PO meets internationally accepted ED criteria. Available evidence indicates that PO does not exhibit endocrine activity via estrogenic, androgenic, steroidogenic, thyroid (EATS), or non-EATS pathways, as supported by negative quantitative structure-activity relationship (QSAR) predictions and absence of mechanistic effects in vivo. Similarly, adverse outcomes observed in repeated-dose, reproductive, and developmental toxicity studies were either secondary to systemic toxicity, inconsistent, or unrelated to endocrine modes of action. Epidemiological findings suggesting associations with breast cancer, diabetes, or obesity were limited by methodological uncertainties and lack of causal inference. Collectively, the WoE demonstrates that PO should not be classified as an endocrine-disrupting chemical for humans or wildlife, although data gaps remain for environmental receptors and metabolites.
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, in silico 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).
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.
Observational studies often guide policy, regulation, litigation, and public health decisions. However, causal claims from such studies can be misleading if key logical and methodological requirements are not met. We synthesized insights from foundational causal theory, contemporary methods, and critiques of common practices to develop a framework of necessary conditions for valid interventional causal inferences predicting the effects of changes in exposure on changes in risk. The framework organizes these conditions into five domains: (A) conceptual and definitional clarity, (B) study design prerequisites, (C) data analysis requirements for valid causal modeling and effect estimation, (D) interpretation and result integrity, and (E) robustness, generalizability, and external validity of results. Each domain includes criteria, rationale, and practical evaluation tools, integrating Potential Outcomes (PO), Structural Causal Models (SCM), Directed Acyclic Graphs (DAG), information-theoretic measures, and machine-learning (ML) approaches for heterogeneity. Summary tables and STROBE-style checklists translate the framework into actionable guidance. Producing trustworthy, decision-relevant causal claims from observational data requires meeting all necessary conditions across the five domains. Modern study designs, methods, and software make it increasingly practical to do so.
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 d = 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.
Between August 1 and December 3, 2020, a 124-day outbreak of nonviral hepatitis occurred in geographically limited regions of Nevada and California, resulting in 21 hospitalized cases (18 in Nevada, 3 in California), including 18 intensive care unit admissions and one fatality in an adult female with preexisting conditions. In March 2021, a multi-agency investigation led by the Southern Nevada Health District (SNHD), Centers for Disease Control and Prevention (CDC), U.S. Food and Drug Administration (FDA), and others identified consumption of Real Water, an alkalinized bottled water product, as the likely cause. On March 24, 2021, a recall was issued and the company ceased production of Real Water. Despite extensive investigation, no definitive causative agent was identified. However, trace concentrations of hydrazine, a known hepatotoxin, were detected in select product batches, prompting concerns regarding its potential role in the outbreak. This study presents a quantitative risk assessment of hydrazine exposure from daily consumption of retail bottled Real Water products during the outbreak period. Estimated intake was calculated based on age-, sex-, and body weight-specific water consumption patterns and measured hydrazine concentrations (mean: 0.0505 mg/L; maximum: 0.3 mg/L). Sub-chronic acceptable daily intakes (ADIs) of 0.09 mg/kg-day for adults and 0.04 mg/kg-day for children were developed based on toxicological data from isoniazid (INH) studies. Hydrazine and INH share similar profiles regarding hepatotoxicity, with hydrazine acting as a major mediator of INH-induced liver injury. Calculated hazard quotients for all demographic groups were <1.0, with the highest estimated intake (0.005 mg/kg-day) resulting in an HQ of 0.12. These findings indicate that hydrazine exposure via retail Real Water consumption could not have caused the observed hepatic injuries, supporting the conclusion of the Centers for Disease Control (CDC) that the etiologic agent remains unidentified.
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.
A comprehensive review was conducted of existing toxicity and consumer exposure data for the ultraviolet (UV) filter octocrylene (2-ethylhexyl-2-cyano-3,3-diphenylacrylate) as currently used in over-the-counter sunscreen formulations. Octocrylene has a long history of safe use, and there are sufficient in vitro studies, in vivo toxicity studies in animal models, and clinical data to characterize octocrylene's pharmacokinetics, pharmacodynamics, and potential toxicologic properties. Although no harmonized dermal absorption value was available, in vitro studies using human skin samples revealed very low percutaneous absorption (0.33% of the applied dose). There are no specific data on the distribution of octocrylene; however, there is some information on background levels of octocrylene and its metabolism, and it has limited presence in plasma and urine from human biomonitoring studies. Six tentative metabolites of octocrylene have been identified, although metabolite-specific toxicity profiles were not available. Octocrylene generally did not cause eye or skin irritation, skin sensitization, or phototoxicity, but dermal sensitization has been reported in some clinical case studies. Octocrylene is not acutely toxic. The no-observed-adverse-effect level (NOAEL) from a 90-day rat dietary toxicity study was 175 mg/kg/day, based on liver, thyroid, and pituitary effects at higher dose levels that produced hepatic enzyme induction. The NOAEL for parental systemic, reproductive, and developmental toxicity from an extended one-generation reproductive toxicity study in rats was 153/163 mg/kg/day (males/females). There was no evidence of octocrylene effects on neurodevelopment, immune tissues, or androgenic, estrogenic, or thyroid endpoints. Although there are no formal 2-year carcinogenicity studies for octocrylene, a 90-day subchronic dietary toxicity study in rats did not show an increase in hyperplasia of any tissue or evidence of cytotoxicity. Furthermore, octocrylene has not triggered any indications for genotoxicity either in vitro or in vivo. Together, these data indicate that carcinogenicity in humans is unlikely. In a mouse photocarcinogenicity study, octocrylene significantly reduced tumor number and tumor volume resulting from exposure to solar-simulated UV radiation. Based on the most health-protective rat NOAEL (153 mg/kg/day, for reproductive effects and general toxicity) and conservative assumptions for estimating the systemic exposure dose from the application of sunscreen products, margins of safety for octocrylene were greater than 100. Therefore, the available data show that octocrylene poses no human health risks when used in sunscreen products at concentrations up to 10%, which is consistent with existing global regulatory safety acceptance and approval of the ingredient.
