Statins are the main medications prescribed to improve lipid profiles and avoid cardiovascular risks in humans. Preclinical studies have shown that statins may impair male reproduction; however, their effects on female reproduction remain unclear. This study conducted a systematic review of the literature regarding preclinical primary studies that assessed female reproductive outcomes in rodent models after exposure to statins. The studies were searched in the databases PubMed, Scopus, Embase, Web of Science, LILACS, and SciELO, using distinct combinations of the search terms "statins", "ovary", "uterus", "female reproduction", "mice", "rats", followed by the Boolean operators AND or OR. Subsequently, duplicities and studies that did not meet the eligibility criteria were excluded from this review. Afterward, the risk of bias was evaluated through the 10 points of the SYRCLE's risk of bias tool. Extraction and qualitative analysis of the data were carried out, and whenever possible, a meta-analysis was applied to assess the data quantitatively. The results indicated that normocholesterolemic female rodents exposed to statins showed ovarian morphological changes, such as impaired follicular dynamics. Additionally, when rodents were induced with endometriosis or reproductive-related cancer, there was a reduction in the volume of endometriotic implants and a complementary action on the reduction of tumor proliferation, respectively. As a limitation, there were no studies assessing the effects of statins in hyperlipidemic rodents, which may make it difficult to translate the adverse effects of statins observed in normolipidemic rodents to humans.

Benzo[a]pyrene (B[a]P), a widespread environmental carcinogen, exerts multifaceted toxicity beyond direct DNA damage. Recent studies highlight the profound capacity of B[a]P to disrupt epigenetic landscapes, particular histone modifications, across diverse biological systems. This review synthesizes both in vitro and in vivo experimental findings to elucidate the mechanisms and consequences of B[a]P-induced histone modifications. In vitro studies demonstrate that B[a]P and its ultimate metabolite, BPDE, significantly alter key histone marks, including phosphorylation (γH2AX), acetylation (H3K9/14/18/27ac, H4K5/12/16ac), methylation (H3K4/9/27/36/79 me), lactylation (H4K12la), and ubiquitination (uH2A), in epithelial and connective cells. These changes are driven through multiple interconnected pathways: (1) Direct interference, where BPDE-dG adducts physically widen the DNA minor groove, entrapping histone tails and sterically blocking modifying enzymes; (2) Regulation of epigenetic enzymes, via modulating the expression/activity of HDACs, HATs, HMTs, and ubiquitin ligases; and (3) Oxidative stress and receptor signaling, primarily through AhR activation and ROS generation, altering metabolite pools and downstream kinase cascades. In vivo evidence from animal models and occupational human exposure confirms these alterations, linking specific histone code disruptions (e.g. decreased H3K36me3, H3K79me2; increased H3K9me2) to functional outcomes such as genomic instability, impaired DNA repair, aberrant gene expression, stemness promotion, and ultimately carcinogenicity in lung, liver, and reproductive tissues. Notably, B[a]P toxicity exhibits tissue, cell-type, and species specificity, and can be transgenerational. Emerging as potential biomarkers and therapeutic targets, these B[a]P-driven epigenetic alterations represent a critical, non-mutational axis of its toxicity. This mechanistic understanding bridges genetic and epigenetic carcinogenesis, offering novel insights for its risk assessment and intervention strategies.

Consumption of alcoholic beverages is common around the world, and its risks and benefits continue to be debated. In the last several years, meta-analyses of human epidemiological data have provided strong evidence for risk of alcohol-associated cancers at seven body sites. It is now well accepted that several cancers are associated with alcohol consumption, and that risk increases with dose. In publications of epidemiological studies, statements like, "…the safest level of drinking is none" (Lancet 2018; 392: 1015-1035) have been interpreted to mean that any level of alcoholic beverage consumption is harmful. An official of the World Health Organization-Europe declared that "It doesn't matter how much you drink - the risk to the drinker's health starts from the first drop of any alcoholic beverage." Recently, "one-drop" statements like this have been echoed by news outlets and in social media posts. If such pronouncements are unfounded, potential outcomes are that they raise unnecessary fear and hysteria among the alcohol-consuming public and sow distrust of respected sources. This commentary addresses the likelihood that very small amounts (e.g. one drop) of alcohol increase cancer risk. Examples of results from meta-analyses of human epidemiological studies that link alcohol consumption with human cancers are presented, with a focus on dose-response relationships. Next, what animal and in vitro studies suggest about alcohol-associated cancer thresholds is discussed. Thirdly, alcohol contents in common foods and production of alcohol from intestinal fermentation are explored, and how exposures from these compare to one drop of an alcoholic beverage is addressed. Finally, comments are offered on the consequences of issuing unsupported claims of cancer risk from consuming alcoholic beverages in moderation, and perspectives are shared on the responsibilities of researchers, public health agencies and the lay press to issue pronouncements that are evidence-based.

Environmental endocrine disruptors (EEDs) are common environmental pollutants. A close association exists between EEDs exposure and depression. However, related research findings have shown inconsistencies due to the wide variety of EEDs. This study aimed to evaluate, through a systematic meta-analysis, the associations between exposure to Phthalate Esters (PAEs), Per- and polyfluoroalkyl substances (PFAs), Bisphenol A (BPA), and Hexachlorobenzene (HCB) and the risk of depression. We systematically searched PubMed, Web of Science, and Embase, and finally enrolled 28 eligible studies involving 81,154 participants who underwent assessment of EEDs exposure and were evaluated for incident depression or depression-related outcomes. Relevant studies published between 2004 and December 2024 were included in this study. The biological samples used for human exposure assessment in the included studies included peripheral serum, urine, breast milk, maternal serum, and umbilical cord serum. A meta-analysis was then conducted, and the results showed that: Mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) (Odds Ratio [OR] = 1.19, 95% Confidence intervals [CI]: 1.06, 1.33), Mono (2-ethyl-5-oxohexyl) phthalate (MEOHP) (OR = 1.21, 95% CI: 1.07, 1.36), Mono-benzyl phthalate (MBzP) (OR = 1.14, 95% CI: 1.07, 1.22), Mono-N-butyl phthalate (MnBP) (OR = 1.18, 95% CI: 1.02, 1.37), Mono-isobutyl phthalate (MiBP) (OR = 1.16, 95% CI: 1.07, 1.25), Mono-n-butyl phthalate (MBP) (OR = 1.28, 95% CI: 1.13, 1.45), and Mono (2-ethyl-5-carboxypentyl) phthalate (MECPP) (OR = 1.22,95% CI: 1.04, 1.43) were all positively associated with the risk of depression. Additionally, exposure to ∑ PAEs (OR = 1.11, 95% CI: 1.08, 1.14) was identified as a risk factor for depression. The exposure to Perfluorononanoic acid (PFNA) (OR = 1.24, 95% CI: 1.01, 1.51) and ∑ PFAs (OR = 1.09, 95% CI: 1.01, 1.17) was significantly positively associated with postpartum depression among women. Human exposure to PAEs significantly increases the prevalence of depression, and a significant positive association exists between PFAs exposure in women and postpartum depression.

The increasing use of hair dyes reinforces the need to identify potential toxicological hazards associated with their constituents and formulations. These products may release aromatic amines that, after dermal absorption, can induce oxidative stress and cellular damage, with potential cytotoxic, mutagenic, and carcinogenic effects. We reviewed in vivo evidence on toxicological hazards associated with isolated hair dye ingredients and finished commercial formulations in experimental animal models. Searches were conducted in PubMed, Web of Science, Embase, and Scopus, without language or year restrictions. Eligible studies assessed toxicity related to hair dye ingredients or formulations; secondary studies were excluded. Risk of bias was assessed using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool. Twenty-five articles were included. The evidence indicated multifactorial toxicity affecting cardiac, hepatic, renal, testicular, respiratory, dermatological, hematological, genotoxic, hormonal, and developmental endpoints. However, relevance varied according to exposure route, dose, species, model, publication period, and whether the tested material was an isolated ingredient or complete formulation. Topical studies were the most relevant to cosmetic exposure, whereas oral, subcutaneous, intravenous, and embryo immersion models primarily supported hazard identification under non-usual or high-bioavailability conditions. SYRCLE assessment showed a predominance of unclear risk of bias, with methodological weaknesses in nearly all studies. Hair dye ingredients and finished formulations can produce toxicological hazard signals under specific experimental conditions. Nevertheless, these findings should not be interpreted as direct estimates of real-world consumer risk. More standardized, exposure-relevant, and robust studies are needed to improve hazard characterization and support risk interpretation, particularly for occupational exposure scenarios.

Human exposure to micro- and nanoplastics (MNPs) is increasingly documented, yet their potential effects on reproductive and developmental health remain inadequately explored. Preliminary findings presented in scientific literature suggest that MNPs may translocate systemically and localize in reproductive tissues, prompting growing concern among both researchers and regulators. However, existing toxicological studies differ in terms of methodological adequacy and regulatory applicability. The aim of this study is to provide a systematic evaluation of current scientific evidence regarding the reproductive and developmental effects of MNPs, addressing both scientific findings and study quality for regulatory purposes. We structured our study by first conducting a systematic review focused on in vivo mammalian studies examining the effects of MNPs on reproductive and developmental endpoints. This was followed by an assessment of the quality of these studies in terms of regulatory reliability and relevance using the Science in Risk Assessment and Policy (SciRAP) tool, version 2.3, originally developed for evaluating chemical toxicity studies. Recognizing that this tool does not fully capture MNPs-specific challenges, we supplemented the evaluation with additional criteria, including polymer type, particle size and shape, preparation methods, and plastic test item characterization. Due to common gaps in reporting, particularly regarding exposure doses, we incorporated a "not reported" option in the Relevance assessment. Each study's overall Critical Appraisal of Evidence Score was then estimated based on its SciRAP score and the extent to which it addressed MNPs-specific criteria. To our knowledge, this represents the first systematic application of SciRAP to studies on MNPs toxicity. Following a tiered and targeted search strategy, the review included 102 studies, with findings grouped into three categories: Biodistribution, Reproductive System, and Fertility and Development. Our analysis found evidence of MNPs presence in reproductive organs, resulting in disruptions to testicular, ovarian, and uterine functions. Both male and female gamete quantity and quality were negatively affected. Additionally, we identified studies indicating maternal transfer of MNPs via the placenta and lactation, with consequences for fetal development and offspring fertility. The outcome of the critical appraisal of evidence evaluation was that 7 studies were classified as strong, 89 as moderate, and 6 as weak for risk assessment e.g. in a weight of evidence assessment of MNPs effects on biodistribution, the reproductive system, fertility and development. Although many studies report adverse reproductive and developmental outcomes following MNPs exposure, methodological shortcomings and insufficient reporting hinder data synthesis and integration into structured assessments, such as weight-of-evidence approaches. Critical information, such as particle characterization, administered dose, and dose-response relationships, was often missing. In addition to calling for more studies performed in accordance with SciRAP criteria, we emphasize the need to improve the design, documentation, and reporting quality of MNPs studies to enhance the overall evidence base for risk assessment. With this work, we provide valuable insights for the academic and testing communities, along with a robust overview of current critical appraisal of evidence on the potential reproductive and developmental toxicity of MNPs based on existing literature.

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) and per- and polyfluoroalkyl substances (PFAS) increasingly co-occur across aquatic, terrestrial, and biological systems, yet their combined toxicological behavior remains poorly resolved. To address this gap, we conducted a systematic review and meta-analysis of 47 controlled experimental studies encompassing aquatic organisms, soil invertebrates, and mammalian models. Using standardized mean differences (Hedges' g) under a random-effects REML framework, supported by subgroup analysis, meta-regression, and bias diagnostics, we quantitatively compared biological responses induced by MPs, PFAS, and their co-exposure. PFAS produced the strongest and most consistent toxic effects across systems (g = 4.71; 95% CI: 2.32-7.09), with pronounced impacts on oxidative balance, hepatic function, immune regulation, and reproductive performance. MPs also induced widespread biological stress, though with lower and more variable intensity (g = 2.19; 95% CI: -0.29-4.66), affecting oxidative, reproductive, and inflammatory pathways. Notably, co-exposure to MPs and PFAS frequently resulted in attenuated or antagonistic responses rather than additive toxicity (g = -2.98; 95% CI: -8.89-2.93), suggesting that PFAS adsorption onto MP surfaces can reduce bioavailability and tissue uptake. However, synergistic effects emerged under specific conditions, particularly at high PFAS concentrations, with small or weathered particles and prolonged exposure durations. Dose response relationships were evident across exposure categories, with aquatic species displaying the greatest sensitivity. Overall, these findings demonstrate that mixture toxicity is context-dependent and cannot be inferred from single-compound data alone. This study provides a quantitative foundation for advancing mixture-aware environmental risk assessment and regulatory frameworks.

Since the 1950s, regulation of occupational carcinogen exposure has progressed from hazard identification to quantitative evaluation, driven by advances in cancer biology. This narrative review compares two approaches for setting Occupational Exposure Limits (OELs) for carcinogens, focusing on benzene. The first one applies a mode of action (MOA)-based approach to genotoxicity stratification, using linear extrapolation for direct genotoxicants and non-linear extrapolation for indirect genotoxicants. The second approach quantifies in vivo genotoxicity data, employing mathematical modeling to define the point of departure (POD) for non-linear extrapolation, regardless of the MOA. As benzene is an indirect genotoxicant, it is considered to have a threshold value. Applying the MOA-based approach to genotoxicity stratification, different European institutions and commissions have proposed OELs ranging from 0.05 to 0.25 ppm. The ACGIH has recommended a TLV-TWA of 0.02 ppm (skin notation). Based on a quantitative genotoxicity approach, the proposed OELs range from 0.021 to 0.07 ppm for benzene. Current evidence indicates that workplace benzene concentrations above 0.3 ppm do not adequately protect the health of exposed workers. Extending follow-up of existing cohorts and conducting robust quantitative genotoxicity assays in well-designed epidemiological and experimental studies are essential to reduce uncertainties and to confirm the most sensitive toxic effect, thereby supporting the establishment of a more realistic OEL for benzene and minimizing the likelihood of over- or underestimating the associated risks.

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.