Regulatory frameworks, informed by robust and transparent scientific evidence, can significantly benefit society when thoughtful and measured regulation is promulgated. However, regulations founded on incomplete or misinterpreted science often result in unintended consequences. As was the case with the polychlorinated dibenzodioxin and polychlorinated dibenzofuran (PCDD/PCDF) chemicals, for the past 50 years, there has been a lack of scientific consensus on the adverse health effects of per- and polyfluoroalkyl substances (PFAS) in humans at current blood concentrations (about 4 ppb TEQ) or even concentrations 10-300-fold higher (40-1200 ppb TEQ). Despite their distinctly different chemical structures, the dioxins, particularly 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and perfluorooctanoic acid (PFOA)/perfluorooctanesulfonic acid (PFOS), share notable similarities: environmental persistence, biological recalcitrance, slightly unpredictable acute toxicity, a lack of genotoxicity, and suggestive data on adverse health effects in humans; across a wide range of doses. Both substances display varying degrees of acute toxicity across species, and both have been associated with the onset of wasting syndrome in certain animals at fairly high doses, but wasting syndrome is not seen in humans. Although there is moderate to high acute toxicity in multiple animal species for both families of chemicals, there is low acute toxicity in humans. In humans, both compounds interact with fatty acid metabolism. The evidence indicates that both are either weakly genotoxic or non-genotoxic. The dioxins can cause cancer in a variety of animal species, but even in humans exposed to high doses, no increased cancer risk is apparent. PFAS chemicals are similar; weakly carcinogenic in animals and, perhaps, lacking carcinogenic potency in humans. However, unlike with dioxins, high human exposure to PFAS has only occurred in the workplace; thus, few data from highly exposed human populations are available to rigorously evaluate the human cancer risk or other potential effects at elevated doses. Similar to the widespread presence of dioxins reported in the 1970s-1980s, PFAS chemicals are now globally ubiquitous, with detectable concentrations in nearly every individual, fish, and wildlife species. As awareness has increased over time, pressure to prevent the release or manufacture of PFOA and PFOS has decreased the blood concentrations in Americans by 10-fold over the past 15 years, paralleling trends observed with the dioxins when global concerns surfaced. The dioxins were regulated in a heavy-handed manner despite scientific uncertainty regarding their human health risks over a range of exposure levels, as well as a lack of consensus on dose-response relationships, thresholds for adverse effects, and human relevance of high-dose animal studies. The regulatory actions that occurred with the dioxins ultimately resulted in substantial economic and societal costs, even in the face of much uncertainty. This paper examines the parallels between the development of scientific understanding of the health hazards and the eventual regulation of dioxins and PFAS chemicals. For both families of chemicals, the precautionary principle was followed by most agencies rather than solid scientific data during the rulemaking process.

The paper explores a content of the recent International Agency for Research on Cancer (IARC) Monograph (Volume 136) where pure talc was reclassified from the Group 2B ("Possibly carcinogenic to humans") to the Group 2 A ("Probably carcinogenic to humans"). The Monograph is considered in the context of the history of the IARC program for classification of carcinogens as well as in the framework of basic principles of toxicological science. It is demonstrated that reclassification was made not based on any new scientific information available, but rather because of a change in some of the methodological approaches or preferences employed by IARC. In particular, it is demonstrated that there are significant mineralogical issues in characterization of talc by the recent IARC Monograph. It is shown why weight-of-evidence for carcinogenicity of pure talc in experimental animals cannot be estimated higher than "limited", and in human study higher than "inadequate". It will also be argued that utilization of separated mechanistic criteria (key characteristics of carcinogens) without contextual analysis and proven mode-of-action (MoA) can cause significant uncertainties in the determination of carcinogenicity in humans. There is a need for comprehensive risk assessment for various agents and processes, rather than just hazard identification that the IARC continues to exercise with questionable relevance for global cancer prevention.

Food contamination has been a major health issue since the beginning of human existence. Some food contaminants trigger important psychological manifestations, such as delirium, hallucinations, and psychosis, which may cause distress, aggravate pre-existing conditions, and dangerously interact with certain medications. Exposure to psychoactive food contaminants can ultimately lead to severe health problems or even death. As such, it is important to further study these substances to prevent contamination and identify and treat intoxications. Among these substances, three classes of food contaminants are addressed herein due to their toxicological relevance: (i) ergot alkaloids (ergotamine and ergometrine), (ii) tropane alkaloids (atropine, hyoscyamine, and scopolamine), and (iii) opium alkaloids (codeine and morphine). An historical perspective relative to each contaminant is briefly described in this review, as well as the dietary sources and key chemical properties. Guidance values and analytical methods that allow the detection and quantification of these toxic agents are also provided. In addition, relevant toxicokinetic and toxicodynamic aspects are summarized. Finally, for each xenobiotic, registered intoxication cases, from epidemics and outbreaks to case reports, are described, as well as the detection of contaminants in screening procedures. Overall, this review reinforces that dietary exposure to psychoactive contaminants constitutes a toxicological issue that should be duly considered.

This study evaluates whether fresh frozen plasma (FFP) improves outcomes compared to conventional therapy alone in organophosphorus poisoning (OP). Relevant literature was searched in PubMed, Web of Science, Embase, Cochrane Library, CNKI, Wanfang, and VIP databases, applying predefined inclusion/exclusion criteria to select studies. Data from included studies were extracted for analysis. Seven randomized clinical trials involving 391 patients were included in the analysis, with 191 patients in the FFP combined with conventional therapy group (combination therapy group) and 200 patients in the conventional therapy alone group (control group). Compared with the control group, the combination therapy group demonstrated a lower case fatality rate (relative risk (RR) = 0.58, 95% confidence interval [CI] [0.34, 0.97],  < .05), reduced utilization of mechanical ventilation (RR = 0.78, 95% CI [0.64, 0.95],  < .05), and superior cholinesterase recovery levels (standardized mean difference (SMD) = 1.70, 95% CI [-0.02, 3.43],  = .05). However, no significant differences were observed between the two groups in hospitalization duration or ICU length, incidence of intermediate syndrome, and duration of mechanical ventilation maintenance ( > .05). Current evidence indicates that FFP combined with conventional therapy may reduce mortality rates, mechanical ventilation utilization, and enhance cholinesterase activity recovery levels in OP patients. Nevertheless, multicenter randomized double-blind controlled trials remain necessary to validate these findings in the future.

Statins are the drugs recommended for the treatment of dyslipidemia and for preventing cardiovascular risks in humans. However, it is reported that statins may impair reproductive parameters in males at different periods of exposure in pre-clinical studies. This work carried out a systematic review of the literature concerning the primary studies that evaluated the reproductive outcomes in male rats and mice exposed to several statins available on the market. The literature search was performed employing several databases, including Embase, Web of Science, PubMed, LILACS, Scopus, and SciELO, by using different combinations of the search terms "statins," "mice," "rats," "male reproduction," "fertility" and "sperm," followed by the Boolean operators AND or OR. Then, duplicated articles or studies that did not meet the eligibility criteria were excluded. Posteriorly, the risk of bias was assessed following the essential ten points of the ARRIVE guidelines. Afterward, the extraction and qualitative analysis of the data were performed, and when possible, a meta-analysis was carried out. The results indicated that normolipidemic healthy rodents exposed to statins showed reproductive impairment, such as reduced sperm quality, diminished testosterone production, and delayed puberty onset. Additionally, and studies demonstrated a decrease in testosterone synthesis after statin exposure. However, when rodents were induced to diabetes and erectile dysfunction or were fed a high-fat diet, these diseased animals exposed to statins exhibited improved erectile function, increased sperm quality, and no changes or augmented testosterone levels. Given the reproductive toxicity generated by statin exposure in healthy male rodents without any previous dysfunction, these drugs should be reserved for treating dyslipidemia or, when appropriate, as an adjunct therapy for erectile dysfunction.

Constitutive androstane receptor (CAR) activators have long been known to enhance hepatocellular carcinogenesis in rodents, with the prototypic chemical being phenobarbital (PB). This has raised an ongoing controversy for the past 50 years as to whether this is relevant to human cancer risk. The established mode of action (MOA) for rodent liver tumor formation by CAR activators includes receptor activation, increased hepatocellular proliferation, altered liver foci and ultimately liver tumors. We previously published a critical review indicating the pivotal species difference that CAR activators are mitogenic agents in mouse and rat hepatocytes, but they do not stimulate hepatocellular proliferation in humans based on molecular downstream interaction differences, thus CAR activators pose no liver carcinogenic risk to humans (Yamada et al. ). Peroxisome proliferator-activated receptor alpha (PPARα) activators induce rodent liver tumors through a similar MOA, again involving increased hepatocellular proliferation, but are generally considered not relevant to human cancer risk. As with CAR activators, PPARα activators are mitogenic in rodent liver but not in other species, including humans. This species-specific effect of CAR and PPARα activators provides critical information useful for the overall risk assessments of these molecules, including pharmaceuticals, agrochemicals, food additives, and other chemicals. Overall, based on the available data for the specific molecular effects of these agents, the time has come to consider that chemicals for which the MOA of liver carcinogenicity observed in rodents has been clearly identified as either CAR- or PPARα-mediated (with other MOAs having been excluded) can be judged as having no relevance to human cancer risk without further investigations being necessary.

Current evidence on the prevalence of neurodevelopmental disorders has raised concerns over the environmental etiology for developmental neurotoxicity. As the use of standardized developmental neurotoxicity methods has been restricted due to high costs, limited testing capacity and extrapolation uncertainties, a shift to implementation of higher throughput technologies is urgently needed. A fit-for-purpose Developmental Neurotoxicity Battery based on New Approach Methodologies has been recently developed to support the regulatory decision-making process. To increase confidence in its predictive performance and readiness, the authors, under the auspices of European Food Safety Authority, have created a curated database of study results from developmental neurotoxicity guideline or guideline-like studies. Methods, data and results from publicly available US Environmental Protection Agency Data Evaluation Records have been entered into a standardized data extraction model, developed to facilitate quantitative data collection and harmonization. The goal of the present work was to build a transparent and publicly available database of developmental neurotoxicity data from guideline studies, suitable for comparison with outputs from NAM assays such as the Developmental Neurotoxicity battery. This effort represents a significant advancement for future analyses and will serve as a key stone for the development of transparent and publicly accessible databases of developmental neurotoxicity data.

The Adverse Outcome Pathway (AOP) framework is a foundational approach in environmental pollutant research, encompassing the detrimental effects of pollutants across biological levels from molecules to populations. Toxicogenomics (TGx), which integrates omics technologies with toxicology, plays a crucial role in AOPs by elucidating the relationships between chemical exposure, molecular initiating events (MIEs), and key events (KEs) across various biological levels using animal and cell model-based data. However, since some MIEs (e.g. changes in specific enzyme activities or receptor binding/activation) cannot be confirmed by omics data alone, TGx data must be integrated with classical enzymatic assays, receptor function analyses, and related methods when constructing AOPs to ensure comprehensive, accurate identification of MIEs and their associated KEs. Epidemiology examines the links between environmental exposures, KEs and adverse outcomes (AOs) in human populations, contributing to the understanding of population-level disease outcomes. With the advent of big data, both epidemiology and TGx studies have generated substantial datasets. To synthesize these extensive data resources, meta-analysis emerges as a robust tool, effectively integrating environmental epidemiology and TGx data to provide a coherent and strong evidence base, revealing the correlative and causative relationships between environmental pollutants and human health outcomes. This review focuses on the role of meta-analysis in environmental health research, particularly on integrating environmental health epidemiology and TGx data. Additionally, we explore the challenges in applying meta-analysis and discuss future directions. Our aim is to provide researchers with a comprehensive understanding of meta-analysis methods and processes in environmental health research, encouraging wider adoption and further development of this analytical approach.

The increase in global temperatures associated with climate change has intensified the frequency, duration, and severity of wildfires, resulting in exposure to a range of hazardous compounds, including polycyclic aromatic hydrocarbons (PAHs). The work of wildland firefighters involves exposure to several physical, chemical, and biological hazards. The present study evaluated the health effects of PAH exposure from wildfires on firefighters. A systematic literature review was conducted using the Web of Science, PubMed, Scopus, CINAHL, and Lilacs databases, covering the period from January 2019 to June 2025, according to PRISMA guidelines. Out of 766 papers retrieved, 16 met the inclusion criteria. Biomonitoring was employed to quantify the levels of biomarkers of exposure, specifically monohydroxylated PAHs (OH-PAHs), in most studies, and biomarkers of effect, such as biochemical or cellular changes, in over half of them. Most studies have indicated significant post-exposure increases (up to 12-fold) in urinary PAH metabolite levels, either during simulated burn training or actual wildfire events. The primary health effects observed were oxidative stress, increased DNA damage, and alterations in inflammatory markers and immunological cells. Both respiratory and dermal exposure routes are significant, with dermal absorption identified as a key pathway even when respiratory protection is used. However, there is no specific certified respiratory personal protective equipment (PPE) for use in wildfires. In consideration of these findings, it is recommended that specialized equipment be developed for forest firefighting to reduce smoke exposure. The review highlights the need to mitigate these risks as the workers presented a high body burden of PAHs, and current exposure limits may be insufficient. Further occupational exposure studies, particularly in under-researched, high-impact geographical regions, are crucial to guide the development of public health policies and enhance risk management strategies for wildland firefighters.

Per- and polyfluoroalkyl substances (PFAS) continue to be an emerging chemical class of concern due to their long half-lives in nature and in the human body. There have been many epidemiology studies published in the scientific literature on PFAS and various health effects. Until recently, these studies have focused on assessing exposure to individual PFAS rather than exposure to mixtures of PFAS. Over the past two decades, mixture methods-statistical methods for investigating the association of mixtures-have been developed, making it possible to more accurately assess the risk of adverse health effects associated with exposure to PFAS. To help provide a resource for the overall evaluation of potential health effects of PFAS mixtures, we applied a consistent set of examination methods and criteria for all epidemiology studies that examined the potential relationship between exposure to PFAS mixtures and various types of health outcomes. We identified 233 cohort studies, 39 case-control studies, and 89 cross-sectional studies that evaluated general background-level exposures, exposure from contaminated sites, and occupational exposure to PFAS mixtures and health outcomes including metabolic, cardiovascular, and immune system effects, fetal development, pregnancy outcomes, reproductive effects, liver function, and respiratory effects. We extracted study characteristics and results in a systematic manner and performed a formal study quality evaluation and classified studies into tiers based on their methodological strengths and weaknesses. We found 42 prospective cohort studies, five nested case-control studies, and one traditional case-control study that qualified for inclusion in the highest tier of quality (Tier I). Overall, the weight of evidence from this systematic review indicates that the available epidemiology studies currently support an association between exposure to PFAS mixtures and adiposity, increased total cholesterol, and hypertension, while the evidence for all other health outcomes is suggestive or limited.

Per- and polyfluoroalkyl substances (PFAS) are persistent synthetic chemicals widely used in industrial and consumer products, leading to environmental contamination and human exposure. This review focuses on perfluoroalkyl acids, a subset of PFAS, which are primarily encountered through diet, including drinking water, and other pathways such as dust ingestion, and dermal contact. Impaired vaccine antibody response has been identified as the most critical effect for risk assessment by the European Food Safety Authority. Furthermore, human epidemiological studies have linked exposure to certain PFAS to various immune-related outcomes, such as asthma, allergies, and inflammatory bowel disease. This review examines potential immunomodulatory effects of perfluoroalkyl acids at the primary sites of exposure: lungs, intestines, and skin, using human epidemiological data as the basis for investigating these impacts. While animal studies are referenced for context, this paper highlights the need for further human-based research to address key questions about PFAS and their immunological impacts. The state of toxicity testing related to these effects is thoroughly reviewed and critical issues pertaining to this topic are discussed.

Hydrogen sulfide (HS), while historically recognized as a poisonous substance, also serves as a gasotransmitter that mediates a wide spectrum of physiological processes across species and is involved in the mechanisms of various exogenous toxicants. The is a valuable tool in toxicology, featuring both a conserved enzymatic HS metabolic pathway and a unique dietary bacteria-derived HS generation mechanism. Notably, existing data demonstrate that HS can extend lifespan, strengthen stress resistance, and preserve mitochondrial function in . Its molecular mechanisms may be related to regulating HIF-1 and SKN-1 signaling, enhancing deacetylase SIR-2.1 activity, and exerting epigenetic effects, including methylation of histone H3K4 and protein persulfidation. More recently, HS has also been utilized to develop novel multi-target drugs for Alzheimer's disease using the model. The present review summarizes recent advances in HS-based detection, metabolism and its functional outcomes, as well as molecular underpinnings of HS effects in , offering valuable insight into the potential of this alternative model system for investigating HS-related physiological and toxicological mechanisms.

Malathion and diazinon are pesticides widely used in agriculture as well as for domestic and veterinary purposes to control pests, such as scale insects, aphids, and fleas. However, these compounds may have harmful effects on the female genital system in humans and animals. This study conducted a systematic review of the scientific literature on the female reproductive effects in humans and rodents exposed to malathion or diazinon. The search was conducted from March to September 2024 and was updated in July 2025. It was carried out in the Embase, LILACS, PubMed, SciELO, Scopus, and Web of Science databases by using different combinations of the terms "diazinon", "malathion", "ovary", "uterus", "female reproduction", "humans", "rats", and "mice" accompanied by the Boolean operators AND or OR. A total of 241 articles were found when the search was conducted using rats or mice as exposed organisms. After removing the duplicates and excluding the articles that showed administration routes not applicable to humans and the studies that were unavailable in full, only seven articles were included in this systematic review. These studies were assessed in relation to the risk of bias as recommended by the SYRCLE's risk of bias tool. For the search involving human studies, 291 articles were found; however, only four articles were deemed relevant for this review after removing the duplicates and the studies that did not meet the eligibility criteria. Then, the included studies were evaluated in relation to the risk of bias as recommended by the Newcastle-Ottawa Scale. Afterwards, the extraction of the results was performed, and the outcomes were organized in tables. When possible, a meta-analysis was carried out with all the studies that assessed the same sexual steroid and gonadotrophic hormones in females. In this review, the results demonstrated that malathion and diazinon impair female reproduction in rodents by reducing ovarian hormone production, increasing oxidative stress, diminishing oocyte quality, and inducing histopathological changes in the reproductive organs. In humans, the included studies demonstrated that exposure to these pesticides is associated with a higher risk for developing endometriosis and an increased risk of ovarian, uterine, and thyroid cancers. After assessing the effects of these organophosphates on hormonal levels by meta-analysis in this review, it was shown a reduction in progesterone concentrations (reduction of 37.43%; overall effect size:  = 2.05,  = 0.04; mean difference and confidence interval: -9.33 [-18.23, -0.43]) but there were no effects in estradiol (overall effect size:  = 0.31,  = 0.76; mean difference and confidence interval: 2.66 [-14.21, -19.54]), testosterone (overall effect size:  = 0.91,  = 0.36; mean difference and confidence interval: 0.08 [-0.09, 0.24]), FSH (overall effect size:  = 0.86,  = 0.39; mean difference and confidence interval: -0.40 [-1.31, 0.51]), and LH (overall effect size:  = 1.38,  = 0.17; mean difference and confidence interval: -0.75 [-1.82, 0.32]) levels. Additionally, the studies suggested that these pesticides interfere with hormonal production mechanisms by promoting cell apoptosis and autophagy in ovarian cells, which may compromise fertility in the long term. As a limitation of this review, there was a small number of included studies and a higher heterogeneity of these studies (I ≥ 79%). In summary, female rodent exposure to these organophosphates was associated with hormonal dysregulation, impaired ovarian and uterine structure, and oxidative stress in reproductive tissues. In humans, this exposure was related to increased risk of endometriosis and hormonally associated cancers. When considering the negative impact observed on the female genital system of both rodents and humans, it is crucial to reconsider the use of these pesticides, as well as adopt less harmful alternatives to protect the reproductive health of non-target animals and human populations exposed to these substances.

A comprehensive review of existing toxicity and human exposure data for the ultraviolet filter avobenzone (butyl methoxydibenzoylmethane) was conducted to assess its safety as currently used in over-the-counter sunscreen formulations. Avobenzone has a suitable safety profile without any clear markers of toxicity or endpoints of concern. There are sufficient clinical studies and and toxicity studies in animal models to assess avobenzone's pharmacokinetics, pharmacodynamics, and potential toxicological properties, supportive of its long history of safe use. No harmonized dermal absorption value was available, but the clinical data indicate low percutaneous absorption of avobenzone in humans (≤0.59% of the applied dose). There were no data to characterize the distribution of avobenzone; however, four tentative metabolites of avobenzone have been identified, and limited excretion in urine was demonstrated in human biomonitoring studies. Avobenzone generally did not cause dermal irritation or sensitization, but indications of photoallergy have been reported in clinical case studies. The acute toxicity profile indicated that avobenzone has minimal toxicity. The no-observed-adverse-effect level (NOAEL) for general toxicity from a rat dietary subchronic toxicity study was 450 mg/kg/day. There was no evidence of avobenzone effects on immune tissues or the estrogen, androgen, or thyroid systems. Although there were no formal 2-year carcinogenicity studies for avobenzone, a 90-day dietary exposure study in rats did not show any increase in hyperplasia of any tissue or evidence of cytotoxicity, and avobenzone has not shown any indication of genotoxicity either or . Together, this indicates that key events for modes of action for avobenzone are absent and carcinogenicity in humans is unlikely. Based on the selected rat subchronic NOAEL and conservative assumptions for estimating the systemic exposure dose (SED) from the application of sunscreen products, margins of exposure (defined as the ratio of NOAEL to SED) greater than 100 were obtained for avobenzone. Therefore, the available data show that avobenzone is unlikely to pose a risk to human health when used in sunscreen products at concentrations up to the permitted maximum usage levels in the United States and Canada, which is 3%.

There is a concern on the safety of cosmetic ingredients and their endocrine-disrupting (ED) potential. Frequent use as well as the use of a diverse range of cosmetics pose a concern for a potential health risk via aggregate exposure to endocrine disrupting chemicals (EDCs). In this study, a list of ingredients available in cosmetic products that were recently introduced to the Dutch market was retrieved from the commercially accessible Mintel database and screened for the presence of EDCs. To achieve this, a workflow was developed to crosscheck the list of cosmetic ingredients with information on potential EDCs derived from open-source initiatives (i.e. chemical lists from the European Chemicals Agency, national authorities, and non-governmental organizations). Using this workflow, 27 chemicals were identified that were categorized as "indications for ED properties" and one chemical as "no concern for ED properties" out of the 890 cosmetic ingredients reviewed. For one of these chemicals, geraniol, a preliminary safety assessment was performed. Aggregated exposure to geraniol via cosmetics was modeled using PACEMweb and compared to the lowest observed adverse effect level on thyroid histopathology derived from an extended-one-generation study. This exercise showed that, based on the current information available, geraniol can be used safely in cosmetics with regard to endocrine-related health risks. Next, the cosmetic ingredients that are currently not identified as an EDC (i.e. not present on one of the crosschecked lists,  = 862), were prioritized based on an aggregate exposure score for further screening of their endocrine disrupting properties ( = 58). For eight out of the 58 prioritized chemicals data retrieved from a literature search indicated an endocrine-mediated relationship, and were categorized as "limited indications of ED properties". Overall, the developed workflow is a useful tool to screen cosmetics for the presence of potential EDCs and to prioritize chemicals for further evaluation of their ED properties, as well as assessment of their safe use in cosmetics.

A comprehensive review of existing toxicity and human exposure data for the ultraviolet filter ensulizole (2-phenylbenzimidazole-5-sulfonic acid) as currently used in over-the-counter sunscreen formulations was conducted. Authorized maximum ensulizole usage levels in consumer end-use products worldwide range from 3% to 8%, with the maximum usage level limited to 4% in the United States, Canada, and Australia. Postmarketing clinical safety studies of ensulizole have reported only occasional local skin effects, none of which were associated with systemic toxicity. Ensulizole has been investigated , in animal toxicity studies, and in human studies for its pharmacokinetics, pharmacodynamics, and potential toxicological properties. Experimentally determined values of 4% for oral absorption in rats and of 0.26% for dermal absorption in humans were used for risk calculation purposes. There was no evidence of ensulizole bioaccumulation from rat studies, consistent with its high water solubility and low octanol/water partition coefficient. Ensulizole is not classifiable as an irritant, although local skin irritation with no systemic effects was noted in a 3-month repeated-dose dermal toxicity study in rabbits. Ensulizole is non-(photo)sensitizing, non-phototoxic, and has demonstrated low toxicity in acute (oral, dermal, and intraperitoneal) and subchronic repeated-dose studies in mammalian species. Subchronic 3-month no-observed-adverse-effect levels (NOAELs) were identified at 100 mg/kg/day (dermal rabbit) and 1000 mg/kg/day (oral rat OECD 408 study), the highest doses tested, respectively. Ensulizole is considered non-genotoxic, based on negative studies. No genotoxicity or long-term carcinogenicity studies were identified. Carcinogenicity risk is not expected based on the negative genotoxicity data, empirical evidence from repeated-dose toxicity and developmental toxicity studies, and the absence of effects on the androgen, estrogen, thyroid, immune, developmental, or reproductive systems. Based on the selected rat subchronic NOAEL of 1000 mg/kg/day and conservative assumptions for estimating the systemic exposure dose (SED) from the application of sunscreen products, margins of safety (defined as NOAEL/SED) >100 were obtained for ensulizole. Therefore, the available data show that ensulizole does not pose risks to human health when used in sunscreen products at concentrations up to 4%, the permitted maximum usage level in the United States, Canada, and Australia.

The rising prevalence of electronic-cigarettes (E-cigs) use during pregnancy and lactation can be attributed, in part, to advertising campaigns promoting their safety. Nevertheless, the integrity of E-cigs as a secure substitute for conventional cigarettes necessitates further exploration. Some studies emphasize the toxic role of nicotine in E-cigs, while others underscore the significance of other distinct components whose toxicity cannot be disregarded. Increasingly, researchers are employing rodent models to elucidate the potential toxicological implications of e-cig use. Various paradigms of E-cigs exposure in early life frequently yield divergent health outcomes for offspring. This review first presents different animal model approaches to E-cig-exposure during pregnancy and lactation, referring to E-cig liquid, E-cig devices, puff topography, and inhalation methods, which would be related to the health outcomes. Moreover, the mechanisms underlying the hazardous impacts of maternal E-cig-exposure on offspring are also elucidated. Maternal exposure to E-cigs has been found to induce adverse effects on lung function, neurobehavior, glycolipid metabolism and energy homeostasis in offspring, which are probably mediated through inflammation, oxidative stress, and epigenetic modifications.

Chlorpyrifos (CPF) is one of the most widely used pesticides globally, despite being strictly regulated and banned in several developed countries. It remains in use across many developing and underdeveloped nations. While its primary mechanism of action is acetylcholinesterase inhibition, multiple preclinical and clinical studies have reported developmental and cognitive alterations at lower doses that do not trigger this mechanism. These effects are particularly concerning during early development, when the central nervous system is immature and more vulnerable. Although various alternative molecular targets have been proposed, growing attention has been given to neurotransmitter systems beyond the cholinergic pathway. However, empirical data is inconsistent, and no qualitative or quantitative reviews have provided a clear understanding of these mechanisms. This systematic review aims to address this gap, focusing on preclinical rodent studies. Using a rigorous methodology, 41 studies were included in the qualitative analysis, covering 126 outcomes related to the dopaminergic, serotonergic, GABAergic, glutamatergic, and endocannabinoid systems. Overall, the included studies showed a low level of methodological quality and a high risk of bias. Only a few molecular targets were systematically investigated. We introduce two new evaluative metrics-Weight of Evidence and Percentage of Convergence-to highlight five key findings. Notably, preweaning CPF exposure consistently reduced the activity of endocannabinoid-degrading enzymes (FAAH and MAGL), resulting in elevated endocannabinoid tone, particularly increased levels of AEA. Additionally, there is consistent support for CPF-induced serotonergic alterations, particularly upregulation of 5HT2 and 5HT1A receptors following neonatal exposure. Due to insufficient data convergence across laboratories, a meta-analysis was deemed inappropriate. In conclusion, while numerous molecules have been linked to low-dose developmental CPF exposure, only a limited number show consistent empirical support, and only under postnatal exposure conditions. Future research should investigate prenatal exposure effects more systematically and replicate postnatal findings across independent laboratories to strengthen the reliability of these promising results through robust, quantitative analyses.

In March 2023, the EPA proposed a 4.0 ppt maximum contaminant level (MCL) for perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) (each) and a hazard index approach for four other PFAS. The EPA sought public feedback on the proposed MCL in early 2023 and received 1626 comment submissions the PFAS docket website (Docket ID: EPA-HQ-OW-2022-0114). Final MCLs were promulgated on April 10, 2024. Our analysis of the PFAS docket identified 128 comments that had a reasonable degree of scientific merit, with 57 comments endorsing the regulations and 71 questioning the MCLs public health utility. Critics noted the lack of evidence for adverse health effects at low PFAS exposures, the rule's significant impact on the economy, and the EPA's selection of published papers which the Agency chose to support their views. Many well-substantiated comments highlighted that few, if any, adverse health effects were reported at doses as much as 100-1000 times above those associated with the proposed drinking water guidelines. We found that the comments which discussed the evidence linking PFAS exposures below 200 ppt in drinking water to adverse health effects were equivocal. Most of the well-documented science based comments indicated that the data did not justify setting a 4.0 ppt MCL. It was noted that the EPA MCL was quite different from drinking water standards in other countries (up to 8-140 fold lower). During the review, it became apparent that a 4.0 ppt MCL may have little effect on PFAS blood concentrations in most Americans since drinking water accounts for less than 20% of their total PFAS intake. Additionally, a significant portion of the American population consumes minimal amounts of tap water. Commenters noted that the financial burden for treatment and cleanup was much higher than what was reported in the justification for the final MCL which was submitted to the Office of Management and Budget (OMB) and eventually promulgated. It is possible that EPA underestimated the financial impact on the nation by up to 100 to 200-fold. Our analysis indicates that many, if not most, of the scientifically rigorous comments on the EPA's proposed MCL were not acknowledged or considered by the Agency. We conclude the article by offering sixteen recommendations for the EPA to consider if Congress or the courts choose to reopen the evaluation of these MCLs. These included convening an international expert panel, reevaluating the appropriateness of the LNT model for PFAS, ensuring adequate time for study quality assessment and cost-benefit analysis, considering an approach to implementing a series of MCLs, critically reevaluating scientific studies, adhering to EPA risk assessment guidelines, addressing SDWA compliance concerns, revisiting the Hazard Index approach, and ensuring thorough and transparent review of public comments.

Early brain development is dependent on the supply of thyroid hormone (TH) to the fetal brain. Disruption of TH concentrations in early brain development is associated with lower IQ and delayed motor development in children. How TH system disruption may affect brain development has mainly been studied in animal models that are not always relevant to humans and do not reflect the TH system in the developing brain. Furthermore, using animal models for safety assessments also raises ethical concerns, is still low-throughput and associated with high costs. All these reasons stress the need to develop new approach methodologies (NAMs), including methods that help to improve human relevant risk assessment. Initiatives are taken to develop assays for important key events in the fetal brain, but before TH can enter the fetal brain, it has to pass the developing blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). During brain development, the composition of the barriers change over time, as well as the interplay between the two different barriers. Therefore, barrier models need to be included in testing strategies for TH system disruption in the developing brain and these models should take the timepoint of development into account. Barriers are crucial for the supply of TH in the brain. TH is actively transported through these barriers via TH transmembrane transporters (THTMTs) such as MCT8 and OATP1C1, but alternatively, other THTMTs may be involved too. Furthermore, transport of TH across the brain barriers can be disrupted by chemicals. Currently, the extent of THTMT inhibition and its subsequent adverse effects on brain development is largely undiscovered. To further investigate TH transport across the BBB and BCSFB, human cell-based NAMs are being developed that more closely resemble the human brain barriers. These models take the complex cellular composition of the brain barriers into account and in case of organ-on-chip models, the blood/cerebrospinal fluid flow as well. In this review, aspects of accurate models ranging from simple mono-cultures to extended 3D cultures of the brain barriers are discussed as well as how (a combination of) these models can be utilized to study TH transport and its disruption in the brain.