Critical Reviews in Toxicology最新文献

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.

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.

Pyrethroids are synthetic products derived from natural pyrethroids present in flowers and are extensively used as pesticides for agriculture, animal husbandry, and household pest control. However, excessive and prolonged usage of pyrethroid insecticides can result in adverse effects on both non-target and target species. Therefore, effective technologies need to be developed to remove pyrethroid contamination and ensure environmental safety. Microbial remediation of various pesticide contaminants is highly practicable, low cost, and eco-friendly compared to physical and chemical methods. Different microbiota are screened to eliminate or degrade the contaminants. Microbial remediation technology utilizes the natural ability of microbiota to treat contaminated areas. Previous studies have mostly focused on the isolation and screening of microorganisms for pyrethroid biodegradation, as well as on the kinetics and pathways of pyrethroid biodegradation. In order to develop effective bioremediation strategies, further research based on molecular biology and bioengineering is required for a comprehensive exploration of pyrethroid-degrading microorganisms. To date, the microbial degradation of pyrethroid pesticides and the underlying mechanisms have been rarely reviewed. Therefore, this critical review encompasses the latest knowledge on synthetic pyrethroids from structural properties, bio-toxicity, and characterization of microbial degradation strains to degradation characteristics, intrinsic mechanisms, and microbial degradation pathways. The future of microbial remediation depends on combining advanced gene technology with traditional bioremediation methods to sustainably degrade pesticide contaminants. It also summarizes the factors affecting degradation efficiency and concludes with prospects, along with current challenges and limitations.

While progress has been made in recent years, there are still no suitable and accepted in silico, in vitro, or in vivo models that can be used to accurately predict whether a chemical substance has the intrinsic property to cause immune-mediated chemical respiratory allergy, typically manifested as allergic asthma or allergic rhinitis which represents a severe health hazard. Regulatory authorities have relied primarily on clinical evidence (case reports, clinical databases, worker exposure studies) to classify substances as respiratory sensitizers, but this evidence can lack a proven immunological mechanism which is necessary to identify substances which can cause life-long sensitization and clinically relevant allergic symptoms in the respiratory tract in an exposed population (such respiratory allergens may be considered as "true" sensitizers, in analogy to the definition of skin sensitization, and in contrast to respiratory irritants). In light of this, the European Center for Ecotoxicology and Toxicology of Chemicals convened a Task Force to evaluate the types of clinical methods and data sources and the implications of relying on such data for regulatory decision making from a scientific perspective. Recognizing that there are benefits and important insights from using such data, significant shortcomings were identified. With clinical work being focused on treatment and diagnosis of individual patients, the approaches and methods used for clinical guidance, diagnostics and reporting have serious limitations in proving the respiratory sensitization potential of a specific chemical, definitely restricting their suitability in deriving legally binding hazard classifications for human health protection. Even within the current broader regulatory definition of respiratory sensitization, a robust assessment and sound evidence of causation by a specific chemical seems mandatory in order to avoid misclassifications. Application of a systematic weight-of-evidence approach is considered suitable to determine the level of confidence, including a thorough assessment of the specificity or non-specificity of observed bronchial hyperreactivity. Recommendations proposed in this publication may not only aid industry and regulators in their decision making but also facilitate a further exchange between stakeholders to improve the data used to (a) more precisely identify true respiratory sensitizers to effectively protect human health, (b) aid evaluation of potential predictive models, and (c) encourage regulators to clarify guidance and to consider a re-evaluation of the current regulatory definition of respiratory sensitizers.

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 in vitro toxicity testing related to these effects is thoroughly reviewed and critical issues pertaining to this topic are discussed.

Hydrogen sulfide (H₂S), 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 Caenorhabditis elegans (C. elegans) is a valuable tool in toxicology, featuring both a conserved enzymatic H₂S metabolic pathway and a unique dietary bacteria-derived H₂S generation mechanism. Notably, existing data demonstrate that H₂S can extend lifespan, strengthen stress resistance, and preserve mitochondrial function in C. elegans. 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, H₂S has also been utilized to develop novel multi-target drugs for Alzheimer's disease using the C. elegans model. The present review summarizes recent advances in H₂S-based detection, metabolism and its functional outcomes, as well as molecular underpinnings of H₂S effects in C. elegans, offering valuable insight into the potential of this alternative model system for investigating H₂S-related physiological and toxicological mechanisms.

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 in vitro methods that help to improve human relevant risk assessment. Initiatives are taken to develop in vitro 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 in vitro models ranging from simple mono-cultures to extended 3D cultures of the brain barriers are discussed as well as how (a combination of) these in vitro models can be utilized to study TH transport and its disruption in the brain.

Current evidence on the prevalence of neurodevelopmental disorders has raised concerns over the environmental etiology for developmental neurotoxicity. As the use of standardized in vivo 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 In Vitro 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 in vivo study results from developmental neurotoxicity guideline or guideline-like in vivo 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 In Vitro 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.