Critical Reviews in Toxicology最新文献

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.

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.

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.

Thyroid hormone (TH) is crucial for proper neurodevelopment. Insufficient TH concentrations in early life are associated with lower IQ and delayed motor development in children. Intracellular levels of TH are modulated via the transmembrane transport of TH and intracellular deiodination, and can mediate gene transcription via binding to the nuclear TH receptor. Chemical exposure can disrupt TH homeostasis via modes of action targeting intracellular mechanisms, thereby potentially influencing TH transport, deiodination or signaling. Understanding the cause and effect relationships of chemical hazards interfering with TH homeostasis in the developing brain is necessary to identify how chemicals might disturb brain development and result in neurodevelopmental disorders. Adverse Outcome Pathways (AOPs) can provide a template for mapping these relationships, and so far multiple AOPs have been developed for TH homeostasis and adverse effects on cognition. The present review aims to expand current AOP networks by (1) summarizing the most important factors in the regulation of brain development under influence of TH, (2) integrating human-based mechanistic information of biological pathways which can be disturbed by TH disrupting chemicals, and (3) by incorporating brain-specific TH-mediated physiology, including barriers and cell specificity, as well as clinical knowledge. TH-specific pathways in the fetal brain are highlighted and supported by distinguishing cell type specific Molecular Initiating Events (MIEs) and downstream Key Events (KEs) for astrocytes, neurons and oligodendrocytes. Two main pathways leading to adverse outcomes (AOs) in the areas of 'cognition' and 'motor function' are decreased myelination due to oligodendrocyte dysfunction, and decreased synaptogenesis and network formation via the neurons. The proposed AOP framework can form a basis for selecting developmental neurotoxic in vitro and in silico test systems for an innovative human-focused hazard testing strategy and risk assessment of chemical exposure.

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 via 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.

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 vitro, 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 in vivo 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 in vitro studies. No in vivo 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.

Bisphenol A (BPA), a synthetic chemical widely used in the production of polycarbonate plastic and epoxy resins, has been associated with a variety of adverse effects in humans including metabolic, immunological, reproductive, and neurodevelopmental effects, raising concern about its health impact. In the EU, it has been classified as toxic to reproduction and as an endocrine disruptor and was thus included in the candidate list of substances of very high concern (SVHC). On this basis, its use has been banned or restricted in some products. As a consequence, industries turned to bisphenol alternatives, such as bisphenol S (BPS) and bisphenol F (BPF), which are now found in various consumer products, as well as in human matrices at a global scale. However, due to their toxicity, these two bisphenols are in the process of being regulated. Other BPA alternatives, whose potential toxicity remains largely unknown due to a knowledge gap, have also started to be used in manufacturing processes. The gradual restriction of the use of BPA underscores the importance of understanding the potential risks associated with its alternatives to avoid regrettable substitutions. This review aims to summarize the current knowledge on the potential hazards related to BPA alternatives prioritized by European Regulatory Agencies based on their regulatory relevance and selected to be studied under the European Partnership for the Assessment of Risks from Chemicals (PARC): BPE, BPAP, BPP, BPZ, BPS-MAE, and TCBPA. The focus is on data related to toxicokinetic, endocrine disruption, immunotoxicity, developmental neurotoxicity, and genotoxicity/carcinogenicity, which were considered the most relevant endpoints to assess the hazard related to those substances. The goal here is to identify the data gaps in BPA alternatives toxicology and hence formulate the future directions that will be taken in the frame of the PARC project, which seeks also to enhance chemical risk assessment methodologies using new approach methodologies (NAMs).