Critical Reviews in Toxicology最新文献

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.

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.

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).

Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals used widely in industrial and commercial applications. Concerns exist about their potential link to cancer risk as possible endocrine-disrupting chemicals. We conducted a meta-analysis to evaluate the dose-response relationship between PFAS, perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluorohexanesulfonic acid (PFHxS) exposure and risk of breast, prostate, colorectal, and ovarian cancers. We systematically searched major databases through May 2022 and identified 13 observational studies for inclusion. Using random-effects models, we calculated summary odds ratios (ORs) and 95% confidence intervals (CIs) comparing the highest versus lowest PFAS exposure categories. Additionally, we analyzed the dose-response correlation between PFAS and cancer risk in a subset of studies. The study revealed no substantial correlation between exposure to PFASs and the incidence of breast cancer (BC) (OR_PFOS = 1.15, 95% CI = 0.91-1.46, OR_PFOA = 1.01, 95% CI = 0.68-1.50, OR_PFNA = 0.88, 95% CI = 0.64-1.21, OR_PFHxS = 1.22, 95% CI = 0.40-3.77, and OR_PFDA = 1.29, 95% CI = 0.41-4.10), ovarian cancer (OR_PFOA = 1.43, 95% CI = 0.84-2.42), prostate cancer (OR_PFOA = 1.05, 95% CI = 0.88-1.26), and colorectal cancer (OR_PFOA = 0.77, 95% CI = 0.53-1.12) in the highest versus lowest exposure analysis. However, dose-response analysis showed that for every 1 ng/ml increase in PFNA and 2 ng/ml increase in PFOA, the relative risk for BC decreased significantly (RR 0.67, 95% CI 0.45-0.99 and RR 0.94, 95% CI 0.89-0.98, respectively). Non-linear dose-response analysis found no significant changes in BC risk with increasing PFAS levels. In conclusion, while the highest versus lowest analysis does not support associations between PFAS exposure and the risk of these cancers, linear dose-response analysis suggests potential inverse relationships between PFNA/PFOA levels and BC risk. Further research is warranted on these potential protective effects.

Asbestos is a group of naturally occurring fibrous minerals that were commonly used in the construction of cement pipes for drinking water distribution systems. These pipes deteriorate and can release asbestos fibers into drinking water, raising concerns about potential risk to human health. The objective of this work was to synthesize human, animal, and in vitro evidence on potential health risks due to ingested asbestos in drinking water and evaluate the weight of evidence (WoE) of human health risk. A systematic review of epidemiological evidence was conducted, along with critical review of animal and in vitro evidence, followed by WoE evaluation that integrated human, animal, and in vitro evidence. The systematic review included 17 human studies with health outcomes mostly related to various cancer sites, with the majority focusing on the gastrointestinal system. The WoE evaluation resulted in very low levels of confidence or insufficient evidence of a health effect for cancers in 15 organ systems and for three non-cancer endpoints. While eight studies reported possible associations with stomach cancer in males, few high-quality studies were available to verify a causal relationship. Based on high-quality animal studies, an increased risk for cancer or non-cancer endpoints was not supported, aligning with findings from human studies. Overall, the currently available body of evidence is insufficient to establish a clear link between asbestos contamination in drinking water and adverse health effects. Due to the lack of both high-quality epidemiological studies and a validated kinetic model for ingested asbestos, additional research on this association is warranted.

Air pollution is a significant environmental health risk for urban areas and developing countries. Air pollution may contribute to the incidence of cardiopulmonary and metabolic diseases. Evidence also points to the role of air pollution in worsening or developing neurological and neuropsychiatric conditions. Inhaled pollutants include compositionally differing mixtures of respirable gaseous and particulate components of varied sizes, solubilities, and chemistry. Inhalation of combustibles and volatile organic compounds (VOCs) or other irritant particulate matter (PM) may trigger lung sensory afferents which initiate a sympathetic stress response via activation of the hypothalamic-pituitary-adrenal (HPA) and sympathetic-adrenal-medullary (SAM) axes. Activation of SAM and HPA axes are associated with selective inhibition of hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-thyroid (HPT) axes following exposure. Regarding chronic exposure in susceptible hosts, these changes may become pathological by causing neuroinflammation, neurotransmitter, and neuroendocrine imbalances. Soluble PM, such as metals and nano-size particles may translocate across the olfactory, trigeminal, or vagal nerves through retrograde axonal transport, or through systemic circulation which may disrupt the blood-brain barrier (BBB) and deposit in neural tissue. Neuronal deposition of metallic components can have a negative impact through multiple molecular mechanisms. In addition to systemic translocation, the release of pituitary and stress hormones, altered metabolic hormonal status and resultant circulating metabolic milieu, and sympathetically and HPA-mediated changes in immune markers, may secondarily impact the brain through a variety of regulatory adrenal hormone-dependent mechanisms. Several reviews covering air pollution as a risk factor for neuropsychiatric disorders have been published, but no reviews discuss the in-depth intersection between molecular and stress-related neuroendocrine mechanisms, thereby addressing adaptation and susceptibility variations and link to peripheral tissue effects. The purpose of this review is to discuss evidence regarding neurochemical, neuroendocrine, and molecular mechanisms which may contribute to neuropathology from air pollution exposure. This review also covers bi-directional neural and systemic interactions which may raise the risk for air pollution-related systemic illness.