Critical Reviews in Toxicology最新文献

Xylene is a high production volume chemical that is widely used as a solvent and polymer precursor, and is currently undergoing substance evaluation under Registration, Evaluation, Authorization and Restriction of Chemicals (REACH). Xylenes recently received testing decisions on one-generation reproductive toxicity (EOGRT) studies with additional developmental neurotoxicity (DNT) cohorts for each of the three isomers. Xylene presents a unique opportunity to investigate the need for additional animal DNT toxicology testing because it is a legacy industrial chemical for which a significant amount of animal and human data already exists on its toxicity profile, including central nervous system effects. Therefore, to address the need for further vertebrate testing, a comprehensive weight of evidence (WOE) review of published and previously unpublished new studies of xylene substances was performed. Evidence topics included the pharmacokinetics, narcotic effects in humans and animals, narcotic mode of action (MOA), and strength of DNT signal for xylene. Pharmacokinetic data indicate minimal distribution of the unmetabolized parent compound to the fetus relative to parental brain tissue, and rapid metabolism of xylene to methyl hippuric acid (MHA), which is also rapidly excreted in both humans and animals. Xylene exposure has also resulted in transient, nonspecific neurological effects including delays in reaction time of human volunteers and reductions in motor activity of animals. This narcotic MOA for xylene occurs by the nonspecific perturbation of nervous cell membrane phospholipids, such that membrane-bound proteins and their respective functions are impaired. Furthermore, an in-depth review of the available DNT data indicates significant methodological deficiencies in several studies in the literature purported to provide evidence of a DNT concern following xylene exposure and no DNT concern reported in one reliable study. In conclusion, based on xylene's pharmacokinetics, narcotic effects on the central nervous system observed in animal and human studies, its narcotic MOA, and the lack of a robust signal from the published DNT studies, there is no trigger for the additional EOGRT study DNT cohort to be conducted for xylene. Further, the findings on narcotic effects and MOA underscore the difficulty in separating transient, acute intoxication effects via direct exposure of the offspring from investigating DNT effects (as investigated in a standard guideline (426) DNT study) in the EOGRT study, therefore producing unreliable data, which is ethically at odds with REACH and 3 R principles.

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).

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.

Many recent articles in public health risk assessment have stated that causal conclusions drawn from observational data must rely on inherently untestable assumptions. They claim that such assumptions ultimately can only be evaluated by informed human judgments. We call this the subjective approach to causal interpretation of observational results. Its theoretical and conceptual foundation is a potential outcomes model of causation in which counterfactual outcomes cannot be observed. It risks depriving decision-makers and the public of the key benefits of traditional objective science, which invites scrutiny and independent verification through testable causal models and interventional hypotheses. We introduce an alternative objective approach to causal analysis of exposure-response relationships in observational data. This is designed to be more objective in the specific sense that it is independently verifiable (or refutable) and data-driven, requiring no inherently untestable assumptions. This approach uses empirically testable interventional causal models, specifically causal Bayesian networks (CBNs), instead of untestable potential outcomes models. It enables empirical validation of causal claims through Invariant Causal Prediction (ICP) tests across multiple studies. We explain how to use CBNs and individual conditional expectation (ICE) plots to quantify the effects on health risks of changing exposures while taking into account realistic complexities such as imperfectly controlled confounding, missing data, and measurement error. By ensuring that all causal assumptions are explicit and empirically testable, our framework may help to improve the reliability and transparency of causal inferences in health risk assessments.

This article aims to provide a comprehensive critical, yet readable, review of general interest to the chemistry community on molecular similarity as applied to chemical informatics and predictive modeling with a special focus on read-across (RA) and read-across structure-activity relationships (RASAR). Molecular similarity-based computational tools, such as quantitative structure-activity relationships (QSARs) and RA, are routinely used to fill the data gaps for a wide range of properties including toxicity endpoints for regulatory purposes. This review will explore the background of RA starting from how structural information has been used through to how other similarity contexts such as physicochemical, absorption, distribution, metabolism, and elimination (ADME) properties, and biological aspects are being characterized. More recent developments of RA's integration with QSAR have resulted in the emergence of novel models such as ToxRead, generalized read-across (GenRA), and quantitative RASAR (q-RASAR). Conventional QSAR techniques have been excluded from this review except where necessary for context.

Dieldrin is an organochlorine insecticide that was widely used until 1970 when its use was banned because of its liver carcinogenicity in mice. Several long-term rodent bioassays have reported dieldrin to induce liver tumors in in several strains of mice, but not in rats. This article reviews the available information on dieldrin liver effects and performs an analysis of mode of action (MOA) and human relevance of these liver findings. Scientific evidence strongly supports a MOA based on CAR activation, leading to alterations in gene expression, which result in increased hepatocellular proliferation, clonal expansion leading to altered hepatic foci, and ultimately the formation of hepatocellular adenomas and carcinomas. Associative events include increased liver weight, centrilobular hypertrophy, increased expression of Cyp2b10 and its resulting increased enzymatic activity. Other associative events include alterations of intercellular gap junction communication and oxidative stress. Alternative MOAs are evaluated and shown not to be related to dieldrin administration. Weight of evidence shows that dieldrin is not DNA reactive, it is not mutagenic, and it is not genotoxic in general. Furthermore, activation of other pertinent nuclear receptors, including PXR, PPARα, AhR, and estrogen are not related to dieldrin-induced liver tumors nor is there liver cytotoxicity. In previous studies, rats, dogs, and non-human primates did not show increased cell proliferation or production of pre-neoplastic or neoplastic lesions following dieldrin treatment. Thus, the evidence strongly indicates that dieldrin-induced mouse liver tumors are due to CAR activation and are specific to the mouse, which are qualitatively not relevant to human hepatocarcinogenesis. Thus, there is no carcinogenic risk to humans. This conclusion is also supported by a lack of positive epidemiologic findings for evidence of liver carcinogenicity. Based on current understanding of the mode of action of dieldrin-induced liver tumors in mice, the appropriate conclusion is that dieldrin is a mouse specific liver carcinogen and it does not pose a cancer risk to humans.

Embryofetal development (EFD) studies are performed to characterize risk of drugs in pregnant women and on embryofetal development. In line with the ICH S5(R3) guideline, these studies are generally conducted in one rodent and one non-rodent species, commonly rats and rabbits. However, the added value of conducting EFD studies in two species to risk assessment is debatable. In this study, rat and rabbit EFD studies were evaluated to analyze the added value of a second species. Information on rat and rabbit EFD studies conducted for human pharmaceuticals submitted for marketing authorization to the European Medicines Agency between 2004 and 2022 was collected from the database of the Dutch Medicines Evaluation Board, along with EFD studies conducted for known human teratogens. In total, 369 compounds were included in the database. For 55.6% of the compounds similar effects were observed in rat and rabbit EFD studies. Discordance was observed for 44.6% of compounds. Discordance could often be explained based on occurrence of maternal toxicity or the compound's mechanism of action. For other compounds, discordance was considered of limited clinical relevance due to high exposure margins or less concerning EFD toxicity. For 6.2%, discordance could not be explained and was considered clinically relevant. Furthermore, for specific therapeutic classes, concordance between rat and rabbit could vary. In conclusion, in many cases the added value of conducting EFD studies in two species is limited. These data could help identify scenarios in which (additional) EFD studies could be waived or create a weight-of-evidence model to determine the need for (additional) EFD studies.

Herbicide safeners are agrochemicals added to herbicide formulations to protect crops from herbicide damage without reducing the effectiveness of the herbicide against weeds. While safeners are typically structurally similar to their co-formulated herbicides, they are classified as "inert" in the United States, meaning they are not held to the same regulatory standards as the herbicides. This review systematically examines the toxicity of safeners, which is important given their large-scale global use and potential for exposure to wildlife, livestock, and humans. A systematic review of peer-reviewed literature identified only seven studies examining safener toxicity. Regulatory toxicity data, compiled from the European Chemicals Agency (ECHA) database, included data for 9 of the 18 commercial safeners. Most safeners have low acute ecotoxicity and mammalian toxicity; however, chronic effects and the underlying mechanism are less clear. Benoxacor showed enantioselective metabolism and depletion by drug-metabolizing enzymes. In conclusion, despite the widespread use of safeners, significant knowledge gaps exist regarding their toxicity. More research is needed to fully characterize the potential risks of safeners to human health and the environment. Regulatory agencies should consider reclassifying safeners as active ingredients to ensure adequate toxicity testing and risk assessment.