Critical Reviews in Toxicology最新文献

{"title":"A critical evaluation of rodent carcinogenicity studies on butyl methacrylate demonstrates a lack of carcinogenic potential.","authors":"Susan A Elmore, Joseph K Haseman, Mark Pemberton, B Bhaskar Gollapudi, Samuel M Cohen","doi":"10.1080/10408444.2025.2451885","DOIUrl":"10.1080/10408444.2025.2451885","url":null,"abstract":"<p><p>Assessments of a chemical agent's carcinogenicity based on rodent bioassays rely on their appropriate interpretation. This involves attention to study details, including reliable histopathologic diagnoses, and proper statistical analyses, including consideration of multiple comparisons, concurrent and historical controls. A major factor is evaluation of their likely mode of action and the human relevance of any identified tumors. We present a critical evaluation of the assessment of the 2-year inhalation bioassays of n-butyl methacrylate (n-BMA) in rats and mice performed by the Japan Bioassay Research Center (JBRC) and an assessment of the International Agency for Research on Cancer (IARC) review and classification as Group 2B, possible human carcinogen. The tumors of concern for assessment of its carcinogenicity included mononuclear cell leukemia (MCL) in male rats, thyroid C-cell tumors in female rats, liver tumors and histiocytic sarcomas in male mice, and hemangiosarcomas in female mice. Our review of these studies raises concerns regarding the accuracy of histopathology diagnoses and human relevance of MCL. Most critically, the statistical evaluation/interpretation of all tumor types indicates no carcinogenic effects, since the frequency of increases (at <i>p</i> < 0.05) in tumor incidences in the study is totally consistent with chance expectation (i.e. not treatment related). Furthermore, the plausibility of n-BMA being carcinogenic is questionable since it is non-genotoxic, and the weight of evidence including read-across to the close structural analog methyl methacrylate indicates no concern for cancer. After thorough review of these bioassays, we conclude that there is no convincing evidence of carcinogenicity for n-BMA, contrary to the conclusion of the JBRC and the decision by the IARC.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"105-123"},"PeriodicalIF":5.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A quantitative weight-of-evidence review of preclinical studies examining the potential developmental neurotoxicity of acetaminophen.","authors":"Daniel G Kougias, Evren Atillasoy, Michael D Southall, Anthony R Scialli, Sadaff Ejaz, Christopher Chu, Bamidele O Jeminiwa, Andrey Massarsky, Kenneth M Unice, Tammi H Schaeffer, Michael Kovochich","doi":"10.1080/10408444.2024.2442344","DOIUrl":"10.1080/10408444.2024.2442344","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Acetaminophen [paracetamol; &lt;i&gt;N&lt;/i&gt;-acetyl-&lt;i&gt;para&lt;/i&gt;-aminophenol (APAP)] is an antipyretic/analgesic commonly used in the treatment of fever and mild to moderate pain, headache, myalgia, and dysmenorrhea. Recent literature has questioned the safety of acetaminophen use during pregnancy, with an emphasis on whether exposure to the developing nervous system results in behavioral changes consistent with autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and/or other cognitive deficits in the offspring. No previous review has used a fully detailed, quantitative weight-of-evidence (QWoE) approach to critically examine the preclinical acetaminophen data with regards to potential developmental neurotoxicity (DNT). Following regulatory guidance, a QWoE framework using prespecified scoring criteria was developed consistent with previous approaches to characterize potential adverse DNT outcomes with considerations for biological relevance of the response to adverse outcomes (outcome score) and the strength of methods and study design (methods score). Considerations for the methods score included (1) experimental design, (2) details/reliability of measurement(s), (3) data transparency, and (4) translational/methodological relevance. Considerations for the outcome score included response-related (1) statistical significance, (2) dose-response, (3) relevance/reliability/magnitude, (4) plausibility, and (5) translational relevance, including consideration of systemic toxicity/hepatotoxicity and therapeutic and/or non-systemically toxic doses and durations of use. Application of this QWoE framework to the 34 &lt;i&gt;in vivo&lt;/i&gt; studies identified that assess the potential DNT of acetaminophen resulted in 188 QWoE entries documented across 11 DNT endpoints: social behavior, stereotypic behavior, behavioral rigidity, attention/impulsivity, hyperactivity, anxiety-like behavior, sensorimotor function, spatial learning/memory, nonspatial learning/memory, neuroanatomy, and neurotransmission. For each endpoint, the mean outcome score and methods score were calculated for total entries and for entries segregated by sex to assist in determining data quality and potential adversity. Informed by all 188 entries, the QWoE analysis demonstrated data of moderate quality showing no consistent evidence of DNT in male and female rodents following exposure to acetaminophen at therapeutic and/or nonsystemically toxic doses. Although some of the DNT endpoints (behavioral rigidity, attention/impulsivity, spatial learning/memory, neuroanatomy, and neurotransmission) generally displayed a more limited dataset and/or relatively lower data quality, similar conclusions were drawn based on results indicating a lack of biological relevance and reliability of reported adverse effects. Overall, this QWoE analysis on the preclinical &lt;i&gt;in vivo&lt;/i&gt; data demonstrates no consistent evidence of adverse effects following developmental exposure to acetaminophen at","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"124-178"},"PeriodicalIF":5.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mode of action approach supports a lack of carcinogenic potential of six organic UV filters.","authors":"Samuel M Cohen, Alan R Boobis, David Jacobson-Kram, Rita Schoeny, Thomas J Rosol, Gary M Williams, Norbert E Kaminski, Gary M Eichenbaum, F Peter Guengerich, J F Nash","doi":"10.1080/10408444.2025.2462642","DOIUrl":"https://doi.org/10.1080/10408444.2025.2462642","url":null,"abstract":"<p><p>Ultraviolet (UV) filters, the active ingredients in sunscreens, have been used for several decades to reduce the risk of acute and chronic damage to the skin from solar UV radiation, which can lead to skin cancer. Based on recent clinical studies showing that certain UV filters are absorbed systemically at low levels in humans, the US Food and Drug Administration (FDA) has requested supplementing existing safety data with preclinical studies including oral and dermal 2-year rodent carcinogenicity studies. Although the conduct of 2-year rodent carcinogenicity studies has been the standard approach for evaluating the carcinogenic potential of chemicals and new drugs for approximately 6 decades, there are multiple examples showing that such studies are not predictive of human cancer risk. Given these concerns with 2-year rodent carcinogenicity studies, we have developed and applied an alternative approach for supplementing existing data related to carcinogenic potential for six of the most commonly used UV filters in sunscreen products (i.e. avobenzone, ensulizole, homosalate, octinoxate, octisalate, and octocrylene). This approach evaluates their mode of action (MOA) based on <i>in vivo</i>, <i>in vitro</i>, and <i>in silico</i> data combined with an assessment of exposure margins. This approach is based on the substantial progress in understanding the MOAs that are responsible for tumor induction in humans. It is consistent with those being developed by the International Council for Harmonization (ICH) and other health authorities to replace 2-year carcinogenicity studies given their limitations and questionable biological relevance to humans. The available data for the six UV filters show that they are not genotoxic and show no evidence of biologically relevant carcinogenic MOAs. Furthermore, their systemic exposure levels in humans fall well below concentrations at which they have biologic activity. In conclusion, these data support the continued safe use of these six filters in sunscreen products.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":"55 2","pages":"248-284"},"PeriodicalIF":5.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A quantitative weight-of-evidence review of preclinical studies examining the potential developmental and reproductive toxicity of acetaminophen.","authors":"Daniel G Kougias, Michael D Southall, Anthony R Scialli, Evren Atillasoy, Sadaff Ejaz, Tammi H Schaeffer, Christopher Chu, Bamidele O Jeminiwa, Andrey Massarsky, Kenneth M Unice, Michael Kovochich","doi":"10.1080/10408444.2024.2446471","DOIUrl":"10.1080/10408444.2024.2446471","url":null,"abstract":"<p><p>We previously developed a quantitative weight-of-evidence (QWoE) framework using prespecified scoring criteria for preclinical acetaminophen data to characterize potential developmental neurotoxicity outcomes with considerations for biological relevance of the response to adverse outcomes and the strength of methods and study design. The current analysis uses this framework to characterize potential developmental and reproductive toxicity (DART) outcomes following exposure to acetaminophen. Two-hundred forty-two QWoE entries were documented from <i>in vivo</i> rodent studies identified in 110 publications across five categories: DART endpoints in the context of (1) periadolescent/adulthood (nonpregnancy) exposures; (2) pregnant female exposures; and, for <i>in utero</i> or other developmental exposures, (3) anatomical abnormalities, (4) reproductive development, and (5) other physical development. A mean outcome score and methods score were calculated for 242 QWoE entries. Data analyzed in our framework were of moderate quality showing no consistent evidence of DART in male and female rodents following exposure to acetaminophen at therapeutic and/or non-systemically toxic doses. Similar results were found for the individual context- and outcome-related endpoint analyses and as segregated by sex. Overall, this QWoE analysis on the <i>in vivo</i> rodent data demonstrated no consistent evidence of adverse effects following exposure to therapeutic and/or non-systemically toxic acetaminophen on development or on the structure and function of the reproductive system.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"179-226"},"PeriodicalIF":5.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The IARC re-classification of talc carcinogenicity: a move in the wrong direction?","authors":"Andrey A Korchevskiy, Ann G Wylie","doi":"10.1080/10408444.2025.2585870","DOIUrl":"10.1080/10408444.2025.2585870","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"867-889"},"PeriodicalIF":4.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145630989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nomograms applicability in clinical toxicology - enhancing precision in clinical decision-making: a systematic review.","authors":"Asmaa Fady Sharif, Zeinab A Kasemy, Khalid Saeed Alshalawi, Zahraa Khalifa Sobh","doi":"10.1080/10408444.2024.2445021","DOIUrl":"10.1080/10408444.2024.2445021","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Nomograms represent powerful predictive tools that could be easily applied to guide managing acutely intoxicated patients. Thus, several nomograms were developed and validated in the last few decades to predict various outcomes following acute poisoning. However, the adopted nomograms remain sporadic efforts of researchers that limited their usefulness in clinical settings. We aimed to bridge the gap between theoretical formulation and hands-on application of the developed nomograms to benefit acutely poisoned patients. In this context, this systematic review was conducted to be a reference guide for implementing these nomograms in clinical toxicology practice. This review included 27 studies that were published over 60 years. A total of 60,883 patients ranging between 2 and 91 years were enrolled. These studies elaborated 38 nomograms; 13 nomograms addressed acute poisoning in general, and 25 nomograms were specially designed for six poisons/categories, including pesticides (&lt;i&gt;n&lt;/i&gt; = 9), psychotropic drugs (&lt;i&gt;n&lt;/i&gt; = 5), alcohol (&lt;i&gt;n&lt;/i&gt; = 4), analgesics, and anti-inflammatory medications (&lt;i&gt;n&lt;/i&gt; = 3), carbon monoxide (&lt;i&gt;n&lt;/i&gt; = 2), and digoxin (&lt;i&gt;n&lt;/i&gt; = 2). Despite the first nomogram was published in 1960, 81.5% of nomograms emerged after 2016, with a significant increase in the trend of published nomograms (&lt;i&gt;p&lt;/i&gt; &lt; .001). The Glasgow Coma Scale, patient age, poison concentration, bicarbonate level, and blood pressure were the most frequently used predictors. The nomograms were designed to predict eight outcomes, including mortality (&lt;i&gt;n&lt;/i&gt; = 14, 36.8%), need for intensive care unit (ICU) admission (&lt;i&gt;n&lt;/i&gt; = 9, 23.7%), complications of poisoning (&lt;i&gt;n&lt;/i&gt; = 6, 15.8%), optimization of therapy (&lt;i&gt;n&lt;/i&gt; = 4, 10.5%), and poisoning severity (&lt;i&gt;n&lt;/i&gt; = 2, 5.3%). Also, the need for mechanical ventilation (MV), diagnosis of poisoning, and suicidal poisoning were predicted by one nomogram for each of them. The developed nomograms' performances were tested using receiver operating characteristic analysis and the area under a curve of 26 derived nomograms ranged between 0.839 and 0.999. External validation was conducted on 16 nomograms only; 15 nomograms were validated using validation cohorts within the same studies that developed the nomograms. However, only one nomogram was subjected to external validation by other studies. The externally validated nomograms consist of 10 nomograms for managing particular poisoning and, six nomograms for un-specified poisoning. The poison-specific nomograms were concerned with acute poisoning with pesticides (&lt;i&gt;n&lt;/i&gt; = 4), methanol (&lt;i&gt;n&lt;/i&gt; = 2), opioid (&lt;i&gt;n&lt;/i&gt; = 1), clozapine (&lt;i&gt;n&lt;/i&gt; = 1), carbon monoxide (&lt;i&gt;n&lt;/i&gt; = 1), and digoxin (&lt;i&gt;n&lt;/i&gt; = 1). Regarding six validated nomograms in a general poisoning approach, two nomograms predicted mortality. Nevertheless, four separate nomograms were concerned with the prediction of poisoning complications, the need for ICU admission, the need for ","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"285-303"},"PeriodicalIF":4.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143406209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive review of avobenzone (butyl methoxydibenzoylmethane) toxicology data and human exposure assessment for personal care products.","authors":"Kimberly G Norman, Lewis E Kaufman, Carl D'Ruiz, Linda Loretz, Alexandra Kowcz, Samuel M Cohen, Anthony R Scialli, Alan R Boobis, David Jacobson-Kram, Rita Schoeny, Thomas J Rosol, Gary M Williams, Norbert E Kaminski, F Peter Guengerich, J F Nash","doi":"10.1080/10408444.2025.2535394","DOIUrl":"10.1080/10408444.2025.2535394","url":null,"abstract":"<p><p>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 <i>in vitro</i> and <i>in vivo</i> 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 <i>in vitro</i> or <i>in vivo</i>. 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%.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"662-692"},"PeriodicalIF":4.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive review of octocrylene toxicology data and human exposure assessment for personal care products.","authors":"Kimberly G Norman, Lewis E Kaufman, Peter Griem, Carl D'Ruiz, Linda Loretz, Alexandra Kowcz, Samuel M Cohen, Anthony R Scialli, Alan R Boobis, David Jacobson-Kram, Rita Schoeny, Thomas J Rosol, Gary M Williams, Norbert E Kaminski, F Peter Guengerich, J F Nash","doi":"10.1080/10408444.2025.2593603","DOIUrl":"10.1080/10408444.2025.2593603","url":null,"abstract":"<p><p>A comprehensive review was conducted of existing toxicity and consumer exposure data for the ultraviolet (UV) filter octocrylene (2-ethylhexyl-2-cyano-3,3-diphenylacrylate) as currently used in over-the-counter sunscreen formulations. Octocrylene has a long history of safe use, and there are sufficient <i>in vitro</i> studies, <i>in vivo</i> toxicity studies in animal models, and clinical data to characterize octocrylene's pharmacokinetics, pharmacodynamics, and potential toxicologic properties. Although no harmonized dermal absorption value was available, <i>in vitro</i> studies using human skin samples revealed very low percutaneous absorption (0.33% of the applied dose). There are no specific data on the distribution of octocrylene; however, there is some information on background levels of octocrylene and its metabolism, and it has limited presence in plasma and urine from human biomonitoring studies. Six tentative metabolites of octocrylene have been identified, although metabolite-specific toxicity profiles were not available. Octocrylene generally did not cause eye or skin irritation, skin sensitization, or phototoxicity, but dermal sensitization has been reported in some clinical case studies. Octocrylene is not acutely toxic. The no-observed-adverse-effect level (NOAEL) from a 90-day rat dietary toxicity study was 175 mg/kg/day, based on liver, thyroid, and pituitary effects at higher dose levels that produced hepatic enzyme induction. The NOAEL for parental systemic, reproductive, and developmental toxicity from an extended one-generation reproductive toxicity study in rats was 153/163 mg/kg/day (males/females). There was no evidence of octocrylene effects on neurodevelopment, immune tissues, or androgenic, estrogenic, or thyroid endpoints. Although there are no formal 2-year carcinogenicity studies for octocrylene, a 90-day subchronic dietary toxicity study in rats did not show an increase in hyperplasia of any tissue or evidence of cytotoxicity. Furthermore, octocrylene has not triggered any indications for genotoxicity either <i>in vitro</i> or <i>in vivo.</i> Together, these data indicate that carcinogenicity in humans is unlikely. In a mouse photocarcinogenicity study, octocrylene significantly reduced tumor number and tumor volume resulting from exposure to solar-simulated UV radiation. Based on the most health-protective rat NOAEL (153 mg/kg/day, for reproductive effects and general toxicity) and conservative assumptions for estimating the systemic exposure dose from the application of sunscreen products, margins of safety for octocrylene were greater than 100. Therefore, the available data show that octocrylene poses no human health risks when used in sunscreen products at concentrations up to 10%, which is consistent with existing global regulatory safety acceptance and approval of the ingredient.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"890-915"},"PeriodicalIF":4.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145898823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The modes of action for rodent liver tumor formation by activators of the constitutive androstane receptor (CAR) and the peroxisome proliferator-activated receptor alpha (PPARα) are not relevant to human cancer risk: an updated critical evaluation.","authors":"Tomoya Yamada, Samuel M Cohen, Brian G Lake","doi":"10.1080/10408444.2025.2513332","DOIUrl":"10.1080/10408444.2025.2513332","url":null,"abstract":"<p><p>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. <i>Crit Rev Toxicol 2021</i>). 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.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"549-586"},"PeriodicalIF":4.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144505066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A weight of evidence review on the mode of action, adversity, and the human relevance of xylene's observed thyroid effects in rats.","authors":"Keith Morris-Schaffer, Larry Higgins, Neslihan Aygun Kocabas, Frank Faulhammer, Alexandra Cordova, Elaine Freeman, Hennicke Kamp, Muna Nahar, Emily Richmond, Martijn Rooseboom","doi":"10.1080/10408444.2024.2422890","DOIUrl":"10.1080/10408444.2024.2422890","url":null,"abstract":"<p><p>Xylene substances have wide industrial and consumer uses and are currently undergoing dossier and substance evaluation under Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) for further toxicological testing including consideration of an additional neurotoxicological testing cohort to an extended one-generation reproduction toxicity (EOGRT) study. New repeated dose study data on xylenes identify the thyroid as a potential target tissue, and therefore a weight of evidence review is provided to investigate whether or not xylene-mediated changes on the hypothalamus-pituitary-thyroid (HPT) axis are secondary to liver enzymatic induction and are of a magnitude that is relevant for neurological human health concerns. Multiple published studies confirm xylene-mediated increases in liver weight, hepatocellular hypertrophy, and liver enzymatic induction <i>via</i> the oral or inhalation routes, including an increase in uridine 5'-diphospho-glucuronosyltransferase (UDP-GT) activity, the key step in thyroid hormone metabolism in rodents. Only minimal to slight increases in thyroid follicular cell hypertrophy have been observed in some xylene repeated dose studies, with no associated robust or consistent perturbance of thyroid hormone changes across the studies or carried through to offspring indicating adaptive homeostatic maintenance of the HPT axis. Also importantly, <i>in vitro</i> human cell line data from the United States Environmental Protection Agency (US EPA) Toxicity Forecasting (ToxCast) provides supporting evidence of xylene's inability to directly perturb thyroidal functionality. A further supplemental in-depth metabolomics analysis (MetaMap^®Tox) of xylene showed a tentative match to compounds that also demonstrate extra-thyroidal effects on the HPT axis as a consequence of liver enzyme induction. Lastly, the slight HPT axis changes mediated by xylene were well-below the published literature thresholds for developmental neurotoxicological outcomes established for thyroidal changes in animals and humans. In summary, the data and various lines of scientific evidence presented herein individually and collectively demonstrate that xylene's mediated changes in the HPT axis, <i>via</i> a secondary extra-thyroidal MOA (i.e. liver enzyme induction), do not raise a human health concern with regards to developmental neurotoxicity. As such, the available toxicological data do not support the classification of xylene as a known or suspected endocrine disruptor, specifically through the thyroid modality, per Regulations Commission Delegated Regulation (EU) 2023/707 of 19 December 2022 amending Regulation (EC) No 1272/2008 and do not support the need for a neurotoxicological cohort evaluation in any subsequent EOGRTS.</p>","PeriodicalId":10869,"journal":{"name":"Critical Reviews in Toxicology","volume":" ","pages":"1-26"},"PeriodicalIF":5.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}