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Dioxins and the emerging dioxin-like compounds (DLCs) have recruited increasing concerns about their environmental contamination, toxicity, health impacts, and mechanisms. Based on the structural similarity of dioxins and many DLCs, their toxicity was predominantly mediated by the dioxin receptor (aryl hydrocarbon receptor, AHR) in animals (including human), which can be different in expression and function among species and then possibly produce the species-specific risk or toxicity. To date, characterizing the AHR of additional species other than human and rodents can increase the accuracy of toxicity/risk evaluation and increase knowledge about AHR biology. As a key model, the medaka AHR has not been clearly characterized. Through genome survey and phylogenetic analysis, we identified four AHRs (olaAHR1a, olaAHR1b, olaAHR2a, and olaAHR2b) and two ARNTs (olaARNT1 and olaARNT2). The medaka AHR pathway was conserved in expression in nine tested tissues, of which olaAHR2a represented the predominant subform with greater abundance. Medaka AHRs and ARNTs were functional and could be efficiently transactivated by the classical dioxin congener 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), although olaAHR1a did not seem to cooperate with olaARNT2. In terms of function/sensitivity, the EC 50 values of medaka olaAHR1a (9.01 ± 1.43 nM), olaAHR1b (4.00 ± 1.10 nM), olaAHR2a (8.75 ± 3.34 nM), and olaAHR2b (3.06 ± 0.81 nM) showed slight differences; however, they were all at the nM level. The sensitivity of four medaka AHRs to TCDD was similar to that of zebrafish dreAHR2 (the dominant form, EC 50  = 3.14 ± 4.19 nM), but these medaka AHRs were more sensitive than zebrafish dreAHR1b (EC 50  = 27.05 ± 18.51 nM). The additional comparison also indicated that the EC 50 values in various species were usually within the nM range, but AHRs of certain subforms/species can vary by one or two orders of magnitude. In summary, the present study will enhance the understanding of AHR and help improve research on the ecotoxicity of dioxins/DLCs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Due to the significant POPs characteristics, dioxins caused concern in public health and environmental protection. Evaluating the toxicity risk of dioxin degradation pathways is critical. OCDD, 1,2,3,4,6,7,8-HpCDD, and 1,2,3,4,6,7,8-HpCDF, which are highly abundant in the environment and have strong biodegradation capabilities, were selected as precursor molecules in this study. Firstly, their transformation pathways were deduced during the metabolism of biometabolism, microbial aerobic, microbial anaerobic, and photodegradation pathways, and density function theory (DFT) was used to calculate the Gibbs free energy to infer the possibility of the occurrence of the transformation pathway. Secondly, the carcinogenic potential of the precursors and their degradation products was evaluated using the TOPKAT modeling method. With the help of the positive indicator (0-1) normalization method and heat map analysis, a significant increase in the toxic effect of some of the transformation products was found, and it was inferred that it was related to the structure of the transformation products. Meanwhile, the strength of the endocrine disrupting effect of dioxin transformation products was quantitatively assessed using molecular docking and subjective assignment methods, and it was found that dioxin transformation products with a higher content of chlorine atoms and molecules similar to those of thyroid hormones exhibited a higher risk of endocrine disruption. Finally, the environmental health risks caused by each degradation pathway were comprehensively assessed with the help of the negative indicator (1-2) standardization method, which provides a theoretical basis for avoiding the toxicity risks caused by dioxin degradation transformation. In addition, the 3D-QSAR model was used to verify the necessity and rationality of this study. This paper provides theoretical support and reference significance for the toxicity assessment of dioxin degradation by-products from inferred degradation pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This comprehensive review critically examines the detrimental impacts of endocrine-disrupting chemicals (EDCs) on bone health, with a specific focus on substances such as bisphenol A (BPA), per- and polyfluoroalkyl substances (PFASs), phthalates, and dioxins. These EDCs, by interfering with the endocrine system's normal functioning, pose a significant risk to bone metabolism, potentially leading to a heightened susceptibility to bone-related disorders and diseases. Notably, BPA has been shown to inhibit the differentiation of osteoblasts and promote the apoptosis of osteoblasts, which results in altered bone turnover status. PFASs, known for their environmental persistence and ability to bioaccumulate in the human body, have been linked to an increased osteoporosis risk. Similarly, phthalates, which are widely used in the production of plastics, have been associated with adverse bone health outcomes, showing an inverse relationship between phthalate exposure and bone mineral density. Dioxins present a more complex picture, with research findings suggesting both potential benefits and adverse effects on bone structure and density, depending on factors such as the timing and level of exposure. This review underscores the urgent need for further research to better understand the specific pathways through which EDCs affect bone health and to develop targeted strategies for mitigating their potentially harmful impacts.

Background: Dioxin-like chemicals are a group of ubiquitous environmental toxicants that received intense attention in the last two decades of the 20th century. Through extensive mechanistic research and validation, the global community has agreed upon a regulatory strategy for these chemicals that centers on their common additive activation of a single receptor. Applying these regulations has led to decreased exposure in most populations studied. As dioxin-like chemicals moved out of the limelight, research and media attention has turned to other concerning contaminants, including per- and polyfluoroalkyl substances (PFAS). During the 20th century, PFAS were also being quietly emitted into the environment, but only in the last 20 years have we realized the serious threat they pose to health. There is active debate about how to appropriately classify and regulate the thousands of known PFAS and finding a solution for these "forever chemicals" is of the utmost urgency., Objectives: Here, we compare important features of dioxin-like chemicals and PFAS, including the history, mechanism of action, and effective upstream regulatory strategies, with the objective of gleaning insight from the past to improve strategies for addressing PFAS., Discussion: The differences between these two chemical classes means that regulatory strategies for dioxin-like chemicals will not be appropriate for PFAS. PFAS exert toxicity by both receptor-based and nonreceptor-based mechanisms, which complicates mixtures evaluation and stymies efforts to develop inexpensive assays that accurately capture toxicity. Furthermore, dioxin-like chemicals were unwanted byproducts, but PFAS are useful and valuable, which has led to intense resistance against efforts to restrict their production. Nonetheless, useful lessons can be drawn from dioxin-like chemicals and applied to PFAS, including eliminating nonessential production of new PFAS and proactive investment in environmental remediation to address their extraordinarily long environmental persistence. https://doi.org/10.1289/EHP14449.

Polycyclic aromatic hydrocarbons (PAHs) and dioxins are potential causes of multiple diseases by activating the aryl hydrocarbon receptor (AhR) pathway. Health risk assessment of chemicals primarily relies on the relative potency factor (RPF), although its accuracy may be limited when solely using EC50 values. The induction of cytochrome P4501A1 (CYP1A1) serves as a biomarker for AhR activation and is an integrator of dioxin-like toxicity. Here, we present a method for evaluating the risks associated with AhR activation using mathematical models of dose-CYP1A1 induction. The dose-effect curves for certain PAHs and dioxins, including Ant, BghiP, 1,2,3,4,7,8-HxCDD, and others, exhibited a non-classical S-shaped form. The toxic equivalent factor (TEF) profiles revealed a broad range of toxic equivalent factor values. The TEFs for PAHs ranged from approximately 0.01 to 6, with higher values being observed when the concentration was less than 10 -10 M, with the exceptions of Ace, Phe, and BghiP. Most congeners of dioxins got the lowest TEF value at around 10 -10 M, ranging from 0.04 to 1.00. The binding affinity of AhR to ligands did not display a strong correlation with the EC50 of CYP1A1 expression, suggesting that the AhR-mediated effects of PAHs and dioxins are not fixed but instead fluctuate with the dose. Air samples acquired from a parking area were used to compare the proficiency of RPF and our current approach. In the current method, naphthalene and chrysene were the primary contributors of PAHs to AhR-mediated risks in parking lots air samples, respectively. However, the contributions of naphthalene and chrysene could be disregarded in the RPF approach., Competing Interests: Declaration of Competing Interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled “A novel approach to assess the health risk of aryl hydrocarbon receptor-bound contaminants via inhalation exposure usingCYP1A1expression as a biomarker”., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aberrant regulation of signal transduction pathways can adversely derail biological processes for tissue development. One such process is the embryonic eyelid closure that is dependent on the mitogen-activated protein kinase kinase kinase 1 (MAP3K1). Map3k1 KO in mice results in defective eyelid closure and an autosomal recessive eye-open at birth phenotype. We have shown that in utero exposure to dioxin, a persistent environmental toxicant, induces the same eye defect in Map3k1 +/- heterozygous but not WT pups. Here, we explore the mechanisms of the Map3k1 (gene) and dioxin (environment) interactions (GxE) underlying defective eyelid closure. We show that, acting through the aryl hydrocarbon receptor, dioxin activates epidermal growth factor receptor signaling, which in turn depresses MAP3K1-dependent Jun N-terminal kinase (JNK) activity. The dioxin-mediated JNK repression is moderate but is exacerbated by Map3k1 heterozygosity. Therefore, dioxin exposed Map3k1 +/- embryonic eyelids have a marked reduction of JNK activity, accelerated differentiation and impeded polarization in the epithelial cells. Knocking out Ahr or Egfr in eyelid epithelium attenuates the open-eye defects in dioxin-treated Map3k1 +/- pups, whereas knockout of Jnk1 and S1pr that encodes the sphigosin-1-phosphate (S1P) receptors upstream of the MAP3K1-JNK pathway potentiates the dioxin toxicity. Our novel findings show that the crosstalk of aryl hydrocarbon receptor, epidermal growth factor receptor, and S1P-MAP3K1-JNK pathways determines the outcome of dioxin exposure. Thus, gene mutations targeting these pathways are potential risk factors for the toxicity of environmental chemicals., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Chemical contamination and pollution are an ongoing threat to human health and the environment. The concern over the consequences of chemical exposures at the global level continues to grow. Because resources are constrained, there is a need to prioritize interventions focused on the greatest health impact. Data, especially related to chemical exposures, are rarely available for most substances of concern, and alternate methods to evaluate their impact are needed., Structured Expert Judgment (sej) Process: A Structured Expert Judgment (Research Outreach, 2021) process was performed to provide plausible estimates of health impacts for 16 commonly found pollutants: asbestos, arsenic, benzene, chromium, cadmium, dioxins, fluoride, highly hazardous pesticides (HHPs), lead, mercury, polycyclic-aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), Per- and Polyfluorinated Substances (PFAs), phthalates, endocrine disrupting chemicals (EDCs), and brominated flame retardants (BRFs). This process, undertaken by sector experts, weighed individual estimations of the probable global health scale health impacts of each pollutant using objective estimates of the expert opinions' statistical accuracy and informativeness., Main Findings: The foremost substances, in terms of mean projected annual total deaths, were lead, asbestos, arsenic, and HHPs. Lead surpasses the others by a large margin, with an estimated median value of 1.7 million deaths annually. The three other substances averaged between 136,000 and 274,000 deaths per year. Of the 12 other chemicals evaluated, none reached an estimated annual death count exceeding 100,000. These findings underscore the importance of prioritizing available resources on reducing and remediating the impacts of these key pollutants., Range of Health Impacts: Based on the evidence available, experts concluded some of the more notorious chemical pollutants, such as PCBs and dioxin, do not result in high levels of human health impact from a global scale perspective. However, the chemical toxicity of some compounds released in recent decades, such as Endocrine Disrupters and PFAs, cannot be ignored, even if current impacts are limited. Moreover, the impact of some chemicals may be disproportionately large in some geographic areas. Continued research and monitoring are essential; and a preventative approach is needed for chemicals., Future Directions: These results, and potential similar analyses of other chemicals, are provided as inputs to ongoing discussions about priority setting for global chemicals and pollution management. Furthermore, we suggest that this SEJ process be repeated periodically as new information becomes available., Competing Interests: The nonprofit Pure Earth (David Hanrahan, Kate Porterfield, and Richard Fuller) has received funding historically from Open Philanthropy, GiveWell, Clarios Foundation, Trafigura Foundation, and Takeda Foundation. The other authors declare no competing interests. No funding was allocated for this project., (Copyright: © 2024 Marti et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The neurotoxicity induced by dioxins has been recognized as a serious concern to sensitive population living near waste incineration plants. However, investigating the intracellular neurotoxicity of dioxin in humans and the corresponding mitigation strategies has been barely studied. Thus, a domestic waste incineration plant was selected in this study to characterize the neurotoxicity risks of sensitive populations by estimating the ratio of dioxin in human cells using membrane structure dynamics simulation; and constructing a complete dioxin neurotoxicity adverse outcome pathway considering the binding process of AhR/ARNT dimer protein and dioxin response element (DRE). Six dioxins with high neurotoxicity risk were identified. According to the composite neurotoxicity risk analysis, the highest composite neurotoxicity risk appeared when the six dioxins were jointly exposed. Dietary schemes were designed using 1/2 partial factor experimental design to mitigate the composite neurotoxicity risk of six dioxins and No. 16 was screened as the optimum combination which can effectively alleviate the composite neurotoxicity risk by 29.52%. Mechanism analysis shows that the interaction between AhR/ARNT dimer protein and DRE was inhibited under the optimal dietary scheme. This study provides theoretical feasibility and reference significance for assessing composite toxicity risks of pollutants and safety mitigation measures for toxic effects., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In 2022 the World Health Organization (WHO) published updated 'Toxic Equivalence Factors' (TEFs) for a wide variety of chlorinated dioxins, dibenzofurans and PCBs [collectively referred to as 'dioxin-like chemicals'; DLCs) that interact with the aryl hydrocarbon receptor (AHR)]. Their update used sophisticated statistical analysis of hundreds of published studies that reported estimation of 'Relative Effective Potency' (REP) values for individual DLC congeners. The weighting scheme used in their assessment of each study favored in vivo over in vitro studies and was based largely on rodent studies. In this Commentary, we highlight the large body of published studies that demonstrate large species differences in AHR-ligand activation and provide supporting evidence for our position that the WHO 2022 TEF values intended for use in human risk assessment of DLC mixtures will provide highly misleading overestimates of 'Toxic Equivalent Quotients' (TEQs), because of well-recognized striking differences in AHR ligand affinities between rodent (rat, mouse) and human. The data reviewed in our Commentary support the position that human tissue-derived estimates of REP/TEF values for individual DLC congeners, although uncertain, will provide much better, more realistic estimates of potential activation of the human AHR, when exposure to complex DLC mixtures occurs., Competing Interests: Declaration of competing interest DLE and TWS have served as consultants to industries, agencies and other organizations involved in risk assessment of DLCs. NSK, GHP and DWN have no conflicts to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of competing interest DLE and TWS have served as consultants to industries, agencies and other organizations involved in risk assessment of DLCs. NSK, GHP and DWN have no conflicts to declare.

Aquatic animals and consumers of aquatic animals are exposed to increasingly complex mixtures of known and as-yet-unknown chemicals with dioxin-like toxicities in the water cycle. Effect- and cell-based bioanalysis can cover known and yet unknown dioxin and dioxin-like compounds as well as complex mixtures thereof but need to be standardized and integrated into international guidelines for environmental testing. In an international laboratory testing (ILT) following ISO/CD 24295 as standard procedure for rat cell-based DR CALUX un-spiked and spiked extracts of drinking-, surface-, and wastewater were validated to generate precision data for the development of the full ISO-standard. We found acceptable repeatability and reproducibility ranges below 36 % by DR CALUX bioassay for the tested un-spiked and spiked water of different origins. The presence of 17 PCDD/Fs and 12 dioxin-like PCBs was also confirmed by congener-specific GC-HRMS analysis. We compared the sum of dioxin-like activity levels measured by DR CALUX bioassay (expressed in 2,3,7,8-TCDD Bioanalytical Equivalents, BEQ; ISO 23196, 2022) with the obtained GC-HRMS chemical analysis results converted to toxic equivalents (TEQ; van den Berg et al., 2013)., Competing Interests: Declaration of competing interest The authors are not involved in water production, recycling of water, or any other activity related to the product water, except for the analyses of contaminants. Therefore, we declare no conflict of interest. Peter Behnisch, Harrie Besselink and Abraham Brouwer are employee of BioDetection Systems. All stable transfected rat cell-lines were provided by the company., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

PCDD/Fs are dioxins produced by waste incineration and pose risks to human health. We aimed to detail the health risks of airborne and soil PCDD/Fs near a municipal solid-waste incinerator (MSWI) for the surrounding population and develop a new model that improves upon existing methods. Thus, we conducted field sampling and then investigated a MSWI in the Pearl River Delta (2016-2018). Our results showed that the carcinogenic and non-carcinogenic risk values of PCDD/Fs exposed to residents in nearby areas were acceptable, with hazard index (HI) values lower than 1.0 and a total carcinogenic risk lower than 1.0E-6. Notably, the results raised concerns regarding higher non-carcinogenic risks in children than in adults. Comparative analysis of the frequency accumulation diagram, accumulated probability risk, and the absolute value of error (δ) between the 95% confidence interval (CI) and the 90% CI of the Monte Carlo stochastic simulation-triangular fuzzy number (MCSS-TFN) and the MCSS model, respectively, demonstrated that the MCSS-TFN exhibited less uncertainty than the MCSS model, regardless of the health risk value of PCDD/Fs in ambient air or in soil. This observation underscores the superiority of the MCSS-TFN model over other models in assessing the health risks associated with PCDD/Fs in situations with limited data. Our new method overcomes the limited dataset size and high uncertainty in assessing the health risks of dioxin substances, providing a more comprehensive understanding of their associated health risks than MCSS models., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The World Health Organization (WHO) assesses potential health risks of dioxin-like compounds using Toxic Equivalency Factors (TEFs). This study systematically updated the relative potency (REP) database underlying the 2005 WHO TEFs and applied advanced methods for quantitative integration of study quality and dose-response. Data obtained from fifty-one publications more than doubled the size of the previous REP database (∼1300 datasets). REP quality and relevance for these data was assessed via application of a consensus-based weighting framework. Using Bayesian dose-response modeling, available data were modeled to produce standardized dose/concentration-response Hill curves. Study quality and REP data were synthesized via Bayesian meta-analysis to integrate dose/concentration-response data, author-calculated REPs and benchmark ratios. The output is a prediction of the most likely relationship between each congener and its reference as model-predicted TEF uncertainty distributions, or the 'best estimate TEF' (BE-TEF). The resulting weighted BE-TEFs were similar to the 2005 TEFs, though provide more information to inform selection of TEF values as well as to provide risk assessors and managers with information needed to quantitatively characterize uncertainty around TEF values. Collectively, these efforts produce an updated REP database and an objective, reproducible approach to support development of TEF values based on all available data., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SF, AB, LH, KF, CR, and DW reports financial support provided by European Food Safety Authority and Tierra Solutions. DW serves as an Associate Editor at Regulatory Toxicology and Pharmacology. KvE and EAF reports funding to perform the external QC was provided by the European Food Safety Authority. MDV served as an ad-hoc expert at the 2022 World Health Organization consultation on Toxic Equivalency Factors. LH, DW, KvE, and EAF served as contractors to the European Food Safety Authority to support the WHO expert consultation; funding for travel to the consultation meeting was provided by the WHO., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In October 2022, the World Health Organization (WHO) convened an expert panel in Lisbon, Portugal in which the 2005 WHO TEFs for chlorinated dioxin-like compounds were reevaluated. In contrast to earlier panels that employed expert judgement and consensus-based assignment of TEF values, the present effort employed an update to the 2006 REP database, a consensus-based weighting scheme, a Bayesian dose response modeling and meta-analysis to derive "Best-Estimate" TEFs. The updated database contains almost double the number of datasets from the earlier version and includes metadata that informs the weighting scheme. The Bayesian analysis of this dataset results in an unbiased quantitative assessment of the congener-specific potencies with uncertainty estimates. The "Best-Estimate" TEF derived from the model was used to assign 2022 WHO-TEFs for almost all congeners and these values were not rounded to half-logs as was done previously. The exception was for the mono-ortho PCBs, for which the panel agreed to retain their 2005 WHO-TEFs due to limited and heterogenous data available for these compounds. Applying these new TEFs to a limited set of dioxin-like chemical concentrations measured in human milk and seafood indicates that the total toxic equivalents will tend to be lower than when using the 2005 TEFs., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: WHO has been working with EFSA in order to share the financial burden to update the TEF values for dioxin etc. The preparatory work done by KeyToxicology (KvE, EAFG) and ToxStrategies (LH, DW) including the update of the database was financed by EFSA. The selection of the invited experts was done solely by WHO and the costs for organizing the expert consultation was done by WHO funds. None of the WHO invited experts have indicated any conflicting interests in their WHO declarations of interests which were evaluated prior to the meeting., (Copyright © 2023. Published by Elsevier Inc.)

Emerging classes of dioxin-like compounds (DLCs) like hydroxylated/methoxylated polybrominated diphenyl ethers (HO-/MeO-PBDEs) and polychlorinated diphenyl sulfides (PCDPSs) could lead to diverse adverse outcomes in humans and wildlife, yet knowledge gaps exist in their molecular mechanisms associated with different structures following early life environmental exposure. This study integrated a genetic knockout technique and concentration-dependent reduced zebrafish transcriptome approach (CRZT) to unravel the toxicological pathways underpinning developmental toxicity of four HO-/MeO-PBDEs and five PCDPSs at environmentally relevant doses. Generally, the dependence of aryl hydrocarbon receptor (AhR) on the embryotoxicity and transcriptomic potencies induced by the HO-PBDEs and PCDPSs varied across different congeners. The knockout of the ahr2 gene led to 1.02- to 76.48-fold decreases of DLC-induced embryotoxicities and reduced the transcriptome-based potencies ranging from 1.38 to 2124.74 folds in the CRZT test. The fold changes denoting AhR-mediated potentials significantly increased with the increasing chlorination degrees of MeO-PBDEs and PCDPSs ( p < 0.05). Moreover, ahr2 knockout primarily affected the DLC-induced early molecular responses relevant to DNA damage, enzyme activation, and organ development. Our integrated approach revealed the differential role of AhR in mediating the developmental toxicity of emerging DLCs possessing varied structures at environmentally relevant doses.

The toxic equivalency factors (TEFs) approach for dioxin-like chemicals (DLCs) is currently based on a qualitative assessment of a heterogeneous data set of relative estimates of potency (REPs) spanning several orders of magnitude with highly variable study quality and relevance. An effort was undertaken to develop a weighting framework to systematically evaluate and quantitatively integrate the quality and relevance for development of more robust TEFs. Six main-study characteristics were identified as most important in characterizing the quality and relevance of an individual REP for human health risk assessment: study type, study model, pharmacokinetics, REP derivation method, REP derivation quality, and endpoint. Subsequently, a computational approach for quantitatively integrating the weighting framework parameters was developed and applied to the REP 2004 database. This was accomplished using a machine learning approach which infers a weighted TEF distribution for each congener. The resulting database, weighted for quality and relevance, provides REP distributions from >600 data sets (including in vivo and in vitro studies, a range of endpoints, etc.). This weighted database provides a flexible platform for systematically and objectively characterizing TEFs for use in risk assessment, as well as providing information to characterize uncertainty and variability. Collectively, this information provides risk managers with information for decision making., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Daniele Wikoff, Caroline Ring, Laurie Haws reports financial support was provided by Tierra Solutions. Linda Birnbaum reports a relationship with Defense Expert in Dioxin-Related Litigation that includes: paid expert testimony. DW serves as an Associate Editor at Regulatory Toxicology and Pharmacology.MD served as an ad-hoc expert at the 2022 World Health Organization consultation on Toxic Equivalency Factors. LH and DW served as contractors to the European Food Safety Authority to support the WHO expert consultation., (Copyright © 2023. Published by Elsevier Inc.)

As modern agricultural practices increase their use of chemical pesticides, it is inevitable that we will find a number of these xenobiotics within drinking water supplies and disseminated throughout the food chain. A major problem that arises from this pollution is that the effects of most of these pesticides on cellular mechanisms in general, and how they interact with each other and affect human cells are still poorly understood. In this study we make use of cultured human cancer cells to measure by qRT-PCR how pesticides affect gene expression of stress pathways. Immunoblotting studies were performed to monitor protein expression levels and activation of signaling pathways. We make use of immunofluorescence and microscopy to visualize and quantify DNA damage events in those cells. In the current study, we evaluate the potential of a subset of widely used pesticides to activate the dioxin receptor pathway and affect its crosstalk with estrogen receptor signaling. We quantify the impact of these chemicals on the p53-dependent cellular stress response. We find that, not only can the different pesticides activate the dioxin receptor pathway, most of them have better than additive effects on this pathway when combined at low doses. We also show that different pesticides have the ability to trigger crosstalk events that may generate genotoxic estrogen metabolites. Finally, we show that some, but not all of the tested pesticides can induce a p53-dependent stress response. Taken together our results provide evidence that several xenobiotics found within the environment have the potential to interact together to elicit significant effects on cell systems. Our data warrants caution when the toxicity of substances that are assessed simply for individual chemicals, since important biological effects could be observed only in the presence of other compounds, and that even at very low concentrations., (© 2023. The Author(s).)

Fifty-five children aged 2 years from a birth cohort in the largest dioxin-contaminated area in Bien Hoa city, Vietnam participated in this survey to examine gaze behavior. Exposure levels were indicated by 2,3,7,8-tetrachlorodibenzo-p-dibenzodioxin (TCDD) and toxic equivalent of polychlorinated dibenzo-p-dioxin and polychlorinated dibenzofuran (TEQ-PCDD/Fs) levels in maternal breast milk. The percentage of the total fixation duration on the face (% Face), mouth (% Mouth), and eye areas (% Eyes) when viewing silent and conversation scenes was used as gaze behavior indices. When they reached 3-year-old, autistic behavior was assessed using the Autism Spectrum Rating Scale (ASRS). A general linear model adjusted for confounding factors was used to compare gaze indices and ASRS scores between high and low dioxin exposure groups. Effects of perinatal dioxin exposure on gaze behavior were found only when viewing conversation scenes indicated by lower % Face for boys in high TCDD exposure group and lower % Eyes for girls in high TEQ-PCDD/Fs group. Increased autistic traits showed by higher ASRS scores at 3-year-old were found in both gender in the high TCDD exposure group. These findings indicate that perinatal TCDD and TEQ-PCDD/Fs exposure may reduce gaze behavior in 2-year-old children, predicting increased autistic traits at 3-year-old., (© 2023. The Author(s).)

Human exposure to environmental pollutants can disrupt embryonic development and impact juvenile and adult health outcomes by adversely affecting cell and organ function. Notwithstanding, environmental contamination continues to increase due to industrial development, insufficient regulations, and the mobilization of pollutants as a result of extreme weather events. Dioxins are a class of structurally related persistent organic pollutants that are highly toxic, carcinogenic, and teratogenic. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most potent dioxin compound and has been shown to induce toxic effects in developing organisms by activating the aryl hydrocarbon receptor (AHR), a ligand activated transcription factor targeted by multiple persistent organic pollutants. Contaminant-induced AHR activation results in malformations of the craniofacial cartilages and neurocranium; however, the mechanisms mediating these phenotypes are not well understood. In this study, we utilized the optically transparent zebrafish model to elucidate novel cellular targets and potential transcriptional targets underlying TCDD-induced craniofacial malformations. To this end, we exposed zebrafish embryos at 4 h post fertilization to TCDD and employed a mixed-methods approach utilizing immunohistochemistry staining, transgenic reporter lines, fixed and in vivo confocal imaging, and timelapse microscopy to determine the targets mediating TCDD-induced craniofacial phenotypes. Our data indicate that embryonic TCDD exposure reduced jaw and pharyngeal arch Sox10+ chondrocytes and Tcf21+ pharyngeal mesoderm progenitors. Exposure to TCDD correspondingly led to a reduction in collagen type II deposition in Sox10+ domains. Embryonic TCDD exposure impaired development of tissues derived from or guided by Tcf21+ progenitors, namely: nerves, muscle, and vasculature. Specifically, TCDD exposure disrupted development of the hyoid and mandibular arch muscles, decreased neural innervation of the jaw, resulted in compression of cranial nerves V and VII, and led to jaw vasculature malformations. Collectively, these findings reveal novel structural targets and potential transcriptional targets of TCDD-induced toxicity, showcasing how contaminant exposures lead to congenital craniofacial malformations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Humans are constantly exposed to lipophilic persistent organic pollutants (POPs) that accumulate in fatty foods. Among the numerous POPs, dioxins, in particular 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), can impact several organ systems. While the hazard is clearly recognized, it is still difficult to develop a comprehensive understanding of the overall health impacts of dioxins. As chemical toxicity testing is steadily adopting new approach methodologies (NAMs), it becomes imperative to develop computational models that can bridge the data gaps between in vitro testing and in vivo outcomes. As an effort to address this challenge, we propose a multiscale computational approach using a "template-and-anchor" (T&A) structure. A template is a high-level umbrella model that permits the integration of information from various, detailed anchor models. In the present study, we use this T&A approach to describe the effect of TCDD on cholesterol dynamics. Specifically, we represent hepatic cholesterol biosynthesis as an anchor model that is perturbed by TCDD, leading to steatosis, along with alterations of plasma cholesterol. In the future, incorporating pertinent information from all anchor models into the template model will allow the characterization of the global effects of dioxin, which can subsequently be translated into overall - and ultimately personalized - human health risk assessment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Human exposure to lipophilic persistent organic pollutants (lipPOP) is ubiquitous and life-long, beginning during foetal development. Exposure to lipPOP elicits a number of species and tissue specific responses including dioxin-like activity which involve the activation of aryl hydrocarbon receptor (AhR). This study aims i) to describe the combined dioxin-like activity in serum from Danish pregnant women collected during 2011-2013; ii) to assess the association between maternal serum dioxin-like activity, gestational age at birth and foetal growth indices. The serum lipPOP fraction was extracted using Solid Phase Extraction and cleaned-up on Supelco multi-layer silica and florisil columns. The combined dioxin-like activity of the extract was determined using the AhR reporter gene bioassay, expressed as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxic equivalent (TEQ) [AhR-TEQ (pg/g lipid)]. The associations of AhR-TEQ and foetal growth indices (birth weight, birth length and head circumference) and gestational age were assessed by linear regression models. We detected AhR-TEQ in 93.9 % of maternal first trimester serum samples, with a median level of 185 pg/g lipid. Each ln-unit increase in AhR-TEQ was associated with an increase in birth weight of 36 g (95 % CI: 5; 68), birth length of 0.2 cm (95 % CI: 0.01; 0.3) and pregnancy duration of 1 day (95 % CI: 0; 1.5). In women who never smoked, higher AhR-TEQ values were associated with higher birth weight and longer duration of gestation, while in smokers the association was the opposite. Mediation analyses suggested that gestational age may mediate the association of AhR-TEQ with foetal growth indices. We conclude that AhR activating substances are present in the bloodstream of almost all pregnant women in Denmark and the AhR-TEQ level was around four times higher than previously reported. The AhR-TEQ was associated with slightly longer gestational duration and thereby higher birth weight and birth length., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Dioxin and dioxin-like compounds are chlorinated organic pollutants formed during the manufacturing of other chemicals. Dioxins are ligands of the aryl hydrocarbon receptor (AHR), that induce AHR-mediated biochemical and toxic responses and are persistent in the environment. 2,3,7,8- tetrachlorodibenzo para dioxin (TCDD) is the prototypical AHR ligand and its effects represent dioxins. TCDD induces toxicity, immunosuppression and is a suspected tumor promoter. The role of TCDD in cancer however is debated and context-dependent. Environmental particulate matter, polycyclic aromatic hydrocarbons, perfluorooctane sulfonamide, endogenous AHR ligands, and cAMP signaling activate AHR through TCDD-independent pathways. The effect of activated AHR in cancer is context-dependent. The ability of FDA-approved drugs to modulate AHR activity has sparked interest in their repurposing for cancer therapy. TCDD by interfering with endogenous pathways, and overstimulating other endogenous pathways influences all stages of cancer. Herein we review signaling mechanisms that activate AHR and mechanisms by which activated AHR modulates signaling in cancer including affected metabolic pathways., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: This study aimed to evaluate exposure to various hazardous substances emitted by incineration facilities and their likely effect on the health for residents of Bugi-myeon, Cheongju, Korea, which has three incineration facilities., Methods: Heavy metals, polycyclic aromatic hydrocarbons (PAHs), and dioxin concentrations in the air and soil of exposed and control areas were measured. Moreover, the exposure levels to harmful substances and its effects on health were investigated in 1,124 exposed and 232 control adults., Results: PAHs and dioxin concentrations in the air in the exposed area were significantly higher than in the control area. Urinary cadmium and PAHs metabolite concentrations were significantly higher in the exposed group than in the control group. The exposure group also had a higher prevalence of depression and self-reported allergic symptoms than the control group., Conclusion: The possibility of residents in Bugi-myeon being exposed to hazardous substances at incineration facilities cannot be ruled out. To prevent them from further exposure to hazardous substances, it is necessary to prohibit the expansion of additional incineration facilities in this area and to implement continuous monitoring projects for residents., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2023 The Korean Academy of Medical Sciences.)

Increasing evidence points towards a causal link between exposure to persistent organic pollutants (POPs) with increased incidence and aggressivity of various cancers. Among these POPs, dioxin and PCB-153 are widely found in our environment and represent a significant source of contamination. Dioxin exposure has already been linked to cancer such as non-Hodgkin's lymphoma, but remains to be more extensively investigated in other cancers. Potential implications of dioxin and PCB-153 in prostate cancer progression spurred us to challenge both ex vivo and in vivo models with low doses of these POPs. We found that dioxin or PCB-153 exposure increased hallmarks of growth and metastasis of prostate cancer cells ex vivo and in grafted NOD-SCID mice. Exposure induced histopathological carcinoma-like patterns in the Pten pc-/- mice. We identified up-regulation of Acetyl-CoA Acetyltransferase-1 (ACAT1) involved in ketone bodies pathway as a potential target. Mechanistically, genetic inhibition confirmed that ACAT1 mediated dioxin effect on cell migration. Using public prostate cancer datasets, we confirmed the deregulation of ACAT1 and associated gene encoded ketone bodies pathway enzymes such as OXCT1, BDH1 and HMGCL in advanced prostate cancer. To further explore this link between dioxin and ACAT1 deregulation, we analyzed a unique prostate-tumour tissue collection from the USA veterans exposed to agent orange, known to be highly contaminated by dioxin because of industrial production. We found that ACAT1 histoscore is significantly increased in exposed patients. Our studies reveal the implication of dioxin and PCB-153 to induce a prometastatic programme in prostate tumours and identify ACAT1 deregulation as a key event in this process., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

In 2005, the World Health Organization (WHO) re-evaluated Toxic Equivalency factors (TEFs) developed for dioxin-like compounds believed to act through the Ah receptor based on an updated database of relative estimated potency (REP)(REP 2004 database). This re-evalution identified the need to develop a consistent approach for dose-response modeling. Further, the WHO Panel discussed the significant heterogeneity of experimental datasets and dataset quality underlying the REPs in the database. There is a critical need to develop a quantitative, and quality weighted approach to characterize the TEF for each congener. To address this, a multi-tiered approach that combines Bayesian dose-response fitting and meta-regression with a machine learning model to predict REPS' quality categorizations was developed to predict the most likely relationship between each congener and its reference and derive model-predicted TEF uncertainty distributions. As a proof of concept, this 'Best-Estimate TEF workflow' was applied to the REP 2004 database to derive TEF point-estimates and characterizations of uncertainty for all congeners. Model-TEFs were similar to the 2005 WHO TEFs, with the data-poor congeners having larger levels of uncertainty. This transparent and reproducible computational workflow incorporates WHO expert panel recommendations and represents a substantial improvement in the TEF methodology., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Partial funding for ToxStrategies authors ( Caroline Ring, Alexander Blanchette, William Klaren, Seneca Fitch, Laurie Haws, Daniele Wikoff) was initially provided by Tierra Solutions, Inc., and subsequently by Glenn Springs Holdings, Inc., entities involved with TCDD-related litigation. No external funding was provided for the remaining efforts for ToxStrategies authors; the work was carried out as part of the normal course of employment (no personal fees were received). Michael DeVito, Nigel Walker, and Matthew Wheeler did not receive any funding from these sources; they were supported by their own institutions (NIH/NIEHS). During the drafting of this manuscript, Michael DeVito and Caroline Ring left their former positions (NIH/NIEHS and ToxStrategies, respectively) and became employees of the U.S. Environmental Protection Agency, after which they were supported only by that institution. During the conceptualization, implementation, and drafting of this manuscript, Michael DeVito and Nigel Walker were supported, in part, by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. DanieleWikoff serves as an Associate Editor at Regulatory Toxicology and Pharmacology. Michael DeVito served as an ad-hoc expert at the 2022 World Health Organization consultation on Toxic Equivalency Factors. Laurie Haws and Daniele Wikoff served as contractors to the European Food Safety Authority to support the WHO expert consultation. The information in this document has been funded wholly or in part by the US Environmental Protection Agency. The contents of this paper reflect the opinions and views of the authors, and do not necessarily reflect the views of the U.S. EPA, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. The paper has been subjected to the U.S. EPA review process and approved for publication., (Copyright © 2023. Published by Elsevier Inc.)

A core challenge for ecological risk assessment is to integrate molecular responses into a chain of causality to organismal or population-level outcomes. Bioenergetic theory may be a useful approach for integrating suborganismal responses to predict organismal responses that influence population dynamics. We describe a novel application of dynamic energy budget (DEB) theory in the context of a toxicity framework (adverse outcome pathways [AOPs]) to make quantitative predictions of chemical exposures to individuals, starting from suborganismal data. We use early-life stage exposure of Fundulus heteroclitus to dioxin-like chemicals (DLCs) and connect AOP key events to DEB processes through "damage" that is produced at a rate proportional to the internal toxicant concentration. We use transcriptomic data of fish embryos exposed to DLCs to translate molecular indicators of damage into changes in DEB parameters (damage increases somatic maintenance costs) and DEB models to predict sublethal and lethal effects on young fish. By changing a small subset of model parameters, we predict the evolved tolerance to DLCs in some wild F. heteroclitus populations, a data set not used in model parameterization. The differences in model parameters point to reduced sensitivity and altered damage repair dynamics as contributing to this evolved resistance. Our methodology has potential extrapolation to untested chemicals of ecological concern. Environ Toxicol Chem 2023;42:2040-2053. © 2023 Oak Ridge National Laboratory and The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC., (© 2023 Oak Ridge National Laboratory and The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.)

Understanding the environmental and human impacts associated with polychlorinated dibenzo-p-dioxins/dibenzofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (DL-PCBs) exposure from municipal solid waste incinerators (MSWIs) is challenging because information on ambient and dietary exposure levels, spatial characteristics, and potential exposure routes is limited. In this study, 20 households from two villages located on the upwind and downwind sides of a MSWI were selected to characterize the concentration and spatial distribution of PCDD/F and DL-PCB compounds in ambient and food samples, such as dust, air, soil, chicken, egg, and rice samples. The source of exposure was identified using congener profiles and principal component analysis. Overall, the dust and rice samples had the highest and lowest mean dioxin concentrations, respectively. Significant differences were observed (p < 0.01) in PCDD/F concentrations in chicken samples and DL-PCB concentrations in rice and air samples between the upwind and downwind villages. The exposure assessment indicated that the primary risk source was dietary exposure, especially from eggs, which had a PCDD/F toxic equivalency (TEQ) range of 0.31-14.38 pg TEQ/kg body weight (bw)/day, leading to adults in one household and children in two households exceeding the World Health Organization-defined threshold of 4 pg TEQ/kg bw/day. Chicken was the main contributor to the differences between upwind and downwind exposure. Based on the established congener profiles, the exposure routes of PCDD/Fs and DL-PCBs from the environment to food to humans were clarified., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Dioxins are widely known to bioaccumulate in the body and produce a wide spectrum of toxic effects on both humans and wildlife. In addition, some novel sorts of compounds that were similar in structure and effect were gradually identified and termed dioxin-like compounds (DLCs). The toxicity of dioxins as well as DLCs is predominantly mediated by the dioxin receptor (aryl hydrocarbon receptor, AHR) in animals, which is usually differentially expressed and functionally distinct (especially the sensitivity to dioxins) among species, possibly resulting in species-specific variations in the toxicity of dioxins. Therefore, detailed functional exploration of the AHRs of a given species, such as the common carp (which is a vital wild and commercial species with a broad geological distribution) in the current study, will enable a comprehensive ecotoxicity evaluation. Through genome survey and phylogenetic analysis, we identified three AHRs (AHR1a, AHR1b, and AHR2) and two ARNTs (ARNT1 and ARNT2). AHR2 was observed to have greater expression abundance in the gill and brain, and may serve as the predominant subform. Those AHRs and ARNTs are functional, and the AHRs can be efficiently transactivated by the classical dioxin congener 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We individually determined the EC 50 values of AHR1a (0.41 ± 0.24 nM), AHR1b (12.80 ± 3.28 nM), and AHR2 (0.64 ± 0.49 nM), and found that: 1) The AHR sensitivities of common carp and zebrafish (phylogenetically close species) are relatively similar. AHR1a and the predominant form AHR2 have greater sensitivity to TCDD. 2) ARNT1 and ARNT2 do not produce different sensitivities, but with distinct induction fold, of a given AHR transactivation when cooperating as the partner; 3) Distinct AHR subforms of the same or distinct species can have even one or two orders of magnitude differences in sensitivity. In summary, the current study will add to the knowledge of AHR biology and help improve ecotoxicology research on dioxins and DLCs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) is the most toxic congener of dioxin and has serious long-term effects on the environment and human health. Pyruvate Kinase L/R (PKLR) gene expression levels and gene variants are associated with pyruvate kinase enzyme deficiency, which has been identified as the cause of several diseases linked to dioxin exposure. In this study, we estimated PKLR gene copy number and gene expression levels using real-time quantitative PCR (RT-qPCR) assays, genotyped PKLR SNP rs3020781 by Sanger sequencing, and quantified plasma pyruvate kinase enzyme activity in 100 individuals exposed to Agent Orange/Dioxin near Bien Hoa and Da Nang airfields in Vietnam and 100 healthy controls. The means of PKLR copy numbers and PKLR gene expression levels were significantly higher, while pyruvate kinase enzyme activity was significantly decreased in Agent Orange/Dioxin-exposed individuals compared to healthy controls (P < 0.0001). Positive correlations of PKLR gene copy number and gene expression with 2,3,7,8-TCDD concentrations were observed (r = 0.2, P = 0.045 and r = 0.54, P < 0.0001, respectively). In contrast, pyruvate kinase enzyme activity was inversely correlated with 2,3,7,8-TCDD concentrations (r = -0.52, P < 0.0001). PKLR gene copy number and gene expression levels were also inversely correlated with pyruvate kinase enzyme activity. Additionally, PKLR SNP rs3020781 was found to be associated with 2,3,7,8-TCDD concentrations and PKLR gene expression. In conclusion, PKLR copy number, gene expression levels, and pyruvate kinase enzyme activity are associated with 2,3,7,8-TCDD exposure in individuals living in Agent Orange/Dioxin-contaminated areas., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The effects of environmental pollution are associated with higher rates of mortality, morbidity, and years of life lost. It is known that these produce alterations in the human body, including changes in body composition. Research has focused on the association between contaminants and BMI through cross-sectional studies. The objective of this study was to synthesize the evidence for the association of pollutants on different measures of body composition. The PECOS strategy was defined, in which "P": participants of any age, sex, or ethnicity, "E": a higher level of environmental pollution, "C": a lower level of environmental pollution, "O": body composition measurements and "S": longitudinal studies. Studies from the following databases were included: MEDLINE, EMBASE, SciELO, LILACS, Scopus, Web of Science, SPORTDiscus, and gray literature from inception to January 2023.3069 studies were identified, 18 were included in the systematic review, and 13 in the meta-analysis. These studies included 8.563 people, 47 environmental contaminants, and 16 measures of body composition. The meta-analysis by subgroup found that the association between dioxins, furans, PCBs, and waist circumference was β = 1.0 (95% CI: 0.85 to 1.16; I 2 : 95%), and the sum of four skinfolds β = 1.02 (95% CI: 0.88 to 1.16; I 2 : 24%). The association between pesticides and waist circumference was β = 1.00 (95% CI: 0.68 to 1.32; I 2 : 98%), and the fat mass was β = 0.99 (95% CI: 0.17 to 1.81; I 2 : 94%). Pollutants, especially endocrine-disrupting chemicals, among which dioxins, furans, PCBs, and pesticides, are associated with changes in body composition, mainly with waist circumference and the sum of four skinfolds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Dioxins are stable, ubiquitous, persistent, and halogenated environmental pollutants that have recently garnered increasing attention. This study constructed a microcosmic system to simulate the real breeding conditions of the Chinese mitten crab (Eriocheir sinensis) to evaluate the impact of environmental dioxins on these aquaculture animals. Histological observation and detection of antioxidant enzyme activities revealed that dioxin exposure for different durations substantially damaged the hepatopancreas of Chinese mitten crabs, increasing the enzymatic activities of total superoxide dismutase (T-SOD) and catalase (CAT) but decreasing that of malondialdehyde (MDA). We also obtained the gene expression profiles of the hepatopancreas corresponding to different periods of dioxin exposure using RNA-seq technology. Compared with the control group, 2999 and 941 differentially expressed genes (DEGs) corresponding to different periods of dioxin exposure were identified in the hepatopancreas. Enrichment analysis indicated that some pathways, such as those governing carbohydrate metabolism, fatty acid metabolism, and immune disease, also responded to dioxin exposure. Subsequently, we selectively analyzed DEGs involved in oxidoreductase activity, carbohydrate metabolic processes, and other processes, identifying that increased expression of Hsp70, Ldh, and Trx1 and decreased expression of Lgbp, Bgal1, and Acsbg2 were potentially caused by sensitivity to environmental dioxin exposure. Therefore, we contend that, although crabs exposed to unfavorable environmental pollutants, such as dioxin, may adapt via antioxidant and immune response modulation. However, continued dioxin exposure would disrupt such homeostatic restorative capabilities. Thus, this study may provide new insights into the toxicological effects exerted by dioxin on aquatic organisms, such as E. sinensis, as well as the mechanisms underlying such toxicity., Competing Interests: Declaration of competing interest The authors attest that this study was conducted without any business or financial relationships that could be interpreted as potential conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) are unintentionally produced, toxic environmental chemicals that persist for long years and bioaccumulate along the food chain, contaminating humans through diet. A particularly critical population subgroup is pregnant women given the adverse health effects on fetuses and newborns. Several anthropogenic sources of exposure to PCDD/Fs exist in Lebanon. Therefore, the aim of the present cross-sectional study is to measure the levels of PCDD/Fs in a sample of pregnant women in Lebanon and to explore potential associated factors. In this study, we measured serum concentrations of seven dioxins and ten furans, among 423 pregnant women recruited at delivery, using gas chromatography MS/MS. Among 269 participants, maternal sociodemographic information was collected including vicinity to landfills, incineration, pesticide use, industrial activity, and smoking. Anthropometric data were registered regarding pre-pregnancy body mass index (BMI), pre-pregnancy weight loss from restrictive diet, and gestational weight gain. Intake of major food groups generally related to PCDD/Fs was reported (fish, red meat, poultry, and dairy). Bivariate and multivariate analyses were performed to identify associations. PCDD/Fs were detected in 0 to 56.1% of the sample. Geometric mean concentrations were 75.5 (2.35) pg/g lipid and 2.25 (1.39) TEQ 2005 pg/g lipid for total dioxins, and 2.66 (1.76) pg/g lipid and 0.34 (1.78) TEQ 2005 pg/g lipid for total furans. Levels were relatively lower than levels previously observed in France, Germany, Mexico, Ghana, and Japan. Red meat consumption was the most consistently associated factor with a 2.38-2.57 fold increase in PCDD/F levels. Pre-pregnancy weight loss showed inverse associations with PCDD/F congeners. Vicinity to illegal incineration was also associated with a 2.32-2.43 fold increase in PCDD/F levels. In conclusion, results showed the importance of dietary, anthropometric, and environmental factors in the present sample's exposure to PCDD/Fs, in a region that contains anthropogenic sources of contamination., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

World Health Organization toxic equivalency factors (WHO-TEFs) are recommended for risk management of brominated dioxins in aquatic environments because limited information is available on their toxicity to fish. To validate this approach, we obtained the relative potencies of polybrominated dibenzo-p-dioxins and polybrominated dibenzofurans and mixed-halogenated furans (PXDF, X = Cl/Br) against 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) based on their toxicity to the early-life stage of Japanese medaka (Oryzias latipes). 2,3,7,8-substituted brominated dibenzofurans caused typical dioxin exposure effects, such as blue-sac disease. The TCDD-relative potency factors (REPs) of test substances were calculated based on the concentrations in water and eggs that caused 20% lethality on day 28 post-fertilization, and were in the order of: 2-chloro-3,7,8-tribromodibenzofuran (REP water 3.3, REP egg 4.6) > 2,3,7,8-tetrabromodibenzofuran (0.85, 0.92) > 2,3,4,7,8-pentabromodibenzofuran (0.053, 0.55) > 1,2,3,7,8-pentabromodibenzofuran (0.0091, 0.19). The transfer rate from water to eggs was lower for pentabrominated furans than tetrabrominated congeners, and was expected to decrease with the log K ow of the test substance. Although the REP egg value can be used to compare the toxicity potential of brominated dioxins, REP water may be more suitable for environmental risk assessment because the uptake potential of these compounds from water should be considered. This study is the first to report higher toxicity of a PXDF congener compared with TCDD in vivo, further investigations of the toxicity of mixed-halogenated dioxins and environmental behavior are necessary for environmental risk assessment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The etiology of cryptorchidism remains poorly understood. Endocrine disrupting chemicals can impact estrogen signaling by interacting with aryl hydrocarbon receptor (AhR) activity., Objective: To evaluate whether AhR activity in breast milk samples is associated with cryptorchidism., Method: We conducted a case-control study based on 199 mother-child pairs (n = 91 cases/108 controls) selected from the Norwegian Human Milk Study (2002-2009). We defined cases for cryptorchidism based on maternal reports at 1-, 6-, 12-, and 24- months after birth. Chemically- and biologically stable AhR activity (pg 2,3,7,8-TCDD equivalent (TEQ)/g lipid) was determined by DR- CALUX® assay in the mothers' milk collected at a median of 33 (10th-90th percentile: 18-57) days after delivery. We used multivariate logistic regression to compare AhR activity levels between cases and controls, and linear regression separately, to establish the relationship with the presence of 27 potential EDCs measured in breast milk and AhR activity., Results: The average estimated daily intake (EDI) of dioxin and (dioxin-like (dl)-compounds via breast milk is 33.7 ± 17.9 pg TEQ/kg bodyweight per day among Norwegian children. There were no significant differences in AhR activation in breast milk samples between cases with cryptorchidism and controls. Among the 27 chemicals measured in breast milk, AhR activity was (borderline) significantly associated with all dl-PCBs, three non-dioxin-like (ndl)-PCBs (PCB-74, PCB-180, PCB-194) and two organochlorine pesticides (OCPs; HCB, β-HCH). No associations between AhR activity and brominated flame retardants (PBDEs) or poly- and perfluoroalkyl substances (PFASs)., Conclusion: No association between AhR activity and cryptorchidism was found among Norwegian boys. The average EDI of dioxin and dl-compounds in exclusively breastfed Norwegian infants remains above the safety threshold and, therefore requires further reduction measures. Consistent with a possible role in the observed AhR activity, all dl-PCBs were associated with AhR activity whereas the association was null for either PBDEs or PFASs., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Previous studies on the relationship between dioxin exposures and hyperuricemia have usually been based on multi-chemical linear models. However, the complex nonlinear relationship and interaction between mixed dioxin exposures and hyperuricemia have seldom been studied. In this study, we applied three different statistical models to assess the joint effect of 12 dioxins on hyperuricemia., Methods: A total of 7 dioxin-like polychlorinated biphenyls (DL-PCBs), 3 polychlorinated dibenzo-p-dioxins (PCDDs), and 2 polychlorinated dibenzofurans (PCDFs) were measured in the serum of adults by the National Health and Nutrition Examination Survey (NHANES) from 2003 to 2004. We fitted multivariable logistic regression, weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) models to estimate the association of individual and mixed dioxin exposures with hyperuricemia., Results: Among the 1008 individuals included in our analysis, 20.04% had hyperuricemia. In the multivariable logistic regression established for each single dioxin, PCB28, PCB74, PCB105, PCB118, and 1,2,3,4,6,7,8-HPCDD were positively associated with hyperuricemia. With including all dioxins in the multivariable logistic regression model simultaneously, only PCB28 and 1,2,3,4,6,7,8-HPCDD were positively associated with hyperuricemia. In the WQS regression model, the WQS index was significantly associated (OR (95% CI): 2.32 (1.26, 4.28)) with hyperuricemia, and 1,2,3,4,6,7,8-HPCDD (weighted 0.22) had the largest contribution. In BKMR analysis, a significant positive association was found between mixed dioxin exposure and hyperuricemia when all dioxins were at their 60th percentile or above, compared to their 50th percentile. The univariate exposure-response function showed that PCB105 and PCB118 were positively associated with hyperuricemia., Conclusion: By comparing the three statistical models, we concluded that the whole-body burden of 12 dioxins was significantly positively associated with hyperuricemia. PCB105, PCB118, and 1,2,3,4,6,7,8-HPCDD played the most important roles in hyperuricemia., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Bien Hoa airbase is the most dioxin-polluted hotspot in Vietnam. In 2012, a birth cohort living around Bien Hoa airbase was recruited for assessment of physical and neurological development. In the present study, neurodevelopment scores at 5 years of age were assessed by the Kaufman Assessment Battery for Children, Second Edition and the Movement Assessment Battery for Children, Second Edition for 185 children in Bien Hoa and 104 children in Ha Dong (unexposed control group) to clarify the effects of dioxin. 2,3,7,8-tetrachlorodibenzo-p-dioxin concentrations in breast milk of women in Bien Hoa were approximately three times higher than those of women in Ha Dong (2.33 vs. 0.69 pg/g fat, p < 0.001). In general, neurodevelopment scores were lower in Bien Hoa children than in Ha Dong children. In boys, scores differed for number recall (12.6 vs. 14.0, p = 0.036), triangles (10.7 vs. 12.4, p = 0.005), manual dexterity (8.3 vs. 9.7, p = 0.037), balance (7.4 vs. 10.3, p < 0.001), and total movement scores (8.0 vs. 10.1, p = 0.003). After adjusting for covariates, linear regression analysis indicated that the scores of the triangles, balance, and total movement tests were inversely associated with levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin and of toxic equivalency of polychlorinated dibenzodioxins and polychlorinated dibenzofurans. In girls, scores differed for the triangles test (11.0 vs. 12.6, p = 0.005), hand movement test (9.6 vs. 11.3, p = 0.003), and balance test (9.1 vs. 10.7, p = 0.050); toxic equivalency of polychlorinated dibenzofurans was inversely associated with hand movement and balance scores. Overall, perinatal dioxin exposure appears to have a long-term impact on neurodevelopment., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Semen quality in men continues to decline in Western countries, but the contours of the issue remain obscure, in relation to contributing chemicals., Objectives: To obtain more clarity about the chemicals that drive the deterioration of semen quality, we conducted a mixture risk assessment based on European exposures., Methods: We included chemicals capable of affecting semen quality after prenatal exposures, among them androgen receptor antagonists, substances that disrupt prostaglandin signalling, suppress testosterone synthesis, inhibit steroidogenic enzymes or activate the aryl hydrocarbon receptor. We employed the Hazard Index approach (HI), based on risk quotients of exposures in Europe and reference doses for reductions in semen quality. By summing up the risk quotients of the 29 chemicals included in the assessment we examined fold-exceedances of "acceptable" mixture exposures relative to an index value of 1. For bisphenols A, F, S, phthalates DEHP, DnBP, BBzP, DiNP, n-butyl paraben and paracetamol we relied on biomonitoring studies in which these 9 chemicals were measured together in the same subjects. This allowed us to construct personalised Hazard Indices., Results: Highly exposed subjects experienced combined exposures to the 9 chemicals that exceeded the index value of 1 by more than 100-fold; the median was a 17-fold exceedance. Accounting for median background exposures to the remaining 20 chemicals added a Hazard Index of 1.39. Bisphenol A made the largest contribution to the HI, followed by polychlorinated dioxins, bisphenols S and F and DEHP. Eliminating bisphenol A alone would still leave unacceptably high mixture risks. Paracetamol is also a driver of mixture risks among subjects using the drug., Conclusions: Tolerable exposures to substances associated with deteriorations of semen quality are exceeded by a large margin. Bisphenols, polychlorinated dioxins, phthalates and analgesics drive these risks. Dedicated efforts towards lowering exposures to these substances are necessary to mitigate risks., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Previous studies have indicated that prenatal exposure to dioxin-like compounds (DLC) or polychlorinated biphenyl (PCB) has a negative association with neurodevelopment in school-aged children. Event-related brain potentials (ERP) can reveal subtle and specific differences in the modulation of cognitive processes that are assumed when they are associated with lower levels of prenatal exposure to DLC or PCBs. This prospective birth cohort study was conducted to examine the association between prenatal exposure to relatively low levels of DLC, PCB or methylmercury (MeHg), and ERP. A total of 55 children who were 13 years old participated in a 3-stimulus oddball task to detect P3a and P3b waves. The task required participants to respond to a target among random stimuli at two difficulty levels. The P3a amplitude reflects an automated attention capture process, and P3b reflects a voluntary attention allocation process. We analyzed DLC congeners in blood samples from four groups, including 7 polychlorinated dibenzo-p-dioxins (PCDD), 10 polychlorinated dibenzofuranes (PCDF), 4 non-ortho PCBs, and 8 mono-ortho PCBs. PCB-153 was chosen as an indicator because of its high correlation with the sum of 58 NDL (non-dioxin-like)-PCBs. MeHg exposure level was assessed by the mercury concentration in hair samples (HHg) taken during the perinatal period. The reaction time to the target stimulus during the oddball task shortened with the increasing MeHg exposure level. Furthermore, P3b latency, which reflect response decision and correlates with reaction time, was also shortened with increasing MeHg level in the difficult condition. These results are counterintuitive because shorter reaction times or rapid decision making reflected by P3 latency are generally favorable. This might be due to nutritional factors such as fatty acids, which have beneficial effects on brain development. The P3a amplitude decreased with non- and mono-ortho PCB and HHg levels, regardless of the difficulty level, and with PCDD, PCDF, and total DLC levels, especially in the difficult condition. P3b latency shortened with HHg, and P3b amplitude decreased with mono-ortho PCBs and PCB-153 in both conditions and with PCDD, PCDF, non-ortho PCBs, and total DLC in the difficult condition. In conclusion, we found an association between prenatal exposure to DLC and a decrease in both P3a and P3b amplitude, even when DLC levels were lower than in most previous studies. Additionally, our results suggest that the automated attention capture process reflected by P3a is associated with maternal MeHg exposure and that the voluntary attention allocation process reflected by P3b is associated with PCB-153. However, these results should be interpreted with caution because of the limitations on sample size, population bias, and statistical analyses., (Copyright © 2022. Published by Elsevier B.V.)

In the present study, ninety-five halogenated dioxins and related chemicals (dibenzo-p-dioxins, dibenzofurans, biphenyls, and naphthalene) with endpoint pEC 50 were used to develop twelve quantitative structure toxicity relationship (QSTR) models using inbuilt Monte Carlo algorithm of CORAL software. The hybrid optimal descriptor of correlation weights (DCW) using a combination of SMILES and HSG (hydrogen suppressed graph) was employed to generate QSTR models. Three target functions i.e. TF 1 (W IIC =W CII =0), TF 2 (W IIC = 0.3 & W CII =0) and TF 3 (W IIC = 0.0 &W CII =0.3) were employed to develop robust QSTR models and the statistical outcomes of each target function were compared with each other. The correlation intensity index (CII) was found a reliable benchmark of the predictive potential for QSTR models. The numerical value of the determination coefficient of the validation set of split 1 computed by TF 3 was found highest (R Valid 2 =0.8438). The fragments responsible for the toxicity of dioxins and related chemicals were also identified in terms of the promoter of increase/decrease for pEC 50 . Three random splits (Split 1, Split 2 and Split 4) were selected for the extraction of the promoter of increase/decrease for pEC 50 . In the last, consensus modelling was performed using the intelligent consensus tool of DTC lab (https://dtclab.webs.com/software-tools). The original consensus model, which was created by combining four distinct models employing the split 4 arrangement, was more predictive for the validation set and the numerical value of the determination coefficient of the test set (validation set) was increased from 0.8133 to 0.9725. For the validation set of split 4, the mean absolute error (MAE 100%) was also lowered from 0.513 to 0.2739., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Agent Orange (AO) was the dominant weaponized herbicide employed by the United States (US) military during the Vietnam war. AO, however, was found to be regularly contaminated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic dioxin known; furthermore, AO was commonly diluted in the field with other aromatic hydrocarbons to assist with delivery mechanisms. Unbeknownst to the US military and the millions exposed, these events have likely contributed to the development of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) that has affected many veterans. Null studies regarding an association between AO exposure and AML/MDS are limited in their methodology and application. The acknowledgement that the known carcinogen TCDD was a contaminant in AO when paired with a strong biological plausibility for its leukemogenicity and an observed increased risk of AML/MDS in TCDD-exposed individuals should suffice to establish causal association and that veterans to whom this might apply should be awarded appropriate indemnity.

Background: Prenatal exposure to persistent organic pollutants, including polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), dioxin-like polychlorinated biphenyls (DL-PCBs), and nondioxin-like PCBs (NDL-PCBs), has been hypothesized to have a detrimental impact on neurodevelopment. However, the association of prenatal exposure to a dioxin and PCB mixture with neurodevelopment remains largely inconclusive partly because these chemical levels are correlated., Objectives: We aimed to elucidate the association of in utero exposure to a mixture of dioxins and PCBs with neurodevelopment measured at 6 months of age by applying multipollutant methods., Methods: A total of 514 pregnant women were recruited between July 2002 and October 2005 in the Sapporo cohort, Hokkaido Study on Environment and Children's Health. The concentrations of individual dioxin and PCB isomers were assessed in maternal peripheral blood during pregnancy. The mental and psychomotor development of the study participants' infants was evaluated using the Bayley Scales of Infant Development-2nd Edition (n = 259). To determine both the joint and individual associations of prenatal exposure to a dioxin and PCB mixture with infant neurodevelopment, Bayesian kernel machine regression (BKMR) and quantile-based g-computation were employed., Results: Suggestive inverse associations were observed between in utero exposure to a dioxin and PCB mixture and infant psychomotor development in both the BKMR and quantile g-computation models. In contrast, we found no association of a dioxin and PCB mixture with mental development. When group-specific posterior inclusion probabilities were estimated, BKMR suggested prenatal exposure to mono-ortho PCBs as the more important contributing factors to early psychomotor development compared with the other dioxin or PCB groups. No evidence of nonlinear exposure-outcome relationships or interactions among the chemical mixtures was detected., Conclusions: Applying the two complementary statistical methods for chemical mixture analysis, we demonstrated limited evidence of inverse associations of prenatal exposure to dioxins and PCBs with infant psychomotor development., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Several naturally occurring dioxins, including 1,3,7-tribromodibenzo-p-dioxin (1,3,7-TriBDD), synthesized by red algae, have been detected in the marine environment. As 1,3,7-TriBDD is accumulated in mussels and fish, predators, such as marine birds, are exposed to this congener, similar to anthropogenic dioxins (including 2,3,7,8-tetrachlorodibenzo-p-dioxin TCDD). However, little is known about the impact of 1,3,7-TriBDD exposure on the bird health. To understand the effects of 1,3,7-TriBDD on birds, the phenotypic effects and hepatic transcriptome were investigated in chicken (Gallus gallus) embryos treated with 27 μM (2.9 ng/g egg) and 137 μM (14.4 ng/g egg) 1,3,7-TriBDD. The blood glucose levels in the 1,3,7-TriBDD-treated groups were lower than those in the control group. The transcriptome analysis of 6520 sequences in the 27 and 137 μM 1,3,7-TriBDD-treated groups identified 733 and 596 differentially expressed genes (DEGs). Cytochrome P450 1A4 and 1A5 were also identified as DEGs, suggesting that the aryl hydrocarbon receptor is activated by this congener. Pathway and network analyses with DEGs suggested that 1,3,7-TriBDD may induce carcinogenic effects and metabolic alterations. These results were similar to the effects on TCDD-treated embryos. Nevertheless, the overall transcriptome results suggested that compared with TCDD, 1,3,7-TriBDD has a unique impact on insulin- and peroxisome-signaling pathways in chicken embryos. Differences in altered transcriptome profiles between 1,3,7-TriBDD- and TCDD-treated embryos may lead to different phenotypic effects: less severe effects of 1,3,7-TriBDD and more fatal effects of TCDD. Collectively, these findings warrant the further assessment of the hazard and risk of 1,3,7-TriBDD on marine animals, considering increased exposure due to climate change., (Copyright © 2022. Published by Elsevier Inc.)

Despite numerous studies on effects of environmental accumulation of nano-pollutants, the influence of nanoparticles on the biological perturbations of coexisting pollutants in the environment remained unknown. The present study aimed at elucidating the perturbations of six environmental nanoparticles on detoxification of dioxin-induced toxicity at cellular level. We discovered that there was no remarkable difference in the cell uptake and intracellular distributions of these six nanoparticles. However, they have different effects on the detoxification of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD). Multi-walled carbon nanotubes (MWCNTs) inhibited the translocation of aryl hydrocarbon receptor (AhR) from cytosol to the nucleus, leading to the downregulation of cytochrome P450 family 1 subfamily A member 1 (CYP1A1) and inhibition of detoxification function. These findings demonstrate that MWCNTs can impact the potential detoxification of dioxin-induced toxicity through modulating AhR signaling pathway. Co-exposures to MWCNTs and dioxin may cause even more toxicity than single exposure to dioxin or MWCNTs alone., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The suitability of the AhR reporter gene bioassays to screen the presence of polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dl-PCBs) in sewage sludge (SL) and related hydrochar (HC) was here investigated. Samples of SL obtained from six WWTPs were processed by hydrothermal carbonization to obtain the resultant HCs and both tested with DR-CALUX® bioassay. Levels of PCDD/Fs and dl-PCBs were also determined analytically in the same samples by GC-MS/MS. Bioanalytical Toxicity Equivalent values (BEQ) resulted in one order of magnitude higher in HC compared to SL samples and those obtained from the dl-PCBs fraction higher than those from PCDD/Fs. BEQ and TEQ WHO values, the latter obtained by GC-MS/MS analysis on the same matrices, were highly correlated showing also a similar trend in the six WWTPs (R S = 0.8252, p < 0.001; Pearson's R R P =0.8029, p < 0.01). The suitability of AhR bioassays and in particular of the DR-CALUX® to screen the presence and biological activity of legacy organohalogen compounds in both SL and HC matrices was demonstrated for the first time which support their usage for the assessment of potential risks associated with their further environmental applications., (Copyright © 2022 Elsevier B.V. All rights reserved.)

In January 2019, the French Agency for Food, Environmental and Occupational Health and Safety (ANSES) published an opinion on risks related to the presence of hazardous chemicals in infant diapers. ANSES found that health reference values were largely exceeded for polycyclic aromatic hydrocarbons (PAHs), dioxins (PCCD/Fs) and dioxin-like polychlorobiphenyls (DL-PCBs). The levels of formaldehyde and some fragrances were also considered potentially unsafe. Therefore, ANSES concluded that actions have to be taken to restrict levels of these contaminants in diapers. Under the exposure scenario deemed the most reliable by ANSES, estimates of cancer risks of the most potent PAHs detected in diapers exceeded 10 -3 and hazard quotients for neurobehavioral effects attained values up to 66. Regarding dioxins and DL-PCBs, ANSES derived a hazard quotient of 12 for the risk of decreased sperm count at adult age. The aim of this study was to examine whether the exposure and risk assessment conducted by ANSES contained potential flaws that could explain such a high exceedance of health reference values. This study also put into perspective the exposure from diapers with that from breast milk whose benefits for children's health are undisputable despite contamination by PAHs, dioxins and DL-PCB S .

The aryl hydrocarbon receptor (AHR) is a member of the basic helix-loop-helix/Per-ARNT-Sim (bHLH-PAS) family of transcription factors and has broad biological functions. Early after the identification of the AHR, most studies focused on its roles in regulating the expression of drug-metabolizing enzymes and mediating the toxicity of dioxins and dioxin-like compounds (DLCs). Currently, more diverse functions of AHR have been identified, indicating that AHR is not just a dioxin receptor. Dioxins and DLCs occur ubiquitously and have diverse health/ecological risks. Additional research is required to identify both shared and compound-specific mechanisms, especially for emerging DLCs such as polyhalogenated carbazoles (PHCZs), polychlorinated diphenyl sulfides (PCDPSs), and others, of which only a few investigations have been performed at present. Many of the toxic effects of emerging DLCs were observed to be predominantly mediated by the AHR because of their structural similarity as dioxins, and the in vitro TCDD-relative potencies of certain emerging DLC congeners are comparable to or even greater than the WHO-TEFs of OctaCDD, OctaCDF, and most coplanar PCBs. Due to the close relationship between AHR biology and environmental science, this review begins by providing novel insights into AHR signaling (canonical and non-canonical), AHR's biochemical properties (AHR structure, AHR-ligand interaction, AHR-DNA binding), and the variations during AHR transactivation. Then, AHR ligand classification and the corresponding mechanisms are discussed, especially the shared and compound-specific, AHR-mediated effects and mechanisms of emerging DLCs. Accordingly, a series of in vivo and in vitro toxicity evaluation methods based on the AHR signaling pathway are reviewed. In light of current advances, future research on traditional and emerging DLCs will enhance our understanding of their mechanisms, toxicity, potency, and ecological impacts., (Copyright © 2021. Published by Elsevier B.V.)

Dioxin-like polychlorinated biphenyls (dl-PCBs) are ubiquitous chemicals which mediate toxicity in a way similar to polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans. In silico modeling was used to predict the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of eight dioxin-like PCBs in soil samples of 12 power stations in Lagos, Nigeria. Concentrations of Σdl-PCB 8 in soil samples ranged from 490 to 61,000 pg g -1 , with mean concentrations of 17,000 pg g -1 . The corresponding toxic equivalent (TEQ) concentrations of Ʃdl-PCB 8 ranged from 0.01 to 450 pg TEQ g -1 , with a mean value of 42 pg TEQ g -1 . Mean TEQ concentrations for Ʃdl-PCB 8 in soil samples from all but one of the sites exceeded the Canadian guideline value of 4 pg TEQ g -1 and the US and German guideline values of 5-10 pg TEQ g -1 . However, the TEQ concentrations obtained were all below the US action level of 1000 pg TEQ g -1 . The ADMET predictions revealed that all studied dl-PCBs are inhibitors of three major isoforms (1A2, 2C9, and 2C19) of cytochrome P450 enzyme. Acute oral toxicity (median lethal dose) predictions revealed that all target dl-PCBs were class III compounds. Hepatotoxicity and carcinogenicity were positive, signifying that the studied compounds all have a tendency to elicit these effects. Occupational daily TEQ exposure via soil ingestion was estimated for an average adult worker weighing 70 kg. The maximum exposure obtained was 0.14 pg TEQ kg -1  body weight day -1 , which is half of the European Food Safety Authority (EFSA) tolerable daily intake (TDI) for dioxin-like compounds. This raises concern over the possible exceedance of the EFSA TDI for these workers if other dietary and nondietary exposure pathways and dioxin-like compounds are considered. Environ Toxicol Chem 2022;41:800-809. © 2021 SETAC., (© 2021 SETAC.)

Following the reduction of incinerator emission, enacted by the Korean Government in 2001, the levels of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) in the air (-96%) have significantly decreased. However, their levels in the human serum of the general Korean population have not reduced at the same rate (-36%), indicating that humans may also be unintentionally exposed to these compounds, primarily through food ingestion. In this study, the risk of dietary exposure was assessed on a large scale, to provide toxicological information and guide the development of food safety policies. The food consumption data of the extreme (95th percentile) group and various subgroups (by age, pregnancy, and lactation), as well as the average group, were utilized. Compared to the tolerable daily intake (TDI) established by the World Health Organization (WHO), the average daily dietary exposure of the general Korean population, calculated using a deterministic method, was 11.9% of the WHO TDI (4 pg-TEQ WHO05 kg body weight -1 d -1 ). For additional comparison, a probabilistic method using a Monte Carlo simulation was applied to the same data. Finally, the associated potential health risk was quantitatively characterized, and the results suggest the importance of non-dioxin-like congeners in future risk assessments., (Copyright © 2021 Elsevier Ltd. All rights reserved.)