Chemical Risk Assessment Research Articles

Tracking and optimizing toxic chemical exposure pathways through food trade: A case study in SCCPs contaminated seafood in China

Abstract Food safety is related to human health and sustainable development. International food trade poses food safety risks through the collateral transport of toxic chemicals that are detrimental to human health. Domestic interprovincial trade has similar effects within countries but has not been comprehensively investigated previously. Here we assessed the effects of interprovincial trade on food safety and human dietary exposure to short-chain chlorinated paraffins (SCCPs), a group of emerging persistent toxic chemicals, in seafood across China by synthesizing data from field observation and various models. Our findings indicate that there is a higher level of SCCPs exposure risk in coastal provinces compared to inland provinces. Approximately 70.3% of human exposure to SCCPs through seafood consumption in China was embodied in the interprovincial seafood trade in 2021. Specifically, the domestic trade led to a remarkable increase in SCCPs exposure in the coastal provinces in South China, attributable to low SCCPs pollution in these provinces and imported seafood from those provinces with high SCCPs pollution. In contrast, human exposure to SCCPs decreased in those coastal provinces in East China due to importing seafood from those provinces with low SCCPs concentrations. The interprovincial seafood trade routes were optimized by linear programming to minimize human exposure to SCCPs considering both shipping cost and health risk constraints. The optimized trade routes reduced the national per capita SCCPs exposure through seafood consumption by over 12%. This study highlights the importance of interprovincial food trade in the risk assessment of toxic chemicals.

Mechanistic screening of reproductive toxicity in a novel 3D testicular co-culture model shows significant impairments following exposure to low-dibutyl phthalate concentrations

To improve the mechanistic screening of reproductive toxicants in chemical-risk assessment and drug development, we have developed a three-dimensional (3D) heterogenous testicular co-culture model from neonatal mice. Di-n-butyl phthalate (DBP), an environmental contaminant that can affect reproductive health negatively, was used as a model compound to illustrate the utility of the in vitro model. The cells were treated with DBP (1 nM to 100 µM) for 7 days. Automated high-content imaging confirmed the presence of cell-specific markers of Leydig cells (CYP11A1 +), Sertoli cells (SOX9 +), and germ cells (DAZL +). Steroidogenic activity of Leydig cells was demonstrated by analyzing testosterone levels in the culture medium. DBP induced a concentration-dependent reduction in testosterone levels and decreased the number of Leydig cells compared to vehicle control. The levels of steroidogenic regulator StAR and the steroidogenic enzyme CYP11A1 were decreased already at the lowest DBP concentration (1 nM), demonstrating upstream effects in the testosterone biosynthesis pathway. Furthermore, exposure to 10 nM DBP decreased the levels of the germ cell-specific RNA binding protein DAZL, central for the spermatogenesis. The 3D model also captured the development of the Sertoli cell junction proteins, N-cadherin and Zonula occludens protein 1 (ZO-1), critical for the blood–testis barrier. However, DBP exposure did not significantly alter the cadherin and ZO-1 levels. Altogether, this 3D in vitro system models testicular cellular signaling and function, making it a powerful tool for mechanistic screening of developmental testicular toxicity. This can open a new avenue for high throughput screening of chemically-induced reproductive toxicity during sensitive developmental phases.

A novel approach to assess the health risk of aryl hydrocarbon receptor-bound contaminants via inhalation exposure using CYP1A1 expression as a biomarker

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.

Comparative toxicological assessment of 2 bisphenols using a systems approach: evaluation of the behavioral and transcriptomic responses of Danio rerio to bisphenol A and tetrabromobisphenol A.

The zebrafish (Danio rerio) is becoming a critical component of new approach methods (NAMs) in chemical risk assessment. As a whole organism in vitro NAM, the zebrafish model offers significant advantages over individual cell-line testing, including toxicokinetic and toxicodynamic competencies. A transcriptomic approach not only allows for insight into mechanism of action for both apical endpoints and unobservable adverse outcomes, but also changes in gene expression induced by lower, environmentally relevant concentrations. In this study, we used a larval zebrafish model to assess the behavioral and transcriptomic alterations caused by subphenotypic concentrations of 2 chemicals with the same structural backbone, the endocrine-disrupting chemicals bisphenol A and tetrabromobisphenol A. Following assessment of behavioral toxicity, we used a transcriptomic approach to identify molecular pathways associated with previously described phenotypes. We also determined the transcriptomic point of departure for each chemical by modeling gene expression changes as continuous systems which allows for the identification of a single concentration at which toxic effects can be predicted. This can then be investigated with confirmatory cell-based testing in an integrated approach to testing and assessment to determine risk to human health and the environment with greater confidence. This paper demonstrates the impact of using a multi-faceted approach for evaluating the physiological and neurotoxic effects of exposure to structurally related chemicals. By comparing phenotypic effects with transcriptomic outcomes, we were able to differentiate, characterize, and rank the toxicities of related bisphenols, which demonstrates methodological advantages unique to the larval zebrafish NAM.

The use of effect biomarkers in chemical mixtures risk assessment – Are they still important?

Human epidemiological studies with biomarkers of effect play an invaluable role in identifying health effects with chemical exposures and in disease prevention. Effect biomarkers that measure genetic damage are potent tools to address the carcinogenic and/or mutagenic potential of chemical exposures, increasing confidence in regulatory risk assessment decision-making processes. The micronucleus (MN) test is recognized as one of the most successful and reliable assays to assess genotoxic events, which are associated with exposures that may cause cancer. To move towards the next generation risk assessment is crucial to establish bridges between standard approaches, new approach methodologies (NAMs) and tools for increase the mechanistically-based biological plausibility in human studies, such as the adverse outcome pathways (AOPs) framework. This paper aims to highlight the still active role of MN as biomarker of effect in the evolution and applicability of new methods and approaches in human risk assessment, with the positive consequence, that the new methods provide a deeper knowledge of the mechanistically-based biology of these endpoints.

Avoiding a reproducibility crisis in regulatory toxicology—on the fundamental role of ring trials

The ongoing transition from chemical hazard and risk assessment based on animal studies to assessment relying mostly on non-animal data, requires a multitude of novel experimental methods, and this means that guidance on the validation and standardisation of test methods intended for international applicability and acceptance, needs to be updated. These so-called new approach methodologies (NAMs) must be applicable to the chemical regulatory domain and provide reliable data which are relevant to hazard and risk assessment. Confidence in and use of NAMs will depend on their reliability and relevance, and both are thoroughly assessed by validation. Validation is, however, a time- and resource-demanding process. As updates on validation guidance are conducted, the valuable components must be kept: Reliable data are and will remain fundamental. In 2016, the scientific community was made aware of the general crisis in scientific reproducibility—validated methods must not fall into this. In this commentary, we emphasize the central importance of ring trials in the validation of experimental methods. Ring trials are sometimes considered to be a major hold-up with little value added to the validation. Here, we clarify that ring trials are indispensable to demonstrate the robustness and reproducibility of a new method. Further, that methods do fail in method transfer and ring trials due to different stumbling blocks, but these provide learnings to ensure the robustness of new methods. At the same time, we identify what it would take to perform ring trials more efficiently, and how ring trials fit into the much-needed update to the guidance on the validation of NAMs.

Physiologically based kinetic (PBK) modeling as a new approach methodology (NAM) for predicting systemic levels of gut microbial metabolites

There is a clear need to develop new approach methodologies (NAMs) that combine in vitro and in silico testing to reduce and replace animal use in chemical risk assessment. Physiologically based kinetic (PBK) models are gaining popularity as NAMs in toxico/pharmacokinetics, but their coverage of complex metabolic pathways occurring in the gut are incomplete. Chemical modification of xenobiotics by the gut microbiome plays a critical role in the host response, for example, by prolonging exposure to harmful metabolites, but there is not a comprehensive approach to quantify this impact on human health. There are examples of PBK models that have implemented gut microbial biotransformation of xenobiotics with the gut as a dedicated metabolic compartment. However, the integration of microbial metabolism and parameterization of PBK models is not standardized and has only been applied to a few chemical transformations. A challenge in this area is the measurement of microbial metabolic kinetics, for which different fermentation approaches are used. Without a standardized method to measure gut microbial metabolism ex vivo/in vitro, the kinetic constants obtained will lead to conflicting conclusions drawn from model predictions. Nevertheless, there are specific cases where PBK models accurately predict systemic concentrations of gut microbial metabolites, offering potential solutions to the challenges outlined above. This review focuses on models that integrate gut microbial bioconversions and use ex vivo/in vitro methods to quantify metabolic constants that accurately represent in vivo conditions.

New approach methods to assess developmental and adult neurotoxicity for regulatory use: a PARC work package 5 project.

In the European regulatory context, rodent in vivo studies are the predominant source of neurotoxicity information. Although they form a cornerstone of neurotoxicological assessments, they are costly and the topic of ethical debate. While the public expects chemicals and products to be safe for the developing and mature nervous systems, considerable numbers of chemicals in commerce have not, or only to a limited extent, been assessed for their potential to cause neurotoxicity. As such, there is a societal push toward the replacement of animal models with in vitro or alternative methods. New approach methods (NAMs) can contribute to the regulatory knowledge base, increase chemical safety, and modernize chemical hazard and risk assessment. Provided they reach an acceptable level of regulatory relevance and reliability, NAMs may be considered as replacements for specific in vivo studies. The European Partnership for the Assessment of Risks from Chemicals (PARC) addresses challenges to the development and implementation of NAMs in chemical risk assessment. In collaboration with regulatory agencies, Project 5.2.1e (Neurotoxicity) aims to develop and evaluate NAMs for developmental neurotoxicity (DNT) and adult neurotoxicity (ANT) and to understand the applicability domain of specific NAMs for the detection of endocrine disruption and epigenetic perturbation. To speed up assay time and reduce costs, we identify early indicators of later-onset effects. Ultimately, we will assemble second-generation developmental neurotoxicity and first-generation adult neurotoxicity test batteries, both of which aim to provide regulatory hazard and risk assessors and industry stakeholders with robust, speedy, lower-cost, and informative next-generation hazard and risk assessment tools.

Should Transformation Products Change the Way We Manage Chemicals?

When chemical pollutants enter the environment, they can undergo diverse transformation processes, forming a wide range of transformation products (TPs), some of them benign and others more harmful than their precursors. To date, the majority of TPs remain largely unrecognized and unregulated, particularly as TPs are generally not part of routine chemical risk or hazard assessment. Since many TPs formed from oxidative processes are more polar than their precursors, they may be especially relevant in the context of persistent, mobile, and toxic (PMT) and very persistent and very mobile (vPvM) substances, which are two new hazard classes that have recently been established on a European level. We highlight herein that as a result, TPs deserve more attention in research, chemicals regulation, and chemicals management. This perspective summarizes the main challenges preventing a better integration of TPs in these areas: (1) the lack of reliable high-throughput TP identification methods, (2) uncertainties in TP prediction, (3) inadequately considered TP formation during (advanced) water treatment, and (4) insufficient integration and harmonization of TPs in most regulatory frameworks. A way forward to tackle these challenges and integrate TPs into chemical management is proposed.

Pollution characteristics and prospective risk of microplastics in the Zhengzhou section of Yellow River, China

The ubiquitous occurrence of microplastics (MPs) in the freshwater has attracted widespread attention. The Zhengzhou section of the Yellow River was the most prosperous region in ancient China, and the rapid urbanization, industrialization, and agricultural practices contributed to MPs pollution in aquatic systems recently, whereas the contamination status of MPs in the area is still not available. In this study, a total of fourteen sampling cross-sections were selected in the region to collect water samples systematically for the analysis of MPs pollution characteristics and potential risks. Results showed that abundance of MPs in the water were ranged from 2.33 to 15.50 n/L, with an average value of 6.40 ± 3.40 n/L, which was higher than it in other inland rivers from China. Moreover, the MPs of 0.5–2 mm were the dominant sizes in Yellow River of Zhengzhou region, and most of them were black fibres. The top three polymers were Polyethylene terephthalate (PET), Polyamide (PA) and Polypropylene (PP). High diversity indices of MPs observed at S3, S4, S5, S6, S7, and S8 for size, colour, polymer and shape indicated diverse and complex sources of MPs in those cross-sections. The MPs in water from Zhengzhou area of Yellow River probably degraded from textiles, fishing net, plastic bags, mulching film, packaging bags, and tire wear. The chemical risk assessment revealed a level III risk for study area, while S8 and S11 in which PVA or PAN with higher hazard score detected were categorised as class V risk. Coincidentally, probabilistic risk assessment showed a considerable ecological risk of MPs from Yellow River in Zhengzhou City, with possibility of 99.48 and 98.01 % adverse effect for food dilution and translocation-mediated mechanism, respectively. The results are expected to assistance for development of policies and ultimately combating MPs pollution.

Effects of Chemicals in Reporter Gene Bioassays with Different Metabolic Activities Compared to Baseline Toxicity.

High-throughput cell-based bioassays are used for chemical screening and risk assessment. Chemical transformation processes caused by abiotic degradation or metabolization can reduce the chemical concentration or, in some cases, lead to the formation of more toxic transformation products. Unaccounted loss processes may falsify the bioassay results. Capturing the formation and effects of transformation products is important for relating the in vitro effects to in vivo. Reporter gene cell lines are believed to have low metabolic activity, but inducibility of cytochrome P450 (CYP) enzymes has been reported. Baseline toxicity is the minimal toxicity a chemical can have and is caused by the incorporation of the chemical into cell membranes. In the present study, we improved an existing baseline toxicity model based on a newly defined critical membrane burden derived from freely dissolved effect concentrations, which are directly related to the membrane concentration. Experimental effect concentrations of 94 chemicals in three bioassays (AREc32, ARE-bla and GR-bla) were compared with baseline toxicity by calculating the toxic ratio (TR). CYP activities of all cell lines were determined by using fluorescence-based assays. Only ARE-bla showed a low basal CYP activity and inducibility and AREc32 showed a low inducibility. Overall cytotoxicity was similar in all three assays despite the different metabolic activities indicating that chemical metabolism is not relevant for the cytotoxicity of the tested chemicals in these assays. Up to 28 chemicals showed specific cytotoxicity with TR > 10 in the bioassays, but baseline toxicity could explain the effects of the majority of the remaining chemicals. Seven chemicals showed TR < 0.1 indicating inaccurate physicochemical properties or experimental artifacts like chemical precipitation, volatilization, degradation, or other loss processes during the in vitro bioassay. The new baseline model can be used not only to identify specific cytotoxicity mechanisms but also to identify potential problems in the experimental performance or evaluation of the bioassay and thus improve the quality of the bioassay data.

6PPD induced cardiac dysfunction in zebrafish associated with mitochondrial damage and inhibition of autophagy processes

The compound 6PPD is widely acknowledged for its antioxidative properties; however, concerns regarding its impact on aquatic organisms have spurred comprehensive investigations. In our study, we advanced our comprehension by revealing that exposure to 6PPD could induce cardiac dysfunction, myocardial injury and DNA damage in adult zebrafish. Furthermore, our exploration unveiled that the exposure of cardiomyocytes to 6PPD resulted in apoptosis and mitochondrial injury, as corroborated by analyses using transmission electron microscopy and flow cytometry. Significantly, our study demonstrated the activation of the autophagy pathway in both the heart of zebrafish and cardiomyocytes, as substantiated by transmission electron microscopy and immunofluorescent techniques. Importantly, the increased the expression of P62 in the heart and cardiomyocytes suggested an inhibition of the autophagic process. The reduction in autophagy flux was also verified through in vivo experiments involving the infection of mCherry-GFP-LC3. We further identified that the fusion of autophagosomes and lysosomes was impaired in the 6PPD treatment group. In summary, our findings indicated that the impaired fusion of autophagosomes and lysosomes hampered the autophagic degradation process, leading to apoptosis and ultimately resulting in cardiac dysfunction and myocardial injury. This study discovered the crucial role of the autophagy pathway in regulating 6PPD-induced cardiotoxicity. Synopsis6PPD exposure inhibited the autophagic degradation process and induced mitochondrial injury and apoptosis in the heart of adult zebrafish.

Chemical speciation and environmental risk assessment of heavy metals in ash from smouldering combustion of oily sludge

Smouldering combustion of oily sludge (OS) was carried out to learn the characteristics of heavy metals (HMs) in ash products. Ash collected from four different height layers of the column reactor was analysed for the chemical speciation and environmental risk of six HMs, including Cr, Ni, Cu, Zn, As, and Pb. The results showed that after smouldering combustion, only 21.3–32.2 % of the total HMs was remained in the ash products. The retention of HMs in ash was closely relevant to the carbonaceous destruction efficiency of OS. Smouldering combustion led to the decrease of HMs in acid-soluble/exchangeable fraction from 21.5–49.3 to 0.8–19.8% and oxidizable fraction from 22.6–49.6 to 5.3–21.3, and the increase of reducible fraction from 13.6–38.0 to 30.5–89.1% and residue fraction from 7.8–27.3 to 24.1–63.6%. Upward migration of HMs during smouldering was evidenced by their occurrence in the top clean sand layer, which was dominated in acid-soluble/exchangeable and reducible fractions, accounting for 89.7–99.1% in total. Toxicity extraction and environmental risk studies indicated that smouldering combustion would effectively reduce the toxicity and pollution risk of HMs; however, attention should be paid to the disposal of the top sand layer after smouldering operation due to its high pollution risk of HMs according to the evaluation of Risk assessment code.

Public views of animal testing and alternatives in chemical risk assessment

Next-Generation Risk Assessment (NGRA) aims to implement New Approach Methodologies (NAMs) into risk assessment and to rely on new in vivo testing in animals only as a last resort. However, various technical and regulatory hurdles impede their regulatory implementation. Assumptions about the public's expectations could act as barriers to the acceptance of NAMs. This study aimed at investigating public views of animal testing and potential alternatives, namely in vitro and in silico testing. An online survey was conducted (N = 965). The results suggest that people make trade-offs, as they experience negative affect regarding in vivo testing, which partly might explain their openness regarding certain alternatives. In vitro tests were attributed the highest ability to determine harmful effects of chemicals for different endpoints, followed by in vivo and in silico tests. Our results further showed that many people accept chemicals to be only tested with alternatives, with highest acceptance for household consumer products, food contact material or building materials and less accepting for medicines and foods. This article addresses potential challenges that might arise from public perceptions and thus, contributes to the bottom-up initiatives to overcome the hurdles to the implementation of NAMs in regulatory risk assessment.

Chemical Speciation, Leaching Behavior, and Environmental Risk Assessment of Trace Elements in the Bottom Ash from Biomass Power Plant.

Biomass combustion for power generation stands as a pivotal method in energy utilization, offering a promising approach for renewable energy utilization. However, the substantial volume of slag produced by biomass burning plants poses environmental challenges, impeding sustainable energy practices. This article systematically studies the characteristics of ash generated from typical biomass direct combustion power plant ash and analyzes the chemical composition, trace element content characteristics, leaching characteristics, and chemical forms of biomass bottom ash. Furthermore, it assesses the environmental ecology and bioavailability of trace elements in bottom ash using the ecological risk assessment method and RAC method. The results demonstrate that the biomass bottom ash contains plant nutrients, such as K, Ca, Mg, and P, while the content of harmful trace elements is lower than the relevant Chinese standards. In dissolution experiments, the leaching rate of nearly all elements remains exceptionally low, primarily due to the distribution of trace elements within the lattice structure of stable minerals. Trace elements predominantly exist in the residual phase, Cu and Zn primarily found in organic compounds and sulfide bound states, while other elements mostly exist in the form of iron manganese oxide bound states. Ecological risk assessment indicates a significant risk level for Cd, contrasting with the slight risk associated with other elements. RAC results indicated no ecological risk of all of the trace elements. Consequently, the utilization of bottom ash in agricultural and forestry soils is deemed to be viable. These findings serve as a crucial foundation for biomass bottom ash resource utilization and underpin the sustainable utilization of biomass energy.

Simultaneous detection of mycotoxins and pesticides in human urine samples: A 24-h diet intervention study comparing conventional and organic diets in Spain

Pesticides and mycotoxins, prominent chemical hazards in the food chain, are commonly found in plant-based foods, contributing to their pervasive presence in the human body, as evidenced by biomonitoring programs. Despite this, there is limited knowledge about their co-occurrence patterns. While intervention studies have demonstrated that organic diets can significantly reduce pesticide levels, their impact on mycotoxin exposure has been overlooked.To address this gap, this study pursued two objectives: first, to characterize the simultaneous presence of mycotoxins and pesticides in human urine samples by means of the control of the biomarkers of exposure, and second, to investigate the influence of consuming organic foods on these co-exposure patterns. A pilot study involving 20 healthy volunteers was conducted, with participants consuming either exclusively organic or conventional foods during a 24-h diet intervention in autumn 2021 and spring 2022 to account for seasonal variability. Participants provided detailed 24-h dietary records, and their first-morning urine samples were collected, minimally treated and analysed using LC-Q-ToF-MS by means of a multitargeted method in order to detect the presence of these residues.Results indicated that among the 52 screened compounds, four mycotoxins and seven pesticides were detected in over 25% of the samples. Deoxynivalenol (DON) and the non-specific pesticide metabolite diethylphosphate (DEP) exhibited the highest frequency rates (100%) and concentration levels. Correlations were observed between urine levels of mycotoxins (DON, ochratoxin alpha [OTα], and enniatin B [ENNB]) and organophosphate pesticide metabolites DEP and 2-diethylamino-6-methyl-4-pyrimidinol (DEAMPY). The pilot intervention study suggested a reduction in ENNB and OTα levels and an increase in β-zearalenol levels in urine after a short-term replacement with organic food. However, caution is advised due to the study's small sample size and short duration, emphasizing the need for further research to enhance understanding of the human chemical exposome and refine chemical risk assessment.

Occurrence and Ecological Risk of Alkylamine Triazines in Chinese Estuarine Sediments: An Emerging Class of Persistent, Mobile, and Toxic Substances.

Identifying persistent, mobile, and toxic (PMT) substances from synthetic chemicals is critical for chemical management and ecological risk assessment. Inspired by the triazine analogues (e.g., atrazine and melamine) in the original European Union's list of PMT substances, the occurrence and compositions of alkylamine triazines (AATs) in the estuarine sediments of main rivers along the eastern coast of China were comprehensively explored by an integrated strategy of target, suspect, and nontarget screening analysis. A total of 44 AATs were identified, of which 23 were confirmed by comparison with authentic standards. Among the remaining tentatively identified analogues, 18 were emerging pollutants not previously reported in the environment. Tri- and di-AATs were the dominant analogues, and varied geographic distributions of AATs were apparent in the investigated regions. Toxic unit calculations indicated that there were acute and chronic risks to algae from AATs on a large geographical scale, with the antifouling biocide cybutryne as a key driver. The assessment of physicochemical properties further revealed that more than half of the AATs could be categorized as potential PMT and very persistent and very mobile substances at the screening level. These results highlight that AATs are a class of PMT substances posing high ecological impacts on the aquatic environment and therefore require more attention.

Predictions of tissue concentrations of myclobutanil, oxyfluorfen, and pronamide in rat and human after oral exposures via GastroPlusTM physiologically based pharmacokinetic modelling

ABSTRACT Heritage agrochemicals like myclobutanil, oxyfluorfen, and pronamide, are extensively used in agriculture, with well-established studies on their animal toxicity. Yet, human toxicity assessment relies on conventional human risk assessment approaches including the utilization of animal-based ADME (Absorption, Distribution, Metabolism, and Excretion) data. In recent years, Physiologically Based Pharmacokinetic (PBPK) modelling approaches have played an increasing role in human risk assessment of many chemicals including agrochemicals. This study addresses the absence of PBPK-type data for myclobutanil, oxyfluorfen, and pronamide by generating in vitro data for key input PBPK parameters (Caco-2 permeability, rat plasma binding, rat blood to plasma ratio, and rat liver microsomal half-life), followed by generation of PBPK models for these three chemicals via the GastroPlusTM software. Incorporating these experimental input parameters into PBPK models, the prediction accuracy of plasma AUC (area under curve) was significantly improved. Validation against rat oral administration data demonstrated substantial enhancement. Steady-state plasma concentrations (Css) of pronamide aligned well with published data using measured PBPK parameters. Following validation, parent-based tissue concentrations for these agrochemicals were predicted in humans and rats after single or 30-day repeat exposure of 10 mg/kg/day. These predicted concentrations contribute valuable information for future human toxicity risk assessments of these agrochemicals.

Chemical release risk assessment in earthquake: Natech event scenario

IntroductionIn recent decades, an increase in natural disasters has led to the Natech events occurrence, which are technological accidents triggered by natural hazards. This study aims to assess the risk of chemical release of the H2S toxic gas following an earthquake from the refinery. MethodThe Natech risk assessment was carried out in potential earthquake risk scenarios via a semi-quantitative method using Rapid-N software. The reference scenario was obtained using the Australian SMUG Model, which has presented precise prioritization. FindingsThe Natech risk assessment has shown 40 possible earthquake risk scenarios from 5 enclosing Faults in Tehran (North Tehran, Mosha, North Ray, South Ray, and Kahrizak) with an extension of more than 15 km. The earthquake moment magnitudes of 7.5, 7.1, 6.5, and 5.9 were obtained on the Richter scale and at two Focal depths of 5 and 10 km. The South-Ray Fault (HSR-1) was selected as the reference scenario with a moment magnitude of 7.5 on the Richter scale at a Focal depth of 5 km and a distance of 5.5 km from the earthquake epicenter. The highest probability of Natech risk has shown the release of H2S toxic gas in an area with a radius of 6.59 km from the studied vessel in atmospheric stability conditions. ConclusionLegislation in line with risk reduction, planning for the transfer of potentially dangerous industries to outside urban areas, monitoring land use laws, and promoting coordination between the government, industries, and people in the management of risks caused by industries containing hazardous substances and processes, assessing the risk of Natech events and their consequences, strengthening risk communication and the installation of early warning systems, and public education to adopt personal and socially safe behaviors when facing natural disasters are recommended.

The Conflict between Regulatory Agencies over the 20,000-Fold Lowering of the Tolerable Daily Intake (TDI) for Bisphenol A (BPA) by the European Food Safety Authority (EFSA).

The European Food Safety Authority (EFSA) recommended lowering their estimated tolerable daily intake (TDI) for bisphenol A (BPA) 20,000-fold to . BPA is an extensively studied high production volume endocrine disrupting chemical (EDC) associated with a vast array of diseases. Prior risk assessments of BPA by EFSA as well as the US Food and Drug Administration (FDA) have relied on industry-funded studies conducted under good laboratory practice protocols (GLP) requiring guideline end points and detailed record keeping, while also claiming to examine (but rejecting) thousands of published findings by academic scientists. Guideline protocols initially formalized in the mid-twentieth century are still used by many regulatory agencies. EFSA used a 21st century approach in its reassessment of BPA and conducted a transparent, but time-limited, systematic review that included both guideline and academic research. The German Federal Institute for Risk Assessment (BfR) opposed EFSA's revision of the TDI for BPA. We identify the flaws in the assumptions that the German BfR, as well as the FDA, have used to justify maintaining the TDI for BPA at levels above what a vast amount of academic research shows to cause harm. We argue that regulatory agencies need to incorporate 21st century science into chemical hazard identifications using the CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity) nonguideline academic studies in a collaborative government-academic program model. We strongly endorse EFSA's revised TDI for BPA and support the European Commission's (EC) apparent acceptance of this updated BPA risk assessment. We discuss challenges to current chemical risk assessment assumptions about EDCs that need to be addressed by regulatory agencies to, in our opinion, become truly protective of public health. Addressing these challenges will hopefully result in BPA, and eventually other structurally similar bisphenols (called regrettable substitutions) for which there are known adverse effects, being eliminated from all food-related and many other uses in the EU and elsewhere. https://doi.org/10.1289/EHP13812.