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Three decades ago, several articles on the subjectivity in chemical risk judgments (i.e., labeled "intuitive toxicology") measured the divide between the public and toxicologists with different backgrounds regarding the validity of predicting health effects based on in vivo studies. Similar divides with impacts on societal discourse and chemical risk assessment practices might exist concerning alternative toxicity testing methods (i.e., in vitro and in silico). However, studies to date have focused either on the public's views of in vivo or stem cell testing or on experts' views of in vivo testing and potential alternatives (i.e., toxicologists and medical students), which do not allow for a direct investigation of potential divides. To fill this knowledge gap, we conducted two online surveys, involving members of the German‐speaking public in Switzerland and European human health risk assessors, respectively. This article presents the results of these two surveys regarding the divide in the public's and risk assessors' perspectives on risk assessment based on in vivo, in vitro, and in silico testing. Particularly, the survey with the risk assessors highlights that, beyond scientific and regulatory barriers, alternatives to in vivo testing may encounter individual hurdles, such as higher uncertainty associated with them. Understanding and addressing these hurdles will be crucial to facilitate the integration of new approach methodologies into chemical risk assessment practices as well as a successful transition toward next‐generation risk assessment, bringing us closer to a fit‐for‐purpose and more efficient regulatory landscape. [ABSTRACT FROM AUTHOR]

Chemical risk assessment plays a pivotal role in safeguarding public health and environmental safety by evaluating the potential hazards and risks associated with chemical exposures. In recent years, the convergence of artificial intelligence (AI), machine learning (ML), and omics technologies has revolutionized the field of chemical risk assessment, offering new insights into toxicity mechanisms, predictive modeling, and risk management strategies. This perspective review explores the synergistic potential of AI/ML and omics in deciphering clastogen-induced genomic instability for carcinogenic risk prediction. We provide an overview of key findings, challenges, and opportunities in integrating AI/ML and omics technologies for chemical risk assessment, highlighting successful applications and case studies across diverse sectors. From predicting genotoxicity and mutagenicity to elucidating molecular pathways underlying carcinogenesis, integrative approaches offer a comprehensive framework for understanding chemical exposures and mitigating associated health risks. Future perspectives for advancing chemical risk assessment and cancer prevention through data integration, advanced machine learning techniques, translational research, and policy implementation are discussed. By implementing the predictive capabilities of AI/ML and omics technologies, researchers and policymakers can enhance public health protection, inform regulatory decisions, and promote sustainable development for a healthier future.

Chemical exposures from consumer products are a major concern in modern society. To address the need for accurate health risk estimation, particularly for chronic chemical hazards that may be less evident such as those contained in consumer products, this study reports on the development of the Population Attributable Risk Screening Tool (PAR Tool) Version 1.0. The PAR Tool was designed for the use of professional staff at the Consumer Product Safety Commission (CPSC), and assumes some prior knowledge of chemical risk assessment. This tool provides reasonable estimates of potential acute and chronic health impacts and mortality resulting from exposure to chemicals in consumer products. The PAR Tool provides the ability to integrate diverse data sources, including consumer product composition, user exposures, chemical toxicity data, consumer use patterns, and other pertinent factors to estimate the Population Attributable Risk associated with exposures to chemical components in consumer products. By generating PAR estimates on a chemical-by-chemical basis, the tool will assist the CPSC in assessing potential health risks and prioritizing efforts for risk reduction. Output from the tool provides an estimate of the number of specific health outcomes that may occur in the population of users of a specific consumer product. Interim steps produce exposure percentiles that are used along with dose–response data for a selected chemical and exposure pathway to calculate the proportion of the population at risk. The output is an estimated number of cases of an adverse health effect or mortality in a product user population potentially related to exposures to a single chemical in a product. These results are based primarily on user inputs, and the rationale for selection of these inputs is documented. All inputs and calculations within the PAR Tool are traceable and based on accepted practices and resources. The ongoing development of the PAR Tool aims to enhance its functionalities, incorporating features such as uncertainty analysis, increased automation, and user support. For example, future iterations may allow CPSC users to analyze multiple chemicals and health endpoints simultaneously and introduce sensitivity analysis capabilities for exposure and toxicity parameters. Ultimately, the PAR Tool represents a valuable advancement in comprehending product risks related to consumer product exposure, contributing to enhanced consumer protection and improved health outcomes. [ABSTRACT FROM AUTHOR]

The introduction and implementation of chemical risk assessment is difficult, especially at small and medium-sized manufacturing and construction companies. This study aimed to identify the factors that inhibit or facilitate such assessment. Twelve individuals in charge of risk assessment at one medium-sized client company and eight small and medium-sized contract companies and responsible for innovation in the manufacturing and construction industries were interviewed. The interview transcripts were analyzed via text mining using KH Corder ver. 3 and a co-occurrence network was used to identify the keywords' connections and each factor in consideration of the interviews. Six factors inhibited or facilitated risk assessment: (1) education on hazardous work in the workplace, (2) improvement suggestions and reduction measures from client and staff, (3) cooperation between employees and contractors in the workplace, (4) thoroughly explanation of SDS content for better understanding, (5) risk awareness based on accident examples, and (6) difficulties imagining the hazards of chemical substances. Factors (1), (2), (3), and (5) were positive, facilitating factors; (4) and (6) were negative, inhibiting factors. This study highlights that it is necessary to educate workers about chemical substance risks using safety data sheets and accident examples in chemical risk assessment. [ABSTRACT FROM AUTHOR]

Many jurisdictions require ecological risk assessments for terrestrial wildlife (i.e., terrestrial vertebrates) to assess potential adverse effects from exposure to anthropogenic chemicals. This occurs, for example, at contaminated sites and when new pesticides are proposed, and it occurs for chemicals that are in production and/or proposed for wide‐scale use. However, guidance to evaluate such risks has not changed markedly in decades, despite the availability of new scientific tools to do so. In 2019, the Wildlife Toxicology World Interest Group of the Society of Environmental Toxicology and Chemistry (SETAC) initiated a virtual workshop that included a special session coincident with the annual SETAC North America meeting and which focused on the prospect of improving risk assessments for wildlife and improving their use in implementing chemical regulations. Work groups continued the work and investigated the utility of integrating emerging science and novel methods for improving problem formulation (WG1), exposure (WG2), toxicology (WG3), and risk characterization (WG4). Here we provide a summary of that workshop and the follow‐up work, the regulations that drive risk assessment, and the key focus areas identified to advance the ability to predict risks of chemicals to wildlife. Integr Environ Assess Manag 2024;20:645–657. © 2024 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC). Key Points: Emerging methods and science that support problem formulation, conceptualizing the problem relative to regulatory statute and management goals in wildlife ecological risk assessment, provide opportunities to improve accuracy and make sound environmental decisions.Development and use of a priori, scenario‐based approaches, operationalization of animal‐friendly techniques for exposure assessment, and establishment and implementation of postregistration, remediation, and/or restoration monitoring guidance will improve exposure assessment in wildlife risk assessment.Effect assessments for wildlife would benefit from addressing critical knowledge gaps in the sensitivity of amphibians, reptiles, and bats in addition to birds and mammals, and from further development of regulatory guidance on holistic effect assessment at individual and population level in wildlife.Development and implementation of weight of evidence approaches may help address uncertainty in risk characterization, which may be supported by developing probabilistic approaches and systematic reviews and improved evidence‐integration techniques. [ABSTRACT FROM AUTHOR]

The further optimization of consumer safety through risk assessment of chemicals present in food will require adaptability and flexibility to utilize the accelerating developments in safety science and technology. New Approach Methodologies (NAMs) are gaining traction as a systematic approach to support informed decision making in chemical risk assessment. The vision is to be able to predict risk more accurately, rapidly and efficiently. The opportunity exists now to use these approaches which requires a strategy to translate the science into future regulatory implementation. Here we discuss new insights obtained from three recent workshops on how to translate the science into future regulatory implementation. To assist the UK in this endeavor, the Food Standards Agency (FSA) and the scientific advisory committee on chemical toxicity (COT) have been developing a roadmap. In addition, we discuss how these new insights fit into the bigger picture of the new chemical landscape for better consumer safety and the importance of international harmonization. [ABSTRACT FROM AUTHOR]

In the European Union, Occupational Safety and Health legislation generally refers to European Regulation (CE) n. 1272/2008 to define and classify carcinogens of concern for occupational risk assessment and exposure assessment. In Europe, the current reference is Directive (UE) 2022/431, regarding carcinogen, mutagen, and reprotoxic agent (CMR) exposure. However, at the worldwide level, different classification approaches are used to establish carcinogenicity of substances and it is often difficult to compare the classifications of carcinogenicity (CoCs) proposed by different international bodies. This study aims to investigate a list of carcinogens of concern in occupational settings based on the CLP (Classification Labelling Packaging) CoC and to create a tool that allows a rapid translation–comparison of some international CoCs with the reference one. CoCs proposed by various sources were consulted and used to apply a translation method, to favor an alignment of different CoCs according to a reference. Results outlined that, considering diverse sources, CoCs can result in different classifications of the same chemicals. Overall, this may have implications for the hazard assessment process, which is the base of risk assessment. The proposed tool is expected to help risk assessors in the occupational field when it is needed to have a comparison with different CoC systems.

In the European Union, Occupational Safety and Health legislation generally refers to European Regulation (CE) n. 1272/2008 to define and classify carcinogens of concern for occupational risk assessment and exposure assessment. In Europe, the current reference is Directive (UE) 2022/431, regarding carcinogen, mutagen, and reprotoxic agent (CMR) exposure. However, at the worldwide level, different classification approaches are used to establish carcinogenicity of substances and it is often difficult to compare the classifications of carcinogenicity (CoCs) proposed by different international bodies. This study aims to investigate a list of carcinogens of concern in occupational settings based on the CLP (Classification Labelling Packaging) CoC and to create a tool that allows a rapid translation–comparison of some international CoCs with the reference one. CoCs proposed by various sources were consulted and used to apply a translation method, to favor an alignment of different CoCs according to a reference. Results outlined that, considering diverse sources, CoCs can result in different classifications of the same chemicals. Overall, this may have implications for the hazard assessment process, which is the base of risk assessment. The proposed tool is expected to help risk assessors in the occupational field when it is needed to have a comparison with different CoC systems. [ABSTRACT FROM AUTHOR]

Soils are a precious resource consistently placed under several threats and urgently in need of protection within a regulatory framework at the European level. Soils are central to the provision of environmental services as well as human existence on earth. The need to protect soil has been identified by several recent European strategies and fortunately, a specific European regulation for soil protection is on the way—the European Soil Monitoring Law (formerly: Soil Health Law). However, efforts need to ensure that the upcoming Soil Monitoring Law closes gaps between existing regulations for chemicals and acknowledges current European strategies for environmental protection and sustainability. This brief communication started from a fruitful discussion among SETAC Global Soils Interest Group members on a recent public consultation on the newly proposed Soil Monitoring Law of the European Commission and highlights critical points focusing on the chemical pollution of soils. We emphasize urgent needs such as the essential definition of a "healthy state" of soils; the implementation of a suitable set of indicators and quality standards for the description of physical, chemical, and biological states of soils; the enforcement of the "polluter‐pays" principle; and the establishment of a Europe‐wide monitoring program. Results from monitoring need to be fed back into regulatory frameworks, including the regulation of chemicals. Guidance documents for the risk assessment of chemicals are outdated and need to be updated. Finally, actions need to be taken to foster healthy soils, stop biodiversity decline, and ensure the functioning of ecosystem services for future generations. Integr Environ Assess Manag 2024;20:316–321. © 2023 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC). Key Points: It must be ensured that the upcoming Soil Monitoring Law closes gaps between existing regulations for chemicals and acknowledges current European strategies for environmental protection and sustainability.Urgent needs must be addressed such as the essential definition of a "healthy state" of soils and the implementation, monitoring, and assessment of a suitable set of indicators and quality standards for the description of physical, chemical, and biological states of soils.Chemical substances with high priority for soils need to be identified and thresholds for those substances need to be defined, monitored, and assessed.We urgently need a holistic approach that bridges upstream regulations, including the "one substance—one assessment principle" on chemicals and the downstream upcoming soil regulation, which should also tackle mixtures of chemicals. [ABSTRACT FROM AUTHOR]

The chemical burden on the environment and human population is increasing. Consequently, regulatory risk assessment must keep pace to manage, reduce, and prevent adverse impacts on human and environmental health associated with hazardous chemicals. Surveillance of chemicals of known, emerging, or potential future concern, entering the environment-food-human continuum is needed to document the reality of risks posed by chemicals on ecosystem and human health from a one health perspective, feed into early warning systems and support public policies for exposure mitigation provisions and safe and sustainable by design strategies. The use of less-conventional sampling strategies and integration of full-scan, high-resolution mass spectrometry and effect-directed analysis in environmental and human monitoring programmes have the potential to enhance the screening and identification of a wider range of chemicals of known, emerging or potential future concern. Here, we outline the key needs and recommendations identified within the European Partnership for Assessment of Risks from Chemicals (PARC) project for leveraging these innovative methodologies to support the development of next-generation chemical risk assessment.

Abstract Current approaches for the prospective regulatory assessment of chemicals do not account sufficiently for elevated mixture risks. The Mixture Assessment Factor (MAF, better labeled a Mixture Allocation Factor) has been suggested for mixtures of industrial chemicals in the EU’s Chemicals Strategy for Sustainability, as a pragmatic tool to account for potential mixture risks already during the risk and safety assessment of individual chemicals. The MAF is to be applied in scenarios in which specific mixture risk assessments are not possible, due to a lack of data and/or the complexity of the relevant exposure scenarios. Several approaches and algorithms for calculating a MAF have been suggested in the literature. The MAFexact, which is a member of the larger MAFceiling class, is defined as the maximum fraction of the risk quotient of each chemical that is still acceptable to occur in a mixture, without the sum of risk quotients exceeding 1. This paper provides a comparative overview of the different MAF types discussed in the literature. It argues that the MAFexact is the most promising approach in the context of chemical registration and authorization under regulatory frameworks such as REACH because this approach ensures a protection level that is similar to the protection level used in the current safety assessment of individual chemicals under REACH. Other MAF approaches either disproportionally impact low-risk substances, without leading to any appreciable risk reduction, or hamper risk communication because they lead to fluctuating residual risks after the MAF application. The paper also presents a case study comparing the different MAF approaches and finally discusses the MAF concept in the wider context of chemical regulation.

Human health risk assessment is historically built upon animal testing, often following Organisation for Economic Co-operation and Development (OECD) test guidelines and exposure assessments. Using combinations of human relevant in vitro models, chemical analysis and computational (in silico) approaches bring advantages compared to animal studies. These include a greater focus on the human species and on molecular mechanisms and kinetics, identification of Adverse Outcome Pathways and downstream Key Events as well as the possibility of addressing susceptible populations and additional endpoints. Much of the advancement and progress made in the Next Generation Risk Assessment (NGRA) have been primarily focused on new approach methodologies (NAMs) and physiologically based kinetic (PBK) modelling without incorporating human biomonitoring (HBM). The integration of toxicokinetics (TK) and PBK modelling is an essential component of NGRA. PBK models are essential for describing in quantitative terms the TK processes with a focus on the effective dose at the expected target site. Furthermore, the need for PBK models is amplified by the increasing scientific and regulatory interest in aggregate and cumulative exposure as well as interactions of chemicals in mixtures. Since incorporating HBM data strengthens approaches and reduces uncertainties in risk assessment, here we elaborate on the integrated use of TK, PBK modelling and HBM in chemical risk assessment highlighting opportunities as well as challenges and limitations. Examples are provided where HBM and TK/PBK modelling can be used in both exposure assessment and hazard characterization shifting from external exposure and animal dose/response assays to animal-free, internal exposure-based NGRA.

This paper assesses the judgments of leading radiation geneticists and cancer risk assessment scientists from the mid-1950s to mid-1970s that background radiation has a significant effect on human genetic disease and cancer incidence. This assumption was adopted by the National Academy of Sciences (NAS) Biological Effects of Atomic Radiation (BEAR) I Genetics Panel for genetic diseases and subsequently applied to cancer risk assessment by other leading individuals/advisory groups (e.g., International Commission on Radiation Protection-ICRP). These recommendations assumed that a sizeable proportion of human mutations originated from background radiation due to cumulative exposure over prolonged reproductive periods and the linear nature of the dose-response. This paper shows that the assumption that background radiation is a significant cause of spontaneous mutation, genetic diseases, and cancer incidence is not supported by experimental and epidemiological findings, and discredits erroneous risk assessments that improperly influenced the recommendations of national and international advisory committees, risk assessment policies, and beliefs worldwide. [ABSTRACT FROM AUTHOR]

BackgroundThis study describes a method whose aim is to help companies assess the chemical occupational risks related to labeled products and industrial chemical emissions. The method is intended to be used by industrial hygienists at the scale of one company. Both inhalation and cutaneous exposure routes are taken into account.MethodsThe method relies on a control-banding scheme. A work situation is described by exposure parameters such as the process or the local exhaust ventilation and by the hazard of the product. Each possible value of the parameters is associated with a “band,” which is associated with an integer value. The multiplication of these values results in a score, which represents a priority for intervention. The higher the score, the more the situation warrants investigation for implementing prevention measures, such as chemical substitution and the addition of local exhaust ventilation. To simplify communication, the priority is associated with a colored priority band: red for “very high priority,” orange for “high priority,” and green for “moderate priority.” The priority bands are computed for all work situations performed in a company.ResultsAn example of the use of this method is described in a French façade insulation company.ConclusionA tool named Seirich was developed to implement this method and promote good practices for helping industrial hygienists in the prioritization of interventions for reducing chemical risk in France.

Noticing the increase in attention given by legislation and national practice to the assessment of occupational health and safety risks of a chemical nature, the article summarizes and explains the results of the research carried out from this perspective in a waste water treatment/purification station. By resorting to a well-established method, especially on the European level, the risks for the safety and health of workers (from the perspective of inhalation and skin risks), fire-explosion risks and environmental risks were evaluated. Based on the results obtained, a preliminary, but extremely necessary and useful, diagnosis of the magnitude of these specific risks was made and - on this basis - prevention/protection measures were proposed which, once implemented, can lead to the minimization of the risk levels associated with the identified hazards specific to the three analysed vectors. Beyond the concrete results of an applied nature, the growth of which the synthesis is systematized can serve as a good practice guide for numerous practitioners in the field of safety and health at work in Romania, in order to increase the efficiency of chemical risk assessments and - implicitly - the effectiveness of mitigation measures for this risk so widespread in industrial activities, processes and operations. [ABSTRACT FROM AUTHOR]

Exposure modeling plays a significant role for regulatory organizations, companies, and professionals involved in assessing and managing occupational health risks in workplaces. One context in which occupational exposure models are particularly relevant is the REACH Regulation in the European Union (Regulation (EC) No 1907/2006). This commentary describes the models for the occupational inhalation exposure assessment of chemicals within the REACH framework, their theoretical background, applications, and limitations, as well as the latest developments and priorities for model improvement. Summing up the debate, despite its relevance and importance in the context of REACH not being in question, occupational exposure modeling needs to be improved in many respects. There is a need to reach a wide consensus on several key issues (e.g., the theoretical background and the reliability of modeling tools), to consolidate and monitor model performance and regulatory acceptance, and to align practices and policies regarding exposure modeling. [ABSTRACT FROM AUTHOR]

Current approaches for the prospective regulatory assessment of chemicals do not account sufficiently for elevated mixture risks. The Mixture Assessment Factor (MAF, better labeled a Mixture Allocation Factor) has been suggested for mixtures of industrial chemicals in the EU's Chemicals Strategy for Sustainability, as a pragmatic tool to account for potential mixture risks already during the risk and safety assessment of individual chemicals. The MAF is to be applied in scenarios in which specific mixture risk assessments are not possible, due to a lack of data and/or the complexity of the relevant exposure scenarios. Several approaches and algorithms for calculating a MAF have been suggested in the literature. The MAFexact, which is a member of the larger MAFceiling class, is defined as the maximum fraction of the risk quotient of each chemical that is still acceptable to occur in a mixture, without the sum of risk quotients exceeding 1. This paper provides a comparative overview of the different MAF types discussed in the literature. It argues that the MAFexact is the most promising approach in the context of chemical registration and authorization under regulatory frameworks such as REACH because this approach ensures a protection level that is similar to the protection level used in the current safety assessment of individual chemicals under REACH. Other MAF approaches either disproportionally impact low-risk substances, without leading to any appreciable risk reduction, or hamper risk communication because they lead to fluctuating residual risks after the MAF application. The paper also presents a case study comparing the different MAF approaches and finally discusses the MAF concept in the wider context of chemical regulation. [ABSTRACT FROM AUTHOR]

One of the most challenging steps in chemical risk assessment is the dietary exposure due to the high percentage of left-censored data (LCD). Mycotoxins are the group of chemical contaminants known to show the highest percentage of LCD among chemical contaminants. These data are extremely important especially if they are used for the development of new legislations with permitted maximum limits. In this study, we address the importance of analytical techniques and current methods of dealing with LCD, with the goal of highlighting the effect of LCD on risk assessment, which could have a potential impact on future regulations of mycotoxins in foods and the economic implications of such regulations. Thirteen European Food Safety Authority (EFSA) Scientific Opinions and Reports on the risk of mycotoxins to humans were evaluated. The most used analytical method was based on Liquid Chromatography-Mass Spectrometry (LC-MS). Most of the occurrence data for mycotoxins in EFSA risk assessments over the last decade were condensed between 80 and 100% LCD. The typical statistical methods to handle LCD, the substitution method and cut-off values approach, frequently lead to the overestimation of the human risk which can ultimately lead to stricter law regulations with economic implication on the agricultural trades. Understanding the obstacles that analysts face and the type of data that risk assessors require will help to close the uncertainties and gaps that currently exist in exposure and risk assessment. Establishing limits of detections (LODs) and limits of quantification (LOQs) while having a clear data purpose can help reduce uncertainties in risk assessment and provide more meaningful exposure evaluations. [Display omitted] • Most of the occurrence data for mycotoxins in EFSA risk assessments were condensed between 80 and 100% LCD. • The most common statistical methods used to handle LCD may lead to overestimating risk assessment. • There is a need for harmonization between analysts and risk assessors in order to improve data quality. • LODs and LOQs should be set based on the purpose of the data. [ABSTRACT FROM AUTHOR]

The quality of chemical management depends more or less on practical procedures used to assess chemicals. This study quantitatively assessed the efficacy of a derivation procedure for calculating no‐effect concentrations for screening assessment of environmental hazards under the Chemical Substance Control Law in Japan. We first evaluated the derivation procedure by applying a series of test ecotoxicity datasets to the procedure and calculating the resulting misclassification rates of the hazardous class of chemicals. In this study, a chemical was deemed to have been misclassified if its classification differed from its classification based on the full dataset (chronic toxicity data for three trophic levels), which was defined as the correct assignment. We also calculated the effects of additional uncertainty factors to decrease the variance (i.e., to improve the consistency) of the misclassification rates among cases with different data availability in the derivation procedure. The results showed that the derivation procedure resulted in very high rates of misclassification when only particular sets of ecotoxicity data were available (e.g., only chronic toxicity data of algae were available). Our analyses also showed that the use of additional uncertainty factors improved the consistency of the misclassification rates within the derivation procedure. Our study presents a broadly applicable calculation framework for quantifying error rates in assessment procedures and serves as a case study for future development and reforms of chemical assessment processes and policies, while additional analyses using more extensive ecotoxicity data with various modes of actions are needed in the future. [ABSTRACT FROM AUTHOR]

Amongst omics technologies, metabolomics should have particular value in regulatory toxicology as the measurement of the molecular phenotype is the closest to traditional apical endpoints, whilst offering mechanistic insights into the biological perturbations. Despite this, the application of untargeted metabolomics for point-of-departure (POD) derivation via benchmark concentration (BMC) modelling is still a relatively unexplored area. In this study, a high-throughput workflow was applied to derive PODs associated with a chemical exposure by measuring the intracellular metabolome of the HepaRG cell line following treatment with one of four chemicals (aflatoxin B1, benzo[a]pyrene, cyclosporin A, or rotenone), each at seven concentrations (aflatoxin B1, benzo[a]pyrene, cyclosporin A: from 0.2048 μM to 50 μM; rotenone: from 0.04096 to 10 μM) and five sampling time points (2, 6, 12, 24 and 48 h). The study explored three approaches to derive PODs using benchmark concentration modelling applied to single features in the metabolomics datasets or annotated metabolites or lipids: (1) the 1st rank-ordered unannotated feature, (2) the 1st rank-ordered putatively annotated feature (using a recently developed HepaRG-specific library of polar metabolites and lipids), and (3) 25th rank-ordered feature, demonstrating that for three out of four chemical datasets all of these approaches led to relatively consistent BMC values, varying less than tenfold across the methods. In addition, using the 1st rank-ordered unannotated feature it was possible to investigate temporal trends in the datasets, which were shown to be chemical specific. Furthermore, a possible integration of metabolomics-driven POD derivation with the liver steatosis adverse outcome pathway (AOP) was demonstrated. The study highlights that advances in technologies enable application of in vitro metabolomics at scale; however, greater confidence in metabolite identification is required to ensure PODs are mechanistically anchored. [ABSTRACT FROM AUTHOR]

The concurrent control group is the most important reference for the interpretation of toxicity studies. However, pooled information on control animals from independent studies, i.e. , historical control data (HCD), is also used for the interpretation of results. Currently, an overview on actual HCD use in regulatory toxicology is lacking. Therefore, we evaluated the HCD use of the Joint FAO/WHO Meeting on Pesticide Residues from 2004 to 2021 and compared it with recommendations in regulatory guidelines and in the literature. We found that HCD was used routinely and exclusively to avoid potential false positive decisions regarding the treatment-relatedness of effects, mostly using the HCD range, i.e., the most extreme values, as a benchmark. HCD were not used to avoid potential false negative decisions or for quality control of the index study. The central assumption of the HCD use, namely that the HCD and control group of the index study follow the same underlying distribution because they are samples of the same data generation process, was not investigated, although numerous factors potentially contribute to effect variation between the different control groups pooled in the HCD. We recommend that the existing guidelines be revised to improve the robustness and transparency of toxicological assessments. • HCD are routinely used to evaluate regulatory pesticide toxicity studies. • The maximum value of HCD range is the main reference value used. • Main purpose of its use is to scrutinize potentially false positive findings. • HCD are not used to identify potentially false negative findings. • HCD are not used for quality control purposes. [ABSTRACT FROM AUTHOR]

The Safe and Sustainable by Design (SSbD) concept integrates safety and sustainability of chemicals and materials, throughout their entire life cycle and minimizes their environmental footprint. The European Commission (EC) in 2022 developed a framework to practically apply SSbD. This study investigated the knowledge on SSbD and the operationalization of such framework among the partners of the Partnership for the Assessment of Risks from Chemicals (PARC) program. Forty-one responses from 32 PARC Institutions were collected through a 21 item-online survey. Seventy-three % of the respondents had knowledge of SSbD, although only 49 % reported to have been directly engaged into SSbD projects. The EC-SSbD framework was applied by the 26 % of participants and in 47 % of cases it included a (re)design phase. With respect to the safety and sustainability, the assessment of the hazard, the human health and safety aspects in the production and processing, and the human health and environmental aspects in the final application of the chemical/material was addressed by the 74 %, 52 % and 65 % of the respondents. Lower percentages of positive responses regarded the environmental, social and economic sustainability assessment: 35 %, 20 % and 13 %, respectively. Overall, while the framework provided the necessary building blocks and opportunities for SSbD, concerted and iterative Research, Industry, and Academia efforts are necessary to develop/improve assessment methods, models and tools to make SSbD as an approach to chemical risk assessment and management to protect human health and the environment, and ensure to operate within the planetary boundaries. • "Safe and Sustainable by Design" (SSbD) regards the entire life cycle of chemicals. • The European Commission developed a framework to practically apply the SSbD. • The study investigates SSbD knowledge and the EC framework operationalization. • The hazard and safety aspects were more frequently addressed than sustainability. • Applying the SSbD approach can protect human health and the environment. [ABSTRACT FROM AUTHOR]

Advances in biosciences, chemistry, technology, and computer sciences have resulted in the unparalleled development of candidate New Approach Methodologies over the last few years. Many of these are potentially invaluable in the safety assessment of chemicals, but very few have been adopted for regulatory decision making. There is an immediate opportunity to use NAMs in safety assessment where the vision is to be able to predict risk more rapidly, accurately, and efficiently to further assure consumer safety. In order to achieve this, the UK Food Standards Agency (FSA) and the Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT) have developed a roadmap towards acceptance and integration of these new approach methodologies into safety and risk assessments for regulatory decision making. The roadmap provides a UK blueprint for the transition of NAMs from the research laboratory to their use in regulatory decision making. This will require close collaboration across disciplines (chemists, toxicologists, informaticians, risk assessors and others), and across chemical sectors, to develop, verify and utilise appropriate models. Linking up internationally, and harmonization will be fundamental. [Display omitted] • Advances in biosciences, chemistry, technology, and computer sciences have resulted in the unparalleled development of candidate New Approach Methodologies. • There is an immediate opportunity to use NAMs in safety assessment where the vision is to be able to predict risk more rapidly, accurately, and efficiently to further assure consumer safety. • In order to achieve this, the UK Food Standards Agency (FSA) and the Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT) have developed a roadmap towards acceptance and integration of these new approach methodologies into safety and risk assessments for regulatory decision making. • This will require close collaboration across disciplines (chemists, toxicologists, informaticians, risk assessors and others), and across chemical sectors, to develop, verify and utilise appropriate models. • We need to link up internationally, and harmonization will be fundamental. [ABSTRACT FROM AUTHOR]

In the EU, any material or article intended to come into contact with food, which is placed on the market, has to comply with the requirements of the Regulation (EC) No 1935/2004 – the so called 'framework regulation' for food contact materials (FCM). FCM covers a wide range of materials, including plastics, paper, metal and glass, which contain chemicals that might migrate into food. These chemicals must not migrate into the foodstuff in quantities that could endanger human health, bring about an unacceptable change in the composition of the food, or bring about a deterioration in the organoleptic characteristics thereof. Despite of this general regulation, the safety of new and specific materials that are not covered must be assessed case‐by‐case. In addition, national authorities can set their own regulations, and in this context, the BfR sets recommendations, which are not legal norms, but represent a standard for the production of materials not subjected to any specific legislation and are well accepted by other European Commission member states according to the mutual recognition principle. The BfR Unit 74 is responsible not only to deal with chemical risk assessment of FCM but also to evaluate application dossiers to include new substances in the positive list of FCM chemicals. In the proposed EU‐FORA programme, the fellow had the opportunity to gain experience in the evaluation of toxicological data from applicant dossiers and in the methodologies of migration tests performed in the laboratories. Moreover, the fellow also made a bibliographic review on scientific literature on the migration studies from starch‐based materials. [ABSTRACT FROM AUTHOR]

A knowledge graph (KG) is a technique for modeling entities and their interrelations. Knowledge graph embedding (KGE) translates these entities and relationships into a continuous vector space to facilitate dense and efficient representations. In the domain of chemistry, applying KG and KGE techniques integrates heterogeneous chemical information into a coherent and user-friendly framework, enhances the representation of chemical data features, and is beneficial for downstream tasks, such as chemical property prediction. This paper begins with a comprehensive review of classical and contemporary KGE methodologies, including distance-based models, semantic matching models, and neural network-based approaches. We then catalogue the primary databases employed in chemistry and biochemistry that furnish the KGs with essential chemical data. Subsequently, we explore the latest applications of KG and KGE in chemistry, focusing on risk assessment, property prediction, and drug discovery. Finally, we discuss the current challenges to KG and KGE techniques and provide a perspective on their potential future developments.

Three decades ago, several articles on the subjectivity in chemical risk judgments (i.e., labeled "intuitive toxicology") measured the divide between the public and toxicologists with different backgrounds regarding the validity of predicting health effects based on in vivo studies. Similar divides with impacts on societal discourse and chemical risk assessment practices might exist concerning alternative toxicity testing methods (i.e., in vitro and in silico). However, studies to date have focused either on the public's views of in vivo or stem cell testing or on experts' views of in vivo testing and potential alternatives (i.e., toxicologists and medical students), which do not allow for a direct investigation of potential divides. To fill this knowledge gap, we conducted two online surveys, involving members of the German-speaking public in Switzerland and European human health risk assessors, respectively. This article presents the results of these two surveys regarding the divide in the public's and risk assessors' perspectives on risk assessment based on in vivo, in vitro, and in silico testing. Particularly, the survey with the risk assessors highlights that, beyond scientific and regulatory barriers, alternatives to in vivo testing may encounter individual hurdles, such as higher uncertainty associated with them. Understanding and addressing these hurdles will be crucial to facilitate the integration of new approach methodologies into chemical risk assessment practices as well as a successful transition toward next-generation risk assessment, bringing us closer to a fit-for-purpose and more efficient regulatory landscape., (© 2024 The Authors. Risk Analysis published by Wiley Periodicals LLC on behalf of Society for Risk Analysis.)

Abstract In the EU, any material or article intended to come into contact with food, which is placed on the market, has to comply with the requirements of the Regulation (EC) No 1935/2004 – the so called ‘framework regulation’ for food contact materials (FCM). FCM covers a wide range of materials, including plastics, paper, metal and glass, which contain chemicals that might migrate into food. These chemicals must not migrate into the foodstuff in quantities that could endanger human health, bring about an unacceptable change in the composition of the food, or bring about a deterioration in the organoleptic characteristics thereof. Despite of this general regulation, the safety of new and specific materials that are not covered must be assessed case‐by‐case. In addition, national authorities can set their own regulations, and in this context, the BfR sets recommendations, which are not legal norms, but represent a standard for the production of materials not subjected to any specific legislation and are well accepted by other European Commission member states according to the mutual recognition principle. The BfR Unit 74 is responsible not only to deal with chemical risk assessment of FCM but also to evaluate application dossiers to include new substances in the positive list of FCM chemicals. In the proposed EU‐FORA programme, the fellow had the opportunity to gain experience in the evaluation of toxicological data from applicant dossiers and in the methodologies of migration tests performed in the laboratories. Moreover, the fellow also made a bibliographic review on scientific literature on the migration studies from starch‐based materials.

Physiologically-based kinetic (PBK) models are effective tools for designing toxicological studies and conducting extrapolations to inform hazard characterization in risk assessment by filling data gaps and defining safe levels of chemicals. In the present work, a generic avian PBK model for male and female birds was developed using PK-Sim and MoBi from the Open Systems Pharmacology Suite (OSPS). The PBK model includes an ovulation model (egg development) to predict concentrations of chemicals in eggs from dietary exposure. The model was parametrized for chicken (Gallus gallus), bobwhite quail (Colinus virginianus) and mallard duck (Anas platyrhynchos) and was tested with nine chemicals for which in vivo studies were available. Time-concentration profiles of chemicals reaching tissues and egg compartment were simulated and compared to in vivo data. The overall accuracy of the PBK model predictions across the analyzed chemicals was good. Model simulations were found to be in the range of 22–79% within a 3-fold and 41–89% were within 10- fold deviation of the in vivo observed data. However, for some compounds scarcity of in-vivo data and inconsistencies between published studies allowed only a limited goodness of fit evaluation. The generic avian PBK model was developed following a “best practice” workflow describing how to build a PBK model for novel species. The credibility and reproducibility of the avian PBK models were scored by evaluation according to the available guidance documents from WHO (2010), and OECD (2021), to increase applicability, confidence and acceptance of these in silico models in chemical risk assessment.

Food contact materials (FCMs) are materials and articles intended to be placed in direct or indirect contact with foodstuffs, or which can reasonably be expected to come into contact with food under normal or foreseeable conditions of use. Substances intentionally used to manufacture FCMs, as well as non‐intentionally added substances resulting from impurities, by‐products and/or degradation products, can migrate from FMCs into food and, consequently, are taken up by humans. To protect consumers' health, EU legislation requires that FCMs must be sufficiently inert to prevent substances from being transferred into the food in quantities that could endanger human health. At the German Federal Institute for Risk Assessment (BfR), Unit 74 'Safety of Food Contact Materials' deals with the risk assessment of FCMs and provides recommendations on the use of substances for the production of FCMs for which no specific European measures exist yet (e.g. silicone, rubber, paper and board). The BfR 'Recommendations on Food Contact Materials' are not legally binding; however, they represent the current state of the scientific and technical knowledge for the conditions under which these materials meet the requirements for consumer safety. As part of the EU‐FORA programme, the fellow was involved in the risk assessment tasks and projects undertaken by Unit 74, which include: (i) the scientific evaluation of analytical and toxicological data from dossiers for adding new substances to the database 'BfR Recommendations on Food Contact Materials'; (ii) the hazard assessment of cyclic volatile methylsiloxanes (cVMS) migrating from silicone FCMs into foodstuff; and (iii) in vitro metabolic stability study of cyclic methylsiloxanes in the presence of S9 fraction, performed in the BfR laboratories. Moreover, the EU‐FORA fellowship was a great opportunity for the fellow to build a strong network of food safety experts and to be part of an international community of risk assessment professionals. [ABSTRACT FROM AUTHOR]

Synthetic chemicals are widely used in food, agriculture, and medicine, making chemical safety assessments necessary for environmental exposure. In addition, the rapid determination of chemical drug efficacy and safety is a key step in therapeutic discoveries. Cell-based screening methods are non-invasive as compared with animal studies. Cellular phenotypic changes can also provide more sensitive indicators of chemical effects than conventional cell viability. Array-based cell sensors can be engineered to maximize sensitivity to changes in cell phenotypes, lowering the threshold for detecting cellular responses under external stimuli. Overall, array-based sensing can provide a robust strategy for both cell-based chemical risk assessments and therapeutics discovery. [ABSTRACT FROM AUTHOR]

Abstract Food contact materials (FCMs) are materials and articles intended to be placed in direct or indirect contact with foodstuffs, or which can reasonably be expected to come into contact with food under normal or foreseeable conditions of use. Substances intentionally used to manufacture FCMs, as well as non‐intentionally added substances resulting from impurities, by‐products and/or degradation products, can migrate from FMCs into food and, consequently, are taken up by humans. To protect consumers’ health, EU legislation requires that FCMs must be sufficiently inert to prevent substances from being transferred into the food in quantities that could endanger human health. At the German Federal Institute for Risk Assessment (BfR), Unit 74 ‘Safety of Food Contact Materials’ deals with the risk assessment of FCMs and provides recommendations on the use of substances for the production of FCMs for which no specific European measures exist yet (e.g. silicone, rubber, paper and board). The BfR ‘Recommendations on Food Contact Materials’ are not legally binding; however, they represent the current state of the scientific and technical knowledge for the conditions under which these materials meet the requirements for consumer safety. As part of the EU‐FORA programme, the fellow was involved in the risk assessment tasks and projects undertaken by Unit 74, which include: (i) the scientific evaluation of analytical and toxicological data from dossiers for adding new substances to the database ‘BfR Recommendations on Food Contact Materials’; (ii) the hazard assessment of cyclic volatile methylsiloxanes (cVMS) migrating from silicone FCMs into foodstuff; and (iii) in vitro metabolic stability study of cyclic methylsiloxanes in the presence of S9 fraction, performed in the BfR laboratories. Moreover, the EU‐FORA fellowship was a great opportunity for the fellow to build a strong network of food safety experts and to be part of an international community of risk assessment professionals.

Environmental chemicals, including endocrine disrupting chemicals (EDCs), pose a threat to human health. Actions are taken by scientists, assessors, regulators, and policymakers around the world to improve testing strategies for chemical substances, including pushing towards greater reliance on data from new approach methodologies to replace animal toxicity studies. This paradigm shift is envisioned to ultimately replace animal testing altogether for many purposes. As regards identification and regulation of EDCs, this poses certain challenges in that current guidelines—at least within the European regulatory framework—stipulate that adverse outcomes are to be demonstrated in an intact organism. The new testing paradigm is, of course, to find ways of dealing with this dilemma. However, another challenge still remains, even if the “intact organisms” definition changes or is replaced, namely the challenge of predicting apical adverse effects resulting from endocrine disruption. The adverse outcome pathway (AOP) framework provides a good platform for identifying and regulating EDCs based on both non-animal and animal (or human) data, but also here we are confronted with the same challenge: how to predict adverse effects in complex organism from simple test assays that are based on reductionist principles? In this article, the challenge of “emergent properties” in predictive toxicology is highlighted as a cautionary footnote because, although a future relying far less on animal toxicity testing is both desirable and sensible, the pace at which we transition to the new paradigm should ensure that human health, and the environment, is safeguarded from harmful chemical substances.

In France, laws require each company to draw up an inventory of the risks that may threaten employees' health in order to prioritize the preventive actions to be implemented. Focusing on chemical risk, databases on hazards or exposures are widely available but they lack information regarding chemical risks resulting from combining the hazards of chemicals with their conditions of use, thus generating exposures. Our objective is to build a matrix of French work situations associated with their chemical risk. Eighty-eight work situations were collected from reports written by professionals from the French public health insurance service. Each work situation is defined by descriptive parameters of the task, the exposure, and the hazard. According to an expert elicitation method (Delphi, n = 21 experts), each work situation was assessed and a chemical risk score defined, taking into account all the descriptive exposure and hazard parameters. Chemical risk scores were expressed as a range of values from 0 to 100, with the size of the range chosen by the experts themselves according to their uncertainty. The experts' assessments were merged to assign one risk score for each work situation, variability, and confidence. The results showed that 50% of the work situations had a risk score between 40 and 60. The average variability and confidence were around 15% and 82%, respectively. This work situation matrix constructed from French data can be used by occupational safety and health managers that have similar work situations in their company (Western European industrial sector). In this context, it may be useful to easily determine the level of risks for similar tasks and prioritize those that are most risky. Moreover, it could be used to compare and define the differences between a risk assessment performed by "expertise" and another defined by a software. [ABSTRACT FROM AUTHOR]

The long-term investment in new approach methodologies (NAMs) within the EU and other parts of the world is beginning to result in an emerging consensus of how to use information from in silico, in vitro and targeted in vivo sources to assess the safety of chemicals. However, this methodology is being adopted very slowly for regulatory purposes. Here, we have developed a framework incorporating in silico, in vitro and in vivo methods designed to meet the requirements of REACH in which both hazard and exposure can be assessed using a tiered approach. The outputs from each tier are classification categories, safe doses, and risk assessments, and progress through the tiers depends on the output from previous tiers. We have exemplified the use of the framework with three examples. The outputs were the same or more conservative than parallel assessments based on conventional studies. The framework allows a transparent and phased introduction of NAMs in chemical safety assessment and enables science-based safety decisions which provide the same level of public health protection using fewer animals, taking less time, and using less financial and expert resource. Furthermore, it would also allow new methods to be incorporated as they develop through continuous selective evolution rather than periodic revolution. [ABSTRACT FROM AUTHOR]

Plastic packaging materials (PPMs) protect food from contamination, maintain quality, and ease transportation and distribution. Additives included during the manufacturing and processing of PPMs improve flexibility, durability, barrier properties, and sometimes aid the processing itself. During processing, these additives, even the monomers used to produce the plastics, can produce side products or breakdown products as a result of degradation and various chemical reactions. These starting substances and reaction products include 2,2-bis(4-hydroxyphenyl)propane (bisphenol A), phthalates/phthalic acid esters, alkylphenols, and bis(2-ethylhexyl) adipate, which are considered endocrine-disrupting chemicals (EDCs) that may interfere with the human endocrine system and produce adverse reproductive, neurological, developmental, and immune effects. When in contact with food, EDCs can migrate into food if conditions are appropriate, thereby possibly jeopardizing food safety. Chemical risk assessment and regulatory control were developed to reduce human exposure to harmful migrated EDCs. This article gives an overview of the migration of EDCs from PPMs and control measures to reduce the risk of adverse impacts on human health. [ABSTRACT FROM AUTHOR]

Introduction: High-throughput screening (HTS) is emerging as an approach to support decision-making in chemical safety assessments. In parallel, in vitro metabolomics is a promising approach that can help accelerate the transition from animal models to high-throughput cell-based models in toxicity testing. Objective: In this study we establish and evaluate a high-throughput metabolomics workflow that is compatible with a 96-well HTS platform employing 50,000 hepatocytes of HepaRG per well. Methods: Low biomass cell samples were extracted for metabolomics analyses using a newly established semi-automated protocol, and the intracellular metabolites were analysed using a high-resolution spectral-stitching nanoelectrospray direct infusion mass spectrometry (nESI-DIMS) method that was modified for low sample biomass. Results: The method was assessed with respect to sensitivity and repeatability of the entire workflow from cell culturing and sampling to measurement of the metabolic phenotype, demonstrating sufficient sensitivity (> 3000 features in hepatocyte extracts) and intra- and inter-plate repeatability for polar nESI-DIMS assays (median relative standard deviation < 30%). The assays were employed for a proof-of-principle toxicological study with a model toxicant, cadmium chloride, revealing changes in the metabolome across five sampling times in the 48-h exposure period. To allow the option for lipidomics analyses, the solvent system was extended by establishing separate extraction methods for polar metabolites and lipids. Conclusions: Experimental, analytical and informatics workflows reported here met pre-defined criteria in terms of sensitivity, repeatability and ability to detect metabolome changes induced by a toxicant and are ready for application in metabolomics-driven toxicity testing to complement HTS assays. [ABSTRACT FROM AUTHOR]

Background and aims: One of the major health issues in developed countries is the workplace air pollution. Cement factories are one of the industries where many workers worked in them. Workers in this industry are exposure with many harmful factors, such as ergonomics factor, physical factors, and in particular various chemical agents, during their job. The most important factors that threaten the health of workers in the cement industry are dust and respirable particles of cement. Respirable particles of cement contains some elements such as arsenic, calcium, aluminum, cadmium, lead, cobalt, zinc, iron, and chromium. Recent studies concluded that the concentrations of arsenic, chromium, lead, and cadmium within the particles are higher than the other metals. Exposure to heavy metals within cement respirable particles can lead to some adverse health effects among exposed workers. Expanding of industries and emission of respirable particles containing heavy metals in the workplace ambient causes higher exposure for workers within various industries and therefore has become a major problem in these industries, including the cement industry. To arrive the health goal that is protection of the workers, exposure to chemicals and the dangers of exposure to these substances need to be scrutinized. Risk assessment is defined as the process of assessing the risks arising from risks in the workplace by taking control measures and deciding whether or not to accept them. Risk assessment is a basic action for evaluation of danger in the workplace and the first step for risk management. Quantitative health risk assessment for different chemical agents in industries is necessary to decide on control of risk and management measures to reduce risk and determine risk level of these substances. This process combines scientific information about the toxic properties of chemicals as well as the results of chemical measurements in the workplace can provide comprehensive information on the measure of risk and how best to deal with these potential risks. The aim of this study was to assess the risk level of workers occupational exposure to heavy metals (lead, chromium, cadmium) within cement respirable particles for exposed workers in a cement factory. Methods: This cross-sectional study was conducted in one of the cement industries during warm and cold air condition during 3 months (March 2016 to May 2016). In this study, the concentration of respirable particles within the breathing zone of 70 workers who were working at different production worksites of a cement factory (Packing worksite, Cement mill, Grill and Greater cooler, kiln, blending, Raw material storage and Mine and crushing) was evaluated. The standard method of 0600 recommended by the National Institute of Occupational Safety and Health (NIOSH) was use to evaluate time weighted average (TWA) of workerschr('39') exposure to respirable cement particles. Workerchr('39')s exposure was measured using a personal sampling pump (SKC, model 224-44MTX, UK) with a 2.5 L.min-1 flow rate, air was passing through an aluminum cyclone (SKC, UK) with a 37 mm 2 micrometer pore size poly vinyl chloride (PVC) filter (SKC, UK) bedding on a plastic cassette. The filters were placed in the desiccator for 24 hours before sampling time. To weigh the filters, a microbalance accurate to 6 decimal places (1 µg sensitivity Sartorius, Model ME5, Germany) was used. Critical orifice was used to keep the flow constant during sampling period. Workers personal sampling carried out continuously during a complete shift time. A blank filter was used for each batch of samples to eliminate sampling errors. To evaluate workerschr('39') exposure to heavy metals including lead, chromium and cadmium within the cement respirable particles, the standard method of ID121 recommended by the Occupational Safety and Health Administration (OSHA) was applied. Each filter was dissolved separately at 100 ° C in concentrated nitric acid and perchloric acid until its metals were dissolved in the solution phase. Then, the solution obtained with deionized water was diluted to the lowest level of detection (LOD). The US-made FAAS Model VARIAN 240FS atomic absorption device was used for analysis. Firstly the standard curve was obtained using standard solutions with different concentrations of meals. Samples were then transferred to the atomic absorption apparatus to determine the concentration of the metals within solution. By measuring the sample absorption rate and comparing with the calibration curve and using Bier Lambertchr('39')s law, the amount of metal elements in the unknown sample was obtained. Semi quantitative risk assessment of heavy metals among exposed workers was carried out using a standard method provided by the Institute of the occupational health and Safety in Singapore. Finally, the risk level for each of the heavy metals (lead, chromium and cadmium) in the respirable cement particles was obtained. The degree of exposure (ER) for all parts of the plant was obtained. Since the mean concentrations of these metal in the air of all sections of the cement plant were below the exposure limit recommended by the Iranian Occupational Health Technical Committee (OEL) and the (TLV) recommended by the ACGIH, the E/OEL ratio was lower than one. The hazard rating (HR) of the chemicals was determined using a standard table. Then, the exposure rating (ER) was calculated and determined using air monitoring results using E that is the weekly exposure in milligram per cubic meter or parts per million, F is the number of exposures per week, D is the average time of each exposure in hours, M is the exposure rate in parts per million or milligram per cubic meter, W is the average working hours per week (40 h). Finally, the risk rate (RR) was calculated using the chemical hazard risk (HR) and exposure rate (ER) values. Results: This study showed that the mean concentrations of cadmium, lead and chromium elements were measured as 2.41, 10.39, and 1.36 microgram per cubic meter respectively. The highest average exposure to lead metal in the respirable cement particles was 15.09 ± 4.45 µg / m3 and the lowest mean was 8.48 ± 3.11 µg / m3. The highest mean chromium concentration in cement respirable particles was 2.27 ± 1.15 µg / m3 and the lowest mean was 1.11 ± 0.48 µg / m3. The highest mean concentration of cadmium in the cement respirable particles was 2.78 ± 0.62 µg / m3 and the lowest mean was 2.17±0.37 µg / m3. Most workers in the various cement worksites were exposed to heavy metals less than the OEL suggested by the Iranian Occupational Health Technical Committee and the TLV recommended by the ACGIH. Due to the toxicity of lead metal, the grade 3 risk was considered for this metal. According to the E / OEL ratio, the exposure rate (ER) for all parts of the plant was 1, and since the concentration of this metal in all parts of the cement plant was less than the OEL designed by the Iranian Occupational Health Technical Committee and the TLV recommended by the ACGIH. the risk score for all parts of the plant was 1.73, and finally the risk score for lead in all parts of the plant was low. Due to the toxicity level of chromium metal, the hazard rate (HR) for this metal was considered 5. According to the E / OEL ratio, the exposure rate (ER) for all parts of the plant was obtained 1and since the concentration of this metal in all parts of the cement plant is less than the OEL designed by the Iranian Occupational Health Technical Committee and the TLV recommended by the ACGIH, the risk score was 2.23 in all parts of the plant. And the risk rating for chromium metal was low in all parts of the plant. Due to the toxicity level of cadmium metal the (HR) was considered 4 for this metal. Risk score was obtained in all parts of factory number 2 and as a result the risk rating for cadmium metal in all parts of factory was low. Since all workers in a section are exposed to cement respirable particles and therefore exposed to lead, chromium and cadmium metal elements in these particles are different. The risk of exposure to workers exposed to the highest concentrations of the studied metals in the three sections of kiln, blending, and Cement mill was calculated separately. The results showed that workers exposed to cadmium and lead metals were in the medium risk exposure kiln and blending worksites, respectively and workers exposed to chrome metal working in the cement mill were also at low risk. Conclusions: According to the present study, concentrations of chromium, cadmium and lead in the respirable cement particles were lower than the exposure limit set by the Occupational Health Technical Committee of Iran (OEL) and (TLV) recommended by the ACGIH. Exposure to lead, chromium and cadmium elements in cement respirable particles were at a low risk rates for all worksites of the plant However, some workers in the kiln silo and milling materials that exposed to higher particle concentrations containing cadmium and lead had an average risk rate. Therefore, engineering and management control strategies for heavy metal exposure in those sectors are recommended to reduce the risk and prevent injury to these workers.

Adverse outcome pathways (AOPs) include a sequence of events that connect a molecular-level initiating event with an adverse outcome at the cellular level for human health endpoints, or at the population level for ecological endpoints. When there is enough quantitative understanding of the relationships between key events in an AOP, a mathematical model may be developed to connect key events in a quantitative AOP (qAOP). Ideally, a qAOP will reduce the time and resources spent for chemical toxicity testing and risk assessment and enable the extrapolation of data collected at the molecular-level by in vitro assays, for example, to predict whether an adverse outcome may occur. Here, we review AOPs in the AOPWiki, an AOP repository, to determine best practices that would facilitate conversion from AOP to qAOP. Then, focusing on a particular case study, acetylcholinesterase inhibition leading to neurodegeneration, we describe specific methods and challenges. Examples of challenges include the availability and collection of quantitative data amenable to model development, the lack of studies that measure multiple key events, and model accessibility or transferability across platforms. We conclude with recommendations for improving key event and key event relationship descriptions in the AOPWiki that facilitate the transition of qualitative AOPs to qAOPs.

Chemical points of departure (PODs) for critical health effects are crucial for evaluating and managing human health risks and impacts from exposure. However, PODs are unavailable for most chemicals in commerce due to a lack of in vivo toxicity data. We therefore developed a two-stage machine learning (ML) framework to predict human-equivalent PODs for oral exposure to organic chemicals based on chemical structure. Utilizing ML-based predictions for structural/physical/chemical/toxicological properties from OPERA 2.9 as features (Stage 1), ML models using random forest regression were trained with human-equivalent PODs derived from in vivo data sets for general noncancer effects ( n = 1,791) and reproductive/developmental effects ( n = 2,228), with robust cross-validation for feature selection and estimating generalization errors (Stage 2). These two-stage models accurately predicted PODs for both effect categories with cross-validation-based root-mean-squared errors less than an order of magnitude. We then applied one or both models to 34,046 chemicals expected to be in the environment, revealing several thousand chemicals of moderate concern and several hundred chemicals of high concern for health effects at estimated median population exposure levels. Further application can expand by orders of magnitude the coverage of organic chemicals that can be evaluated for their human health risks and impacts.

• Extensive literature search of human kinetic parameters and enzyme activities for in vivo CES-1 and CES-2 probe substrates. • Hierarchical Bayesian meta-analysis to quantify inter-individual differences. • Human variability in CES ranges from 30-55% for CES1 and CES2 across probe substrates. Carboxylesterases (CES) are an important class of enzymes involved in the hydrolysis of a range of chemicals and show large inter-individual variability in vitro. An extensive literature search was performed to identify in vivo probe substrates for CES1 and CES2 together with their protein content and enzymatic activity. Human pharmacokinetic (PK) data on Cmax, clearance, and AUC were extracted from 89 publications and Bayesian meta-analysis was performed using a hierarchical model to derive CES-related variability distributions and related uncertainty factors (UF). The CES-related variability indicated that 97.5% of healthy adults are covered by the kinetic default UF (3.16), except for clopidogrel and dabigatran etexilate. Clopidogrel is metabolised for a small amount by the polymorphic CYP2C19, which can have an impact on the overall pharmacokinetics, while the variability seen for dabigatran etexilate might be due to differences in the absorption, since this can be influenced by food intake. The overall CES-related variability was moderate to high in vivo (

Urban areas in the Brazilian Amazon have grown at an unprecedented rate during the last years. About 90% of the wastewater produced by these urban areas are discharged untreated into Amazonian freshwater ecosystems, constituting a potential environmental pathway for pharmaceuticals and other chemicals consumed by modern societies (e.g. psychostimulants, personal-care products, hormones). The distribution of these chemicals into the Amazon River and their potential risks for freshwater biodiversity have not been evaluated so far. Here, we show the results of the largest chemical monitoring campaign conducted in the Amazon region. We assessed exposure patterns for 43 pharmaceuticals and other urban contaminants in 40 sampling sites distributed along the Amazon River, three major tributaries (Negro, Tapajós and Tocantins Rivers), and four large cities of the Brazilian Amazon (Manaus, Santarém, Macapá, Belém). We assessed risks for freshwater biodiversity using species sensitivity distributions and mixture toxicity approaches. We found that urban areas constitute important hot-spots for chemical contamination, with mixtures containing up to 40 different compounds and exposure concentrations reaching the world’s maxima for some of them. We show that chemical pollution can result in long-term effects for up to 50–80% of aquatic species next to urban areas. Moreover, we identified several ubiquitous compounds which can be used as tracers of anthropogenic pressure in the Amazon basin. We conclude that the chemical burden created by urbanization significantly contributes to a biodiversity loss in the region and should be further controlled.

Contextualization: A large number of chemical products are used in industry and technological sectors, generating health risks for those who are exposed, and may induce alterations depending on the concentration, manipulation, exposure, and susceptibility of the worker. These chemical agents can produce a variety of irritating allergic, toxic and even carcinogenic effects. Knowledge gap: Lack of knowledge of the danger, together with the operating conditions of chemical carcinogenic chemicals that occur in the exercise of daily activities in the industry may affect human health. Purpose: The objective of the study is to identify and classify the risk related to these chemical substances in a meat food processing plant in the department of Cauca (Colombia). Methodology: In the first stage of diagnosis, an information search was carried out in specialized databases; in the second stage it was developed from the information collected through the inventory of chemical substances in the plant, which are distributed at different storage sites where there is probability of exposure. To identify the chemical risk identification, a qualitative analysis is applied using the risk characterization criterion "international chemical control toolbox". Subsequently, a review of the regulations in force in Colombia related to the handling, applications and corresponding requirements of these substances was made, establishing necessary control and prevention measures for the chemical nature of these agents. Results and conclusions: Through the inventory, 407 substances present in the plant were identified, 91% of which are classified as dangerous chemicals and 3% corresponds to chemicals with a potential carcinogenic effect. The risk assessment took into account the combination of risk factors for health and potential exposure that determines the level of control desired, divided into four levels of approach (1, 2, 3, 4), with approach 4 being considered Special for being the most critical and most dangerous point. Finally, it was determined that the substances of greatest attention in the plant are: portland cement, COD solution B, Gasoline, Sikadur 32 Primer Comp B, Sikadur Panel Comp B, for being within the approach 4. [ABSTRACT FROM AUTHOR]

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. • Acceptability of in vivo testing was low, but highest for medicine and food. • In vitro tests elicited the highest expected ability to determine harmful effects. • Testing substances with alternatives to in vivo tests did not elicit public concern. • People apply affect and trust heuristics when confronted with different tests. [ABSTRACT FROM AUTHOR]

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