Chemical Risk Assessment Research Articles

Radiological and Chemical Risk Assessment of Uranium in Underground Water around Mining Site, Saki, Nigeria

Uranium is present in most underground water sources and it properties as a heavy metal and radioactive elements can determine the safety of such water when consumed. Consumption of elevated uranium as a heavy metal and a radioactive element in drinking water can lead to non-cancer. The activity concentrations of Uranium in 20 well and 20 borehole water in Saki around mining site were measured using Sodium Iodide detector. The results obtained were used to calculate chemical and radiological risk over lifetime consumption by the population in the area. The mass concentration values in the borehole water samples ranged from 139.84 to 378.40 Bql-1 and that of well water samples ranged from 233.73 to 367.12 Bql-1. Both the mass concentration values of borehole water and well water samples exceeded the recommended safe limit of uranium in drinking water of agencies like WHO and USEPA. This shows a chemical risk associated to the consumption of the water samples. The excess cancer mortality risk of the samples investigated ranged from 2.02x10-4to 5.41 x10-4 for the borehole and 3. x10-4to 5.32 x 10-4 the well water while the excess cancer morbidity risk of uranium in the samples are 3.06 x 10-4 to 8.30 x 10-4 and 5.13 x10-4 to 8.15 x10-4 for borehole and well water respectively. Both its excess mortality and morbidity risk fell below the permissible value of 10-3. Therefore the water samples are radiologically safe for drinking and pose no radiological hazard to the consumers.

Predictive classification-based read-across for diverse functional vitiligo-linked chemical exposomes (ViCE): A new approach for the assessment of chemical safety for the vitiligo disease in humans.

We have explored a new approach using a similarity measure-based read-across derived hypothesis to address the precise risk assessment of vitiligo active chemicals. In this analysis, we initially developed a data set by combining vitiligo active compounds taken from the previous literature with non-vitiligo chemicals, which are non-skin sensitizers reported in another literature. Afterward, we performed the manual curation process to obtain a curated dataset. Furthermore, the optimum similarity measure was identified from a validation set using a pool of 47 descriptors from the analysis of the most discriminating features. The identified optimum similarity measure (i.e., Euclidean distance-based similarity along with seven close source compounds) has been utilized in the read-across derived similarity-based classification studies on close source congeners concerning target compounds. In this study, we identified the positive and negative contributing features toward the assessment of vitiligo potential as well, including the estimation of target chemicals with better accuracy. The applicability domain status of the reported compounds was also studied, and the outliers were identified. As there are no comparative studies in this regard to the best of our knowledge, we can further affirm that it is the first report on the in-silico identification of potential vitiligo-linked chemical exposomes (ViCE) based on the similarity measure of the read-across.

Chemical safety and risk assessment of bio-based and/or biodegradable polymers for food contact: A review

Chemical safety and risk assessment of bio-based and/or biodegradable polymers for food contact: A review

High-throughput screening to identify endocrine disruptors: Contribution of low-resolution tandem MS and high-resolution MS.

Considering the large diversity of chemicals present in the environment and the need to study their effects (alone or as mixtures), the development of high-throughput in vitro assays in line with the Replacement, Reduction, Refinement (3R) strategy is essential for chemical risk assessments. We developed a robust analytical workflow based on both low resolution tandem mass spectrometry (MS/MS) and high-resolution mass spectrometry (HRMS) to quantify 13 steroids in NCI-H295R cell culture medium, human plasma and serum. The workflow was validated by screening media from the NCI-H295R cell line exposed in dose-response experiments to 5 endocrine disruptors (EDs) such as bisphenol A, prochloraz, ketoconazole, atrazine and forskolin. Absolute quantifications of the 13 steroids performed on a triple quadrupole (QqQ) MS/MS demonstrated that the performances obtained were in line with OECD recommendations. HRMS (MS1-HRMS) provided measurements nearly as sensitive and as reproducible as those obtained using multiple reaction monitoring (MRM) and ELISA. A bioinformatics workflow, using HRMS, was implemented to detect and annotate disrupted metabolites. HRMS allowed to detect disruptions in pathways associated to fatty acids, purines and amino acids metabolisms after exposure to the EDs tested, in addition to that linked to steroidogenesis. We developed a robust MS1-HRMS workflow, from sample preparation to compound quantification or annotation, compatible with absolute steroid quantification, to screen NCI-H295R cell media exposed to potential EDs. Using only 200μL of medium, the method integrates MS/MS and HRMS analyses, 96-well plate solid-phase extraction for high throughput, and automated pre-annotation for cost efficiency. This optimized workflow identifies EDs in cell assays by detecting disruptions in steroidogenesis and other biological pathways.

Studying interaction effects on toxicokinetics in zebrafish combining experimental and modelling approaches.

Humans and wildlife are exposed to a complex mixture of anthropogenic chemicals of which only a few have been subjected to regulations. Chemical risk assessment is currently based on evaluating single chemicals, which is costly, time-consuming, and neglect toxicokinetic and toxicodynamic mixture effects. This study focused on interaction effects on the absorption, distribution, metabolism and excretion (ADME) processes of selected chemicals representing potential modulators of these processes. Adult female zebrafish (Danio rerio) were exposed to selected mixture of 11 chemicals and bioconcentration factors (BCFs) on tissue level were determined for 9 of them: bisphenol A (BPA), bisphenol AF (BPAF), bisphenol Z (BPZ), triclosan, tribromophenol, pentachlorophenol, heptafluorobutyric acid (PFBA), perfluorobutanesulfonic acid (PFBS), and perfluorooctanesulfonic acid (PFOS). Comparison of BCFs of bisphenols obtained from single chemical exposure experiments versus the current study revealed no statistically significant differences (p>0.05), implying no mixture effects on kinetics of bisphenols at investigated concentrations. The same conclusion was reached using two physiologically based kinetic (PBK) models, developed for individual bisphenols and per- and polyfluoroalkyl substances (PFAS), showing good model fit for BPA, BPZ, BPAF, and PFOS. To simulate exposure scenarios where kinetic interaction effects may occur through competitive protein binding in blood, a new PBK model was developed. Simulations where zebrafish were dosed with BPA and BPZ, individually, and combined with varying levels of PFOS, showed that competitive binding to serum proteins alter tissue levels of bisphenols when levels of PFOS exceeded 1μg/L. This indicates that chemicals acting in concert could perturb ADME but only at higher levels or in complex mixtures.

Development of the fish invitrome for animal-free environmental risk assessment of chemicals.

Given the need to reduce animal testing for environmental risk assessment, we aim to develop a fish invitrome, an alternative fish modular framework capable of predicting chemical toxicity in fish without the use of animals. The central module of the framework is the validated RTgill-W1 cell line assay that predicts fish acute toxicity of chemicals (Organization for Economic Cooperation and Development Test Guideline (OECD TG) 249). Expanding towards prediction of chronic toxicity, the fish invitrome includes two other well-advanced modules for chemical bioaccumulation/biotransformation and inhibition of fish growth. This framework is expected to continuously evolve with the development of modules that predict, for instance, neurotoxicity and reproductive toxicity. We envisage the fish invitrome framework to become part of the broader academic field of New Approach Methodologies (NAMs), where it will remain flexible and open to integration of new developments from research groups around the world. To accelerate the development and uptake of this framework, we strive for transdisciplinarity, integrating both natural and social sciences, along with broader stakeholder interactions. A stepwise socio-technical approach has been chosen, where mainstreaming the fish invitrome involves progressive adoption across various ecotoxicological contexts. The framework will be co-designed with stakeholders from academia, industry, and regulatory bodies. Rather than aiming for immediate regulatory acceptance, this approach aims to build trust and familiarity with fish cell line-based testing among stakeholders. By doing so, it encourages broader use of the framework in practical applications while gradually overcoming institutional, cultural, and technical barriers. Additionally, establishing a clear roadmap for mainstreaming the fish invitrome will help identify and address challenges to its uptake, ensuring a smoother transition to non-organismal testing methodologies.

Oxidative and nitrative DNA damage induced by industrial chemicals in relation to carcinogenesis.

Many chemicals have been used for industrial purposes, and some of them are carcinogenic to humans. However, their molecular mechanisms have not been well understood. Reactive oxygen species are generated from industrial chemicals and contribute to carcinogenesis. Particles and fibers are accumulated in respiratory systems by inhalation exposure and cause chronic inflammation. Under inflammatory conditions, reactive nitrogen species are generated from inflammatory and epithelial cells. These species cause oxidative and nitrative DNA damage, leading to carcinogenesis. We carried out experiments on DNA damage induced by various industrial chemicals and investigated their molecular mechanisms. We examined oxidative DNA damage induced by industrial chemicals using DNA fragments derived from human cancer-relevant genes by polyacrylamide gel electrophoresis. We also examined the formation of 8-nitroguanine (8-nitroG), a DNA lesion formed under inflammatory conditions, in lung tissues and cultured cells exposed to industrial chemicals by immunohistochemistry and immunocytochemistry. Benzene and o-toluidine metabolites caused oxidative damage to DNA fragments in the presence of Cu(II). H2O2 and Cu(I) were generated during oxidation of these chemicals and involved in DNA damage. 8-NitroG formation was observed in lung tissues of asbestos-exposed mice and humans. Carbon nanomaterials and indium compounds induced 8-nitroG formation in human lung epithelial cells via the release of damage-associated molecular patterns from exposed cells. Various industrial chemicals are considered to induce carcinogenesis by causing oxidative and nitrative DNA damage. These findings would provide an insight into risk assessment of industrial chemicals and prevention of carcinogenesis that occurs in workplaces.

It's about time: moving away from statistical analysis of ecotoxicity data.

Environmental risk assessment of chemicals (ERA) relies on single-species laboratory testing to establish the toxic properties of a compound. However, ERA is not concerned with toxicity under laboratory conditions: it needs to assess the impacts of the compound in the real world. Data-driven statistical analyses (e.g., hypothesis testing and interpolation) are the common approaches for analysing toxicity data, but such approaches are the wrong tool for the job at hand. ERA does not need a statistical description of the effects in the toxicity test (at the end of the standardised test duration), it needs to extrapolate from the laboratory test to longer and time-varying exposure. Such extrapolation requires mechanistic process models, providing a simplified representation of the mechanisms underlying toxicity. Any useful model for the toxicity process should explicitly consider both dose (e.g., exposure concentration) and time. In the history of effects analysis for ERA, the factor of time does not get as much attention as the dose, hence common use of the term 'dose-response analysis'. However, this is a historical oversight: time is a crucial factor for understanding toxicity and thereby essential for meaningful extrapolation from laboratory to field. Mechanistic models for ecotoxicity, considering both dose and time, have been around for quite some time and are classified as toxicokinetic-toxicodynamic (TKTD) models. TKTD models are starting to find their way into pesticide ERA in Europe, next to the classical statistical approaches. In this opinion paper, I argue that it is about time to leave statistical analysis of toxicity data behind us. Statistics remains important for ERA's effects assessment, but its role lies in the definition of appropriate 'error models', explaining the deviations between model output and observations, which is essential for parameter estimation, uncertainty quantification, and error propagation. The 'process model', essential for extrapolation, firmly belongs to TKTD modelling.

Multidisciplinary perspectives on cumulative impact assessment for vulnerable communities: expert elicitation using a Delphi method.

Prompted by a series of executive orders, the U.S. Environmental Protection Agency (USEPA) is promoting cumulative impact assessment (CIA) to integrate numerous factors that have the potential to impact community health, which include nonchemical stressors such as socioeconomic conditions, pre-existing health conditions, and many others that historically have not been addressed by USEPA's chemical risk assessment paradigm. Understanding the cumulative impact of all stressors on responses to environmental exposures requires multidisciplinary input from social scientists, economists, and others not traditionally involved in chemical risk assessments. To gather input from these disciplines, a group of 13 independent experts with perspectives on CIA as a social scientist, economist, public health expert, or decision analyst participated in a virtual workshop to obtain their perspectives regarding key aspects of CIA. The independent experts, who have decades of experience studying cumulative impacts in vulnerable population groups and environmental justice (EJ), responded anonymously to charge questions specific to their expertise and then were asked to review and comment on other's responses within and outside their discipline. The questions and responses were organized by the authors into general topics (e.g., screening tools and indexes, role of nonchemical stressors in cumulative impacts, uncertainties), and discussions across and within the four disciplines were summarized by the authors. The expert's opinions were used to frame a set of future research objectives to advance the development of CIA and improve its use in the EJ context. Specifically, the experts' recommendations addressed the need for regulatory impact analysis, the appropriate use of screening tool information and indexes, the role and measurement of nonchemical stressors, relevance of a risk modifier approach to CIA, inclusion of uncertainty and causality, metrics to assess effectiveness of interventions, and methods for community communication.

Enhancing ecological risk assessment of chemicals for terrestrial ecosystems through ecosystem services approach.

Enhancing ecological risk assessment of chemicals for terrestrial ecosystems through ecosystem services approach.

Advancing the quantitative understanding of adverse outcome pathways: current status, methodologies, and future directions.

An adverse outcome pathway (AOP) framework maps the sequence of events leading to adverse outcomes from chemical exposures, providing a mechanistic understanding often absent in traditional methods. The quantitative AOP (qAOP) advances AOP by integrating quantitative data and mathematical modeling, thereby providing a more precise comprehension of relationships between molecular initiating events, key events, and adverse outcomes. This review critically examines three primary methodologies: systems toxicology, regression modeling, and Bayesian network modeling, highlighting their strengths, limitations, and specific data requirements within toxicology. Through an analysis of current methodologies and challenges, this review emphasizes the integration of experimental and computational approaches to elucidate key event relationships and proposes strategies for overcoming limitations through standardized protocols and advanced computational tools. By outlining future research directions and the potential of qAOPs to transform chemical risk assessment, this review aims to contribute to the advancement of regulatory science and the protection of public health and the environment.

A web-based histology atlas for the freshwater sentinel species Daphnia magna.

Daphnia are keystone species of freshwater habitats used as model organisms in ecology and evolutionary biology. Their small size, wide geographic distribution, and sensitivity to chemicals make them useful as environmental sentinels in regulatory toxicology and chemical risk assessment. Biomolecular (-omic) assessments of responses to chemical toxicity, which reveal detailed molecular signatures, become more powerful when correlated with other phenotypic outcomes (such as behavioral, physiological, or histopathological) for comparative validation and regulatory relevance. However, the lack of histopathology or tissue phenotype characterization of this species presently limits our ability to assess cellular mechanisms of toxicity. Here, we address the central concept that interpreting aberrant tissue phenotypes requires a basic understanding of species normal microanatomy. We introduce the female and male DaphniaHistology Reference Atlas (DaHRA) for the baseline knowledge of Daphnia magna microanatomy. We also include developmental stages of female D. magna in the atlas. This interactive web-based resource of adult D. magna features overlaid vectorized demarcation of anatomical structures whose labels comply with an anatomical ontology created for this atlas. We demonstrate the potential utility of DaHRA for toxicological investigations by presenting aberrant phenotypes of acetaminophen-exposed D. magna. We envision DaHRA to facilitate the future integration of molecular and phenotypic data from the scientific community as we seek to understand how genes, chemicals, and environment interactions determine organismal phenotype.

Sunlight-mediated environmental risks of tinidazole in seawater: A neglected ocular toxicity of photolysis mixtures.

Tinidazole (TNZ), a common nitroimidazole antibiotic, is pervasive in aquatic ecosystems, posing potential threats to marine organisms. The environmental fate of TNZ, particularly under solar irradiation, and the associated secondary risks are not well characterized. Herein, the photochemical reactivity of TNZ and four other typical nitroimidazoles (i.e., metronidazole, ornidazole, dimetridazole, and secnidazole) were quantified for multiple photoreactive species. The photolysis products of these nitroimidazoles were identified under solar irradiation, from which the reaction pathways were tentatively proposed. Furthermore, the photo-induced toxicity evolution mechanisms of TNZ were investigated by comparing phenotypic, transcriptomic, and metabolomic changes in marine medaka embryos (Oryzias melastigma) after exposure to TNZ and its photo-irradiated mixtures. Our results indicated that the photo-irradiated TNZ enhanced visual toxicity to marine medaka embryos compared to the parent compound. The photolysis mixtures induced embryonic ocular malformation and significantly affected the expression of the associated genes with the initiation/termination of the phototransduction cascade, leading to metabolite changes related to visual impairment. This work reported the first comprehensive assessment of the photolysis-mediated environmental fate and secondary risks of TNZ in seawater. The findings highlighted the necessity of including complex photolysis mixtures under solar irradiation in future chemical risk assessments of marine environments.

Report of the First ONTOX Hackathon: Hack to Save Lives and Avoid Animal Suffering. The Use of Artificial Intelligence in Toxicology - A Potential Driver for Reducing/Replacing Laboratory Animals in the Future.

The first ONTOX Hackathon of the EU Horizon 2020-funded ONTOX project was held on 21-23 April 2024 in Utrecht, The Netherlands (https://ontox-project.eu/hackathon/). This participatory event aimed to collectively advance innovation for human safety through the use of Artificial Intelligence (AI), and hence significantly reduce reliance on animal-based testing. Expert scientists, industry leaders, young investigators, members of animal welfare organisations and academics alike, joined the hackathon. Eight teams were stimulated to find innovative solutions for challenging themes, that were selected based on previous discussions between stakeholders, namely: How to drive the use of AI in chemical risk assessment?; To predict or protect?; How can we secure human health and environmental protection at the same time?; and How can we facilitate the transition from animal tests to full implementation of human-relevant methods? The hackathon ended with a pitching contest, where the teams presented their solutions to a jury. The most promising solutions will be presented to regulatory authorities, industry, academia and non-governmental organisations at the next ONTOX Stakeholder Network meeting and taken up by the ONTOX project in order to tackle the above-mentioned challenges further. This report comprises two parts: The first part highlights some of the lessons learnt during the planning and execution of the hackathon; the second part presents the outcome of the ONTOX Hackathon, which resulted in several innovative and promising solutions based on New Approach Methodologies (NAMs), and outlines ONTOX's intended way forward.

In Vitro-to-In Vivo Extrapolation on Lung Toxicity Induced by Metal Oxide Nanoparticles via Data-Mining.

While in silico analyses are commonly employed for chemical risk assessments, predicting chronic lung toxicity induced by engineered nanoparticles (ENMs) in vivo still faces many challenges due to complex interactions at multiple nanobio interfaces. In this study, we developed a rigorous method to compile published evidence on the in vivo lung toxicity of metal oxide nanoparticles (MeONPs) and revealed previously overlooked in vitro-to-in vivo extrapolation (IVIVE) relationships. A comprehensive multidimensional data set containing 1102 in vivo data points, 75 pulmonary toxicological biomarkers, and 20 features (covering in vitro effects, physicochemical properties, and exposure conditions) was constructed. An IVIVE approach that related effects at the cellular level to in vivo lung toxicity in rodent model was established with prediction accuracy reaching 89 and 80% in training and test sets. Experimental validation was conducted by testing chronic lung fibrosis of 8 new MeONPs in 32 independent mice, with prediction accuracy reaching 88%. The IVIVE model indicated that the proinflammatory cytokine IL-1β in THP-1 cells could serve as an in vitro marker to predict lung toxicity. The IVIVE model showed great promise for minimizing unnecessary animal tests and understanding toxicological mechanisms.

Increasing the utility of epidemiologic studies as key evidence in chemical risk assessment.

The Society of Toxicology 2024 meeting assembled risk assessors, epidemiologists, and toxicologists to discuss the utility of integrating epidemiologic data into thederivation of reference values. Advantages of the use of epidemiologic evidence include (i) human relevance; (ii) increased likelihood that exposure levels are relevant to risk assessment; and (iii) incorporation of uncertainties attributed to co-exposures or other population-based considerations. The workshop panelists discussed the challenges of incorporating epidemiologic evidence due to uncertain exposure measurements, confounding, heterogeneity, and inherent study design limitations. Capturing uncertainty is a critical step. In summary, epidemiologic evidence can be a valuable tool for risk analysis. This workshop brief captures constructive considerations from practitioners in the field that can increase the utility of epidemiologic studies in chemical risk assessment and harmonize the approach for use in dose-response assessment that will ultimately reduce uncertainty related to chemical exposures.

Conceptual basis for the development of guidance for the use of biomarkers of effect in regulatory risk assessment of chemicals.

This Scientific Report was carried out in the context of the self-task mandate (M-2023-00097) of the EFSA's Scientific Committee on 'Guidance on the use of biomarkers of effect in regulatory risk assessment of chemicals'. In the first phase, the project on biomarkers of effect started with a feasibility study (EFSA-Q-2024-00128), with the intention to look closer at definitions and descriptions of biomarkers of effect, as well as to explore several concepts related to the context of application and other scientific principles to be further considered for its development. In addition, relevant activities, initiatives and knowledge in this area were collected and analysed within a complementary mapping study. The outcome of this phase aimed to create a structured basis for future guidance, to identify challenges and to recommend a way forward for its development. The recommendations refer especially to terminologies, the scope of the guidance and several scientific and technical aspects of the selection and interpretation of biomarkers of effect that need to be addressed in future guidance. Moreover, further recommendation refers to the collaborative process to be established with other regulatory organisations that should support the harmonisation and reduce divergencies in the application of methodologies across organisations or sectors.

Assessment of chemical risks and benefits connected with macroalgae consumption.

Reducing animal-based food production and consumption due to environmental issues and undergoing upcoming changes in food dietary patterns is pushing European society to search for new protein sources. Consuming macroalgae (seaweed) is one of the possible solutions, and it is an exciting alternative for both sustainability and consumers' health. The aim of this work, implemented under the EU-FORA fellowship programme, was to evaluate the current and projected consumption of macroalgae in terms of possible beneficial and detrimental effects on consumers. The risk-benefit assessment methodology was selected as a tool for this task, and a broad range of qualitative analyses of raw material composition (e.g. fatty acids, micro-, macroelements, heavy metals, biogenic amines). The current levels of macroalgae consumption in the EU are deficient; therefore, alternate scenarios using data from other countries and substitution scenarios are needed. Iodine turned out to be the most pivotal constituent - on the one hand; it is an element essential for life, often fortified in foods like milk or salt; on the other, its overdosing leads to serious thyroid complications. A very high variance in iodine levels between algal species was observed; therefore, it was suggested that this valuable knowledge is helpful in dietary recommendations.

Chemical and microbial risk assessment of wild edible plants and flowers.

The document focuses on the chemical and microbial risk assessment of wild edible plants (WEPs) and flowers, highlighting potential risks from heavy metals, pesticides and microorganisms. WEPs are valuable for human nutrition and gastronomy, offering essential compounds and health benefits. They are also seen as a sustainable food source. The study used various data sources and methodologies, including microbiological load and heavy metals' analysis, to assess the risks associated with WEPs. Consumption data were gathered to comprehensively assess exposure assessment. This document provides detailed recommendations for risk characterisation and management to mitigate potential health hazards associated with WEPs. The document was developed as part of the EU-FORA fellowship programme, which aims to enhance food risk assessment expertise through training to ensure preparedness for future risk analysis needs.

Global expansion of microphysiological systems (MPS) and Japan's initiatives: Innovation in pharmaceutical development and path to regulatory acceptance.

Microphysiological systems (MPS) are gaining global attention as potential game-changers in pharmaceutical development. Since 2013, MPS suppliers from university laboratories in the United States and Europe have competed to develop these devices. After the development phase, the focus shifted to the accumulation of applications using MPS for pharmaceutical companies and end users. In Japan, the AMED-MPS project was launched in 2017, and since then, several MPS devices have been marketed by project participated suppliers. Initially, while Japanese pharmaceutical companies adopted foreign products, they also exhibited interest in domestically produced MPS devices. The utilization of new approach methodologies, including MPS, is expanding in the field of chemical substances risk assessment, and the Organization for Economic Co-operation and Development test guidelines are expected to adopt in vitro evaluation systems as alternatives to animal testing. This publication reviews global and Japanese trends surrounding MPS and outlines activities aimed at the regulatory acceptance of MPS as evaluation systems for medical drugs and chemicals.