Hazard Assessment Of Chemicals Research Articles

A 2024 inventory of test methods relevant to thyroid hormone system disruption for human health and environmental regulatory hazard assessment

Thyroid hormone system disruption (THSD) is a growing concern in chemical hazard assessment due to its impact on human and environmental health and the scarce methods available for assessing the THSD potential of chemicals. In particular, the general lack of validated in silico and in vitro methods for assessing THS activity is of high concern. This manuscript provides an inventory of test methods relevant to THSD. Building on the Organisation for Economic Co-operation and Development (OECD) Guidance Document 150 and recent international developments, we highlight progress in in silico and in vitro methods, as well as in vivo assays. The provided inventory categorizes available methods according to the levels of the OECD Conceptual Framework, with an assessment of the validation status of each method. At Level 1, 12 in silico models that have been statistically validated and are directly related to THSD have been identified. At Level 2, 67 in vitro methods have been listed including those assessed in key initiatives such as the European Union Network of Laboratories for the Validation of Alternative Methods (EU-NETVAL) validation study to identify potential thyroid disruptors. At Levels 3-5, THSD-sensitive endpoints are being included in existing fish-based OECD Test Guidelines to complement amphibian assays. In total, the inventory counts 108 entries comprising established methods (e.g., OECD Test Guidelines) as well as citable methods that are under further development and in some cases are ready for validation or in the initial stages of validation. This work aims to support the ongoing development of strategies for regulatory hazard assessment, such as integrated approaches to testing and assessment (IATAs), for endocrine disruptors, addressing critical gaps in the current testing landscape for THSD in both human and environmental health contexts.

Computational modeling of air pollutants for aquatic risk: Prediction of ecological toxicity and exploring structural characteristics

Assessing the aquatic toxicity originating from air pollutants is essential in sustaining water resources and maintaining the ecosystem's safety. Quantitative structure-activity relationship (QSAR) models provide a computational tool for predicting pollutant toxicity, facilitating the identification/evaluation of the contaminants and identifying responsible structural fragments. One-vs-all (OvA) QSAR is a tailored approach to address multi-class QSAR problems. The study aims to determine five distinct levels of aquatic hazard categories for airborne pollutants using OvA-QSAR modeling containing 254 air contaminants. This QSAR analysis reveals the critical descriptors of air pollutants to target for molecular modification. Various factors, including the selection of relevant mechanistic descriptors, data quality, and outliers, determine the reliability of QSAR models. By employing feature selection and outlier identification approaches, the robustness and accuracy of our QSAR models were significantly increased, leading to more reliable predictions in chemical hazard assessment. The results revealed that models using the Random Forest algorithm performed the best based on the selected descriptors, with internal and external validation accuracy ranging from 71.90% to 97.53% and 76.47%–98.03%, respectively. This study indicated that the aquatic risk of air contaminants might be attributed predominantly to their sp3/sp2 carbon ratio, hydrogen-bond acceptor capability, hydrophilicity/lipophilicity, and van der Waals volumes. These structures can be critical in developing innovative strategies to mitigate or avoid the chemicals' harmful effects. Supporting air quality improvement, this study contributes to the rapid implementation of measures to protect aquatic ecosystems affected by air pollution.

OS03-04 Integration of New Approach Methodologies (NAMs) data into hazard assessment of chemicals: a case study on three Azole Fungicides- Tebuconazole, Propiconazole, and Cyproconazole regulated under K-BPR

OS03-04 Integration of New Approach Methodologies (NAMs) data into hazard assessment of chemicals: a case study on three Azole Fungicides- Tebuconazole, Propiconazole, and Cyproconazole regulated under K-BPR

CEC02-04 The virtual human approach to animal-free chemical hazard and risk assessment in developmental toxicology

CEC02-04 The virtual human approach to animal-free chemical hazard and risk assessment in developmental toxicology

AOP Report: An Upstream Network for Reduced Androgen Signaling Leading to Altered Gene Expression of Androgen Receptor-Responsive Genes in Target Tissues.

Adverse outcome pathways (AOPs) can aid with chemical risk assessment by providing plausible links between chemical activity at the molecular level and effect outcomes in intact organisms. Because AOPs can be used to infer causality between upstream and downstream events in toxicological pathways, the AOP framework can also facilitate increased uptake of alternative methods and new approach methodologies to help inform hazard identification. However, a prevailing challenge is the limited number of fully developed and endorsed AOPs, primarily due to the substantial amount of work required by AOP developers and reviewers. Consequently, a more pragmatic approach to AOP development has been proposed where smaller units of knowledge are developed and reviewed independent of full AOPs. In this context, we have developed an upstream network comprising key events (KEs) and KE relationships related to decreased androgen signaling, converging at a nodal KE that can branch out to numerous adverse outcomes (AOs) relevant to androgen-sensitive toxicological pathways. Androgen signaling represents an extensively studied pathway for endocrine disruption. It is linked to numerous disease outcomes and can be affected by many different endocrine-disrupting chemicals. Still, pathways related to disrupted androgen signaling remain underrepresented in the AOP-wiki, and endorsed AOPs are lacking. Given the pivotal role of androgen signaling in development and function across vertebrate taxa and life stages of both sexes, this upstream AOP network serves as a foundational element for developing numerous AOPs. By connecting the upstream network with various downstream AOs, encompassing different species, it can also facilitate cross-species extrapolations for hazard and risk assessment of chemicals. Environ Toxicol Chem 2024;43:2329-2337. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Chemical Risk Assessment for Small Businesses: Development of the Chemical Hazard Assessment and Prioritization Risk (CHAP-Risk) Tool

Chemical Risk Assessment for Small Businesses: Development of the Chemical Hazard Assessment and Prioritization Risk (CHAP-Risk) Tool

The OECD (Q)SAR Assessment Framework: A tool for increasing regulatory uptake of computational approaches

There is international interest in using alternatives to animal testing, including (Q)SARs, in chemical hazard assessments. The regulatory acceptance of alternative methods requires principles for considering the scientific rigour of methods and their results. The OECD (Q)SAR assessment Framework (QAF) was developed as guidance for regulators when considering (Q)SAR models and predictions in chemical evaluation. The QAF builds on existing principles for evaluating models and, learning from the longstanding regulatory experience in assessing (Q)SAR predictions, establishes new principles for evaluating predictions and results from multiple predictions. Assessment elements, identified for all principles lay out criteria for assessing the confidence and uncertainties in (Q)SAR models and predictions, while maintaining the flexibility necessary to adapt to different regulatory contexts and purposes. Using the QAF, assessors can consistently and transparently evaluate and decide on the validity of (Q)SARs, and model developers and users have clear requirements to meet. The publication of the QAF is expected to increase the regulatory use and acceptance of (Q)SARs and may become an example to buildsimilar prescriptive frameworks for other new approach methodologies (NAMs). This article provides an overview of the main scientific aspects of the QAF guidance and provides context for how this guidance can promote the use of alternative methods in chemical assessments.

Risk Assessment of Chemical (H3po3) Plant and Storage Tank Hazards

Risk Assessment of Chemical (H3po3) Plant and Storage Tank Hazards

Methodology for developing data-rich Key Event Relationships for Adverse Outcome Pathways exemplified by linking decreased androgen receptor activity with decreased anogenital distance

The Adverse Outcome Pathway (AOP) framework has gained widespread acceptance in toxicological disciplines as a tool for aiding chemical hazard assessment. Despite increased activity in AOP development, progress towards a high volume of fully endorsed AOPs has been slow, partly due to the challenging task of constructing complete AOPs according to the AOP Developer’s Handbook. To facilitate greater uptake of new knowledge units onto the open-source AOP-wiki platform, a pragmatic approach was recently proposed. This approach involves considering Key Event Relationships (KERs) for individual development through systematic approaches, as they represent essential units of knowledge from which causality can be inferred; from low complexity test data to adverse outcomes in intact organisms. However, more broadly adopted harmonized methodologies for KER development would be desirable. Using the AOP Developer’s Handbook as a guide, a KER linking 'decreased androgen receptor (AR) activity' with 'reduced anogenital distance (AGD)' was developed to demonstrate a methodology applicable for future developments of KERs requiring systematic literature retrieval approaches.

Addressing chemically-induced obesogenic metabolic disruption: selection of chemicals for in vitro human PPARα, PPARγ transactivation, and adipogenesis test methods.

Whilst western diet and sedentary lifestyles heavily contribute to the global obesity epidemic, it is likely that chemical exposure may also contribute. A substantial body of literature implicates a variety of suspected environmental chemicals in metabolic disruption and obesogenic mechanisms. Chemically induced obesogenic metabolic disruption is not yet considered in regulatory testing paradigms or regulations, but this is an internationally recognised human health regulatory development need. An early step in the development of relevant regulatory test methods is to derive appropriate minimum chemical selection lists for the target endpoint and its key mechanisms, such that the test method can be suitably optimised and validated. Independently collated and reviewed reference and proficiency chemicals relevant for the regulatory chemical universe that they are intended to serve, assist regulatory test method development and validation, particularly in relation to the OECD Test Guidelines Programme. To address obesogenic mechanisms and modes of action for chemical hazard assessment, key initiating mechanisms include molecular-level Peroxisome Proliferator-Activated Receptor (PPAR) α and γ agonism and the tissue/organ-level key event of perturbation of the adipogenesis process that may lead to excess white adipose tissue. Here we present a critical literature review, analysis and evaluation of chemicals suitable for the development, optimisation and validation of human PPARα and PPARγ agonism and human white adipose tissue adipogenesis test methods. The chemical lists have been derived with consideration of essential criteria needed for understanding the strengths and limitations of the test methods. With a weight of evidence approach, this has been combined with practical and applied aspects required for the integration and combination of relevant candidate test methods into test batteries, as part of an Integrated Approach to Testing and Assessment for metabolic disruption. The proposed proficiency and reference chemical list includes a long list of negatives and positives (20 chemicals for PPARα, 21 for PPARγ, and 11 for adipogenesis) from which a (pre-)validation proficiency chemicals list has been derived.

Chemical hazard assessment toward safer electrolytes for lithium-ion batteries.

Commercialization of rechargeable lithium-ion (Li-ion) batteries has revolutionized the design of portable electronic devices and is facilitating the current transition to electric vehicles. The technological specifications of Li-ion batteries continue to evolve through the introduction of various high-risk liquid electrolyte chemicals, yet critical evaluation of the physical, environmental, and human health hazards of these substances is lacking. Using the GreenScreen for Safer Chemicals approach, we conducted a chemical hazard assessment (CHA) of 103 electrolyte chemicals categorized into seven chemical groups: salts, carbonates, esters, ethers, sulfoxides-sulfites-sulfones, overcharge protection additives, and flame-retardant additives. To minimize data gaps, we focused on six toxicity and hazard data sources, including three empirical and three nonempirical predictive data sources. Furthermore, we investigated the structural similarities among selected electrolyte chemicals using the ChemMine tool and the simplified molecular input line entry systeminputs from PubChem to evaluate whether chemicals with similar structures exhibit similar toxicity. The results demonstrate that salts, overcharge protection additives, and flame-retardant additives contain the most toxic components in the electrolyte solutions. Furthermore, carbonates, esters, and ethers account for most flammability hazards in Li-ion batteries. This study supports the complementary use of quantitative structure-activity relationship modelsto minimize data gaps and inconsistencies in CHA. Integr Environ Assess Manag 2024;20:2231-2244. © 2024 The Author(s). Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Identification and Overcome the Harmful Situations Related to Chemical with the Help of Hazard Identification and Risk Assessment Using Failure Mode and Effective Analysis (FMEA) Method

Exposure of Chemical are a major occupational health and safety issue in chemical work place industry. Management of chemical hazards requires the combined efforts of occupational health and safety specialists, including generalist OHS professionals, occupational hygienists, and occupational health practitioners. This Research is about analysis of Hazards and their developed Control Measures in industrial chemicals, the manner in which their toxicity is assessed and the use of such assessments in regulatory decision-making. It begins with general points concerning toxicological data availability and hazard identification, then moves on to risk assessment and occupational exposure limits, and finally looks briefly at some standard specific toxicological issues, where the science is far from resolved after brief consideration of the historical context of chemical reactivity and toxicity issues, acute and chronic exposure, chemical hazard classification systems, and the identification, risk assessment, and control of chemical hazards

Advancing Toxicity Predictions: A Review on in Vitro to in Vivo Extrapolation in Next-Generation Risk Assessment.

As a key step in next-generation risk assessment (NGRA), in vitro to in vivo extrapolation (IVIVE) aims to mobilize a mechanism-based understanding of toxicology to translate bioactive chemical concentrations obtained from in vitro assays to corresponding exposures likely to induce bioactivity in vivo. This conversion can be achieved via physiologically-based toxicokinetic (PBTK) models and machine learning (ML) algorithms. The last 5 years have witnessed a period of rapid development in IVIVE, with the number of IVIVE-related publications increasing annually. This Review aims to (1) provide a comprehensive overview of the origin of IVIVE and initiatives undertaken by multiple national agencies to promote its development; (2) compile and sort out IVIVE-related publications and perform a clustering analysis of their high-frequency keywords to capture key research hotspots; (3) comprehensively review PBTK and ML model-based IVIVE studies published in the last 5 years to understand the research directions and methodology developments; and (4) propose future perspectives for IVIVE from two aspects: expanding the scope of application and integrating new technologies. The former includes focusing on metabolite toxicity, conducting IVIVE studies on susceptible populations, advancing ML-based quantitative IVIVE models, and extending research to ecological effects. The latter includes combining systems biology, multiomics, and adverse outcome networks with IVIVE, aiming at a more microscopic, mechanistic, and comprehensive toxicity prediction. This Review highlights the important value of IVIVE in NGRA, with the goal of providing confidence for its routine use in chemical prioritization, hazard assessment, and regulatory decision making.

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

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

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

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

Should Transformation Products Change the Way We Manage Chemicals?

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

Addressing Cardiovascular Toxicity Risk of Electronic Nicotine Delivery Systems in the Twenty-First Century: "What Are the Tools Needed for the Job?" and "Do We Have Them?"

Cigarette smoking is positively and robustly associated with cardiovascular disease (CVD), including hypertension, atherosclerosis, cardiac arrhythmias, stroke, thromboembolism, myocardial infarctions, and heart failure. However, after more than a decade of ENDS presence in the U.S. marketplace, uncertainty persists regarding the long-term health consequences of ENDS use for CVD. New approach methods (NAMs) in the field of toxicology are being developed to enhance rapid prediction of human health hazards. Recent technical advances can now consider impact of biological factors such as sex and race/ethnicity, permitting application of NAMs findings to health equity and environmental justice issues. This has been the case for hazard assessments of drugs and environmental chemicals in areas such as cardiovascular, respiratory, and developmental toxicity. Despite these advances, a shortage of widely accepted methodologies to predict the impact of ENDS use on human health slows the application of regulatory oversight and the protection of public health. Minimizing the time between the emergence of risk (e.g., ENDS use) and the administration of well-founded regulatory policy requires thoughtful consideration of the currently available sources of data, their applicability to the prediction of health outcomes, and whether these available data streams are enough to support an actionable decision. This challenge forms the basis of this white paper on how best to reveal potential toxicities of ENDS use in the human cardiovascular system-a primary target of conventional tobacco smoking. We identify current approaches used to evaluate the impacts of tobacco on cardiovascular health, in particular emerging techniques that replace, reduce, and refine slower and more costly animal models with NAMs platforms that can be applied to tobacco regulatory science. The limitations of these emerging platforms are addressed, and systems biology approaches to close the knowledge gap between traditional models and NAMs are proposed. It is hoped that these suggestions and their adoption within the greater scientific community will result in fresh data streams that will support and enhance the scientific evaluation and subsequent decision-making of tobacco regulatory agencies worldwide.

A problem formulation framework for the application of in silico toxicology methods in chemical risk assessment

The first step in the hazard or risk assessment of chemicals should be to formulate the problem through a systematic and iterative process aimed at identifying and defining factors critical to the assessment. However, no general agreement exists on what components an in silico toxicology problem formulation (PF) should include. The present work aims to develop a PF framework relevant to the application of in silico models for chemical toxicity prediction. We modified and applied a PF framework from the general risk assessment literature to peer reviewed papers describing PFs associated with in silico toxicology models. Important gaps between the general risk assessment literature and the analyzed PF literature associated with in silico toxicology methods were identified. While the former emphasizes the need for PFs to address higher-level conceptual questions, the latter does not. There is also little consistency in the latter regarding the PF components addressed, reinforcing the need for a PF framework that enable users of in silico toxicology models to answer the central conceptual questions aimed at defining components critical to the model application. Using the developed framework, we highlight potential areas of uncertainty manifestation in in silico toxicology PF in instances where particular components are missing or implicitly described. The framework represents the next step in standardizing in silico toxicology PF component. The framework can also be used to improve the understanding of how uncertainty is apparent in an in silico toxicology PF, thus facilitating ways to address uncertainty.

New approach methodologies (NAMs): identifying and overcoming hurdles to accelerated adoption.

New approach methodologies (NAMs) can deliver improved chemical safety assessment through the provision of more protective and/or relevant models that have a reduced reliance on animals. Despite the widely acknowledged benefits offered by NAMs, there continue to be barriers that prevent or limit their application for decision-making in chemical safety assessment. These include barriers related to real and perceived scientific, technical, legislative and economic issues, as well as cultural and societal obstacles that may relate to inertia, familiarity, and comfort with established methods, and perceptions around regulatory expectations and acceptance. This article focuses on chemical safety science, exposure, hazard, and risk assessment, and explores the nature of these barriers and how they can be overcome to drive the wider exploitation and acceptance of NAMs. Short-, mid- and longer-term goals are outlined that embrace the opportunities provided by NAMs to deliver improved protection of human health and environmental security as part of a new paradigm that incorporates exposure science and a culture that promotes the use of protective toxicological risk assessments.

In Silico Acute Aquatic Hazard Assessment and Prioritization Using a Grouped Target Site Model: A Case Study of Organic Substances Reported in Permian Basin Hydraulic Fracturing Operations.

Hydraulic fracturing (HF) is commonly used to enhance onshore recovery of oil and gas during production. This process involves the use of a variety of chemicals to support the physical extraction of oil and gas, maintain appropriate conditions downhole (e.g., redox conditions, pH), and limit microbial growth. The diversity of chemicals used in HF presents a significant challenge for risk assessment. The objective of the present study is to establish a transparent, reproducible procedure for estimating 5th percentile acute aquatic hazard concentrations (e.g., acute hazard concentration 5th percentiles [HC5s]) for these substances and validating against existing toxicity data. A simplified, grouped target site model (gTSM) was developed using a database (n = 1696) of diverse compounds with known mode of action (MoA) information. Statistical significance testing was employed to reduce model complexity by combining 11 discrete MoAs into three general hazard groups. The new model was trained and validated using an 80:20 allocation of the experimental database. The gTSM predicts toxicity using a combination of target site water partition coefficients and hazard group-based critical target site concentrations. Model performance was comparable to the original TSM using 40% fewer parameters. Model predictions were judged to be sufficiently reliable and the gTSM was further used to prioritize a subset of reported Permian Basin HF substances for risk evaluation. The gTSM was applied to predict hazard groups, species acute toxicity, and acute HC5s for 186 organic compounds (neutral and ionic). Toxicity predictions and acute HC5 estimates were validated against measured acute toxicity data compiled for HF substances. This case study supports the gTSM as an efficient, cost-effective computational tool for rapid aquatic hazard assessment of diverse organic chemicals. Environ Toxicol Chem 2024;43:1161-1172. © 2024 ExxonMobil Petroleum and Chemical BV. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.