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. Author manuscript; available in PMC: 2026 Nov 1.
Published in final edited form as: Regul Toxicol Pharmacol. 2026 Jul 4;171:106173. doi: 10.1016/j.yrtph.2026.106173

Cardiovascular Toxicity as a Globally Harmonized System Hazard Trait: The Evidence and the Path Forward

Ivan Rusyn 1, Christina Tsitsimpikou 2, Martyn T Smith 3, Nicole C Kleinstreuer 4, Jean-Pierre Valentin 5
PMCID: PMC13634185  NIHMSID: NIHMS2213125  PMID: 42400995

Abstract

Cardiovascular disease is the leading cause of death globally, yet cardiovascular risks from environmental pollutants remain underrecognized and are not considered a stand-alone hazard trait. Growing evidence shows that industrial and environmental chemicals, including air pollutants, metals, solvents, pesticides and other chemicals, may be hazardous to human cardiovascular health. Indeed, many human and animal studies demonstrate that environmental chemicals can act through oxidative stress, inflammation, and endothelial dysfunction, potentially causing hypertension, arrhythmias, and other cardiovascular conditions. This commentary reviews the state of the science for recognizing chemical cardiotoxicity under the Organisation for Economic Co-operation and Development (OECD) Working Party on Hazard Assessment project [ENV/CBC/HA(2024)13]. New approach methodologies (NAMs) provide organizing principles for assembling mechanism-based data on cardiovascular toxicants and evaluating potential cardiovascular hazards. Case studies demonstrate how broad toxicity testing programs like ToxCast and cardiovascular-specific NAMs can assess hazards and risks for environmental chemical cardiovascular toxicity. The pharmaceutical industry’s approach and strategies for de-risking cardiovascular toxicities serve as an example of regulatory applicability of a tiered context-of-use-focused approach consisting of in silico, in vitro and targeted animal and human studies. Overall, a framework for integrating clinical, animal, and NAM data to support decisions regarding potential chemical cardiovascular toxicity is proposed.

Graphical Abstract

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The Case for Cardiotoxicity as a Regulatory Hazard Trait

Although exposure to chemicals is estimated to contribute significantly to the global burden of cardiovascular disease, environmental and industrial exposures have not yet been systematically assessed or regulated for their impact on cardiovascular health. Existing frameworks, such as the United Nations Globally Harmonized System (GHS) do not specifically consider cardiovascular toxicity. This omission creates not only the scientific imperatives but also the regulatory, ethical, and public health gaps.

The rationale for recognizing cardiotoxicity as a regulatory hazard trait begins with the staggering statistics: cardiovascular diseases kill millions of people annually worldwide (estimated to be 20.5 million in 2025), and the burden continues to rise amidst demographic shifts, environmental challenges, and changing lifestyles with projected 35.6 million cardiovascular deaths in 2050 (Chong et al., 2025). While genetic predisposition and lifestyle factors are well documented, less characterized – but increasingly evident – are environmental and industrial contributors, such as air pollution, heavy metals, and various chemical agents (Blaustein et al., 2024). The spectrum of cardiovascular outcomes linked to various exposures is multi-dimensional and may manifest years or decades after initial insult or be a result of cumulative factors (Conrad et al., 2025).

Despite scientific advances in understanding cardiovascular disease (Blaustein et al., 2024), there is a profound regulatory gap – cardiotoxicity is not recognized as a distinct hazard class for non-pharmaceuticals. For example, even though the cardiovascular hazards of nanomaterials have been demonstrated (Huang et al., 2024), the regulators cannot formally request data because no official criteria for this type of hazard exists. In absence of defined regulatory starting points, criteria, and guidelines for cardiovascular hazard assessment, both industry and regulators are unable to act decisively to protect public health. Such regulatory impasse stands in sharp contrast to pharmaceutical regulation, where cardiac risk is a core concern throughout drug development and post-marketing surveillance (Mladěnka et al., 2018). Introducing cardiotoxicity into environmental and industrial regulations would enable tailored safety protocols, guidance for exposure limits, labeling, and protective measures for workers and consumers (Georgiadis et al., 2022).

Mechanistic Evidence for Cardiovascular Toxicity: Building the Biological Story

Mechanistic evidence underpins both hazard identification and regulatory action. Traditional constructs such as Mode of Action (MOA) (Sonich-Mullin et al., 2001), Adverse Outcome Pathways (AOPs) (Villeneuve et al., 2014), and Key Characteristics (KCs) (Smith et al., 2016) are commonly used to organize and explain the evidence that supports hazard identification. MOA is a chemical-specific construct that is required in many hazard evaluations, such as U.S. Environmental Protection Agency (EPA) guidelines for carcinogens (U.S. Environmental Protection Agency, 2005). It maps the sequence of biological events leading to toxicity, but is sometimes overly simplistic, potentially biased, or insufficiently comprehensive, especially for multifaceted diseases like cardiotoxicity. AOPs map molecular initiating events to observable outcomes at the individual or population level. They are increasingly used for development and interpretation of data from new approach methodologies (NAMs), offering structured insight into disease pathways and mechanisms. The AOP Wiki (Jaylet et al., 2024) has become a major repository, though only a fraction of pathways is independently reviewed or endorsed due to time-consuming review procedures. KCs define objective properties of chemicals known to cause specific toxicities. They have been developed to organize mechanistic data through systematic reviews, reduce bias, and inform both hazard and risk evaluations. KCs for cardiovascular toxicants were recently formalized by an interdisciplinary expert group and published (Lind et al., 2021), cataloguing both mechanistic actions and relevant bioassays/biomarkers for cardiac and vascular toxicity.

With respect to cardiovascular toxicity of both drugs and other chemicals, there is no well-defined MoA because it is not a regulatory-recognized hazard trait; likewise, currently available cardiovascular-relevant AOPs are limited to a small number of mechanisms and pathways. To the contrary, potential cardiac failure modes and their testing using in vivo, in vitro and in silico models are well defined for applications in drug development where they aim to facilitate drug development and improve study designs (Pierson et al., 2024), but are not captured under GSH Specific Target Organ Toxicity categories. Accordingly, the KC approach for cardiovascular toxicants builds on the failure modes framework and is designed to be applicable for both drugs and chemicals. The 12 KCs proposed by a group of experts in 2021 (Lind et al., 2021) defined cardiac, vascular and common key characteristics of known cardiovascular toxicants (Table 1). The publication also catalogued relevant bioassays, from patch clamp recordings to electrocardiograms (ECG), in vitro/ex vivo models for contractility, biomarkers like troponin for acute cardiac injury, and imaging such as echocardiography for functional outcomes. It also presented a number of case studies showing that cardiovascular toxicants can act via one or many KCs. Interestingly, while many pharmaceuticals are known to act via these KCs (antiarrhythmic drugs, antimalarials, antibiotics), the understanding of environmental chemicals’ role in cardiotoxicity is low among clinical practitioners and regulators alike. Environmental agents often act through multiple pathways: particulate matter, lead, arsenic, and bisphenol A interact with cardiac and vascular systems, autonomic regulation, lipid metabolism, immune cells, and platelets, thus producing multifactorial toxicity.

Table 1.

Key Characteristics of Cardiovascular Toxicants as a construct that provides a mechanistic framework to support hazard identification and organization of evidence for cardiovascular toxicity. From (Lind et al., 2021).

Cardiac Impairs regulation of cardiac excitability
Impairs cardiac contractility and relaxation
Induces cardiomyocyte injury and death
Induces proliferation of valve stroma
Vascular Impacts endothelial and vascular function
Alters hemostasis
Causes dyslipidemia
Cardiac & Vascular Impairs mitochondrial function
Modifies autonomic nervous system activity
Induces oxidative stress
Causes inflammation
Alters hormone signaling
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It is also important to note the latency in cardiotoxicity – exposures decades earlier may result in events much later, meaning that regulators must account for this temporal spectrum and integrate evidence of early, subtle changes which may precede irreversible, life-threatening outcomes. In addition, because few environmental chemicals are recognized as cardiotoxic, most reference compounds remain pharmaceuticals. This aligns with previous regulatory approaches in endocrine disruption, where pharmaceutical data was used as a comparator for environmental substances by utilizing structural and mechanistic parallels (Judson et al., 2019). Cross-referencing mechanisms, such as ion channel modulation or mitochondrial impairment, sets a foundation for method validation and regulatory benchmarks.

Using Existing Human, Animal and NAMs Data to Prioritize Chemicals Potentially Hazardous to the Cardiovascular System

Robust assessment of the potential role of environmental chemicals in cardiovascular disease and chemical prioritization for further testing requires a multi-faceted approach, integrating epidemiological evidence, traditional animal data, and especially NAMs. Environmental epidemiology already provides strong evidence linking environmental exposures, particularly ambient air pollution (PM2.5), heavy metals (lead, arsenic, cadmium), and chemical contaminants, to increased cardiovascular disease morbidity and mortality (Munzel et al., 2025); however, causality and risk characterization requires additional studies and dose-response analyses. Traditional animal studies are not designed to evaluate cardiovascular effects, and accidental findings of cardiomyopathy or histopathological changes in the heart or blood vessels can be hardly considered as acceptable hazard identification. Despite major differences in human and rodent cardiovascular physiology (Berridge et al., 2013), assessment of cardiac function (ultrasound and electrocardiography) can be performed in live rodents (Popp et al., 2025). Still, these studies are not routine and require specialized equipment. Fortuitously, a plethora of NAMs approaches to cardiovascular toxicity studies is available (Burnett et al., 2021b), and these methods are already widely used in drug safety studies (Pierson et al., 2024; Yang et al., 2022).

NAMs encompass human-based in vitro models, high-throughput screening assays, and computational tools designed to capture subtle, early, and human-relevant cardiovascular effects that animal models often miss (Krishna et al., 2021). NAMs are critical for navigating complex molecular and cellular mechanisms, such as oxidative stress, apoptosis, ion-channel modulation, and contractile function, where animal physiology may differ significantly from humans; this is especially true for endpoints like QT prolongation and arrhythmic risk (Pang et al., 2019). The FDA, NIH, and EPA have invested heavily in platforms such as Tox21 and ToxCast (Thomas et al., 2018), offering thousands of high-throughput assays for molecular targets, including those pertinent for cardiovascular hazard such as voltage-gated ion channels, mitochondrial targets, and oxidative stress pathways. The NIH’s Integrated Chemical Environment (NICE) is a pivotal resource (Bell et al., 2020), aggregating curated in vitro data, exposure predictions, and computational workflows. These resources enable in silico screening of vast numbers of chemicals, mapping their bioactivity profiles against cardiovascular-relevant targets and linking those profiles to predicted human exposures. Notably, screening data can be cross-referenced with functional endpoints from human-derived cardiomyocytes to assess risk of arrhythmias, contractility disturbances, or failure modes.

A compelling case study included nearly 800 chemicals that were analyzed using ToxCast data and exposure modeling to derive bioactivity-exposure ratios as indicators of potential human health risk (Krishna et al., 2026). For 96% of chemicals with in vitro and animal data, the in vitro data were more sensitive and provided a more protective point of departure for risk assessment. While predicted human exposure was below concentrations required for cardiovascular bioactivity for the majority of chemicals, a subset of ~100 chemicals demonstrated exposures at or above bioactive concentrations, highlighting them for further assessment and potentially regulatory action.

Human Cardiac and Endothelial Cell Models for Hazard Assessment and Risk Characterization

The rapid evolution of human-relevant cell models for cardiovascular toxicity testing is based on the pioneering work of Drs. Gurdon and Yamanaka (Colman, 2013) who demonstrated that human adult cells can be reprogrammed into induced pluripotent stem cells (iPSC) and then into functional cardiomyocytes. The gold standard for in vitro cardiovascular toxicity testing now includes human iPSC-derived cardiomyocytes (Ando et al., 2017; Burnett et al., 2021b; Yang et al., 2022) and endothelial cells (Fonoudi and Burridge, 2020; Iwata et al., 2017). For example, iPSC-Derived Cardiomyocytes faithfully recapitulate human cardiac electrophysiology, contractile function, and response to drugs/toxicants. They are especially powerful for detecting risks such as QT prolongation and arrhythmias, endpoints that are poorly modeled in traditional animal models (Blanchette et al., 2019; Strauss et al., 2021; Wallis et al., 2018). In addition, population-based iPSC panels allow screening across diverse genetic backgrounds, enhancing detection of susceptibility and variability (Blanchette et al., 2020; Blinova et al., 2019; Burnett et al., 2019). In these cell-based studies, functional endpoints such as calcium flux, contractility, and ECG-like recordings are matched with molecular markers, e.g., troponin, C-reactive protein, and oxidative stress markers, and with gene expression or other -omics readouts. Likewise, various human endothelial cell models, either primary cells derived from the umbilical vein, iPSC-derived or endothelial progenitor cells, can be used to assess cytotoxicity, angiogenesis, and vascular network performance. Standardized protocols and commercial availability ensure reproducibility and reliability of both cardiomyocytes and endothelial cells. Furthermore, various microphysiological systems for both vascular system (Zhang et al., 2020) and the heart (Vuorenpaa et al., 2023) have been developed to enable mechanistic testing and disease modeling. Still, none of these models or endpoints are included in current regulatory testing methods, highlighting a need for updates and expansion of protocols to capture cardiovascular hazards.

Both cardiomyocytes and endothelial cells have been used to test potential cardiovascular hazards of not only drugs (Blinova et al., 2017; Yang et al., 2022), but also environmental chemicals (Burnett et al., 2021a; Burnett et al., 2019) and mixtures (Hsieh et al., 2021; Tsai et al., 2024). Many of these studies have considered both hazard and risk characterization by comparing in vitro effects to human exposures and showed that human epidemiology data on cardiovascular disease associations with exposures to lead, pesticides, polycyclic aromatic compounds and flame retardants can be corroborated by NAMs data conducted in concentration-response (Blanchette et al., 2022; Burnett et al., 2021a; Ford et al., 2024).

Learning from the Pharmaceutical Sector: From Systematic and Mechanistic Frameworks to Tiered Fit-for-Purpose Testing to Ensure Human safety

Pharmaceuticals are screened for cardiovascular toxicity liabilities, a core concern throughout drug discovery, preclinical, clinical development, and post-marketing, and the industry has spent decades building structured, mechanistic frameworks for cardiovascular safety assessment (Pierson et al., 2024). Thus, the pharmaceutical sector’s experience is highly instructive for environmental chemical regulation of cardiovascular hazards. Scientists and regulators have worked collaboratively to integrate knowledge of molecular targets (ion channels, mitochondrial function), cellular effects (arrhythmias, contractility), and tissue/organ responses. AOP thinking and key characteristics frameworks are intrinsic to safety pharmacology and regulatory decision-making, largely dependent on the “failure modes” (Berridge et al., 2024; Pierson et al., 2024). Based on mapping key events to assays, pharmaceutical industry employs a staged approach, starting with early hazard identification via in silico and in vitro assays, progressing selectively into in vivo models or clinical studies based on preliminary findings. This structured approach to risk management maximizes resource efficiency and ensures high-risk compounds are prioritized for deeper study. Early hazard identification is done using high-throughput in silico/in vitro screens to eliminate unsuitable candidates early. Integrated risk assessment is based on comprehensive evaluation of nonclinical, preclinical, and clinical data. Risk mitigation involves adjusting dosages, monitoring biomarkers, labeling, or even withdrawing drugs if risks become unacceptable.

Indeed, the pharmaceutical sector has been a pioneer in adopting iPSC-derived cardiomyocytes and other human cell models, enabling functional screening for liabilities like QT prolongation (Strauss et al., 2021). Regulatory agencies, such as Food and Drug Administration (FDA) and European Medicines Agency (EMA) accept NAMs in regulatory dossiers, lending validation and credibility (Tieghi et al., 2025; Yang et al., 2022). The rigorous requirements in pharmaceutical applications for assay robustness, reproducibility, and context-specific analytics (Blinova et al., 2018), even in absence of formal model qualification, should serve as a guide for environmental toxicology. Indeed, industry-regulatory agencies interactions are critical because decisions are often made based on incomplete validation of new methods, underscoring the need for flexible yet transparent criteria.

Even though there are many differences between drug development and environmental chemical safety evaluations (Table 2), the shared language and scientific logic of mechanistic toxicology and translational science can overcome endpoint differences, exposures and decision contexts. For example, knowledge of dose-response relationships, exposure modeling, and population variability shared from the pharmaceutical sector is directly transferable to environmental hazard and risk assessment. Pharmaceutical industry also has advanced biomarker development for cardiovascular endpoints, linking them to regulatory dialogue and decision-making. Environmental regulators can leverage these biomarkers, functional, blood-borne, or imaging-based, to identify subclinical or latent toxicity and inform regulatory policy. Collaboration between pharmaceutical and environmental sectors is increasing and the value of learning from pharma’s post-marketing surveillance, integration of biomarkers, and cumulative risk assessment is clear. In addition, the One Substance One Assessment principle that is being promoted by the European Union Commission is another reason to harmonize assessment of chemicals regardless of their intended use. Weight of evidence frameworks, harmonized databases, and shared reference lists can streamline cross-sectoral hazard identification. Still, unlike drug regulators, the environmental sector deals with thousands of chemicals, often with limited cardiovascular liability data. Chronic low-dose exposure, bioaccumulation, and compound mixtures also pose unique challenges.

Table 2.

Comparison of Cardiovascular Safety Assessment in Pharmaceuticals and Environmental Chemicals.

Pharma CV Safety Environmental CV Considerations
Defined exposure Variable real-world exposure
Defined test substance (drug/metabolites) Cocktail of substances
Margin-based decisions Hazard-based decisions
Lifecycle monitoring Population surveillance
Mechanistic anchoring (on/off-target) Emerging AOP frameworks (organ systems)
Defined route of exposure (e.g., oral, parenteral) Multiple routes of exposure (e.g. inhalation, cutaneous…)
Management or mitigation by dosing discontinuation or withdrawal No approaches are readily available
ICH S1 integrated WoE model REACH WoE & AOP framework
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Comparison of key features distinguishing cardiovascular safety assessment approaches in pharmaceutical development versus environmental chemical risk evaluation. Differences include exposure conditions, decision frameworks, mechanistic anchoring, and regulatory paradigms. AOP: Adverse Outcome Pathway; ICH: International Council for Harmonisation; OECD: Organisation for Economic Co-operation and Development; REACH: Registration, Evaluation, Authorisation and Restriction of Chemicals; WoE: Weight of Evidence

Path Forward to Defining Criteria for Cardiovascular Toxicity as a Hazard Trait

The need to recognize cardiovascular toxicity as a Globally Harmonized System hazard trait is clear: integrating cardiovascular endpoints into regulatory frameworks is overdue and will catalyze scientific, technological, and policy advances, ultimately protecting human health more comprehensively. The roadmap to accomplish this is through established initiatives, such as the OECD Working Party on Hazard Assessment project [ENV/CBC/HA(2024)13], aiming to define criteria, frameworks, and methods for recognizing cardiotoxicity as a regulatory hazard class. A multinational effort has been organized into several working teams to set definitions, develop and evaluate testing models, integrate peer-reviewed evidence, and harmonize NAMs for a global approach. While the key themes and directions for protecting populations from adverse cardiovascular outcomes due to environmental chemical exposures are clear: building scientific consensus, integrating mechanistic evidence, harnessing the power of NAMs, learning from pharmaceutical safety science, and charting a collaborative path forward for regulation, operationalizing them into action still needs scientific community effort in the following areas.

  1. Defining Hazard Classes and Criteria: Cardiotoxicity should be considered for inclusion as GHS Specific Target Organ Toxicity category for both single and repeated exposures. A formal recognition of cardiotoxicity as a relevant regulatory hazard trait is fundamental, this will allow inclusion of cardiovascular endpoints as Standard Information Requirements. Criteria must be developed to cover acute, sub-acute, and chronic cardiovascular effects, encompassing cardiac and vascular endpoints, acute and latent outcomes, direct and indirect mechanisms.

  2. Integration of Evidence Streams: Regulatory assessment for cardiotoxicity should integrate already available animal and human data, epidemiology, with mechanistic and other NAMs data and computational predictions. Weight of evidence frameworks must be developed for systematic collation and evaluation of such data.

  3. Development of Dedicated Testing Guidelines: Existing testing programs, both animal and NAMs-based, capture cardiovascular effects by accident, not design. New OECD-endorsed testing strategies, focused specifically on cardiac and vascular endpoints, are needed. This approach may evolve into a tiered testing strategy that creates a “funnel” for prioritizing chemicals. Tier One could include molecular screening (in silico, quantitative structure–activity relationship (QSAR), high-throughput screening (HTS) assays) to identify chemicals with structures or targets suggestive of cardiotoxicity. Tier Two may include human cell-based in vitro assays (e.g., iPSC cardiomyocytes, endothelial cells) to confirm functional hazard potential and explore the degree of potential population variability in toxic effects. Tier Three will involve effective dose extrapolation to juxtapose bioactive concentrations with predicted exposures for risk characterization. Finally, Tier Four will need integration with other evidence (e.g. animal, clinical, epidemiological) to further contextualize hazard and inform regulatory action. While traditional animal studies provide histopathological and structural information (heart weight, tissue morphology), they often lack functional specificity. NAMs fill this gap, offering sensitivity to early molecular and cellular alterations, greater relevance for human risk assessment, and capability for modeling chronic and latent effects.

  4. Promotion and Qualification of Human-Relevant Methods: NAMs (iPSC cardiomyocytes, endothelial cells, high-throughput assays, computational models) should be prioritized, qualified, and integrated into regulatory testing. Acceptance hinges on clear definition of the contexts of use, benchmarking, and alignment with risk assessment goals. This goal requires defining a bridging list of reference pharmaceuticals and environmental chemicals with known mechanisms. Structural and mechanistic similarities should guide cross-sector analysis and regulatory criteria.

  5. International Collaboration and Leadership: Projects such as OECD WPHA, ICH guidelines, NIH Common Fund, and the California EPA’s efforts to define key characteristics for major hazard traits are examples of the international initiatives that exemplify multidisciplinary, cross-sector collaboration. Sustainable funding, agile leadership, and global consensus are needed to drive method development and regulatory harmonization, similar to the efforts in cardiotoxicity working groups for pharmaceuticals under Health and Environmental Sciences Institute (HESI) (Pierson et al., 2024). Both regulatory agencies and industry should encourage cross-sector collaboration; sharing methods, tools, and human-relevant models will drive innovation and accelerate progress.

  6. Regulatory Acceptance Through Toolbox Development: Acceptance of cardiotoxicity as a hazard trait requires flexibility, openness, and adaptation of evolving scientific knowledge into living regulatory documents. The workshop mapped a vision: define traits, gather evidence, publish criteria, and pursue regulatory acceptance. Many case studies and informative examples of using NAMs and other data to demonstrate cardiovascular hazard of non-pharmaceuticals notwithstanding, a key challenge is context of use: regulatory agencies have historically relied on animal data, especially histopathology, for hazard classification. Transitioning to NAMs requires robust validation, benchmarking, and harmonization of methods, often using pharmaceuticals as reference compounds. Nevertheless, evidence from NAMs increasingly demonstrates superior sensitivity to establish both protective exposure limits and relevance for human outcomes (Paul Friedman et al., 2025), and regulatory acceptance is growing. The cosmetics industry, for example, already deploys NAMs for hazard assessment, combining assay batteries and computational modeling for robust biological coverage and risk estimation (Carmichael et al., 2022; Dent et al., 2021). Environmental chemical regulation could emulate this “toolbox” approach, extending it to prioritize and filter chemicals efficiently.

Conclusions

Cardiotoxicity is an under-recognized hazard associated with environmental and industrial chemicals. The present commentary unifies scientific, regulatory, and industry perspectives, building a comprehensive narrative for systematic recognition, assessment, and regulation of cardiovascular toxicity. It is acknowledged that the field of regulatory science is well positioned to recognize cardiotoxicity among Specific Organ Toxicity categories and develop targeted safety protocols, protect public health, and catalyze innovation through leveraging mechanistic evidence, key characteristics, advanced human-relevant cell models, and lessons from the pharmaceutical sector. Ultimately, it is impossible to effectively manage cardiovascular risk without first identifying the underlying hazard. Relying on population-level disease data is a reactive strategy that constitutes crisis management rather than proactive protection. Formally recognizing cardiotoxicity as a hazard trait under the GHS, and harnessing human-based science to assess it, provides the ‘missing link’ in the safety infrastructure. This approach ensures that chemicals are evaluated for their ability to harm the heart, the very foundation of human health and longevity.

Highlights.

  • Cardiovascular toxicity is a major but under-recognized hazard of environmental chemicals.

  • Current regulatory frameworks do not include cardiotoxicity as a distinct hazard class.

  • Mechanistic evidence, including key characteristics and NAMs, supports hazard identification.

  • Human-relevant in vitro models improve detection of cardiovascular risks.

  • Integration of multi-source data can enable regulatory recognition and decision-making.

Acknowledgements

The present commentary summarizes the presentations and discussion during 2026 Society of Toxicology Workshop on Cardiovascular Toxicity (65th Annual Meeting of Society of Toxicology, 22-25 March 2026, San Diego, USA). The authors thank Annie Delaunois (UCB) and Anissa Alami (UCB) who contributed to the development of Dr. Valentin SOT presentation and Dr. Shagun Krishna for her contribution to Dr. Kleinstreuer’s presentation.

Funding

This work was supported in part by the NIH Intramural Research Program and grants from NIH (P42 ES027704 and P42 ES004705). All views represented in this manuscript are those of the authors and do not represent official government policy.

List of Abbreviations

AOP

Adverse Outcome Pathway

EPA

Environmental Protection Agency

ECG

Electrocardiogram

EMA

European Medicines Agency

FDA

Food and Drug Administration

GHS

United Nations Globally Harmonized System

HESI

Health and Environmental Sciences Institute

HTS

High-Throughput Screening

ICH

International Council for Harmonisation

iPSC

Induced Pluripotent Stem Cells

IVIVE

In Vitro to In Vivo Extrapolation

KC(s)

Key Characteristic(s)

MOA

Mode of Action

NAM(s)

New Approach Methodology(ies)

NIH

National Institutes of Health

OECD

Organisation for Economic Co-operation and Development

PBPK

Physiologically Based Pharmacokinetic

PM2.5

Particulate Matter ≤2.5 μm

QSAR

Quantitative Structure–Activity Relationship

REACH

Registration, Evaluation, Authorisation and Restriction of Chemicals

WoE

Weight of Evidence

Footnotes

Declaration of generative AI and AI-assisted technologies in the manuscript preparation process

During the preparation of this work the author(s) used Otter.ai in order to transcribe the audio recording of the Workshop on Cardiovascular Toxicity (65th Annual Meeting of Society of Toxicology, 22–25 March 2026, San Diego, USA) in which all of them were speakers and discussants. After using this tool/service, the author(s) used the transcript to prepare this commentary and take full responsibility for the content of the published article.

Conflict of Interest

The views and opinions expressed in this article are those of the sole authors, and do not necessarily represent the views, opinions and/or policies of their current employers or scientific societies or organizations they are members of. The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The authors are employees of pharmaceutical companies and may have access to share and/or stock options.

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the content of this paper. Jean-Pierre Valentin reports a relationship with UCB that includes employment. Martyn Smith is President and CEO of 1Tox and also conducts research in areas of interest similar to the business interests of 1Tox.

Data availability

No de novo data was used for the research described in the article.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

No de novo data was used for the research described in the article.

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