Toxicology and epidemiology are the two traditional public health scientific disciplines which can contribute to investigate harmful health effects of exposure to toxic substances. Several frameworks for integrating different lines of evidence were proposed since 2011, evolving based of the emergence of new methodologies and approaches. Through the comparison of various theoretical frameworks for evidence integration, we examined similarities, differences, strengths, and weaknesses to provide insights into potential directions for future research. We identified several key challenges of the integration approach to be applied to risk assessment. More specifically, collaboration within a multidisciplinary team of scientists, toxicologists, epidemiologists, and risk assessors, is strongly recommended to be aligned with key regulatory objectives and promote a harmonized approach. Moreover, literature search transparency and systematicity have to be ensured by following validated guidelines, developing parallel protocols for collecting epidemiological and toxicological evidence from various sources, including human, animal, and new approach methodologies (NAMs). Also, the adoption of tailored quality assessment tools is essential to grade the certainty in evidence. Lastly, we recommend the use of the Adverse Outcome Pathway framework to provide a structured understanding of toxicity mechanisms and allow the integration of human, animal, and NAMs data within a single framework.

Exposure to environmental chemicals has been linked to an increased risk of heart failure, but the impact on left ventricular dysfunction (LVD) markers remains uncertain. To establish a foundation of evidence regarding early HF markers and their association with environmental pollutants, a systematic review and meta-analysis was conducted. The search, conducted on October 13th, 2023, encompassed PubMed, Embase, and Web of Science without filters, focusing on observational studies reporting myocardial geometrical, structural, or functional alterations in individuals without a history of heart disease. This included the general adult population, workers, young people, and the elderly. The risk of bias was assessed using the ROBINS-I tool at both study and item levels. The systematic review included 17 studies involving 43.358 individuals exposed to air pollution and 2038 exposed to heavy metals. Approximately 41% of the effect measures of associations reported significant abnormalities in myocardial structure or function. The metanalyses by pollutants categories indicated positive associations between LV systolic and diastolic abnormalities and exposure to PM2.5 [-0.069 (-0.104, -0.033); -0.044 (-0.062, -0.025)] and PM10 [-0.055 (-0.087, -0.022); -0.030 (-0.050, -0.010)] and NO2 [-0.042 (-0.071, -0.013); -0.021 (-0.037, -0.004)], as well as positive associations between lead exposure and LV systolic abnormalities [-0.033 (-0.051, -0.016)]. To strengthen confidence in the findings and improve the attribution of baseline exposures, the authors recommend conducting more longitudinal and case-control studies. These studies should consider co-exposures, account for vulnerable groups, and identify cardiotoxic compounds that may require regulation. When examining the link between myocardial abnormalities and environmental exposure, it is also advisable to explore the supportive use of Adverse Outcome Pathway (AOP) approaches to confirm a causal relationship.

We present a novel Adverse Outcome Pathway (AOP) network for environmental chemical-induced cardiotoxicity using a bottom-up, data-driven AOP development approach. Mechanistic endpoints were systematically extracted from 339 in vitro and in vivo studies, yielding 1,759 Key Event (KE) entries and 4,938 Key Event Relationship (KER) entries, including information on experimental methods, essentiality evidence (intervention experiments demonstrating upstream-downstream dependence), and study metadata. After quality filtering (high risk of bias, confounding cytotoxicity in vitro, excessive toxicity or animal well-being concerns in vivo, and low-frequency observations), 112 unique KEs and 829 unique KERs supported by at least three independent observations were retained for network construction. Network analysis identified oxidative stress and mitochondrial dysfunction as dominant hub processes linking diverse upstream perturbations to downstream cardiomyocyte injury, inflammation, cardiac remodelling (fibrosis and hypertrophy), decreased cardiac contractility, and reduced left ventricular function. Incorporating exposure duration at the KER level enabled time-resolved pathway interpretation and demonstrated that KE timing is relationship-dependent, revealing temporal patterns not apparent when analysing KEs in isolation. This evidence-weighted, time-resolved AOP network can support endpoint prioritisation and exposure-window selection for non-animal method (NAM) test batteries and mechanistically informed cardiotoxicity assessment.

An increasing body of evidence identifies pollutant exposure as a risk factor for cardiovascular disease (CVD), while CVD incidence rises steadily with the aging population. Although numerous experimental studies are now available, the mechanisms through which lifetime exposure to environmental pollutants can result in CVD are not fully understood. To comprehensively describe and understand the pathways through which pollutant exposure leads to cardiotoxicity, a systematic mapping review of the available toxicological evidence is needed. This protocol outlines a step-by-step framework for conducting this review. Using the National Toxicology Program (NTP) Health Assessment and Translation (HAT) approach for conducting toxicological systematic reviews, we selected 362 out of 8111 in vitro (17%), in vivo (67%), and combined (16%) studies for 129 potential cardiotoxic environmental pollutants, including heavy metals (29%), air pollutants (16%), pesticides (27%), and other chemicals (28%). The internal validity of included studies is being assessed with HAT and SYRCLE Risk of Bias tools. Tabular templates are being used to extract key study elements regarding study setup, methodology, techniques, and (qualitative and quantitative) outcomes. Subsequent synthesis will consist of an explorative meta-analysis of possible pollutant-related cardiotoxicity. Evidence maps and interactive knowledge graphs will illustrate evidence streams, cardiotoxic effects and associated quality of evidence, helping researchers and regulators to efficiently identify pollutants of interest. The evidence will be integrated in novel Adverse Outcome Pathways to facilitate regulatory acceptance of non-animal methods for cardiotoxicity testing. The current article describes the progress of the steps made in the systematic mapping review process. Plain language summaryHeart disease is a leading global cause of death. Recent research indicates that certain environmental chemicals can worsen heart problems. We’re conducting a rigorous review of scientific studies to understand how these chemicals affect the heart. This will inform policymakers and promote non-animal testing methods for cardiotoxicity by providing a clear overview of the toxicological evidence. We have reviewed over 8,000 articles and focused on 362 studies about 129 chemicals, including heavy metals, air pollutants and pesticides, and their effects on the heart. The current manuscript describes the used methods and steps made in this process. The outcome of our systematic review of these 362 articles will be a comprehensive database that will aid the development of alternative testing methods for cardiotoxicity.

Environmental pollutants are increasingly associated with adverse cardiovascular effects, posing serious public health concerns. We conducted a systematic mapping review to identify, organize, and make accessible the existing toxicological evidence on pollutant induced cardiotoxicity (PICT). An interactive systematic evidence map was developed to support research prioritization, risk assessment, and policy development. Following our previously published protocol, peer-reviewed studies were included if they reported cardiovascular outcomes resulting from pollutant exposure in animal or in vitro models. Data were extracted on study design, exposure-outcome relationships, and risk of bias (RoB) was assessed for all included studies. Out of 9,317 screened studies, 400 were included. Findings show substantial evidence of cardiotoxic effects from exposure to heavy metals, air pollutants, insecticides, PFAS, and related substances. Animal studies dominate the literature, commonly reporting cardiomyopathy, hypertrophy, fibrosis, and conduction abnormalities at environmentally relevant exposures. In vitro models primarily offer shared mechanistic insights, especially related to oxidative stress and mitochondrial dysfunction. RoB varied across studies, with common limitations in exposure characterization and endpoint validation, while in vivo and in vitro results showed good correlation. To improve data accessibility and reusability, we created an open-access interactive evidence map ( https://cardiotoxdb.org/ ), allowing users to filter by pollutant class, study type, species or cell type and cardiac outcome. This review and the systematic evidence map offer a structured and transparent overview of toxicological data on PICT, enabling stakeholders to explore the evidence base, identify gaps, and prioritize pollutants for further evaluation.

We developed a bottom-up, data-driven approach for constructing a time-informed adverse outcome pathway (AOP) network for environmental chemical-induced cardiotoxicity. Mechanistic end points were systematically extracted from 339 in vitro and in vivo studies, yielding 1759 Key Event (KE) entries and 4938 Key Event Relationship (KER) entries, together with study metadata and essentiality evidence from intervention experiments. After quality filtering and minimum support thresholding, 62 unique KEs and 256 unique KERs were retained for network construction. Network analysis highlighted oxidative stress and mitochondrial dysfunction as prominent, highly connected KEs linking diverse upstream perturbations to downstream cardiomyocyte injury, inflammation, cardiac remodeling (fibrosis and hypertrophy), decreased myocardial contractility, and reduced left ventricular function. A central methodological finding was that temporal information was more informative at the level of KERs than at the level of KEs. The same KE could occur across multiple durations depending on the relationship in which it was embedded, whereas KER-level time-scale annotation resolved distinct acute, subacute, and chronic pathway patterns not apparent from KE timing alone. This framework provides an evidence-weighted synthesis of the most consistently supported cardiotoxicity mechanisms and introduces a temporal layer for the mechanistic interpretation of heterogeneous evidence.