{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T15:14:58Z","timestamp":1788362098683,"version":"build-2803163510"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:00:00Z","timestamp":1788307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Toxicol."],"abstract":"<jats:p>Human health is continuously challenged by exposure to complex mixtures of chemicals present in food, products, and the environment. Traditional risk assessment (TRA), rooted in mid-20th-century paradigms, relies on deterministic thresholds and animal testing to define safe exposure levels. This approach, while useful for regulatory simplicity, fails to represent real-world variability, mixture effects, and lifelong events, limiting its relevance for public health protection. Here we show that a probabilistic Next-Generation Risk Assessment (NGRA) framework integrating quantitative modelling, mechanistic biology, and New Approach Methodologies (NAMs), can transform toxicological evidence into probability distributions, estimating the likelihood of adverse outcomes under realistic exposure scenarios. Central to this approach are Health Impact Pathways (HIPs), which connect molecular perturbations to population-level health indicators, bridging toxicology and epidemiology. The framework explicitly distinguishes susceptible groups, such as individuals in physiologically sensitive stages like pregnancy, from vulnerable groups, including those with pre-existing diseases or higher exposure burdens, poorly covered in TRA. By covering these groups, probabilistic NGRA enables more inclusive, relevant, and informative evaluations that align with FAIR (Findable, Accessible, Interoperable, Reusable) data principles and minimize animal testing, offering a scientifically grounded framework for improving chemical safety evaluations and public health protection.<\/jats:p>","DOI":"10.3389\/ftox.2026.1872816","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T14:32:55Z","timestamp":1788359575000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Rewriting paracelsus: linking chemical assessment to public health"],"prefix":"10.3389","volume":"8","author":[{"given":"Ana","family":"Fernandez-Agudo","sequence":"first","affiliation":[{"name":"Spanish National Environmental Health Center, Instituto de Salud Carlos III","place":["Madrid, Spain"]},{"name":"Biomedical Sciences and Public Health, Universidad Nacional de Educaci\u00f3n a Distancia (UNED)","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda del Carmen","family":"Gonz\u00e1lez-Caballero","sequence":"additional","affiliation":[{"name":"Spanish National Environmental Health Center, Instituto de Salud Carlos III","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose V.","family":"Tarazona","sequence":"additional","affiliation":[{"name":"Spanish National Environmental Health Center, Instituto de Salud Carlos III","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"101602","DOI":"10.1016\/j.molmet.2022.101602","article-title":"Exposure to low-dose perfluorooctanoic acid promotes hepatic steatosis and disrupts the hepatic transcriptome in mice","volume":"66","author":"Attema","year":"2022","journal-title":"Mol. Metab."},{"key":"B2","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1093\/toxsci\/kfaa048","article-title":"A next-generation risk assessment case study for coumarin in cosmetic products","volume":"176","author":"Baltazar","year":"2020","journal-title":"Toxicol. Sci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1016\/0273-2300(88)90047-5","article-title":"Reference dose (RfD): description and use in health risk assessments","volume":"8","author":"Barnes","year":"1988","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"S48","DOI":"10.1016\/j.yrtph.2016.05.028","article-title":"Point of departure (PoD) selection for the derivation of acceptable daily exposures (ADEs) for active pharmaceutical ingredients (APIs)","volume":"79","author":"Bercu","year":"2016","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.comtox.2017.10.001","article-title":"Ab initio chemical safety assessment: a workflow based on exposure considerations and non-animal methods","volume":"4","author":"Berggren","year":"2017","journal-title":"Comput. Toxicol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1177\/03400352241270692","article-title":"The FAIRification process for data stewardship: a comprehensive discourse on the implementation of the FAIR principles for data visibility, interoperability and management","volume":"51","author":"Bhat","year":"2025","journal-title":"IFLA J."},{"key":"B7","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1080\/10937404.2024.2338078","article-title":"Relevance and feasibility of principles for health and environmental risk decision-making","volume":"27","author":"Bhuller","year":"2024","journal-title":"J. Toxicol. Environ. Health, Part B"},{"key":"B8","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1186\/s12302-023-00785-6","article-title":"Multiple stressor effects of insecticide exposure and increased fine sediment deposition on the gene expression profiles of two freshwater invertebrate species","volume":"35","author":"Brasseur","year":"2023","journal-title":"Environ. Sci. Eur."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/toxres\/tfac087","article-title":"Risk assessment in the 21st century: where are we heading?","volume":"12","author":"Brescia","year":"2023","journal-title":"Toxicol. Res. (Camb)"},{"key":"B10","doi-asserted-by":"publisher","first-page":"e13831","DOI":"10.1111\/cts.13831","article-title":"The estimation and translation uncertainties in applying NOAEL to clinical dose escalation","volume":"17","author":"Chen","year":"2024","journal-title":"Clin. Transl. Sci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"105483","DOI":"10.1016\/j.yrtph.2023.105483","article-title":"Exposure considerations in human safety assessment: report from an EPAA partners\u2019 forum","volume":"144","author":"Cronin","year":"2023","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/j.tifs.2022.09.014","article-title":"Addressing the need for safe, nutritious and sustainable food: outcomes of the ONE \u2013 Health, environment and society \u2013 conference 2022","volume":"129","author":"Devos","year":"2022","journal-title":"Trends Food Sci. Technol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/j.fct.2004.05.011","article-title":"Human variability in xenobiotic metabolism and pathway-related uncertainty factors for chemical risk assessment: a review","volume":"43","author":"Dorne","year":"2005","journal-title":"Food Chem. Toxicol."},{"key":"B14","volume-title":"Commission Proposes \u201cOne Substance, One Assessment\u201d Chemicals Assessment Reform for Faster, Simplified and Transparent Processes","year":"2024"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e8875","DOI":"10.2903\/j.efsa.2024.8875","article-title":"Guidance on risk\u2013benefit assessment of foods","volume":"22","author":"More","year":"2024","journal-title":"EFSA J."},{"key":"B16","doi-asserted-by":"publisher","first-page":"2759","DOI":"10.1007\/s00204-025-04045-9","article-title":"A tiered next-generation risk assessment framework integrating toxicokinetics and NAM-Based toxicodynamics: \u201cproof of concept\u201d case study using pyrethroids","volume":"99","author":"Fernandez-Agudo","year":"2025","journal-title":"Arch. Toxicol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"110","DOI":"10.3390\/toxics13020110","article-title":"Next generation risk assessment to address disease-related vulnerability\u2014A proof of concept for the sunscreen octocrylene","volume":"13","author":"Fern\u00e1ndez-Mart\u00edn","year":"2025","journal-title":"Toxics"},{"key":"B18","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/S0045-6535(00)00087-4","article-title":"Opportunities for a probabilistic risk assessment of chemicals in the european union","volume":"43","author":"Jager","year":"2001","journal-title":"Chemosphere"},{"key":"B19","volume-title":"A Modelling Approach for the Prioritisation of Chemicals Under the Water Framework Directive","author":"Daginnus","year":"2010"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1723","DOI":"10.1002\/etc.4125","article-title":"Adverse outcome pathway networks I: development and applications","volume":"37","author":"Knapen","year":"2018","journal-title":"Environ. Toxicol. Chem."},{"key":"B21","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1093\/toxsci\/kfi169","article-title":"The threshold of toxicological concern concept in risk assessment","volume":"86","author":"Kroes","year":"2005","journal-title":"Toxicol. Sci."},{"key":"B22","doi-asserted-by":"publisher","first-page":"e2021GH000552","DOI":"10.1029\/2021GH000552","article-title":"Role of the synergistic interactions of environmental pollutants in the development of cancer","volume":"6","author":"Lagunas\u2010Rangel","year":"2022","journal-title":"Geohealth"},{"key":"B23","doi-asserted-by":"publisher","first-page":"100101","DOI":"10.1016\/j.comtox.2019.100101","article-title":"Tiered approaches for screening and prioritizing chemicals through integration of pharmacokinetics and exposure information with in vitro dose-response data","volume":"12","author":"Leonard","year":"2019","journal-title":"Comput. Toxicol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1039\/c8tx00051d","article-title":"Big-data and machine learning to revamp computational toxicology and its use in risk assessment","volume":"7","author":"Luechtefeld","year":"2018","journal-title":"Toxicol. Res. (Camb)"},{"key":"B25","doi-asserted-by":"publisher","first-page":"3","DOI":"10.14573\/altex.2201081","article-title":"Probabilistic risk assessment \u2013 the keystone for the future of toxicology","volume":"39","author":"Maertens","year":"2022","journal-title":"ALTEX"},{"key":"B26","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1016\/j.toxrep.2021.02.012","article-title":"Theophrastus Bombastus Von Hohenheim (Paracelsus) (1493\u20131541): the eminent physician and pioneer of toxicology","volume":"8","author":"Michaleas","year":"2021","journal-title":"Toxicol. Rep."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1133","DOI":"10.1002\/ieam.4660","article-title":"Robust risk assessments require probabilistic approaches","volume":"18","author":"Moe","year":"2022","journal-title":"Integr. Environ. Assess. Manag."},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.2903\/j.efsa.2019.5708","article-title":"Guidance on the use of the threshold of toxicological concern approach in food safety assessment","volume":"17","author":"More","year":"2019","journal-title":"EFSA J."},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.2903\/j.efsa.2021.6479","article-title":"Statement on the derivation of health-based guidance values (HBGVs) for regulated products that are also nutrients","volume":"19","author":"More","year":"2021","journal-title":"EFSA J."},{"key":"B30","volume-title":"Using 21st Century Sciente to Improve Risk-Related Evaluations. Advances in Epidemiology. Nih.Gov","year":"2017"},{"key":"B31","first-page":"6","volume-title":"Revised Guidance Document on Developing and Assessing Adverse Outcome Pathways. ENV\/JM\/MONO","year":"2017"},{"key":"B32","volume-title":"OECD Series on Testing and Assessment Guiding Principles and Key Elements for Establishing a Weight of Evidence for Chemical Assessment","year":"2019"},{"key":"B33","article-title":"Case study on use of an integrated approach for testing and assessment (IATA) for systemic toxicity of phenoxyethanol when included at 1% in a body lotion","year":"","journal-title":"Ser. Test. Assess."},{"key":"B34","article-title":"Guidance document on integrated approaches to testing and assessment (IATA) for serious eye damage and eye irritation","volume-title":"Third Edition, OECD Series on Testing and Assessment","year":"2024"},{"key":"B35","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1016\/j.jksuci.2017.06.001","article-title":"Big data technologies: a survey","volume":"30","author":"Oussous","year":"2018","journal-title":"J. King Saud Univ. - Comput. Inf. Sci."},{"key":"B36","doi-asserted-by":"publisher","first-page":"100195","DOI":"10.1016\/j.comtox.2021.100195","article-title":"Towards a qAOP framework for predictive toxicology - linking data to decisions","volume":"21","author":"Paini","year":"2022","journal-title":"Comput. Toxicol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"142883","DOI":"10.1016\/j.chemosphere.2024.142883","article-title":"Combination of toxicological and epidemiological approaches for estimating the health impact of atmospheric pollutants. A proof of concept for NO2","volume":"363","author":"Pallar\u00e9s Porcar","year":"2024","journal-title":"Chemosphere"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1058","DOI":"10.1016\/j.chembiol.2017.05.019","article-title":"Joining forces: the chemical biology\u2013medicinal chemistry continuum","volume":"24","author":"Plowright","year":"2017","journal-title":"Cell Chem. Biol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"108474","DOI":"10.1016\/j.envint.2024.108474","article-title":"Human biomonitoring and toxicokinetics as key building blocks for next generation risk assessment","volume":"184","author":"Reale","year":"2024","journal-title":"Environ. Int."},{"key":"B40","doi-asserted-by":"publisher","first-page":"113944","DOI":"10.1016\/j.fct.2023.113944","article-title":"Alternatives to animal testing in toxicity testing: current status and future perspectives in food safety assessments","volume":"179","author":"Reddy","year":"2023","journal-title":"Food Chem. Toxicol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1543","DOI":"10.1016\/j.envsoft.2007.02.004","article-title":"Uncertainty in the environmental modelling process \u2013 a framework and guidance","volume":"22","author":"Refsgaard","year":"2007","journal-title":"Environ. Model. and Softw."},{"key":"B42","volume-title":"Opinion on Phenoxyethanol","year":"2016"},{"key":"B43","doi-asserted-by":"publisher","first-page":"tfae044","DOI":"10.1093\/toxres\/tfae044","article-title":"New approach methodologies (NAMs): identifying and overcoming hurdles to accelerated adoption","volume":"13","author":"Sewell","year":"2024","journal-title":"Toxicol. Res. (Camb)"},{"key":"B44","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1038\/s41370-024-00740-4","article-title":"Refined methodologies for probabilistic dietary exposure assessment for food contaminants based on the observed individual means methodology","volume":"35","author":"Stefano","year":"2025","journal-title":"J. Expo. Sci. Environ. Epidemiol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.cotox.2018.03.006","article-title":"Aggregate exposure pathways in support of risk assessment","volume":"9","author":"Tan","year":"2018","journal-title":"Curr. Opin. Toxicol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.coph.2017.09.009","article-title":"Use of monte carlo simulation and considerations for PK-PD targets to support antibacterial dose selection","volume":"36","author":"Trang","year":"2017","journal-title":"Curr. Opin. Pharmacol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"101157","DOI":"10.1016\/j.jafr.2024.101157","article-title":"Open data ownership and sharing: challenges and opportunities for application of FAIR principles and a checklist for data managers","volume":"16","author":"Ugochukwu","year":"2024","journal-title":"J. Agric. Food Res."},{"key":"B48","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.envsoft.2014.09.017","article-title":"An overview of methods to evaluate uncertainty of deterministic models in decision support","volume":"63","author":"Uusitalo","year":"2015","journal-title":"Environ. Model. and Softw."},{"key":"B49","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1111\/j.1539-6924.2007.00887.x","article-title":"Integration of probabilistic exposure assessment and probabilistic hazard characterization","volume":"27","author":"Van Der Voet","year":"2007","journal-title":"Risk Anal."},{"key":"B50","doi-asserted-by":"publisher","first-page":"2033","DOI":"10.4315\/0362-028X-67.9.2033","article-title":"Application of elements of microbiological risk assessment in the food industry via a tiered approach","volume":"67","author":"Van Gerwen","year":"2004","journal-title":"J. Food Prot."},{"key":"B51","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1126\/science.aay3164","article-title":"The exposome and health: where chemistry meets biology","volume":"367","author":"Vermeulen","year":"2020","journal-title":"Science"},{"key":"B52","doi-asserted-by":"publisher","first-page":"1734","DOI":"10.1002\/etc.4124","article-title":"Adverse outcome pathway networks II: network analytics","volume":"37","author":"Villeneuve","year":"2018","journal-title":"Environ. Toxicol. Chem."},{"key":"B53","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1016\/j.tox.2013.08.011","article-title":"The adverse outcome pathway concept: a pragmatic tool in toxicology","volume":"312","author":"Vinken","year":"2013","journal-title":"Toxicology"},{"key":"B54","volume-title":"Concepts for Analyzing Human Exposure to Complex Chemical Mixtures","author":"Vivo","year":"2025"},{"key":"B55","doi-asserted-by":"crossref","DOI":"10.5206\/EXFO3999","article-title":"The FAIR principles and research data management","volume-title":"Research Data Management in the Canadian Context: A Guide for Practitioners and Learners","author":"Wang","year":"2023"},{"key":"B56","doi-asserted-by":"publisher","first-page":"3709","DOI":"10.1038\/s41598-025-88440-3","article-title":"Understanding collective behavior in biological systems through potential field mechanisms","volume":"15","author":"Zhang","year":"2025","journal-title":"Sci. Rep."},{"key":"B57","doi-asserted-by":"publisher","first-page":"107955","DOI":"10.1016\/j.ijfatigue.2023.107955","article-title":"Bayesian model averaging for probabilistic S-N curves with probability distribution model form uncertainty","volume":"177","author":"Zou","year":"2023","journal-title":"Int. J. Fatigue"}],"container-title":["Frontiers in Toxicology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/ftox.2026.1872816\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T14:33:04Z","timestamp":1788359584000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/ftox.2026.1872816\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,2]]},"references-count":57,"alternative-id":["10.3389\/ftox.2026.1872816"],"URL":"https:\/\/doi.org\/10.3389\/ftox.2026.1872816","relation":{},"ISSN":["2673-3080"],"issn-type":[{"value":"2673-3080","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,2]]},"article-number":"1872816"}}