{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T15:03:08Z","timestamp":1790434988607,"version":"4.1.0"},"reference-count":48,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Regulatory Toxicology and Pharmacology"],"published-print":{"date-parts":[[2026,9]]},"DOI":"10.1016\/j.yrtph.2026.106252","type":"journal-article","created":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T14:56:09Z","timestamp":1790434569000},"page":"106252","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":0,"title":["Suitability of the ICH S1B(R1) Weight-of-Evidence Framework to Evaluate Glucagon-Like Protein-1 Receptor Agonist (GLP-1RA) Carcinogenicity Risk"],"prefix":"10.1016","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6059-3528","authenticated-orcid":false,"given":"Katherine A.","family":"Roach","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manoochehr","family":"Khazaee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac","family":"Mohar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denali","family":"Boon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2584-9317","authenticated-orcid":false,"given":"Brigitte","family":"Cronin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex G.","family":"Gauthier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"issue":"7","key":"10.1016\/j.yrtph.2026.106252_bib1","doi-asserted-by":"crossref","first-page":"2439","DOI":"10.2337\/db12-1747","article-title":"X-box binding protein 1 is essential for insulin regulation of pancreatic \u03b1-cell function","volume":"62","author":"Akiyama","year":"2013","journal-title":"Diabetes"},{"issue":"1","key":"10.1016\/j.yrtph.2026.106252_bib2","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1186\/s12933-025-02828-z","article-title":"The dual GLP-1 and GIP receptor agonist tirzapetide provides an unintended interaction with the \u03b2-adrenoceptors and plays a role in glucose metabolism in hyperglycemic or senescent cardiac cells","volume":"24","author":"Aydos","year":"2025","journal-title":"Cardiovasc Diabetol"},{"key":"10.1016\/j.yrtph.2026.106252_bib3","doi-asserted-by":"crossref","DOI":"10.3389\/ftox.2024.1370045","article-title":"Developing a pragmatic consensus procedure supporting the ICH S1B(R1) weight of evidence carcinogenicity assessment","volume":"6","author":"Bassan","year":"2024","journal-title":"Front Toxicol"},{"issue":"1","key":"10.1016\/j.yrtph.2026.106252_bib4","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1089\/thy.2024.0387","article-title":"Glucagon-Like Peptide 1 Receptor Agonists and Risk of Thyroid Cancer: An International Multisite Cohort Study","volume":"35","author":"Baxter","year":"2025","journal-title":"Thyroid\u00ae"},{"key":"10.1016\/j.yrtph.2026.106252_bib5","doi-asserted-by":"crossref","DOI":"10.1016\/j.phrs.2022.106320","article-title":"The anti-inflammatory and immunological properties of GLP-1 Receptor Agonists","volume":"182","author":"Bendotti","year":"2022","journal-title":"Pharmacol Res"},{"issue":"3","key":"10.1016\/j.yrtph.2026.106252_bib6","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1111\/dom.12824","article-title":"Occurrence of nausea, vomiting and diarrhoea reported as adverse events in clinical trials studying glucagon-like peptide-1 receptor agonists: A systematic analysis of published clinical trials","volume":"19","author":"Bettge","year":"2017","journal-title":"Diabetes Obes Metab"},{"issue":"6","key":"10.1016\/j.yrtph.2026.106252_bib7","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.2337\/dc18-2028","article-title":"Changes in Serum Calcitonin Concentrations, Incidence of Medullary Thyroid Carcinoma, and Impact of Routine Calcitonin Concentration Monitoring in the EXenatide Study of Cardiovascular Event Lowering (EXSCEL)","volume":"42","author":"Bethel","year":"2019","journal-title":"Diabetes Care"},{"issue":"2","key":"10.1016\/j.yrtph.2026.106252_bib8","first-page":"163","article-title":"Improving prediction of carcinogenicity to reduce, refine, and replace the use of experimental animals","volume":"54","author":"Bourcier","year":"2015","journal-title":"J. Am. Assoc. Lab. Anim. Sci."},{"issue":"7","key":"10.1016\/j.yrtph.2026.106252_bib9","doi-asserted-by":"crossref","DOI":"10.1210\/en.2014-1722","article-title":"Chronic Toxicity and Carcinogenicity Studies of the Long-Acting GLP-1 Receptor Agonist Dulaglutide in Rodents","volume":"156","author":"Byrd","year":"2015","journal-title":"Endocrinology"},{"key":"10.1016\/j.yrtph.2026.106252_bib10","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1038\/nrc1408","article-title":"Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms","volume":"4","author":"Calle","year":"2004","journal-title":"Nat Rev Cancer"},{"issue":"6","key":"10.1016\/j.yrtph.2026.106252_bib11","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/j.cmet.2013.04.008","article-title":"Pharmacology, physiology, and mechanisms of incretin hormone action","volume":"17","author":"Campbell","year":"2013","journal-title":"Cell Metab"},{"issue":"2","key":"10.1016\/j.yrtph.2026.106252_bib12","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1007\/s12020-019-02055-z","article-title":"GLP-1 receptor agonists and risk of cancer in type 2 diabetes: An updated meta-analysis of randomized controlled trials","volume":"66","author":"Cao","year":"2019","journal-title":"Endocrine"},{"issue":"6","key":"10.1016\/j.yrtph.2026.106252_bib13","doi-asserted-by":"crossref","first-page":"687","DOI":"10.3390\/biom14060687","article-title":"Implications of GLP-1 Receptor Agonist on Thyroid Function: A Literature Review of Its Effects on Thyroid Volume, Risk of Cancer, Functionality and TSH Levels","volume":"14","author":"Capuccio","year":"2024","journal-title":"Biomolecules"},{"issue":"1","key":"10.1016\/j.yrtph.2026.106252_bib14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3109\/10408444.2013.835784","article-title":"Mode of action framework analysis for receptor-mediated toxicity: The peroxisome proliferator-activated receptor alpha (PPAR\u03b1) as a case study","volume":"44","author":"Corton","year":"2014","journal-title":"Crit Rev Toxicol"},{"issue":"8","key":"10.1016\/j.yrtph.2026.106252_bib15","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1038\/s41573-025-01183-8","article-title":"GLP-1-based therapies for diabetes, obesity and beyond","volume":"24","author":"Drucker","year":"2025","journal-title":"Nat Rev Drug Discov"},{"issue":"4","key":"10.1016\/j.yrtph.2026.106252_bib16","first-page":"403","article-title":"Glucagon-like peptide-1 receptor agonists and thyroid cancer: A narrative review","volume":"34","author":"Espinosa De Ycaza","year":"2024","journal-title":"Thyroid"},{"key":"10.1016\/j.yrtph.2026.106252_bib17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.yrtph.2017.11.003","article-title":"Human relevance of rodent liver tumors: Key insights from a Toxicology Forum workshop on nongenotoxic modes of action","volume":"92","author":"Felter","year":"2018","journal-title":"Regul Toxicol Pharmacol"},{"issue":"1","key":"10.1016\/j.yrtph.2026.106252_bib18","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1210\/jc.2011-2407","article-title":"Glucagon like peptide-1 receptor expression in the human thyroid gland","volume":"97","author":"Gier","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"issue":"6","key":"10.1016\/j.yrtph.2026.106252_bib19","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1007\/s40261-016-0389-8","article-title":"Tumour risk with once-weekly glucagon-like peptide-1 receptor agonists in type 2 diabetes mellitus patients: A systematic review","volume":"36","author":"Guo","year":"2016","journal-title":"Clin. Drug Investig."},{"issue":"3","key":"10.1016\/j.yrtph.2026.106252_bib20","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1210\/jc.2010-2318","article-title":"GLP-1 and calcitonin concentration in humans: lack of evidence of calcitonin release from sequential screening in over 5000 subjects with type 2 diabetes or nondiabetic obese subjects treated with the human GLP-1 analog, liraglutide","volume":"96","author":"Heged\u00fcs","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"issue":"12","key":"10.1016\/j.yrtph.2026.106252_bib21","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1001\/jama.2024.18219","article-title":"GLP-1 Medication Use for Type 2 Diabetes Has Soared","volume":"332","author":"Hegland","year":"2024","journal-title":"JAMA"},{"key":"10.1016\/j.yrtph.2026.106252_bib22","doi-asserted-by":"crossref","DOI":"10.3389\/fendo.2022.927859","article-title":"Use of GLP-1 receptor agonists and occurrence of thyroid disorders: A meta-analysis of randomized controlled trials","volume":"13","author":"Hu","year":"2022","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"10.1016\/j.yrtph.2026.106252_bib23","unstructured":"International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). August 4, 2022. \"ICH Harmonised Guideline: Testing for Carcinogenicity of Pharmaceuticals S1B(R1) (Final Version).\" 25p."},{"key":"10.1016\/j.yrtph.2026.106252_bib24","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s13048-015-0161-3","article-title":"Short term monotherapy with GLP-1 receptor agonist liraglutide or PDE 4 inhibitor roflumilast is superior to metformin in weight loss in obese PCOS women: a pilot randomized study","volume":"8","author":"Jensterle","year":"2015","journal-title":"J Ovarian Res"},{"key":"10.1016\/j.yrtph.2026.106252_bib25","doi-asserted-by":"crossref","DOI":"10.3389\/fendo.2024.1465881","article-title":"Glucagon-like peptide-1 receptor agonists in neoplastic diseases","volume":"15","author":"Ji","year":"2024","journal-title":"Front. Endocrinol. (Lausanne)"},{"issue":"4","key":"10.1016\/j.yrtph.2026.106252_bib26","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1210\/en.2009-1272","article-title":"Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation","volume":"151","author":"Knudsen","year":"2010","journal-title":"Endocrinology"},{"key":"10.1016\/j.yrtph.2026.106252_bib27","doi-asserted-by":"crossref","first-page":"155","DOI":"10.3389\/fendo.2019.00155","article-title":"The Discovery and Development of Liraglutide and Semaglutide","volume":"10","author":"Knudsen","year":"2019","journal-title":"Front. Endocrinol."},{"issue":"2","key":"10.1016\/j.yrtph.2026.106252_bib28","doi-asserted-by":"crossref","first-page":"216","DOI":"10.7326\/ANNALS-25-02237","article-title":"Risk for Cancer With Glucagon-Like Peptide-1 Receptor Agonists and Dual Agonists : A Systematic Review and Meta-analysis","volume":"179","author":"Ko","year":"2026","journal-title":"Ann Intern Med"},{"issue":"1","key":"10.1016\/j.yrtph.2026.106252_bib29","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s40364-025-00765-3","article-title":"Glucagon-like peptide 1 receptor agonists and cancer risk: advancing precision medicine through mechanistic understanding and clinical evidence","volume":"13","author":"Lin","year":"2025","journal-title":"Biomark Res"},{"issue":"3","key":"10.1016\/j.yrtph.2026.106252_bib30","doi-asserted-by":"crossref","first-page":"1538","DOI":"10.1210\/en.2011-1864","article-title":"GLP-1 receptor agonists and the thyroid: C-cell effects in mice are mediated via the GLP-1 receptor and not associated with RET activation","volume":"153","author":"Madsen","year":"2012","journal-title":"Endocrinology"},{"key":"10.1016\/j.yrtph.2026.106252_bib31","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1038\/nrendo.2012.140","article-title":"GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus","volume":"8","author":"Meier","year":"2012","journal-title":"Nat Rev Endocrinol"},{"issue":"9","key":"10.1016\/j.yrtph.2026.106252_bib32","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1111\/dom.12926","article-title":"Safety issues with glucagon-like peptide-1 receptor agonists (pancreatitis, pancreatic cancer and cholelithiasis): Data from randomized controlled trials","volume":"19","author":"Monami","year":"2017","journal-title":"Diabetes Obes. Metab."},{"key":"10.1016\/j.yrtph.2026.106252_bib33","doi-asserted-by":"crossref","first-page":"141","DOI":"10.3389\/fendo.2012.00141","article-title":"Structural and molecular conservation of glucagon-like Peptide-1 and its receptor confers selective ligand-receptor interaction","volume":"3","author":"Moon","year":"2012","journal-title":"Front. Endocrinol. (Lausanne)"},{"issue":"8","key":"10.1016\/j.yrtph.2026.106252_bib34","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.2337\/dc25-0154","article-title":"Risk of Thyroid Tumors With GLP-1 Receptor Agonists: A Retrospective Cohort Study","volume":"48","author":"Morales","year":"2025","journal-title":"Diabetes Care"},{"issue":"Suppl 1","key":"10.1016\/j.yrtph.2026.106252_bib35","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/dom.13129","article-title":"Incretin hormones: Their role in health and disease","volume":"20","author":"Nauck","year":"2018","journal-title":"Diabetes Obes Metab"},{"issue":"5","key":"10.1016\/j.yrtph.2026.106252_bib36","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.2337\/db11-0936","article-title":"The human GLP-1 analog liraglutide and the pancreas: evidence for the absence of structural pancreatic changes in three species","volume":"61","author":"Nyborg","year":"2012","journal-title":"Diabetes"},{"key":"10.1016\/j.yrtph.2026.106252_bib37","unstructured":"Ozmosi, 2025. Market Overview: GLP-1 Agonists and the Obesity Market | Blog | Ozmosi. Accessed at: https:\/\/www.ozmosi.com\/market-overview-glp-1-agonists-and-the-obesity-market\/."},{"issue":"9","key":"10.1016\/j.yrtph.2026.106252_bib38","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1056\/NEJMp1001578","article-title":"Weighing risks and benefits of liraglutide--the FDA's review of a new antidiabetic therapy","volume":"362","author":"Parks","year":"2010","journal-title":"N Engl J Med"},{"issue":"1","key":"10.1016\/j.yrtph.2026.106252_bib39","doi-asserted-by":"crossref","first-page":"2375","DOI":"10.1038\/s41598-019-38956-2","article-title":"Glucagon-like peptide-1 receptor agonists and pancreatic cancer: A meta-analysis with trial sequential analysis","volume":"9","author":"Pinto","year":"2019","journal-title":"Sci. Rep."},{"issue":"19","key":"10.1016\/j.yrtph.2026.106252_bib40","doi-asserted-by":"crossref","first-page":"5830","DOI":"10.1021\/bi062309m","article-title":"Differential structural properties of GLP-1 and exendin-4 determine their relative affinity for the GLP-1 receptor N-terminal extracellular domain","volume":"46","author":"Runge","year":"2007","journal-title":"Biochemistry"},{"issue":"3","key":"10.1016\/j.yrtph.2026.106252_bib41","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1111\/dom.15382","article-title":"Glucagon-like peptide-1 receptor agonists and risk of thyroid cancer: A systematic review and meta-analysis of randomized controlled trials","volume":"26","author":"Silverii","year":"2024","journal-title":"Diabetes Obes. Metab."},{"issue":"8","key":"10.1016\/j.yrtph.2026.106252_bib42","doi-asserted-by":"crossref","first-page":"4688","DOI":"10.1097\/JS9.0000000000001514","article-title":"Association of glucagon-like peptide-1 receptor agonists with risk of cancers - evidence from a drug target Mendelian randomization and clinical trials","volume":"110","author":"Sun","year":"2024","journal-title":"Int. J. Surg."},{"issue":"18","key":"10.1016\/j.yrtph.2026.106252_bib43","doi-asserted-by":"crossref","first-page":"8641","DOI":"10.1073\/pnas.89.18.8641","article-title":"Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1","volume":"89","author":"Thorens","year":"1992","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.1016\/j.yrtph.2026.106252_bib44","doi-asserted-by":"crossref","DOI":"10.1016\/j.comtox.2021.100191","article-title":"In silico approaches in carcinogenicity hazard assessment: Current status and future needs","volume":"20","author":"Tice","year":"2021","journal-title":"Comput. Toxicol."},{"issue":"7","key":"10.1016\/j.yrtph.2026.106252_bib45","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1177\/0192623315588999","article-title":"Effects of the GLP-1 Receptor Agonist Dulaglutide on the Structure of the Exocrine Pancreas of Cynomolgus Monkeys","volume":"43","author":"Vahle","year":"2015","journal-title":"Toxicol Pathol"},{"key":"10.1016\/j.yrtph.2026.106252_bib46","article-title":"GLP-1 receptor agonist-associated tumor adverse events: A real-world study from 2004 to 2021 based on FAERS","volume":"13","author":"Yang","year":"2022","journal-title":"Front. Pharmacol."},{"key":"10.1016\/j.yrtph.2026.106252_bib47","doi-asserted-by":"crossref","DOI":"10.3389\/fendo.2021.721135","article-title":"GLP-1 receptor agonists: Beyond their pancreatic effects","volume":"12","author":"Zhao","year":"2021","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"10.1016\/j.yrtph.2026.106252_bib48","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/s41392-024-01931-z","article-title":"Glucagon-like peptide-1 receptor: mechanisms and advances in therapy","volume":"9","author":"Zheng","year":"2024","journal-title":"Sig Transduct Target Ther"}],"container-title":["Regulatory Toxicology and Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0273230026002254?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0273230026002254?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T14:56:18Z","timestamp":1790434578000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0273230026002254"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9]]},"references-count":48,"alternative-id":["S0273230026002254"],"URL":"https:\/\/doi.org\/10.1016\/j.yrtph.2026.106252","relation":{},"ISSN":["0273-2300"],"issn-type":[{"value":"0273-2300","type":"print"}],"subject":[],"published":{"date-parts":[[2026,9]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Suitability of the ICH S1B(R1) Weight-of-Evidence Framework to Evaluate Glucagon-Like Protein-1 Receptor Agonist (GLP-1RA) Carcinogenicity Risk","name":"articletitle","label":"Article Title"},{"value":"Regulatory Toxicology and Pharmacology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.yrtph.2026.106252","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 Published by Elsevier Inc.","name":"copyright","label":"Copyright"}],"article-number":"106252"}}