{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T11:10:30Z","timestamp":1788952230650,"version":"build-2803163510"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["963845"],"award-info":[{"award-number":["963845"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004907","name":"IHI","doi-asserted-by":"publisher","award":["101172693"],"award-info":[{"award-number":["101172693"]}],"id":[{"id":"10.13039\/501100004907","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    Excipients make up the majority of most medicines by mass, yet they are still called \u201cinactive,\u201d still largely qualified against a 2005 guidance, and still assessed product by product with animal studies that answer the wrong questions. The past decade has dismantled the \u201cinactive\u201d assumption: polyethylene glycol and polysorbate anaphylaxis, benzyl alcohol gasping syndrome, propylene glycol acidosis, benzalkonium bronchospasm, and the recurrent diethylene glycol mass poisonings of children all show that excipient risk is real, but that it is contextual rather than intrinsic. I argue that this contextual character makes excipients an almost ideal proving ground for New Approach Methodologies (NAMs). Excipient hazard depends on route, dose, duration, formulation, impurities, and patient population\u2014exactly the variables that exposure science, computational toxicology, and human\n                    <jats:italic>in vitro<\/jats:italic>\n                    systems handle well and that whole-animal testing handles poorly. I propose replacing the test-list mentality with a context-of-use excipient safety passport, sketch where NAMs already carry decisions and where they only inform them and offer a phased implementation agenda. The goal is to convert excipient safety from a static checklist into a human-relevant, exposure-led, mechanistic discipline.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1896544","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T10:17:19Z","timestamp":1788949039000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["All things are active \u2026 new approach methods for excipient safety"],"prefix":"10.3389","volume":"17","author":[{"given":"Thomas","family":"Hartung","sequence":"first","affiliation":[{"name":"Center for Alternatives to Animal Testing (CAAT), Johns Hopkins Bloomberg School of Public Health","place":["Baltimore, MD, United States"]},{"name":"CAAT-Europe, University of Konstanz","place":["Konstanz, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"149","DOI":"10.14573\/altex.1601251","article-title":"Toward good read-across practice (GRAP) guidance","volume":"33","author":"Ball","year":"2016","journal-title":"ALTEX"},{"key":"B2","first-page":"1","article-title":"Harmful excipients for pediatric patients","volume":"39","author":"Clouser","year":"2022","journal-title":"Contemporary Pediatrics"},{"key":"B3","doi-asserted-by":"publisher","first-page":"402","DOI":"10.14573\/altex.2403261","article-title":"Trust your gut: establishing confidence in gastrointestinal models \u2013 an overview of the state of the science and contexts of use","volume":"41","author":"Debad","year":"2024","journal-title":"ALTEX"},{"key":"B4","volume-title":"European Pharmacopoeia Bids Adieu to the Rabbit Pyrogen Test in Its Monographs (Press Release, July 2024); Deletion of the Rabbit Pyrogen Test and Introduction of General Chapter 5.1.13 Pyrogenicity, Implementation 1 July 2025","year":"2024"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e06585","DOI":"10.2903\/j.efsa.2021.6585","article-title":"Safety assessment of titanium dioxide (E 171) as a food additive","volume":"19","author":"Younes","year":"2021","journal-title":"EFSA J."},{"key":"B6","volume-title":"Nanotechnology-Based Medicinal Products for Human Use: EU-IN Horizon Scanning Report (EMA\/20989\/2025)","year":"2025"},{"key":"B7","volume-title":"Guidance for Industry: Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients","year":"2005"},{"key":"B8","volume-title":"Using the Inactive Ingredient Database: Guidance for Industry (Draft)","year":"2019"},{"key":"B9","article-title":"Center for drug evaluation and research office of new drugs novel excipient review pilot program","volume-title":"Federal Register","year":"2021"},{"key":"B10","volume-title":"Control of Nitrosamine Impurities in Human Drugs: Guidance for Industry, Revision 2","year":"2024"},{"key":"B11","volume-title":"Roadmap to Reducing Animal Testing in Preclinical Safety Studies","year":"2025"},{"key":"B65","volume-title":"General Considerations for the Use of New Approach Methodologies in Drug Development: Draft Guidance for Industry","year":"2026"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1590","DOI":"10.1016\/S0959-8049(01)00171-X","article-title":"Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation","volume":"37","author":"Gelderblom","year":"2001","journal-title":"Eur. 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