02730nas a2200397   4500000000100000000000100001008004100002260001200043653001200055653001800067653001400085653001700099653001100116653000900127653003100136653001500167653001500182653002000197653002000217653001500237100002500252700001800277700002000295700001700315700001600332700001800348700002700366700001800393700001900411700002200430245008500452300001400537490000700551520176000558022001402318       2022                            d  c2022-1110aAnimals10aEcotoxicology10aFramework10aHuman health10aHumans10aNAMs10anew approach methodologies10aPesticides10aRegulatory10aResearch Design10aRisk Assessment10aValidation1 aAnna J. van der Zalm1 aJoão Barroso1 aPatience Browne1 aWarren Casey1 aJohn Gordon1 aTala R. Henry1 aNicole C. Kleinstreuer1 aAnna B. Lowit1 aMonique Perron1 aAmy J. Clippinger00aA framework for establishing scientific confidence in new approach methodologies  a2865-28790 v963 aRobust and efficient processes are needed to establish scientific confidence in new approach methodologies (NAMs) if they are to be considered for regulatory applications. NAMs need to be fit for purpose, reliable and, for the assessment of human health effects, provide information relevant to human biology. They must also be independently reviewed and transparently communicated. Ideally, NAM developers should communicate with stakeholders such as regulators and industry to identify the question(s), and specified purpose that the NAM is intended to address, and the context in which it will be used. Assessment of the biological relevance of the NAM should focus on its alignment with human biology, mechanistic understanding, and ability to provide information that leads to health protective decisions, rather than solely comparing NAM-based chemical testing results with those from traditional animal test methods. However, when NAM results are compared to historical animal test results, the variability observed within animal test method results should be used to inform performance benchmarks. Building on previous efforts, this paper proposes a framework comprising five essential elements to establish scientific confidence in NAMs for regulatory use: fitness for purpose, human biological relevance, technical characterization, data integrity and transparency, and independent review. Universal uptake of this framework would facilitate the timely development and use of NAMs by the international community. While this paper focuses on NAMs for assessing human health effects of pesticides and industrial chemicals, many of the suggested elements are expected to apply to other types of chemicals and to ecotoxicological effect assessments.  a1432-0738