The Future of Uncertainty Factors With In Vitro Studies Using Human Cells

New approach methodologies (NAMs), including in vitro toxicology methods such as human cells from simple cell cultures to 3D and organ-on-a-chip models of human lung, intestine, liver, and other organs, are challenging the traditional “norm” of current regulatory risk assessments. Uncertainty Factors continue to be used by regulatory agencies to account for perceived deficits in toxicology data. With the expanded use of human cell NAMs, the question “Are uncertainty factors needed when human cells are used?” becomes a key topic in the development of 21st-century regulatory risk assessment. M.D., PhD, the coauthor of an article detailing uncertainty factors within the U.S. EPA, and L.E., PhD., Executive Vice President, Science, Emulate, who is involved in developing organ-on-a-chip models, debated the topic. One important outcome of the debate was that in the case of in vitro human cells on a chip, the interspecies (animal to human) uncertainty factor of 10 could be eliminated. However, in the case of the intraspecies (average human to sensitive human), the uncertainty factor of 10, additional toxicokinetic and/or toxicodynamic data or related information will be needed to reduce much less eliminate this factor. In the case of other currently used uncertainty factors, such as lowest observable adverse effect level to no-observed adverse effect level extrapolation, missing important toxicity studies, and acute/subchronic to chronic exposure extrapolation, additional data might be needed even when using in vitro human cells. Collaboration between traditional risk assessors with decades of experience with in vivo data and risk assessors working with modern technologies like organ chips is needed to find a way forward.