PROJECT SUMMARY Einstein-Jefferson will continue to recruit cases for the three DILIN protocols; prospective, retrospective, and acute, and to participate in all of its procedures and ancillary studies. At Einstein-Jefferson, our main objective is to study liver injury due to Herbal and Dietary Supplements (HDS). Specifically, our approach will entail, through Aim 1, ongoing recruitment of patients with drug and supplement induced liver injury, with several alliances built to promote the enrollment of patients from under-represented minority (URM) groups. Such enhanced enrollment of URMs will not only expand access to our study but will also support our analyses. Related to this aim, we will validate for HDS induced liver injury (HILI) a recently published form of causality assessment; the RECAM. In aim 2, through the DILIN HDS repository housed at Einstein, we will continue to collect products from patients enrolled at all DILIN sites that have been implicated in liver injury for chemical analysis at the National Center for Natural Products Research (NCNPR). Related to this aim, we will work with the NCNPR to explore mechanisms of HILI, and also expand our collaboration on chemical analysis to include other organizations, such as the National Toxicology Program (NTP) and the Botanical Safety Consortium (BSC). The expanded collaboration (NCNPR, NTP, BSC) will allow us to develop new analytical techniques that will form the foundation for the design of human safety and therapeutic trials of multi-ingredient supplements. The critical innovation of our research is explained in aim 3, with the formation of a multi- stakeholder panel to conduct pharmacovigilance for HILI. This panel, comprising the DILIN group, FDA, CDC, and the NTP will focus on detecting case clusters of HILI. Detection of case clusters will, in turn, facilitate response to improve supplement safety through the FDA's regulatory actions, support the CDC's scientific investigations to prove the association of injury with a product, and support the development of better analytical techniques to detect injurious products through our collaboration with the NCNPR, NTP and the BSC. Related to this aim, our research will update our prior work which defined the incidence of drug and supplement induced liver injury in the State of DE, a state that is demographically similar to the U.S. This is an important study to provide context to the importance of HILI pharmacovigilance.