Applying Existing Assessments for Problem Formulation in the IRIS Program: Case Example for the Uranium Oral Toxicological Review
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Using existing assessments to refine systematic reviews and develop a focused research strategy is an approach that has been proposed (U.S. EPA, 2022). The U.S. EPA IRIS Program is developing a Toxicological Review of the noncancer health effects of depleted and natural uranium after oral exposure. The scientific literature review and analysis contained in ATSDR’s 2013 Toxicological Profile is being used to streamline the IRIS assessment. ATSDR derived Minimal Risk Levels (MRLs) for oral exposure to uranium compounds. These MRLs are based on uranium-induced developmental and kidney toxicity. ATSDR also identified uranium-induced hepatic, neurological, and reproductive effects as adverse human health outcomes. The IRIS assessment examines whether newly available evidence indicate a need to update these conclusions and consider other noncancer effects for hazard evaluation and/or a reference value derivation. A Systematic Evidence Map (SEM) of the uranium toxicological and epidemiological evidence (from 2011 to early 2023) was developed to explore newly available data. The analysis to determine whether newly identified studies may identify new outcomes for hazard evaluation relied on expert judgement by at least two reviewers. Toxicological and epidemiological studies were screened according to Populations, Exposure, Comparators and Outcomes (PECO) criteria and then considered for comparison against principal health outcomes from the 2013 ATSDR Toxicological Profile. Based on the analysis of findings reported in PECO-relevant studies, the newly considered outcomes for hazard evaluation and development of evidence integration conclusions are: musculoskeletal, endocrine, cardiometabolic, immune,, and respiratory effects. For dose-response re-analysis, the following established effects will be considered: developmental, reproductive, hepatic, urinary, and neurological effects. No re-analysis will be performed on metabolic, hematologic, gastrointestinal, or body weight effects due to lack of new evidence. For the outcomes with new data, the IRIS Risk of Bias analysis, data extraction, and evidence synthesis will be performed across the new studies and the studies cited in ATSDR 2013. This approach is aimed to leverage existing assessments to develop a literature search strategy and analysis that is focused on outcomes for which there is new evidence that can inform hazard evaluation and dose-response. Disclaimer: The views expressed are those of the authors and do not necessarily represent the views or policies of the US EPA.