Use of Existing Assessments for Problem Formulation in the IRIS Program: A Case Example for the Reassessment of Uranium-Induced Toxicity
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The IRIS Program is undertaking a reassessment of the noncancer health effects of uranium via oral exposure. The literature review and scientific analysis contained in ATSDR’s 2013 Toxicological Profile is being used to streamline the IRIS assessment. The ATSDR derived Minimal Risk Levels (MRLs) for oral exposure to uranium compounds are based on uranium-induced renal and developmental toxicity. ATSDR 2013 also identified neurological, reproductive, and hepatic effects as adverse health outcomes induced by uranium exposure. The IRIS assessment is examining whether newly available data indicate a need to revise these conclusions and considering other potential noncancer hazards for toxicity value derivation. A systematic evidence map (SEM) of the uranium evidence from 2011 to early 2022 was generated to explore newly available data. The analysis of whether newly identified studies appeared to alter ATSDR’s conclusions (or identified new outcomes to consider) relied on expert judgement by two reviewers. Epidemiological and toxicological endpoints were screened according to Populations, Exposure, Comparators and Outcomes (PECO) criteria and analyzed to compare against principal health outcomes from the 2013 ATSDR Toxicological Profile. PECO-relevant studies were examined to determine whether there was a “clear study limitation” which would reduce the confidence level in the study for use in an IRIS assessment. Any PECO-relevant study not having a clear limitation was considered “possibly impactful.” Based on the findings of the “possibly impactful” studies, outcomes that will be considered for hazard evaluation and development of evidence integration conclusions are: cardiometabolic, endocrine, immune, musculoskeletal, and respiratory effects. For dose-response re-analysis the following outcomes will be considered: urinary, developmental, hepatic, neurological, and reproductive effects. No re-analysis will be performed on metabolic, hematologic, gastrointestinal, or body weight effects. For identified outcomes with new data, the IRIS Program is conducting evidence synthesis across the new studies and the studies cited in ATSDR 2013. This approach leverages existing assessments to develop a literature search strategy and analysis that is focused on outcomes for which there is new relevant 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.