The U.S. Environmental Protection Agency’s (EPA) Integrated Risk Information System (IRIS) program develops human health assessments that focus on hazard identification and dose-response analyses for chemicals in the environment. The ORD Staff Handbook for Developing IRIS Assessments (the handbook) provides guidance to scientists who perform the IRIS assessments in order to foster consistency in the assessments and enhance transparency about the IRIS assessment process. At the request of the EPA, this report reviews the procedures and considerations for operationalizing the principles of systematic reviews and the methods described in the handbook for determining the scope of the IRIS assessments, evidence integration, extrapolation techniques, dose-response analyses, and characterization of uncertainties.