Systematic Review, An Illustration of Increased Transparency in a Framework for Evaluating Immunotoxicity Associated with PFOA and PFOS Exposure

Abstract

Background: Systematic review methodologies were first developed to assess the efficacy of health care interventions, but these approaches can be adapted to evaluations of environmental health questions such as immunotoxicity associated with PFOA and PFOS exposure. This structured approach provides objectivity and transparency to the process of collecting, synthesizing, and reaching conclusions based on the scientific evidence available. Objectives: To outline the process of systematic review and evidence integration and demonstrate each step by following a single research question from start to finish. The example systematic review will evaluate the evidence that PFOA and PFOS exposure are associated with immunotoxicity – using a subset of the available evidence to illustrate concepts, not to develop hazard identification conclusions. Methods: The Office of Health Assessment and Translation (OHAT) Approach to evaluating the scientific evidence for immunotoxicity of PFOA and PFOS is detailed in a protocol that is laid out in seven steps: scoping and problem formulation, search for and select studies for inclusion, extract data from studies, assess quality of individual studies, rate confidence in the body of evidence, translate confidence ratings into level of evidence, and integrate evidence to develop hazard identification conclusions incorporating human, animal, and mechanistic evidence. Results and Discussion: Eligibility criteria for identifying important exposures and outcomes were presented as the basis for assembling the relevant studies for evaluating whether or not PFOA or PFOS exposure is associated with immunotoxicity (human, n = 18; animal, n = 80; and mechanistic/in vitro assays, n = 19). A tool for assessing study quality in terms of risk of bias or internal validity was tailored to the research question – particularly for evaluating PFC exposure and assessing immunological outcomes. An example of an evidence profile is provided to illustrate the basis for confidence ratings using a hypothetical set of studies of PFOS and functional antibody response. Finally, a discussion is presented on how the hazard identification conclusions would be reached and interpreted by integrating the human, animal, and mechanistic evidence. Conclusion: The OHAT Approach to hazard identification of health effects of PFCs is illustrated with a case study on PFOA/PFOS and immunotoxicity. Communication of the evaluation process is enhanced by using objective, reproducible methods that transparently document scientific judgments and the scientific basis for hazard identification conclusions.