Lost in the woods: Finding our way back to the scientific method in systematic review.

Systematic review has become the preferred approach to addressing causality and informing regulatory and other decision-making processes, including chemical risk assessments. While advocates of systematic reviews acknowledge that they hold great potential for increasing objectivity and transparency in assessments of chemicals and human health risks, standardizing and harmonizing systematic review methods have been challenging. This review provides a brief summary of the development of systematic review methods and some of the frameworks currently in use in the US and Europe. We also provide an in-depth evaluation and comparison of two "competing" US EPA systematic review frameworks, informed by the constructively critical recommendations from the US National Academies of Science, Engineering and Medicine. We conclude with suggestions for moving forward to harmonize systematic review methods, as we believe that further criticism of individual available frameworks likely will be unproductive. Specifically, we issue a call to action for an international collaboration to work toward a blueprint that embraces the most scientifically critical elements common to most systematic review frameworks, while necessarily accommodating adaptations for specific purposes. Despite the array of available systematic review methods, it is clear that there is a shared goal and desire to promote objective assessment and synthesis of scientific evidence informing globally important issues regarding disease causality and human health risk evaluation.