The Food Additives Amendment of 1958 is the foundation for the U.S. food additive regulatory program, which oversees most substances added to food. This article is a comprehensive review of the program, including original analysis of pre-and postmarket safety standards for various categories and subcategories of substances and their uses; assigning the more than 10000 substances currently allowed in human food to those categories; and analyzing the U.S. Food and Drug Administration's (FDA) review of more than 1900 petitions and notifications received from 1990 to 2010. Overall, federal agencies made approximately 40% of the 6000 safety decisions allowing substances in human food. These decisions allowed an estimated 66% of the substances currently believed to be used in food. Manufacturers and a trade association made the remaining decisions without FDA review by concluding that the substances were generally recognized as safe (GRAS). Robust premarket safety decisions are critical since FDA has limited resources to monitor potentially significant scientific developments and changing uses of a substance after it enters commerce and only has access to published data or data submitted to it. In the late 1990s, FDA moved from promulgating rules for its decisions for food contact and GRAS substances to reviewing manufacturer safety decisions and posting the results of the review on the agency's website. This shift appears to have encouraged manufacturers to submit their decisions to FDA for review but has limited public opportunity to provide input.

Food additives and substances considered "generally recognized as safe" must not be allowed in food unless there is a reasonable certainty in the minds of competent scientists that the substance is not harmful under the intended conditions of use. Scientists determine safety by ensuring that the expected exposure is less than the acceptable daily intake. The U.S. Food and Drug Administration (FDA) provides guidance documents to assist safety assessors in this analysis. A November 2011 workshop sponsored by The Pew Charitable Trusts, the Institute of Food Technologists, and the journal Nature reviewed the agency's exposure assessment approaches. More than 70 experts from government (including FDA), industry, academia, and public interest organizations examined the principles underlying dietary exposure assessments for substances added to human food, and responded to questions about current methods. FDA's approach was seen as serving the agency reasonably well, but participants identified opportunities for improvement. Although reaching a consensus was not a goal, general agreements emerged that FDA should develop a science-based framework to prioritize and reassess prior safety decisions, and conduct more extensive postmarket monitoring. Participants discussed the possibility of harmonizing different approaches to assess dietary exposure. They generally agreed that collaboration, communication, and exchanging scientific information between agencies and stakeholders would help assessors use the most current information to make better decisions. Participants identified data gaps and opportunities to fill the gaps using new tools and technologies. Participants generally agreed on the need to consider all dietary sources in a cumulative dietary exposure assessment. Executive SummaryTo determine whether substances added to human food are safe, the U.S. Food and Drug Administration (FDA) asks 2 basic questions: First, how much of that substance will people consume on a daily basis over a lifetime? And 2nd, how much of that substance is considered a safe amount to eat daily based on scientific studies?The answers to these questions are informed by the calculation of the estimated daily intake (EDI) and acceptable daily intakes (ADI), respectively. These are complex scientific principles and not easy to determine. Complicating matters, the answers may change over time as consumer behavior shifts (for example, more people may seek out specialized diets, such as meat-free or low-carb), or as business practices change (such as when a new sweetener is developed). Similarly, the answers may change as the science of toxicology advances and more information becomes available MS