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This article is one of a series of 4 that report on a task of the NanoRelease Food Additive project of the International Life Science Institute Center for Risk Science Innovation and Application to identify, evaluate, and develop methods that are needed to confidently detect, characterize, and quantify intentionally produced engineered nanomaterials (ENMs) released from food along the alimentary tract. This particular article focuses on the problem of detecting and characterizing ENMs in the various compartments of the alimentary tract after they have been ingested from dietary sources. An in depth analysis of the literature related to oral toxicity of ENMs is presented, paying particular attention to analytical methodology and sample preparation. The review includes a discussion of model systems that can be used to study oral uptake of ENMs in the absence of human toxicological data or other live-animal studies. The strengths and weaknesses of various analytical and sample preparation techniques are discussed. The article concludes with a summary of findings and a discussion of potential knowledge gaps and targets for method development in this area.

Scientists participating in 2 multistakeholder meetings in 2011 and in other events have identified a number of ways in which the methods the U.S. Food and Drug Administration (FDA) uses to assess the safety of chemicals in human food should be improved and updated. We evaluated whether FDA's current methods, including its decision-making process, are outdated, as alleged by its critics. We examined a 1982 report by the Select Committee on GRAS Substances (SCOGS) that included suggestions to enhance food additive safety. FDA established SCOGS to review the safety of "generally recognized as safe" (GRAS) substances in response to a directive by President Nixon. When evaluating FDA's response to SCOGS' suggestions, we found that many remain unresolved and relevant today. Our analysis demonstrates that in many cases FDA has not kept pace with scientific developments. Although difficult to pinpoint, we concluded that this situation became more significant after 1997, when FDA launched the voluntary GRAS notification program aimed at enticing manufacturers to inform the agency of their own safety decisions. Looking forward, we recommend that the agency convene an unbiased and independent expert workgroup to conduct a comprehensive review of FDA's science and decision making and develop a path to modernize food additives safety assessment. Areas of concern include toxicology test guidelines, tools used to predict health outcomes, conflict of interest in manufacturers' decisions, lack of a reassessment strategy, and lack of a definition of harm.

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.

Objective Multinucleated cells are relatively resistant to classic apoptosis, and the factors initiating cell death and damage in myositis are not well defined. We hypothesized that nonimmune autophagic cell death may play a role in muscle fiber damage. Recent reports indicate that TRAIL may induce both NF-κB activation and autophagic cell death in other systems. We undertook this study to investigate the role of TRAIL in cell death and pathogenesis in vitro and in vivo, using myositis muscle tissues from humans and mice. Methods Gene expression profiling was performed in myositis patient and control muscle specimens. Immunohistochemistry analysis was performed to confirm the gene array findings. We also analyzed TRAIL-induced cell death (apoptosis and autophagy) and NF-κB activation in vitro in cultured cells. Results TRAIL was expressed predominantly in myositis muscle fibers, but not in biopsy specimens from normal or other dystrophic-diseased muscle. Autophagy markers were up-regulated in humans with myositis and in mouse models of myositis. TRAIL expression was restricted to regenerating/atrophic areas of muscle fascicles, blood vessels, and infiltrating lymphocytes. TRAIL induced NF-κB activation and IκB degradation in cultured cells that are resistant to TRAIL-induced apoptosis but that undergo autophagic cell death. Conclusion Our data demonstrate that TRAIL is expressed in myositis muscle and may mediate both activation of NF-κB and autophagic cell death in myositis. Thus, this nonimmune pathway may be an attractive target for therapeutic intervention in myositis.

Science and expert judgment are the foundation for safety assessments of chemicals added to food to ensure their use is safe. Hazard characterization is the first step in a safety assessment. Advances in science and technology pose challenges to the regulatory system and raise questions about whether the current hazard identification and characterization process is able to systematically and transparently encompass such advances while remaining defensible. An April 2011 workshop sponsored by The Pew Charitable Trusts, the Institute of Food Technologists, and the journal Nature brought together over 80 experts in science and food policy from government, industry, academia, and public interest organizations to examine the principles underlying the development and use of scientific evidence needed for chemical hazard characterization. Participants discussed challenges of identifying adverse health effects, advances in science, uses of new screening technologies and human biomonitoring data, updating of study designs, and development and review of toxicity test guidelines. Brainstorming sessions allowed participants to propose alternatives to enhance FDA's evaluation of science for safety assessment. Although there was no intention to reach a consensus, several themes emerged including the need for clear procedures to develop validated toxicity tests; importance of regularly updating guidance documents relied upon by regulators and industry; benefits of transparency and public access to information; potential for greater interagency collaboration; opportunities to improve hypothesis-based research to make it more useful to regulatory decision making; and importance of staying abreast of scientific developments to ensure that safety assessments are made using sensitive and relevant methods.

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.