doi: / Vol.12,2013 ComprehensiveReviewsinFoodScienceandFoodSafety 439 C 2013 The Pew Charitable Trust

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1 Looking Back to Look Forward: A Review of FDA s Food Additives Safety Assessment and Recommendations for Modernizing its Program Maricel V. Maffini, Heather M. Alger, Erik D. Olson, and Thomas G. Neltner Abstract: 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 We evaluated whether FDA s current methods, including its decision-making process, are outdated, as alleged by its critics.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. Introduction In 1969, President Richard Nixon requested that the U.S. Food and Drug Administration (FDA) reexamine the structure and procedures used by the agency to approve chemical additives to ensure they were fully adequate. The administration initiated a full review of food additives with particular focus on the safety evaluation of chemicals that FDA designated as generally recognized as safe (GRAS) (Nixon 1969). In response, FDA established the Select Committee on GRAS Substances (SCOGS) with the task of evaluating the safety of more than 450 GRAS substances. The committee conducted its analysis from 1972 to 1982; it was made up of experts in biochemistry, pharmacology, and medicine and was operated by a 3rd party (Contract Nr FDA ). Its final report, Insights on Food Safety Evaluation (SCOGS 1982), published in 1982, contained SCOGS conclusions for each of the chemicals and provided FDA with a roadmap to evaluate the safety of additives by making suggestions to enhance the agency s program. Since that time, an array of peer-reviewed scientific studies and published reports has questioned the safety of certain artificial MS Submitted 3/15/2013, Accepted 4/20/2013. Authors are with The Pew Charitable Trusts, 901 E St., NW, Washington, DC 20004, U.S.A. Direct inquiries to author Maffini ( mmaffini@pewtrusts.org). colors, sweeteners, preservatives, and pesticide residues in food. The controversy over bisphenol-a intensified the questions about whether FDA uses the best scientific evidence to make safety decisions. The food additive safety issue came to a head in 2010 with a commentary by the editors of the journal Nature (Nature 2010) calling for scientific reform to limit the approval of chemicals of questionable safety. The editorial prompted a thoughtful response by 2 senior FDA scientists (Lorentzen and Hattan 2010). They stated that safety regulation depends upon scientific consensus and that without a consensus over the state of science for a particular issue, there is no end in sight to the claims that can be made for which a consensus does not exist. They continue by saying that [t]o abandon this conceptual objective for any temporary, subjective, personal convenience is a formula for a general regulatory impasse. The discussion initially focused on bisphenol-a because of its impacts on the hormonal system; however, the questions about FDA s use of science in safety decision making have expanded beyond endocrine disruption. In light of these criticisms, The Pew Charitable Trusts, Nature, and the Institute of Food Technologists hosted 2 multistakeholders events (hereafter Pew workshops) in 2011 to explore the roots of these criticisms. FDA was a key participant in the discussions and material preparation. The discussions made clear that there are significant questions about hazard assessment, estimating C 2013 The Pew Charitable Trust doi: / Vol.12,2013 ComprehensiveReviewsinFoodScienceandFoodSafety 439

2 dietary exposure, and the decision-making process for food additives (Maffini and others 2011; Alger and others 2013). Tasked with both assessing the science and making policy decisions, FDA s actions have enormous public health implications, significant consequences for the food industry, and could have impacts on the cost and availability of foods. Therefore, controversies should be expected. The objective for a regulatory agency grounded in science, such as FDA, is to base decisions on the best available and most up-to-date data and develop science-based policies. To earn the confidence of industry, public health advocates, and consumers, the agency s methods must also be clearly explained and transparent. Here we present a detailed evaluation of FDA s use of science to identify whether the agency s safety assessment methods are outdated, as alleged by its critics. We compared the current controversies surrounding food chemical safety identified by the Pew workshops participants with the suggestions made by SCOGS in 1982 and analyzed the common areas of concern. We used SCOGS final report as a reference because it was the most comprehensive and structured analysis of the science and decision making used in food additive safety available and was prepared in close coordination with FDA. We conclude with our recommendations for FDA looking forward. Methods We reviewed SCOGS final report and identified statements where the committee members explicitly described a measure that, in their opinion, would enhance safety assessment. For simplicity, we refer to each of SCOGS points as suggestions, although the committee may have characterized them as an insight, opinion, recommendation, or action the agency should take. For each suggestion, we evaluated FDA s handling of them and also determined whether a similar issue was raised by participants at either of the Pew workshops. We also reviewed the proceedings from 2 Pew workshops held on 2011 to identify whether the issued raised by SCOGS were also raised as concerns by the workshop participants. These workshops dealt with chemical hazard identification and characterization and dietary exposure assessment (Maffini and others 2011; Alger and others 2013). We identified the SCOGS suggestions that FDA did not implement and compared them to the ongoing concerns raised in the workshop proceedings. Where we found matches, we consolidated them into broad areas of concern. For simplicity, when we use the term food additives we include food and color additives as well as GRAS substances. In addition, we refer to FDA only in the context of its food additive regulatory program. Background FDA s criteria for food additives safety assessment In 1982, the same year of SCOGS final report, FDA released its Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food, also known as the Redbook, which contained guidance for industry in performing toxicological tests. The 1st edition was more than a compilation of recommended test methods. It contained FDA s criteria for assessing safety and ensuring that chemicals remain safe after their approval and introduction into the market (FDA 1982). The criteria were based on the concept of concern where the degree of concern was determined by the extent of human exposure and the toxicity of the additive. The concern levels determined the extent and type of basic toxicological testing of an additive (FDA 1982; Rulis and Hattan 1985). The levels were developed using: Estimated per capita exposure based on information that food and additive manufacturers voluntarily submitted to the National Academy of Sciences; and Chemical structure based on a qualitative decision tree assigning chemicals to 3 broad categories established by inferences between structure and known toxicity. The higher the concern level, the higher the extent of toxicity testing. The levels are still used today to determine the minimum toxicity tests to be performed for safety evaluation of direct food additives and color additives (FDA 1982, 2006b). The 1982 Redbook also recognized that additional toxicity information may be needed because either the original data were insufficient to make a final determination or [a]dditives once approved do not always remain static relative to the exposure and toxicological criteria used originally to evaluate their safety. The agency developed a framework for reassessment that considered public health concerns, demonstrated toxic potential at levels present in the food, and accounted for economic and administrative realities (FDA 1982). Since 1982, science and technology have made great strides and, as a result our knowledge of normal body functions and disease development and our capability to measure chemicals have grown dramatically over time. Historically, as our understanding of new scientific findings has developed, regulatory programs have incorporated them into guidance and rules. Introduction to SCOGS suggestions The SCOGS report provides a useful starting point for understanding FDA s response to scientific progress and the origin of some of the current controversies for 3 reasons: 1st FDA established the committee and concurred that a critique of the experience was appropriate (SCOGS REF) so it was fully aware of the suggestions; 2nd, the SCOGS report was the most comprehensive and structured analysis of the science and decision making used in food additive safety available; and 3rd, FDA has had sufficient time to respond to the suggestions. Introduction to the Pew workshops The 2 workshops held in 2011 were hosted by the Pew Charitable Trusts, Nature, and the Institute of Food Technologists. More than 80 scientists, lawyers, and public health advocates representing industry, academia, public interest organizations, and government agencies. These workshops dealt with chemical hazard identification and characterization and dietary exposure assessment. When the organizers developed the agendas, they were not aware of the SCOGS report. Therefore, there was not any attempt to synchronize the topics of discussion with the committee s suggestions. Several months after the last workshop, the authors of this article read SCOGS final publication and noticed startling similarities between many of the issues even though 30 y had passed. Results Analysis of SCOGS suggestions SCOGS made 35 suggestions some of which overlapped. We grouped them into 9 topics: 1. Substance identification 2. Exposure assessment 3. General toxicity testing 4. Specific testing needs 440 Comprehensive Reviews in Food Science and Food Safety Vol. 12, 2013 C 2013 The Pew Charitable Trust

3 5. Role of human studies 6. Evaluating evidence 7. Consistency in approaches 8. Definition of safety 9. Revisiting assessments. Table 1 summarizes the suggestions and our analysis of their current status based on whether FDA addressed each of them. The 1st column contains SCOGS suggestions; we kept much of the original language and structure. The 2nd column contains their current status. It is important to note that SCOGS was not tasked with evaluating FDA s food additives decision making; rather, its final report contained the expert opinions of scientists who spent 10 y reassessing the safety of chemicals already on the market. The agency was not obligated to implement the committee s suggestions. However, FDA has acted on several of them. For example, the agency: Developed sophisticated methods to use food consumption data provided by the National Health and Nutrition Examination Survey (NHANES) to more accurately estimate human exposure to food additives; Created methods to estimate migration from food contact materials, including use of modeling to complement its test protocols; Embraced the use of in vitro testing for genotoxicity and computational methods to gather biological data on related substances; Established methods to routinely consider differences between animal models and human scenarios and recommends animal feeding studies; Recommended a battery of tests in the Redbook and integrated predictive models into the toxicity analysis. There are, however, a number of SCOGS suggestions not followed that are similar to those indicated by the Pew workshop participants 30 y later. Comparison of SCOGS suggestions to workshop proceedings We reviewed the workshop materials and determined that 29 of the 35 suggestions were related to issues on the agenda for discussion. Participants did not raise concerns with one issue related to a SCOGS suggestion involving estimating migration of chemicals from packaging. Excluding these 6 suggestions not raised and the 1 not raising concerns, we identified 28 SCOGS suggestions that were similar to concerns raised by Pew workshops participants in Table 2 provides a side-by-side comparison between these suggestions and what the participants said. Areas of concern still relevant 3 decades later After reviewing Table 1 to identify those suggestions not implemented by FDA and Table 2 to identify those issues that were still relevant in 2011, we consolidated the common issues into 9 broad areas of concern. They are: Behavioral impacts; Endocrine systems; Subpopulations; Toxicological insignificance; Absorption, distribution, metabolism and excretion (ADME); Classifying assessment decisions for consistency and clarity; Personal bias and conflicts of interest; Reassessment and consistency across substances; and Weight of evidence. Because science has substantially advanced since 1982, the workshops participants also raised concerns about FDA s considerations of new scientific developments such as nanotechnology, the interagency Tox21 program designed to screen chemicals for potential toxicity, and biomonitoring. However, we did not include these issues in our analysis since they did not exist at the time of SCOGS. Additionally, there was an overarching issue that concerned workshop participants: the lack of definitions of harm or adverse effects in FDA rules and public guidance documents. Participants noted that this gap resulted in FDA interpreting adverse effects on a case-by-case basis, an approach considered less than predictable (Maffini and others 2011). In contrast, other agencies dealing with chemical safety, such as the U.S. Environmental Protection Agency (EPA) (EPA 2013) and the Joint World Health Organization/Food and Agriculture Organization Expert Committee on Food Additives (JECFA) have formal definitions of adverse effects (IPCS 2011). We did not include this issue as an area of concern; rather, we briefly mentioned discussions about harm or adverse effects in the context of the areas of concern Behavioral impacts and Endocrine systems. Below is a detailed discussion of the 9 areas of concern listed above. Behavioral impacts. At the time SCOGS was reviewing GRAS substances, a pediatrician proposed that some children may have heightened susceptibility for certain additives in the diet that are manifested by hyperactive behavior and some brain dysfunction (Feingold 1975). The proposal prompted scientists and physicians to gather evidence suggesting that artificial colors and flavors, as well as other additives, in the diet influence the behavior of some children (Weiss 2012). With this scientific debate as a backdrop, SCOGS recommended that FDA develop guidelines for behavioral testing concluding that [m]uch effort is needed in the development of animal tests of relative simplicity that may provide quantifiable and reproducible information on behavioral effects in animals at the levels of intake relevant to human exposure. It stated that to answer whether foods and food ingredients may cause or aggravate some behavioral disorders, the development of such tests should command a far more aggressive attack than it has up to now, concluding that a firm foundation can then be achieved within the next decade or two. Participants at the Pew workshops (Maffini and others 2011) raised similar issues stating that: A definition for what constitutes harm in the context of behavioral impacts is needed; Existing screens do not detect more subtle effects on the structural or functional integrity of the nervous system, such as learning, memory, anxiety, or hyperactivity; and Animal tests need to be better designed to reflect complex human behaviors. They also noted that, although there are many endpoints listed in the Redbook, they capture obviously abnormal behavior and will not detect more subtle effects. The current Redbook Neurotoxicity Studies guidance (FDA 2000) recommends a flexible, tiered approach, based on a caseby-case assessment of the available toxicity information of a given compound. FDA recommends performing a systematic clinical evaluation of animals used for basic toxicology testing to include endpoints such as seizure, tremor, paralysis, or other signs of neurological disorder; the level of motor activity and alertness; and any other signs of abnormal behavior or nervous system toxicity. It also C 2013 The Pew Charitable Trust Vol. 12, 2013 Comprehensive Reviews in Food Science and Food Safety 441

4 Table 1 Summary of the current status of the suggestions SCOGS made to FDA in What did SCOGS say? Topic 1. Substance identification Fully characterize chemicals to ensure material actually used in food is the same as the product on which toxicity tests were performed. Use Food Chemicals Codex (FCC) specifications to facilitate process. (Chapter III, Identity and characterization of substances added to foods) Clearly establish the identity of all food ingredients. Include in specification the levels of toxicologically relevant components. (Chapter VI, Specific suggestions, Identity of substances added to foods) Carefully consider byproducts of reactions of chemicals in food. (Chapter III, Identity of substances consumed) Topic 2. Exposure assessment Estimate migration from packaging. (Chapter III, Identity of substances consumed) Develop accurate estimates of consumption of food products using data from those who eat the food and determine upper percentiles of intake. (Chapter III, Food consumption data) Need to know total quantity added to foods and per capita disappearance when chemical is widely distributed in food supply. (Chapter VI, Specific suggestions, Consumer exposure data) Consider subpopulations who: Are particularly susceptible; Consume substantial quantities of a type of food; and May benefit from nutrient supplementation. (Chapter VI, Specific suggestions, Consumer exposure data) Topic 3. General toxicology testing Do not assume there is no hazard below an arbitrary threshold. (Chapter IV, Toxicological insignificance) Know how chemicals are absorbed, distributed, metabolized and excreted (ADME) by the body. In studies, use doses at levels relevant to human exposure. Develop tools to measure relevance of different test methods. (Chapter V, Relevancy) Use health statistics to set priorities to develop and implement test methods considering cardiovascular disease, cancer, hyperactivity, neurological effects, immune system impacts, and reversibility of potential danger. (Chapter VI, Future priorities) Develop reliable test methods to evaluate the significant health hazards relevant to food ingredients. (Chapter VI, Future priorities) Maintain a balance between a comprehensive battery of tests and simpler, less time-consuming and less expensive model systems to evaluate toxicity. (Chapter VI, Future priorities) Topic 4. Specific testing needs Use in vitro tests as an indicator of need for in vivo tests for potential carcinogenicity. (Chapter IV, Single-cell systems and submammalian models) As tissue hormone receptor tests become available, use them to identify potential toxicity concerns for further evaluation. Test at doses relevant to actual exposure, combined with potentially interactive chemicals. (Chapter IV, Nonhuman mammalian systems) Develop animal tests of relative simplicity to provide quantifiable and reproducible information on behavioral effects at levels relevant to human exposure. (Chapter VI, Specific suggestions, Behavioral tests) Develop methods to detect and study hypersensitivity. (Chapter VI, Specific suggestions, Hypersensitivity) Authors summary of current status FDA has explicit requirements that petitions for agency approval must have detailed characterization of the chemical. Its decisions establish specifications in rules and frequently reference the FCC. As the FCC has been updated, these references are outdated. In the late 1990s, FDA moved away from petitions for direct additives to an informal voluntary notification approach without rulemaking or regulations. Our review of a representative sample of notifications indicates that 50% do not adequately describe the chemical. OFAS considers byproducts on a case-by-case basis. FDA developed methods to measure chemical migration from packaging and published guidance of their use. It continues to refine the methods. FDA developed sophisticated methods to use federal food consumption information and supplements it with market research reports. It assesses safety based on the exposure by high consumers, typically those who consume quantities of food at the 90th percentile level. FDA monitors postmarket exposure by analyzing retail food for selected elements, nutrients, pesticides, and pollutants. It does not have the authority to systematically collect information from food manufacturers after approving an additive s use. FDA typically does not consider all dietary sources such as pesticides, chemicals in drinking water and dietary supplements, which limits the accuracy of the exposure assessment. The accuracy is also limited by uses allowed through GRAS determinations made by food manufacturers about which the agency is not notified. See Subpopulations,and Reassessment and consistency across substances sections for more information. In 1995, FDA exempted chemicals from all toxicological testing if they are not suspected carcinogens and the amount in the diet is estimated to be less than 0.5 ppb. It also calls for only genotoxicity testing for chemicals with estimated cumulative exposure between 0.5ppb and equal or less than 50 ppb. These levels were based on a limited set of data that do not consider hormonal or behavioral impacts. See Toxicological insignificance section for additional analysis. FDA Redbook requests ADME information for all but direct additives with the lowest level of concern. These levels define minimum toxicology testing needs. Authors reviewed a representative sample of GRAS notices for which FDA had no questions and found that the notifier did not provide ADME information in 50% of the notices. Level of concern was not identified in any of the notices. See ADME section for additional analysis. FDA does not call for animal studies to use doses relevant to consumers exposure. FDA considers health statistics on a case-by-case basis. For example, it is evaluating the contribution of the additives sodium and trans fats to cardiovascular disease. In response to concerns with cancer, OFAS calls for genotoxicity tests for all direct additives and for food contact substances that may exceed 0.5 ppb in the diet. FDA does not systematically reassess safety of substances or set priorities for review of prior decisions. See Reassessment and consistency across substances section for additional analysis. In 1982, FDA was on the leading edge of safety assessment, releasing its Redbook guidance for industry in performing toxicological studies. It updated the document in 1993 and 2000, and periodically since then. However, the document has fallen behind guidance by the Organisation for Economic Co-Operation and Development (OECD) and EPA. See Endocrine systems, Subpopulationsand Behavioral impacts sections for additional analysis. FDA established a battery of tests in the Redbook and integrates predictive models into that analysis. It is participating in Tox21 to develop less expensive tests and has supported and used computational models. See Behavioral impacts and Endocrine systems sections for additional analysis. FDA systematically uses in vitro tests for genotoxicity. FDA s Redbook considers endpoints such as reproductive toxicity that may result from endocrine disruption. It does not recommend measuring more sensitive but less evident endpoints that reflect potentially significant harm from hormonally active chemicals. Nor does it require doses that are relevant to actual human exposure. When alerted to potential problems, FDA considers these issues on a case-by-case basis. FDA does not recommend any of the available validated screening tests. See Endocrine systems section for additional analysis. FDA s Redbook recommends screening for neurotoxicity by observing animals for seizures, paralysis, and so on and examining the histopathology of the brain and nervous system. When problems are identified, FDA recommends further testing on a case-by-case basis. The Redbook makes no use of the many available tests to quantify behavior impacts of significance to humans, such as those for learning and memory adopted by EPA and OECD. See Behavioral impacts section for additional analysis. FDA does not recommend tests for hypersensitivity or severe allergic reactions. See Subpopulations section for additional analysis. (Continued) 442 Comprehensive Reviews in Food Science and Food Safety Vol. 12, 2013 C 2013 The Pew Charitable Trust

5 Table 1 Continued What did SCOGS say? Topic 5. Role of human studies Take special care to consider subpopulations for nutrients and consider human prospective studies when possible. Do not ignore behavioral tests to assess safety. (Chapter IV, Observations on human subjects) Evaluate special risks of subpopulations, especially for nutrients. (Chapter IV, Subpopulations) Require controlled evaluation in human subjects. (Chapter VI, Specific suggestions, Human data) If hypersensitivity is possible, conduct human prospective studies considering subpopulations with different sensitivities. (Chapter IV, Subpopulations) Topic 6. Evaluating evidence Conduct literature search for relevant biological information on related substances to assure direct functional ties between literature compilation and safety evaluation. (Chapter III, Literature surveys and data collection) Consider bioavailability of nutrients since their safety issues are different from other additives. (Chapter III, Efficacy of substances added to foods) Carefully consider reproducibility and coherence with other data in the overall pattern of the biological response. (Chapter V, Credibility of data) Be cautious when animal consumption scenarios are not similar to human scenarios and effects on animals may be manifested differently in humans. (Chapter V, Particularization of judgment) Rely on independent evaluations by nongovernment scientists without conflicts of interest where there is a public controversy. (Chapter III, Selection of scientific panel) Ensure experts are sensitive to their personal bias regarding safety, adequacy of data, conventional wisdom, and unconfirmed studies. (Chapter V, Extra-scientific factors) Topic 7. Consistency in approaches Phase out the GRAS list. Assess potential health hazards of chemicals using a single system. (Chapter VI, Specific suggestions, Phaseout of GRAS list) Develop consistent approach between food, drugs, and environmental contaminants. (Chapter VI, Future priorities) Topic 8. Definition of safety For nutrients, potential health benefits should be compared to risks. (Chapter V, Risk/Benefits) Require demonstration of efficacy of GRAS-listed substances. (Chapter VI, Specific suggestions, Efficacy of substances added to foods) Seek modification of Delaney Clause to provide flexibility. (Chapter VI, Specific suggestions, Modification of Delaney Clause, Page 34) Topic 9. Revisiting assessments Assign its conclusions assessing the evidence of safety to one of 5 conclusions that cover the majority of situations. These statements identify situations where the use is not clearly safe or unsafe, such as when postmarket studies or monitoring is needed because of limited data. The statements are most useful as a trigger for reassessing safety. (Chapter III, Formulation of questions and answers) Stay current as rapidly advancing science develops, and be prepared to change prior decisions. Adapt to changing public perceptions of acceptable degree of risk. (Chapter V, Dynamics of safety evaluation) Develop consistent approach to treat new information, reversing standing approvals, and burden of proof in borderline cases. (Chapter VI, Future priorities) Develop mechanism to provide temporary clearance followed by monitoring of health complaints and appropriate epidemiological surveys. (Chapter VI, Future priorities) Authors summary of current status FDA considers human studies on a case-by-case basis and does not call for their use. There are several examples where FDA relied on and, in at least one case, requested, human studies. Its analysis of nutrient exposure in diet may be incomplete since FDA s exposure model does not include consumption of nutrients from dietary supplements even though that information is available through NHANES. FDA does not systematically consider subpopulations except for infants and young children. See Subpopulationsand Behavioral impacts sections for additional analysis. FDA guidance examines potential hypersensitivity concerns for genetically engineered plants. However, it recommends no tests for hypersensitivity or severe allergic reaction and does not expect human prospective studies to be conducted. See Subpopulations section for additional analysis. FDA requires labeling for 8 common ingredients associated with severe allergic reactions. The agency accepts consumer reports of allergic reactions, but the system is rudimentary and not consumer-friendly. FDA requests that industry compile and summarize the literature and relevant data in the notifications and petitions it receives. It conducts additional searches to confirm completeness. FDA does not appear to consider nutrients differently from other additives. FDA closely scrutinizes all available studies. However, its analysis is often based on professional judgment and does not make use of the more rigorous methods that have been developed, such as the Cochrane system, to compare various studies in a transparent or reproducible manner. See Weight of the evidence section for additional analysis. Current guidance does not call for testing at doses relevant to consumers. As a result of various federal initiatives, FDA conscientiously manages personal bias in its own decisions through ethics standards, as well as requirements for peer review of its decisions and conflicts of interests for advisory panel members. However, it does not have standards for conflicts of interest for scientists making safety determinations for GRAS substances despite situations where the person is an employee or consultant for the company marketing the product. The problem is especially significant when FDA is not informed of the determination. See Personal bias and conflicts of interest section for additional analysis. GRAS list still exists. FDA has not resolved issues raised by SCOGS for 18 of the chemicals on the GRAS list. FDA has harmonized its analysis of the additives it regulates: color additives, food additives and nonflavor GRAS substances. However, the system takes a significantly different approach than EPA for pesticides and chemicals in consumer products. As a result, the agencies may reach and, in some cases, have reached different outcomes for the same chemical. See Weight of the evidence section for additionalanalysis. FDA definition of safety at 21 CFR does not allow the agency to consider the benefits of a substance or its potential efficacy. FDA narrowly interprets the Delaney Clause. FDA does not assign its safety conclusions to one of the 5 SCOGS conclusions. It believes that it approves only chemicals that SCOGS would conclude are safe and unlikely to warrant future review. Chemicals that SCOGS would assign to one of the 4 other conclusion categories are rejected. FDA does not have a system to reassess the safety of existing chemicals. The authors reviewed FDA s database tracking the toxicology data on almost 4,000 chemicals allowed to be added directly to food. They found that OFAS s own comments on almost 25% of these chemicals stated that there were no or insufficient toxicology data. See Formulation of questions and answers and Reassessment and consistency across substances sections for additional analysis. FDA reassesses prior safety decisions when prompted by stakeholders through citizen petitions, food additive petitions, and to a limited extent, notifications. In 2011, it revoked the GRAS status of a chemical combination. The U.S. Government Accountability Office reported in 2010 on FDA s poor response to various citizen petitions involving GRAS decisions. FDA has not established a consistent or systematic approach to prioritizing or conducting its review of existing safety decisions. In the 1970s, it adopted standards granting interim approval of 4 chemicals but has not used this approach since the SCOGS report. By contrast, for pesticides and chemicals in consumer products, EPA and the European Food Safety Authority have reassessment programs well underway. Both agencies have significantly greater authority than FDA to require additional testing, obtain use and exposure information, and be alerted to unpublished toxicology studies. See Reassessment and consistency across substances sections for additional analysis. C 2013 The Pew Charitable Trust Vol. 12, 2013 Comprehensive Reviews in Food Science and Food Safety 443

6 Table 2 Similarities between the suggestions SCOGS made to FDA in 1982 and the concerns raised by Pew workshops participants in What did SCOGS say? a Topic 1. Substance identification Fully characterize chemicals to ensure material actually used in food is the same as the product on which toxicity tests were performed. Use Food Chemicals Codex (FCC) specifications to facilitate process. (Chapter III, Identity and characterization of substances added to foods) Clearly establish the identity of all food ingredients. Include in specification the levels of toxicologically relevant components. (Chapter VI, Specific suggestions, Identity of substances added to foods) Topic 2. Exposure assessment Develop accurate estimates of consumption of food products using data from those who eat the food and determine upper percentiles of intake. (Chapter III, Food consumption data) Need to know total quantity added to foods and per capita disappearance when chemical is widely distributed in food supply. (Chapter VI, Specific suggestions, Consumer exposure data) Consider subpopulations who: Are particularly susceptible; Consume substantial quantities of a type of food; and May benefit from nutrient supplementation. (Chapter VI, Specific suggestions, Consumer exposure data) Topic 3. General toxicology testing Do not assume there is no hazard below an arbitrary threshold. (Chapter IV, Toxicological insignificance) Know how chemicals are absorbed, distributed, metabolized and excreted (ADME) by the body. In studies, use doses at levels relevant to human exposure. Develop tools to measure relevance of different test methods. (Chapter V, Relevancy) Use health statistics to set priorities to develop and implement test methods considering cardiovascular disease, cancer, hyperactivity, neurological effects, immune system impacts, and reversibility of potential danger. (Chapter VI, Future priorities) Develop reliable test methods to evaluate the significant health hazards relevant to food ingredients. (Chapter VI, Future priorities) Maintain a balance between a comprehensive battery of tests and simpler, less time-consuming and less expensive model systems to evaluate toxicity. (Chapter VI, Future priorities) Topic 4. Specific testing needs As tissue hormone receptor tests become available, use them to identify potential toxicity concerns for further evaluation. Test at doses relevant to actual exposure, combined with potentially interactive chemicals. (Chapter IV, Nonhuman mammalian systems) Develop animal tests of relative simplicity to provide quantifiable and reproducible information on behavioral effects at levels relevant to human exposure. (Chapter VI, Specific suggestions, Behavioral tests) Develop methods to detect and study hypersensitivity. (Chapter VI, Specific suggestions, Hypersensitivity) Topic 5. Role of human studies Take special care to consider subpopulations for nutrients and consider human prospective studies when possible. Do not ignore behavioral tests to assess safety. (Chapter IV, Observations on human subjects) Evaluate special risks of subpopulations, especially for nutrients. (Chapter IV, Subpopulations) Require controlled evaluation in human subjects. (Chapter VI, Specific suggestions, Human data) If hypersensitivity is possible, conduct human prospective studies considering subpopulations with different sensitivities. (Chapter IV, Subpopulations) What did workshop participants say? At November 2011 workshop, concerns were raised with the agency s ability to ensure compliance when substances are poorly characterized. At April 2011 workshop, concerns were raised about proper characterization of nanomaterials. At November 2011 workshop, participants generally acknowledged the significant improvements FDA has made in exposure estimation; in particular, the use of the National Health and Nutrition Examination Survey (NHANES). Concerns were raised with: Cumulative exposure to all dietary sources; Analysis for sensitive subpopulations such as children and pregnant women; and Standards based on protecting 90th percentile of people who may consume the additive. At April 2011 workshop, concerns were raised about FDA s use of thresholds to determine the needed toxicology testing or to exempt some chemicals from any testing, especially in cases where scientific evidence indicates that chemicals may have adverse effects at very low doses. At April 2011 workshop, participants generally agreed that ADME data were important for all chemicals but particularly for nanomaterials and endocrine disruptors. While acknowledging challenges, concerns were raised that NHANES biomonitoring data are not used to inform ADME, and that toxicology guidance does not call for using doses relevant to human exposure. At April 2011 workshop, concerns were raised that FDA needs to develop a prioritization system for validating new test guidelines to focus FDA s limited resources on the most pressing public health concerns and with known relationships to the national rates of morbidity and mortality such as diabetes, obesity and high blood pressure. At November 2011 workshop, participants generally agreed that FDA should use the NHANES biomonitoring data to set reassessment priorities. At April 2011 workshop, concerns were raised that the Redbook has not kept pace with scientific developments and needs tests and endpoints that serve as early markers of health problems: for example, diabetes, obesity and high blood pressure. At April 2011 workshop, concerns were raised about the need for priorities between limited resources and benefits of additional tests. At April 2011 workshop, concerns were raised with: Whether current methods were sufficiently sensitive to identify endocrine disruption; Lack of screening methods for potential hormonally active chemicals; and No definition of harm for endocrine impacts. At April 2011 workshop, concerns were raised with: The lack of definition of harm for behavioral impacts; and The existing animal tests, which may not capture the subtle yet complex human behaviors that may be of concern At November 2011 workshop, concerns were raised about methods to evaluate severe allergic reactions. At November 2011 workshop, concerns were raised that FDA does not appear to consider subpopulations that rely on nutrients from dietary supplements when evaluating additives that are similar. At April 2011 workshop, some participants observed that guidance is needed for clinical behavioral studies. At November 2011 workshop, concerns were raised about severe allergic reactions. (Continued) 444 Comprehensive Reviews in Food Science and Food Safety Vol. 12, 2013 C 2013 The Pew Charitable Trust

7 Table 2 Continued What did SCOGS say? a Topic 6. Evaluating evidence Carefully consider reproducibility and coherence with other data in the overall pattern of the biological response. (Chapter V, Credibility of data) Be cautious when animal consumption scenarios are not similar to human scenarios and effects on animals may be manifested differently in humans. (Chapter V, Particularization of judgment) Rely on independent evaluations by nongovernment scientists without conflicts of interest where there is a public controversy. (Chapter III, Selection of scientific panel) Ensure experts are sensitive to their personal bias regarding safety, adequacy of data, conventional wisdom, and unconfirmed studies. (Chapter V, Extra-scientific factors) Topic 7. Consistency in approaches Phase out the GRAS list. Assess potential health hazards of chemicals using a single system. (Chapter VI, Specific suggestions, Phaseout of GRAS list) Develop consistent approach between food, drugs, and environmental contaminants. (Chapter VI, Future priorities) Topic 9. Revisiting assessments Assign its conclusions assessing the evidence of safety to one of 5 conclusions that cover the majority of situations. These statements identify situations where the use is not clearly safe or unsafe, such as when postmarket studies or monitoring is needed because of limited data. The statements are most useful as a trigger for reassessing safety. (Chapter III, Formulation of questions and answers) Stay current as rapidly advancing science develops, and be prepared to change prior decisions. Adapt to changing public perceptions of acceptable degree of risk. (Chapter V, Dynamics of safety evaluation) Develop consistent approach to treat new information, reversing standing approvals, and burden of proof in borderline cases. (Chapter VI, Future priorities) Develop mechanism to provide temporary clearance followed by monitoring of health complaints and appropriate epidemiological surveys. (Chapter VI, Future priorities) What did workshop participants say? At April 2011 workshop, concerns were raised about reproducibility and transparency of the safety assessment when the assessor evaluates multiple studies with conflicting results. Participants also suggested that testing should include doses relevant to human exposure. At April 2011 workshop, concerns were raised about impacts of the safety assessor s professional judgment, especially in comparing hypothesis- and guideline-based studies. At November 2011 workshop, participants generally agreed on the need for a harmonized system between agencies with respect to the science. At April 2011 workshop, participants raised similar concerns. At November 2011 workshop, participants generally agreed that methods were needed to identify and fill gaps in exposure and toxicology data. At April 2011 workshop, concerns were raised about gaps in toxicology data At both workshops, concerns were raised about the lack of a systematic reassessment of prior safety decisions and the slow rate of incorporation of scientific knowledge into guidance documents in particular, and safety assessment in general. a The workshop participants and its organizers were not aware of the 1982 SCOGS report. The authors reviewed the workshop materials and determined that 29 of the 35 suggestions were related to issues on the agenda for discussion. Participants did not raise concerns with one issue related to a SCOGS suggestion involving estimating migration of chemicals from packaging. The 6 suggestionsnot raised and the 1 not raising concerns were excluded from this table. recommends conducting a pathological examination of the brain, spinal cord, and peripheral nervous system (FDA 2000). Finally, it suggests that [a]s appropriate, more sensitive and objective indices of neurotoxicity, such as tests of learning and memory, and quantitative measures of sensory function and motor behavior, could be included as part of the screen (FDA 2000); however, there are no endpoints or tests recommended. During the Pew workshops (Maffini and others 2011), FDA scientists noted that the cost and efficiency of some of these studies have precluded the inclusion of testing for some of the more subtle aspects of behavior into the guidelines. However, others have reached different conclusions. During the 1980s, EPA promulgated regulations describing how to conduct behavioral and developmental neurotoxicity testing, respectively, and adopted specific behavioral tests for learning and memory. In the late 1990s, EPA updated its toxicology data requirements for pesticides used on food (40 CFR Subpart F ). It established screening tests that rely on a semiquantitative evaluation of a functional observational test. It includes evident behavior endpoints and requires developmental neurotoxicity tests. Similarly, the Organization for Economic Co-operation and Development (OECD) has published a guidance document for neurotoxicity testing (OECD 2004) as well as guidelines (OECD 1997, 2007) to be used in chemical testing programs. For OECD, behavioral testing and endpoints provide one of the most sensitive strategies to reveal subtle functional deficits, adding that behavioral endpoints can uncover alterations in neural or extraneural substrates for which no compensatory alternate behavioral response is available. Its guideline (OECD 2007) provides details of study design, frequency of observations, and endpoints, including a section on learning and memory tests. In summary, FDA has not aggressively pursued the development of test methodologies for behavioral impacts. It has not incorporated into its Redbook methods that EPA and OECD adopted years ago. Endocrine systems. Hormones have been known for hundreds of years to play fundamental roles in basic physiological functions. This understanding led to the development of drugs to manipulate the endocrine system either by correcting problems such as low levels of hormones or by blocking natural hormones from acting in target organs. Furthermore, scientists have shown that some manmade chemicals, not specifically designed to affect human health, can also bind to hormone receptors and trigger agonistic or antagonistic biological effects. Similarly, these chemicals can also interfere with the synthesis or the breakdown of hormones. Chemicals with such actions are called endocrine disruptors (Wingspread Conference 1992). Recognizing the potential for additives to affect the endocrine system, SCOGS said: Recent advances of knowledge on specific tissue receptors disclose additional potential targets for chemical effects or competitive interactions of an added substance with endogenous messengers. For example, in the case of estrogenic hormone receptors and an agent with a high-binding affinity for the receptor, modification of hormonal response might occur at very low concentrations of the agent. While reliable tests of such effects are not currently available, it can be expected that a number will be developed in the future. These tests might indicate unusual binding affinity of agents that cause certain teratogenic effects or influence reproductive or growth patterns by interactions with the relevant hormonal receptors regulating these physiological processes. As predicted by SCOGS, in the last 2 decades, scientists have produced a large body of research results on endocrine disrupting chemicals (Arbuckle and others 2008; Woodruff and others 2011; Vandenberg and others 2012). C 2013 The Pew Charitable Trust Vol. 12, 2013 Comprehensive Reviews in Food Science and Food Safety 445

8 Participants at the Pew workshops (Maffini and others 2011) identified several issues regarding FDA s handling of endocrine disruptors, including: Disagreement on what should be considered an adverse effect and its relevance to human health; Difficulty in selecting health-related endpoints such as biomarkers that could predict disease outcomes; Disagreement over whether current Redbook tests and endpoints are sufficiently sensitive and encompass significant modes of action, including those important during early life or that become apparent long after exposure; and Agreement on the need to understand ADME for endocrine disruptors. We did not find evidence that FDA acted on or attempted to address SCOGS suggestion. Its scientists have maintained that the studies recommended in the Redbook (such as multigenerational reproductive and developmental testing) can and do provide valuable insights into potential endocrine activity due to the possible manifestations of adverse effects (Lorentzen and Hattan 2010). Although open to the possibility of using alternative methods, FDA has yet to recommend that stakeholders use available screening tests for endocrine disruption. By comparison, other offices at FDA have acted on endocrine disruptors. In the mid-1990s, the agency initiated the Endocrine Disruptor Knowledge Base (EDKB) project (FDA 2010b) with the intention to serve as a resource for research and regulatory scientists to foster the development of computational predictive toxicology models and reduce dependency on slow and expensive animal experiments (Ding and others 2010). The project resulted in the development of the EDKB database, which is based on quantitative structure-activity relationships coupled with an integrated system of experimentation and modeling that predicts biological activities. These core features underwent a rigorous validation (Tong and others 2002) via the interagency agreement with EPA. The free database currently includes more than 1,800 chemicals, of which more than 200 are allowed in foods. EPA has also developed and validated screening tests for endocrine disruptors. In response to a 1996 Congressional mandate (Food Quality Protection Act of 1996 P.L U.S.C. 346(a)(p); Amendment to the Safe Drinking Water Act of U.S.C. 300j-17, 1996), in 2009, the agency launched its Endocrine Disruptor Screening Program (EPA 2012), making available test guidelines for validated in vitro and in vivo assays. FDA has expressly rejected the use of at least one of these assays despite the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) determining the assay was validated as a screening test to identify substances with in vitro ER [estrogen receptor] agonist or antagonist activity (Birnbaum 2012). FDA responded that ICCVAM test recommendations are not acceptable for satisfactorily fulfilling the test needs for FDA regulated products and that FDA does not envision a use for this method in its current regulatory framework (Goodman 2012). EPA (Sanders 2012) and the Consumer Product Safety Commission (Hinson 2012) have accepted the new test, and OECD added it to its guidelines (OECD 2012). Lastly, a battery of new tests and predictive tools to identify potential endocrine disruptors is being developed and undergoing validation within the Tox21 program. The program is a collaboration of FDA, EPA, and the National Institutes of Health to use robotics technology to screen thousands of chemicals for potential toxicity, use screening data to predict the potential toxicity of chemicals, and develop a cost-effective approach to prioritizing the thousands of chemicals that need toxicity testing (EPA 2012). The Office of Food Additives Safety joined the intergovernmental project when it was underway; it has nominated chemicals to be tested, and provided toxicological data from its files. In summary, FDA has not taken a leadership role in the development and validation of new technologies to identify and evaluate additives for potential endocrine disrupting activity. Unlike EPA, it has not adopted or made use of validated screening tests and predictive models. Subpopulations. SCOGS made it clear that, during the safety evaluation of additives, regulators must pay particular attention to susceptible populations. The committee identified these groups based on age, gender, and physiologic state (adolescence, pregnancy, lactation), and noted that groups with specific food preferences and individuals with chronic diseases should also be taken into consideration. It said: When the benefits are related not to health, but to organoleptic, technologic, or economic considerations, substantial risk even to a relatively small subgroup of the population is not generally acceptable. A major need in future food safety evaluations is the identification of the population subgroups at special risk, and the extent of the risk. Participants at a Pew workshop (Alger and others 2013) noted that, while FDA currently considers one subpopulation (young children), it should include more groups on a routine basis. Participants mentioned that EPA regularly assesses exposure for a wide variety of subpopulations. FDA routinely assesses exposure for all people aged 2 y and older as one group, as well as children between ages 2 and 5 y as another. It calculates exposure by identifying all of the foods in which the substance will be added, the amount in each food, and the quantity of food consumed by individuals in the United States. The estimated daily intake of an additive is then calculated based on the amount consumed by the so-called high consumer represented by the 90th percentile of the people who eat the food containing the chemical (FDA 2006a). For infant formula, the agency uses an approach tailored to infants likely to be fed the formula (FDA 2004). It evaluates other subpopulations on a case-by-case basis. SCOGS was especially concerned about individuals hypersensitive to food and food additives and described nonspecific cutaneous, gastrointestinal, respiratory, immunologic, and neurologic manifestations as adverse reactions to additives. Although the most common allergens are proteins and peptides found in common foods (for example, soy, nuts, milk, and seafood, as well as glutencontaining food products), certain chemicals commonly used as food additives (such as sulfites) also cause adverse reaction in some individuals. SCOGS wanted FDA to take a proactive role saying that advances [in cell biology and clinical immunology] may aid in the development of simpler and more reliable procedures for the detection of hypersensitivity. FDA only dealt with hypersensitivity in the context of genetically engineered plants. The 1992 policy (FDA 1992) encouraged developers of new plants to consult with FDA early in the genetic engineering process. EPA also lacks guidance to test for hypersensitivity. In 2011, the European Food Safety Authority released draft guidance underscoring the need for hypersensitivity testing (EFSA 2011). In summary, FDA has not systematically considered the exposures to sensitive populations except for infants. For hypersensitivity, it has not 446 Comprehensive Reviews in Food Science and Food Safety Vol. 12, 2013 C 2013 The Pew Charitable Trust