U. S. Food and Drug Administration's (FDA) Safety Assessment of

Chapter 9

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U. S. Food and Drug Administration’s (FDA) Safety Assessment of Food Ingredients T. S. Thurmond* U.S. Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of Food Additive Safety, 5100 Paint Branch Pkwy., HFS-265, College Park, Maryland 20740 *E-mail: [email protected].

The FDA’s Center for Food Safety and Applied Nutrition (CFSAN) and Center for Veterinary Medicine have regulatory responsibility for approximately 80% of foods and food-related products consumed in the United States. The safety assessment of ingredients added directly to foods meant for human consumption is an important component of this responsibility. Before food ingredients such as certified colors, colors derived from natural sources, artificial sweeteners, leavening agents, etc., can be introduced into the food supply they require a safety decision that they present “… a reasonable certainty in the minds of competent scientists that the substance is not harmful under the intended conditions of use.” This section will present a brief summary of the safety assessment process conducted for chemicals added to our food supply as food additives or color additives. It will also briefly discuss the current FDA draft regulatory guidance for the use of food-related products developed using nanotechnology, as well as some of the issues associated with toxicology testing of food ingredients developed using this technology. Lastly, it will discuss the potential for the incorporation of alternative in vitro and in vivo toxicity testing methods into the overall safety assessment paradigm.

Not subject to U.S. Copyright. Published 2014 by American Chemical Society In Food Additives and Packaging; Komolprasert, V., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.


Chemicals Added to Food The FDA regulates chemicals added to foods per the requirements in section 409 of the Federal Food, Drug, and Cosmetic Act (FD&C Act). Section 409 of the FD&C Act establishes the processes to be used for authorizing new uses of food additives. Similarly, Section 721 of the FD&C Act establishes the requirements for listing new uses of color additives in food as well as in other FDA regulated products. In both cases, the additives must be determined to be safe by FDA before they are authorized for their intended use. The term safe means a “reasonable certainty of no harm” and is defined in Title 21 of the Code of Federal Regulations Part 170.3(i) (21 CFR 170.3(i)). When the FDA is petitioned to allow the addition of a substance (food additive or color additive used in food) to the US food supply, the petitioner is required to present evidence that the petitioned compound is safe for its intended use(s). The guidance to industry that FDA provides for assessing toxicity is its Redbook 2000: Toxicological Principles for the Safety Assessment of Food Ingredients (1). This guidance is intended to assist petitioners in 1) determining the minimum toxicity studies needed to establish safety, 2) designing and conducting toxicology studies, 3) reporting the results of toxicity studies, 4) conducting statistical analyses of toxicology data, and 5) submitting this information to the FDA as part of the overall petition package. The petitioner is also encouraged to solicit feedback from FDA prior to conducting any safety assessment studies. The need for specific toxicity testing can vary based on the level of potential exposure of the petitioned compound to the population, its structure and its history of published research (i.e., available literature on safety research conducted for the product). Petitioned products that have the potential for high population exposure levels, or have chemical structures associated with cancer initiation, may require a greater number and variety of toxicity studies. For instance, a petition for an ingredient for which high exposure might be anticipated may contain multiple different in vitro and in vivo toxicity studies, including two-year rodent carcinogenicity bioassays. Although not required by FDA, a submission of this type may also include human clinical tolerance studies. On the other hand, a petition for an additive in which exposure is estimated to be low for the intended conditions of use or for which there is already a large body of safety data may only require a small number of additional safety assessment studies. A petitioner would also need to identify the impurities in the additive, determine their concentrations, and assess their potential to produce toxicity. If the petitioner were requesting additional uses of an already approved additive such that there will be an increase in exposure, a determination will need to be made whether the increased exposure would represent a safety concern and thus would require additional toxicity testing. The toxicology data submitted in support of a petitioned additive is reviewed and FDA determines whether the information demonstrates that the proposed use of the additive is safe. In some cases, it may be necessary to request additional studies to answer questions that arise during the review process. Such additional studies may involve testing conducted to address specific issues, such as an immunotoxicology study to address questions regarding potential effects on the 92 In Food Additives and Packaging; Komolprasert, V., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.


immune system (e.g., on immune function or alterations of immune cells). It also may be necessary to request assistance from specialists in evaluating the submitted data, such as the review of pathology information. Once all data requirements have been satisfied and the review is completed, an acceptable daily intake (ADI) may be calculated based on the study results in the most sensitive animal species. The ADI is calculated using the No Observed Effect Level (NOEL) or No Observed Adverse Effect Level (NOAEL) dose of the test compound, which is then divided by a safety factor (e.g., for a well conducted chronic, 1 year study the safety factor would typically be 100 (a factor of 10 for interspecies difference multiplied by a factor of 10 for differences between humans)). The safety factor may be higher, or lower, depending on the quality and/or quantity of the supporting toxicology information. The use of an additive is determined to be safe if the Estimated Daily Intake (EDI) for the additive does not exceed the ADI.

Nanomaterials as Food Additives or Color Additives The emerging field of nanotechnology presents some new challenges for regulatory agencies when products developed using this technology are added to the food supply. Although at present there have been no petitioned uses for nanomaterials as food additives or color additives, they are present in other FDA-regulated products (2). FDA has prepared draft guidance for industry that addresses the use of nanomaterials in regulated products. The first of these, Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology (3) sets forth the points to consider when determining whether an FDA-regulated product involves the application of nanotechnology. A second guidance for industry, Assessing the Effects of Significant Manufacturing Process Changes, Including Emerging Technologies, on the Safety and Regulatory Status of Food Ingredients and Food Contact Substances, Including Food Ingredients that are Color Additives (4), describes the factors manufacturers should consider when determining whether changes in the manufacturing processes, including those that involve nanotechnology, affect the identity, safety, or regulatory status of a food substance. At present, FDA is taking a case-by-case approach to the safety evaluation of nanomaterials in products under its regulatory purview. Safety assessment methodologies for nanomaterials for use in food ingredients are under development. Assays that are currently used to assess the safety of chemical substances as food additives and color additives may or may not be appropriate for toxicity testing of some nanomaterials. As an example, the Ames test (bacterial reverse mutation test), which is recommended by FDA for in vitro analysis of compounds for their potential as mutagens, may not be useful for additives such as titanium dioxide or silver nanoparticles due to the inability of these particulate nanomaterials to penetrate the walls of the bacteria used in the assay (5). Other issues also may need to be addressed before a test method can be validated for assessing the safety of a nanomaterial. Further research will need to be conducted on the optimization of in vitro and in vivo toxicity testing paradigms for different types of nanomaterials (e.g., metallic nanoparticles, 93 In Food Additives and Packaging; Komolprasert, V., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.

liposome nanocapsules, etc.) and on improved tests for determining the fate of nanomaterials in the alimentary tract and their bioaccessibility in the small intestine.


Alternative in Vitro and in Vivo Safety Assessment Paradigms In recent years, there has been increased concern over the expense of some of the more commonly recommended safety assessment tests, as well as the large number of animals that may be used in such tests. For instance, a standard chronic/carcinogenicity bioassay lasts one to two years, can cost several millions of dollars, and include nearly 900 animals in the in utero, chronic and carcinogenicity phases. In light of this, FDA CFSAN has started evaluating the potential utility of alternative approaches to traditional animal safety studies. To this end we are currently evaluating a number of alternate safety assessment models such as, the use of non-mammalian species (e.g., zebra fish, C. elegans), computational toxicology (Quantitative Structure Activity Relationships (QSAR)), high throughput in vitro test systems (e.g., Tox21), organ-on-a-chip systems, short-term mammalian alternatives, and other novel in vitro assays that would result in reduced numbers of study animals, lower overall cost, and/or shorter study durations. We have previously adopted alternative methods such as the QSAR computational toxicology method that is used to evaluate the mutagenic and/or carcinogenic potential for contaminants that may be found in food contact materials for which there are little toxicity data (6). The FDA also currently receives data from in vitro genetic toxicity and mutagenicity studies in support of the approval process for food contact materials, for comparison with the QSAR results. The main concerns regarding these alternative testing paradigms are their ability to give dose/response and time-related information on food-related products that may be consumed at various concentrations over a lifetime. Overall, our focus in our evaluation of these alternative methods is to determine whether they can produce results that will satisfy the determination of a “reasonable certainty of no harm” for a food additive or color additive.

References 1.

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U.S. Food and Drug Administration. Guidance to industry: Redbook 2000, Toxicological Principles for the Safety Assessment of Food Ingredients; July 2007. Sánchez-Pomales, G.; Mudalige, T. K.; Lim, J.; Linder, S. W. Rapid Determination of Silver in Nanobased Liquid Dietary Supplements Using a Portable X-ray Fluorescence Analyzer. J. Agric. Food Chem. 2013, 61, 7250–7257. U.S. Food and Drug Administration. Guidance to industry: Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology; June 2011. U.S. Food and Drug Administration. Guidance to industry: Assessing the Effects of Significant Manufacturing Process Changes, Including Emerging 94 In Food Additives and Packaging; Komolprasert, V., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.

5.


6.

Technologies, on the Safety and Regulatory Status of Food Ingredients and Food Contact Substances, Including Food Ingredients that are Color Additives; April 2012. Woodruff, R.; Li, Y.; Yan, J.; Bishop, M.; Jones, M.; Watanabe, F.; Biris, A.; Rice, P.; Zhou, T.; Chen, T. Genotoxicity evaluation of titanium dioxide nanoparticles using the Ames test and Comet assay. J. Appl. Toxicol. 2012, 32, 934–43. U.S. Food and Drug Administration. Regulatory Report: Assessing the Safety of Food Contact Substances; April 2013.

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U. S. Food and Drug Administration's (FDA) Safety Assessment of

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