Regulatory Toxicology and Food Flavors - ACS Symposium Series

Chapter 3

Regulatory Toxicology and Food Flavors Downloaded by UNIV OF CALIFORNIA SAN DIEGO on January 11, 2016 | http://pubs.acs.org Publication Date: October 3, 1989 | doi: 10.1021/bk-1989-0409.ch003

Charles J. Kokoski Division of Toxicological Review and Evaluation, Center for Food Safety and Applied Nutrition, Food and Drug Administration, 200 C Street, SW, Washington, DC 20204 Flavors constitute perhaps the largest technically functional group of substances and additives used in food. Flavors really cannot be separated from food. This paper will discuss the regulatory toxicology aspects of food safety, with emphasis on the use of flavors in food, and in particular with the recent innovations of flavor product development.

The primary consideration of products intended for h u m a n consumption is safety. The Food and D r u g Administration (FDA) administers the Food, Drug, a n d Cosmetic Act, and part of the Act includes the Food Additives Amendment of 1958. This amendment places on the regulated industry the burden of responsibility to demonstrate the safety of food additives. However, for many other ingredients used i n food, the burden of demonstrating a lack of safety remains on the government, where it has been for centuries (1). Ideally, we would like everything we eat to be perfectly safe. A point of fact is that since we do not live i n a n ideal, perfect world, we should not expect our food to be perfect. With everything there are inherent risks. The law, therefore, speaks of reasonable certainty that no h a r m will result. Prior to the 1958 Food Additives Amendment, the safety of additives i n food was based on a harmless per se concept. Regardless of the level of animal testing or exposure, if an additive i n food could cause h a r m or injury, it was considered unsafe. That a substance must be nontoxic at any test level was a n absolute and impractical concept. This concept does not recognize that chemicals have thresholds for inducing toxicity. Section 409 of the Act requires that a food additive be shown to be safe under its intended conditions of use before it is allowed i n food. Congress recognized the impossibility of determining with absolute certainty that no h a r m shall result from the intended use of an additive. Therefore, the legislation did not follow a standard of absolute safety. Congress described the safety standard as follows (2): "Safety requires proof of a reasonable certainty that no h a r m will result from the intended use of an additive. It does not - and cannot ~ require proof beyond any possible doubt that no h a r m will result under any conceivable circumstances...The safety of a given additive involves informed judgement based on educated estimates by scientists of the anticipated ingestion of an additive by m a n or animals under likely patterns of use." This chapter not subject to U.S. copyright Published 1989 American Chemical Society In Thermal Generation of Aromas; Parliment, Thomas H., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

Downloaded by UNIV OF CALIFORNIA SAN DIEGO on January 11, 2016 | http://pubs.acs.org Publication Date: October 3, 1989 | doi: 10.1021/bk-1989-0409.ch003

24

THERMAL GENERATION OF AROMAS

In placing the burden of proof of safety through premarket approval on the manufacturer of a new food additive, Congress recognized that it would be impractical to require safety testing of the large number of ingredients that were already i n commercial use i n 1958 without evidence of adverse health effects. Therefore, Congress specified that "generally recognized as safe" (GRAS) substances were exempt from premarket approval. According to the food additive procedural regulations established by the FDA (21 C F R 170.30), general recognition of safety may be based only on the views of experts qualified by scientific training and experience to evaluate the safety of substances added to food. This recognition may be based on either 1) a history of safe common use i n food prior to 1958, or 2) scientific procedures that demonstrate safety. The concept of general recognition of safety requires common knowledge about the substance throughout the portion of the scientific community that is knowledgeable about the safety of substances added to food. To affirm G R A S status of a food ingredient on the basis of scientific procedures, the FDA requires that the sponsor provide the same quality and quantity of scientific evidence to establish safety of the intended use as would be required for approval of a food additive. In addition, G R A S status i s ordinarily based on published studies which may be corroborated by unpublished information. F D A regulatory toxicologists evaluate relevant data, including, i n large measure, data from animal toxicology testing. The potential for adverse health effects are assessed i n order to determine the safety of food additives under conditions of use. Scientific judgment i s excercised i n determining what specific toxicology studies are recommended to demonstrate the safety of a food additive. The F D A must take into account what i s already known about the properties of the additive, its intended conditions of use, and current standards for toxicology testing. Requirements for Demonstrating Safety of Food Additives In 1982 the FDA published its guidelines Toxlcological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used i n Food (3). The guidelines i n this so-called "Redbook" define a system of recommended tiered testing for additives i n food. Not only does the "Redbook" provide testing guidance, it sets out a priority-based ranking scheme for compounds according to level of health concern based on extent of h u m a n exposure and assessed or presumptive toxicological effects. In the absence of actual test data, presumptive toxicity also c a n be anticipated from chemical structure-activity relationships or from the nature of the substance and the known biological activity of substances of the same or similar structural class. This information can provide guidance on how m u c h toxicology testing should be done for certain levels of h u m a n exposure. Tiered Approach to Testing Determinations of "Levels of Concern" of additives, therefore, are based on: - Population exposure, and - Potential toxicity. Concern levels derived from exposure and chemical structure, are used for determining the amount of toxicology data needed for a direct food additive (Figure 1). The concern levels reflect the potential hazard of specified compounds Level I being of least concern, Level II of intermediate concern, and Level III of highest concern. Because there are many exceptions to structure-activity relationships, the FDA gives more weight to exposure data t h a n to chemical structure information i n determining the m i n i m u m testing level for a food

In Thermal Generation of Aromas; Parliment, Thomas H., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.


3. KOKOSKI

DEGREE OP CONCERN

HIGHER

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Regulatory Toxicology and Food Flavors

! STRUCTURE C

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I STRUCTURE B

I STRUCTURE A

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CL I I I

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CL I I I 0.5 ppB

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Figure 1. Concern level from exposure and structure for direct food additives. Data from ref. 3.


26

T H E R M A L GENERATION OF AROMAS

additive. A s seen i n Figure 1, there is only a 4-fold difference i n breakpoints across structure categories A, B, a n d C, while there is a 20-fold difference i n exposure breakpoints w i t h i n a given structure category. Typical Toxicological Test Data Recommended Substances that fall into Concern Level I require only minimal toxicological data. The recommended tests include:


- A short-term feeding study (usually of 28 days duration) i n a rodent, and - A battery of short-term tests for carcinogenicity potential. The feeding study is expected to detect acute, life-threatening toxicity and to indicate the target organs and appropriate doses for longer-duration toxicology testing when results of the short-term tests indicate the need. Concern Level II indicates a need for toxicity tests of intermediate sensitivity, to detect most toxic phenomena other than late-developing histopathological changes. The recommended tests are: - 90-day feeding study i n a rodent, - 90-day feeding study i n a nonrodent, - 2-generation reproduction study with a teratology phase i n a rodent, and - Battery of short-term tests for carcinogenicity potential. The short-term tests indicate whether or not chronic testing is necessary. Results of the reproduction study indicate whether there is need for teratology or reproduction testing i n more generations or need for a feeding study employing in utero exposure. Direct food additives that fall into Concern Level III require comprehensive, long-term toxicology studies, including: - Carcinogenicity feeding studies i n two rodent species, - Chronic toxicity feeding study of at least one year i n a rodent — usually undertaken as a combined carcinogenicity/chronic toxicity study, - Long-term, at least one-year, feeding study i n a nonrodent, - Multigeneration reproduction feeding study i n a rodent, carried to a m i n i m u m of two generations, with a teratology phase, and - Short-term tests for carcinogenicity potential to assist i n evaluating results of such bioassays. Although testing i n humans is not a requirement for approval of a food additive, availability of h u m a n data or experience based on common use i n food may reduce the amount of animal safety data that will be required, may signal requirements for special studies, or may influence the safety factor applied i n making the ultimate safety evaluation. What is Involved i n the Evaluation of Data Submitted to Demonstrate the Safety of a Food Additive? First, we recognize that every substance has a toxicity level. A n y substance will produce some adverse effect at a high enough test level. Evaluating safety requires that this potential adverse effect be identified and that adequate toxicological data are available to determine the level at which exposure to the substance can be considered safe. This is done by determining a "no-adverse-effect" level i n



3.

KOKOSKI


27

appropriate animal studies and then applying a safety factor i n order to arrive at a level of m a x i m u m acceptable dairy intake (ADI). The ADI is an official term of the World Health Organization (WHO). Second, select appropriate dosage levels of test material. Toxicology feeding studies for a food additive should be performed with several dosage levels (usually three) plus a control. The highest dose should be sufficient to stress the animal and ideally produce some toxic response, but not so high as to cause early death and inanition. Multiple dosage levels are used so that a dose-response curve can be constructed. By knowing what the toxic response to a compound is at the high level, one can focus more clearly on the target tissues for a more confident assessment of a "no-adverse-effect" level at the lower test levels. Third, safety factors are based on a "no-adverse-effect" level. Testing i n more t h a n one animal species provides a better reflection of what to expect i n the human, and allows extrapolation of safety data from the animal to the h u m a n by the use of a safety factor. In determining an ADI for humans, the FDA applies a safety factor to the highest "no-adverse-effect" level determined i n an appropriate animal study. The safety factor is intended to account for differences between the animal and h u m a n and to provide an adequate margin of safety for the consumer. Applying Safety Factors The safety factor itself may vary, depending upon the nature of the test data available and on other judgmental factors. W h e n long-term animal studies are available, the 100-fold safety factor generally is applied. The food additive procedural regulations (21-CFR 170.22) refer to a safety factor of 100 to 1 i n applying animal test data to humans. Exceptions to the 100-fold safety factor may be allowed for certain substances and under certain circumstances of use; for example. In the case of micronutrients or macronutrients, or when information on dose-response effects i n h u m a n s is available. To estimate the ADI for the human, take the highest amount of tested compound demonstrating a "no-effect" level and divide that by a safety factor (e.g., safety factor of 100), expressed i n milligrams of compound per kilogram of body weight of the human. The "no-effect" level may be expressed as mg compound/kg body weight of the animal or as a percentage or ppm (parts per million) of the test diet of the animal. A food additive would be considered safe for its intended use if the probable reasonable h u m a n daily exposure to the food additive does not exceed the ADI. Unique Problems with Evaluating Safety of Flavors Consideration of flavors used i n food presents some unique problems not typically associated with other food additives. For example, there are a vast number — well over a thousand ~ of different substances that are used as ingredients for the single technical purpose of imparting flavor to foods. These, of course, do not include the flavors already naturally occurring i n foods themselves. The number of flavor additives alone far exceeds the total number of other direct or intentional food additives used for all other purposes (4). A n ever increasing population, limited supplies, and expensive sources of flavors of natural origin have prompted the chemical and flavor industries to develop m a n y synthetic counterparts. M a n y synthetic flavors have relatively simple chemical structures and are used i n very low amounts. Components of natural foods are being identified chemically i n greater numbers today and i n many cases are being reproduced synthetically (4). The industry is working hard to develop innovative methods of producing new materials having potential use as



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flavors i n foods. Evaluating the safety of this vast number of flavoring compounds and substances certainly presents challenges. It i s expected that flavor manufacturers will be making use of new techniques, such as biotechnology, to create new and novel compounds or, alternatively, to find more efficient ways to produce existing compounds. "FDA intends to review new methods of manufacturing for biotechnology products by the same criteria used for products produced by traditional means." (5). This symposium deals with the technological aspects of generating new flavor materials b y applying various thermal processes to substances, many of w h i c h are commonly found i n food. In any safety evaluation of such additives, it is necessary to consider changes i n chemical identity, new or altered levels of impurities, a n d increases i n dietary exposure. In this regard, it is possible that even G R A S compounds produced by these new techniques might be considered for evaluation. If the F D A does not agree that the food ingredient manufactured by a new process is GRAS, the ingredient would be subject to the food additive provisions of section 409 of the Act (§). The law does not preclude a n ingredient produced by a novel method from being affirmed as GRAS. "However, to be affirmed as GRAS, the food ingredient m u s t be shown to meet the criteria of a GRAS food ingredient, including a wide recognition of safety based largely o n published information concerning the intended use of the ingredient." (5). Information Required for G R A S Affirmation bv the F D A The information required for both food additive a n d G R A S affirmation petitions is described i n detail i n the Code of Federal Regulations (21 C F R 171.1 and 170.35, respectively). It considers the following general areas: - identity of the ingredient and impurities that may be present, - safety — toxicological and/or relevant data to support safety under conditions of use, - functionality i n food — to show that it serves its intended technical effect, - analytical method — to identify and quantify the ingredient i n food — is needed w h e n a tolerance is required to assure safety i n use, and - potential environmental impact of its manufacture and use. To assess safety even for novel food ingredients or products, such as those from new biotechnology, the agency believes that new laws or regulations are not necessary (5). The Food, Drug, and Cosmetic Act states that GRAS substances are exempt from the premarketing clearance required for food additives. The C F R defines G R A S as the general recognition of safety by experts qualified by scientific training and experience to evaluate the safety of substances o n the basis of scientific data derived from the published literature. The C F R also indicates that expert judgment is to be based o n the evaluation of results of credible toxicological testing for those substances used i n food prior to January 1,1958, and o n a reasoned judgment founded i n experience with common food use. The evaluation is to take into account reasonably anticipated patterns of consumption, cumulative effects i n the diet, a n d safety factors appropriate for the utilization of animal experimental data (6.7). Recognizing the possibility of potential hazard, the F D A studied the toxicity of about 200 of the approximately 1100 flavoring substances i n use at that time (8.9). Those selected were most widely used and had structures similar to compounds of k n o w n toxicity or were suspected of being toxic. The various oral feeding studies were done i n several species for acute to short-term (90 to 120 days) or for chronic testing periods. These studies i n part served as a basis for F D A listing a number of


3. KOKOSKI


29

the F E M A (The Flavor a n d Extract Manufacturers Association) G R A S flavors i n the C F R A t that time, a 2000-fold margin of safety, with no other evidence of untoward effects, resulted in permitted use. In many cases, F D A sanction was made without such testing, but was based o n reasoned judgment from knowledge of natural occurrence, data on metabolism, and low self-limited use (g). The F D A lists of flavoring substances published i n the C F R either o n the G R A S list or by food additive regulation have remained essentially unchanged since 1965.


F E M A Approach to G R A S Affirmation Through Expert Panel Review The Code of Federal Regulations does not identify all GRAS substances such as natural a n d synthetic flavorings used i n foods. The statutes do not specifically state how recognition of safety is to be established or who the qualified experts are to be. The F E M A interpreted the statutes as allowing creation of expert panels outside the FDA or other agencies. O n this basis, the F E M A in 1958 selected a n Expert Panel to review flavoring materials used as food ingredients (4). Since 1958, the F E M A Expert Panel has periodically surveyed manufacturers and users to obtain information o n identity, quantities produced, levels of use, manner of use, a n d toxicological data related to natural a n d synthetic flavoring substances. The F E M A Expert Panel developed criteria for evaluating the flavors i n a n evolutionary manner (6). F r o m this process, the F E M A established a G R A S list of flavors which is continually updated by the F E M A and to which the F D A has not voiced objection. The FDA, under contract with the National Academy of Sciences (NAS), also monitors market disappearance of food additives, including flavors that the F D A regulates. This is done by surveys of manufacturers. Presently these surveys take place every five years. A cogent point i n the F E M A evaluation process is that relatively small amounts of flavoring substances are generally added to foods. It was reported from 1971 F E M A survey information that 7 3 % of the flavors were used at average levels of less than 100 ppm in food (6). A n y one flavoring substance is not used i n all foods. Therefore, the overall daily dietary exposure is well diluted. For example, the survey indicated that 7 1 % of the flavors are used industry-wide i n amounts of less than 1000 pounds per year. It was estimated earlier that the total quantity of flavoring substances consumed was about 26 grams per person per year (4). This estimate made i n 1968 was based o n approximately 1100 flavor additives that were used i n food. This, of course, excluded flavoring already naturally present in food or generated during cooking. The guidelines of the F E M A Expert Panel were similar to those developed i n 1969 by the Food Protection Committee, NAS National Research Council (10). The NAS expressed the opinion that 1) if a chemical was i n use five years or more without evidence of harm, 2) was not a heavy metal, and 3) was not intended for use because of biological activity, dietary exposure at less than 0.1 ppm could be considered toxicologically insignificant. At levels above 0.1 p p m and below 1 ppm in the h u m a n diet, use of accumulated scientific evidence and structure analogy to other chemicals of k n o w n metabolism or toxicity would be justifiable to arrive at a conclusion of toxicological insignificance. The F E M A Expert Panel used the following criteria i n reaching decisions on the flavoring substances it considered: - analogy with chemically-related substances with known toxicity or metabolism, - the nature, level, and volume of use in food, - toxicological significance of the levels of use, - available toxicity data, - metabolic pattern of the compound in the body, a n d - natural occurrence of the substance in foods.


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Much emphasis was placed on natural occurrence in foods in presumptions of safety. Of course, natural occurrence is not an assurance of safety. Many naturally occurring substances possess toxicity; in fact, some are quite toxic. Chemical analogy also presents some problems in presumptions of safety. As mentioned earlier, the "Redbook" decision-tree system for determining toxicological testing of food additives falls into three levels of concern (3.11). whereas there are four FEMA concern levels, each determined by combining information about the human exposure levels to a compound with the information about its chemical structure derived from a 33-question "decision tree" (12).


WHO Consideration of Flavors The Codex Committee on Food Additives of the WHO/FAO has for many years given "temporary endorsement" to a large number of substances, particularly the flavor materials on Codex Lists B l and B2. This was done for one of the following reasons: the Joint Expert Committee on Food Additives (JECFA) did not allocate ADI levels mainly because of lack of "adequate" classical toxicological or specification data (these were placed on list Bl), or the materials were never evaluated by JECFA (these were placed on list B2). Recently the WHO Codex Committee has been working toward devising a system for priority ranking of the many flavor compounds in order to consider what toxicological data are available and to resolve the long standing "temporary endorsements." The Committee will consider, among others, the FDA "Redbook" process, including the three levels of concern, as well as the FEMA four-concernlevel decision-tree approach. The goal is to devise a priority-level ranking system for decisions on final endorsement of ADIs. As yet, no final agreement on the use of any specific approach has been reached by the WHO Codex Committee. Summary In summary, safety evaluations of the more than one thousand flavors substances currently in use, and of the many others under development or yet to be envisioned, present unique challenges to the toxicologists not only in industry but also in regulatory agencies. Different approaches have been devised for setting priorities and using available information to make decisions on safe use in food, and for undertaking additional testing when indicated to demonstrate safety under conditions of use. In the regulatory scene under the current food additive law, the approaches of GRAS affirmation and food additive regulation assure safe use of substances added to food. Literature Cited 1. 2. 3.

4. 5.

Hutt, P. B. Food, Drug Cosmetic Law J. 1982, 37, 123-137. Senate Report; U.S. Government Print Office: Washington, D.C., 1958; No. 2422, p 6. Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food, U.S. Food and Drug Administration, Bureau of Foods. 1982, Order Number PB-83-170696, National Technical Information Service, 5285 Port Royal Rd., Springfield, VA 22150. Hall, R. L.; Oser, B. L. Residue Rev. 1968, 24, 1-17. Maryanski, J. H. "Legal Aspects of the Use of Food Products from Biotechnology," presented at the Food and Biotechnology International Symposium, University of Laval, Quebec, Canada, August 21, 1986.


3. KOKOSKI 6. 7. 8. 9.


10. 11. 12.


Criteria for Evaluation of The Health Aspects of Using Flavoring Substances as Food Ingredients, Federation of Am. Soc. for Exp. Biol., Life Sciences Research Office, Bethesda, MD, June, 1976. Code of Federal Regulations, Food and Drugs, Title 21, Parts 170 to 199, U.S. Government Print Office: Washington, DC, April 1, 1988, Part 170.30, 5-9. Jenner, P. M.; Hagan, E. C.; Taylor, J. M.; Cook, E. L.; Fitzhugh, O. G. Food Cosmet. Toxicol. 1964, 2, 327-343. Hagan, E. C.; Hansen, W. C.; Fitzhugh, O. G.; Jenner, P. M.; Jones, J. M.; Taylor, J. M.; Long, E. L.; Nelson, A. A.; Brouwer, J. B. Food Cosmet. Toxicol. 1967, 5, 141-157. Guidelines for estimating toxicologicallv insignificant levels of chemicals in food, National Research Council, Food Protection Committee, National Academy of Sciences, Washington, DC, 1969. Rulis, A. et al. Reg. Toxicol. & Pharmacol. 1984,4, 37-56. Cramer, G. M. et al. Food. Cosmet. Toxicol. 1978, 16, 255-276.

Received July 6, 1989


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Regulatory Toxicology and Food Flavors - ACS Symposium Series

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