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The safety evaluation of macronutrient substitutes Joseph F. Borzelleca Ph.D.
a
a
Dept. of Pharmacology and Toxicology , Medical College of Virginia , Richmond, VA Published online: 29 Sep 2009.
To cite this article: Joseph F. Borzelleca Ph.D. (1992) The safety evaluation of macronutrient substitutes, Critical Reviews in Food Science and Nutrition, 32:2, 127-139, DOI: 10.1080/10408399209527587 To link to this article: http://dx.doi.org/10.1080/10408399209527587
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Critical Reviews in Food Science and Nutrition, 32(2):127-139 (1992)
The Safety Evaluation of Macronutrient Substitutes* Joseph F. Borzelleca, Ph.D. Dept. of Pharmacology and Toxicology, Medical College of Virginia, Richmond, VA
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*Presented at the conference on New Foods and Food Chemicals, NAS, May 1-2, 1990.109-1D Idlewild St., Bel Air, MD 21014
KEY WORDS: macronutrient substitutes, bulking agents, microadditives, high-intensity sweeteners.
I. INTRODUCTION Macronutrient substitutes are products that are used to replace macronutrients (fats or carbohydrates, especially sugar, in the diet; they replace the organoleptic and/or functional properties of fats or sugars in foods. Macronutrient substitutes are less energy dense that the nutrients they replace. These agents provide the "pleasure (organolepsis) but not the pain (calories)." The fat substitutes include protein-based agents (e.g., whey/egg protein); carbohydrate-based agents (e.g., gums, modified starches, maltodextrins, pectin); synthetic agents (e.g., sucrose polyester). The replacements for sugar include the nonnutritive, high-intensity sweeteners (e.g., aspartame, alitame, sucralose, acesulfame K). Bulking agents (e.g., polydextrose) and/or fibers (both water-insoluble and water-soluble) are also used to decrease the caloric content of certain foods. The safety evaluation of macronutrient substitutes poses special problems for the toxicologist due to the unique nature of these substances, including the high intake level. Most traditional food additives may be considered microadditives; they are consumed in less than gram quantities per day. Macronutrient substitutes will probably
be consumed in gram quantities per day. It is the broad use of these agents that contributes to their uniqueness and poses new challenges in thensafety evaluation. The usual methods for evaluating the safety of traditional food chemicals may not be appropriate for macronutrient substitutes for many reasons, including the amount that can be fed to animals. The limit (5%) placed on nonnutritive additives in the diet of laboratory animals may not be high enough for macronutrient substitutes if conventional methods of extrapolating these data to humans are employed. Alternative/innovative approaches must be considered. It is recommended that more data be generated from laboratory animals and from properly designed and implemented studies in humans. The need for special studies in animals and/or humans, based on data generated, should also be considered. These could include possible interactions of the macronutrient substitutes with other components of the diet or with drugs, and the effect of these agents on food intake patterns. Guidelines for the safety evaluation of macronutrient substitutes are presented below. These guidelines are based on generally recognized principles of safety assessment, demonstrated
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need for the scientific data (previous studies), the uniqueness of macronutrient substitutes, current methods for the evaluation of the safety of food additives, the need to conserve resources, current U.S. Food and Drug Administration (FDA) regulatory practices and procedures, and studies in humans. The proposed scheme allows for scientific judgment. Regulatory guidelines often provide the basis for determining the types of data necessary to establish safety. These regulatory guidelines may vary from country to country. However, in this article, the FDA has been chosen as a model. Some of the issues addressed in this article have already been considered by others.1-5-7-11 The following information should be considered prior to the initiation of testing: recognition of the potential benefits to be derived from the introduction of the macronutrient substitute into the food supply; the unique nature of the macronutrient substitute; chemical, physical, and functional characterization of the test material; extent of potential exposure, including potentially heavy users and sensitive subpopulations (in the absence of reliable exposure data, 100% replacement should be assumed); the source (if natural) or the synthetic processes) to the extent feasible; stability during processing, storage or consumer use; biological and other data on chemically similar compounds; and approved materials in the same functional category as the macronutrient to be replaced. The extent of safety testing is based on the chemistry of the test material; the extent of exposure/consumption; and the absorption, distribution, biotransformation, excretion, and kinetics of the macronutrient substitute in animals and humans. Evaluation in humans is initiated only after adequate (in quality and quantity) animal data are fully and critically evaluated. The conditions of exposure in the human studies are determined by the animal data, the anticipated consumer exposure, and the nature of the macronutrient substitute. A postmarketing surveillance program that follows introduction of the macronutrient substitute into the marketplace will provide additional human exposure data, including patterns and levels of consumption and potentially adverse health effects. The safety of macronutrient substitutes is expressed relative to conditions of exposure (how much of what, for how long, and to whom). 128
A. Safety Evaluation Program 1. Test Material Characterization, Exposure Assessment, and Initial Safety Assessment a. Test Material Characterization Test material characterization involves the generation and evaluation of information on the uniqueness of the test material; its composition (single compound or mixture); its source (if natural) or the synthetic process(es) involved in its production (in sufficient detail to enable an assessment of the potential toxicity of the starting materials, contaminants, intermediates, or interaction byproducts); its properties (chemical, physical, functional) and specifications; and its stability during processing, storage, and consumer use. A comprehensive search of the scientific literature on the test material, on chemically related materials, and on approved functionally equivalent materials is an essential component of this phase.
b. Exposure Assessment The anticipated level of consumption should be based on the maximum anticipated replacement level (if known) or on the assumption that the test material will be a 100% replacement for an approved product (for which reliable exposure data are available). These data should be developed for realistic maximum levels of exposure (e.g., the 90th percentile because it is reflective of heavy users). Potentially sensitive populations should also be identified and appropriate exposures anticipated. Reliable exposure data are essential because the extent of testing is determined by the nature, of the test material and the extent of exposure.
c. Initial Safety Assessment A critical evaluation of available data by competent toxicologists should result in a determination that the data satisfy existing regulations for a generally recognized as safe (GRAS) substance or a food additive (FA) or that the data
are inadequate for filing such petitions and the deficiencies are identified.
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2. Safety Assessment for GRAS Status The GRAS process was developed in 1958 by the enactment of the Food Additives Amendment of the Federal Food, Drug, and Cosmetic Act. This required premarketing approval for FAs but two exemptions were permitted: those substances recognized as GRAS and those substances that had been sanctioned prior to 1958. A GRAS substance was defined as a substance that is generally recognized by experts who are qualified by training and experience to evaluate the safety of the substance to be safe (through scientific procedures) under the conditions of its use. GRAS status is determined by experts on the basis of scientific procedures or on the history of use in food. The FDA has compiled a list of approximately 600 GRAS substances (21 CFR Part 182 and 21 CFR 170.30). The criteria for GRAS recognition through scientific procedures require the same data that would be required to demonstrate safety for a FA (however, only published data may be considered for GRAS recognition). Recognition of GRAS through common use in foods requires data on the history of consumption by a substantial number of consumers but does not require the same toxicological data as a FA. All data are critically evaluated by a panel of experts (GRAS panel) and a determination is made that the test material meets the criteria for GRAS or it does not. If the criteria for GRAS are met, information on the digestive and nutritional effects of the test material in appropriate animal species and in humans should be generated. If no adverse effects are produced by the test material at the maximum anticipated level of human exposure (or at a multiple of it), a meeting (presubmission conference) with the FDA should be planned. If the criteria for GRAS are not met, then the options are to meet with the FDA to determine if GRAS status is possible (determine data requirements), to proceed as a FA, or to stop development. If, during the presubmission conference, the FDA does not recommend generating additional data, then a GRAS Petition (GRASP) may be
filed. Once the GRASP is accepted for filing, the macronutrient substitute may be sold and used. However, it is recommended that no action be taken until the FDA formally affirms GRAS status. When GRAS status is affirmed and/or the material is commercialized, a post-marketing surveillance (PMS) program is initiated. If GRAS status is not affirmed by the FDA, a determination is made to generate the data required by the FDA for GRAS status, to proceed as a FA, or to stop development. If additional data are required for GRAS status by the FDA, a determination is made either to generate the additional data and then file the GRASP, to proceed as a FA, or to stop development. If GRAS status is subsequently not affirmed by the FDA, the options are to proceed with the Food Additive Petition (FAP) or to stop development.
3. Safety Assessment of a Food Additive If the macronutrient substitute does not satisfy the criteria for GRAS status, it can be evaluated as a FA. All studies to evaluate the safety of food chemicals should be conducted according to rigorous scientific standards, utilizing protocols that reflect human exposure conditions, and using adequate numbers of both sexes of appropriate animal species. Appropriate animal species are those species in which the response to the test material, and its disposition, are very similar (or identical) to the human (determined in vitro or in vivo). If the appropriate species has not been identified, then the most sensitive species may be considered the appropriate species. Studies may be required in the rat even if it is not the appropriate/sensitive species.
a. Acute Toxicity These single-exposure studies are designed to develop profiles of acute toxicity, to develop/ characterize dose-response relationships, to identify sex and species differences, to identify probable sites (target organs) and mechanisms of toxicity, and to provide a basis for dosage selection for further testing. Acute toxicity studies are conducted using adequate numbers of both sexes of
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several species (because the appropriate/sensitive species are usually unknown at this stage of testing).
c. Genetic Toxicity Genetic toxicity studies are conducted to assess potential mutagenicity/carcinogenicity. Both in vitro (initial) and in vivo tests are conducted.
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b. Short-Term (Repeated-Dosing) Toxicity These studies are designed to develop profiles of repeated dosing toxicity, to establish/ characterize dose-response relationships, to identify probable sites (target organs) and mechanisms of toxicity, to provide data on cumulative effects, and to provide a basis for dosage selection for further testing. Repeated dosing studies are conducted using adequate numbers of both sexes of the appropriate/sensitive species (if known or, in several species, if not known). A palatability study of the dietary admixture is conducted initially to determine acceptability so that a decrease in food intake followed by a decrease in body weight will not be misinterpreted as toxicity (due to an unwillingness of the animals to consume the diet). If palatability is a problem, alternate methods of administration are used (e.g., gavage). Satellite groups may be included for special studies and/or for repeated blood sampling. Repeated-dosing studies usually involve 14 to 28 consecutive days of repeated exposure, three to five exposure levels, and appropriate controls. Nutritional and toxicological parameters evaluated include: food intake; body weight gain; food efficiency; hematology, serum chemistry, urinalysis; blood levels of selected micronutrients; and gross and microscopic examination of tissues. Consideration should be given to generating physiological/pharmacological data (e.g., effects on behavior, cardiovascular effects [electrocardiogram]) in satellite animals or as special studies to be conducted later. As much relevant data as possible should be collected without compromising the major objective of the study. If no significant compound-related and dose-dependent adverse nutritional and/or toxicological effects are identified in these studies, and if the genotoxicity studies do not identify compoundrelated adverse effects, limited human safety studies may be undertaken.
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d. Initial Human Exposure (Sensory Evaluation) Initial sensory evaluation of the organoleptic properties of the test material ("taste and spit") is conducted in healthy, drug-free adult males and nonpregnant females to assess human responsiveness. The test material is not swallowed, and systemic effects are unlikely to occur because absorption from the oral cavity is assumed to be nil. If the desired sensory effect is realized, then a single oral dosing disposition study, as discussed in the following section, is conducted.
e. Disposition Absorption, distribution, metabolism (biotransformation), elimination, and kinetic (ADMEK) studies are conducted in several animal species (including the appropriate/sensitive species) and in humans to determine if the material is absorbed from the gastrointestinal tract, its distribution, biotransformation, and elimination; the kinetics of these processes; and the identification of the appropriate species for further testing, if not already known. The test material is administered orally as a single dose. The dose administered to healthy, drug-free adult males and/or nonpregnant females is based on the animal data and the exposure estimates in humans. If humans do not respond adversely to a single oral dose of the test material, then a 90-d subchronic oral dosing study in the appropriate/sensitive species should be conducted.
f. Subchronic Oral Toxicity Subchronic toxicity studies are conducted to
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develop profiles of subchronic oral toxicity; to characterize dose-response relationship following subchronic exposure; to evaluate nutritional and toxicological effects; to identify probably sites (target organs) and mechanisms of toxicity; to determine reversibility of effects; to identify doses for possible further toxicity testing; to provide data on cumulative effects; and to assist in determining safe conditions of consumption for humans. Subchronic studies usually involve 90 d of repeated exposure, at least three levels of exposure, and appropriate controls. To increase the sensitivity of these studies, in utero exposed animals (F/l a generation) are used. This will also provide preliminary information on potential reproductive effects. Developmental effects (teratological effects) can be evaluated in other litters. This design will significantly reduce the number of animals required without compromising the subchronic toxicity. If the test material is to be administered as a dietary admixture, an appropriate palatability study is conducted prior to the subchronic exposure (unless the results of the palatability study conducted earlier are adequate). If the diet is not palatable at any concentration, alternate methods of dosing must be considered (such as gavage). Satellite groups are included to evaluate reversibility of effects produced; for ADMEK studies; for assessment of nutritional status; and for special studies, if indicated. These subchronic studies provide an opportunity to assess levels of nutrients and test material (and/or its metabolites) through sampling of blood and urine from the satellite groups during the study. The frequency of sampling and other experimental details will be partly determined by the results of the ADMEK studies. The following nutritional and toxicological parameters are evaluated in subchronic studies: food and water consumption; body weight gain; food efficiency; bioavailability of the test material and selected nutrients; hematology, serum chemistry and urinalysis; blood levels of selected micronutrients, and gross and microscopic examination of tissues. Physiological and/or pharmacological studies can be conducted on satellite groups or as special studies to be conducted later. If there
are no significant compound-related and dosedependent adverse nutritional or toxicological effects, a repeated-dosing study in humans, generally 7 to 14 d, can be conducted. Reproductive and developmental toxicity and additional in vivo genetic toxicity studies may also be conducted at this time.
g. Multiple-Dose Studies in Humans Repeated-dosing studies are conducted in healthy, drug-free adult males and/or nonpregnant females to evaluate effects of the test material and to assess acceptability. The doses to be tested are based on anticipated exposure levels, the results of the animal and the single-dose human studies, and the nature of the test material. Parameters evaluated include dietary intake; body weight changes; hematology, serum chemistry, and urinalysis; and blood levels of the test material (and its metabolites) and selected micronutrients. If no significant compound-related and dose-dependent adverse effects are observed in these studies, a presubmission conference with the FDA is planned. The FDA may recommend proceeding with formal submission of the FAP or may recommend further testing. If significant compound-related and dose-dependent adverse effects are observed in these human studies, appropriate special studies are conducted to evaluate the significance of these findings or to stop development of the test material. All studies involving humans are to be conducted safely and with maximum protection of human subjects, by competent investigators, in approved institutions, using protocols and consent forms approved by the Institutional Review Boards (IRBs) (21 CFR parts 50, 56).
h. Reproductive and Developmental Toxicity These studies are conducted to evaluate effects on reproductive performance and intrauterine and postnatal development; to characterize
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dose-response relationships; and to identify probable sites (target organs of toxicity and/or interference) and mechanisms of toxicity. Reproductive and developmental toxicity can be evaluated in the parents (Fo) of animals used in the subchronic study and their offspring using currently accepted procedures in appropriate studies, or the studies can be conducted separately using currently accepted procedures. A two-generation reproduction study in the appropriate/sensitive species and/or one rodent species in which both sexes are exposed by the oral route to at least three levels and including appropriate controls is usually adequate for assessing potential reproductive effects.
/. In vivo Genotoxicity Potential genotoxicity and genotoxic carcinogenicity is evaluated in suitable in vivo systems. Data from these tests, together with data from the ADMEK studies and the estimates of human exposure to the test substance, are useful in determining the need to conduct a lifetime study for carcinogenicity.
j. Special Studies Special studies are undertaken in response to the data generated in the aforementioned studies and are conducted in appropriate animals or humans to investigate or confirm earlier findings or elucidate probable mechanisms of toxicity.
appropriate/sensitive species, usually at three levels of exposure and with appropriate controls using the oral route of administration (preferably diet); the duration of exposure is usually more than half the lifetime of the animal (e.g., 18 to 24 months for rodents). In utero exposed rats are recommended. Satellite groups are included to evaluate reversibility, to permit interim sacrifices, and to conduct appropriate clinical studies (e.g., hematology, serum chemistry, urinalysis, levels of micronutrients). Blood sampling to asses levels of micronutrients and test material and/or its metabolites is conducted regularly throughout the study; the frequency of sampling and other experimental details are determined by the results of previous studies. Nutritional and toxicological parameters evaluated include: physical evidence of compound-related effects; body weight gain; food intake; food efficiency; hematology, serum chemistry, urinalysis; and gross and microscopic examination of tissues. Quantitation of tissue concentrations of the test material (and/or its metabolites) should be considered. If there are no carcinogenic effects, a NOAEL can be identified and an acceptable daily intake (ADI) can be established. If there are no significant compoundrelated and dose-dependent adverse effects, a 90to 180-d repeated human dosing study should be conducted. If compound-related carcinogenic effects are demonstrated, either conduct studies to determine the mechanisms of these effects and their applicability to humans or stop development. The use of satellite animals may obviate the need for two separate studies, chronicity and carcinogenicity, thereby reducing the number of animals used.
k. Chronic Toxicity/Carcinogenicity /. Long-Term Exposure in Humans These studies are designed to establish profiles of chronic toxicity, to characterize doseresponse relationships, to identify probable sites (target organs) and mechanisms of toxicity, to provide data on cumulative effects and reversibility, to establish a no observed adverse effect level (NOAEL), and to determine the carcinogenic potential of the test material. Studies of chronic toxicity and/or carcinogenicity are conducted using adequate numbers of both sexes of
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After data from appropriate and adequate animal and repeated-dosing human studies are critically evaluated, long-term studies are conducted in healthy, drug-free adult males and nonpregnant females to assess the effects of subchronic or long-term exposure to the test material, to determine acceptance of the test material, and to identify levels of exposure that do not elicit adverse effects. The levels of exposure in these
studies should be multiples of the estimated daily intake (EDI, 90th percentile). The highest tolerated dose (HTD), the highest dose tested that did not produce adverse effects, should be identified. The following are monitored: daily dietary intake; weekly body weights; hematology, serum chemistry, urinalysis; and any special parameters indicated from previous studies.
n. Post-Marketing Surveillance (PMS) PMS is conducted following the introduction of a product into the marketplace and should be designed to collect consumption data to determine consumption patterns and acceptability of the macronutrient substitute. It is also used to identify sensitive subpopulations and potentially adverse effects. A PMS should be conducted for both GRAS substances and FAs.
m. Acceptable Daily Intake (ADI)
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CONCLUSIONS The ADI for traditional FAs is usually determined by applying a safety/uncertainty factor (UF) (usually 100) to the NOAEL (ADI = NOAEL/UF). This may not be appropriate for macronutrient substitutes because animals may not have received high enough doses. Other approaches to establishing the ADI must be considered. Animal data are used to demonstrate the relative safety of the test material up to the highest level fed (usually 5%). If concentrations greater than 5% are used, nutritional deficiencies may occur and these can confound interpretation of the data (these deficiencies may be misinterpreted as toxic effects). If 5% is the maximum level of the nonnutrient tested in the animals studies, and if this approaches the maximum anticipated human exposure, application of traditional safety/ uncertainty factors would not be suitable. However, data from properly designed and executed chronic and other animal studies evaluated in conjunction with data from properly designed and conducted human studies would provide an acceptable basis for the use of a lower UF in establishing the ADI. Human studies provide many advantages in the evaluation of safety: the human is the target species (eliminating extrapolation) and subjective (often subtle) effects can be determined and evaluated (impossible in nonhuman species). The need for scientific judgment in developing an ADI from animal and human data is essential; a simple formula will not be applicable in every instance suggesting a case-by-case approach within general guidelines.
The uniqueness of macronutrient substitutes necessitates the use of special procedures for their safety evaluation. Methods currently used for the safety evaluation of traditional FAs involve limiting the level of the test material that can be incorporated into the diet of test animals. This level may be too low for the evaluation of macronutrient substitutes if traditional methods for determining the ADI are used. The approach to the evaluation of the safety evaluation of macronutrient substitutes described in this article recognizes the uniqueness of these materials and the limitations of current methods and proposes the utilization of animal and human data, consideration of nutritional and toxicological effects, special attention to kinetic and dispositional data, the use of nontraditional UFs, and the use of PMS. It may be necessary to design studies on a case-by-case basis. ACKNOWLEDGMENTS The author and editors express their thanks to Eric W. Nealley, USAMRICD, APG, MD, for his assistance in the preparation of Figures 1 and 2. The author expresses his appreciation for the valuable contributions of Zara Abraham, James L. Allen, G. Harvey Anderson, Carolyn Bergholz, David Bechtel, Mark Bleber, Leonard Czuba, John Hallagan, Suzanne Harris, Christopher Hassall, John Kllle, Gilbert Levellle, Lawrence Masten, Harry Salem, Daniel Skrypec and Marshall Spearman.
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SAFETY EVALUATION OF MACRONUTRIENT SUBSTITUTES
• - STOP
FIGURE 1. Schematic overview of pathway for safety evaluation. (To assist in tracking Figure 2.)
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SAFETY EVALUATION OF MACRONUTRIENT SUBSTITUTES IDENTIFY BEUEFITS
CHARACTERIZE MATERIAL
ASSESS EXPOSURE
IDENTIFY/EVALUATE SOURCE
TRACK FATE DURING PROCESSING
COMPREHENSIVE SURVEY OF LITERATURE
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EVALUATE DATA
DATA ADEQUATE FOR PROPER EVALUATION OF SAFETY
DATA INADEQUATE FOR PROPER EVALUATION OF SAFETY
I HUMAN STUDIES BIOAVAJLABILITY ANIMAL
STUDIES
DIGESTABILITY BI0AVA1 LABILITY
INTERACTIONS
DIGESTIBILITY |INTERACTIONS| I | NUTRITIONAL |
NONSIGNIFICANT EFFECTS
SIGNIFICANT EFFECTS
NUTRITIONAL
SIGNIFICANT EFFECTS
NONSIGNIFICANT EFFECTS
REPEAT OR SPECIAL STUDIES
REPEAT
STOP
RE-EVALUATE RE-EVALUATE STOP STOP
CONFERENCE WITH FDA
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ADDITIONAL DATA STOP
NO ADDITIONAL DATA
CONDUCT STUDIES
±
RE-EVALUATE STOP
FAP
GRASP
ACCEPTED NOT ACCEPTED FOR FILING
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WITHDRAW GRASP
STOP
FAP
ACCEPTED FOR FILING
CONDUCT STUDIES
RE-EVALUATE
STOP
RESUBMIT
E
NOT ACCEPTED FOR FILING
ACCEPTED FOR FILING
NOT APPROVED
_L STOP
FAP
NOT AFFIRMED GRAS
PMS AFFIRMED GRAS
I STOP
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FAP
APPROVED
PMS
IDENT1KY DEFICIENCIES
| PREPARE WTOCOLS |
CONDUCT STUDIES
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| EVALUATE DATA
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K NONSIGNIFICANT EFFECTS
SIGKIFICAHT EFFECTS
CONFERENCE WITH FDA
REPEAT OR SPECIAL STUDIES
i
FAP
NOT APPROVED
RE-EVALUATE STOP
i
STOP
REPEATED DOSIBG ETDDIES IN HUMANS
1
APPROVED
CONDUCT STUDIES
STOP
EVALUATE
SIGNIFICANT EFFECTS
NONSIGNIFICANT EFFECTS
STOP
_L
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SPECIAL STUDIES
NOT APPROVED
ZL
APPROVED
PMS
RE-EVALUATE STOP
RESUBMIT
REPRO/DEVELOP TOXICITY
FIGURE 2.
Detailed pathway for safety evaluation.
REFERENCES SIGNIFICANT EFFECTS
NONSIGNIFICANT EFFECTS
SPECIAL STUDIES
RE-EVALUATE
STOP
CONFERENCE WITH FDA
ADDITIONAL DATA STOP
NO ADDITIONAL DATA
CONDUCT STUDIES
SPECIAL STUDIES
CHRONIC TOXICITY
EVALUATE STOP
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ESTABLISH RDI
1. Cranmer, G. M., Ford, R., and Hall, R. L., Estimation of toxic hazard — a decision tree approach, Fd. Cosmet. Toxicol., 16, 255, 1978. 2. Food Safety Council, Proposed system for food safety assessment. Report of the Scientific Committee of the Food Safety Council, Fd. Cosmet. Toxicol. 16(Suppl. 2), 1, 1978. 3. Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Foods — Redbook. U.S. Food and Drug Administration, Washington, D.C., 1982. 4. Memorandum on the Testing of Novel Foods: incorporating Guidelines for Testing for the Advisory Committee on Irradiated and Novel Foods. Ministry of Agriculture, Fisheries and Food, Scottish Home and Health Department, Welch Office Department of Health and Social Services, Northern Ireland, 1984. 5. EHC 70: Principles for the Safety Assessment of Food Additives and Contaminants in Food, World Health Organization, Geneva, 1987. 6. Cohrrsen, J. J. and Covello, V. T., Risk analysis: a guide to principles and methods for analyzing health and environmental risks, U.S. Council on Environmental Quality, Office of the President, Washington, D.C., 1989.
10. Rulis, A. M., The Food and Drug Administration's Food Additive Petition review process, Food Drug Cosmetic Law J., 45, 533, 1990. 11. Kroes, R. and Hicks, R. M., Eds., Re-evaluation of current methodology of toxicity testing including gross nutrients, Fd. Chem. Toxicol., 28, 733, 1990. 12. Advisory Committee on Novel Foods and Processes. Guidelines on the Assessment of Novel Foods and Processes, Department of Health, Report on Health and Social Subjects (38), Her Majesty's Stationery Office, London, 1991.
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7. International Food Biotechnology Council, Biotechnologies and Food: assuring the safety of foods produced by genetic modification, Reg. Toxicol. and Pharmacol., 12, S1, 1990. 8. Munro, I. C., Issues to be considered in the safety evaluation of fat substitutes, Fd. Chem. Toxicol., 28, 751, 1990. 9. New Food and Food Chemicals: Safety and Regulatory Considerations 01-02 May 1990, National Academy of Sciences, Washington, D.C., 1990.
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Critical Reviews in Food Science and Nutrition Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/bfsn20
The safety evaluation of macronutrient substitutes Joseph F. Borzelleca Ph.D.
a
a
Dept. of Pharmacology and Toxicology , Medical College of Virginia , Richmond, VA Published online: 29 Sep 2009.
To cite this article: Joseph F. Borzelleca Ph.D. (1992) The safety evaluation of macronutrient substitutes, Critical Reviews in Food Science and Nutrition, 32:2, 127-139, DOI: 10.1080/10408399209527587 To link to this article: http://dx.doi.org/10.1080/10408399209527587
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Critical Reviews in Food Science and Nutrition, 32(2):127-139 (1992)
The Safety Evaluation of Macronutrient Substitutes* Joseph F. Borzelleca, Ph.D. Dept. of Pharmacology and Toxicology, Medical College of Virginia, Richmond, VA
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*Presented at the conference on New Foods and Food Chemicals, NAS, May 1-2, 1990.109-1D Idlewild St., Bel Air, MD 21014
KEY WORDS: macronutrient substitutes, bulking agents, microadditives, high-intensity sweeteners.
I. INTRODUCTION Macronutrient substitutes are products that are used to replace macronutrients (fats or carbohydrates, especially sugar, in the diet; they replace the organoleptic and/or functional properties of fats or sugars in foods. Macronutrient substitutes are less energy dense that the nutrients they replace. These agents provide the "pleasure (organolepsis) but not the pain (calories)." The fat substitutes include protein-based agents (e.g., whey/egg protein); carbohydrate-based agents (e.g., gums, modified starches, maltodextrins, pectin); synthetic agents (e.g., sucrose polyester). The replacements for sugar include the nonnutritive, high-intensity sweeteners (e.g., aspartame, alitame, sucralose, acesulfame K). Bulking agents (e.g., polydextrose) and/or fibers (both water-insoluble and water-soluble) are also used to decrease the caloric content of certain foods. The safety evaluation of macronutrient substitutes poses special problems for the toxicologist due to the unique nature of these substances, including the high intake level. Most traditional food additives may be considered microadditives; they are consumed in less than gram quantities per day. Macronutrient substitutes will probably
be consumed in gram quantities per day. It is the broad use of these agents that contributes to their uniqueness and poses new challenges in thensafety evaluation. The usual methods for evaluating the safety of traditional food chemicals may not be appropriate for macronutrient substitutes for many reasons, including the amount that can be fed to animals. The limit (5%) placed on nonnutritive additives in the diet of laboratory animals may not be high enough for macronutrient substitutes if conventional methods of extrapolating these data to humans are employed. Alternative/innovative approaches must be considered. It is recommended that more data be generated from laboratory animals and from properly designed and implemented studies in humans. The need for special studies in animals and/or humans, based on data generated, should also be considered. These could include possible interactions of the macronutrient substitutes with other components of the diet or with drugs, and the effect of these agents on food intake patterns. Guidelines for the safety evaluation of macronutrient substitutes are presented below. These guidelines are based on generally recognized principles of safety assessment, demonstrated
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need for the scientific data (previous studies), the uniqueness of macronutrient substitutes, current methods for the evaluation of the safety of food additives, the need to conserve resources, current U.S. Food and Drug Administration (FDA) regulatory practices and procedures, and studies in humans. The proposed scheme allows for scientific judgment. Regulatory guidelines often provide the basis for determining the types of data necessary to establish safety. These regulatory guidelines may vary from country to country. However, in this article, the FDA has been chosen as a model. Some of the issues addressed in this article have already been considered by others.1-5-7-11 The following information should be considered prior to the initiation of testing: recognition of the potential benefits to be derived from the introduction of the macronutrient substitute into the food supply; the unique nature of the macronutrient substitute; chemical, physical, and functional characterization of the test material; extent of potential exposure, including potentially heavy users and sensitive subpopulations (in the absence of reliable exposure data, 100% replacement should be assumed); the source (if natural) or the synthetic processes) to the extent feasible; stability during processing, storage or consumer use; biological and other data on chemically similar compounds; and approved materials in the same functional category as the macronutrient to be replaced. The extent of safety testing is based on the chemistry of the test material; the extent of exposure/consumption; and the absorption, distribution, biotransformation, excretion, and kinetics of the macronutrient substitute in animals and humans. Evaluation in humans is initiated only after adequate (in quality and quantity) animal data are fully and critically evaluated. The conditions of exposure in the human studies are determined by the animal data, the anticipated consumer exposure, and the nature of the macronutrient substitute. A postmarketing surveillance program that follows introduction of the macronutrient substitute into the marketplace will provide additional human exposure data, including patterns and levels of consumption and potentially adverse health effects. The safety of macronutrient substitutes is expressed relative to conditions of exposure (how much of what, for how long, and to whom). 128
A. Safety Evaluation Program 1. Test Material Characterization, Exposure Assessment, and Initial Safety Assessment a. Test Material Characterization Test material characterization involves the generation and evaluation of information on the uniqueness of the test material; its composition (single compound or mixture); its source (if natural) or the synthetic process(es) involved in its production (in sufficient detail to enable an assessment of the potential toxicity of the starting materials, contaminants, intermediates, or interaction byproducts); its properties (chemical, physical, functional) and specifications; and its stability during processing, storage, and consumer use. A comprehensive search of the scientific literature on the test material, on chemically related materials, and on approved functionally equivalent materials is an essential component of this phase.
b. Exposure Assessment The anticipated level of consumption should be based on the maximum anticipated replacement level (if known) or on the assumption that the test material will be a 100% replacement for an approved product (for which reliable exposure data are available). These data should be developed for realistic maximum levels of exposure (e.g., the 90th percentile because it is reflective of heavy users). Potentially sensitive populations should also be identified and appropriate exposures anticipated. Reliable exposure data are essential because the extent of testing is determined by the nature, of the test material and the extent of exposure.
c. Initial Safety Assessment A critical evaluation of available data by competent toxicologists should result in a determination that the data satisfy existing regulations for a generally recognized as safe (GRAS) substance or a food additive (FA) or that the data
are inadequate for filing such petitions and the deficiencies are identified.
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2. Safety Assessment for GRAS Status The GRAS process was developed in 1958 by the enactment of the Food Additives Amendment of the Federal Food, Drug, and Cosmetic Act. This required premarketing approval for FAs but two exemptions were permitted: those substances recognized as GRAS and those substances that had been sanctioned prior to 1958. A GRAS substance was defined as a substance that is generally recognized by experts who are qualified by training and experience to evaluate the safety of the substance to be safe (through scientific procedures) under the conditions of its use. GRAS status is determined by experts on the basis of scientific procedures or on the history of use in food. The FDA has compiled a list of approximately 600 GRAS substances (21 CFR Part 182 and 21 CFR 170.30). The criteria for GRAS recognition through scientific procedures require the same data that would be required to demonstrate safety for a FA (however, only published data may be considered for GRAS recognition). Recognition of GRAS through common use in foods requires data on the history of consumption by a substantial number of consumers but does not require the same toxicological data as a FA. All data are critically evaluated by a panel of experts (GRAS panel) and a determination is made that the test material meets the criteria for GRAS or it does not. If the criteria for GRAS are met, information on the digestive and nutritional effects of the test material in appropriate animal species and in humans should be generated. If no adverse effects are produced by the test material at the maximum anticipated level of human exposure (or at a multiple of it), a meeting (presubmission conference) with the FDA should be planned. If the criteria for GRAS are not met, then the options are to meet with the FDA to determine if GRAS status is possible (determine data requirements), to proceed as a FA, or to stop development. If, during the presubmission conference, the FDA does not recommend generating additional data, then a GRAS Petition (GRASP) may be
filed. Once the GRASP is accepted for filing, the macronutrient substitute may be sold and used. However, it is recommended that no action be taken until the FDA formally affirms GRAS status. When GRAS status is affirmed and/or the material is commercialized, a post-marketing surveillance (PMS) program is initiated. If GRAS status is not affirmed by the FDA, a determination is made to generate the data required by the FDA for GRAS status, to proceed as a FA, or to stop development. If additional data are required for GRAS status by the FDA, a determination is made either to generate the additional data and then file the GRASP, to proceed as a FA, or to stop development. If GRAS status is subsequently not affirmed by the FDA, the options are to proceed with the Food Additive Petition (FAP) or to stop development.
3. Safety Assessment of a Food Additive If the macronutrient substitute does not satisfy the criteria for GRAS status, it can be evaluated as a FA. All studies to evaluate the safety of food chemicals should be conducted according to rigorous scientific standards, utilizing protocols that reflect human exposure conditions, and using adequate numbers of both sexes of appropriate animal species. Appropriate animal species are those species in which the response to the test material, and its disposition, are very similar (or identical) to the human (determined in vitro or in vivo). If the appropriate species has not been identified, then the most sensitive species may be considered the appropriate species. Studies may be required in the rat even if it is not the appropriate/sensitive species.
a. Acute Toxicity These single-exposure studies are designed to develop profiles of acute toxicity, to develop/ characterize dose-response relationships, to identify sex and species differences, to identify probable sites (target organs) and mechanisms of toxicity, and to provide a basis for dosage selection for further testing. Acute toxicity studies are conducted using adequate numbers of both sexes of
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several species (because the appropriate/sensitive species are usually unknown at this stage of testing).
c. Genetic Toxicity Genetic toxicity studies are conducted to assess potential mutagenicity/carcinogenicity. Both in vitro (initial) and in vivo tests are conducted.
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b. Short-Term (Repeated-Dosing) Toxicity These studies are designed to develop profiles of repeated dosing toxicity, to establish/ characterize dose-response relationships, to identify probable sites (target organs) and mechanisms of toxicity, to provide data on cumulative effects, and to provide a basis for dosage selection for further testing. Repeated dosing studies are conducted using adequate numbers of both sexes of the appropriate/sensitive species (if known or, in several species, if not known). A palatability study of the dietary admixture is conducted initially to determine acceptability so that a decrease in food intake followed by a decrease in body weight will not be misinterpreted as toxicity (due to an unwillingness of the animals to consume the diet). If palatability is a problem, alternate methods of administration are used (e.g., gavage). Satellite groups may be included for special studies and/or for repeated blood sampling. Repeated-dosing studies usually involve 14 to 28 consecutive days of repeated exposure, three to five exposure levels, and appropriate controls. Nutritional and toxicological parameters evaluated include: food intake; body weight gain; food efficiency; hematology, serum chemistry, urinalysis; blood levels of selected micronutrients; and gross and microscopic examination of tissues. Consideration should be given to generating physiological/pharmacological data (e.g., effects on behavior, cardiovascular effects [electrocardiogram]) in satellite animals or as special studies to be conducted later. As much relevant data as possible should be collected without compromising the major objective of the study. If no significant compound-related and dose-dependent adverse nutritional and/or toxicological effects are identified in these studies, and if the genotoxicity studies do not identify compoundrelated adverse effects, limited human safety studies may be undertaken.
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d. Initial Human Exposure (Sensory Evaluation) Initial sensory evaluation of the organoleptic properties of the test material ("taste and spit") is conducted in healthy, drug-free adult males and nonpregnant females to assess human responsiveness. The test material is not swallowed, and systemic effects are unlikely to occur because absorption from the oral cavity is assumed to be nil. If the desired sensory effect is realized, then a single oral dosing disposition study, as discussed in the following section, is conducted.
e. Disposition Absorption, distribution, metabolism (biotransformation), elimination, and kinetic (ADMEK) studies are conducted in several animal species (including the appropriate/sensitive species) and in humans to determine if the material is absorbed from the gastrointestinal tract, its distribution, biotransformation, and elimination; the kinetics of these processes; and the identification of the appropriate species for further testing, if not already known. The test material is administered orally as a single dose. The dose administered to healthy, drug-free adult males and/or nonpregnant females is based on the animal data and the exposure estimates in humans. If humans do not respond adversely to a single oral dose of the test material, then a 90-d subchronic oral dosing study in the appropriate/sensitive species should be conducted.
f. Subchronic Oral Toxicity Subchronic toxicity studies are conducted to
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develop profiles of subchronic oral toxicity; to characterize dose-response relationship following subchronic exposure; to evaluate nutritional and toxicological effects; to identify probably sites (target organs) and mechanisms of toxicity; to determine reversibility of effects; to identify doses for possible further toxicity testing; to provide data on cumulative effects; and to assist in determining safe conditions of consumption for humans. Subchronic studies usually involve 90 d of repeated exposure, at least three levels of exposure, and appropriate controls. To increase the sensitivity of these studies, in utero exposed animals (F/l a generation) are used. This will also provide preliminary information on potential reproductive effects. Developmental effects (teratological effects) can be evaluated in other litters. This design will significantly reduce the number of animals required without compromising the subchronic toxicity. If the test material is to be administered as a dietary admixture, an appropriate palatability study is conducted prior to the subchronic exposure (unless the results of the palatability study conducted earlier are adequate). If the diet is not palatable at any concentration, alternate methods of dosing must be considered (such as gavage). Satellite groups are included to evaluate reversibility of effects produced; for ADMEK studies; for assessment of nutritional status; and for special studies, if indicated. These subchronic studies provide an opportunity to assess levels of nutrients and test material (and/or its metabolites) through sampling of blood and urine from the satellite groups during the study. The frequency of sampling and other experimental details will be partly determined by the results of the ADMEK studies. The following nutritional and toxicological parameters are evaluated in subchronic studies: food and water consumption; body weight gain; food efficiency; bioavailability of the test material and selected nutrients; hematology, serum chemistry and urinalysis; blood levels of selected micronutrients, and gross and microscopic examination of tissues. Physiological and/or pharmacological studies can be conducted on satellite groups or as special studies to be conducted later. If there
are no significant compound-related and dosedependent adverse nutritional or toxicological effects, a repeated-dosing study in humans, generally 7 to 14 d, can be conducted. Reproductive and developmental toxicity and additional in vivo genetic toxicity studies may also be conducted at this time.
g. Multiple-Dose Studies in Humans Repeated-dosing studies are conducted in healthy, drug-free adult males and/or nonpregnant females to evaluate effects of the test material and to assess acceptability. The doses to be tested are based on anticipated exposure levels, the results of the animal and the single-dose human studies, and the nature of the test material. Parameters evaluated include dietary intake; body weight changes; hematology, serum chemistry, and urinalysis; and blood levels of the test material (and its metabolites) and selected micronutrients. If no significant compound-related and dose-dependent adverse effects are observed in these studies, a presubmission conference with the FDA is planned. The FDA may recommend proceeding with formal submission of the FAP or may recommend further testing. If significant compound-related and dose-dependent adverse effects are observed in these human studies, appropriate special studies are conducted to evaluate the significance of these findings or to stop development of the test material. All studies involving humans are to be conducted safely and with maximum protection of human subjects, by competent investigators, in approved institutions, using protocols and consent forms approved by the Institutional Review Boards (IRBs) (21 CFR parts 50, 56).
h. Reproductive and Developmental Toxicity These studies are conducted to evaluate effects on reproductive performance and intrauterine and postnatal development; to characterize
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dose-response relationships; and to identify probable sites (target organs of toxicity and/or interference) and mechanisms of toxicity. Reproductive and developmental toxicity can be evaluated in the parents (Fo) of animals used in the subchronic study and their offspring using currently accepted procedures in appropriate studies, or the studies can be conducted separately using currently accepted procedures. A two-generation reproduction study in the appropriate/sensitive species and/or one rodent species in which both sexes are exposed by the oral route to at least three levels and including appropriate controls is usually adequate for assessing potential reproductive effects.
/. In vivo Genotoxicity Potential genotoxicity and genotoxic carcinogenicity is evaluated in suitable in vivo systems. Data from these tests, together with data from the ADMEK studies and the estimates of human exposure to the test substance, are useful in determining the need to conduct a lifetime study for carcinogenicity.
j. Special Studies Special studies are undertaken in response to the data generated in the aforementioned studies and are conducted in appropriate animals or humans to investigate or confirm earlier findings or elucidate probable mechanisms of toxicity.
appropriate/sensitive species, usually at three levels of exposure and with appropriate controls using the oral route of administration (preferably diet); the duration of exposure is usually more than half the lifetime of the animal (e.g., 18 to 24 months for rodents). In utero exposed rats are recommended. Satellite groups are included to evaluate reversibility, to permit interim sacrifices, and to conduct appropriate clinical studies (e.g., hematology, serum chemistry, urinalysis, levels of micronutrients). Blood sampling to asses levels of micronutrients and test material and/or its metabolites is conducted regularly throughout the study; the frequency of sampling and other experimental details are determined by the results of previous studies. Nutritional and toxicological parameters evaluated include: physical evidence of compound-related effects; body weight gain; food intake; food efficiency; hematology, serum chemistry, urinalysis; and gross and microscopic examination of tissues. Quantitation of tissue concentrations of the test material (and/or its metabolites) should be considered. If there are no carcinogenic effects, a NOAEL can be identified and an acceptable daily intake (ADI) can be established. If there are no significant compoundrelated and dose-dependent adverse effects, a 90to 180-d repeated human dosing study should be conducted. If compound-related carcinogenic effects are demonstrated, either conduct studies to determine the mechanisms of these effects and their applicability to humans or stop development. The use of satellite animals may obviate the need for two separate studies, chronicity and carcinogenicity, thereby reducing the number of animals used.
k. Chronic Toxicity/Carcinogenicity /. Long-Term Exposure in Humans These studies are designed to establish profiles of chronic toxicity, to characterize doseresponse relationships, to identify probable sites (target organs) and mechanisms of toxicity, to provide data on cumulative effects and reversibility, to establish a no observed adverse effect level (NOAEL), and to determine the carcinogenic potential of the test material. Studies of chronic toxicity and/or carcinogenicity are conducted using adequate numbers of both sexes of
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After data from appropriate and adequate animal and repeated-dosing human studies are critically evaluated, long-term studies are conducted in healthy, drug-free adult males and nonpregnant females to assess the effects of subchronic or long-term exposure to the test material, to determine acceptance of the test material, and to identify levels of exposure that do not elicit adverse effects. The levels of exposure in these
studies should be multiples of the estimated daily intake (EDI, 90th percentile). The highest tolerated dose (HTD), the highest dose tested that did not produce adverse effects, should be identified. The following are monitored: daily dietary intake; weekly body weights; hematology, serum chemistry, urinalysis; and any special parameters indicated from previous studies.
n. Post-Marketing Surveillance (PMS) PMS is conducted following the introduction of a product into the marketplace and should be designed to collect consumption data to determine consumption patterns and acceptability of the macronutrient substitute. It is also used to identify sensitive subpopulations and potentially adverse effects. A PMS should be conducted for both GRAS substances and FAs.
m. Acceptable Daily Intake (ADI)
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CONCLUSIONS The ADI for traditional FAs is usually determined by applying a safety/uncertainty factor (UF) (usually 100) to the NOAEL (ADI = NOAEL/UF). This may not be appropriate for macronutrient substitutes because animals may not have received high enough doses. Other approaches to establishing the ADI must be considered. Animal data are used to demonstrate the relative safety of the test material up to the highest level fed (usually 5%). If concentrations greater than 5% are used, nutritional deficiencies may occur and these can confound interpretation of the data (these deficiencies may be misinterpreted as toxic effects). If 5% is the maximum level of the nonnutrient tested in the animals studies, and if this approaches the maximum anticipated human exposure, application of traditional safety/ uncertainty factors would not be suitable. However, data from properly designed and executed chronic and other animal studies evaluated in conjunction with data from properly designed and conducted human studies would provide an acceptable basis for the use of a lower UF in establishing the ADI. Human studies provide many advantages in the evaluation of safety: the human is the target species (eliminating extrapolation) and subjective (often subtle) effects can be determined and evaluated (impossible in nonhuman species). The need for scientific judgment in developing an ADI from animal and human data is essential; a simple formula will not be applicable in every instance suggesting a case-by-case approach within general guidelines.
The uniqueness of macronutrient substitutes necessitates the use of special procedures for their safety evaluation. Methods currently used for the safety evaluation of traditional FAs involve limiting the level of the test material that can be incorporated into the diet of test animals. This level may be too low for the evaluation of macronutrient substitutes if traditional methods for determining the ADI are used. The approach to the evaluation of the safety evaluation of macronutrient substitutes described in this article recognizes the uniqueness of these materials and the limitations of current methods and proposes the utilization of animal and human data, consideration of nutritional and toxicological effects, special attention to kinetic and dispositional data, the use of nontraditional UFs, and the use of PMS. It may be necessary to design studies on a case-by-case basis. ACKNOWLEDGMENTS The author and editors express their thanks to Eric W. Nealley, USAMRICD, APG, MD, for his assistance in the preparation of Figures 1 and 2. The author expresses his appreciation for the valuable contributions of Zara Abraham, James L. Allen, G. Harvey Anderson, Carolyn Bergholz, David Bechtel, Mark Bleber, Leonard Czuba, John Hallagan, Suzanne Harris, Christopher Hassall, John Kllle, Gilbert Levellle, Lawrence Masten, Harry Salem, Daniel Skrypec and Marshall Spearman.
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SAFETY EVALUATION OF MACRONUTRIENT SUBSTITUTES
• - STOP
FIGURE 1. Schematic overview of pathway for safety evaluation. (To assist in tracking Figure 2.)
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SAFETY EVALUATION OF MACRONUTRIENT SUBSTITUTES IDENTIFY BEUEFITS
CHARACTERIZE MATERIAL
ASSESS EXPOSURE
IDENTIFY/EVALUATE SOURCE
TRACK FATE DURING PROCESSING
COMPREHENSIVE SURVEY OF LITERATURE
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EVALUATE DATA
DATA ADEQUATE FOR PROPER EVALUATION OF SAFETY
DATA INADEQUATE FOR PROPER EVALUATION OF SAFETY
I HUMAN STUDIES BIOAVAJLABILITY ANIMAL
STUDIES
DIGESTABILITY BI0AVA1 LABILITY
INTERACTIONS
DIGESTIBILITY |INTERACTIONS| I | NUTRITIONAL |
NONSIGNIFICANT EFFECTS
SIGNIFICANT EFFECTS
NUTRITIONAL
SIGNIFICANT EFFECTS
NONSIGNIFICANT EFFECTS
REPEAT OR SPECIAL STUDIES
REPEAT
STOP
RE-EVALUATE RE-EVALUATE STOP STOP
CONFERENCE WITH FDA
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ADDITIONAL DATA STOP
NO ADDITIONAL DATA
CONDUCT STUDIES
±
RE-EVALUATE STOP
FAP
GRASP
ACCEPTED NOT ACCEPTED FOR FILING
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WITHDRAW GRASP
STOP
FAP
ACCEPTED FOR FILING
CONDUCT STUDIES
RE-EVALUATE
STOP
RESUBMIT
E
NOT ACCEPTED FOR FILING
ACCEPTED FOR FILING
NOT APPROVED
_L STOP
FAP
NOT AFFIRMED GRAS
PMS AFFIRMED GRAS
I STOP
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FAP
APPROVED
PMS
IDENT1KY DEFICIENCIES
| PREPARE WTOCOLS |
CONDUCT STUDIES
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| EVALUATE DATA
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K NONSIGNIFICANT EFFECTS
SIGKIFICAHT EFFECTS
CONFERENCE WITH FDA
REPEAT OR SPECIAL STUDIES
i
FAP
NOT APPROVED
RE-EVALUATE STOP
i
STOP
REPEATED DOSIBG ETDDIES IN HUMANS
1
APPROVED
CONDUCT STUDIES
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EVALUATE
SIGNIFICANT EFFECTS
NONSIGNIFICANT EFFECTS
STOP
_L
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SPECIAL STUDIES
NOT APPROVED
ZL
APPROVED
PMS
RE-EVALUATE STOP
RESUBMIT
REPRO/DEVELOP TOXICITY
FIGURE 2.
Detailed pathway for safety evaluation.
REFERENCES SIGNIFICANT EFFECTS
NONSIGNIFICANT EFFECTS
SPECIAL STUDIES
RE-EVALUATE
STOP
CONFERENCE WITH FDA
ADDITIONAL DATA STOP
NO ADDITIONAL DATA
CONDUCT STUDIES
SPECIAL STUDIES
CHRONIC TOXICITY
EVALUATE STOP
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ESTABLISH RDI
1. Cranmer, G. M., Ford, R., and Hall, R. L., Estimation of toxic hazard — a decision tree approach, Fd. Cosmet. Toxicol., 16, 255, 1978. 2. Food Safety Council, Proposed system for food safety assessment. Report of the Scientific Committee of the Food Safety Council, Fd. Cosmet. Toxicol. 16(Suppl. 2), 1, 1978. 3. Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Foods — Redbook. U.S. Food and Drug Administration, Washington, D.C., 1982. 4. Memorandum on the Testing of Novel Foods: incorporating Guidelines for Testing for the Advisory Committee on Irradiated and Novel Foods. Ministry of Agriculture, Fisheries and Food, Scottish Home and Health Department, Welch Office Department of Health and Social Services, Northern Ireland, 1984. 5. EHC 70: Principles for the Safety Assessment of Food Additives and Contaminants in Food, World Health Organization, Geneva, 1987. 6. Cohrrsen, J. J. and Covello, V. T., Risk analysis: a guide to principles and methods for analyzing health and environmental risks, U.S. Council on Environmental Quality, Office of the President, Washington, D.C., 1989.
10. Rulis, A. M., The Food and Drug Administration's Food Additive Petition review process, Food Drug Cosmetic Law J., 45, 533, 1990. 11. Kroes, R. and Hicks, R. M., Eds., Re-evaluation of current methodology of toxicity testing including gross nutrients, Fd. Chem. Toxicol., 28, 733, 1990. 12. Advisory Committee on Novel Foods and Processes. Guidelines on the Assessment of Novel Foods and Processes, Department of Health, Report on Health and Social Subjects (38), Her Majesty's Stationery Office, London, 1991.
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7. International Food Biotechnology Council, Biotechnologies and Food: assuring the safety of foods produced by genetic modification, Reg. Toxicol. and Pharmacol., 12, S1, 1990. 8. Munro, I. C., Issues to be considered in the safety evaluation of fat substitutes, Fd. Chem. Toxicol., 28, 751, 1990. 9. New Food and Food Chemicals: Safety and Regulatory Considerations 01-02 May 1990, National Academy of Sciences, Washington, D.C., 1990.
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