Aspartame

Physiology and Biochemistry

Filer Stegink

• Publisher: CRC Press
• Year: 2020
• Print ISBN:
  9780367840907
• eBook ISBN:
  9781000146523
• Topic: Physical Sciences
• Subtopic: Chemistry
• Index: Chemistry

This book summarizes the research that resulted in aspartame's approval as a food additive as well as related topics regarding its function as a potential sweetening agent. It complies specific issues relating to human consumption of aspartame.

PRECLINICAL STUDIES

14 Preclinical Studies of Aspartame in Nonprimate Animals

Samuel V. Molinary
PepsiCo, Inc., Valhalla, New York

INTRODUCTION

Aspartame, [3-amino-N-(2-carboxyphenethyl)succinamic acid methyl ester], the methyl ester of L-aspartyl-L-phenylalanine, and its principal decomposition product, 3-carboxymethyl-6-benzyl-2,5-diketopiperazme (diketopiperazine, or DKP) have been extensively studied for their toxicological potential for the past 15 years. Over 112 studies concerning the metabolism, pharmacology, and toxicology of these two compounds were filed by G. D. Searle & Company with the Food and Drug Administration (FDA) as proof of the safety of aspartame (APM) as a food additive.* In approving APM as a sweetener in 1981, Commissioner Hayes said (1), “The safety evaluation of aspartame has been a long and arduous process, spanning the tenure of several FDA commissioners. Few compounds have withstood such detailed testing and repeated, close scrutiny, and the process through which aspartame has gone should provide the public with additional confidence of its safety.” While APM may not be the most studied food additive, it probably has had the largest number of studies carried out prior to FDA approval.

Of these 112 safety studies submitted to the FDA, 93 are or pertain to reports of studies of aspartame and its DKP in animals. Many of these studies have been reviewed and evaluated by the Joint Expert Committee on Food Additives (JEC/FA) of the Food and Agricultural Organization of the United Nations and the World Health Organization (FAO/WHO) in 1975, 1976, 1977, and 1980. A monograph on the toxicological evaluation was written following the 1980 JEC/FA meeting in Rome (2). This review will be confined to those animal studies carried out early in the development of aspartame (1968-1974). Some of these studies, especially the carcinogenicity studies in the rat, became the focal point for questions that were considered by the Public Board of Inquiry in 1980; the interpretation of these is discussed in depth elsewhere in this book (3-5).

These studies are contained in the so-called “E-File” at the Food and Drug Administration, Hearing Clerk File, Administrative Record, Aspartame 75F-0355, Rockville, Maryland.

In proposing a novel compound as a food additive, especially a sweetener which will be consumed by all segments of the population, it is important that the sponsor prove that this compound is safe to a reasonable certainty. The development of a data base for product safety assessment typically starts in three scientific areas: metabolism (including absorption, tissue distribution, pharmacokinetics, and elimination), pharmacology, and toxicology. Metabolism studies are carried out in a number of different species, ultimately including man, and the data obtained are used to design and interpret studies in the other two areas. In this specific case pharmacology studies are performed to discover if the compound has any biological activity other than that of creating the perception of a sweet taste. Pharmacological activity is not a desirable property for a food additive. Toxicology studies are carried out in two parts, acute and chronic exposure, and are undertaken to determine what harm may accrue as a result of ingesting the food additive, especially under conditions of high intake. Each of these areas will be considered as they relate to the studies of animals administered aspartame or its DKP.

The metabolism of aspartame and its diketopiperazine have been extensively studied in mice, rats, rabbits, dogs, monkeys, and man (2,6-19). The major point to emerge from the metabolism studies is that in all species tested, aspartame is broken down in the gastrointestinal tract to its constitutents L-phenylalanine, L-aspartic acid, and methanol. These findings suggest that outside the gastrointestinal tract, any toxicological activity of aspartame would result from systemic imbalances caused by increases in the plasma concentration of these two amino acids and methanol. This finding also suggests that if the dipeptide (aspartyl-phenylalanine) per se had any pharmacological activity, it would be in the gastrointestinal tract itself. This was considered possible since the dipeptide sequence aspartyl-phenylalanine is found at the carboxy terminal end of the gastrointestinal hormones gastrin and cholecystokinin (20).

Studies were undertaken by Bianchi et al. (21) to delineate any pharmacological effects that aspartame might have on the gastrointestinal system. Rats were given 200 mg/kg body weight of aspartame intragastrically and observed for effects on appetite suppression, inhibition or stimulation of gastric secretion, acid secretion, and proteolytic activity. No compound-related effects were observed.

In addition to tests on the gastrointestinal system, other pharmacological tests were carried out in a variety of in vivo and in vitro model systems (22). As pointed out by Potts et al. (23), “some of thes...

Table of contents

• Cover
• Half Title
• Series Page
• Title Page
• Copyright Page
• Preface
• Contributors
• Contents
• HISTORY AND BACKGROUND
• METABOLISM
• SENSORY AND DIETARY ASPECTS
• PRECLINICAL STUDIES
• STUDIES OF ASPARTAME METABOLISM IN HUMANS
• Index