Aspartame: An Artificial Sweetener

Since 1973 when the Food and Drug Administration first approved the artificial sweetener, aspartame, for use in food products, some researchers have raised questions about possible health effects associated with its consumption. This paper provides an overview of the regulatory history and possible health problems associated with the use of aspartame.

84-649 SPR -. . 4 Congrsssional Research Service The Library of Congress ASPARTAME: .XV XRTLFICIAL SkXETSNER Donna V . P o r t e r A n a l y s t i n Life S c i e n c e s Science Policy Research Division Xarch 2 3 , 1984 S i n c e 1 9 7 3 ohen t h e Food and Drug A d m i n i s t r a t i o n f i r s t approved t h e a r t i f i c i a l s w e e t e n e r , aspartame, f o r u s e i n food products, s o a e r e s e a r c h e r s have r a i s e d q u e s t l o a s about p o s s i b l e h e a l t h e f f e c t s a s s o c i a t e d v i t h i t s consumption. T h i s paper p r o v i d e s an o v e r v i e w o f t h e r e g u l a t o r y h i s t o r y and p o s s i b l e h e a l t h prohlems a s s o c i a t e d v i t h t h e u s e . o f aspartame. CONTENTS HEALTH ASPECTS OF ASPARTAME ................................................ 1 ................................ 2 ............................................ 5 LEGISLATIVE HISTORY OF FOOD ADDITIVE POLICY REGULATORY HISTORY OF ASPUTAWE CURRENT STATUS OF ASPARTAME APPENDIX I . ASPARTAME: ................................................ SELECTED CHRONOLOGY OF EVENTS ..................... 8 16 .. ASPARTAME: AN ARTIFICIAL SWEETENER Aspartame is an artificial sweetener synthesized from two amino acids, aspartic acid and phenylalanine. It vas discovered accidentally in 1965 by a scientist at G. D. Searle & Company (Skokie, Illinois) who was doing research on nev drugs to treat ulcers. Since 1965, G. D. Searle & Company has conducted extensive testing in a n attempt to demonstrate that aspartame is safe for aort people when added to food products. On July 7, 1981, after considerable debate, the Food and Drug Administration (FDA) approved the use of aspartame in dry food products. On July 8, 1983, FDA approved the use o f the sweetener in carbonated beverages. This report provides an overview of aspartame, dis- c u s e s the regulatory his.tory of artificial sveeteners and identifies some of the current controversy over this recently approved substance. HEALTH ASPECTS OF ASPARTAME In terms of caloric value, aspartame contains four calories per gram, the same as table sugar. However, because i t has a sweetening power 180 times greater than table sugar, aspartame can be used in much smaller quantities to achieve the same level of sweetness. In practical terms, the smount of aspartame with an equivalent sweetening power of two teaspoons of sugar (32 calories) contains only 0.4 calories. l-/ Aspartame has a fu-ther advantage as a sweetening 1/ Jemison, Terry. Aspartame Firm Eyes Saccharin's Populari-ty. U.S. ~ e d i c y n e ,v. 18, Sept. 15, 1982. p. 27. agent because, unlike sugar, it does fiat provide a good aedium in the mouth to encourage the growth of bacteria that cavse dental caries. W e n digested by humans, aspartame breaks down into its component parts, aspartic acid, phenylalanine, and small amounts of methanol. Although both of the amino acids end methanol are naturally present in a number of commonly eaten foods, concern about their health implications has been raised in the scientific community. A small proportion of the population suffers from the genetic disease called phenylketonuria (PKU), a condition vhich prevents the metabolism of the amino acid, phenylalanine. These individuals must restrict their intake of this amino acid in order to prevent its buildup in the brain which can lead to mental retardation. The intake of foods containing phenylalanine must be carefully monitored in individuals with this disorder. Concerns have also been raised about the safety of aspartic acid. Animal studies have shown that extremely high doses of certain amino acids, such as aspartic acid, can cause focal brain lesions and associated neuroendocrine changes. The safety of aspartame has also been questioned in relation to the formation of brain neoplasms (tumors), the effect on neurotransmitters, and the production of methanol as a metabolic endproduct. LEGISLATIVE HISTORY OF FOOD ADPZTIVE POLICY Federal policy concerned vith food regulation began in the United States vith the Pure Food and Drug Act of 1906, which stated that food is deemed adulterated "if it contains any added poisonous or other deleterious ingredients which may 2/ Aspartame; Commissioner's Final Decision. no. 1z2, July 24, 1981. p. 38284-38308. Federal Register, v . 46, render such a r t i c l e i n j u r i o u s t o health." The F e d e r a l Food, Drug, and C o s m e t i c Act of 1 9 3 8 (FD62 A c t ) expanded t h e d e f i n i t i o n of a d u l t e r a t e d food t o i n c l u d e foods c o n t a i n i n g any p o i s o n a t s o r d e l e t e r i o u s s u b s t a n c e which may r e n d e r i t f n j u r i o u s t o h e a l t h ; b u t i n c a s e t h e s u b s t a n c e is n o t an added s u b s t a n c e , s u c h f o o d s h a l l n o t be c o n s i d e r e d a d u l t e r a t e d under t h i s c l a u s e i f t h e q u a n t i t y of s u c h s u b s t a n c e i n s u c h food does n o t o r d i n a r i l y render it injurious to health. / I n 1 9 5 8 , t h e Food A d d i t i v e Amendment, which i n c l u d e s t h e c o n t r o v e r s i a l Delaney ( a n t i - c a n c e r ) c l a u s e , v a s added t o t h e FDK Act. ?/ Three c a t a g o r i e s of food a d d i t i v e s a r e r e c o g n i z e d by t h i s Amendment: 1. Food a d d i t i v e s g e n e r a l l y r e c o g n i z e 8 a s s a f e ( P A S ) ; 2. Food a d d i t i v e s v l t h p r i o r s a n c t i o n ( a p p r o v a l ) ; and 3. Nev food and c o l o r a d d i t i v e s . Under t h e a n t i - c a n c e r c l a u s e , any food o r c o l o r a d d i t i v e o r a n i a n l Iruq t h a t may be d e t e m i n e d t o c a u s e c a n c s r i n man o r animal i s r e q u i r e d t o b e banned from t h e m a r k e t . The Amendment f u r t h e r s t a t e s t h a t t h e Surden of p r o v i n g an a d d i t i v e s a f e i s t h e r e s p o n s i b i l i t y of t h e m a n u f a c t u r e r . In seeking approval f o r a s p a r t a m e , S e a r l e h Company needed t o d e m o n s t r a t e compliance v i t h both g e n e r a l s a f e t y and a n t i - c a n c e r p r o v i s i o n s of t h e FDLC Act. FGGJLATIOU OF ARTIFICIAL S'XETENEPS years, FDA h a s banned t h e use of s e v e r a l p r e v i o u s l y approved f ~ o da d d i t i v e s , i n c l u d i n g some a r t i f i c i a l s w e e t e n e r s , on t h e grounds t h a t t h e s e s u b s t a n c e s may have n e g a t i v e h e a l t h e f f e c t s . One e x a a p l e i s c y c l a m a t e , t h e -3 1 The F e d e r a l Food, Drug, and Cosmetic Act. -4/' The F e d e r a l F o ~ d ,Drug and Cosmetic Act. S e c t i o n 402 ( a ) ( I ) . S e c t i o n 109 ( c ) ( 3 ) ( . 4 ) . primary a r t i f i c i a l sweetener i n use d u r i n g t h e 1950s and 1960s. On O c k b e r 2 1 , 1969, FDA banned t h e u s e of cyclamate from foods, beverages, and drugs s f t ? r s t u d i e s w i t h l a b o r a t o r y a n i m a l s r e v e a l e d t h a t t h i s a r t i f i c i a l s v e e t e n e r may cause bladder cancer. ?/ S i n c e t h a t t i m e FDA h a s received a number of p e t i t i o n s t o r e v e r s e c h i s d e c i s i o n on t h e b a s i s of new d a t a . However, t o d a t e , a l l s u c h r e q u e s t s have been denied. S a c c h a r i n ,was t h e o n l y n o n - r m t r i t i v e from 1970 t h r o u g h 1981. a r t i f i c i a l s v e e t e n e r on t h e market A product of p e t r o l e u a m a t e r i a l s produced by Shervin- W i l l l a u s P a i n t Company, i t has been under s c f e n t i f i c s c r u t i n y s i n c e i t s d i s c o v e r y i n 1879. I n 1977, FDA proposed a ban on s a c c h a r i n a f t e r a n i m a l s t u d i e s i n d i c a t e d t h a t i t t o o may c a u s e b l a d d e r c a n c e r i n a n f m l s . k/ This proposed ban, however, was o v e r r u l e d by Congress because of s t r o n g p u b l i c demand f o r a n a r t i f i c i a l s v e e t e n e r t o be a v a i l a b l e on t h e market. 13 Uovem- b e t 1977, Congress i q o s e d a n l d l n o n t h moratorium a g a i n s t such a ban. L/ T h i s moratorium was extended i n n a y 1979 and a g a i n i n Xugust 1931. In April 1983, a 24-month e x t e n s i o n of t h e moratorium was signed i n t o lav. The s e a r c h f o r low-calorie s v e e t e n e r s t h a t do not pose h e a l t h hazards h a s been s t i m u l a t e d by c o n c e r n s a b o u t t h e cancer-causing p o t e n t i a l of cyclamate and s a c c h a r i n , and by t h e market demand f o r such a n a r t f f f c i a l s v e e t e n e r . -5 / 34 Fed. Reg. 17063, Oct. 2 1 , 1969. 6 / S a c c h a r i n and I t s S a l t s : Proposed R*dc %king. v. 4 2 , no. 73, Apr. 1 5 , 1977. p. 19996. -7 / S a c c h a r i n Study and L a b e l i n g Act--?.La Federal Register, 95-203 (S. l75O), 1977. REGULATORY HISTORY OF ASPARTAME In an attempt to demonstrate the safety of aspartame, G.D. Searle 6 Company has subjected the artificial sweetner to extensive tzsting. On March 5, 1973, Searle reported its findings, together with a petition for approval, to FDA. According to the 1973 studies, aspartame does not have any negative health implications for the general population, but i t is recormended that people who suffer from the rare condition phenylketonuria (PKU) not consume aspartont-containing products. Oa July 26, 1974, FDA approved Searle's petition for aspartame as: a cnnetener for table use; a tablet for hot beverages; an ingredient in cold cereals; a dry base svtcteaet for powdered beverages, instant coffee and tea, gelatins, fillihgs, and dessert toppings; and a flavoring agent in chewing gum. In reviewing the characteristics of aspartame, FDA imposed the following additional conditions on the marketing of this artificial sweetener: 1. The label of any food containing aspartame must bear the atatement "Phenylketonurics: contains Phenylalanine." (The purpose of this statement is to alert persons vho must avoid foods containing phenylalanine.); 2. When aspartame is to be used as a table top sweetener, its label is required to bear instructions not to use aspartame in cooking or baking. (This statement is to inform the consumer that aspartame breaks down to an undesirable compound, diketopiperazine (DKP), when exposed to prolonged heat.); and 3. If a food containing aspartame claims to have special dietary uses, such as a lorcalorie product, i t is required to comply with FDA's special dietary food regulations. z/ At the time of FDA's initial (1974) approval of aspartame, several formal objections were raised. Specifically, John W. Olney, M.D., Washington University 8/ Food Additives Permitted in Food for Human Consumption. RegisTer, v. 39, no. 145, July 26, 1974. p. 27320. Federal School of Medicine, St. Louis, and James S. Turner, Esq. representing Label, Inc. (Legal Action for Buyers' Education and Labeling) filed objections to aspartame's approval on the grounds that its use by children may cause brain damage and result in mental retardation, endocrine dyrfunction, or both. On December 5, 1975, FDA placed a stay on the regulation allowing the marketing of aspartame and planned a comprehensive reviev of research data on aspartaw. 9/ . On December 13, 1978, the results of a two year study of Searle's research investigations confirmed that the test experiments were valid. On June 1, 1979, FDA established a Public Board o f Inquiry (Board) consisting of three independent scientists to clarify the following issues: 1. Whether the ingestion of aspartame, either alone or together vith glutasate, poaee a risk contributing to mental retardation, brain damage, or undesirable effects on neuroendocrine regulatory systems; 2. Whether the ingestion of aspartame may induce brain neoplasms (tumors) in the rat; and 3. Based o n answers to the above questiofls, a. Should aspartame be alljwcd Eor use in foods, or instead, should approval of aspartame be withdraw? b. If aspartame is allovtd for use in foods, i.e., i f its approval is not withdraw, what conditions for use and label statements should be required, if any? 101 - After hearing and reviewing testimony from various scientists and groups, the Board issued its decision on October 1, 1980. Specifically, i t concluded that aspartame consumption would not pose an increased risk of brain damage 1 E in mental retardation or endocrine dysfunction. resultqng -9/ 11/ It did 4 0 Fed. Reg. 56907, Dec. 5, 1975. 101 Aspartame; ~ u l i n gon Objections and Notice of Hearing Before a ~ u b l i c ~ o a ' rof d Inquiry. Federal Register, v. (4, no. 107, June 1, 1979. p. 31717. 11/ Aspartame; Commissioner's Final Decision. no. I=, July 24, 1981. p. 38286. Federal Register, v. 46, n o t , however, r u l e o u t t h e p o s s i b i l i t y of aspartame c a u s i n g b r a i n tumors and even s u g g e s t e d t h a t t h e e v i d e n c e may i n d i c a t e t h a t aspartame induces b r a i n tumors Because of t h e unresolved q u e s t i o n on t h e b r a i n tumor t s o u e , t h e i n animals. Soard d i d n o t recommtnd a p p r o v a l sf S e a r l e ' s food a d d i t i v e p e t i t i o n . &?-/ A s t u d y s u b s e q u e n t l y completed on t h e b r a i n tumor i s s u e r e s o l v e d t h i s q u e s t i o n t o t h e s a t i s f a c t i o n of t h e agency. h i t e r c o n s i d e r i n g t h e r e s u l t s of a p e r i m e n t a l s t u d i e s , comments trom FDA s t a f f , and t h e recouunendations of t h e Board, on J u l y 1 8 , 1981, A r t h u r R u f l Hayes, Jr., t h e n Comtuissfoner of PDA, o r d e r e d approval of t h e food a d d i t i v e p e t i t i o n f o r asp art am^ dition. as o u t l i n e d i n t h e 197b a p p r o v a l w i t h t h e a d d i t i o n of one f u r t h e r conS e a r l e i s t o m n i t o r t h e actual u s e l e v e l of a s p a r t a n e and p r w i d e t h i s i n f o r m a t i o n t o t h e FDA Bureau of Foods when requested. e f f e c t i v e O c t o b e r 22, 1981. T h i s a p p r o v a l became z/ U n t i l J u l y 1983, a s p a r t a m e c o u l d be used only i n d r y p r o d u c t s . 4spartane was n o t p r e v i o u s l y approved f o r u s e i n l i q u i d a e d i a because i t may b r e a k down i n t o d i k e t o p i p e r a t i n e (DKP) o v c r time. qovever, on J u l y 8 , 1983, FDA a n e d e d t h e food a d d i t i v e r e g u l a t i o n s t o a l l o w f o r t h e u s e of aspartame i c c a r b o n a t e d beverages and c a r b o n a t e d beverage s y r u p bases. I n a p e t i t L o n t h a t had been f i l e d i n O c t o b e r L982, S e a r l e & Company provided s u f f i c i e n t e v i d e n c e t o s ? t i s f y FDA t h a t 1) t h e sweetener i s s u f f i c i e n t l y s t a b l e f o r t h e normal s h e l f - l i f e or' c a r b o n a t e d b e v e r a g e s , and 2 ) a d d i t i o n a l consumption of t h e s w e e t e n e r w i l l n o t c a u s e t o x i c o l o g i c a l problems. z/Approval of S e a r l e ' s p e t i t i o n has been delayed f o r s e v e r a l months w h i l e FDA s t u d i e d s c i e n t i f i c d a t a and comments. 12/ - Ibid., p. 38286. 13/ - Ibid., p. 38288. 14/ Food Addi t i v e s P e m i t t e d f o r D i r e c t A d d i t i o n t o Food f o r Human C o n s G t i o n ; Aspartame. F e d e r a l R e g i s t e r , v. 4 8 , no. L32, J u l y 8 , 1983. p. 31376-31382. Searle 6 Company markets aspartame under the trade names "Equal" for ure at the table and "Nu~raSwaet" for manufacturing purposes. Searle 6 Company has the exclusive right to produce arpartaw. Currently, This right has been extended by an amendment to the patent regulations approved January 4, 1983. The amendment stater that for products such as aspartame, whose approval for use is withdrawn and then reinstated, "the lengtk ci -'rc of the patent's duration is to be measured from the date such stay oi crs~!afion of approval uu imposed until such proceedings are finally resolved and c-rcial keting permitted." mar- g/ At the present ti=, the carbonated beverage industry accounts for 70 percent of the market b e of saccharin. E/ The diet soda industry could be a potentially profitable market for aspartame. Unlike saccharin, aspartame does not leave a bitter aftertaste and is an FDA-approved food additive. Use of saccharin in food products is legal because the moratorium enacted by Congress prevents FDA from banning its use. The FDA decision to approve aspartame for addition to carbonated beverages provides diet soda manufacturers a choice of two artificial sweeteners--aspartame and saccharin--for use in their products. The Cocr-Cola Company and Royal Crown Cola Company were the first to contract with Searle to use aspartame in their diet soda products. B y the end of 1983 both companies were manufacturing beverages containing a mixture of aspartame and saccharin. 15/ - x/Other soft drink manufacturers have since contracted USC 35 Sec. ll(a). 6 Personal Communication with Neil Sweig, Health Care Industry Analyst for ~ E a r s o n / ~ m e r i c aExpress. n New York City, N.Y. on Aug. 9 , 1983. 171 - Ibid. for the ure o f aspartame in order to remain coypetitive. It is currently eetieated that the majority of diet carbonated beverages contain aspartame, either alone or in combination with sacc!~arin. According to a reprerentative at Searle & Company, a number o f food companies are filing petitions with FDA requesting approval to uee anpartame. in other liquid media, such as juicer, jams, yogurt, and toothpaste. Because FDA has approved the use of the sweetener in carbonated beverages, i t is expected that approval for use in these products vill also be granted. E/ In September 1983 Searle filed a petition with FDA proposing that the food additive regulations be amended to provide for the safe ure of aspartame as a sweetener available to the c o n s m e t in bulk package form. E/ In December 1983 the agency prcpored to declare aspartame suitzble for use as an active ingredient in hlrrnan drug products .provided that the lab21 and labeling of the drug products declare the presence and amount of the component phenylalanine - that is contained ia the drug product per dosage unit. 211 Research continuing at Searle & Company is directed at develooing less expensive methods o f producing aspartame. A cost comparison of aspartame with sugar and saccharin reveals that aspartame is the most costly of the three sweeteners. =U - For a sweetening power equivalent of a pound o f sugar, Cola Challenee. Consumer Reports, Feb. 1984. p. 58. 19/ Personal ccuuni.:~t ion with Dick McGraw, Public RelatLons Office at G. ~ . S e a r l e& Co. Glenvitw, Ill. on July 20, 1983. 20/ G. D. Searle h Co. Filing of Food Additive Petition. ~ e g i s t e r ~v .. 48, no. 175, Sept. 8, 1983. p. 40562. Notice. Federal 21/ Aspartame as an Inactive Ingredient in Human Drug Products; Labeling ~ e ~ u i r e m e n t s Proposed : Rule. Federal Register, v. 48, no. 237, Dec. 8, 1983. p. 54993. a s p a r t a m e c o s t s 45 c e n t s , s u g a r c o s t s 29 c e n t s , and s a c c h a r i n c o s t 1 . 3 c e n t s . 2/ By r e d u c i n g t h e c o s t of a s p a r t a m e , t h e ' f i n a l c o s t o f t h e food p r o d u c t s t o which i t i s added would be reduced. I n o r d e r t o reduce. t h e c o s t of t h e raw m a t e r i a l s , S e a r l e has r e c e n t l y contracted with a g e n e t i c engineering f i r m t o supply phenylalanine. The g e n e t i c e n g i n e e r i n g f i r m ' s new p r o c e s s is e x p e c t e d t o produce t h i s key i n g r e d i e n t more r a p i d l y and a t l o w e r c o s t t h a n i t has b e e n produced i n the past. g/ I n s p i t e o f FDA's a p p r o v a l , a s p a r t a m e is n o t e n t i r e l y f r e e from q u e s t i o n s concerning its s a f e t y . The C e n t e r f o r S c i e n c e i n t h e P u b l i c I n t e r e s t h a s a s k e d FDA t o respond t o q u e s t i o n s o f a s p a r t a m e s a f e t y f o r u s e i n h o t foods, t h e p o s s i b i l i t y of n f t r o s a m i n e f o r m a t i o n , t h e s a f e t y o f f o r m a t i o n o f m e t h y l a l c o h o l t h r o u g h breakdown o f a s p a r t a m e ; t h e t o x i c i t y o f d i k e t o p i p e r a z i n e , and t h e adequacy of l a b e l u a r n i n g s f o r p h e n y l k e t o n u r i c s and ~ t h e rp e o p l e who need t o a v o i d p h e n y l a l a n i n e , a n d , t h e r e f o r e , a s p a r t a m e . 241 D r . Woodrw Monte, A s s i s t a n t P r o f e s s o r of Food S c i e n c e a t A r i z o n a S t a t e U n i v e r s i t y , r e p o r t s numerous a c c o u n t s from consumers who have f e l t t h e i r cons u m p t i o n of ? r o d u c t s c o n t a i n i n g a s p a r t a m had c a u s e d s u c h c o m p l a i n t s a s g r a n d ma1 s e i z u r e s , s u i c i d a l deep depression, s e v e r e headaches, mental d i s o r i e n t a t i o n , l o s s of e q u i l i b r i u m , s p e e c h i m p a i r m e n t , c o n f u s i o n , f a t i g u e , v a g i n a l s p o t t i n g , menses c h a n g e s mimicking e a r l y o n s e t of menopause, v i s u a l i m p a i r m e n t , d i z z i n e s s and ever! a p o s s i b i l i t y of b r a i n a b s c e s s e s and f e t a l a b n o m a l i t i e s . He c o n c l u d e s t h a t 1) t h e s e c o m p l a i n t s c a n be e x p l a i n e d by t o x i c e f f e c t s of t h e v a r i o u s components of a s p a r t a m e a f f e c t i n g t h e body e i t h e r a l o n e o r t o g e t h e r , and 22/ B y l i n s k i , Gene. ~ u l y6 , 1982. p. 30. 23/ p. ~ 7 24/ Feb. The B a t t l e f o r A m e r i c a ' s Sweet T o o t h . Cenex J o i n s S e a r l e t o Make S w e e t e n e r s . W a s h i r ~ g t o nP o s t , Aug. 1 6 , 1983. Sew Q u e s t i o n s on X ~ p a r t a n e ' s S a f e t y R a i s e d by CSPI. p. 4. z, 1983. Fortune, Food Chemical N e w s , 7: t h a t many of t h e c o m p l a L n t s a r e t o b e f o u n d i n S e a r l e ' s own s t u d i e s d o n e v i t h hrrma-s and p r i m a t e s . 951 l l f l l i a m P a r d r i d g e , A s s o c i a t e P r o f e s s o r of Y e d f c f n e a t UCLA, h a s Dr. q u e s t i o n e a FDA on tw p o i n t s c o n c e r n i n g a s p a r t a m e : 1 ) t h e intended dose i n a n d 2 ) what c o n s t i t u t e s a h a r m f u l e f f e c t of t h e c m p o u n d i n t h e mg:kg/day, D r . P a r d r i d g e c o n t e n d s t h a t FDA h a s u n d e r e s t i n a t e d t h e ?rejected food suppl;. u s a g e of a s p a r t a n e e v e n b e f o r e i t h a s b e e n a p p r o v e d f o r u s e i n a l l p o s s i b l e food product*. FDA h a s e s t i m a t e d t h a t a t y p i c a l d a i l y d o s e of a s p a r t a m e v i l l b e 8 t o 10 mglkg, t h e a l l w a b l e d a i l y i n t a k e v t l l be 2 3 mg/kg and t h e 9 9 t h p e r c e n t i l e of aspartame i n t a k e v i l l b e 3 1 ng/kg/day. a -re 261 Pardridge believes t y p i c a l d a i l y i n t a k e of a s p a r t a m e vill be i n t h e o r r i e r of 30 t o 50 mg/kg/day, particularly i n children. Y i s second concern d e a l s with t h e n e u r o t o x i c c r i t e r i a b e i n g u s e d t o j u d g e t h e p o s s i b l e h a r u f u l e f f e c t of t h e aspartame intake. 1Ie s u g g e s t s t h a t t h e w a s u r e m e n t s o f m e n t a l r e t a r d a t i o n . EU; . a b n o r m a l i t i e s and s e i z u r e s a r e i n a p p r o p r i a t e and t h a t new c r i t e r i a s h o u l d be e s t a b l i s h e d t h a t i n c l u d e a ) s u b t l e c h a n g e s i n human p r e n a t a l d e v e l o p m e n t ; b ) b e h a v i o r a l c h a n g e s ; and 3 ) s u b t l e e f f e c t s on n e u r o e n d o c r i n e p h y s i o l o g y . . D r . Pardridge contends t h a t while t h e s e i s s u e s remain h y p o t h e t i c a l a t t h i s time, t h e r e is s u f f i c i e n t evidence i n t h e . w d i c a l l i t e r a t u r e t o suggest t h a t a g i v e ? d o s e of p h e n y l a l a n i n e i n p e o p l e c a n c a u s e n e u r o c h e m i c a l c h z n g e s in the brain. 1 1 2 5 1 Y o n t e , Dr. Woodrow. S t a t e m e n t f i l e d w i t h Y o t i o n f o r Temporary ?!estrzninq 3 r d e r . J a n . 1934. . 2 6 1 Food A d d i t i v e s P e r m i t t e d f o r D i r e c t A d d i t i o n t o Food f o r Yuman Cons u m p t i o n . Aspartame. F e d e r a l X e g f s t e r , v. 4 8 , n o . 1 3 2 . J u l y 8 , 1953. p. 31377. 27i of P a r d r i d g e . ! i i l l i a m , Y.D., L e t t e r t o S a n f o r d Y i l l e r , D i r e c t o r of Bureau a n d Drug A d m i n i s t r a t i o n . Nov. 2 3 , 1 9 8 3 . FOZS, Food D r . Richard J. Yurtman, P r o f e s s o r of Neuroendocrine R e g u l a t i o n a t M a s s a c h u s e t t s I n e t i t u t e of Technology, h a s a l s o r a i s e d q u e s t i o n s c o n c e r n i n g aspartameve safety. S p e c i f i c a l l y , he h a s r e p o r t e d t h a t combining a s p a r t a m e and g l u c o s e may a l t e r b r a i n n e u r o t r a n s m i t t e r l e v e l s and, i n t u r n , a f f e c t behavior . =/ I n J u l y 1983 James T u r n e r , o n b e h a l f o f h i m s e l f and t h e Community N u t r i t i o n I n s t i t u t e (CNI), and D r . Monte f i l e d w i t h FDA o b j e c t i o n s t o t h e J u l y 8 , 1983 r e g u l a t i o n approving t h e u s e of a s p a r t a m e i n c a r b o n a t e d beverages. The o b j e c t i o n s contended t h a t numerous s a f e t y i s s u e s had n o t been a d e q u a t e l y c o n s i d e r e d by t h e agency b e f o r e p r o m u l g a t i o n of t h e r e g u l a t i o n , and r e q u e s t e d t h a t a s t a y be placed on t h e rcgu1a:ion i n a public hearing. pending e x d a a t i o a of t h o s e issues FDA d e n i e d t h e r e q u e s t t o s t a y t h e e f f e c t i v e n e s s of t h e c a r b o n a t e d beverage r e g u l a t i o n on t h e grounds t h a t t h e o b j e c t i o n s f a i l e d t o c r e a t e s i g n i f i c a n t d o u b t s about t h e s a f e t y of t h e s w e e t e n e r t o w a r r a n t such a move. E/ The agency has a l s o d e n i e d t h e r e q u e s t f o r a p u b l i c h e a r i n g on t h e s a t ? ? j i s s u e s r e l a t e d t o t h e r e g u l a t i o n a l l o w i n g t h e use of aspartame i n c a r b o n a t e d beverages and c a r b o n a t e d beverage s y r u p b a s e s . A f t e r reviewing t h e o b j e c t i o n s , FDA concluded t h a t t h e s a f e t y i s s u e s r a i s e d had been f u l l y d e a l t v i t h i n e a r l i e r proceedings and t h a t t h e r e w a s a l a c k of a d e q u a t e new d a t a t o convene a p u b l i c h e a r i n g a t t h i s time. g/ I n December 1983 Mr. T u r n e r , C N I , t h e A r i z o n a D i e t e t i c A s s o c i a t i o n , t h e C e n t r a l h r i 2 0 ~D i s t r i c t D i e t e t i c A s s o c i a t i o n , and D r . Monte f i l f d a motion 28/ Wurtman, Richard J. L e t t e r t o t h e E d i t o r : Neurochemical Changes ~ o l l o z nHigh-Doses ~ of Aspartame v i t h D i e t a r y C a r b o h y d r a t e s . New England J o u r n a l of Medicine, v . 309, no. 7 . Aug. 1 8 , 1983. p . 429-430. 29/ - 48 Fed. Reg. 52899, Nov. 30/ - 49 Fed. Reg. 6672, Feb. 22, 1984. 27. 1983. i n t h e U . S . d i s t r i c t c o u r t t o compel t h e a g e n c y t o h o l d h e a r i n g s o n t h e s a f e t y o f adding t h e sweetener t o carboaate? beverages and t o p r o h i b i t t h e s a l e of carbonated beverages containing aspartame u n t i l t h e h e a r i n g s a r e held. In the m o t i o n t h e p a r t i e s a s k e d t b a t t h e c o u r t d i r e c t FDA t o i n c l u d e a t t h e h e a r i n g s e v i d e n c e b e a r i n g o n t h e q u a l i t y o f t h e s c i e n t i f i c s t u d i e s r e l i e d upon by FDA t o s u p p o r t t h e s a f e t y o f a s p a r t a m e as w e l l as o t h e r e v i d e n c e c h a l l e n g i n g t h e s a f e t y of a s p a r t a m e . 311 On January 2 4 , 1 9 8 4 , T u r n e r e t a l . f i l e d a m o t i o n f o r a Temporary Res t r a i n i n g O r d e r , a s k i n g t h e 1 5. District C o u r t f o r t h e D i s t r i c t o f Columbia t o s t o p FDA "from c o n t i n u i n g t o p e r m i t t h e a d d i t i o n o f t h e f o o d a d d i t i v e aspart- t o a n y food p r o d u c t s , i n c l u d i n g d i e t s o d a s , povdered d r i n k s , c e r e a l s a n d d e s e r t s s o l d i n che U.S. and t h e use o f a s p a r t a m e as f o o d u n t i l s u c h t i m e a s FDA c o n v e n e s ard c o n c l u d e s a p u b l i c , h e a r i n g o n t h e s a f e t y of a s p a r t a m e . - z/ The g r o u p b e l i e v e s t h a t new e v i d e n c e h a s a c c u m u l a t e d t h a t s e r i o u s harm i s b e i n g s u f f e r e d by c o n s l m e r s of food p r o d u c t s c o n t a i n i n g a s p a r t a m e , e s t a b l i s h i n & t h e f a c t t h a t t h e continued use of aspartame i n t h e food supply poses a s e r i o u s fmminent h a z a r d t o food c o n s u m e r s . =/ The c o u r t t u r n e d d o u n t h e m o t i o n c i t i n g a l a c k o f s u f f i c i e n t e v t d e n c e t o b a r t h e sale o f a s p a r t a m e a n d aspartame-containing products. 311 Jan. x/ T u r n e r , James. p. 30. 30, 1984. CNI To H a l t S a l e o f A s p a r t a m e . Food C h e m i c a l Sews, 3 2 1 U.S. District C o u r t f o r t h e District o f C o l u m b i a . ? l o t i o n f o r T e u p o r a r y ~ e s t r x nng i Order, Preliminary I n j u n c t i o n , P r o h i b i t o r y and Mandatory I n j u n c t i o n . C i v i l A c t i o n No. 83-3846. Community N u t r i t i o n I n s t i t u t e e t a l . v . D r . :-lark Novitch. F i l e d J a n . 2 4 , 1984. 341 No R u l i n g o n Aspartame TRO M o t i o n : P a r k e r T a k e s I s s u e "Under Advisement." F o o d C h e a i c a l News, Feb. 2 7 , 1984. p . 9 . CRS- 14 The motion f o r a Temporary R e s t r a i n i n g O r d e r was r e s u b m i t t e d o n February 15, 1984, by T u r n e r e t a l . , a l o n g w i t h new e v i d e n c e a v a i l a b l e s i n c e t h e i n i t i a l rr,otion was t u r n e d dovn by t h e C o u r t . =/ At a F e b r u a r y 2 3 , 1984 h e a r i n g , t h e judge s t a t e d he w a s t a k i n g t h e i s s u e under a d v i s e m e n t and t h a t a r u l i n g would be made a t a l a t e r d a t e . On March 2 2 , 1984, J u d g e B a r r i n g t o n P a r k e r r u l e d t h a t t h e p l a i n t i f f s w u l d have t o t u r n t o t h e U.S. c o u r t o f a p p e a l s f o r a i d because t h e FDA d e c i s i o n t o deny t h e r e q u e s t f o r a h e a r i n g had e f f e c t i v e l y removed h i s j u r i s d i c t i o n over t h e matter. %/ I n t h e meantime on March 8 , 1984, A r i z o n a r e g u l a t o r s r e f u s e d t o ban t h e sale o f c a r b o n a t e d b e v e r a g e s sweetened v i t h aspartame. The S t a t e had been asked by D r . Monte t o ban t h e s w e e t e n e r b e c a u s e i t c a n d e t e r i o r a t e i n t o methanol ( m e t h y l a l c o h o l ) under c e r t a i n conditions. The Arizona h e a l t h d e p a r t m e n t c o a c l u d e d t h a t FDA h a s l o o k e d i n t o t h e methanol q u e s t i o n a d e q u a t e l y . ?/ FDA h a s responded t o t h e s e s a f e t y q u e s t i o n s i n much t h e same way t h e y responded t o s i m i l a r i s s u e s i n 1981. The a g e n c y b e l i e v e s t h a t a t normal con- s u m p t i o n l e v e l s , a s p a r t a m e d o e s n o t c a u s e harm t o any segment of t h e p o p u l a t i o n 35/ U.S. D i s t r i c t C o u r t f o r t h e District of Columbia. Motion f o r Temporary ~ e s t r x n i nO~r d e r , P r e l i m i n a r y I n j u n c t i o n , P r o h i b i t o r y and Fiandatory I n j u n c t i o n . C i v i l A c t i o n Eo. 83-3846. Community N u t r i t i o n I n s t i t u t e e t a l . v . D r . Hark F i l e d Feb. 15, 1984. '- News. 36/ P a r k e r R u l e s Be Has No J u r i s d i c t i o n i n Aspartame Case. Mar. 2 6 , 1984. p. 55. Food Chemical 37/ Arizona R e f u s e s To Ban S a l e of D r i n k s t h a t Use S e a r l e ' s Aspartame. Wall S t r e e t J o u r n a l , Mar. 9 , 1984. p. 6. other than phenylketonurics. 381 However, FDA and the Centers for Oisease Control (CPC) have been investigating complaints from the use of aspartame. A standardized questionnaire is being used in FDA field offices tci follow up investigations of complaints by contacting consumers and their attending physicians, particularly for cases reported since June 1983. 391 Because of the continuing concerns by some individuals about the safety of aspartame, legislation was introduced in the 98th Congress to control its use. As introduced by Rep. Gejdenson on October 6, 1983, H.R. 4112 would require the Secretary of Health and Human Services to establish, through regulations, maximum coacentration levels for aspartame as a faod additive. 2 1 vae referred to the House Caaanittee on Energy and Commerce. The bill To date no action has been taken on the bill. Aspartame has found its way into the American market place as an approved food additive. -: The future of this closely watched sweetener, however, is yet be determined. 38/ U.S. Dept. of Health and Human Services. Food and Drug Administration. ~ s ~ a r F a min e Carbonated Beverages Questioned FDA Talk Paper T84-4. Jan. 20, 1984. . 391 FDA Issues Questionnaire To Follow Up on Aspartame Complaints. ~ h e m i z lNews, Mar. 12, 1984. p. 13. Food 401 Gejdenson, Sam. Aspartame: Not A Sure Bet. Remarks in the House of ~e~resentatives. Congressional Record, v. 129, Oct. 7, 1983. p. 4866. APPENDIX 1. ASPARTAME: DATE SELEZTED CHRONOLOGY OF EVENTS EVENT 1965 Aspart- 1969 (act. Cyclamate banned 1973 (Mar.) S e a r l e f i l e s p e t i t i o n f o r a p p r o v a l of aspartame as food a d d i t i v e 1974 ( ~ u l y ) FDA approves aspartame as a food a d d i t i v e 1975 (Dez.) FDA places s t a y i g n (JU~Y) FDA proposes ban on s a c c h a r i n (Nov. ) discovered on r e g u l a t i o n a l l o v i n g m a r k e t i n g of aspartame Congress i m a s e d 18 months mbratorium a g a i n a t ban on s a c c h a r i n 1978 (Dec.) Study on S e a r l e ' s r e s e a r c h i n v e s t i g a t i o n s c ~ n i fn n s v a l i d i t y of experiPcnts 1979 ( J u n e ) FDA e s t a b l i s h e d P u b l i c Board of I n q u i r y t o examine aspartame i s s u e 1980 ( O c t . ) P u b l i c Board of I n q u i r y r e p o r t s 1981 ( J u l y ) FDA approves aspartame f o r u s e i n d r y p r o d u c t s 1983 ( J u l y ) FDA approves aspartame f o r u s e i n c a r b o n a t e d b e v e r a g e s ; O b j e c t i o n s f i l e d w i t h FDA r e q u e s t i n g s t a y on r e g u l a t i o n a1 loving use i n carbonated b e v e r a g e s and r e q u e s t i n g p u b l i c h e a r i n g (fall) F i r s t carbonated b e v e r a g e s w i t h aspartame s o l d tact.> H.R. 4112 i n t r o d u c e d t o r e q u i r e S e c r e t a r y of H e a l t h and Hurmn S e r v i c e s t o s e t maximum c o n c e n t r a t i o n l e v e l s f o r aspartame as a food a d d i t i v e FL\A d e n i e s r e q u e s t t o s t a y c a r b o n a t e d beverage r e g u l a t i o n on aspartarn? (Dec .) 1984 ( J a n . ) Motion f i l e d t o compel FDA t o hold p u b l i c h e a r i n g Motion f i l e d t o r e q u i r e FDA t o s t o p a l l uses of aspartame and compel t h e agency t o hold a p u b l i c h e a r i n g Motion denied f o r l a c k of s u f f i c i e n t e v i d e n c e FDA d e n i e s r e q u e s t f o r a p u b l i c h e a r i n g ; Court h e a r i n g on r e s u b m i t t e d motion f o r Temporary R e s t r a i n i n g Order taken under advisement w i t h r u l i n g t o be made sometime in t h e f u t u r e FDA and CCC i n v e s t i g a t i n g r e p o r t e d c a s e s of a d v e r s e e f f e c t s from t h e consumption of a s p a r t a n e Judge Parker r u l e s - U.S. d i s t r i c t c o u r t h a s no j u r i s d i c t i o n i n aspartame case.