Novel Sweeteners - ACS Symposium Series (ACS Publications)

Chapter 23

Novel Sweeteners R e g u l a t o r y Issues a n d Implications S. W. Gunner

Downloaded by CORNELL UNIV on September 8, 2016 | http://pubs.acs.org Publication Date: December 31, 1991 | doi: 10.1021/bk-1991-0450.ch023

Food Directorate, Health Protection Branch, Health and Welfare Canada, Tunney's Pasture, Ottawa, Ontario K1A 0L2, Canada

Novel sweeteners, in common with other novel substances intended for use in the food supply, must undergo rigorous review by government health agencies as a prerequisite to market approval. Novel sweeteners - that is to say sweetening materials not previously known or used in the food supply - would generally be classified as food additives and as such would normally be reviewed within existing regulations which deal with food additives. Thus, the process of review and evaluation of novel sweeteners does not, a priori, involve any new regulatory needs. The regulations under which other substances such as novel preservatives or emulsifiers can be examined also encompasses materials which function to impart a sweet taste to foods. This overview of such regulatory requirements, although based on United States and Canadian regulations, will also serve to illustrate the situation in most developed countries. The focus will deal with food additive concerns and will also address some additional needs specific to novel sweeteners as a class. P o o d Additive Preclearance Requirements National governments have a responsibility to ensure thehealth a n d safety o f their p o p u l a t i o n s , a n d nowhere i s t h i s m o r e i m p o r t a n t o r visible t h a n i n r e l a t i o n to t h e food s u p p l y . C o n s u m e r c o n c e r n s a b o u t food safety a n d t h e p r o l i f e r a t i o n of food a d d i t i v e s provide a n ongoing b a c k d r o p against w h i c h government regulatory agencies m u s t m a k e informed decisions a s to t h e safety a n d acceptability of additives, often i n controversial c i r c u m s t a n c e s . Sweeteners, a s a class, have i n the past engendered considerable controversy, particularly i n the case of s a c c h a r i n a n d cyclamates because of their a s s o c i a t i o n w i t h c a r c i n o g e n i c effects a n d , a s a c o n s e q u e n c e , regulatory agencies take a very conservative a p p r o a c h w h e n dealing n o t o n l y w i t h these s u b s t a n c e s b u t w i t h food additives generally.

0097-6156/91/0450-0302$06.00/0 © 1991 American Chemical Society

Walters et al.; Sweeteners ACS Symposium Series; American Chemical Society: Washington, DC, 1991.


23.

GUNNER

Regulatory Issues and Implications for Novel Sweeteners

It i s i n s t r u c t i v e t o n o t e a t y p i c a l d e f i n i t i o n o f a f o o d a d d i t i v e . U n d e r S e c t i o n B . 0 1 . 0 0 1 of the C a n a d i a n F o o d a n d D r u g R e g u l a t i o n s , a food additive is defined as " a n y s u b s t a n c e , the u s e of w h i c h r e s u l t s or m a y r e a s o n a b l y be expected to r e s u l t i n it or i t s b y - p r o d u c t s b e c o m i n g a p a r t of or affecting the c h a r a c t e r i s t i c s of a food." This d e f i n i t i o n , w h i c h a l s o goes o n to define s o m e e x c l u s i o n s s u c h a s drugs or a g r i c u l t u r a l chemicals that are covered u n d e r other r e q u i r e m e n t s , is quite b r o a d a n d c a n be s e e n to i n c l u d e a l l s u b s t a n c e s w h i c h are not foods themselves or w h i c h are covered b y other classifications. For example, i n the United States G R A S [ G e n e r a l l y R e c o g n i z e d a s Safe] food i n g r e d i e n t s are s u b s t a n c e s w h i c h m a y b e a d d e d to f o o d s b u t w h i c h , b e c a u s e o f a h i s t o r y o f u s e , differ f r o m food additives i n t h e i r legal r e q u i r e m e n t s respecting safety evaluation. In general, government agencies e v a l u a t i n g a novel food additive s u c h a s a n o v e l s w e e t e n e r w i l l n e e d to a d d r e s s f i v e m a i n a r e a s a s p a r t o f t h e p r e m a r k e t r e v i e w p r o c e s s : 1. T h e i d e n t i t y a n d n a t u r e o f the s u b s t a n c e ; 2. T h e types of i n t e n d e d u s e a n d p o t e n t i a l i n t a k e levels; 3. T e c h n i c a l effects of the additive; 4. A n a l y t i c a l m e t h o d o l o g y i n f o o d ; 5 . S t u d i e s to d e t e r m i n e s a f e t y . D e t a i l s of t h e s t a t u t o r y r e q u i r e m e n t s for food a d d i t i v e p e t i t i o n s i n t h e U n i t e d S t a t e s are o u t l i n e d i n S e c t i o n 409(b)(2) of t h e U n i t e d States Federal Food, D r u g a n d Cosmetic Act, a n d the data r e q u i r e m e n t s are d e s c r i b e d i n g r e a t e r d e t a i l i n S e c t i o n 171(c) of Title 2 1 , C o d e of F e d e r a l R e g u l a t i o n s . Similarly, Section B. 16.002 of t h e C a n a d i a n F o o d a n d D r u g R e g u l a t i o n s d e s c r i b e s the requirements w h i c h a petitioner m u s t meet w h e n requesting a m e n d m e n t s to the F o o d A d d i t i v e s T a b l e s of t h e F o o d a n d D r u g Regulations. I d e n t i t y a n d Nature o f the S u b s t a n c e s A prerequisite i n the regulatory e v a l u a t i o n of a n y novel s u b s t a n c e is t h e n e e d for a c o m p l e t e d o s s i e r of i n f o r m a t i o n o n i t s i d e n t i t y , s t a b i l i t y , c o m p o s i t i o n , m e t h o d of m a n u f a c t u r e a n d s p e c i f i c a t i o n s . T h i s r e q u i r e s t h e petitioner to c o m p i l e a n d s u b m i t d a t a i n c l u d i n g the c o m m o n or u s u a l name, IUPAC or chemical abstracts names, c h e m i c a l formula, molecular weight, compositional analysis a n d p u r i t y , a n d p r o p e r t i e s o f t h e s u b s t a n c e , e.g. m e l t i n g p o i n t , s p e c i f i c gravity a n d optical rotation. It is of particular importance to provide food-grade specifications w h i c h will encompass the product intended for c o m m e r c i a l d i s t r i b u t i o n a n d w h i c h w i l l also relate to the m a t e r i a l that was employed i n the toxicological testing program. S p e c i f i c a t i o n s i n t h e f o r m a t of the F o o d C h e m i c a l s C o d e x , 3 r d e d i t i o n (J), a r e a c c e p t a b l e i n b o t h t h e U n i t e d S t a t e s a n d C a n a d a a n d s h o u l d i n c l u d e a d e s c r i p t i o n of the s u b s t a n c e , i d e n t i f i c a t i o n tests, a n a s s a y test a n d l i m i t s of i m p u r i t i e s together w i t h v a l i d a t e d m e t h o d s of a n a l y s e s for t h e p a r a m e t e r s i n q u e s t i o n . T h e r e s u l t s of


303


304

SWEETENERS:

DISCOVERY, M O L E C U L A R DESIGN, A N D

CHEMORECEPTION

a n a l y s i s of several t y p i c a l p r o d u c t i o n b a t c h e s of the s u b s t a n c e s h o u l d a l s o be p r o v i d e d to i n d i c a t e c o n f o r m i t y w i t h t h e p r o p o s e d specifications. A l s o r e q u i r e d is a d e s c r i p t i o n of the m a n u f a c t u r i n g p r o c e s s , i n c l u d i n g a list of reagents, solvents, c a t a l y s t s , r e a c t i o n c o n d i t i o n s , p u r i f i c a t i o n p r o c e d u r e s , etc. Regulatory agencies are p a r t i c u l a r l y interested i n a s s u r a n c e s that the p r o d u c t w i l l be routinely prepared u n d e r conditions w h i c h control its composition a n d properties a n d t h a t specifications w i l l c o n s i s t e n t l y be met. It i s t o b e e x p e c t e d t h a t different m e t h o d s of m a n u f a c t u r e w i l l give rise to differences in impurities and by-products. F o r e x a m p l e , i n t h e case of s a c c h a r i n , o - t o l u e n e s u l f o n a m i d e (OTS) c a n a r i s e a s a n i m p u r i t y i n certain m a n u f a c t u r i n g processes a n d not i n others. A t one time, O T S w a s considered a causative factor i n b l a d d e r t u m o r i n d u c t i o n i n a n i m a l s . A s a r e s u l t , t h e n e e d to c o n t r o l t h e p r e s e n c e of O T S i n saccharin was considered imperative a n d strict specification limits (not m o r e t h a n 0 . 0 0 2 5 % ) w e r e i m p o s e d o n i t s p r e s e n c e i n t h e p r o d u c t (OTS w a s later r u l e d o u t as the c a u s a t i v e factor). A t y p i c a l s p e c i f i c a t i o n w o u l d a l s o i n c l u d e l i m i t s for h e a v y m e t a l s a n d a r s e n i c . A s m o r e i n t e r e s t is s h o w n i n b i o t e c h n o l o g y as a r o u t e to t h e b i o s y n t h e s i s of novel c h e m i c a l entities, cognizance s h o u l d also be t a k e n of the n e e d to a d d r e s s the differences, if a n y , i n s p e c i f i c a t i o n s a r i s i n g o u t of differences i n m e t h o d of m a n u f a c t u r e . Of e q u a l i m p o r t a n c e i s t h e q u e s t i o n o f s t a b i l i t y o f t h e c o m p o u n d , i.e. d o e s it d e c o m p o s e over time, i s it s e n s i t i v e to h u m i d i t y , d o e s it r e a c t to o t h e r c o m p o u n d s , etc. In the c a s e of a s p a r t a m e , for e x a m p l e , the p r e s e n c e of 5-benzyl-3,6-dioxo-2-piperazineacetic a c i d (a c y c l i z a t i o n p r o d u c t o f a s p a r t a m e ) w a s r e c o g n i z e d a s a n i m p u r i t y i n the c o m m e r c i a l product w i t h the result that a specific a t i o n l i m i t w a s d e e m e d n e c e s s a r y a n d set at " n o t m o r e t h a n 1.5%". A l t h o u g h specifics m a y differ i n different j u r i s d i c t i o n s , t h e essence of w h a t r e g u l a t o r y a g e n c i e s w i l l r e q u i r e relates to information that describes the substance, indicates that it is prepared i n accordance w i t h good m a n u f a c t u r i n g practices a n d that q u a l i t y c o n t r o l w i l l b e e x e r c i s e d to e n s u r e c o n s i s t e n c y of p r o d u c t i n conformity w i t h accepted specifications. U s e s a n d T e c h n i c a l Effects o f t h e S u b s t a n c e T h e p r o p o s e d u s e s of t h e s u b s t a n c e i n q u e s t i o n d e p e n d s to a large e x t e n t o n i t s i n t e n d e d effect a n d i t s p r o p e r t i e s . In the case of s w e e t e n e r s , t h e objective i s clear, t h a t i s , to i m p a r t a s w e e t t a s t e to foods, a n d t h u s a p o t e n t i a l l y w i d e r a n g e of a p p l i c a t i o n s c a n b e foreseen. R e g u l a t o r y agencies require i n f o r m a t i o n o n the a m o u n t s of the s u b s t a n c e to be a d d e d to foods, t h e t y p e s of foods, fate of t h e c o m p o u n d i n the v a r i o u s food a p p l i c a t i o n s , the a m o u n t of the s u b s t a n c e a n d its b y - p r o d u c t s t h a t are l i k e l y to be c o n s u m e d a n d d a t a to s u p p o r t t e c h n o l o g i c a l efficacy, i.e., w i l l the c o m p o u n d



23. GUNNER


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a c c o m p l i s h t h e i n t e n d e d effect o f i m p a r t i n g s w e e t n e s s t o t h e f o o d i n q u e s t i o n over a n o r m a l expected s h e l f life? Two aspects are p a r t i c u l a r l y i m p o r t a n t . T h e first r e l a t e s t o t h e f a t e i n f o o d . While s o m e s u b s t a n c e s m a y be stable at r o o m temperature, t h e y m a y be p r o n e to r a p i d d e g r a d a t i o n b y h e a t a n d / o r l o w p H . T h u s , t h e y m a y be i n h e r e n t l y u n s u i t a b l e i n soft d r i n k s or i n p r o d u c t s t h a t are b a k e d . E v i d e n c e m u s t b e s u p p l i e d to j u s t i f y t h e level of u s e of t h e s u b s t a n c e , a n d types of a p p l i c a t i o n s i n c l u d i n g d a t a d e m o n s t r a t i n g extended s t a b i l i t y of the c o m p o u n d u n d e r c o n d i t i o n s of u s e . A r e a s w h i c h are technologically inappropriate or self-limiting s h o u l d also be pointed out. A s e c o n d k e y a r e a d e a l i n g w i t h the p r o p o s e d u s e s of a s u b s t a n c e s u c h a s a n o v e l s w e e t e n e r r e l a t e s to t h e n e e d to p r o v i d e e s t i m a t e s of i n t a k e of the s u b s t a n c e a n d p o s s i b l y of i t s b y - p r o d u c t s b y consumers. T h i s s h o u l d include not only the average or typical c o n s u m e r b u t also the so-called h i g h c o n s u m e r . From this information, regulatory agencies determine the E s t i m a t e d D a i l y I n t a k e (EDI) w h i c h i s of c r i t i c a l i m p o r t a n c e i n r e l a t i o n to s a f e t y c o n s i d e r a t i o n s a n d i n r e g a r d to d e t e r m i n i n g t h e e x t e n t a n d r a n g e of u s e s t h a t c a n be permitted. Table I indicates the u s e s of aspartame currently permitted i n Canada. T a b l e I. Additive Aspartame

P e r m i t t e d U s e s of A s p a r t a m e i n C a n a d a

Permitted i n or upon Table-top sweeteners Breakfast cereals

Beverages; Beverage concentrates; Beverage mixes Desserts; Dessert mixes; Toppings; Topping mixes; Fillings; Filling mixes Chewing gum; Breathfreshener products Source: Adapted from Food B . 1 6 . 1 0 0 , T a b l e VIII, p. 6 7 - 2 2 ,

P u r p o s e of U s e Sweetener a n d flavour enhancer Sweetener and flavour enhancer Sweetener a n d flavour enhancer

M a x i m u m Level of U s e Good Manufacturing Practice 0.5%

0.1% in beverages as consumed

Sweetener a n d flavour enhancer

0.3% in product as consumed

Sweetener and flavour enhancer

1.0%

and Drug 1989.

Regulations

Section


306

SWEETENERS:

DISCOVERY, M O L E C U L A R

DESIGN, A N D

CHEMORECEPTION


Analytical Methodology i n Poods I n a d d i t i o n to the a n a l y t i c a l m e t h o d o l o g y t h a t is r e q u i r e d w i t h r e s p e c t to t h e s p e c i f i c a t i o n of t h e s u b s t a n c e a n d i t s i m p u r i t i e s , a n a l y t i c a l m e t h o d s to d e t e r m i n e the q u a n t i t y of the m a t e r i a l or i t s b y - p r o d u c t s i n foods m u s t also be developed b y the petitioner. This is particularly important i n cases where regulatory l i m i t a t i o n s h a v e b e e n e s t a b l i s h e d o n the a m o u n t of the s u b s t a n c e t h a t c a n be p e r m i t t e d i n p a r t i c u l a r foods. T h u s , the m e t h o d s have a role i n the enforcement of tolerances as w e l l a s i n the a s s u r a n c e of t h e a c c u r a c y of e s t i m a t e s of e x p o s u r e or E D I c o n s i d e r a t i o n s . M e t h o d s m u s t be easily reproducible u n d e r n o r m a l laboratory c o n d i t i o n s w i t h o u t the n e e d for s o p h i s t i c a t e d e q u i p m e n t a n d certain specially t r a i n e d personnel. M e t h o d s m u s t be specific, accurate, precise a n d reliable a n d have the required sensitivity. M o s t i m p o r t a n t l y i n a regulatory context, the methods m u s t be able to w i t h s t a n d s c r u t i n y i n c o u r t r o o m settings. Safety Studies T h e a r e a w h i c h i s m o s t c r i t i c a l for d e c i s i o n - m a k i n g b y r e g u l a t o r y agencies a n d w h i c h is also the m o s t d e m a n d i n g a n d time c o n s u m i n g for t h e i n d u s t r y c o n c e r n s the n e e d to p r o v i d e a s s u r a n c e of t h e s a f e t y - i n - u s e of t h e p r o p o s e d n o v e l s u b s t a n c e . T h e p r i n c i p a l m e t h o d o l o g y e m p l o y e d i n the g e n e r a t i o n of t h i s type of s u p p o r t d a t a involves t h e u s e of e x p e r i m e n t a l a n i m a l s a s s u r r o g a t e s for m a n a n d t h e a p p l i c a t i o n of a w i d e r a n g e of t o x i c o l o g i c a l tests. These encompass both acute, short term a n d chronic studies u s u a l l y d e s i g n e d to a s s e s s c a r c i n o g e n i c p o t e n t i a l . F u r t h e r tests i n c l u d e g e n o t o x i c i t y tests, to d e t e r m i n e t h e p o t e n t i a l for a d v e r s e effects o n t h e g e n o m e i n g e r m a n d s o m a t i c cells, m u t a g e n i c i t y s t u d i e s , t e r a t o g e n i c i t y s t u d i e s to e x a m i n e p o t e n t i a l for c o n g e n i t a l m a l f o r m a t i o n s a n d r e p r o d u c t i o n s t u d i e s to a s s e s s p o t e n t i a l effects o n the r e p r o d u c t i v e c a p a c i t i e s of b o t h the p a r e n t a l g e n e r a t i o n a n d their offspring. In a d d i t i o n , p h a r m a c o k i n e t i c studies w h i c h a d d r e s s the a b s o r p t i o n , d i s t r i b u t i o n , m e t a b o l i s m a n d e x c r e t i o n of t h e s u b s t a n c e are p i v o t a l to t h e s e l e c t i o n of t h e m o s t a p p r o p r i a t e a n i m a l s p e c i e s for t o x i c i t y t e s t i n g a n d i n the d e t e r m i n a t i o n of the m o s t a p p r o p r i a t e d o s e levels to b e e m p l o y e d . D e p e n d i n g o n t h e n a t u r e of the c o m p o u n d a n d w h a t is k n o w n a b o u t its c h e m i c a l structure, properties, metabolism, potential exposure and r e l a t i o n s h i p to o t h e r t e s t e d c h e m i c a l s , a l l or o n l y s o m e of t h e b a t t e r y of s t u d i e s i n d i c a t e d m a y be r e q u i r e d . T h e overall objective of the toxicological t e s t i n g of a n o v e l c h e m i c a l e n t i t y i s to d e t e r m i n e t h e m a x i m u m d o s a g e level w h i c h produces no discernible injury w h e n the s u b s t a n c e is administered o v e r t h e m a j o r p o r t i o n of t h e life s p a n of t h e t e s t a n i m a l s . This level is called the "No Observable Adverse Effect Level" (NOAEL) a n d is expressed as the a m o u n t ingested i n m g / k g body weight/day



23. GUNNER


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b y the a n i m a l s i n question i n a given test procedure. The value is t h e n u s e d to e s t a b l i s h a c r i t i c a l p a r a m e t e r for t h e e s t i m a t i o n of r i s k to the h u m a n p o p u l a t i o n . T h e p a r a m e t e r , c a l l e d t h e A c c e p t a b l e D a i l y I n t a k e f o r m a n o r (ADI) i s d e f i n e d a s t h e a m o u n t o f a f o o d additive (expressed i n m g / k g b o d y weight) that a n i n d i v i d u a l c a n c o n s u m e d a i l y i n t h e d i e t , o v e r a l i f e t i m e , w i t h o u t risk. T h e A D I i s u s u a l l y d e t e r m i n e d b y d i v i d i n g t h e N O A E L for t h e m o s t s e n s i t i v e a n i m a l species a n d a p p l y i n g a safety factor or m a r g i n of safety. W h i l e the safety factor m a y v a r y d e p e n d i n g o n the n a t u r e of a n y effects n o t e d , a v a l u e of 1 0 0 - f o l d i s u s u a l l y e m p l o y e d to derive a n ADI. T h u s , i n the case of a s p a r t a m e , C a n a d i a n a u t h o r i t i e s c o n s i d e r e d t h e N O A E L f r o m l o n g - t e r m a n i m a l s t u d i e s to b e 4 g / k g b o d y weight/day. W i t h the a p p l i c a t i o n of a 100-fold safety factor to a l l o w for e x t r a p o l a t i o n f r o m a n i m a l s to m a n , the C a n a d i a n a u t h o r i t i e s e s t a b l i s h e d a n A D I of 4 0 m g / k g b o d y w e i g h t / d a y . Table II i n d i c a t e s i n t e r n a t i o n a l l y e s t a b l i s h e d A D I s f o r s o m e c o m m o n sweeteners. T a b l e II.

A c c e p t a b l e D a i l y I n t a k e (ADI) V a l u e s f o r Sweeteners as Established b y J E C F A

Some

a

Aspartame

0-40

S a c c h a r i n a n d its C a , Κ a n d N a Salts

Temporary Group ADI 0-2.5 mg/kg/dayc

Thaumatin

ADI Not

Mannitol

A D I Not Specified

a

b

c

d

e

mg/kg/day

b

Specifled

d

e

F A O / W H O Joint Expert Committee on Food Additives (JECFA) 2 5 t h R e p o r t of J E C F A , W H O T e c h n i c a l R e p o r t S e r i e s (TRS) No. 669, 1981. 2 8 t h R e p o r t of J E C F A , W H O T R S N o . 7 1 0 , 1 9 8 4 . T e m p o r a r y A D I allocated—further safety d a t a r e q u i r e d . 2 9 t h R e p o r t of J E C F A , W H O T R S No. 7 3 3 , 1 9 8 6 . A D I n o t specified—no u p p e r l i m i t of i n t a k e a s s i g n e d i n v i e w of very low toxicity. 3 0 t h R e p o r t of J E C F A , W H O T R S No. 7 5 1 , 1 9 8 7 .

The A D I is the toxicological endpoint w h i c h governs the a l l o c a t i o n of p e r m i t t e d u s e s of a food additive assuming t e c h n o l o g i c a l efficacy h a s b e e n d e m o n s t r a t e d . In the e v a l u a t i o n of r e q u e s t s for s p e c i f i c u s e a l l o c a t i o n s of a g i v e n food a d d i t i v e , t h e e s t i m a t e d d a i l y i n t a k e (EDI) f i g u r e s a r e c o m p a r e d w i t h t h e A D I o f the additive or, i n the case of a m a j o r i m p u r i t y , to the A D I of t h a t i m p u r i t y . A s a m a t t e r of p r u d e n c e , the e s t i m a t e d or p r o b a b l e d a i l y i n t a k e s (EDI) s h o u l d n o t e x c e e d t h e A D I . I n t h o s e i n s t a n c e s w h e r e


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the estimated intakes are low or where a n A D I is h i g h or not specified, t h e r i s k to h u m a n h e a l t h i n p e r m i t t i n g the p r o p o s e d u s e s of the s u b s t a n c e w o u l d be low. H o w e v e r , a h e a l t h r i s k f r o m a f o o d a d d i t i v e i s , inter alia, g o v e r n e d b y the two factors of i n h e r e n t toxicity of the additive a n d its exposure pattern. In those c a s e s w h e r e p o t e n t i a l e x p o s u r e of t h e h u m a n p o p u l a t i o n c a n be e x p e c t e d to be a s h i g h a s w o u l d b e the case w i t h novel sweeteners, regulatory agencies will always take a c a u t i o u s a p p r o a c h i n the a l l o c a t i o n of p e r m i t t e d u s e s . T h i s w o u l d be p a r t i c u l a r l y so i n the case of additives w i t h l o w A D I s .


S p e c i a l C o n s i d e r a t i o n s for Sweeteners T h e r e q u i r e m e n t s for t h e a p p r o v a l of a food a d d i t i v e are o n e r o u s i n d e e d a n d i n v o l v e a c o n s i d e r a b l e e x p e n d i t u r e of s c i e n t i f i c effort, time a n d m o n e y . However, the a d d i t i o n of a novel c h e m i c a l entity to t h e f o o d s u p p l y i s a s e r i o u s m a t t e r w h i c h c o u l d h a v e a s i g n i f i c a n t i m p a c t o n t h e h e a l t h a n d w e l f a r e o f t h e c o n s u m e r . It i s , t h e r e f o r e , no s u r p r i s e that government h e a l t h agencies are quite conservative w h e n dealing w i t h these substances. In the case of novel s w e e t e n e r s , s o m e a d d i t i o n a l c o n s i d e r a t i o n s are g e r m a n e to t h e e v a l u a t i o n p r o c e s s f o r t h e f o l l o w i n g r e a s o n s : i) n o v e l s w e e t e n e r s w i t h o u t the caloric c o n t e n t of s u g a r or other t r a d i t i o n a l sweeteners h a v e the p o t e n t i a l for e x t r e m e l y w i d e scale e x p o s u r e a c r o s s a l l s e c t o r s o f t h e p o p u l a t i o n ; ii) b e c a u s e o f t h i s e x p o s u r e , t h e p o t e n t i a l for a s i g n i f i c a n t n u m b e r of t h e p o p u l a t i o n to e x h i b i t effects n o t discernible by present day a n i m a l toxicological testing protocols specifically allergic or hypersensitivity reactions - c a n n o t be i g n o r e d ; iii) n o v e l n o n - c a r b o h y d r a t e sweeteners m a y be of s i g n i f i c a n t i n t e r e s t to specific v u l n e r a b l e p o p u l a t i o n s u b g r o u p s e.g., d i a b e t i c s - for w h i c h g r o u p s a d d i t i o n a l s t u d i e s m a y be r e q u i r e d ; iv) s p e c i f i c l a b e l l i n g m a y b e r e q u i r e d t o a d v i s e on p o t e n t i a l a d v e r s e effects for s p e c i f i c p o p u l a t i o n s u b g r o u p s a n d to advise c o n s u m e r s of n u t r i e n t changes. Exposure Considerations I n a r e c e n t p u b l i c a t i o n (2), t h e U n i t e d S t a t e s C a l o r i e C o n t r o l C o u n c i l n o t e d the r e s u l t s of a n a t i o n a l l y s p o n s o r e d s u r v e y w h i c h i n d i c a t e d t h a t m o r e people are leading "low-cal" lifestyles a n d are c o n t r o l l i n g c a l o r i e s a s p a r t of the a d o p t i o n of a n overall h e a l t h y lifestyle. Some ninety-three million A m e r i c a n s n o w c o n s u m e lowcalorie foods a n d beverages. T h i s figure r e p r e s e n t s a n i n c r e a s e of s o m e 15 m i l l i o n c o n s u m e r s since 1986, a n d is m o r e t h a n double the n u m b e r of s u c h c o n s u m e r s since 1978. W i t h a n ever-increasing health a n d calorie-conscious population a s a n eager a n d receptive g r o u p for l o w - c a l o r i e food a n d beverage products, novel intense sweeteners, together with novel fat s u b s t i t u t e s , h a v e the p o t e n t i a l for extensive and escalating



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309

d i s t r i b u t i o n a n d u s e i n the food s u p p l y . T h i s factor w a s recognized i n C a n a d a d u r i n g the d e l i b e r a t i o n s p e r t a i n i n g to the a p p r o v a l p r o c e s s for t h e u s e o f a s p a r t a m e i n foods. T h u s , the c o n c e p t of " p o s t - m a r k e t s u r v e i l l a n c e " i n a d d i t i o n to the traditional "pre-market evaluation" was introduced i n 1979 as p a r t of H e a l t h a n d Welfare C a n a d a ' s p r o p o s a l o n the r e g u l a t o r y s t a t u s of a s p a r t a m e . A t the time there was a concern that the a c c e p t a b l e D a i l y I n t a k e (ADI) w o u l d b e e x c e e d e d i n c e r t a i n p o p u l a t i o n s u b g r o u p s . It s h o u l d b e s t r e s s e d t h a t e x c e e d i n g a n A D I b y i n d i v i d u a l s o n o c c a s i o n i s of n o p r a c t i c a l c o n s e q u e n c e i n t e r m s o f o v e r a l l r i s k s t o h e a l t h . It i s , h o w e v e r , a m a t t e r o f c o n c e r n f o r health agencies w h e n habitual intakes exceed ADI values particularly i n vulnerable subgroups s u c h as children. C a n a d i a n regulators subsequently decided that the use-pattern a n d i n t a k e of a s p a r t a m e s h o u l d be m o n i t o r e d b y i n d u s t r y to a s s e s s i t s safety u n d e r p r a c t i c a l c o n d i t i o n s of u s e . S u c h post-market s u r v e i l l a n c e s t u d i e s w e r e to be d e s i g n e d to p r o v i d e d a t a r e g a r d i n g the d i s t r i b u t i o n of a s p a r t a m e i n t a k e , i n c l u d i n g m e a n a n d u p p e r p e r c e n t i l e s for h i g h u s e r s . It w a s a l s o n o t c o n s i d e r e d u s e f u l t o initiate a n y s u c h p r o g r a m u n t i l it c o u l d be s h o w n that adequate i n f o r m a t i o n o n c o n s u m p t i o n p a t t e r n s c o u l d b e o b t a i n e d , i.e. after product sales a n d use h a d been established. Further, and most i m p o r t a n t b o t h for t h e i n d u s t r y a n d the H e a l t h D e p a r t m e n t , it w a s i n d i c a t e d a s a m a t t e r of p o l i c y t h a t m o n i t o r i n g c o n s u m p t i o n d a t a w o u l d be t a k e n i n t o c o n s i d e r a t i o n as p a r t of the a s s e s s m e n t of a n y r e q u e s t s for f u t u r e e x t e n s i o n s of a s p a r t a m e u s e . In compliance w i t h this policy, the NutraSweet Company c o n t r a c t e d to u n d e r t a k e a d i e t a r y s u r v e y to m e a s u r e aspartame i n t a k e i n C a n a d a (3). T h i s s u r v e y w a s u n d e r t a k e n i n 1 9 8 7 a f t e r u s e p a t t e r n s w e r e c o n s i d e r e d to h a v e b e e n s u f f i c i e n t l y e s t a b l i s h e d a n d involved two time periods, utilizing nationally representative s a m p l e s of 5 5 4 4 a n d 4 8 7 2 C a n a d i a n s . T h e r e s u l t s i n d i c a t e d the average d a i l y i n t a k e of t h e t o t a l s a m p l e to b e 0 . 6 m g / k g p e r day. E x t r e m e i n t a k e s at t h e 9 0 t h a n d 9 5 t h p e r c e n t i l e s for t h e t o t a l p o p u l a t i o n w e r e 3.8 a n d 5.2 m g / k g b o d y w e i g h t / d a y respectively. S u b g r o u p s s u c h as diabetics were also studied. In a l l cases, the i n t a k e of a s p a r t a m e w a s f o u n d to be far b e l o w t h e A D I of 4 0 mg/kg/day. T h i s study, w h i c h m a y well serve as a model, provides results w h i c h are of i m p o r t a n c e not o n l y as a g e n e r a l r e v i e w of c o n s u m p t i o n a n d intake patterns b u t w h i c h will be particularly relevant i n r e g a r d to the e v a l u a t i o n of n e w r e q u e s t s for a d d i t i o n a l u s e s of a s p a r t a m e . W h i l e all n e w sweetener petitions w i l l be e x a m i n e d o n a c a s e - b y - c a s e b a s i s , the n e e d for post-market s u r v e i l l a n c e d a t a p a r t i c u l a r l y for l o w A D I s u b s t a n c e s w i l l r e m a i n a general policy requirement i n C a n a d a .


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DISCOVERY, M O L E C U L A R

DESIGN, A N D

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P o t e n t i a l for A d v e r s e R e a c t i o n s In the a s s e s s m e n t of safety of a n o v e l s u b s t a n c e , a n i m a l species h a v e t r a d i t i o n a l l y s e r v e d a s s u r r o g a t e s for m a n a n d t h e r e b y a s tools for t h e p r e d i c t i o n of p o t e n t i a l a d v e r s e c o n s e q u e n c e s i n t h e h u m a n . These toxicological approaches, supplemented by newer i n vitro t e c h n i q u e s s u c h as the A m e s test a n d other tests not involving large scale a n i m a l models have, i n the m a i n , b e e n good predictors of t h e safety of a v a r i e t y of c h e m i c a l s u b s t a n c e s . H o w e v e r , tests are n o t yet a v a i l a b l e for t h e p r e - m a r k e t p r e d i c t i o n of a r a n g e of consequences u s u a l l y classified as "adverse or hypersensitivity r e a c t i o n s " t h a t m a y be c a u s e d b y or associated w i t h the u s e of a particular additive i n m a n . Examples include reported adverse r e a c t i o n s d u e to the food c o l o u r t a r t r a z i n e , t h e seasoning m o n o s o d i u m glutamate a n d the sweetener aspartame. A s a c o n s e q u e n c e , the r e p o r t i n g a n d m o n i t o r i n g of adverse r e a c t i o n s is a l s o s e e n a s a n e c e s s a r y p o s t - m a r k e t r e q u i r e m e n t for l a r g e e x p o s u r e a d d i t i v e s . It i s s e e n a s a n e x e r c i s e w h i c h i n v o l v e s not only the public, m e d i c a l practitioners a n d h e a l t h agencies, b u t the i n d u s t r y as well. F o r example, a n aspartame adverse reaction report is compiled quarterly by the U n i t e d States F o o d a n d D r u g A d m i n i s t r a t i o n C e n t e r for F o o d Safety a n d A p p l i e d N u t r i t i o n . T h i s m o n i t o r s the n a t u r e , severity a n d n u m b e r s of c o m p l a i n t s f r o m a variety of s o u r c e s . R e s u l t s are a n a l y z e d as to t r e n d s a n d as d e t e r m i n a n t s of f u t u r e policy. S i m i l a r r e p o r t s are also m o n i t o r e d b y o t h e r g o v e r n m e n t s for a r a n g e of s u b s t a n c e s . F r o m a p o l i c y perspective, the q u e s t i o n a r i s e s as to the a c c e p t a b i l i t y of a s u b s t a n c e for u s e i n food w h i c h h a s t h e p o t e n t i a l to c a u s e allergies o r h y p e r s e n s i t i v i t y r e a c t i o n s . T h i s m a t t e r i s one w h i c h i s of c o n s i d e r a b l e c o n c e r n to g o v e r n m e n t s . Some guidance h a s been provided b y the F A O / W H O J o i n t E x p e r t C o m m i t t e e o n F o o d A d d i t i v e s (4, 5). I n c o n s i d e r i n g t h i s p r o b l e m t h e C o m m i t t e e w a s of t h e v i e w t h a t n o a p p r o v a l s h o u l d b e g i v e n to s u b s t a n c e s c a u s i n g serious or w i d e s p r e a d hypersensitivity reactions. For s u b s t a n c e s c a p a b l e o f c a u s i n g o n l y a l o w i n c i d e n c e of, o r m i n o r hypersensitivity reactions, the C o m m i t t e e w a s of the view t h a t A D I s s h o u l d be established. However, the Committee stated that appropriate labelling s h o u l d also be considered as a possible m e c h a n i s m to e n a b l e s e n s i t i v e i n d i v i d u a l s a n d t h e i r p h y s i c i a n s to i d e n t i f y p o s s i b l e s o u r c e s of allergic r e a c t i o n s a n d to m i n i m i z e s u c h h a z a r d s . W h i l e the specific allergy-related labelling w o u l d be case d e p e n d a n t a n d c o u l d range f r o m a s i m p l e l a b e l d e c l a r a t i o n of the p r e s e n c e of t h e c o m p o u n d i n a food to c a u t i o n a r y s t a t e m e n t s d e t a i l i n g the symptomatology, l a b e l l i n g w o u l d at least afford the c o n s u m e r w i t h s o m e b a s i c i n f o r m a t i o n a n d t h e r e b y w i t h o p t i o n s to r e m e d y h i s or h e r s i t u a t i o n as a m a t t e r of i n d i v i d u a l choice. These C o m m i t t e e views are compatible w i t h m o s t regulatory a g e n c y t h i n k i n g a n d are i n line w i t h the type of p r e c a u t i o n a r y m e a s u r e s t h a t w o u l d a p p e a r reasonable a s s u m i n g a l o w i n c i d e n c e of


23.

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mild reactions. It i s r e c o g n i z e d , h o w e v e r , t h a t t e s t methodologies to p r e d i c t h y p e r s e n s i t i v i t y a n d adverse r e a c t i o n s together w i t h r e g u l a t o r y m e c h a n i s m s to d e a l w i t h t h e m w i l l c o n t i n u e to be the f o c u s of c o n s i d e r a b l e a t t e n t i o n .


Vulnerable Subgroup Considerations A n a d d i t i o n a l c o n s e q u e n c e of extensive a n d p o t e n t i a l l y e s c a l a t i n g u s e of n o v e l s w e e t e n e r s i n the food s u p p l y relates to t h e i r consumption by population subgroups with particular health concerns. D i a b e t i c s , for e x a m p l e , w h o m u s t e x e r c i s e care r e s p e c t i n g s u g a r i n t a k e are p a r t i c u l a r l y interested i n s u g a r substitutes. B e c a u s e of p a r t i c u l a r s r e l a t e d to t h e i r c o n d i t i o n , p o p u l a t i o n s u b g r o u p s t h a t m a y c o n s t i t u t e target g r o u p s for p o t e n t i a l large scale c o n s u m p t i o n s h o u l d be c o n s i d e r e d for specific s t u d i e s s u c h a s m e t a b o l i s m , etc. G r o u p s s u c h a s the v e r y y o u n g a n d the obese m a y also be u s e f u l i n a s s e s s i n g the n a t u r e of a n y p o t e n t i a l u n t o w a r d effects t h a t m a y be a s s o c i a t e d w i t h p a r t i c u l a r n o v e l sweeteners. W i t h r e g a r d to a s p a r t a m e , s u c h s t u d i e s w e r e c a r r i e d o u t i n n o r m a l , obese, diabetic a n d p h e n y l k e t o n u r i c a d u l t h u m a n s . Persons w i t h phenylketonuria, a n i n b o r n error i n metabolism, m u s t r e s t r i c t t h e i r i n t a k e of L - p h e n y l a l a n i n e f r o m c o m m o n foods as w e l l as from aspartame i n w h i c h it is a constituent a m i n o acid. C a n a d i a n a n d U . S . regulators c o n s i d e r e d it n e c e s s a r y to advise t h i s v u l n e r a b l e s u b g r o u p of t h e p r e s e n c e of p h e n y l a l a n i n e a n d , t h u s , t h e C a n a d i a n a n d U . S . label of a n y food c o n t a i n i n g a s p a r t a m e m u s t c a r r y o n its principal display panel the statement "contains phenylalanine". L a b e l l i n g C o n s i d e r a t i o n s P e r t a i n i n g t o N o v e l Sweeteners It i s r e a d i l y u n d e r s t a n d a b l e t h a t t h e p r e s e n c e o f a n o v e l s w e e t e n e r o r a n y c o m b i n a t i o n of novel sweeteners i n a n y foodstuffs w o u l d be e x p e c t e d to b e i n d i c a t e d o n t h e l i s t o f i n g r e d i e n t s o f t h a t p r o d u c t . I n a d d i t i o n , c o n s u m e r s m i g h t f i n d a s t a t e m e n t of the s w e e t n e s s of a s e r v i n g e x p r e s s e d i n t e r m s of the a m o u n t of s u g a r p r o d u c i n g a n e q u i v a l e n t d e g r e e o f s w e e t n e s s to b e q u i t e u s e f u l . T h e u s e of h i g h - i n t e n s i t y novel sweeteners i n foods m a y also r e s u l t i n c o n s i d e r a b l e s h i f t s i n t h e m a c r o n u t r i e n t c o m p o s i t i o n of p r o t e i n , fat a n d c a r b o h y d r a t e i n t h e f i n a l p r o d u c t c o m p a r e d w i t h a s i m i l a r p r o d u c t containing caloric sweeteners. S u c h products may be widely c o n s u m e d b y diabetics w h o require information o n the m a c r o n u t r i e n t c o n t e n t a s a b a s i s for t h e c a l c u l a t i o n of e x c h a n g e values. Furthermore, compositional information on new products sweetened w i t h novel s u b s t a n c e s w i l l n o t be readily available i n food composition handbooks. B e c a u s e of s u c h c o n s i d e r a t i o n s , a l a b e l s t a t e m e n t of the q u a n t i t i e s of a l l m a c r o n u t r i e n t s together w i t h the energy v a l u e s h o u l d be required o n a l l foods c o n t a i n i n g novel sweeteners. In a d d i t i o n , s u c h f o o d s m a y b e s u b j e c t to o t h e r s p e c i f i c l a b e l l i n g


311

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r e q u i r e m e n t s d e p e n d i n g o n t h e i r categorization as, for e x a m p l e , "foods for special dietary use" or "table-top sweetener p r e p a r a t i o n s . " F u l l n u t r i t i o n labelling, i n c l u d i n g the d e c l a r a t i o n of m i c r o n u t r i e n t s , e.g. v i t a m i n s a n d m i n e r a l s c o n t a i n e d i n t h e f o o d p r o d u c t , is a l s o a n o p t i o n to be e x p l o r e d i n v i e w of i n c r e a s i n g c o n s u m e r interest i n n u t r i t i o n . M a n u f a c t u r e r s of foods c o n t a i n i n g novel s w e e t e n e r s s h o u l d be a w a r e of the c o n s i d e r a b l e b o d y of specific regulatory r e q u i r e m e n t s t h a t p e r t a i n to b o t h l a b e l l i n g a n d to t h e u s e o f c l a i m s i n b o t h A m e r i c a n a n d C a n a d i a n r e g u l a t i o n s .


Conclusion T h e d i s c o v e r y of a novel sweetener is b u t the i n i t i a l step i n a l o n g process leading toward potential commercialization. As has been discussed, all novel sweeteners m u s t undergo a complex, extensive a n d t i m e c o n s u m i n g b a t t e r y of tests a s p a r t of the p r e - a n d postm a r k e t r e v i e w p r o c e s s a n d e v a l u a t i o n of the safety a n d a c c e p t a b i l i t y of these s u b s t a n c e s .

Literature Cited

1. Food Chemicals Codex, 3rd ed.; National Academy Press: Washington, DC, 1981. 2. Calorie Control Commentary 1989, 11(2), 1-2. 3. Heybach, J.P.; Ross, C. J. Can. Dietetic Assoc. 1989, 50, 166170. 4. Seventeenth Report of the Joint FAO/WHO Expert Committe Food Additives; World Health Organization Technical Reports Series No. 539, 1973, p 12. 5. Eighteenth Report of the Joint FAO/WHO Expert Committee Food Additives; World Health Organization Technical Reports Series No. 557, 1974, p 10. RECEIVED August 27, 1990


Novel Sweeteners - ACS Symposium Series (ACS Publications)

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