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Studies on transitory laxative effects of sorbitol and maltitol I: Estimation of 50% effective dose and maximum non-effective dose
Chemosphere, Vol.12, No.l, P r i n t e d in Creat Britain
pp 45 - 53,
1983
OO45-6535/83/010045-O9503.OO/O © 1 9 8 3 P e r g a m o n Press Ltd.
STUDIES ON TRANSITORY LAXATIVE EFFECTS OF SORBITOL AND MALTITOL I : ESTIMATION OF 50% EFFECTIVE DOSEAND MAXIMUM NON-EFFECTIVE DOSE
N. Koizumi,*
M. F u j i i , * *
R. Ninomiya,*
Y. Inoue,*
T. Kagawa * and T. Tsukamoto * * Department of Public Health, Hyogo College of Medicine, Hyogo, Japan ** Food Chemistry Division, Environmental Health Bureau, Ministry and Health Welfare, Tokyo, Japan
ABSTRACT The dose-response r e l a t i o n s h i p between low-caloric sweetening agents, s o r b i t o l and m a l t i t o l , administered o r a l l y in single doses, and the induction of diarrheal symptoms was investigated. Seven healthy male and 7 healthy female Japanese each in t h e i r twenties, t h i r t i e s , and f o r t i e s , r e spe c t i v e l y , or a t o t a l of 42 subjects were admitted to the study. The 50% l a x a t i v e e f f e c t i v e dose of s o r b i t o l was estimated to be 0.4 g/kg fo r males and 1.0 g/kg f o r females and that of m a l t i t o l was estimated to be 0.8 g/kg f o r both males and females. The maximum non-effective dose of s o r b i t o l was estimated to be 0.15 g/kg f o r males and 0.3 g/kg f o r females and that of m a l t i t o l was estimated to be 0.3 g/kg for both males and females. INTRODUCTION Sorbitol and m a l t i t o l have recently been used as low-caloric sweetening agents f or food with increasing frequency.
However, i t has been reported that these agents when ingested o r a l l y in
single large doses cause the side e f f e c t of diarrhea.
In the case of Europeans and Americans,
the dose of about 50 g ( I ) of s o r b i t o l caused soft stool or watery stool in the majority of subjects, while 25 g caused diarrhea in 5.8% of subjects (2). There has as yet been no report which has concerned i t s e l f with the use of s o r b i t o l with the Japanese.
The maximum non-effective
dose of m a l t i t o l in Japanese has been reported to be about 20 g in the fasting state and about 40 g in the other state (3). The experiments in which 30 g oral doses were given to 6 men and women (5) of 0.5 g/kg to 5 men (6) in the fasting state e a r ly morning showed that m a l t i t o l had no l a x a t i v e e f f e c t . of subjects (4).
However, 50 g doses have been reported to cause diarrheal symptoms in 62.5%
In a l l the above studies, the number of subjects was small, the dose per body
weight was unknown, and sex and age were not taken into consideration at a l l . I f the practical use of these sweetening agents is assumed to cause diarrhea, even i f t r a n s i e n t l y , i t is important to estimate t h e i r 50% e f f e c t i v e doses (ED50) and maximum non-
45
46
e f f e c t i v e doses.
The r e l a t i o n s h i p between sex, age, alcohol and c i g a r e t t e consumptions, bowel
habit, or a past h i s to r y of g a s t r o i n t e s t i n a l disease and the occurrence of diarrhea is considered to require studies. In the present study, we administered s o r b i t o l and m a l t i t o l in doses of 0.4, 0.8 and 1.6 g/kg to 21 healthy males and 21 healthy females in the twenties, t h i r t i e s , or f o r t i e s and estimated t h e i r ED50 and maximum non-effective doses to cause diarrhea.
In a d d i t i o n , the
r e l a t i o n between bowel habit or a past history of g a s t r o i n t e s t i n a l disease and the occurrence of diarrhea, and abdominal symptoms when diarrhea occurred were discussed. SUBJECTS AND METHODS Seven healthy males and 7 healthy females each in t h e i r twenties, t h i r t i e s , and f o r t i e s matched with age were admitted to the study.
The subjects were questioned as to age, body
weight, d a i l y frequency of defecation, a past history of g a s t r o i n t e s t i n a l disease and ingested foods on the previous day of administration of the test substances.
On the day of administration
of the test substances, the times of onset of abdominal symptoms and diarrhea, type of abdominal symptoms, frequency of defecations, and macroscopic findings of stools a f t e r administration were questioned.
In view of the e f f e c t of s u g g e s t i b i l i t y on the onset of diarrhea, the subjects'
character was judged and the test substances were administered in f i n e granule forms by the blind method. The test substances were two sweetening agents, i . e . s o r b i t o l and m a l t i t o l (Towa Kasei Industries, Ltd.) in f i n e granule forms.
Sugar was used as a control substance.
The two
sweetening agents were used of at least 99% p u r i t y . The two sweetening agents and a control substance, sugar, were given, as a r ule, in doses of 0.4, 0.8 and 1.6 g/kg to each subject, 2 hours a f t e r lunch, or a t o t a l of 9 times per subject. I f subjects presented diarrhea at a low dose of 0.4 g/kg, 0.2 g/kg was administered. g/kg caused diarrhea, 0.I g/kg was administered.
I f 0.2
Thus, the maximum non-effective dose was
estimated. On the other hand, the maximum dose of each sweetening agent given to each subject was the dose which caused diarrhea.
Higher doses were not administered.
A questionaire on diarrheal symptoms included findings of stools, i . e . s o f t , watery, or normal s t o o l , and abdominal symptoms such as upper abdominal pain, lower abdominal pain, tenesmus, gurgle (rumbling noise), f l a t u s , vomiting and fever. The test substances were administered on the day when the g a s t r o i n t e s t i n a l condition was as good as possible.
On the previous day of administration, the ingestion of food and bevarages
which might induce diarrhea was avoided.
On the day of administration, each substance was
administered within about I0 minutes a f t e r each substance had been dissolved in I00 to 200 ml of water or warm water 2 hours a f t e r the meal. RESULTS AND DISCUSSION Table 1 shows the subjects' c h a r a c t e r i s t i c s . the body weight basis.
The sweetening agents were administered on
Calculated doses on the basis of average body weight were 26 g f o r 0.4
g/kg, 51 g f o r 0.8 g/kg, and 102 g f o r 1.6 g/kg f o r males and 20 g f or 0.4 g/kg, 40 g f o r 0.8
47
g/kg, and 80 g f o r 1.6 g/kg f o r females. In the present study, the subjects
Table I . Subject C h a r a c t e r i s t i c s
were p r e v i o u s l y informed t h a t the t e s t
Male
Female
21
21
m ~-s.d.
64.4±5.6
49.9±8.1
0.4 g/kg
25.5±2.4
19.9~3.4
0,8 g/kg
51.0±4.8
39.8±6.7
1,6 g/kg
102~9.5
79.6t13.4
substances might cause diarrhea and t h e i r consent was obtained.
Total
In order to estimate
the ED50 and maximum n o n - e f f e c t i v e dose of
20-29
each t e s t substance, factors which may
Number Age
30-39
i n f l u e n c e the occurrence of diarrhea must be removed as f a r as possible.
40-49
First,
sugar, a control substance, was administer-
Body weight
(g)
ed to males and females in doses of 0.4, 0.8, and 1.6 g/kg by the b l i n d method. subject presented diarrhea.
No
In a d u l t s , the
Mean value
character, bowel h a b i t , a past h i s t o r y of gastrointestinal
m + s.d.
disease, and h a b i t of d r i -
nking and smoking are considered as factors
O p t i m i s t i c nature
53
43
Constipation
I0
59
Ratio Past g a s t r o i n t e s t (%) inal disease
24
14
Alcohol
55
38
Tobacco
45
14
i n f l u e n c i n g diarrhea. Table 2 shows the r e l a t i o n s h i p between these factors and the occurrence rate of diarrhea when 0.8 g/kg doses were administered to subjects.
Because of a small numb-
er of subjects involved, s t a t i s t i c a l
(g)
Habits
analy-
sis were not done. Table 2.
Influence of Various Factors on Laxative E f f e c t (at 0.8 g/kg) Sorbitol
O p t i m i s t i c nature +
Constipation +
Past g a s t r o i n t e s t - inal disease + Alcohol
Tobacco +
Maltitoi
%
Male ( )a
Female % ( )a
%
Male ( )a
Female % ( )a
80
(4/5)
50 (3/6)
57 (4/7)
86
(6/7)
25 (2/8)
60 (3/5)
5o (3/6) 25 (2/8)
67 (6/9)
53 (9/17)
6;' (6/9)
17 (2/12)
50 ( I / 2 )
33 (4/12)
79 (11/14)
39 (7/18)
56 (9/16)
39 (7/18)
67
33 ( I / 3 )
33 ( I / 3 )
80 (12/15) 50 ( I / 2 )
(2/3)
lO0
(8/8)
56 (5/9)
56
(5/9)
60 (6/10)
80 (8/1o) ~ / J
58 (7/12)
71
57 (4/7)
(5/7)
( )a : Subjects with diarrhea / Subjects
I00 (3/3)
48
I t appeared t h a t the c h a r a c t e r , a past h i s t o r y of g a s t r o i n t e s t i n a l
disease, and habits o f
d r i n k i n g and smoking had no i n f l u e n c e on the occurrence o f d i a r r h e a .
As shown in Table I ,
there were many women, who were c h r o n i c a l l y c o n s t i p a t e d , accounting f o r 59%.
As i n d i c a t e d in
Table 2, in females w i t h c o n s t i p a t i o n , the both sweetening agents h a r d l y caused d i a r r h e a on the a d m i n i s t r a t i o n at 0.8 g / k g .
On the o t h e r hand, in males, only 10% of whom showed c o n s t i p a t i o n ,
t h e r e f o r e , the l a x a t i v e e f f e c t o f each sweetening agent appeared to be u n a f f e c t e d .
With these
in mind, the f o l l o w i n g r e s u l t s were o b t a i n e d . Figure 1 represents g r a p h i c a l l y the percentage o f subjects w i t h d i a r r h e a a t various doses of each sweetening agent. of s o r b i t o l ,
There was no sex d i f f e r e n c e in the incidence of d i a r r h e a a t 1.6 g/kg
which caused d i a r r h e a in 100% of s u b j e c t s .
However, a t less than 100% e f f e c t i v e
doses, the sex d i f f e r e n c e was remarkable; a t 0.4 and 0.8 g/kg of s o r b i t o l ,
the incidence of
d i a r r h e a in females was less than 50%, but in males, was found over 50%. sex d i f f e r e n c e was found a t any dose of m a l t i t o l . with sorbitol
than w i t h m a l t i t o l .
and female subjects and m a l t i t o l
On the o t h e r hand, no
The incidence of d i a r r h e a was c l e a r l y higher
At 1.6 g/kg doses, s o r b i t o l
caused d i a r r h e a in 100% of male
d i d so in about 65%.
%
100
I00
MALTITOL
I male ~female
50
50
0.2 Figure I .
0.4
0.8
1.6 g/kg
0.2
0.4
0.8
1.6 g/kg
Percentage o f Subjects w i t h Diarrhea a f t e r Taking the Sweetening Agents
There have been no r e p o r t s d e a l i n g w i t h the d i f f e r e n c e in the incidence of d i a r r h e a between the two sweetening agents.
Studies on the sex d i f f e r e n c e in r e l a t i o n to each sweetening
agent have not been c a r r i e d out. caused d i a r r h e a in most cases ( I ) ,
According to r e p o r t s on r e s p e c t i v e agents, s o r b i t o l while maltitol
d i d so in 62.5% ( 4 ) .
t h a t s o r b i t o l may have a more p o t e n t l a x a t i v e e f f e c t on the i n t e s t i n a l
It
t r a c t than m a l t i t o l .
to bowel h a b i t , c o n s t i p a t i o n was more f r e q u e n t l y found in females than in males. le t h a t the area of the i n t e s t i n a l amount of i n t e s t i n a l
t r a c t w i t h which s o r b i t o l
at 50 g
is thus presumed
is indirect
As
I t is possib-
c o n t a c t depends on the
c o n t e n t s , l e a d i n g to the sex d i f f e r e n c e in the incidence of d i a r r h e a .
49
0
o o O)
0
0
0 ~00
@o
0
0
0
SORBITOL (FEMALE)
SORBITOL (MALE) 0 0 0
0
0 0
(9 0 0 0
0
o o
do
.
5
0
• 0
•0
•
•
o@• "
"~" .oa 0
•
• i
i
50
I00
• • • I
I
taken dose (g)
I
50
0
]OCl tokendose (g)
Gb
o8
OLT,TOL*OLE,
0
0 0 0
"
"I
O•
0
i
0
MALTITOL (FEMALE)
0
0 0
0 o
0
0 0
0 0 0 0
0 0
0 0
de o
o •
o
GNI•
O
o 0
0 •
0
•
0
0
l
•
• 5~
lO~
taken aose
|,
" •
• I
5o
0
lO0
taken dose (g)
Figure 2. Relation Between Dose and Time u n t i l the F i r s t Defecation after Administraion O without diarrhea
O with diarrhea
50
Figure 2 i l l u s t r a t e s first
d e f e c a t i o n of a l l
time u n t i l
the r e l a t i o n between the dose of sweetening agents and time u n t i l subjects.
the
Although there were i n d i v i d u a l v a r i a t i o n s in t h a t t i m e , the
the onset o f d i a r r h e a l symptoms was estimated to be almost less than 6 hours, i r r e s p -
e c t i v e of the d i f f e r e n c e in the dose given to males and females. The f a c t t h a t t h e r e was no d i f ference in the time to the onset o f d i a r r h e a a f t e r a d m i n i s t r a t i o n of each t e s t substance suggested t h a t the mechanism of onset o f d i a f f h e a was the same f o r both sweetening agents and appeared to support t h a t the sex d i f f e r e n c e in the incidence of d i a r r h e a as shown in Figure l depended on the d i f f e r e n c e in the amount of i n t e s t i n a l
contents between males and females.
In the present study, those who presented d i a r r h e a at an i n t e r m e d i a t e dose o f 0.8 g/kg were not given 1.6 g/kg. administered. Figure 3.
However, they were considered to have presented d i a r r h e a i f
The Dose-Effect curve was p l o t t e d on a u n i l a t e r a l
1.6 g/kg was
l o g a r i t h m i c graph as in
From t h i s curve, ED50 of s o r b i t o l was estimated to be 0.4 g/kg f o r males and l.O g/kg
f o r females, r e s p e c t i v e l y , and t h a t o f m a l t i t o l
was estimated to be 0.8 g/kg f o r both males and
females.
% I00
SORBITOL • male ©
MALTITOL
% I00
~
50
ED50
• male 0 female
50
ED50
o
~
0.2
Figure 3. Ellis
0.4
0.8
1.6
I
0.2
g/kg
0.4
0.8
I
1.6 g/kg
Dose-Effect Curve between L a x a t i v e E f f e c t and Taken Dose
e t al ( I ) a d m i n i s t e r e d s o r b i t o l
in a c r y s t a l l i n e
r e p o r t e d t h a t d i a r r h e a occurred in the m a j o r i t y of them. assuming the body w e i g h t of Westerners to be 70 kg.
form a t dose o f 50 g to 12 males and This dose corresponded to 0.71 g / k g ,
Peters e t al (2) r e p o r t e d t h a t 25 g doses
caused marked watery s t o o l s in 5 (5.8%) of 86 s u b j e c t s .
This dose is c a l c u l a t e d as 0.34 g/kg
in a s i m i l a r manner and is presumed to be an approximate value o f the minimum e f f e c t i v e sorbitol.
In the present study, ED50 of s o r b i t o l
g/kg f o r males.
to produce d i a r r h e a was estimated to be 0.4
Our r e s u l t t h a t 0.8 g/kg o f s o r b i t o l
was in good agreement w i t h the r e p o r t o f E l l i s
dose of
caused d i a r r h e a in 100% of male subjects
e t al ( I )
t h a t a t the dose l e v e l o f 0.71 g/kg
( c a l c u l a t e d assuming the body weight o f Westerners to be 70 k g ) , d i a r r h e a occurred in most cases.
This f a c t suggests t h a t there w i l l
be no d i f f e r e n c e in d o s e - e f f e c t on a body w e i g h t
51
basis between the Japanese and Westerners. M a l t i t o l has been reported to cause no diarrhea in some experiments in which 30 g (calculated as 0.5 g/kg assuming the average weight of 6 subjects to be 60 kg) was given to 6 male or female subjects in the e a r l y morning fasting state (5) or 0.5 g/kg was given to 5 males in the e a rly morning fasting state (6).
In the study in which diarrhea occurred, 50 g (0.91 g/kg with
the average body weight of Japanese subjects being taken as 55kg) given in the early morning fasting state caused diarrhea in 62.5% of subjects (4).
This dose was well consistent with the
ED50 estimated in the present study, i . e . 0.8 g/kg. Next, in order to determine the maximum non-effective dose, a lower dose of 0.I g/kg was given to 5 males who had been given 0.2 g/kg of s o r b i t o l and in whom the time i n t e r v a l between administration and the f i r s t defecation was less than 20 hours. presented diarrhea.
In this experiment, no subject
In neither females given 0.2 g/kg of sorbtol nor male and female subjects
given 0.2 g/kg of m a l t i t o l , diarrhea occurred.
From these results, i t was inferred that the
maximum non-effective dose of sorbitol was 0.15 g/kg for males and 0.3 g/kg f o r females, while that of m a l t i t o l was 0.3 g/kg f o r both males and females. There has as yet been no report on the estimation of the maximum non-effective dose of sorb i t o l or m a l t i t o l to produce diarrhea.
Peters et al (2) stated that the minimum e f f e c t i v e dose
of s o r b i t o l was approximately 25g (calculated as 0.34 g/kg, assuming the body weight to be 70kg), which was in good agreement with the upper l i m i t of maximum non-effective doses (0.15 g/kg f o r males and 0.3 g/kg f o r females).
I t has been reported that m a l t i t o l doses not cause dirrhea
when administered in a single dose of 0.5 g/kg in the early morning fasting state (6), in a dose of 30g a f t e r 12 hours fasting (5), in a single dose of 20 to 30g (8), or in a dose of less than about 20g in the f as ti n g state (3).
The ED50 estimated from the present study, 0.3 g/kg, was
s l i g h t l y lower than that reported by Koji et al (5) and l i t o y o et al (6) and was in close agreement with that reported by Inoue et al (3).
The d i s p a r i t y between the r e s u l t in our study and
that of others in Japan (5-6) may be due to a difference in the number of subjects involved, i . e . in other studies (5-6), the number of subjects was as small as 5 or 6.
The d i s p a r i t y betw-
een our r e s u l t and that of Abraham et al (8) may be due to differences in body weight and dosing conditions. Figure 4 represents the findings of diarrheal stools.
With s o r b i t o l , watery stool account-
ed f o r about 80% of the cases in both males and females, while with m a l t i t o l , the percentage of watery stool was smaller in females than in males. females were more frequently constipated.
This seemed to be related to the fact that
Sorbitol caused soft stool at higher percentage than
did m a l t i t o l , since the former caused diarrheal symptoms at r e l a t i v e l y low doses as compared to the l a t t e r .
In general, both sweetening agents caused watery stools in the majority of cases.
Figure 5 represents the abdominal symptoms when diarrhea occurred. apping answers, i f necessary.
Individuals gave o v e r l -
In both sweetening agents, the most frequent complaint reported
was gurgle followed by f l a t u s and lower abdominal pain, i r r e s p e c t i v e of sex.
The incidences
of abdominal symptoms caused by s o r b i t o l and m a l t i t o l were 76% and 69%, r es p e c t iv e ly , f o r gurgle, 48% and 54%, r e s p e c t i v e l y , f o r f l a t u s , and 26% and 31%, r e s pec t iv ely , f o r lower abdominal pain. These abdominal symptoms and diarrhea subsided within 24 hours a f t e r administration of e i t h e r sweetening agent and no complaint was reported t h e r e a f t e r .
52
As described above, sorbitol and maltitol induced diarrhea 2 to 3 hours after oral ingesti. on when the agent reached the intestinal tract, especially the large intestine and induced watery stools in the majority of cases. It is inferred therefore that as reported by Niwa et al (9) sorbitol and maltitol have transitory laxative effects due to the inhibition of water absorption mainly in the large intestine.
SORBITOL male female
MALTITOL m~1~ Tsoft 6%
?>2 t
Figure 4.
I
Findings of Diarrheal Stools
MALTITOL
SORBITOL Imale
% ~Im~le
75% IF]female
75
50
50
25
oll a
I
b
c
d
e
f
25
g
o
a
b
c
d
e
Figure 5. Abdominal Symptoms with Diarrhea a: upper abdominal pain b: lower abdominal pain c: tenesmus d: gurgle e: flatus f: vomiting g: fever
f
53
CONCLUSION The present study was performed in o r d e r to e s t i m a t e the 50% e f f e c t i v e n o n - e f f e c t i v e dose of s o r b i t o l
and m a l t i t o l
to produce t r a n s i t o r y
and twenty-one females in t h e i r t w e n t i e s to f o r t i e s
dose and maximum
diarrhea.
Twenty-one males
received each sweetening agent in oral dose:
of 0.4, 0.8, and 1.6 g/kg w i t h i n I0 minutes, which had been d i s s o l v e d in lO0 to 200ml of water or warm w a t e r , 2hours a f t e r the meal. The 50% e f f e c t i v e
dose o f s o r b i t o l
to induce d i a r r h e a was estimated to be 0.4 g/kg f o r
males and 1.0 g/kg f o r females, the sex d i f f e r e n c e being found, w h i l e thai: o f m a l t i t o l mated to be 0.8 g/kg f o r both males and females.
was e s t i -
The maximum n o n - e f f e c t i v e dose of s o r b i t o l
was e s t i m a t e d to be 0.15 g/kg f o r males and 0.3 g/kg f o r females, w h i l e t h a t of m a l t i t o l 0.3 g/kg f o r both males and females.
There was no d i f f e r e n c e in the time u n t i l
ea a f t e r oral a d m i n i s t r a t i o n between the two sweetening agents.
was
onset o f d i a r r h -
The time i n t e r v a l
between oral
a d m i n i s t r a t i o n and onset of d i a r r h e a was less than 6 hours in the m a j o r i t y of cases, averaging 3 hours, The most f r e q u e n t abdominal symptom w i t h d i a r r h e a was gurgle w i t h both sweetening agents, f o l l o w e d by f l a t u s and lower abdominal pain. ACKNOWLEDGEMENT We are indebted to Iowa Kasei I n d u s t r i e s , Ltd. f o r supply of m a t e r i a l s . REFERENCES I.
F. W. E l l i s
2.
R. Peters and R. H. Lock : Br. Med. J . , No. 5097, 677-678 (1958)
and J. C. Krantz : J. B i o l .
Chem., 141, 147-154 (1941)
3.
T. Inoue and M. Mitsuhashi
4.
M. Kamoi, Y. Shimizu, M. Kawauchi, Y. F u j i i , M. Kibata : Jpn. J. N u t r . ,
5.
: E i y o - t o - S h o k u r y o , 24, 506 (1971) T. K i k u c h i , S. Mizukawa, H. Yoshioka and
30, 153-158 (1972)
11. K o j i , S. Asano, S. Matsuki, K. Kataoka, M. Nakajima, H. Suzuki, Y. Takabayashi and H. Maruyama : Rinshoeiyo, 41, 200-208 (1972)
6.
N. l i t o y o ,
7.
F. Naito : New Food I n d u s t r y , 13, 65-74 (1971)
S. Moriuchi and N. Hosoya : E i y o - t o - S h o k u r y o , 27, 77-81 (1974)
8.
R. R. Abraham, M. Davis, J. Yudkin and R. Williams : J. Hum. N u t r . , 35, 165-172 (1981)
9.
H. Niwa, N. H i k i c h i ,
E. Sakurai, M. Ueda and G. Fukuse : Yakugaku Zasshi, 101, 567-574
(1981)
(Received
in U S A
27 O c t o b e r
1982)
pp 45 - 53,
1983
OO45-6535/83/010045-O9503.OO/O © 1 9 8 3 P e r g a m o n Press Ltd.
STUDIES ON TRANSITORY LAXATIVE EFFECTS OF SORBITOL AND MALTITOL I : ESTIMATION OF 50% EFFECTIVE DOSEAND MAXIMUM NON-EFFECTIVE DOSE
N. Koizumi,*
M. F u j i i , * *
R. Ninomiya,*
Y. Inoue,*
T. Kagawa * and T. Tsukamoto * * Department of Public Health, Hyogo College of Medicine, Hyogo, Japan ** Food Chemistry Division, Environmental Health Bureau, Ministry and Health Welfare, Tokyo, Japan
ABSTRACT The dose-response r e l a t i o n s h i p between low-caloric sweetening agents, s o r b i t o l and m a l t i t o l , administered o r a l l y in single doses, and the induction of diarrheal symptoms was investigated. Seven healthy male and 7 healthy female Japanese each in t h e i r twenties, t h i r t i e s , and f o r t i e s , r e spe c t i v e l y , or a t o t a l of 42 subjects were admitted to the study. The 50% l a x a t i v e e f f e c t i v e dose of s o r b i t o l was estimated to be 0.4 g/kg fo r males and 1.0 g/kg f o r females and that of m a l t i t o l was estimated to be 0.8 g/kg f o r both males and females. The maximum non-effective dose of s o r b i t o l was estimated to be 0.15 g/kg f o r males and 0.3 g/kg f o r females and that of m a l t i t o l was estimated to be 0.3 g/kg for both males and females. INTRODUCTION Sorbitol and m a l t i t o l have recently been used as low-caloric sweetening agents f or food with increasing frequency.
However, i t has been reported that these agents when ingested o r a l l y in
single large doses cause the side e f f e c t of diarrhea.
In the case of Europeans and Americans,
the dose of about 50 g ( I ) of s o r b i t o l caused soft stool or watery stool in the majority of subjects, while 25 g caused diarrhea in 5.8% of subjects (2). There has as yet been no report which has concerned i t s e l f with the use of s o r b i t o l with the Japanese.
The maximum non-effective
dose of m a l t i t o l in Japanese has been reported to be about 20 g in the fasting state and about 40 g in the other state (3). The experiments in which 30 g oral doses were given to 6 men and women (5) of 0.5 g/kg to 5 men (6) in the fasting state e a r ly morning showed that m a l t i t o l had no l a x a t i v e e f f e c t . of subjects (4).
However, 50 g doses have been reported to cause diarrheal symptoms in 62.5%
In a l l the above studies, the number of subjects was small, the dose per body
weight was unknown, and sex and age were not taken into consideration at a l l . I f the practical use of these sweetening agents is assumed to cause diarrhea, even i f t r a n s i e n t l y , i t is important to estimate t h e i r 50% e f f e c t i v e doses (ED50) and maximum non-
45
46
e f f e c t i v e doses.
The r e l a t i o n s h i p between sex, age, alcohol and c i g a r e t t e consumptions, bowel
habit, or a past h i s to r y of g a s t r o i n t e s t i n a l disease and the occurrence of diarrhea is considered to require studies. In the present study, we administered s o r b i t o l and m a l t i t o l in doses of 0.4, 0.8 and 1.6 g/kg to 21 healthy males and 21 healthy females in the twenties, t h i r t i e s , or f o r t i e s and estimated t h e i r ED50 and maximum non-effective doses to cause diarrhea.
In a d d i t i o n , the
r e l a t i o n between bowel habit or a past history of g a s t r o i n t e s t i n a l disease and the occurrence of diarrhea, and abdominal symptoms when diarrhea occurred were discussed. SUBJECTS AND METHODS Seven healthy males and 7 healthy females each in t h e i r twenties, t h i r t i e s , and f o r t i e s matched with age were admitted to the study.
The subjects were questioned as to age, body
weight, d a i l y frequency of defecation, a past history of g a s t r o i n t e s t i n a l disease and ingested foods on the previous day of administration of the test substances.
On the day of administration
of the test substances, the times of onset of abdominal symptoms and diarrhea, type of abdominal symptoms, frequency of defecations, and macroscopic findings of stools a f t e r administration were questioned.
In view of the e f f e c t of s u g g e s t i b i l i t y on the onset of diarrhea, the subjects'
character was judged and the test substances were administered in f i n e granule forms by the blind method. The test substances were two sweetening agents, i . e . s o r b i t o l and m a l t i t o l (Towa Kasei Industries, Ltd.) in f i n e granule forms.
Sugar was used as a control substance.
The two
sweetening agents were used of at least 99% p u r i t y . The two sweetening agents and a control substance, sugar, were given, as a r ule, in doses of 0.4, 0.8 and 1.6 g/kg to each subject, 2 hours a f t e r lunch, or a t o t a l of 9 times per subject. I f subjects presented diarrhea at a low dose of 0.4 g/kg, 0.2 g/kg was administered. g/kg caused diarrhea, 0.I g/kg was administered.
I f 0.2
Thus, the maximum non-effective dose was
estimated. On the other hand, the maximum dose of each sweetening agent given to each subject was the dose which caused diarrhea.
Higher doses were not administered.
A questionaire on diarrheal symptoms included findings of stools, i . e . s o f t , watery, or normal s t o o l , and abdominal symptoms such as upper abdominal pain, lower abdominal pain, tenesmus, gurgle (rumbling noise), f l a t u s , vomiting and fever. The test substances were administered on the day when the g a s t r o i n t e s t i n a l condition was as good as possible.
On the previous day of administration, the ingestion of food and bevarages
which might induce diarrhea was avoided.
On the day of administration, each substance was
administered within about I0 minutes a f t e r each substance had been dissolved in I00 to 200 ml of water or warm water 2 hours a f t e r the meal. RESULTS AND DISCUSSION Table 1 shows the subjects' c h a r a c t e r i s t i c s . the body weight basis.
The sweetening agents were administered on
Calculated doses on the basis of average body weight were 26 g f o r 0.4
g/kg, 51 g f o r 0.8 g/kg, and 102 g f o r 1.6 g/kg f o r males and 20 g f or 0.4 g/kg, 40 g f o r 0.8
47
g/kg, and 80 g f o r 1.6 g/kg f o r females. In the present study, the subjects
Table I . Subject C h a r a c t e r i s t i c s
were p r e v i o u s l y informed t h a t the t e s t
Male
Female
21
21
m ~-s.d.
64.4±5.6
49.9±8.1
0.4 g/kg
25.5±2.4
19.9~3.4
0,8 g/kg
51.0±4.8
39.8±6.7
1,6 g/kg
102~9.5
79.6t13.4
substances might cause diarrhea and t h e i r consent was obtained.
Total
In order to estimate
the ED50 and maximum n o n - e f f e c t i v e dose of
20-29
each t e s t substance, factors which may
Number Age
30-39
i n f l u e n c e the occurrence of diarrhea must be removed as f a r as possible.
40-49
First,
sugar, a control substance, was administer-
Body weight
(g)
ed to males and females in doses of 0.4, 0.8, and 1.6 g/kg by the b l i n d method. subject presented diarrhea.
No
In a d u l t s , the
Mean value
character, bowel h a b i t , a past h i s t o r y of gastrointestinal
m + s.d.
disease, and h a b i t of d r i -
nking and smoking are considered as factors
O p t i m i s t i c nature
53
43
Constipation
I0
59
Ratio Past g a s t r o i n t e s t (%) inal disease
24
14
Alcohol
55
38
Tobacco
45
14
i n f l u e n c i n g diarrhea. Table 2 shows the r e l a t i o n s h i p between these factors and the occurrence rate of diarrhea when 0.8 g/kg doses were administered to subjects.
Because of a small numb-
er of subjects involved, s t a t i s t i c a l
(g)
Habits
analy-
sis were not done. Table 2.
Influence of Various Factors on Laxative E f f e c t (at 0.8 g/kg) Sorbitol
O p t i m i s t i c nature +
Constipation +
Past g a s t r o i n t e s t - inal disease + Alcohol
Tobacco +
Maltitoi
%
Male ( )a
Female % ( )a
%
Male ( )a
Female % ( )a
80
(4/5)
50 (3/6)
57 (4/7)
86
(6/7)
25 (2/8)
60 (3/5)
5o (3/6) 25 (2/8)
67 (6/9)
53 (9/17)
6;' (6/9)
17 (2/12)
50 ( I / 2 )
33 (4/12)
79 (11/14)
39 (7/18)
56 (9/16)
39 (7/18)
67
33 ( I / 3 )
33 ( I / 3 )
80 (12/15) 50 ( I / 2 )
(2/3)
lO0
(8/8)
56 (5/9)
56
(5/9)
60 (6/10)
80 (8/1o) ~ / J
58 (7/12)
71
57 (4/7)
(5/7)
( )a : Subjects with diarrhea / Subjects
I00 (3/3)
48
I t appeared t h a t the c h a r a c t e r , a past h i s t o r y of g a s t r o i n t e s t i n a l
disease, and habits o f
d r i n k i n g and smoking had no i n f l u e n c e on the occurrence o f d i a r r h e a .
As shown in Table I ,
there were many women, who were c h r o n i c a l l y c o n s t i p a t e d , accounting f o r 59%.
As i n d i c a t e d in
Table 2, in females w i t h c o n s t i p a t i o n , the both sweetening agents h a r d l y caused d i a r r h e a on the a d m i n i s t r a t i o n at 0.8 g / k g .
On the o t h e r hand, in males, only 10% of whom showed c o n s t i p a t i o n ,
t h e r e f o r e , the l a x a t i v e e f f e c t o f each sweetening agent appeared to be u n a f f e c t e d .
With these
in mind, the f o l l o w i n g r e s u l t s were o b t a i n e d . Figure 1 represents g r a p h i c a l l y the percentage o f subjects w i t h d i a r r h e a a t various doses of each sweetening agent. of s o r b i t o l ,
There was no sex d i f f e r e n c e in the incidence of d i a r r h e a a t 1.6 g/kg
which caused d i a r r h e a in 100% of s u b j e c t s .
However, a t less than 100% e f f e c t i v e
doses, the sex d i f f e r e n c e was remarkable; a t 0.4 and 0.8 g/kg of s o r b i t o l ,
the incidence of
d i a r r h e a in females was less than 50%, but in males, was found over 50%. sex d i f f e r e n c e was found a t any dose of m a l t i t o l . with sorbitol
than w i t h m a l t i t o l .
and female subjects and m a l t i t o l
On the o t h e r hand, no
The incidence of d i a r r h e a was c l e a r l y higher
At 1.6 g/kg doses, s o r b i t o l
caused d i a r r h e a in 100% of male
d i d so in about 65%.
%
100
I00
MALTITOL
I male ~female
50
50
0.2 Figure I .
0.4
0.8
1.6 g/kg
0.2
0.4
0.8
1.6 g/kg
Percentage o f Subjects w i t h Diarrhea a f t e r Taking the Sweetening Agents
There have been no r e p o r t s d e a l i n g w i t h the d i f f e r e n c e in the incidence of d i a r r h e a between the two sweetening agents.
Studies on the sex d i f f e r e n c e in r e l a t i o n to each sweetening
agent have not been c a r r i e d out. caused d i a r r h e a in most cases ( I ) ,
According to r e p o r t s on r e s p e c t i v e agents, s o r b i t o l while maltitol
d i d so in 62.5% ( 4 ) .
t h a t s o r b i t o l may have a more p o t e n t l a x a t i v e e f f e c t on the i n t e s t i n a l
It
t r a c t than m a l t i t o l .
to bowel h a b i t , c o n s t i p a t i o n was more f r e q u e n t l y found in females than in males. le t h a t the area of the i n t e s t i n a l amount of i n t e s t i n a l
t r a c t w i t h which s o r b i t o l
at 50 g
is thus presumed
is indirect
As
I t is possib-
c o n t a c t depends on the
c o n t e n t s , l e a d i n g to the sex d i f f e r e n c e in the incidence of d i a r r h e a .
49
0
o o O)
0
0
0 ~00
@o
0
0
0
SORBITOL (FEMALE)
SORBITOL (MALE) 0 0 0
0
0 0
(9 0 0 0
0
o o
do
.
5
0
• 0
•0
•
•
o@• "
"~" .oa 0
•
• i
i
50
I00
• • • I
I
taken dose (g)
I
50
0
]OCl tokendose (g)
Gb
o8
OLT,TOL*OLE,
0
0 0 0
"
"I
O•
0
i
0
MALTITOL (FEMALE)
0
0 0
0 o
0
0 0
0 0 0 0
0 0
0 0
de o
o •
o
GNI•
O
o 0
0 •
0
•
0
0
l
•
• 5~
lO~
taken aose
|,
" •
• I
5o
0
lO0
taken dose (g)
Figure 2. Relation Between Dose and Time u n t i l the F i r s t Defecation after Administraion O without diarrhea
O with diarrhea
50
Figure 2 i l l u s t r a t e s first
d e f e c a t i o n of a l l
time u n t i l
the r e l a t i o n between the dose of sweetening agents and time u n t i l subjects.
the
Although there were i n d i v i d u a l v a r i a t i o n s in t h a t t i m e , the
the onset o f d i a r r h e a l symptoms was estimated to be almost less than 6 hours, i r r e s p -
e c t i v e of the d i f f e r e n c e in the dose given to males and females. The f a c t t h a t t h e r e was no d i f ference in the time to the onset o f d i a r r h e a a f t e r a d m i n i s t r a t i o n of each t e s t substance suggested t h a t the mechanism of onset o f d i a f f h e a was the same f o r both sweetening agents and appeared to support t h a t the sex d i f f e r e n c e in the incidence of d i a r r h e a as shown in Figure l depended on the d i f f e r e n c e in the amount of i n t e s t i n a l
contents between males and females.
In the present study, those who presented d i a r r h e a at an i n t e r m e d i a t e dose o f 0.8 g/kg were not given 1.6 g/kg. administered. Figure 3.
However, they were considered to have presented d i a r r h e a i f
The Dose-Effect curve was p l o t t e d on a u n i l a t e r a l
1.6 g/kg was
l o g a r i t h m i c graph as in
From t h i s curve, ED50 of s o r b i t o l was estimated to be 0.4 g/kg f o r males and l.O g/kg
f o r females, r e s p e c t i v e l y , and t h a t o f m a l t i t o l
was estimated to be 0.8 g/kg f o r both males and
females.
% I00
SORBITOL • male ©
MALTITOL
% I00
~
50
ED50
• male 0 female
50
ED50
o
~
0.2
Figure 3. Ellis
0.4
0.8
1.6
I
0.2
g/kg
0.4
0.8
I
1.6 g/kg
Dose-Effect Curve between L a x a t i v e E f f e c t and Taken Dose
e t al ( I ) a d m i n i s t e r e d s o r b i t o l
in a c r y s t a l l i n e
r e p o r t e d t h a t d i a r r h e a occurred in the m a j o r i t y of them. assuming the body w e i g h t of Westerners to be 70 kg.
form a t dose o f 50 g to 12 males and This dose corresponded to 0.71 g / k g ,
Peters e t al (2) r e p o r t e d t h a t 25 g doses
caused marked watery s t o o l s in 5 (5.8%) of 86 s u b j e c t s .
This dose is c a l c u l a t e d as 0.34 g/kg
in a s i m i l a r manner and is presumed to be an approximate value o f the minimum e f f e c t i v e sorbitol.
In the present study, ED50 of s o r b i t o l
g/kg f o r males.
to produce d i a r r h e a was estimated to be 0.4
Our r e s u l t t h a t 0.8 g/kg o f s o r b i t o l
was in good agreement w i t h the r e p o r t o f E l l i s
dose of
caused d i a r r h e a in 100% of male subjects
e t al ( I )
t h a t a t the dose l e v e l o f 0.71 g/kg
( c a l c u l a t e d assuming the body weight o f Westerners to be 70 k g ) , d i a r r h e a occurred in most cases.
This f a c t suggests t h a t there w i l l
be no d i f f e r e n c e in d o s e - e f f e c t on a body w e i g h t
51
basis between the Japanese and Westerners. M a l t i t o l has been reported to cause no diarrhea in some experiments in which 30 g (calculated as 0.5 g/kg assuming the average weight of 6 subjects to be 60 kg) was given to 6 male or female subjects in the e a r l y morning fasting state (5) or 0.5 g/kg was given to 5 males in the e a rly morning fasting state (6).
In the study in which diarrhea occurred, 50 g (0.91 g/kg with
the average body weight of Japanese subjects being taken as 55kg) given in the early morning fasting state caused diarrhea in 62.5% of subjects (4).
This dose was well consistent with the
ED50 estimated in the present study, i . e . 0.8 g/kg. Next, in order to determine the maximum non-effective dose, a lower dose of 0.I g/kg was given to 5 males who had been given 0.2 g/kg of s o r b i t o l and in whom the time i n t e r v a l between administration and the f i r s t defecation was less than 20 hours. presented diarrhea.
In this experiment, no subject
In neither females given 0.2 g/kg of sorbtol nor male and female subjects
given 0.2 g/kg of m a l t i t o l , diarrhea occurred.
From these results, i t was inferred that the
maximum non-effective dose of sorbitol was 0.15 g/kg for males and 0.3 g/kg f o r females, while that of m a l t i t o l was 0.3 g/kg f o r both males and females. There has as yet been no report on the estimation of the maximum non-effective dose of sorb i t o l or m a l t i t o l to produce diarrhea.
Peters et al (2) stated that the minimum e f f e c t i v e dose
of s o r b i t o l was approximately 25g (calculated as 0.34 g/kg, assuming the body weight to be 70kg), which was in good agreement with the upper l i m i t of maximum non-effective doses (0.15 g/kg f o r males and 0.3 g/kg f o r females).
I t has been reported that m a l t i t o l doses not cause dirrhea
when administered in a single dose of 0.5 g/kg in the early morning fasting state (6), in a dose of 30g a f t e r 12 hours fasting (5), in a single dose of 20 to 30g (8), or in a dose of less than about 20g in the f as ti n g state (3).
The ED50 estimated from the present study, 0.3 g/kg, was
s l i g h t l y lower than that reported by Koji et al (5) and l i t o y o et al (6) and was in close agreement with that reported by Inoue et al (3).
The d i s p a r i t y between the r e s u l t in our study and
that of others in Japan (5-6) may be due to a difference in the number of subjects involved, i . e . in other studies (5-6), the number of subjects was as small as 5 or 6.
The d i s p a r i t y betw-
een our r e s u l t and that of Abraham et al (8) may be due to differences in body weight and dosing conditions. Figure 4 represents the findings of diarrheal stools.
With s o r b i t o l , watery stool account-
ed f o r about 80% of the cases in both males and females, while with m a l t i t o l , the percentage of watery stool was smaller in females than in males. females were more frequently constipated.
This seemed to be related to the fact that
Sorbitol caused soft stool at higher percentage than
did m a l t i t o l , since the former caused diarrheal symptoms at r e l a t i v e l y low doses as compared to the l a t t e r .
In general, both sweetening agents caused watery stools in the majority of cases.
Figure 5 represents the abdominal symptoms when diarrhea occurred. apping answers, i f necessary.
Individuals gave o v e r l -
In both sweetening agents, the most frequent complaint reported
was gurgle followed by f l a t u s and lower abdominal pain, i r r e s p e c t i v e of sex.
The incidences
of abdominal symptoms caused by s o r b i t o l and m a l t i t o l were 76% and 69%, r es p e c t iv e ly , f o r gurgle, 48% and 54%, r e s p e c t i v e l y , f o r f l a t u s , and 26% and 31%, r e s pec t iv ely , f o r lower abdominal pain. These abdominal symptoms and diarrhea subsided within 24 hours a f t e r administration of e i t h e r sweetening agent and no complaint was reported t h e r e a f t e r .
52
As described above, sorbitol and maltitol induced diarrhea 2 to 3 hours after oral ingesti. on when the agent reached the intestinal tract, especially the large intestine and induced watery stools in the majority of cases. It is inferred therefore that as reported by Niwa et al (9) sorbitol and maltitol have transitory laxative effects due to the inhibition of water absorption mainly in the large intestine.
SORBITOL male female
MALTITOL m~1~ Tsoft 6%
?>2 t
Figure 4.
I
Findings of Diarrheal Stools
MALTITOL
SORBITOL Imale
% ~Im~le
75% IF]female
75
50
50
25
oll a
I
b
c
d
e
f
25
g
o
a
b
c
d
e
Figure 5. Abdominal Symptoms with Diarrhea a: upper abdominal pain b: lower abdominal pain c: tenesmus d: gurgle e: flatus f: vomiting g: fever
f
53
CONCLUSION The present study was performed in o r d e r to e s t i m a t e the 50% e f f e c t i v e n o n - e f f e c t i v e dose of s o r b i t o l
and m a l t i t o l
to produce t r a n s i t o r y
and twenty-one females in t h e i r t w e n t i e s to f o r t i e s
dose and maximum
diarrhea.
Twenty-one males
received each sweetening agent in oral dose:
of 0.4, 0.8, and 1.6 g/kg w i t h i n I0 minutes, which had been d i s s o l v e d in lO0 to 200ml of water or warm w a t e r , 2hours a f t e r the meal. The 50% e f f e c t i v e
dose o f s o r b i t o l
to induce d i a r r h e a was estimated to be 0.4 g/kg f o r
males and 1.0 g/kg f o r females, the sex d i f f e r e n c e being found, w h i l e thai: o f m a l t i t o l mated to be 0.8 g/kg f o r both males and females.
was e s t i -
The maximum n o n - e f f e c t i v e dose of s o r b i t o l
was e s t i m a t e d to be 0.15 g/kg f o r males and 0.3 g/kg f o r females, w h i l e t h a t of m a l t i t o l 0.3 g/kg f o r both males and females.
There was no d i f f e r e n c e in the time u n t i l
ea a f t e r oral a d m i n i s t r a t i o n between the two sweetening agents.
was
onset o f d i a r r h -
The time i n t e r v a l
between oral
a d m i n i s t r a t i o n and onset of d i a r r h e a was less than 6 hours in the m a j o r i t y of cases, averaging 3 hours, The most f r e q u e n t abdominal symptom w i t h d i a r r h e a was gurgle w i t h both sweetening agents, f o l l o w e d by f l a t u s and lower abdominal pain. ACKNOWLEDGEMENT We are indebted to Iowa Kasei I n d u s t r i e s , Ltd. f o r supply of m a t e r i a l s . REFERENCES I.
F. W. E l l i s
2.
R. Peters and R. H. Lock : Br. Med. J . , No. 5097, 677-678 (1958)
and J. C. Krantz : J. B i o l .
Chem., 141, 147-154 (1941)
3.
T. Inoue and M. Mitsuhashi
4.
M. Kamoi, Y. Shimizu, M. Kawauchi, Y. F u j i i , M. Kibata : Jpn. J. N u t r . ,
5.
: E i y o - t o - S h o k u r y o , 24, 506 (1971) T. K i k u c h i , S. Mizukawa, H. Yoshioka and
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(1981)
(Received
in U S A
27 O c t o b e r
1982)