Sweeteners Issues and Uncertainties (1975) / Chapter Skim
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SACCHARIN
SACCHARIN
Pages 127-176
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From page 127... ...
There is firstly the qualitative assessment. One can say: "Does saccharin cause bladder cancer in man?
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From page 128... ...
The two items I would draw to your attention are the impact of the two world wars on saccharin production in Germany. It would be reasonable to assume that in l922 and l944 the vast majority of saccharin produced was for human consumption.
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From page 129... ...
Another topic discussed yesterday was obesity, and it was said that the place of noncaloric sweeteners had been disappointing in the management of obesity. Nevertheless, it is true that every time someone requires or desires a sweet cup of tea or coffee and uses saccharin or, in some countries still, cyclamate, they are in fact not consuming so many grams of sucrose.
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From page 130... ...
The next subject, and one which provoked the least degree of controversy yesterday, is dental caries. While I would support the conclusion that no one single preventative measure is the answer to dental caries, some control of sugar intake is an important factor.
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From page 131... ...
The benefits that might accrue by the use of saccharin or other agents to meet the need for sweetness in excess of that level have yet to be assessed. The relevant question on economic benefits, the next general heading under types of benefits, might be: Would the availability of noncaloric sweeteners enable the food industry to produce food at lower cost to the consumer?
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From page 132... ...
CRAMPTON: The point I was trying to make arose from the comments yesterday that in spite of the use of the noncaloric sweeteners, they did not seem very successful in promoting the weight reduction or weight control in individuals. It was suggested that perhaps it is a psychological effect.
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From page 133... ...
and even more specifically, Is saccharin a urinary bladder carcinogen? I should indicate that the charge to the committee from the Food and Drug Administration was to determine when the experimental findings are sufficient to conclude that saccharin is or is not carcinogenic when administered orally to test animals, and to prepare and submit a report to the Food and Drug Administration on the safety of saccharin and saccharin salts as they are used in the human diet.
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From page 134... ...
The other process, the Maumee Process, does not start with toluene, but with phthalic anhydride, and the OTS impurity amounts to only l to 3 parts per million in the commercial product. In the Remsen-Fahlberg Process there are other trace impurities, but at the present time the main focus of attention is on the OTS as the major impurity.
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From page 135... ...
The FDA study was carried out at levels of 7.5 and 5 percent in the diet. Only the male animals fed 7.5 percent saccharin in the diet showed a significantly greater incidence of bladder tumors than did the controls.
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From page 136... ...
Secondly, bladder parasites or bladder stones were not ruled out as potential contributing factors in the positive WARF test with 5 percent saccharin. Third, the commercial samples of saccharin used in these two studies contained 200 to about 5,000 parts per million of the OTS impurity, which itself is suspected to produce bladder stones, which in turn produce bladder tumors in rats.
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From page 137... ...
Surveys have shown that about l2 million people consume saccharin in soft drinks and that the top l0 percent of those consumers drink an average of 42 ounces of soft drinks a day. This represents about five ordinary bottles of
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From page 138... ...
= 365 mg/day FDA recommended limit = l000 mg/day = 0.05% of diet Maximum human consumption = 0.02% of diet 5% saccharin in rat diet = 2,500 mg/kg/day 0.02% saccharin in human diet = 6.4 mg/kg/day Rat dose = 390 x human dose 7.5% saccharin in rat diet = 600 x human dose soft drink, in which there are 365 milligrams of saccharin. It is interesting that this is very close to the three-tenths of a gram that President Roosevelt's panel concluded was safe in l9l2.
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From page 139... ...
The final conclusion of the saccharin report was that the results of the toxicity studies thus far reported have not established conclusively whether saccharin is or is not carcinogenic when administered orally to test animals. Because that question could not be answered, the following recommendations for further research were made: Carcinogenesis studies of pure impurities, especially OTS Carcinogenesis study of pure saccharin Carcinogenesis study of mixtures of known amounts of saccharin and OTS Study of interaction of stones or parasites in bladder and saccharin in diet Study of urine composition as affected by high saccharin and of OTS in diet (Na, pH, etc.)
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From page 140... ...
But in terms of the human experience -- and you mention that some people are drinking as much as 42 ounces of soft drinks a day, and soft drinks contain a lot of other chemicals -- there is bound to be interaction between these chemicals and the saccharin and the impurities in the saccharin. Is there any way in which soft drinks or other foods in which the saccharin is contained could be studied, instead of just studying saccharin by itself?
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From page 141... ...
HALL: Well, why not? COON: I would anticipate nutritional difficulties in species such as the rat and mouse if they were fed simulated human diets for a long period of time.
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From page 142... ...
COON: I cannot comment on the industrial pressure factor. But I would suggest that when something has been widely used for 80 years without evidence of injury to the consumer, then it should be demonstrated to be unsafe before it is deleted from the food supply.
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From page 143... ...
Such foods are carbohydrate or calorie reduced to meet the requirements of our regulations. In addition to these restrictions to the use of saccharin, we have label requirements that read as follows: "A food containing saccharin or its salts shall carry on the label a statement to the effect that it contains a nonnutritive artificial sweetener." We have another regulation that reads: "No person shall sell a food containing a nonnutritive sweetening agent unless (a)
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From page 144... ...
Other impurities were present in considerably lesser quantities, some less than one part per million. The water-soluble impurities from saccharin samples used in four different animal studies -- at the Health Protection Branch, FDA, the Eppley Institute, and WARF -- are graphically presented on Figure l.
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From page 145... ...
It is interesting to note that in the investigations conducted by LittonBionetics, the German Cancer Institute, and the Netherlands National Institute for Public Health, the saccharin samples contained relatively high amounts of OTS: 6,l00, 3,075, and 5,050 parts per million, respectively. The Netherlands group used saccharin in the free acid form, while sodium saccharin was used in studies in the United States and Germany.
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From page 146... ...
I would like now briefly to consider the question of placental transfer of OTS and saccharin, their uptake from the neonate from dam's milk, and the residence time in the neonatal bladder. The importance of placental transmission of saccharin, the slow rate of its fetal clearance, and the possible accumulation of saccharin in some tissues is briefly mentioned in the NAS report, pages 22, 24, 25, 50, and 5l.
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From page 147... ...
* T, tablet; L, liquid; C, crystals; B, blends; E, effervescent; Na, sodium salts; Ca, calcium salts; NG, form of salts not given.
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From page 148... ...
Urinary stones measuring l5 to 30 microns in diameter were found on a millipore filter after filtering the urine. If bladder stones can stimulate hyperplastic change in the rat urinary bladder, and if this hyperplastic change can ultimately lead to cancer, then the presence or absence of stones in the rat bladder carcinogenesis studies should be determined.
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From page 149... ...
l974 As above Examination of fresh voided samples or urine of OTS and saccharin treated animals for the presence of stones and parasites using the millipore filter technique Measurement of urinary pH in OTS and saccharin treated rats which is correlated to the incidence of bladder calculi saccharin-treated animals, and this will be correlated with the incidence of bladder calculi. Hopefully, our studies will therefore answer some of the questions posed in the NAS recommendation.
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From page 150... ...
I had been told many times that it was extremely unlikely we would ever obtain any meaningful epidemiological intelligence on the chronic effects of food additives. Doll, his coworkers, and others have demonstrated that this is not so, because in this instance we are, I suppose, in a way lucky enough to have a special population of diabetics.
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From page 151... ...
It had an impurity in it, ethylene glycol, which produced bladder calculi and subsequently bladder tumors. The test was held to be inappropriate to perform for the material itself at this high level.
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From page 152... ...
A variety of substances were produced, including sarcomas. It was deemed by a wide variety of people that experiments by subcutaneous injection are not appropriate for food additives, and I think that was an absolutely correct decision.
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From page 153... ...
Now, if we look at the chemistry of saccharin, it does not appear to be carcinogenic. If we look at the high-dose experiments, saccharin may well produce bladder tumors, as has been shown in rats but not necessarily in other animals.
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From page 154... ...
Future work, I think, could well, in a very limited way as we heard from our colleague from Canada, concern with the impurities as it relates to the material in saccharin, and I think additional studies on sweeteners, at least in my institute, would not be worthwhile to undertake. In the case of epidemiology, I learned that perhaps we should get more data on soft drinks.
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From page 155... ...
It could cost $20 million to reduce it down to the one molecule level! The Academy report states that to resolve the question of whether saccharin is or is not carcinogenic, "The following studies must be carried out." It does not state, as Dr.
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From page 156... ...
When asked what we mean by lowest possible level, we could go further and say, "Well, if we can produce saccharin without any OTS in it, that is fine." It would be on the basis, I think, of good manufacturing practice, that practice by which the lowest possible level of OTS can be achieved and still produce a commercially feasible product. I notice that Canada has limited OTS to l00 parts per million in saccharin, and so has the United States through the Food Chemicals
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From page 157... ...
So I would pose the question, why not use the Maumee Process as good manufacturing practice and produce saccharin by that method? SHUBIK: I think Mr.
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From page 158... ...
This would mean then that you would probably feed the rat more than the total rat weighs." In the same way, if you are going to give 5-percent saccharin to an animal, then 350 times this makes seven times, or whatever it is, the weight of the rat itself I am sure.
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From page 159... ...
I am trying to suggest that what Dr. Shubik was stating may well be one of the focuses of Academy concern: as it begins to get more and more into the scientific component of a public equation, the Academy should be certain that the scientific component be stated in such a fashion that when it gets into the public forum, it will be adequately understood -- as something recommended for the purpose, for example, of acquiring more information
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From page 160... ...
Frequently it is not possible to do this solely on the basis of scientific information, and I think the same thing applies with this problem of food additives, carcinogenesis, and toxic reactions. Perhaps it would be a good idea if scientists themselves recognized more frequently that an element of judgment enters into a decision even when the scientific evidence is very substantial.
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From page 161... ...
Reference was made in the report of the National Academy of Sciences to additional work that needs to be done. Research goes on and on, and additional work does indeed need to be done to establish the validity of in utero or transplacental dosage, on the question of renal calcification, bladder stones, and so on, and on factors causing secondary rather than primary carcinogenesis.
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From page 162... ...
I came here because I was first attracted to this area as a member of the National Advisory Drug Committee, and I have been playing around with cost-benefit analysis in drugs and food additives.
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From page 163... ...
However, as an internist who has been concerned with the day-to-day management of patients, and in an effort to help them manage their diseases, I will readily confess that the presence of saccharin or another artificial sweetening agent has made the patient's life a good deal more tolerable. It is of secondary importance that the use of saccharin has made my job a good deal easier in helping them to manage their diseases.
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From page 164... ...
Just as the Subcommittee on Nonnutritive Sweeteners of the Food and Nutrition Board's Committee on Food Protection could not have made a judgment based solely on the ability of the substance to produce tumors in rat urinary bladders, I do not think that our committee would have been able to judge whether saccharin and its salts products are useful as drugs or drug products on the basis of available studies. Members of this audience may already know that prescription drugs are not evaluated on the basis of the Delaney clause, and that they clearly are evaluated on the basis of entirely different laws that we have to work within.
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From page 165... ...
It concludes that the chemical itself and even common by-products that are made from saccharin are safe enough to be continued as food additives. However, after reviewing what data is available to our committee, and without attempting to detail the specific requirements for the safety of a chemical under an NDA, we point out that much additional data on animal and human pharmacology and toxicology is required to meet the present-day standards required by the FDA for the passage of an NDA.
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From page 166... ...
l66 drug would be consumed regardless of the dosage form of the over-thecounter agents. These opinions clearly have been my own.
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From page 167... ...
Now, before I say something about saccharin, let me say something about dental caries, because we have not had much opportunity to discuss this oral disease. Repeatedly we have agreed that it is a health problem related to sugar intake, but we have gone over it very quickly.
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From page 168... ...
So to summarize my views, sugars have been found to be the ingredient that is responsible for the caries-promoting properties of food snacks, and nonnutritive sweeteners have not been found to be cariespromoting. Therefore, if you were to substitute completely all the
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From page 169... ...
Therefore, the provision of these synthetic sweeteners as over-the-counter products or as food additives is unlikely to have a major influence in terms of dental caries, although I can see that they might be useful in specific circumstances.
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From page 170... ...
So from this point of view, saccharin or other nonnutritive sweeteners have little effectiveness. However, this is a shortsighted view and does not take into account the real importance and essentiality of nonnutritive sweeteners for many people.
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From page 171... ...
But it is also of great importance to the obese individual who wants to lose weight. But how about the use of nonnutritive sweeteners by the general public?
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From page 172... ...
Dr. Stare's comment yesterday concerning 25 percent of sugars did include refined sugars as well as sugars found in normal food.
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From page 173... ...
Miyaji and others (saccharin in Canada is imported mainly from Japan) , I understand that the Japanese industry is making saccharin available on the market with very low OTS levels.
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From page 174... ...
It happened that we had analyzed three saccharin samples produced by the same company during a l5-year period. When we used the same analytical procedure to check for impurities in saccharin produced about l5 years ago, it was unbelievable the number and amount of impurities we found.
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