SPECIAL REPORT

SULFITES AS FOOD ADDITIVES A Scientific Status Summary by the Institute of Food Technologists’ Expert Panel on Food Safety & Nutrition and the Committee on Public Information

Sulfites in various forms have been added to food materials as preservative agents and for other purposes for centuries. The earliest known use was apparently the treating of wines with sulfur dioxide in Roman times. Although no human ailment or untoward effect resulting from such use has been recognized, concern over possible hazard also goes back a considerable length of time, to an article published by Kionka in 1896 on the possible toxicity of sulfites in food. Various forms of sulfites have been used to prevent browning during processing of such light-colored fruits and vegetables as dried apples and instant potatoes. They are also used in wine-making as selective antibacterial agents which do not inhibit the desired development of yeast. Sulfites serve a special function in the wet-milling of corn, where they have the effect of softening the hard kernel to permit removal of cornstarch. They also have a general preservative effect, as for example, in conserving the carotene and vitamin C content of foods. How Much Is Used in Food? Sulfite levels in processed foods, regardless of their specific chemical source, are conventionally expressed as SO2-equivalent, and range from zero to about 3,000 ppm on a dry-weight basis. Dehydrated, light-colored fruits such as apples, apricots, bleached raisins, pears and peaches contain the greatest amounts in this range. Dehydrated vegetables and prepared soup mixes range from a few hundred to about 2,000 ppm; instant potatoes, for example, average about 400 ppm. A worldwide average for wines would be about 100-400 ppm, with beers about 2-8 58

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ppm. Many wines produced in the United States have less than 100 ppm, although the maximum legally permitted by the Food and Drug Administration is 350 ppm. Sulfite is naturally produced from sulfate during the fermentation process itself, and may account for 16-125 ppm of SO2 even when no sulfites are deliberately added (Wurdig and Schlotter, 1967). Some loss of sulfite probably occurs during food storage, either through oxidation by air to sulfate or through volatilization or evaporation. It is likely that even larger losses occur during cooking, but few data are available as to the extent of such losses. How Much Is Consumed in the Diet? It is difficult to estimate accurately the intake of sulfite in the human diet because of the lack of reliable information on diets and the wide variation in individual food consumption patterns, including those for wine and beer. However, the most commonly used figure for per-capita daily intake from solid foods and non-alcoholic beverages in the U S . is approximately 2 mg of SO2. The U . S . wine and beer consumption figures for 1971 correspond to an additional daily sulfite intake of approximately 5 mg of SO2 per capita, assuming that these beverages are consumed by 75% of the population. The wide variations in preferences, however, make this “average” figure almost meaningless. For example, an individual drinking several 12-02 cans of beer daily would be consuming 5 to 15 mg of SO2 per day, whereas a pint of wine contributes 100 mg or more. Thus it is probable that the bulk of the U.S. population consumes no more than

10-15 mg of SO2 per day per capita, although some individuals may consume as much as 120 mg or more per day. Essentially the same levels have been estimated for other developed countries, for example Belgium (Bigwood, 1968; 1970). Extensive data on dietary intake of sulfites in the U S . are contained in a survey prepared by the National Academy of Sciences under contract with the FDA and submitted to that agency in October 1972. These data indicate that consumption of SO2 per capita may reach approximately 600 mg per day. However, the NAS report indicates that the intake data are overstated in most cases, often by considerable margins, because of the basic assumptions involved in their collection. Thus, the NAS is currently re-evaluating these data. The Acceptable Daily Intake (ADI) of sulfites for adults, as established by the United Nations’ FAO/WHO, is 0.70 mg of S02equivalent per kg of body weight, equivalent to 50 mg of SO2 per day for a 70-kg (155-lb) person. It should be noted that in addition to dietary sulfites, the human body is exposed to airborne sulfur dioxides from a variety of sources, both natural and manmade. The levels encountered and their possible toxicity are, however, beyond the scope of this summary. What Happens to the Sulfite? The usual diets in the U.S.provide more of the sulfur-containing essential amino acids cystine and methionine than the body can utilize and retain. The normal metabolic processes of the body convert the excess sulfur in these amino acids first to sulfites and then - with the aid of an enzyme, sulfite oxidase - to sulfates, which are excreted in the urine. Adult human beings “in balance” with respect to the intake and excretion of sulfur normally excrete on the average about 25 millimoles (2,400 mg) of sulfate in the urine per day. Animal studies have indicated that sulfite oxidase is present to some extent in most body tissues. However, the liver, heart, and kidney appear to possess the greatest

capacity to oxidize sulfite (MacLeod et al., 1961), and this capacity generally appears to be quite large in mammals. For example, dog liver has been shown to be capable of metabolizing at least 50 mg of S02/ kg/hr (Wilkins et al., 1968). Rats given oral doses of 200 mg of SOdkg/day for 30 days were apparently able to metabolize all the SO2 without any untoward effects - they did not excrete any unchanged sulfite, their livers weren’t called on to synthesize any additional sulfite oxidase, and no deleterious cellular changes took place. The essential nature of sulfite oxidase in the human was dramatically demonstrated by an infant who was born with a congenital deficiency of this enzyme (Mudd et al., 1967; lrreverre et al., 1967). The child was highly abnormal and lived only about 21/2 years. Its metabolism was such that it excreted inorganic sulfite and related compounds, but almost no sulfate. Sulfites thus appear to be normally formed in the body but must be converted through the agency of sulfite oxidase into sulfate for excretion. Presumably, sulfites added to food materials are metabolized in the same way and, in the amounts normally consumed, contribute less than one millimole (96 mg) to the normal daily sulfate production and excretion. How Safe Are Dietary Sulfites? As countries become more affluent and more urbanized the consumption of sulfited foods tend to rise, and it is possible that their intake may become relatively high in a few cases. Therefore, it is important to evaluate the safety of dietary sulfites to confirm their reported low toxicity. There is, for example, a possibility that destruction of thiamine (vitamin 61)by sulfites might lead to a deficiency of this vitamin. Also, the recent discovery of the action of sulfites on nucleic acid components has raised questions as to possible genetic effects. Mutations have in fact been produced in Escherichia coli and in phage lambda by exposing them to strong (1 to 3-molar) solutions of sodium bisulfite (Mukai et at., 1970). Some studies on the toxicity of sulfites have been performed in such a way that NUTRITION REVIEWSIVOL. 34, NO. PIFEBRUARY 1976 59

their relevance to actual food safety is questionable. Test chemicals administered by direct intravenous or intraperitoneal injection or by gastric gavage expose the animals to a sudden large concentration in a limited area of the body; such methods of administration contrast sharply with the exposure resulting from a similar dose fed in the diet or dissolved in the drinking water and consumed over a considerable time period. Furthermore, investigators working prior to 1935 were unaware of the fact that sulfites can destroy thiamine, and their test results may have been complicated t v deficiency of this vitamin. Also, the fact that the level of sulfite in a test sample can change rapidly with time as a result of oxidation, etc., was often overlooked. As a result, the animals in some tests may have received a different dose from that intended. Tests Show Low Toxicity Despite such difficulties, the relatively low toxicity of sulfites taken in the diet or drinking water has been reliably established for a variety of animal species in tests which have continued over the animals’ lifespan and in some cases through several generations. In recent carefully controlled studies, Ti1 (1970) and Ti1 et al. (1972) showed that the “no-effect level” for the rat is at least 72 mg of SOdkg/day, and that no-effect level for pigs and Japanese quail is approximately 1.5 to 2 times higher, respectively, than for the rat. Applying the usual 100-fold safety factor to this figure yields the 0.70 mg/kg/day figure mentioned earlier as the FAONHO Acceptable Daily Intake. In these studies, the diets were fed to rats for three generations, to quail for four generations, and to pigs for one year. The diets were mixed fresh every two weeks and stored at -18°C (0°F) until used, and were fortified with 50 mg of thiamine per kg of body weight to prevent any deficiency of this vitamin. The animals were examined as to fertility, number of offspring, growth and mortality rates in successive generations, excretion of thiamine by the liver and the kidneys, occurrence of blood in the feces, kidney function, various enzyme activities, 80 NUTRITION REVIEWSIVOL. 34, NO. PIFEBRUARY 1976

organ weights, gross pathology and histopathology, hematological characteristics, and the incidence and types of tumors that developed. Doses much higher than the “no-effect level” also were fed and their toxic effects catalogued. The first evidence of toxicity was the appearance of occult blood in the feces due to altered gastric morphology. However, rats fed as much as 2% sodium metabisulfite (equivalent to 13,400 ppm of SOZ, or 600 mg/kg) lived and reproduced through three generations with no evidence of increased mortality over the controls. These studies indicate that dietary sulfites are not highly toxic, provided that the diets are not stored for long periods after mixing and that adequate thiamine is provided. Lockett and Natoff (1960) administered sodium metabisulfite equivalent to 750 ppm of SOZ in the drinking water of rats through three generations over a period of nearly three years. No effect was observed on the growth, food or water intake, fecal output, fertility, weight of newborn, lactation, or tumor development in any of the animals. Lanteaume et al. (1965) administered aqueous solutions of potassium metabisulfite equivalent to 450 ppm of SO2 and wine containing 450 ppm of SO2 to separate groups of rats during four generations. The only effect observed was a reduction in relative weight gain of 7% in the second-generation males receiving the 450 ppm of SOZ in wine compared to controls receiving no added SO>. No differences were found with respect to litter size, organ weights, histopathology of major organs, or protein utilization efficiency. Thiamine Intake Important Hotzel et at. (1966) found that rats maintained on diets providing adequate thiamine suffered no ill effects attributable to consumption of sulfites in doses of up to 300 mg/kg/day. Thiamine-deficient animals in the same tests, however, showed toxic effects at doses as low as 50 mg/kg/day. Fitzhugh et at. (1946) reported that diets containing sulfites equivalent to 615 ppm of SO2 or less had no significant effect on the

growth of rats. Higher levels, however, were toxic, and the toxicity was only partly counteracted by administration of additional thiamine to the animals. Bhagat and Lockett (1964) observed that diets containing 0.6% sodium metabisulfite (4,044 ppm of SOZ) produced two types of toxic effects in growing rats: Growth was reduced in those rats fed on diets stored for 7 weeks; this was shown to be attributable to lack of thiamine. However, diets stored for 3-4 months produced toxic effects that were not reversed or prevented by thiamine; this may have been due to changes in the fats contained in the diet during storage. Ti1 et al. (1972) found that when rat diets consisting of corn meal, casein, vitamins, soybean oil, cellulose, and minerals were stored in the presence of 1% sodium metabisulfite for 3 months at room temperature, the mixtures became toxic; this is probably because of interaction between sulfite and unsaturated fats. The question of whether thiamine may be destroyed in diets consisting partly of previously sulfited components and partly of unsulfited materials - which would be the case in normal human diets - was investigated by Thomas and Berryman (1949). They concluded that the sulfite content of individual foods would probably not cause significant destruction of the thiamine content in the rest of the diet. A much more ambitious study of the possible relationship between thiamine deficiency and use of sulfited foods was carried out by Hotzel et al. (1969; 1970) on a group of human volunteers. The subjects consumed a thiamine-deficient diet (120 p g of thiamine/ 1,000 kcal) for 50 days, and during 25 days of this period received 400 mg of SO2 per person per day in the form of sodium bisulfite (50 mg of SOZ) plus sodium glucose sulfonate (350 mg of S O Z ) . Exhaustive clinical and biochemical examination of the subjects revealed no demonstrable effects attributable to the sulfite intake. (Sodium glucose sulfonate represents a “bound form” of SOZ, and the ratio between the amount of this form and that of free sulfite used in

this study is comparable to the typical ratio of bound SO2 to free SO2 in wine.) It has been suggested that some of the bound forms of SO2 resulting from chemical reaction of sulfites with proteins, carbohydrates,or fats in foods may actually be more toxic than the free sulfites themselves (Bhagat and Lockett, 1964). However, in a more recent study by Gibson and Strong (1973), bound sulfite fed to rats was found to be excreted in the same way as free sulfite is and was judged not to pose any different hazard to health.

Sulfites Generally Recognized As Safe Searches for mutagenic or carcinogenic effects from dietary sulfites have been unsuccessful in nearly all cases. Although high concentrations of sodium bisulfite do produce mutations in bacteria and viruses (Mukai et al., 1970; Hayatsu and Miura, 1970), fruit flies that ingested a 0.08M solution (5,120 ppm of SO2) showed a mutation rate which did not differ significantly from the control rate (Valencia et al., 1972). The long-term animal feeding studies of Ti1 et al. (1972) failed to show “any tumorigenic effect attributable to sulfite or any alterations in the descendants of the three generations treated with it.” Three other long-term studies led to the same conclusion (Lockett and Natoff, 1960; Lanteaume et al., 1965; Fitzhugh et al., 1946). A thorough review of the safety of all substances on the Generally Recognized As Safe (GRAS) list is being undertaken by the Federation of American Societies for Experimental Biology under contract to the FDA. FASEB will make one of four recommendations to the FDA: (1) That a substance be affirmed as GRAS at current levels and levels expected in the future, not to exceed good manufacturing practices; (2) That it be affirmed as GRAS at specified levels only; (3) That it be regulated as a food additive or interim food additive; or (4) That its use be discontinued.

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As part of this overall review, a Scientific Literature Review on sulfiting agents, teratological screening test reports on sodium bisulfite and sodium metabisulfite, and mutagenic screening test reports on sodium metabisulfite have been prepared; they are available from the National Technical Information Service, 5285 Port Royal Rd., Springfield, VA 22151. FASEB has not yet completed its review of the safety of sulfiting agents. In the meantime, these agents - sodium sulfite, sodium bisulfite, sodium metabisulfite, potassium bisulfite, potassium metabisulfite, and alkali sulfites - continue to be considered generally recognized as safe by the FDA. 0

1. Bhagat, B. and Lockett, M.F. 1964. Food Cosmet. Toxicol. 2:l. 2. Bigwood, E.J. 1968. Arch. Belges Mgdecine Sociale, Hygigne, Mgdecine du Travail et Mgdecine Legal. 26:473. 3. Bigwood, E.J. 1968. Arch. Belges Mgdecine Sociale, Hygigne, Me'decine du Travail et Mgdecine Legal. 28~82. 4. FAO/WHO. 1962. Joint FAO/WHO Expert Committee on Food Additives. WHO Tech. Rept. Ser. No. 228, United Nations, Rome. 5 . FAO/WHO. 1965. Joint FAO/WHO Expert Committee on Food Additives. WHO Tech. Rept. Ser. No. 309, United Nations, Rome. 6. FAO/WHO. 1966. Joint FAO/WHO Expert Committee on Food Additives. WHO Tech. Rept. Ser. No. 339, United Nations, Rome. 7. FAO/WHO. 1973. Joint FAO/WHO Expert Committee on Food Additives. WHO Tech. Rept. Ser. No. 17, United Nations, Rome. 8. Fitzhugh, O.G., Knudsen, L.F. and Nelson, A.A. 1946. J. Pharmacol. 86:37. 9. Gibson, W.B. and Strong, F.M. 1973. Food Cosmet. Toxicol. 11:185. 10. Hayatsu, H. and Miura, A. 1970. Biochem. Biophys. Res. Commun. 39:156.

11. Hayatsu, H., Wataya, Y., Kai, K. and lida, S. 1970. Biochem. 9~2858. 12. Hotzel, D., et al. 1966. Zeit. fur Lebensmiftel Untersuch u. Forsch. 130:25. 13. Hotzel D., et al. 1969. Internat. Z. Vit. Forschung 39:372,384. 14. Hotzel D., et al. 1970. Internat. Z. Vit. Forschung 40:46,52. 15. Irreverre, F., Mudd, S.H., Heizer, W.D. and Laster, L. 1967. Biochem. Med. 1:187. 16. Kionka, H. 1896. Z. Hyg. Infectionskrankh. 22:351. 17. Lanteaume, M.T., Ramel, P., Girard, P., Jaulmes, P., Gasq, M. and Ranau, J. 1965. Annls. Falsif. Expert Chim. 58:16. 18. Locket?, M.F. and Natoff, I.L. 1960. J. Pharm. Pharmacol. 12:488. 19. MacLeod, R.M., Farkas, W., Fridovich, I. and Handler, P. 1961. J. Biol. Chem. 236:1841. 20. Means, G.E. and Feeney, R.E. 1971. "Chemical Modification of Proteins," p. 152. HoldenDay, Inc., San Francisco. 21. Mudd, S.H., Irreverre, F. and Laster, L. 1967. Science 156:1599. 22. Mukai, F., Hawryluk, I. and Shapiro, R. 1970. Biochem. Biophys. Res. Comm. 39:983. 23. Rall, D.P. 1973, Report of Oct. 9, Nat'l. Inst. of Environmental Health Sciences, Research Triangle Park, N.C. 24. Schroeter, L.C. 1966. "Sulfur Dioxide, Applications in Foods, Beverages, and Pharmaceuticals," p. 12. Pergamon Press, New Yorl;. 25. Shtenberg, A.J. and Ignat'ev, A.D. 1970. Food Cosmet. Toxicol. 8:369. 26. Thomas, M.H. and Berryrnan, G.A. 1949. J. Am. Dieter. Assn. 25:941. 27. Til, H.P. 1970. Ph.D. thesis, Univ. of Utrecht. 28. Til, H.P., Feron, V.J. and De Groot, A.P. 1972. Food Cosmet. Toxicol. 10:291,463. 29. Valencia, R., Abrahamson, S. and Wagoner, P. 1972. Annual report, Food Res. Inst., Univ. of Wisconsin, Madison, p. 108. 30. Wilkins, J.W. Jr., Green, J.A. Jr. and Weller, J.M. 1968. Clin. Pharm. Ther. 9:328. 31. Wurdig. G. and Schlotter, H.A. 1967. Zeit. fur Lebensmimel Untersuch u. Forsch. 134:7.

Single copies of the Scientific Status Summaries and Reports may be obtained from the INSTITUTE OF FOOD TECHNOLOGISTS, 221 North LaSalle Street, Chicago, Illinois 60601, for 50 cents.

62 NUTRITION REVIEWSNOL. 34, NO. PIFEBRUARY 7976

Sulfites as food additives.

SPECIAL REPORT SULFITES AS FOOD ADDITIVES A Scientific Status Summary by the Institute of Food Technologists’ Expert Panel on Food Safety & Nutrition...
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