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Coffee, Tea, and Other Nonnutritive Dietary Components

Many different nonnutritive substances are commonly consumed in the daily diet. These include the beverages coffee and tea, direct and indirect food additives such as noncaloric sweeteners and food packaging materials, environmental contaminants such as polycyclic aromatic hydrocarbons (PAHs) and pesticides, and naturally occurring toxicants such as aflatoxins and hydrazines. The complete range of nonnutritive dietary constituents of possible significance to human health is not known.

Evaluation of the health effects of nonnutritive dietary substances is complicated for many reasons. It is necessary to consider both average and peak exposures, the potency or level of activity of the substances, and the quality of the experimental and epidemiologic data. Most additives and known contaminants are present in minute quantities in the average diet; however, many of them have not been studied for their long-term effects on health. This is partly because of the large number of such substances and partly because some food constituents are complex, poorly defined mixtures of natural origin. Furthermore, very little is known about the chronic effects of low levels of chemicals on human health and even less is known about their potential synergistic and antagonistic interactions in the diet and in the body. In the following sections, examples of substances in each class of nonnutritive components are used in an attempt to provide an overall perspective on their significance to human health. Unlike the preceding chapters, data on occurrence and exposure are presented separately for each category of substances before discussions of health effects because of the large number and diversity of these compounds. These discussions are prefaced by a summary of food safety regulations pertinent to the use of these substances in the United States.

Food Safety Laws

In 1938, the U.S. Congress passed the Food, Drug, and Cosmetic Act, which contained food-related provisions such as tolerances for unavoidable toxic substances and prohibited the marketing of any food containing such substances (U.S. Congress, 1938). In 1948, the Miller Pesticide Amendment was passed by Congress to streamline procedures for setting safety limits for pesticide residues in raw agricultural commodities (U.S. Congress, 1948). The Food Additive Amendment, known as the Delaney Clause, was passed on September 6, 1958 (U.S. Congress, 1958). That amendment specifically states that no additive is to be permitted in any amount if it has been shown to produce cancer in animal studies or in other appropriate tests, and that—even if not shown to be carcinogenic—it may be permitted only in the smallest amount necessary to



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Page 465 17— Coffee, Tea, and Other Nonnutritive Dietary Components Many different nonnutritive substances are commonly consumed in the daily diet. These include the beverages coffee and tea, direct and indirect food additives such as noncaloric sweeteners and food packaging materials, environmental contaminants such as polycyclic aromatic hydrocarbons (PAHs) and pesticides, and naturally occurring toxicants such as aflatoxins and hydrazines. The complete range of nonnutritive dietary constituents of possible significance to human health is not known. Evaluation of the health effects of nonnutritive dietary substances is complicated for many reasons. It is necessary to consider both average and peak exposures, the potency or level of activity of the substances, and the quality of the experimental and epidemiologic data. Most additives and known contaminants are present in minute quantities in the average diet; however, many of them have not been studied for their long-term effects on health. This is partly because of the large number of such substances and partly because some food constituents are complex, poorly defined mixtures of natural origin. Furthermore, very little is known about the chronic effects of low levels of chemicals on human health and even less is known about their potential synergistic and antagonistic interactions in the diet and in the body. In the following sections, examples of substances in each class of nonnutritive components are used in an attempt to provide an overall perspective on their significance to human health. Unlike the preceding chapters, data on occurrence and exposure are presented separately for each category of substances before discussions of health effects because of the large number and diversity of these compounds. These discussions are prefaced by a summary of food safety regulations pertinent to the use of these substances in the United States. Food Safety Laws In 1938, the U.S. Congress passed the Food, Drug, and Cosmetic Act, which contained food-related provisions such as tolerances for unavoidable toxic substances and prohibited the marketing of any food containing such substances (U.S. Congress, 1938). In 1948, the Miller Pesticide Amendment was passed by Congress to streamline procedures for setting safety limits for pesticide residues in raw agricultural commodities (U.S. Congress, 1948). The Food Additive Amendment, known as the Delaney Clause, was passed on September 6, 1958 (U.S. Congress, 1958). That amendment specifically states that no additive is to be permitted in any amount if it has been shown to produce cancer in animal studies or in other appropriate tests, and that—even if not shown to be carcinogenic—it may be permitted only in the smallest amount necessary to

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Page 466 produce the intended effect. The amendment does not apply to all food ingredients, since it excludes substances classified as Generally Recognized as Safe (NRC, 1984). The Color Additive Amendment, enacted in 1960, allowed the Food and Drug Administration (FDA) to regulate the conditions of safe use for color additives in foods, drugs, and cosmetics, and to require manufacturers to perform tests to establish safety (U.S. Congress, 1960). The Food, Drug, and Cosmetic Act and its various amendments are administered by the FDA. These regulations affect approximately 60% of the food produced in the United States. The remaining 40% is under state regulations, which in many cases are tailored after federal legislation (McCutcheon, 1975). Coffee and Tea Patterns of Intake Coffee and tea are among the most commonly consumed beverages in the world. Tea came into use in approximately 350 A.D. in  China, whereas the consumption of coffee as a hot beverage is more recent—approximately 1000 A.D. In the United States, coffee and tea consumption is monitored in several different surveys, including the Nationwide Food Consumption Survey (NFCS) and the Continuing Survey of Food Intakes of Individuals (CSFII) of the U.S. Department of Agriculture (USDA) (Pao et al., 1982; USDA, 1986, 1987a) and surveys conducted by the Market Research Corporation of America (Abrams, 1977), the International Coffee Organization (ICO, 1986), and the FDA (Gilbert, 1981). The ICO surveys indicate that in the United States on average, 1.74 cups of coffee were consumed per person per day in 1986. This is a 5% decrease from 1.83 cups/day in 1985 and a 44% decrease from 3.12 cups/day in 1962. Males consumed a slightly higher amount than females (1.8 compared to 1.68 cups/person per day). The percentage of the population drinking coffee decreased from 74.7% in 1962 to 52.4% in 1986. Consumption was highest (77.8%) among those over 60 years old, 67% among those between 30 and 59 years old, 38.4% among 20- to 29-year-olds, and 40.1% among 10- to 19-year-olds. Regular coffee continued to be most frequently selected by coffee drinkers, accounting for nearly 8 out of 10 cups consumed. Consumption of decaffeinated coffee increased from 0.10 cups/day per person in 1962 to 0.41 cups/day per person in 1986. In 1986, approximately 48% of all coffee was consumed at breakfast, slightly more than one-third between meals (0.6 cups/ person per day), and the remainder (@17%) at other meals. The home continued to be the location where most coffee was consumed (accounting for 71% of total consumption), consumption at work accounted for 18%, and eating places accounted for 8%. That year, coffee was the second most popular beverage in the United States (52% of the population drank it), outranked only by soft drinks (consumed by 58.4% of the population). Coffee was followed by milk (consumed by 48.3% of the population), juices (consumed by 45.3% of the population), and tea (consumed by 31% of the population). Overall U.S. coffee consumption was highest in the North Central and the Northeast regions (56.3%), followed by the West (51.9%) and the South (50.3%) (ICO, 1986). In the 1985 NFCS (USDA, 1986, 1987a), mean daily coffee intake was estimated to be 1 g for 1- to 5-year-old children born to low-income women, 300 g for low-income women 19 to 50 years old, and 327 g for men 19 to 50 years old. The mean daily intake of tea was 29 g for children, 144 g for women, and 194 g for men (USDA, 1986, 1987a). Coffee and tea are the greatest contributors to daily intake of caffeine, the alkaloid 1,3,7-trimethylxanthine, accounting for approximately 20% of the intake by adults. Other less important sources of caffeine in the U.S. diet are soft drinks, which contribute approximately 5% of total caffeine intake, and chocolate, which provides approximately 1.5%. Among teenagers, younger children, and infants, however, tea and soft drinks provide a substantially larger percentage of total caffeine intake. Among the heaviest consumers (90th-100th percentile), caffeine intake has been estimated to be approximately 7 mg/kg body weight, or nearly 500 mg/person per day from all sources (Abrams, 1977). Caffeine intake has also been estimated in several surveys. The ICO estimated that caffeine intake by coffee drinkers averaged 217 mg/day. By comparison, the NFCS estimated that average daily caffeine intake by coffee drinkers ranged from 212 to 283 mg in the over-19 age group and that daily caffeine intake from tea ranged from 69 to 87 mg among tea drinkers over age 19 (Pao et al., 1982). The results of other surveys (Gilbert, 1981; Graham, 1978) support these general estimates of caffeine consumption for the average drinker.

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Page 467 Coffee contains a considerable amount of burned material, including the mutagen (Kasai et al., 1982) and carcinogen (Nagao et al., 1986a) methylglyoxal at approximately 500 to 1,000-µg/cup. It also contains the natural mutagen chlorogenic acid (Stich et al., 1981c), the highly toxic atractylosides (Nagao et al., 1986b), the glutathione transferase inducers kahweal palmitate and cafestol palmitate (Lam et al., 1982), and about 100 mg of caffeine (Ames, 1983). Evidence Associating Coffee and Tea with Chronic Diseases Cancer Epidemiologic Studies Bladder Cancer Several cohort studies have been conducted to assess the risk of bladder cancer from coffee consumption. Because of the relative rarity of this disease, results are generally based on small numbers of observed cases. In a cohort study of nearly 24,000 Seventh-Day Adventists, Snowdon and Phillips (1984) found a positive association between deaths from bladder cancer and coffee consumption by people who never smoked. In two other large cohort studies, one in Norway (Jacobsen et al., 1986) and one in Hawaii (Nomura et al., 1986), investigators failed to find an association. Case-control studies provide more meaningful data. In two early studies in the United States (Cole, 1971; Fraumeni et al., 1971), elevated risks for bladder cancer were found among coffee drinkers. In the study by Cole, these risks were restricted to females; in the study by Fraumeni and colleagues, the risks applied to black females; in neither study was there evidence of a dose-response relationship. A finding similar to that of Cole (1971) was reported by Simon et al. (1975), who conducted a case-control study among women in Boston. In two other case-control studies, one in Canada (Howe et al., 1980) and one in the United States (Mettlin and Graham, 1979), elevated risks from coffee were found among males; there was less evidence for an effect among females, but in neither study was a dose-response relationship observed. In contrast, no overall effects of coffee drinking were found in case-control studies conducted in the United States, Great Britain, and Japan (Morrison et al., 1982b; Ohno et al., 1985); in Copenhagen Jensen et al., 1986); and in Canada (Risch et al., 1988). In three case-control studies, associations were found between coffee consumption and risk of bladder cancer: in Greece (Rebelakos et al., 1985), in Connecticut (Marrett et al., 1983), and in a 10-center study in the United States (Hartge et al., 1983). In Connecticut, there was a statistically significant association in males and some evidence of a dose-response relationship. In the 10-center study, based on nearly 3,000 cases and 6,000 controls, there was a statistically significant overall relative risk of 1.4, but there was no evidence of a dose-response relationship. Thus, the epidemiologic studies relating coffee drinking to risk of bladder cancer are inconsistent. In the positive studies, the observed relative risk is small and there is an absence of a dose-response relationship, leading to the conclusion that this association is unlikely to be causal. Residual confounding by cigarette smoking is the most likely explanation for the findings (Morrison et al., 1982b). In this context, a case-control study among nonsmokers that failed to find an association between coffee drinking and bladder cancer (Kabat et al., 1986) is particularly relevant. Lack of an association between tea consumption and bladder cancer risk has been reported consistently in cohort and case-control studies (Hartge et al., 1983; Heilbrun et al., 1986; Howe et al., 1980; Miller et al., 1983; Morgan and Jain, 1974; Sullivan, 1982). Colon Cancer In the cohort study of nearly 24,000 Seventh-Day Adventists by Snowdon and Phillips (1984), no association was observed during the first 10 years, but a positive association was found between coffee consumption and fatal colon cancer during the last 11 years of follow-up. People consuming two or more cups of coffee a day had a relative risk of 1.7 (95% confidence interval, range 1.1 to 2.5) compared to those consuming less than one cup a day. There was a dose-response relationship in the last 11 years, which persisted when meat consumption was included in a multivariate analysis. A statistically significant but small excess risk was found for colon cancer but not for rectal cancer in the case-control study by Graham et al. (1978). In neither of these studies were detailed dietary data collected. It is therefore possible that the association with coffee reflects confounding with another factor, such as dietary fats, that could not be evaluated. Two case-control studies showed no statistically significant association between tea consumption and colorectal cancer (Phillips and Snowdon, 1985; Tajima and Tominaga, 1985) as did a Canadian case-control study for consumption of

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Page 468 combined beverages (tea, coffee, or colas) (Miller et al., 1983). Results of an international geographical correlation study showed a very slight negative association with rectal cancer but a strong positive association with colon cancer (Stocks, 1970). Heilbrun et al. (1986), however, showed a strong dose-response relationship and a positive association of tea consumption with rectal cancer risk over a 16- to 19-year follow-up period, but the mechanism was not apparent and no higher risks were reported at any other sites. Pancreatic Cancer Although a correlation between coffee drinking and rates of death from pancreatic cancer has been found in various countries (Binstock et al., 1983), two large cohort studies—one in the United States (Whittemore et al., 1983) and one in Norway (Heuch et al., 1983)—have failed to find evidence for an association. In contrast, MacMahon et al. (1981) in a case-control study of pancreatic cancer in Boston found a highly significant dose-response relationship between coffee consumption and increased risk of pancreatic cancer. In a second study conducted by some of the same authors (Hsieh et al., 1986), however, the evidence for this association was substantially weaker; in particular, a dose-response relationship was no longer apparent. In other case-control studies (Gold et al., 1985; Mack et al., 1986; Norell et al., 1986; Wynder et al., 1983), investigators also failed to find any consistent evidence of an association between coffee drinking and risk of pancreatic cancer. Tea consumption has been negatively associated with pancreatic cancer (Heilbrun et al., 1986; Mack et al., 1986; MacMahon et al., 1981). One case-control study using data collected in England and Wales during the 1950s showed a positive association between tea intake and risk of pancreatic cancer in men (Kinlen and McPherson, 1984). In the studies of MacMahon et al. (1981) and Kinlen and McPherson (1984), hospital controls were used. Some or all of these controls had cancers of sites other than the pancreas. Potential selection factors among these controls may account for the differences in the results. Breast Cancer In three case-control studies—in Israel (Lubin et al., 1985), the United States (Rosenberg et al., 1985), and France (Lê, 1985)—investigators examined evidence for a possible relationship between coffee drinking and risk of breast cancer. No evidence of such an association was found in any of those studies. Ovarian Cancer In two case-control studies—one in Italy (La Vecchia et al., 1984) and one in Greece (Trichopoulos et al., 1981)—evidence was found for an association between coffee drinking and increased risk of ovarian cancer. In contrast, in North America, Byers et al. (1983) and Miller et al. (1987) failed to find any association. Thus, the evidence is inconsistent for coffee. For tea, however, Miller et al. (1987) found that its consumption did not influence the risk of ovarian cancer in a case-control study in the United States and Canada. Other Sites A weak negative association between tea intake and prostate cancer was reported in a geographical correlation study by Stocks (1970). Another weak negative association between tea consumption and liver cancer risk in men was reported in a prospective study by Heilbrun et al. (1986). Thus, there is no convincing evidence relating tea consumption to any type of cancer. Animal Studies Several studies in rats showed no correlation between coffee consumption and tumor induction (Bauer et al., 1977; Dews et al., 1984; NCI, 1978a; Palm et al., 1984; Würzner et al., 1977; Zeitlin, 1972). Caffeine is found in coffee, tea, cola and other carbonated soft drinks, and several over-the-counter drugs. A positive correlation between caffeine intake and cancer in Wistar rats was demonstrated by Takayama (1981). Because of confounding by the presence of other diseases in the test animals, the results were deemed to be inconclusive. In a later study by Takayama in the same rat strain, no statistically significant differences in the rate, type, or number of tumors were observed in the caffeine-treated rats as compared to the controls (Oser and Ford, 1981). Challis and Bartlett (1975) reported that readily oxidized phenolic compounds that are constituents of coffee catalyze nitrosamine formation from nitrite and secondary amines at gastric pH. On the other hand, caffeic acid (3,4-dihydroxycinnamic acid) was reported to inhibit formation of Nnitroso compounds in vivo (Kuenzig et al., 1984). Small amounts of tannins are present naturally in coffee and tea. When administered subcutaneously, tannic acid produced liver and bile duct tumors in rats (Korpássy and Mosonyi, 1950). Condensed tannins produced sarcomas at the injection site and liver tumors in rats and mice; extracts of hydrolyzable tannins caused liver tu-

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Page 469 mors in mice (Kirby, 1960). Brewed tea caused skin cancers in mice when applied to the neck (Kaiser, 1967), and the tannin-containing fraction of tea produced histiocytomas at the injection site in mice (Kapadia et al., 1976). In general, high doses were used in these animal studies. Lower doses of tannic acid produced no liver damage or liver cancer in mice and only a slight excess of other cancers in experimental animals as compared to control animals (Bichel and Bach, 1968). The lack of adequate oral feeding studies, the inconsistencies in the studies, and the short duration (each study typically spanned 3 to 10 months) cast doubt on the relationship between tea intake and cancer risk. Short-Term Tests Brewed, instant, and decaffeinated coffees were found to be mutagenic to Salmonella typhimurium strain TA100 (Aeschbacher and Würzner, 1980; Aeschbacher et al., 1980a; Nagao et al., 1979) and to Escherichia coli (Kosugi et al., 1983). Roasted coffee was highly mutagenic in the L-arabinose resistance test in S. typhimurium (Dorado et al., 1987). Coffee also induced mutations in Chinese hamster lung cells in vitro (Nakasato et al., 1984). Direct-acting mutagenic activity of coffee in S. typhimurium strains TA100 and TA102 was confirmed by Friederich et al. (1985). This mutagenic activity was decreased by adding 10% rat liver S9 microsomal fraction, by adding reduced glutathione, and by increasing temperatures to 50ºC; this observation led the authors to postulate that the reduction in mutagenic activity could be due to the mammalian enzyme methylglyoxalase, which exhibits similar inactivation properties in vitro (Friederich et al., 1985). Although caffeine has been reported to be mutagenic to bacteria (Clarke and Wade, 1975; Demerec et al., 1948, 1951; Gezelius and Fries, 1952; Glass and Novick, 1959; Johnson and Bach, 1965; Kubitschek and Bendigkeit, 1958, 1964; Novick, 1956), it could not have been responsible for the mutagenicity observed in these studies of coffee, since decaffeinated coffee was as mutagenic as regular coffee and caffeine itself was not detected as a mutagen under the test conditions (Aeschbacher et al., 1980b; Nagao et al., 1979). Caffeine was shown to induce gene mutations in bacteria and fungi, but its ability to induce point mutations in higher organisms is not well documented (Haynes and Collins, 1984). At higher concentrations, approximately 0.01 M, it produces chromosome aberrations in plant and animal cells (Kihlman and Sturelid, 1975; Weinstein et al., 1972). Caffeine can enhance the genotoxic effects of other agents, including radiation and chemicals, presumably because of its ability to inhibit repair of DNA damage induced by these agents (Frei and Venitt, 1975; Haynes and Collins, 1984; Jenssen and Ramel, 1978). Black tea, green tea, and roasted tea behaved as direct-acting mutagens in S. typhimurium strain TA100 (Nagao et al., 1979). The flavonoids quercetin, kaempferol, and myricetin were responsible for most of the mutagenic activity of an acid hydrolysate of green tea (Uyeta et al., 1981). In summary, caffeine causes mutations in microorganisms. Its ability to induce mutations in higher organisms is not certain. Tea was shown to be mutagenic in the Ames Salmonella assay. Coronary Heart Disease (CHD) Epidemiologic Studies Several recent studies suggest an association between coffee intake and increased levels of serum cholesterol. Some of these studies indicate positive associations in men and women (Green and Jucha, 1986; Haffner et al., 1985; Kark et al., 1985; Thelle et al., 1983); one in women only (Mathias et al., 1985); but in some, no relationship between coffee intake and increased serum cholesterol level was apparent (Dawber et al., 1974; Hofman et al., 1983; Kannel, 1977; Kovar et al., 1983; Shekelle et al., 1983; Yano et al., 1977). Overall, the evidence suggests that coffee intake may be positively associated with serum total cholesterol levels, especially low-density-lipoprotein (LDL) cholesterol. In a study of the association of coffee, tea, and whole eggs with serum  lipids in 658 male workers from six factories in Israel, tea consumption was negatively associated with serum cholesterol, whereas coffee was positively associated and egg consumption appeared to have no association (Green and Jucha, 1986). The epidemiologic evidence for a direct association between coffee drinking and CHD is inconsistent. For example, in a cohort study of 16,911 people followed for 11.5 years in the United States, Murray et al. (1981) failed to find any relationship between reported coffee intake and death from ischemic heart disease. However, in a cohort study of 1,130 college students followed for 19 to 35 years, La Croix et al. (1986) found a relative risk of 2.5 (95% confidence interval, range 1.1 to 5.8) for men drinking five cups of coffee or more a day compared to those drinking none, after

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Page 470 adjusting for other factors, including smoking. In a study conducted during 1957-1958 to assess 19-year mortality in 1,191 white men ages 40 to 56 years employed by the Chicago Western Electric Company, higher mortality from CHD and from noncoronary causes, such as cancer and cardiovascular diseases other than chronic heart disease, was found among those consuming six or more cups per day than among those consuming one cup per day (LeGrady et al., 1987). In two early case-control studies (Boston Collaborative Drug Surveillance Program, 1972; Jick et al., 1973), associations were found between coffee drinking and risk of heart disease, but several later case-control studies (Hennekens et al., 1976; Hrubec, 1973; Klatsky et al., 1973; Rosenberg et al., 1980) did not substantiate these findings. Methodological problems, especially the use of hospital controls, may have contributed to these discrepancies. Several studies have also shown that caffeine from such other sources as tea or colas has no association (Curb et al., 1986). In summary, there is evidence that coffee drinking is associated with increased levels of LDL cholesterol, and in view of the established association between LDL cholesterol and the risk of ischemic heart disease, there is a plausible basis for an association between coffee intake and such risk. The failure to observe this in some epidemiologic studies could be due to the relatively small change in risk produced by the typical differences in coffee drinking in North America as compared to Europe. However, the cause of the association between coffee and serum cholesterol remains to be definitively established for the level and type of coffee drinking practiced in North America; it is possible that confounding by dietary factors such as fats could produce the changes in cholesterol level reported. Tea drinking, on the other hand, appears to have no association or a negative association with total serum cholesterol and coronary artery disease. Reproductive Effects Epidemiologic Studies Contradictory results have been found in pregnant women who had consumed caffeine. Mau and Netter (1974) reported an increased risk of low birth-weight infants for women with high coffee intake after controlling for maternal age, parity, father's occupation, maternal weight, and smoking. No attempt was made in this study to determine the quantity or type of coffee consumed. In another study, an association of coffee with prematurity was attributed to smoking  (Van den Berg, 1977). However, when the data were reanalyzed after controlling for smoking and gestational age, a statistically significant relative risk of 1.24 for low birth weight was reported for heavy coffee drinkers (Hogue, 1981). In a retrospective survey, Mormon women with high caffeine consumption had higher rates of spontaneous abortion, stillbirth, and preterm deliveries than did women who consumed no caffeine (Weathersbee et al., 1977). The study, however, is biased in sampling (sampling method and number of women sampled in the population was unspecified) and there was a possible bias in reporting of abnormal pregnancies. In a case-control study, Berkowitz et al. (1982) found no association between preterm delivery and consumption of coffee or tea. Linn et al. (1982) reported no association between low birth weight, preterm delivery, or congenital malformation and heavy coffee consumption after controlling for smoking and other confounders. In a prospective study, Martin and Bracken (1987) reported that the consumption of caffeine in coffee, tea, colas, and drugs appears to cause growth retardation in full-term newborns. In a recent review, Leviton (1988) reported that moderate consumption of caffeine by pregnant women has no adverse effects on their fetuses. Animal Studies A great decrease in fertility was observed in fowls fed caffeine in a standard ration (Ax et al., 1976). Friedman et al. (1979) reported that caffeine fed to Osborne-Mendel rats for 3 to 16 months produced severe testicular atrophy and aspermatogenesis. Caffeine was shown to produce many underweight offspring when given to ICR (hereafter called CD/I) mice at doses up to 39 mg/kg body weight (bw) per day through four generations (Thayer and Kensler, 1973). When given as pellets to mice at 150 mg/kg bw per day, it reduced food intake and produced fetuses with cleft lip or palate (Elmazar et al., 1982), whereas in drinking water at the same dosage, it reduced both food and water intake and decreased ossification of the supraoccipital, sternebral, and xiphistemum  bones (Sullivan, 1981). When fed throughout gestation to Sprague-Dawley rats, caffeine produced offspring with underdeveloped pelvises, decreased humerus density, statistically significant decreased organ-to-body-weight ratios for the brain, lungs, and liver at 30 mg/kg bw per day (equivalent to a woman consuming approximately 10 strong cups of coffee a day) (Palm et al., 1978), and delayed ossification of sternebrae at 80 mg/kg bw per day (Nolen, 1981). Offspring of rats given coffee to drink during gestation had reduced body, liver, and brain weight at birth and behavioral variations 30

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Page 471 days after birth (Groisser et al., 1982). Caffeine given in feed to rats at 1,000 mg/kg bw per day produced offspring with low birth weights (Aeschbacher et al., 1980a). Caffeine given in drinking water ad libitum to pregnant Osborne-Mendel rats at doses of 160.9 and 204.5 mg/kg bw per day decreased implantation efficiency, increased resorptions, and decreased the number of viable fetuses. Furthermore, fetal body weight and length were decreased and sternebral ossification deficiencies were increased, but no dose-related gross anomalies were observed (Collins et al., 1983). In summary, caffeine at high dose causes reproductive defects in rodents. Some studies suggest that it may also lead to low birth weight in humans. The evidence, however, is neither uniform nor conclusive. Nonnutritive Sweeteners Occurrence and Exposure The first artificial sweetener, saccharin, was introduced in the late nineteenth century, primarily in diets requiring restriction of natural and simple sugars and in times of sugar shortage, such as during the two world wars. The introduction of cyclamates coincided with a marked increase in the exposure of the general population to artificial sweeteners in the early 1960s, primarily in diet soft drinks and low-calorie foods. Aspartame, the dipeptide L-aspartyl-L-phenylalanine methyl ester, is approximately 180 times sweeter than sugar (Mazur, 1976). Its use as a sweetener or flavoring agent in foods was first approved by the FDA in 1981 (FDA, 1981). Later, in 1983 and 1984, it was approved for use in soft drinks and vitamin pills (FDA, 1983, 1984). A number of other sugar substitutes are likely to be introduced in the near future. In 1977, an estimated 2.2 million kg of saccharin and sodium saccharin were produced in the United States, and an additional 1.3 million kg were imported (NRC, 1978). At that time, approximately 2.9 million kg (@83% of the total) were used in foods (USDA, 1987b). A survey conducted in 1986 by the USDA showed that the amounts of saccharin and aspartame consumed per capita were equivalent to 5.5 and 13 pounds of sugar, respectively (USDA, 1987b). Evidence Associating Nonnutritive Sweeteners with Chronic Diseases To date, most evidence associating saccharin and cyclamate with chronic diseases relates to bladder cancer. Data from animal studies on saccharin, cyclamate, and aspartame, together with epidemiologic evidence relating saccharin and cyclamate to bladder cancer risk, are reviewed below. Both sweeteners are the only ones on the market long enough to make epidemiologic assessment possible in view of the long latency period needed for the development of bladder cancer. Since cyclamate and saccharin were used as a 10:1 mixture in most studies, it is difficult to distinguish the effect of one or the other on bladder-induced tumorigenesis in epidemiologic studies. Saccharin: Studies of Cancer Epidemiologic Studies In view of the substantial increase in the use of saccharin from 1950 on, any major effect of saccharin on bladder cancer risk should be evident by an increase in bladder cancer rates; however, there is no evidence for any increase in rates of this cancer over the past 30 years and, if anything, there is a decrease among females (Burbank and Fraumeni, 1970). The possibility that a long latency period could mask any secular effect could explain the lack of any trend in the earlier data (Armstrong and Doll, 1974; Kessler, 1970), but one would expect to see some increase in bladder cancer rates within the past decade if saccharin were a bladder carcinogen. People with diabetes use artificial sweeteners extensively. Therefore, any increased bladder cancer risk associated with the use of these products should be observable in this population. Two large-scale studies have evaluated this possibility. Armstrong and Doll (1974) conducted a case-control study in England and Wales using as cases 18,733 deaths from bladder cancer recorded between 1966 and 1972. Controls consisted of a random sample of deaths from other causes. No increased risk was found for diabetes as recorded on the death certificate. In a cohort study of 21,447 diabetics in the United States, Kessler (1970) also found no evidence of any excess risk of bladder cancer. Neither of these studies was able to relate the use of artificial sweeteners by a particular individual to bladder cancer in that same person. A number of case-control studies have been conducted on saccharin and cancer. Kessler (1976) and Kessler and Clark (1978) found no evidence of any increased risk associated with the use of artificial sweeteners per se, dietetic beverages, or low-calorie foods. In contrast, a case-control study conducted in Canada showed a statistically significant association in males using artificial sweeten-

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Page 472 ers (Howe et al., 1977, 1980). The data also showed a significant dose-response relationship. In contrast, no effect was found in females. Subsequently, a much larger case-control study involving almost 9,000 subjects (3,010 cases and 5,783 controls) (Hoover and Strasser, 1980) showed no overall increased risk associated with use of artificial sweeteners. However, small but statistically significant increases of about 50% were found among subjects who reported using tabletop artificial sweeteners and diet drinks, as well as the heavy use of one of these. Other case-control studies of bladder cancer and artificial sweetener use have been reported (Cartwright et al., 1981; Møller-Jensen et al., 1983; Morrison and Buring, 1980; Morrison et al., 1982a; Najem et al., 1982; Risch et al., 1988; Silverman et al., 1983; Wynder and Stellman, 1980). Most results from these studies were negative. Others indicated an increased risk in some subgroups (e.g., Cartwright et al., 1981; Morrison et al., 1982a; Risch et al., 1988), but these findings were not consistent among themselves or with the findings of Hoover and Strasser (1980). Thus, overall the epidemiologic evidence does not suggest that consumption of saccharin materially increases the risk of bladder cancer. Animal Studies No evidence of saccharin-induced carcinogenesis was provided in single-generation studies in which various doses of saccharin were fed to several strains of mice and rats (Furuya et al., 1975; Homburger, 1978; National Institute of Hygienic  Sciences, 1973; Roe  et al., 1970; Schmähl, 1973) and to hamsters and rhesus monkeys (Althoff et al., 1975; McChesney et al., 1977). Other single-generation feeding studies in rats showed that a high incidence of neoplasia occurred at high doses of saccharin (Arnold et al., 1977, 1980; Chowaniec and Hicks, 1979). In a two-generation study, there was no difference in the incidence of tumors in treated or control Swiss specific-pathogen-free mice in either generation (Kroes et al., 1977). In three two-generation studies with Charles River and Sprague-Dawley rats (Arnold et al., 1977, 1980; DHEW, 1973a,b; Taylor and Friedman, 1974; Tisdel et al., 1974), the incidence of bladder tumors in treated male rats of the F1 generation given the highest dose was significantly higher than that in controls in all three studies and in the F0 males in one study (Arnold et al, 1977, 1980). In another two-generation study in which male rats were fed dietary levels of sodium saccharin ranging from 1 to 7.5%, a clear dose-response for urinary bladder tumors was observed in the second-generation male rats; the 1% dietary level was considered to be a no-effect level (Schoenig et al., 1985). Saccharin was shown to have tumor-promoting and cocarcinogenic potential in the bladder of rats, as shown by either increased incidence of, or decreased latency period for, tumor development in animals treated with N-methyl-N-nitrosourea (MNU) (Chowaniec and Hicks, 1979; Hicks et al., 1978) or with N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide (Cohen, 1985; Cohen et al., 1979; Fukushima et al., 1981). Short-Term Tests In several in vitro systems, saccharin produced effects associated with tumor-promoting properties (Brennessel and Keyes, 1985; Milo et al., 1983; Trosko et al., 1980). Sodium saccharin was not reactive to DNA (Ashby, 1985) and is not a gene mutagen in vitro (Clive et al., 1979). At high levels, it has intermittent activity as a very weak germ-cell mutagen (Rao and Qureshi, 1972), is a somatic-cell mutagen in vivo (Fahrig, 1982; Mahon and Dawson, 1982), causes chromosome aberrations in mammalian cells (Abe and Sasaki, 1977; McCann, 1977; S. Yoshida et al., 1978), and leads to sister chromatid exchanges in human cells (Wolff and Rodin, 1978). Its mode of action in these respects may be related to its ability to promote bladder tumors in rats at elevated doses, which defines it as a significant contributor to the biologic medium (solvent) rather than as a trace xenobiotic toxin (solute) (Ashby, 1985). Cyclamate: Studies of Cancer Epidemiologic Studies Since cyclamate is usually formulated as a 10-to-1 cyclamate-saccharin mixture, it has rarely been possible to separate the effects of the two substances in studies in the United States. Thus, most epidemiologic studies focused either on saccharin alone or on the mixture, until cyclamate was banned in the United States in 1969. In Canada, however, saccharin was banned as a food and soft-drink additive in 1978 but cyclamate was not. Thus, in a recent Canadian case-control study, it was possible to separate saccharin and cyclamate use (Risch et al., 1988). No consistent increase in risk was found for either males or females.

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Page 473 Animal Studies In 1985, a National Research Council (NRC) committee conducted a comprehensive review of 22 long-term bioassays in which cyclamate alone was fed to rats or mice or given in drinking water (NRC, 1985). In mice, there were several equivocal findings of carcinogenicity at sites known to have a high incidence of spontaneous tumors (Muranyi-Kovacs et al., 1975, 1976; Rudali et al., 1969). None of these findings were confirmed in later, more extensive tests (Brantom et al., 1973; Homburger et al., 1973; Roe et al., 1970). Multigeneration studies designed specifically to evaluate the production of tumors of the urinary bladder provided no evidence for carcinogenicity (NRC, 1985). In studies of the metabolite cyclohexylamine, no evidence for carcinogenicity has been obtained in rats or mice (Gaunt et al., 1974; Schmähl, 1973). Studies of cyclamate-saccharin mixtures have also been conducted. One study showed an increased incidence of bladder tumors in rats (Price et al., 1970), but in two more detailed studies, investigators failed to find an increase in bladder tumors (Ikeda et al., 1975; Schmähl and Habs, 1984). Overall, studies do not provide convincing evidence that cyclamate-saccharin mixtures are carcinogenic in rats. Two studies, one in rats and one in mice, suggest that cyclamate may enhance the carcinogenic effect of other substances in the urinary bladder. In one of the studies, cyclamate was incorporated into a cholesterol pellet and implanted into the bladders of mice (Bryan and Ertürk, 1970); in the other, it was fed to rats after a carcinogen, N-methyl-N-nitrosourea, had been instilled into the bladder (Hicks et al., 1975). In both experiments, more bladder cancers formed in animals receiving cyclamate in combination with other agents than in those receiving the other agent alone, suggesting that cyclamate has cocarcinogenic as well as tumor-promoting activities. Short-Term Tests Positive cytogenetic effects by themselves were of uncertain significance with regard to carcinogenicity, but they were consistent with the possibility of a neoplasm-promoting action. Likewise, results of five in vitro studies conducted to explore effects associated with tumor-promoting properties were positive for cyclamate (Boyland and Mohiuddin, 1981; Ishii, 1982; Knowles et al., 1986; Lee, 1981; Malcolm et al., 1983). Cyclamate and its major metabolite cyclohexylamine have been extensively subjected to a variety of short-term tests for DNA damage, gene mutations, and chromosome aberrations and have been evaluated by an NRC committee (NRC, 1985). Tests for gene mutations in bacteria have been uniformly negative for cyclamate and cyclohexylamine. A notable deficiency in the data, however, is the absence of assays for mammalian-cell DNA damage and gene mutation for cyclamate and a gene mutation assay for cyclohexylamine. Positive results have been obtained in mammalian cytogenetic tests and in some tests for recessive lethals and chromosome abnormalities in the fruit fly (Drosophila melanogaster). Many of these cytogenetic tests had limitations (e.g., lack of appropriate controls and use of cytotoxic concentrations of cyclamate), indicating a need for more refined studies. The combined evidence from short-term tests, as evaluated by two different techniques (the decision point approach and the carcinogenicity prediction and battery selection method), indicates that neither cyclamate nor cyclohexylamine is likely to be a DNA-reactive carcinogen. Reproductive Effects of Cyclamate At high doses, cyclamate and its metabolite cyclohexylamine appear to induce testicular atrophy. For example, testicular reduction was seen in rats fed a 10-to-1 cyclamate-saccharin mixture at 2,500 mg per kg of body weight per day (Oser et al., 1975), in rats fed calcium cyclamate at 5 to 10% of total diet weight (Nees and Derse, 1967), and in rats fed sodium cyclamate at 5% of total diet (Ikeda et al., 1975). Experiments with cyclohexylamine showed that testicular weight decreases at doses of approximately 5,000 ppm in rats or 250 mg per kg of body weight per day (Gaunt et al., 1974; Mason and Thompson, 1977; Oser et al., 1976). This effect raises concern because of its implication for humans, since microorganisms in the human gut have been shown to convert cyclamate to cyclohexylamine (NRC, 1985). Aspartame: Studies of Cancer Epidemiologic Studies Since aspartame has been on the market only a short time, no relevant epidemiologic studies have been completed. Animal Studies and Short-Term Tests A number of long-term  feeding studies have been conducted in laboratory animals. Charles

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Page 474 River mice fed aspartame at 1, 2, or 4 g/kg body weight per day in their diet for 2 years did not develop  any  tumors (Searle and  Company, 1974b). Mice whose bladders were implanted for 6 weeks with cholesterol pellets containing aspartame or diketopiperazine (DKP), its breakdown product, had no bladder tumors (Searle and Company, 1973b). In a long-term feeding study, male and female Sprague-Dawley rats were fed aspartame at various levels for 2 years and were observed for the development of brain tumors (Searle and Company, 1973c). An independent board of inquiry appointed by the FDA concluded that aspartame may lead to an increase in brain neoplasms (FDA, 1980a). Investigators at G. D. Searle and Company (the manufacturer of aspartame) disagreed. They used current instead of historic controls in their statistical analysis and contended that the FDA board of inquiry made errors regarding the time of death of certain rats (FDA, 1980a). In a follow-up study by the Searle group, the difference in tumor incidence in rats exposed to aspartame in utero for their lifetime at 2 or 4 g/kg body weight per day and controls was not statistically significant (Searle and Company, 1974a). Ishii et al. (1981) reported no evidence that aspartame or DKP was carcinogenic in a chronic feeding study in Wistar rats. No evidence of neoplasia was found in beagle dogs fed aspartame at 1, 2, or 4 g/kg body weight per day in their diet for more than  106 weeks (Searle and Company, 1973a). Other Health Effects of Aspartame Six hundred twenty-three consumer complaints about side effects of aspartame were submitted to the FDA, to Searle, and to several private scientists. In February 1984, the FDA asked the Centers for Disease Control (CDC) to help analyze these complaints. Because of time constraints, CDC made in-depth review of only 231 cases that were received and coded by June 1984. The data did not provide evidence for the existence of serious, widespread, adverse health consequences associated with aspartame use, but some of the symptoms reported could be due to an as yet unconfirmed sensitivity to aspartame in these people. For a more thorough evaluation, focused clinical studies have been recommended (Bradstock et al., 1986); these are under way. Waggoner (1984) and the Council on Scientific Affairs (1985) reviewed the data and concluded that when consumed in amounts two to three times higher than the maximum daily intake—34 mg/kg per day, which is substantially below the acceptable daily intake (ADI) of 50 mg/kg/of body weight set by the FDA (1981)—aspartame is not associated with any harmful effects in the general population. However, in individuals afflicted with phenylketonuria, a genetic disorder in which phenylalanine metabolism is blocked and progressive mental retardation may occur, intake should be strictly limited. Because phenylalanine is one product of the hydrolysis of aspartame in the gut (Waggoner, 1984), it should not be included in the diet of these individuals; hence, the FDA (1983) requires labeling of all foods or soft drinks containing aspartame. Although questions are being raised as to whether nonnutritive sweeteners can contribute to weight reduction, a study of obese subjects by Porikos et al. (1977) showed that covert substitution of aspartame-sweetened products for their sucrose counterparts resulted in an immediate 25% reduction in spontaneous energy intake. Preservatives, Antioxidants, Food Colors, and Other Intentionally Added Substances Nitrites, Nitrates, and N-Nitroso Compounds Occurrence and Exposure Nitrites and to a lesser extent nitrates are used as preservatives in many foods and can be converted to N-nitroso compounds under a variety of conditions (NRC, 1981; Olsen et al., 1984). They can also occur naturally in foods, and because many N-nitroso compounds are strongly carcinogenic in many species (Magee and Barnes, 1967; Rao et al., 1984), there has been much concern during the past two decades about their role in the etiology of cancer in humans. Nitrites are present in saliva and in the urine of people with bladder infections. N-nitroso compounds can be formed in the stomach and bladder from action of the nitrite on ingested amines, which can be naturally present in food, from residues of agricultural chemicals in food, and from drugs and medicines (Lijinsky, 1986). The concentrations of nitrates and nitrites in foods depend on many factors, including agricultural practices and storage conditions. An NRC committee estimated that the average U.S. diet

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Page 475 provides approximately 75 mg of nitrates and 0.8 mg of nitrites daily (NRC, 1981). Vegetables contribute the largest proportion of nitrates, followed by nitrate-rich drinking water and fruit juices. The largest dietary source of nitrites, however, is cured meats, which provide more than one-third of the total dietary nitrites. Baked goods and cereals provide another third of total nitrites, whereas vegetables contribute approximately one-fifth. Preformed nitrosamines may also be present in the diet, chiefly in foods cured with nitrate or nitrite. Beer was the largest single dietary source of nitrosamines until recently, when the malting process was modified. Currently, the most important dietary sources are cured meats, especially bacon, which may provide an average of 0.17 µg of nitropyrrolidine per person daily (NRC, 1981). This amount may be considerably lower if bacon is treated with antioxidants such as ascorbic acid. In the United States, the daily intake of nitrosamines from all dietary sources is estimated to be 1.1 µg/ person (NRC, 1981). Residual nitrites in cured meats and fish are an important source of nitrosating agents in the stomach, since they provide concentrations of nitrites much higher than those in saliva. Many N-nitroso compounds can be formed in vivo from these sources, and the carcinogenic effects of many of them are unknown. All organs are potential targets (Lijinsky, 1986). Evidence Associating Nitrites, Nitrates, and N-Nitroso Compounds with Chronic Diseases Epidemiologic Studies Findings from epidemiologic studies conducted in Colombia, Chile, Japan, Iran, China, England, and Hawaii show an association between increased incidence of cancers of the stomach and the esophagus and exposure to high levels of nitrate or nitrite in the diet or drinking water (Armijo and Coulson, 1975; Armijo et al., 1981; Correa et al., 1975; Cuello et al., 1976; Haenszel et al., 1972; Higginson, 1966; Meinsma, 1964). However, the NRC Committee on Nitrite and Alternative Curing Agents in Food concluded that those studies do not provide conclusive evidence for a causal relationship between exposure to nitrates and nitrites and the occurrence of cancers in humans at those sites (NRC, 1981). Although bladder cancer has been correlated with nitrates in the water supply and with urinary tract infections (Howe et al., 1980; Wynder et al., 1963), no difference in consumption of nitrite-preserved meats such as ham or pork sausages was observed between cases and controls (Howe et al., 1980). Nitrosamines have been found in the urine of patients with urinary tract infections, suggesting that the formation of these compounds may be responsible for bladder carcinogenesis (Radomski et al., 1978). In China, an increased risk of esophageal cancer was associated with the ingestion of moldy food containing N-nitroso compounds, possibly produced by fungal contaminants (Yang, 1980). More recent studies showed a correlation between lesions of the esophageal epithelium and the amount of nitrosamines present in inhabitants of Linxian Province in China (Lu et al., 1986). Earlier studies in Iran, however, showed no differences in nitrosamine levels in foods consumed in regions of high and low risk for esophageal cancer (Joint Iran-International Agency for Research on Cancer Study Group, 1977). Several studies in different parts of the world have shown an association between stomach cancer and frequent consumption of cured pickles or smoked foods (Choi et al., 1971; Joint Iran-International Agency for Research on Cancer Study Group, 1977; Kriebel and Jowett, 1979; Lijinsky and Shubik, 1964). In southern Louisiana, consumption of smoked foods and homemade or home-cured meats was found to increase the risk of gastric cancer in higher-risk blacks but not in lower-risk whites (Correa et al., 1985). In Canada, consumption  of nitrites, smoked  meats, and smoked fish was found to be a risk factor for gastric cancer (Risch et al., 1985). However, it was estimated that the major contributor to risk was consumption of nitrites; each milligram of nitrites increased the odds of cancer by 2.6 (95% confidence intervals, range 1.6-4.2). Thus, although salt, nitrates, nitrites, N-nitroso compounds, and PAHs have all been considered as potential causative agents, it seems most likely that consumption of nitrites and subsequent endogenous production of nitrosamines make a major contribution to the risk of stomach cancer. Animal Studies The few experiments conducted in animals have provided no conclusive evidence that nitrates are carcinogenic (Flamm, 1985; NRC, 1981). There is also no evidence of direct nitrite carcinogenicity in animals (NRC, 1981). However, nitrites may interact with specific components of diets consumed by humans and animals or with endogenous metab-

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