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 thateven if not shown to be carcinogenicit may be permitted only in the smallest amount necessary to
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 recentapproximately 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.
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
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).
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
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.
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 studiesone 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.
In three case-control studiesin 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.
In two case-control studiesone 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.
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.
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-
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.
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)
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
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.
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.
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
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.
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
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-
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.
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).
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
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.
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.
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
Since aspartame has been on the market only a short time, no relevant epidemiologic studies have been completed.
A number of long-term feeding studies have been conducted in laboratory animals. Charles
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).
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 intake34 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
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
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.
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-
olites to produce N-nitroso compounds that induce cancer (NRC, 1981).
N-nitroso compounds comprise a large group of carcinogens and mutagens that have been examined in a number of test systems. There are large differences between species in response to N-nitroso compounds. For example, nitrosoalkylamides induce tumors at many sites in rats, but only in the spleen and forestomach of hamsters (Lijinsky, 1985).
Nitrosamines require metabolic activation to be mutagenic or carcinogenic (Lijinsky, 1985). The carcinogenic action of several N-nitroso compounds can be inhibited in systems where the formation of N-nitroso compounds has been prevented by such agents as ascorbic acid, and its isomers, sorbic acids, some phenols, and a-tocopherol (Mirvish, 1981). Formation of N-nitroso compounds can also be enhanced by a variety of ions that are normally present in foods, especially thiocyanate and iodide, which may catalyze the nitrosation reaction in the stomach (Mirvish et al., 1975).
Nitrates do not appear to be directly mutagenic (Konetzka, 1974). In microbial systems, nitrites may be mutagenic by three different mechanisms (Zimmermann, 1977): deamination of DNA bases in single-strand DNA; formation of 2-nitroinosine and intrastrand or interstrand lesions leading to helix distortions in double-stranded DNA; and formation of mutagenic N-nitroso compounds by combining with nitrosatable substrates. Nitrites were positive in the Ames Salmonella assay and produced chromosome aberrations (Ishidate et al., 1984; Törnquist et al., 1983).
Many N-nitroso compounds have been found to be mutagenic in a variety of test systems, including bacterial assays, mammalian cells in culture, and Drosophila melanogaster under a variety of conditions (Mochizuki et al., 1984; Montesano and Bartsch, 1976) and to induce malignant transformations of human fetal lung fibroblasts in vitro (Huang et al., 1986).
Phenolic AntioxidantsButylated Hydroxyanisole and Butylated Hydroxytoluene
Occurrence and Exposure
The phenolic compounds butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) are widely used as food additives, mainly because of their preservative and antioxidant properties. They are used extensively at levels ranging from 10 to 200 ppm in dry cereals and shortenings as well as in potato sprouts, granules, and flakes. BHA is also permitted as a food additive in active dry yeasts, in dry beverage and dessert mixes, and in beverages made from such mixes. Both BHA and BHT are limited in foods by a total antioxidant content of not more than 0.02% of the fat or oil content of foods. They are also permitted in food packaging materials subject to a migration limit of 0.005% in foods. In 1976, approximately 9 million pounds of BHT were produced for use in foods in the United States (Roberts, 1981). The total average daily intakes of BHA and BHT are 5.6 mg/person and 1.8 mg/person, respectively (D.L. Houston, Food and Drug Administration, personal communication, 1987).
Evidence Associating Phenolic Antioxidants with Chronic Diseases
There is no epidemiologic evidence that relates risk of developing cancer to consumption of BHA.
Repeated intraperitoneal injections of BHA at high doses produced a slight, although not statistically significant, increase in lung tumors in male A/J mice (Witschi et al., 1981). The addition of BHA to the diet of Fischer 344 rats induced a high incidence of papilloma and squamous cell carcinoma of the forestomach in both sexes (Ito et al., 1985). Male hamsters given BHA for 24 weeks also developed papillomas with a downward growth into the submucosa of the forestomach (Hirose et al., 1986). The 3-tert isomer3-tert-butyl-4-hydroxyanisoleseemed to be responsible for the carcinogenicity of crude BHA in the forestomach of rats and hamsters. In two-stage carcinogenesis in rats, after appropriate initiations BHA enhanced carcinogenesis in the forestomach, kidney, and urinary bladder of rats, but inhibited carcinogenesis in the liver (Ito et al., 1985; Tsuda et al., 1984).
However, a diet containing BHA did not enhance the development of lung tumors in A/J mice when fed for 8 weeks after administration of the carcinogens urethane, benzo[a]pyrene, or dimethylnitrosamine (Witschi and Doherty, 1984). BHA was shown to decrease the incidence and density of large-bowel neoplasms in female CF/1 mice given 24 weekly doses of the carcinogen 1,2-dimethylhy-
drazine (Jones et al., 1984) and to decrease colon tumor incidence and multiplicity in animals given the carcinogen methylazoxymethanol acetate (Reddy and Maeura, 1984). BHA has been shown to inhibit the activity of a variety of carcinogens, such as benzo[a]pyrene, dimethylbenz[a]anthracene, 4-nitroquinoline-N-oxide, and urethane (NRC, 1982).
Evidence suggests that exposure to BHA before administration of a carcinogen often has a protective effect, whereas exposure to BHA after an exposure to a carcinogen has sometimes been protective and sometimes has no influence (Witschi, 1984).
There is no evidence that BHA is genotoxic. It does not increase the frequency of sister chromatid exchanges, induce mutations to 6-thioguanine resistance in V79 Chinese hamster lung cells activated by rat or hamster hepatocytes (Rogers et al., 1985), or produce chromosome aberrations in Chinese hamster cells (Abe and Sasaki, 1977). BHA has also been shown to inhibit host-mediated mutagenesis resulting from exposure to hycanthone, mitrifonate, praziquantel, and metronidazole (Batzinger et al., 1978).
Mechanisms Of Action
Data suggest that two factors may be of importance in carcinogenesis induced by the 3-tert isomer (3-BHA): (1) thiol depletion resulting from direct binding of quinone metabolites of 3-BHA to tissue thiols or (2) an attack on tissue constitutents by reactive metabolites of 3-BHA and possibly also by oxygen radicals produced as a result of redox cycling of quinone and hydroxyquinone metabolites of 3-BHA (deStafney et al., 1986).
There is no epidemiologic evidence that relates risk of developing cancer to consumption of BHT.
Female B6C3F1 mice fed a diet containing 0, 0.3, or 0.6% BHT for approximately 2 years developed alveolar/bronchiolar adenomas or carcinomas only at the low dose (NCI, 1979), whereas male C3H mice fed a diet containing BHT had a significant increase in incidence of liver tumors (Lindenschmidt et al., 1986). However, BHT was not found to be carcinogenic in the forestomach of rats, mice, or Syrian hamsters (Hirose et al., 1986; Ito et al., 1985).
In a two-generation study in which Wistar rats were exposed in utero to BHT up to 250 mg/kg per day, a dose-related statistical increase in the number of hepatocellular adenomas and carcinomas was detected in the F1 male rats, whereas in treated F1 female rats, a statistical increase was observed only for adenomas. Hepatocellular tumors were detected in all F1 rats more than 2 years old (Olsen et al., 1986). A diet containing 0.75% BHT enhanced the development of lung tumors in A/J mice when fed for 2 weeks after administration of the carcinogen urethane and for 8 weeks after exposure to 3-methylcholanthrene, benzo[a]pyrene, or N-nitrosodimethylamine (Witschi and Morse, 1983).
Male BALB/c mice treated subcutaneously with the carcinogen dimethylhydrazine and fed a diet containing BHT had a significant increase in the incidence of colon tumors, but male BALB/c mice exposed to the carcinogen N-methyl-N-nitrosourea intrarectally then fed BHT in the diet did not. This observation leads to the conclusion that the effect of BHT on tumor development depends on the exposure route and the carcinogens used (Lindenschmidt et al., 1986).
In studies of the enhancement of hepatocarcinogenesis by BHT, Maeura and Williams (1984) found that BHT fed to rats slightly enhanced hepatocellular foci produced by feeding them N2-fluorenylacetamide for 8 weeks. In rats simultaneously fed N-2-fluorenylacetamide and BHA, hepatocarcinogenesis was inhibited but bladder carcinogenesis was enhanced (Williams et al., 1983). In a two-stage carcinogenesis study on rats, BHT enhanced the induction of urinary bladder tumors, inhibited the induction of liver tumors, and was believed to promote thyroid carcinogenesis (Ito et al., 1985).
The evidence suggests that in certain tissues, exposure first to BHT and then to a carcinogen has no effect on tumorigenesis (Witschi, 1984), whereas in others, it may suppress tumorigenesis, depending on the level of BHT in the diet, the type of diet in which BHT is administered, and the dosage of the carcinogen administered (Cohen et al., 1984, 1986).
BHT was negative in a sister chromatid exchange assay and did not induce chromosome aberrations (Abe and Sasaki, 1977). BHT can either enhance or inhibit mutagenic potency, depending on the substance tested; for example, in the Ames Salmonella assay, BHT is antimutagenic toward benzo[a]py-
rene, but increases the numbers of Salmonella revertants induced by aflatoxin B1 (Malkinson, 1983). BHT inhibited cell-to-cell communication between mammalian cells in vitro, an indication of possible promoting activity (Trosko et al., 1982).
Mechanisms Of Action
BHT is one of the few compounds to have both tumor-prophylactic and tumor-promoting capabilities. The temporal sequence in which BHT and a carcinogen are administered to test animals seems to determine how BHT affects the response to these carcinogens. In common with other antioxidants, BHT inhibits the ability of carcinogens to induce tumors in various rodent organs when the animal is given BHT prior to treatment with a carcinogen. Unlike other antioxidants, however, the number of tumors increases when BHT is administered after exposure to a carcinogen (Malkinson, 1983). The anticarcinogenic activity of BHT may be due, in part, to preferential enhancement of hepatic detoxifying mechanisms, with the result that intracellular concentrations of reactive metabolites are reduced and fewer covalently bound products are formed (Salocks et al., 1984).
Occurrence and Exposure
Approximately 10% of the food consumed in the United States contains added certified colors. In 1982, approximately 2 million pounds of food colors were added to food products (NRC, 1984), amounting to a per-capita exposure of approximately 100 mg/day. The major categories of foods containing added colors are cereals and baked goods, candies, desserts, ice creams and sherbets, sausages, beverages, snack foods, and miscellaneous foods such as salad dressings, jams, and jellies (NRC, 1971). The concentration of colors in these foods ranges from 5 to 600 ppm; the average is approximately 150 ppm. The soft-drink industry is the single largest user of certified colors. The question of whether these colors pose a significant cancer risk has been debated since 1960, when the current regulatory system of toxicologic review was enacted (U.S. Congress, 1960). Food colors that have been examined most carefully for their toxic properties are FD&C Blue No. 2, FD&C Red No. 3 (erythrosine), FD&C Yellow No. 5 (tartrazine), and FD&C Yellow No. 6 (sunset yellow FCF). Only the most recent long-term studies using toxicologic protocols adopted by the FDA are mentioned here (Rulis et al., 1984). There are no relevant epidemiologic studies on food colors.
Evidence Associating Food Colors with Chronic Diseases
FD&C Blue No. 2
In a chronic feeding study in mice and in a companion multigeneration feeding study in rats, no statistically significant compound-related adverse effects, including tumors, were observed (Borzelleca and Hogan, 1985; Borzelleca et al., 1985).
FD&C Red No. 3 (Erythrosine)
In a multigeneration study, Charles River CD rats exposed in utero to 4% erythrosine mixed in diet for 24 months exhibited a significant increase in incidence of follicular thyroid adenomas and carcinomas (Goldenthal, 1982). However, such effects may result from a thyroid hormone imbalance induced by the high concentrations of colorant used (DHHS, 1985).
Erythrosine was tested for its ability to induce mutations in the Bacillus subtilis rec assay; results were negative in one assay (Kada et al., 1972) and positive in another (Fujita et al., 1976). In E. coli, a slight but statistically significant mutagenic effect was observed by some investigators (Lück et al., 1963); no effects were found by others (Fujita et al., 1976). Erythrosine was negative in the Ames Salmonella assay but produced chromosome aberrations in vitro in the Chinese hamster fibroblast cell line (Ishidate et al., 1984).
FD&C Yellow No. 5 (Tartrazine)
FD&C Yellow No. 5 has been approved for general use in foods since 1969. It is not considered to be carcinogenic (Hesser, 1984). However, it exerted dose-dependent mutagenic activities in the Ames Salmonella assay with S. typhimurium TA98 after metabolic activation with rat liver S9 mix (Henschler and Wild, 1985); it induced chromosome aberrations in vitro in Chinese hamster fibroblasts (Ishidate et al., 1984) and in barking deer (Muntiacus mantjak) fibroblasts (Patterson and Butler, 1982); and it has been associated with allergic reactions such as itching, hives, and headaches in humans (Hesser, 1984). In recent analyses, the FDA determined that FD&C Yellow No. 5 contains the carcinogenic impurities 4-aminoazobenzene, 4-aminobiphenyl, aniline, azobenzene, benzidine, and 1,3-diphenyltriazine (DHHS, 1985). A risk evaluation by FDA revealed that the normal
use of this colorant would not result in high exposures to the carcinogenic contaminants, provided that the current low level of contamination is not exceeded (DHHS, 1985.).
FD&C Yellow No. 6 (Sunset Yellow FCF)
FD&C Yellow No. 6 remains provisionally approved for food use, because the most recent chronic feeding studies have not been completely evaluated. It appears to be noncarcinogenic in mice, but studies in rats require further review (DHHS, 1985).
Fat Substitute (Sucrose Polyester)
Sucrose polyester (SPE)a nonabsorbable mixture of hexa-, hepta-, and octa-fatty-acid esters of sucrose with physical and organoleptic properties very similar to those of conventional fatsis now under investigation by the FDA as a potential food substitute that could help people to lose weight while lowering serum levels of cholesterol, LDLs, and triglycerides (Fallat et al., 1976; Mellies et al., 1985). SPE is not absorbed by the gut, which lacks the enzymes to break it down. Among the safety questions being addressed is whether any amount of SPE, however minute, will be absorbed by the body, since if even very minute amounts are absorbed, safety issues become more complex. Another concern is the possibility that SPE decreases the levels of some fat-soluble vitamins in the plasma, especially vitamin E. Mellies et al. (1985) reported a 17% decrease in the mean vitamin E baseline value in SPE-treated subjects, but attributed this decrease to a concomitant reduction in the LDL.
Indirect Additives, Contaminants, and By-Products of Food Processing
Polychlorinated Biphenyls (PCBs)
Occurrence and Exposure
PCBs are highly persistent in the environment and have been detected in human tissues (Kutz and Strassman, 1976). In the United States, the general population may be exposed to small amounts of PCBs through food, water, and air. High exposures may occur among sports fishermen who consume freshwater fish from contaminated steams and lakes. Since fish is also a source of food for domesticated animals, PCBs may be found in milk, eggs, and poultry. In one survey, approximately 20% of all fish were contaminated with PCBs, although only a small percentage exceeded the tolerance level of 5 ppm established by the FDA (McNally, 1978). Recently, the tolerance levels have been lowered for several classes of foodsto 1.5 ppm in milk and dairy products and to 3 ppm in poultry. Other dietary exposures to PCBs can result from contamination of the food supply through industrial accidents and migration of PCBs to foods from packaging materials contaminated with PCBs.
Jelinck and Corneliussen (1975) reported a great reduction of PCB contamination from 1969 to 1975 in all foods except fish, in which no trend was observed. The average daily intake of PCBs per person in the United States from 1980 to 1982 was estimated to be 0.19 µg (Gartrell et al., 1986).
Evidence Associating PCBs with Chronic Diseases
In Japan, more than 1,200 cases of Yusho disease (a disorder involving ocular, dermatologic, and nervous symptoms) were reported over a 9-year period (1968 to 1975) in humans who accidentally consumed rice oil contaminated with PCBs (Higuchi, 1976; Kuratsune, 1976). Nine out of 22 (41%) of the deaths reported as long as 5.5 years after the initial exposure were due to malignant neoplasia (Kuratsune, 1976; Urabe, 1974); however, the investigators did not compare this incidence with the rate of expected deaths from various cancers in the population (NRC, 1982).
Occupational exposure studies have also linked PCBs to cancer. In a retrospective study of 2,567 workers employed for at least 3 months in a plant using PCBs, Brown and Jones (1981) reported more liver cancers than expected (3 versus 1.07), even though total mortality and mortality from cancers were lower than expected. In a follow-up report on this study, two additional deaths from cancer of the liver and biliary passages were found. These resulted in a standard mortality ratio (SMR) for the combined sites of 2.1. However, one of the liver cancers originally reported was found to have metastasized from another site (Brown, 1987).
Bahn et al. (1976, 1977) reported two malignant melanomas among 31 workers heavily exposed to PCBs (20 times the expected incidence) and one melanoma among 41 less heavily exposed workers; however, these workers were also exposed to other chemicals. In an electrical capacitor
manufacturing facility in Italy, 26 malignancies were observed compared to 12.9 expected (Bertazzi et al., 1987). Among males, the excess cancers were in the digestive tract (including one liver cancer); among females, excess cancers were in the lymphatic hematopoietic system. In a study of a small cohort of similar workers in Sweden, no significant excess of cancer deaths was noted (Gustavsson et al., 1986).
The International Agency for Research on Cancer (IARC, 1987) concluded that there is limited evidence for the carcinogenicity of PCBs in humans.
Laboratory experiments indicate that some PCBs produce liver tumors in rodents, but mostly at doses much higher than those generally present in the average U.S. diet (NRC, 1982). Evidence indicates that some PCBs may act primarily as tumor-promoting agents (Preston et al., 1981).
The PCBs Aroclor 1221 and 1268 have been shown to induce microsomal activation in the Ames Salmonella assay (Wyndham et al., 1976). Other PCBs (e.g., Aroclor 1254) are negative in the dominant lethal assay in rats and do not induce chromosome aberrations in human lymphocytes (Hoopingarner et al., 1972). Aroclor 1242 did not induce chromosome aberrations in bone marrow (Green et al., 1973).
Polybrominated Biphenyls (PBBs)
Occurrence and Exposure
PBBs, which are chemically related to PCBs, were used at one time as flame retardants in industrial processes, but their use has been prohibited because of their toxicity and because, like PCBs, they persist in the environment and can accumulate in body fat.
Evidence Associating PBBs with Chronic Diseases
In Michigan in 1973, PBBs were accidently added to animal feed. As a consequence, cattle, poultry, and humans in surrounding areas were widely exposed (Kay, 1977). Because of the short interval between time of exposure and the measurement of effects, no definitive epidemiologic information linking PBBs to cancer were established.
Sherman rats given a single oral dose of PBBs by gavage developed neoplastic liver nodules after 6 months (Kimbrough et al., 1978). In a follow-up study, Sherman rats were given a single large dose of PBBs or 12 divided doses by gavage. Both treatments resulted in a high incidence of hepatocellular carcinomas. In the rats given multiple high doses, the incidence of tumors was higher and some of the liver carcinomas were less differentiated than in rats given the single dose (Kimbrough et al., 1981).
PBBs did not induce mutations either in the Ames Salmonella assay or in Chinese hamster uterine cells. When administered orally to mice, they did not induce chromosome aberrations in bone marrow cells (Wertz and Ficsor, 1978).
Polyvinyl Chloride (PVC)
Occurrence and Exposure
PVC is classified as an indirect food additive by the FDA, whereas the monomer, which may be present at low levels as a residue in PVC, is regarded as a contaminant (CPSC, 1974). PVC is the parent compound for a series of copolymers used in food packaging materials. The monomer may migrate into foods, and PVC has been detected in a variety of alcoholic drinks (0.2 to 1.0 mg/liter) (Williams, 1976a,b), in vinegars (~9 mg/liter) (Williams and Miles, 1975), and in products packaged and stored in PVC containers, for example, edible oils (0.05 to 14.8 mg/liter) (Rösli et al., 1975), margarine and butter (0.5 mg/ kg) (Fuchs et al., 1975), and finished drinking water in the United States (10.0 µg/liter) (EPA, 1975a). There are no estimates of average daily dietary exposure to PVC.
Evidence Associating PVC with Chronic Diseases
No epidemiologic studies on exposure to PVC as a food contaminant have been reported, but serveral studies of occupational exposure have linked PVC exposure to cancer. Creech and Johnson (1974) associated inhalation of PVC with the occurrence of hepatic angiosarcomas. Tabershaw and Gaffey (1974) observed increases in cancer of the alimentary tract, liver, respiratory tract, and lymphomas in male workers exposed to PVC for 1 year. Several other studies
showed associations between exposure to PVC and increased mortality from cancer at various sites (e.g., Duck and Carter, 1976; Fox and Collier, 1977; Monson et al., 1974; Nicholson et al., 1975; Sweeney et al., 1986; Thériault and Allard, 1981; Waxweiler et al., 1976, 1981). Male workers occupationally exposed to PVC were reported to have more chromosome aberrations than were observed in unexposed cohorts (Funes-Cravioto et al., 1975; Heath and Dumont, 1977; Purchase et al., 1975).
IARC (1987) concluded that there is sufficient evidence that PVC is carcinogenic in humans.
Animal studies showed that PVC induces tumors in rats and hamsters (Feron et al., 1975, 1981; Maltoni, 1977; Maltoni et al., 1974, 1975). In short-term tests, PVC vapors induced mutations in Ames Salmonella strains (Andrews et al., 1976; Bartsch et al., 1979), Escherichia coli (Greim et al., 1975), Schizosaccharomyces pombé (Loprieno et al., 1976), Drosophila melanogaster (Verburgt and Vogel, 1977), and mammalian cells (Huberman et al., 1975) and produced gene conversions in yeast (Eckardt et al., 1981). Chromosome aberrations have been observed among workers exposed to PVC vapors (Poncelet et al., 1984).
Polycyclic Aromatic Hydrocarbons (PAHs)
Occurrence and Exposure
Low levels of approximately 100 PAHs have been identified as contaminants in a variety of foods. Major contributors to this contamination are smoking and broiling of foods and the use of curing smokes. The two major sources of PAH contamination of foods are pyrolysis and contact with petroleum and coal-tar products. Charbroiling of meats and fish over an open flame, in which fat drippings can be pyrolyzed, contributes substantially to dietary PAH exposure. Benzo[a]pyrene constitutes a significant portion of the total amount of carcinogenic PAHs in the environment; levels as high as 50 µg/kg have been detected in charcoal-broiled steaks. In contrast, data on dietary exposure to other carcinogenic PAHs are fragmentary (NRC, 1982). There have been no comprehensive surveys of the benzo[a]pyrene content of smoked foods in the United States. In Canada, smoked foods have been reported to contain benzo[a]pyrene at levels ranging from 0.2 to 15 µg/kg (Panalaks, 1976). Foods smoked at home may contain higher levels of benzo[a]pyrene than commercial foods treated with liquid smoke. Edible marine species may contribute substantially to PAH intake. Food packaging materials contaminated with PAHs are also a major dietary source.
PAHs are not monitored by the FDA, and no acceptable daily intake of PAHs has been established. The total daily intake of PAHs in the United States is estimated to range from 1.6 to 16.0 µg (Santodonato et al., 1981).
Evidence Associating PAHs with Chronic Diseases
Of the more than 100 PAHs found in the environment, approximately 20 are carcinogenic in several species of laboratory animals (EPA, 1975b; Lo and Sandi, 1978) and many are potent mutagens (NRC, 1982). The PAHs exert their toxic, carcinogenic, and mutagenic effects only after metabolic activation (Freudenthal and Jones, 1976). Their carcinogenic activity varies from very weak to potent. Of the five PAHs found to be carcinogenic in animals when administered orally and mutagenic in several short-term tests, threebenzo[a]pyrene, dibenz[a,h]-anthracene, and benzanthrazeneoccur in the average U.S. diet (NRC, 1982). Although occupational studies show an association between PAHs and the incidence of skin and lung cancer, there are no epidemiologic studies linking consumption of food contaminated with low levels of PAHs and the occurrence of cancer in humans (NRC, 1982).
The appearance of acrylonitrile in foods as an indirect additive or contaminant may be attributed to its use in food packaging and the migratory quality of the monomer, which is present in small amounts in the polymer. It has been detected in Great Britain in margarine tubs and in food packaging films. In the United States, acrylonitrile has been detected in margarine (13 to 45 µg/kg) and olive oil (38 to 50 µg/liter), and in minute quantities in nuts (C.V. Breder, Food and Drug Administration, personal communication, 1980).
There are no estimates of average daily exposure to acrylonitrile in the United States. The effects of human exposure to acrylonitrile from food packaging or drinking water have not been completely evaluated. However, a retrospective study of male employees exposed to acrylonitrile at a textile plant indicated a trend toward increased risk of cancer at all sites, especially the lung (O'Berg,
1980). This limited evidence, plus the findings that acrylonitrile is carcinogenic in rats upon ingestion or inhalation (Norris, 1977) and mutagenic in three Salmonella strains (Milvy, 1978; Milvy and Wolff, 1977) and in E. coli (Venitt et al., 1977), suggests that acrylonitrile, under certain circumstances, might increase cancer risks in humans.
Among the approximately 20 growth hormones commonly used in animal feed, attention has focused mainly on DES. Residues of this compound have been monitored for many years following reports that it was carcinogenic in animals (Fitzhugh, 1964; Jukes, 1974). The use of DES in humans for various preventive and therapeutic applications terminated in 1978. Until 1979, DES was permitted as a growth promoter for cattle and sheep under certain conditions delineated by the FDA (1979a).
There are no epidemiologic reports on the health effects of DES residues in food. There is, however, sufficient evidence that therapeutic doses of DES during pregnancy produces vaginal and cervical cancer in the female offspring of treated women (Herbst and Cole, 1978). In animals, it produced mainly mammary tumors in mice (Gass et al., 1974), rats (Gibson et al., 1967; Sumi et al., 1985), and Syrian hamsters (Rustia, 1979). In a host of short-term tests, it also induced positive results such as chromosome aberrations in Chinese hamster fibroblasts (Ishidate and Odashima, 1977) and in murine bone marrow cells in vivo (Ivett and Tice, 1981), mutations in mouse lymphoma cells (Clive, 1977), unscheduled DNA synthesis in HeLa cells (Martin et al., 1978), aneuploidy in mice in vivo (Chrisman, 1974), and morphological and neoplastic transformation of Syrian hamster embryo cells in the absence of cell proliferation (McLachlan et al., 1982).
Occurrence and Exposure
Residues of pesticides often remain on agricultural commodities after they have been harvested and prepared for consumer purchase. They are also found in processed foods derived from these commodities. The use of several organochlorine pesticides (e.g., DDT, dieldrin, heptaclor, kepone, chlordane) has been gradually suspended by the Environmental Protection Agency (EPA) because they have a propensity to persist in the environment; to accumulate in fat-containing foods, such as meat, fish, poultry, and dairy products (DHEW, 1969; FDA, 1980b); and to concentrate in body tissues (IARC, 1979). Organophosphate pesticides (e.g., parathion and diazinon) are generally more common in cereal products (FDA, 1980a).
The Market Basket Surveys conducted by the FDA since the 1960s indicate that the levels of pesticides in foods are generally very low and tend to vary only slightly from region to region (Gartrell et al., 1986). In these surveys, pesticides were found most frequently in oils from fats and meat, fish, and poultry. The fewest residues were found in legumes and vegetables. The greatest variety of chemicals was found in the fruit and the oil-fat groups. Of the pesticides measured, only the intake of dieldrin and malathion have approached the ADI in recent years. However, any assessment of the health effects of exposure to pesticide residues must take into account the potential synergistic interactions and the limited nature of the toxicity data on several compounds. In one large-scale survey, Murphy et al. (1983) reported wide-scale contamination of body tissues and detected organochlorine pesticides in 4 to 14% of the serum and 93 to 97% of the adipose tissue samples examined.
There has been considerable concern recently about the use of the halogenated hydrocarbon pesticide ethylene dibromide (EDB) in food products. EDB was used as a soil fumigant to protect agricultural crops from attack by nematodes (root worms), until its emergency suspension by the EPA in September 1983. At the same time, the EPA announced cancellation and phase-out of all other major pesticide uses of EDB such as the postharvest fumigation of fruits and grains to prevent the spread of insects, spot fumigation of vaults, beehives, and timbers, and termite control (U.S. Senate, 1984).
Under its EDB compliance program in 1984, the FDA detected EDB in 462 out of 1,776 samples of grains at trace amounts to 150 ppb, at 150 to 500 ppb in 80 samples, at 500 to 900 ppb in 23 samples, and >900 ppb in 12 samples. No EDB was detected in 1,199 samples. Of 292 ready-to-eat food products analyzed, 277 contained no EDB, 10 contained a trace, and 5 contained 2 to 30 ppb (C. Carnevale, FDA, personal communication, 1988).
Evidence Associating Pesticides with Chronic Diseases
Few epidemiologic studies have examined cancer risk following exposure to pesticides. Several industrial cohort mortality studies of exposure to dioxin or phenoxyacetic acid herbicides did not show an increase in the frequency of death from soft-tissue sarcomas (STS), Hodgkin's disease (HD), or non-Hodgkin's lymphoma (NHL) (Cook et al., 1980; Ott et al., 1980a; Riihimaki et al., 1982; Zack and Suskind, 1980). However, the total number of workers exposed was only 2,705. In the Ranch Hand Studya cohort study conducted by the U.S. Air Force on exposure of 1,247 people to Agent Orange (dioxin) in Vietnamno increase in incidence of or mortality from these cancers was detected as of December 1982, but less than one such death was expected in this small cohort (U.S. Air Force, 1983). In a case-control study based on 217 cases of STS from the files of the Armed Forces Institute of Pathology and 599 controls from the logs of referring pathologists, no evidence was found of increased risk of STS associated with military service in Vietnam (Kang et al., 1987).
In a series of case-control studies conducted in rural Sweden in the 1970s, investigators found highly significant relative risksfive- and sixfold in magnitudefor all three cancers (STS, HD, and NLH) following exposure to the phenoxyacetic acid herbicides and chlorophenols, regardless of whether or not exposures involved contamination by polychlorinated dibenzodioxins or polychlorinated dibenzofurans (Erickson et al., 1981; Hardell and Sandstrom, 1979; Hardell et al., 1981). A case-control study conducted in New Zealand yielded a negative result for STS (Smith et al., 1984).
In several studies, increased incidence of STS and NHL was observed among workers producing phenoxyacetic acid herbicides (Cook, 1981; Honchar and Halperin, 1981; Johnson et al., 1981; Moses and Selikoff, 1981) and among farmers (Buesching and Wollstadt, 1984; Cantor, 1982; Pearce et al., 1985; Stubbs et al., 1984). More recently, a population-based case-control study in rural Kansas (Hoar et al., 1986) indicated that the use of herbicides not likely to be contaminated by dioxins, especially the phenoxyacetic herbicides such as 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) (Cochrane et al., 1981), was associated with a sixfold increase of NHL among farmers exposed to herbicides more than 20 days per year. The positive association was with phenoxyacetic acid herbicide and not insecticide use. Negative findings were reported for STS and HD.
In a population-based case-control study of exposure to phenoxyherbicides conducted in the western part of Washington State (Woods et al., 1987), no excess risk was found for STS. However, excess risk for NHL was found for farmers, forestry herbicide applicators, and others exposed for at least 15 or more years before NHL was diagnosed.
When the analyses were restricted to workers of Scandinavian descent, there was a suggestion of an increase in risk of STS following exposure to phenoxyherbicides. An additional explanation for the differences in findings in Sweden and the United States is the estimation by Woods et al. (1987) that their exposed workers had approximately half the exposure of Swedish workers. Since more than 42 million pounds of phenoxyacetic acid herbicides were applied to U.S. farmlands in 1976 (Eichers et al., 1978), the potential carcinogenic effects from exposure to these herbicides is of concern.
Occupational studies of workers exposed to EDB were not conclusive; the studies had small cohorts, exposure data were incomplete or missing, and exposure periods were short (Ott et al., 1980b; Haar, 1980; Wong et al., 1979).
Animal Studies And Short-Term Tests
The general population is exposed to several common organochlorine pesticides (e.g., toxaphene and chlordane) that cause cancer in mice and in some other animal species (IARC, 1974; NRC, 1982). However, with the exception of parathion, organophosphate pesticides (e.g., malathion and diazinon) have not been found to be carcinogenic in laboratory animals (NRC, 1982). Of the two carbamates currently used, aldicarb does not appear to be carcinogenic in rats or mice, and data on the carcinogenicity of carbaryl are inconclusive. Carbaryl is capable of reacting with nitrites under mildly acidic conditions to produce carcinogenic N-nitroso compounds (Lijinsky and Taylor, 1976). The results of mutagenicity and related short-term tests for some organochlorine pesticides did not coincide with data from carcinogenicity tests in animals (NRC, 1982).
On the basis of studies in animals, and in the absence of adequate data from epidemiologic studies, the NRC Committee on Diet, Nutrition, and Cancer concluded that kepone (chlordecone), toxaphene, hexachlorobenzene, and perhaps hep-
tachlor (with chlordane) and lindane present a carcinogenic risk to humans (NRC, 1982).
EDB was found to produce squamous cell carcinomas of the forestomach in Osborne-Mendel rats and to a lesser extent in B6C3F1 mice when administered by gavage (NCI, 1978b). Van Duuren et al. (1979) reported an increased incidence of skin papillomas, skin carcinomas, and lung tumors in Swiss mice receiving EDB by skin application. In an inhalation study sponsored by the National Toxicology Program and National Cancer Institute, EDB was found to cause tumors of the nasal cavity in Fischer 344 rats and B6C3F1 mice (NCI, 1982). An inhalation study sponsored by the National Institute for Occupational Safety and Health showed EDB to be carcinogenic to Sprague-Dawley rats (Wong et al., 1982). EDB was reported to induce large numbers of sex-linked recessive lethal mutations in Drosophila melanogaster males (Kale and Baum, 1979).
Broad-spectrum fungicidesbenomyl, ethylene-bisdithiocarbamates (EBDCs), captan, captafol, folpet, chlorothalonilare now being studied by the EPA because of their oncogenic potential (NRC, 1987). Their use in agriculture is concentrated in humid regions of the United States, particularly in the East and the Southeast. Fungicides from this group that are widely used and thus may pose considerable health hazards as discussed below.
Benomyl (benlate) and its metabolite methyl-2-benzimidazole carbamate have been characterized as ''moderately severe oncogens" in mice (NRC, 1987). Studies have been conduced on EBDCs, whose major product trade names include Maneb, Zineb, Nabam, Mancozeb, and Metiram, and their conversion product ethylenethiourea (ETU), which is produced during cooking or processing of foods treated with these fungicides. Findings include increased lung adenomas in mice fed EBDCs, increased liver and lung tumors and lymphomas in mice fed ETU, and thyroid carcinomas in rats fed ETU (NRC, 1987).
Captan (Merpan) induces adenocarcinomas and mucosal hyperplasia in both sexes of mice and causes an increase in malignant and benign kidney tumors in rats (Innes et al., 1969; NCI, 1977).
Teratogenesis resulting from exposure to the herbicides 2,4,5-trichlorophenoxyacetic acid and 2,4-dichlorophenoxyacetic acid was found to occur only in mouse strains with a tendency to have a high rate of spontaneous congenital abnormalities and is limited to cleft palate, renal lesions, some other soft-tissue histological changes, and abnormalities in the frontal bones and vertebrae (Pearn, 1985). In contrast, 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) is an unusually potent teratogen in mice, rats, and hamsters (Collins and Williams, 1971; Courtney and Moore, 1971; Khera and Ruddick, 1973). TCDD is transplacentally toxic to embryos and fetuses in rodents and primates, resulting in low fetal weight and reduced litter size (Pearn, 1985).
The herbicide dimethoate, at doses causing toxicity in pregnant female Wistar rats, produced rib abnormalities in embryos and reduced fetal weight (Pearn, 1985). The herbicide diuron was teratogenic in mice at high doses (250 to 500 mg/kg of body weight) and could cause skull abnormalities (Khera and Ruddick, 1973). With the exception of dioxin, it is unlikely that in a real-life situation, humans would experience the massive exposure to herbicides that is sufficient to be teratogenic in a large susceptible mammal (Pearn, 1985).
Among the organochlorine insecticides, DDT was shown to prevent embryotoxic or teratogenic effects of several compounds such as sodium salicylate, benomyl, and chlordane in rats when given during the first 10 to 12 days of pregnancy (Shentberg and Torchinskii, 1976). Moreover, DDT at 200 ppm in diet was shown to prolong the reproductive life of rats to 14 months, as compared to 9 months in control rats (Ottoboni, 1972).
Aldrin produced alterations in the estrous cycle of rats (Ball et al., 1952) and of beagle dogs (Deichmann et al., 1971); dieldrin produced the same phenomenon in mice (Guthrie et al., 1971) and resulted in a reduction in pregnancies in rats (Treon and Cleveland, 1955) and in dogs (Deichmann et al., 1971). High doses of aldrin, dieldrin, and endrin (half the LD50 given as a single oral dose in corn oil) produced teratogenic effects, including cleft palate, open eyes, and webbed feet in hamsters and mice (Ottolenghi et al., 1974).
Kepone adversely affected reproduction in mice, reduced hatchability in chickens at relatively high doses (Naber and Ware, 1965), and produced testicular atrophy in quail (McFarland and Lacy, 1969). Mirex at high doses (6 to 12 mg/kg of body weight) caused a reduction in pregnancies, decreased fetal weight, a significant increase in visceral anomalies, and death (Khera et al., 1976).
Among the organophosphorous insecticides, malathion and related compounds were not shown to be teratogenic. At high doses, however, they may decrease survival and growth of the progeny of
treated animals (IARC, 1983). EDB was shown to induce testicular atrophy at low doses in rats (NRC, 1986).
Mutagens and Carcinogens Produced in Cooked Food
Beef grilled over a gas or charcoal fire was reported to contain a variety of PAHs (Lijinsky and Shubik, 1964; see also above section on PAHs). The source of the PAHs was the smoke generated when pyrolyzed fat dripped from meat onto hot coals (Lijinsky and Ross, 1967). When meat was cooked in a manner that prevented exposure to smoke generated by the dripping fat, contamination was either reduced or eliminated (Lijinsky and Ross, 1967).
The following mutagenic heterocyclic amines are formed from pyrolyzed proteins and amino acids:
· 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3b]indole (Trp-P-2) from a tryptophan pyrolysate (Sugimura et al., 1977);
· 2-amino-6-methyldipyrido[1,2-a:3'2'-d]imidazole (Glu-P-1) and 2-aminodipyrido[1,2-a:3',2'd]imidazole (Glu-P-2) from a glutamic acid pyrolysate (Yamamoto et al., 1978);
· 3,4-cyclopentenopyrido[3,2-a]carbazole (Lys-P-1) from pyrolyzed lysine (Wakabayashi et al., 1983);
· 2-amino-5-phenylpyridine (Phe-P-1) from phenylalanine pyrolysate (Sugimura et al., 1977); and
· amino-a-carboline (AaC) and methylamino-a-carboline (MeAaC) from a pyrolysate of soybean globulin (D. Yoshida et al., 1978).
Mutagenic aminoimidazoquinoline (IQ) and aminomethylimidazoquinoline (MeIQ) were isolated from broiled sun-dried sardines (Kasai et al., 1980), and aminomethylimidazoquinoline (MeIQx) from fried beef (Kasai et al., 1981). All these heterocyclic amines were highly mutagenic toward Salmonella typhimurium TA98 treated with S9 mix (Sugimura et al., 1986). Four of the mutagenic pyrolysatesTrp-P-1, Trp-P-2, Glu-P-1, and AaCinduced sister chromatid exchanges in a permanent line of human lymphoblastoid cells (Tohda et al., 1980), and the basic fraction extracted from pyrolyzed tryptophan caused mutation resulting in resistance to ouabain or 8-azaguanine in cultured Chinese hamster lung cells (Inui et al., 1980). Trp-P-1, Trp-P-2, and Glu-P-1 transformed primary Syrian golden hamster embryo cells (Takayama et al., 1979). Several of these mutagenic pyrolysates were tested for carcinogenicity in rodents.
CD2F1 (BALB)/c AnNCrj x DBA/2NCrjF1, Charles River, Japan, Atsugi, Kanagawa) mice given IQ at 0.03% in the diet produced hepatocellular carcinomas and adenomas, squamous cell carcinomas of the forestomach, and lung tumors (Ohgaki et al., 1984). Hepatocellular carcinomas, adenocarcinomas in the large intestine, squamous cell carcinomas in the skin, Zymbal gland, and clitoral gland, and mammary tumors were induced in Fischer 344 rats given 0.03% IQ (Takayama et al., 1984; Tanaka et al., 1985). Ishikawa et al. (1985) observed that IQ activates Ha-ras and raf oncogenes in rat hepatomas. MeIQ at 0.04% induced a high incidence of squamous cell carcinomas, hepatocellular carcinomas and adenomas, and intestinal adenocarcinomas and adenomas in the forestomach of mice (Ohgaki et al., 1985).
Liver tumors (hepatocellular carcinomas or adenomas) were induced in CDF1 mice fed Trp-P-l and Trp-P-2 at 0.02% (Matsukura et al., 1981). Hepatocellular carcinomas were induced in Fischer 344 rats given Glu-P-1, Glu-P-2, and MeAaC; AaC induced blood vessel tumors (mainly hemangioendothelial sarcomas) as well as liver tumors (mostly hepatocellular carcinomas and adenomas) when given to CDF2 mice at 0.05 and 0.08% (Ohgaki et al., 1984). In Fischer 344 rats, Glu-P-1 and Glu-P-2 at 0.05% induced hepatocellular carcinomas, adenocarcinomas in the small and large intestine, and squamous cell carcinomas in the Zymbal and clitoral glands. Glu-P-2 activated the N-ras oncogene in the small intestine of a rat (Sugimura et al., 1986). MeAaC induced severe atrophy of the salivary glands and cancer cells in pancreas of rats (Takayama et al., 1985).
The presence of a carcinogenic chemical in a pyrolyzed amino acid or protein mixture does not necessarily imply that the carcinogen will also be present in normally cooked, uncharred food (NRC, 1982). Data on the quantities in food indicate that intakes of heterocyclic amines are negligible (one five-thousandths of the dose needed to develop cancers in 50% of animals fed carcinogens over their lifetime). Thus, these compounds may not pose a serious risk for cancer in humans (Sugimura et al., 1986).
Ohnishi et al. (1985) observed the formation of the highly mutagenic and carcinogenic compounds l-nitropyrene and dinitropyrenes in grilled chicken. An activated Ki-ras gene was found in a rat fibrosarcoma induced by repeated subcutaneous injections of 1,8-dinitropyrene, and activation of the Ha-ras gene was reported in a tumor induced in a rat by 1,6-dinitropyrene (Ochiai et al., 1985).
Browning of food results from the reaction of amines with sugars and produces substances that are mutagenic; the increase in mutagenic activity over time parallels the increase in browning (Shinohara et al., 1980). Pyrazine and four of its alkyl products formed by heating mixtures of sugars and amino acids were nonmutagenic in S. typhimurium but induced chromosome aberrations in cultured Chinese hamster ovary cells (Stich et al., 1980). Commercial caramel and caramelized samples of several sugars prepared by heating sugar solutions also caused chromosome aberrations in Chinese hamster ovary cells (Stich et al., 1981a). Furan and six of its derivatives, which can be produced in foods by heating carbohydrates (Maga, 1979), also caused chromosome aberrations in Chinese hamster ovary cells, but they were not mutagenic in bacteria (Stich et al., 1981b).
Cooking accelerates the rancidity reaction of cooking oils and fat in meat (Shorland et al., 1981), thereby leading to increased consumption of mutagens and carcinogens (Ames, 1983).
Metabolites of Animal Origin
Tryptophan and Its Metabolites
Tryptophan is one of the essential amino acids and is present in most proteins. Proteins of animal origin contain @1.4% tryptophan. Most vegetable proteins contain @1%, but corn products have only 0.6% (Orr and Watt, 1957). Average intake of tryptophan in the United States is estimated to be 1.2 g daily, representing about 1.2% of dietary protein (Munro and Crim, 1980).
Animal studies show that tryptophan is carcinogenic in dogs and exerts a promoting effect on the formation of urinary bladder tumors in rats. In addition, four of its metabolites (3-hydroxykynurenine, 3-hydroxyanthranilic acid, 2-amino-3-hydroxyacetophenone, and xanthurenic acid-8-methyl ether) induced bladder tumors when implanted as pellets in the urinary bladders of mice (Clayson and Garner, 1976). However, attempts to relate the development of tumors in the urinary bladder of humans to abnormalities in the metabolism of tryptophan have not been definitive (Clayson and Garner, 1976). Tryptophan and its metabolites were not mutagenic in the Ames Salmonella assay (Bowden et al., 1976).
Ethyl Carbamate (Urethane)
Ethyl carbamate, or urethane, is a product of fermentation in foods and beverages (e.g., wines, bread, beers, and yogurt). It has been detected in a wide range of alcoholic beverages at levels up to several thousand ppb (Mitchell and Jacobson, 1987).
Ethyl carbamate was shown to induce tumors in rodents when administered orally, by inhalation, or by subcutaneous or intraperitoneal injection. The susceptible tissues include the lungs, lymphoid tissue, skin, liver, mammary gland, and Zymbal gland (Iversen, 1984).
The role of naturally occurring ethyl carbamate in foods in the development of cancer in humans is unknown, but the levels found in foods are very low in comparison to those used to induce tumors in laboratory animals (NRC, 1982). Ethyl carbamate was not mutagenic in the Ames Salmonella assay (Simmon, 1979) or in the host-mediated assay (Simmon et al, 1979); however, it induced cell transformations (Pienta, 1981) and sister chromatid exchanges (Goon and Conner, 1984; Neft et al., 1985).
Naturally Occurring Toxicants in Foods
Occurrence and Exposure
Mycotoxins are toxic secondary products produced by the metabolism of molds. At least 45 mycotoxins have been identified as eliciting some type of carcinogenic or mutagenic response; only 17 of them have been reported to occur naturally in food (Stoloff, 1982).
The most thoroughly studied of this group are the aflatoxins, which are generally restricted to crops invaded by the molds Aspergillus flavus and A. parasiticus before harvest. In the United States, humans are unavoidably exposed to aflatoxins mostly in corn and peanuts (FDA, 1979b); cottonseed is also frequently attacked. Other direct dietary sources, such as tree nuts (including almonds, walnuts, pecans, and pistachios), are of minor significance, either because contamination is infrequent or because only small quantities are consumed. It is unlikely that significant exposures result from the ingestion of aflatoxin residues in tissues of animals fed aflatoxin-contaminated feed (Stoloff, 1979). In the United States, the maximum allowable limit for total aflatoxins in peanuts is 20 µg/kg (20 ppb).
Evidence Associating Mycotoxins with Chronic Diseases
Various studies conducted in Africa and Asia have shown strong correlations between estimated levels
of ingested aflatoxins and liver cancer incidence (Linsell and Peers, 1977). Two such studies were conducted in different areas of Swaziland (Keen and Martin, 1971) and Uganda (Alpert et al., 1971). Later studies from Swaziland (Peers et al., 1976, 1987), from the Murang'a district of Kenya (Peers and Linsell, 1973), and from Mozambique, which has perhaps the highest rates of liver cancer in the world (van Rensburg et al., 1974, 1985), have confirmed strong associations between liver cancer incidence and estimated levels of aflatoxins. Oettlé (1965) suggested that the geographic distribution of liver cancer in Africa could be due to differential exposures to aflatoxins in the diet.
In Asia, an overall correlation between estimated aflatoxin intake and liver cancer incidence was found in two regions of Thailand (Shank et al., 1972a,b; Wogan, 1975). In Guangxi Province in China and in Taiwan, the frequency of food contamination with aflatoxins has been correlated with liver cancer mortality (Armstrong, 1980; Tung and Ling, 1968). In several areas of China, Yen and Shen (1986) found that food contamination with aflatoxin B1 is a high-risk factor for primary liver cancer. In a case-control study in the Philippines, Bulatao-Jayme et al. (1982), utilizing data on mean aflatoxin contamination levels in dietary items and relating them to individual consumption, reported an increased risk of hepatocellular cancer for those with high intakes of aflatoxins, suggesting a dose-response relationship.
Several studies have shown a high correlation between exposure to hepatitis B virus and primary hepatocellular carcinoma (Ayoola, 1984; Beasley et al., 1981; Chien et al., 1981; Prince et al., 1975; Simons et al., 1972; Stoloff, 1983; Stora and Dvorackova, 1987; Tong et al., 1971; Vogel et al., 1970). Van Rensburg (1977) and van Rensburg et al. (1985) concluded that preexisting viral infection may be necessary for malignant transformation by aflatoxins.
In three studies, an attempt was made to take serological evidence of chronic hepatitis B infection into account while evaluating elevated aflatoxin ingestion. In China, aflatoxin levels in both diet and urine were found to be related to the incidence of hepatocellular cancer, but corresponding differences in the prevalence of hepatitis B carriers were not found (Sun and Chu, 1984; Yeh et al., 1985). In Swaziland, liver cancer incidence was strongly associated with estimated levels of aflatoxins in food. In this study, exposure to aflatoxins was a more important determinant of liver cancer incidence than was the prevalence of hepatitis B infection in a multivariate analysis (Peers et al., 1987).
Aflatoxin B1, the most potent hepatocarcinogen known, was reported to induce tumors in many animal species, including ducks, hamsters, mice, rats, and trout. The male Fischer 344 rat was most sensitive (NRC, 1982).
Aflatoxin B1 was also shown to be mutagenic to microbial and mammalian cells (Mangold et al., 1986; Ueno and Kubota, 1976; Ueno et al., 1978; Umeda et al., 1977) and to enhance transformation of metabolically activated C3H/10T½ cells in culture (Billings et al., 1985). Aflatoxin M1, the metabolite of aflatoxin B1, was mutagenic in the Ames Salmonella assay (Wong and Hsieh, 1976) but was inactive in the Bacillus subtilis rec assay (Ueno and Kubota, 1976).
Several mycotoxins other than aflatoxins that may be found in food (e.g., sterigmatocystin, ochratoxin A, zearalenone, patulin, griseofulvin, luteoskyrin, and cyclochlorotine) were shown to be mutagenic in bacterial systems and other short-term tests, had promoting activities, or were carcinogenic in laboratory animals (Bendele et al., 1985; Creppy et al., 1985; Curry et al., 1984; NRC, 1982); however, there are no epidemiologic studies on their role in human neoplasia.
Hydrazines in Mushrooms
Several hydrazines and hydrazones known to be carcinogenic in mice and mutagenic in Salmonella typhimurium have been isolated from two commonly eaten mushrooms, Agaricus bisphorus (the commonly eaten mushroom) and Gyromitra esculenta (false morel) (Toth, 1984; Toth and Patil, 1981). The uncooked mushroom A. bisphorus was shown to induce tumors in the bone, forestomach, liver, and lung of mice (Toth and Erickson, 1986). The precise contribution of exposure to these carcinogens to cancers in humans is difficult to determine due to the lack of epidemiologic studies (Palmer and Mathews, 1986). However, Prival (1984) estimated that the consumption of 4-hydroxymethylbenzonium from raw mushrooms in the United States is 0.058 mg/kg or about 1/ 7,000th of the dose that produced tumors in 31% of mice tested. If only 1% of the mushrooms sold in the United States are eaten raw, the cancer risk is estimated to be less than one per million per lifetime in the U.S. population.
Plant Constituents and Metabolites
Occurrence and Exposure
Flavonoid glycosides, especially quercetin and kaempferol glycosides, are found in the edible portion of most food plants, including citrus fruits, berries, leafy vegetables, roots, tubers, spices, cereal grains, tea, and cocoa. Many of these flavonoid glycosides are known to be mutagenic (NRC, 1982). Brown (1980) estimated that the intake of all mutagenic glycosides in the United States was 50 mg/day, i.e., about 1/70th of the dose of quercetin that produced tumors in rats in one study (Pamukcu et al., 1980).
Several alkyl benzene compounds are found in herbs and spices. For example, estragole is found in sweet basil and tarragon, and its daily intake is estimated to be 1 µg/kg. On the basis of the results of a carcinogenesis bioassay in female CD/1 mice fed a 0.23% estragole diet for 12 months, the estimated lifetime carcinogenic risk would be one cancer in 420,000 people (Prival, 1984). Other alkylbenzene derivatives found in herbs include safrole, methyleugenol, b-asarone, and isosafrole. Plants in nature as well as those in the diet of humans synthesize a large amount of toxic chemicals, apparently as a primary defense against varieties of bacteria, fungi, insects, or animal predators (Ames, 1983). Some of these toxins are discussed below.
Evidence Associating Plant Constituents with Chronic Disease
A number of epidemiologic studies have focused on the consumption of fruits and vegetables in the human diet. In several of them, intake of fiber-containing foods was found to have a protective effect against colorectal cancer (see Chapter 10). In other studies, intake of foods containing vitamin A or b-carotene was found to have a protective effect against lung cancer (see Chapter 11). In still others (see Chapter 12), the contribution of vitamin C made by fruit and vegetable consumption was found to have a protective effect against stomach cancer. In one study of colorectal cancer, Macquart-Moulin et al. (1986) found the protective effect of vegetable intake to be strongest for vegetables lowest in fiber, suggesting that some factors other than fiber in vegetables were responsible for the protective effect.
Other epidemiologic studies on the association of fruit or vegetable consumption with cancer risk did not focus specifically on fiber, vitamin A, b-carotene, or vitamin C intake. For example, in a case-control study of colorectal cancer, Graham et al. (1978) found evidence that a protective effect was provided by cabbage and other vegetables of the Brassica genus. The protective effects were particularly related to the frequent ingestion of raw vegetables, especially cabbage, Brussels sprouts, and broccoli. Haenszel et al. (1980) also found an inverse association between cabbage consumption and colorectal cancer in a case-control study in Japan. These associations may be due to the inhibition of the microsomal monooxygenase system, which in turn will inhibit the activation of chemical carcinogens (Wattenberg, 1981). In a subsequent case-control study of colorectal cancer, Miller et al. (1983) found only weak evidence of a protective effect of such vegetables only in females, after taking into account saturated fatty acid intake.
In several epidemiologic studies, evidence that vegetable consumption had a protective effect against lung cancer was found (Hirayama, 1986; MacLennan et al., 1977; Ziegler et al., 1986). These studies have generally been interpreted as providing further evidence for a protective effect of b-carotene. It is possible, however, that other factors in the vegetables may have been responsible for some of the protective effect. Indeed, in the cohort study by Hirayama (1986), a protective effect of green and yellow vegetable consumption was found for several cancer sites, including the stomach, colon, and lung (see Chapters 11 and 12).
In summary, there is consistent evidence that fruit and vegetable consumption is protective against several cancers. Although much of this effect could be due to components of dietary fiber (for colorectal cancer), vitamin C (for stomach cancer), and b-carotene (for lung cancer), the possibility remains that other protective factors in foods may be responsible for at least part of the effects. Therefore, in considering appropriate preventive measures, consumption of the relevant foodsnot the putative protective components of those foodsshould be encouraged.
Pyrrolizidine alkaloids are found in many inedible plant species, including the genera Senecio (ragworts), Cortalaria (rattleboxes), and Heliotropium (heliotropes), in amounts ranging from traces to as much as 5% of the dry weight of the plant. Alkaloids that are derivatives of 1-hydroxymethyl-1,2-dehydropyrrolizine have been shown to induce liver tumors in animals (Hirono et al., 1981; Schoental, 1968). Such lesions have been found in female rats fed these alkaloids during pregnancy
(Newberne, 1968; Schoental, 1959)a phenomenon with a counterpart in some African tribes that prescribe alkaloid-containing herbal mixtures to pregnant women. Several of these alkaloids induce DNA repair synthesis and sister chromatoid exchanges (Bruggeman and van der Hoeven, 1985; Griffin and Segall, 1986; Mori et al., 1985b). Recent studies suggest that the hepatocarcinogenicity of pyrrolizidine alkaloids may be due to their promoting effects on initiated hepatocytes rather than to their very weak initiating activity (Hayes et al., 1985). No epidemiologic studies are available on these compounds.
Bracken fern (Pteridium aquilinum) grows widely in nature and is consumed by humans in several parts of the world, especially in Japan (Hirono, 1981). For at least 30 years, it has been known that consumption of this plant damages the bone marrow and intestinal mucosa of cattle, but the harmful component of this plant has not been identified (Pamukcu et al., 1980). In a cohort study in Japan, high risk of esophageal cancer was associated with daily intake of bracken fern (Hirayama, 1979). On the other hand, in a case-control study in Canada, no association between bladder cancer and consumption of fiddlehead greens (related to bracken fern) was found (Howe et al., 1980). Indirect evidence for carcinogenicity is derived from observations that milk from cows fed high levels of bracken fern contained compounds shown to be carcinogenic in rats (Pamukcu et al., 1980). Carcinomas of the intestine, urinary bladder, and kidney were observed in rats fed high levels of fresh or powdered milk from cows that had consumed 1 g of bracken fern per kilogram of body weight daily for approximately 2 years, but not in rats fed milk from control cows (Pamukcu et al., 1980). In another laboratory, however, dietary administration of quercetin (which occurs as a conjugate in the fern) did not result in a high incidence of tumors in ACI rats (Hirono et al., 1981). Mutagenic components of bracken fern (aquilide A and quercetin) and one that is carcinogenic and mutagenic (ptaquiloside) with a structure similar to aquilide have reportedly been isolated and identified (Hirono, 1986; Mori et al., 1985a; Umezawa et al., 1977; van der Hoeven et al., 1983).
Cycasin (methylazoxymethanol-a-glucoside) is one of the most potent carcinogens found in plants (IARC, 1976; Magee et al., 1976). This compound and at least one related glucoside (macrozamin) are present in the palm-like cycad trees of the family Cycadaceae. These trees have provided food for humans and their livestock in tropical and subtropical regions. The crude flour prepared from the unwashed nuts of these trees induced kidney and liver tumors in rats when fed at 2% of the diet (Zedeck, 1984). When administered orally, cycasin was highly carcinogenic in the liver, kidney, and colon of rats, and induced tumors in other species (Laqueur and Spatz, 1968).
Cycasin was not mutagenic in the standard Ames Salmonella assay (Ames et al., 1975), but it became mutagenic when preincubated with almond a-glucosidase (Matsushima et al., 1979). In Guam and Okinawa, the ingestion of cycasin in cycad nuts has been proposed as an etiologic factor in the development of liver cancer in humans, which occurs at high rates in those countries. However, in a descriptive study conducted in the Miyako Islands of Okinawa, no correlation between mortality from hepatoma and the ingestion of cycad nuts was found (Hirono et al., 1970).
Safrole, estragole, methyleugenol, and related compounds are present in many edible plants and are carcinogenic in rodents; several of their metabolites have mutagenic potential (Miller et al., 1979). Black pepper contains a small amount of safrole and approximately 10% of the closely related compound piperine (Concon et al., 1979). Extracts of black pepper produce tumors in mice at various sites (Concon et al., 1979).
Linear furocoumarins (e.g., psoralen derivatives) are potent light-activated carcinogens and mutagens that are widespread in the Umbelliferae, such as celery, parsnip, figs, and parsley (Ivie et al., 1981). Psoralens are activated by sunlight and then damage DNA, induce tumors (Ashwood-Smith and Poulton, 1981), and produce oxygen radicals (Potapenko et al., 1982).
The glycoalkaloids solanine and chaconine, which are present in potatoes, are strong cholinesterase inhibitors and potential teratogens (Hall, 1979; Jadhav et al., 1981). Quinones and their phenolic precursors act as electrophiles producing semiquinone radicals that either react directly with DNA (Morimoto et al., 1983) or produce superoxide radicals (Kappus and Sies, 1981), which oxidize fat in cell membranes by a peroxidation chain reaction that generates mutagens and carcinogens (Brown, 1980; Levine et al., 1982). Plants such as rhubarb contain mutagenic quinone
derivatives (Brown, 1980). Some dietary phenols (e.g., catechol derivatives) spontaneously autooxidize to quinones, producing hydrogen peroxides (Stich et al., 1981c). Catechol is a strong promotor and induces DNA damage (Carmella et al., 1982).
Allyl isothiocyanate, a major flavor ingredient in oil of mustard and horseradish, is a toxin that causes chromosome aberrations in hamster cells (Kasamaki et al., 1982) and is carcinogenic in rats (Dunnick et al., 1982). Gossypol, a major toxin in cottonseed oil, accounting for approximately 1% of its dry weight, was reported to be a potent initiator and promotor of carcinogens in mouse skin (Haroz and Thomasson, 1980). It also caused dominant lethal mutations (Ames, 1983), produced genetic damage in embryos sired by treated male rats, and caused pathological changes in the testes of rats and humans, leading to abnormal sperm and male sterility (Ames, 1983), probably through production of oxygen radicals (Coburn et al., 1980).
Cyclopropenoid fatty acids present in oils from seed plants of Malvacealidae (e.g., cotton, okra) are carcinogenic in trout and enhance the carcinogenicity of aflatoxins in trout. They are also mitogenic in rats, have a variety of toxic effects in farm animals, and cause atherosclerosis in rabbits, probably through the formation of peroxides and radicals (Hendricks et al., 1980).
Leguminous plants such as lupine contain potent teratogens. One such teratogen is anagyrine, which causes crooked calf abnormality in cows and goats foraging on these plants and passes to humans through milk (Ames, 1983).
Sesquiterpene lactone, a major toxin in the white sap of the poison lettuce Lactuca virosa, has been shown to be mutagenic (Manners et al., 1978). Canavanine, which accounts for 15% of the dry weight of alfalfa sprouts, appears to be the active ingredient causing a severe lupus erythematosus-like syndrome in monkeys. This condition is characterized by defects in the immune system, chromosome breaks, and other types of tissue injury (Malinow et al., 1982) believed to result from the production of oxygen radicals (Emerit et al., 1980).
The toxins vicine and convicine, which account for 2% of the dry weight of the broad bean Vicia faba, can lead to severe hemolytic anemia in some humans. This is caused by enzymatic hydrolysis of vicine to its aglyconedivicinewhich forms a quinone that generates oxygen radicals in sensitive individuals ingesting the fava beans (Chevion and Navok, 1983).
Other plant constituents and metabolites, such as allylic propenylic benzene derivatives, estrogenic compounds, methylxanthines, thiourea, tannic acid and tannins, coumarin, and parasorbic acid, have been shown to be carcinogenic in animals or mutagenic in short-term tests. Many of these naturally occurring mutagens and carcinogens act by producing free radicals that damage DNA and thus may lead to cancer and mutations (Ames, 1983). Ames et al. (1987) suggested that the hazards from several man-made chemicals are much less severe than those of natural substances, but he did not conclude whether the natural exposure is of major or minor importance. Epstein and Swartz (1988) and Perera and Boffetta (1988) have argued against the conclusions of Ames.
There is no convincing epidemiologic evidence relating coffee or tea to any type of cancer. Results of mutagenicity and carcinogenicity studies show that caffeine is mutagenic in microorganisms, but its ability to induce mutations in higher organisms or to produce tumors in animals is not certain. There are no adequate carcinogenicity studies on tea or tannins. A few short-term tests in microorganisms showed that tea is mutagenic. The strongest evidence for a possible deleterious health effect of coffee drinking is its association with increased LDL cholesterol levels. However, there is no convincing evidence from epidemiologic studies that the level of coffee consumed in North America increases risk of death from cardiovascular diseases. Caffeine, however, has been shown to cause reproductive defects, to be teratogenic in rodents, and, possibly, to lead to spontaneous abortion, stillbirth, preterm deliveries, and low birth weight in humans.
Nearly 3,000 substances are intentionally added to foods during processing in the United States. Another estimated 12,000 chemicals, such as polyvinyl chloride and acrylonitrile, which are used in food packaging, are classified as indirect additives. However, the annual per-capita exposure to most of these substances is very small. Except for the studies on nonnutritive sweeteners and on nitrates, nitrites, and N-nitroso compounds, very few epidemiologic studies have been conducted to examine the effect of food additives on cancer incidence.
Of the few direct food additives that have been tested and found to be carcinogenic in animals, all except saccharin have been banned from use in the
food supply. The major deleterious health effect of artificial sweetener use, for which animal data provide evidence, is increased risk of bladder cancer. The substantial amount of epidemiologic evidence collected to date, however, indicates that the levels of saccharin and cyclamate in most diets do not confer an increased risk of bladder cancer in humans. Animal studies and short-term tests indicate that saccharin and possibly cyclamate have tumor-promoting potential. Cyclamate and its conversion metabolite cyclohexylamine have been shown to cause testicular atrophy in rodents. The nonnutritive sweetener aspartame does not appear to be carcinogenic.
Nitrates appear to be neither carcinogenic nor mutagenic. Nitrites are probably not direct carcinogens, but they are mutagenic in microbial systems. There is some epidemiologic evidence that nitrites and N-nitroso compounds play a role in the development of gastric and esophageal cancer.
There are no epidemiologic data on the relationship between the antioxidants BHA and BHT and human health. Animal studies showed that BHA induces carcinogenesis in the forestomach of rats and hamsters. The isomer 3-tert-butyl-4-hydroxyanisole seems responsible for this effect. It also has an inhibitory effect on the development of tumors, depending on the time of administration. It is not genotoxic, i.e., it does not damage DNA. Animal studies show that BHT enhances liver tumors and has a tumor-promoting effect. It can inhibit neoplasia induced by a number of chemicals depending on its level in the diet, the type of diet in which it is administered, and the dosage of the carcinogen given. It does not appear to be genotoxic and can either enhance or inhibit the mutagenic potency of other chemicals.
In the absence of epidemiologic studies, experimental evidence to date would suggest that exposure to individual food colors is unlikely to increase the burden of cancer in humans. Minute residues of a few indirect contaminants from food packaging known to produce cancer in animals (e.g., polyvinyl chloride and acrylonitrile) or to be carcinogenic in humans (e.g., polyvinyl chloride) are occasionally detected in foods. There is no evidence suggesting that such contamination or the increasing use of other food additives has contributed significantly to the overall risk of cancer for humans. Indeed, the decreasing incidence of stomach cancer (see Chapter 5) suggests that they have had little or no adverse effect. However, the lack of a detectable effect could be due to the relatively recent use of some of these substances, to lack of carcinogenicity, or to the inability of epidemiologic techniques to detect weak effects of contaminants against the background of common cancers from other causes.
The results of standard chronic toxicity tests indicate that a number of environmental contaminants in foods (e.g., some organochlorine pesticides, PCBs, and PAHs) cause cancer in laboratory animals. Some epidemiologic studies have shown a five- to sixfold increase in non-Hodgkin's lymphoma in workers exposed to phenoxyacetic acid herbicides. These herbicides were also found to be teratogenic in mice. Reproductive and teratogenic defects have been attributed to some of the phenoxyacetic acid herbicides and dioxin, as well as to some organochlorine insecticides (aldrin, dieldrin, endrin, kepone, and mirex).
Various mutagens and carcinogens are formed during broiling, charring, and grilling of meat and fish, and browning of foods. However, the amounts formed may be too small to pose a serious risk for the developement of cancer in humans.
Aflatoxins, mycotoxins that occur naturally in grains and other food commodities, are carcinogenic in several species of animals, including mice, rats, trout, ducks, and monkeys, and there is evidence of a dose-response. In addition, they have been shown to be mutagenic in bacterial and mammalian systems. Several other mycotoxins found in food are carcinogenic or mutagenic in laboratory tests. With the exception of aflatoxins, which have been implicated in liver cancer in some parts of the world, there is no epidemiologic evidence concerning other mycotoxins and neoplasia in humans. Because levels of aflatoxins in foods in the United States are generally controlled, the risk to human health is considered negligible.
Hydrazine derivatives of two mushroomsAgaricus bisporus and Gyromitra esculentaboth of which are consumed throughout the world, appear to be carcinogenic in mice and, under certain conditions, in hamsters. They are also mutagenic in bacteria. The significance of these findings for risk to humans cannot be determined, since there are no epidemiologic data.
Several pyrrolizidine alkaloids are carcinogenic in animals or mutagenic in several test systems. Cycad nuts, which are eaten in some parts of the world, contain cycasin (methylazoxymethanol-b-glucoside), a compound known to be carcinogenic in animals. It is also mutagenic in the Ames Salmonella assay after addition of b-glucosidase. Long- and short-term tests showed that bracken fern is carcinogenic in animals and may also be
mutagenic. No evidence has been presented for the carcinogenicity of pyrrolizidine alkaloids, bracken fern, and cycasin in humans. Other constituents of plants, such as methylxanthines, thiourea, tannins, coumarin, parasorbic acid, safrole, estragole and eugenol, furocoumarins, glycolalkaloids, quinones and their phenolic precursors, allyl isothiocyanate, gossypol, cyclopropenoid fatty acids, and plant estrogens such as zearalenone, are carcinogenic in laboratory animals or mutagenic in bacterial or mammalian cell systems.
Overall, there is shortage of data on the complete range of nonnutritive substances present in the diet. Thus, no reliable estimates can be made of the most significant exposures. Exposure to individual nonnutritive chemicals, in the minute quantities normally present in the average diet, is unlikely to contribute to the overall cancer risk to humans in the United States. The risk from simultaneous exposure to many such compounds cannot be quantified on the basis of current knowledge.
The life span of humans in Western countries is steadily increasing, and age-specific mortalities from most common cancers such as breast and colon cancer show, at most, small increases over the past generation and many were decreased. These facts suggest that our society as a whole is not facing a health crisis posed by environmental agents. Nevertheless, potentially teratogenic, carcinogenic, or mutagenic chemicals and other pollutants do exist. Therefore, various regulatory decisions regarding avoidance of exposure need to be made. These decisions are difficult to reach, since they must be based on studies conducted in other organisms and the resulting data are difficult to extrapolate to humans. In many cases human exposure standards are inaccurate; therefore a conservative stance not to allow the introduction of potentially noxious agents is mandatory. Factors affecting risk assessment include interspecies variation and human variability due to intraspecies genetic variation. Since the latency period between initiation and clinical cancer may last a generation, careful epidemiologic surveillance for various cancers needs to be continued.
Directions for Research
There are two major limitations to drawing definitive conclusions about the association between nonnutritive dietary constituents and chronic diseases: a dearth of precise data on the range of these chemicals in the diet and the poorly understood potential for synergistic or antagonistic interactions among nutritive and nonnutritive dietary substances. The following directions for research are aimed at filling these gaps in knowledge. With the exception of coffee, which has been weakly linked to hypercholesterolemia and cardiovascular diseases, nonnutritive substances are generally associated primarily with cancer risk. Therefore, the majority of the recommendations apply only to cancer.
· Research is needed on the mechanisms by which coffee and its constituents affect serum cholesterol levels. Possible modifiers of such adverse effectse.g., additives such as cream, milk, lemon, and sugar, and the temperature at which beverages are consumedshould also be investigated. Studies should also be undertaken to obtain accurate measures of the intake of these beverages and to examine the methods used to decaffeinate them.
· There is a need for better measurements of the average intake of food additives as well as the distribution of intake among population subgroups. Such studies should assess exposure to both direct and indirect additives. If populations with significantly different levels of exposure are identified, epidemiologic studies should be undertaken to examine the effect of major additives on health.
· Additional studies should be conducted to determine the relevance of the tumor-promoting effects of BHT and the tumor-inhibiting effects of both BHT and BHA.
· Data from the series of USDA's Nationwide Food Consumption Surveys and the National Center for Health Statistics' Health and Nutrition Examination Surveys should be examined to see what information they can provide about exposure to and the long-term health effects of additives. Future surveys might be designed to include such data after appropriate markers are identified.
· Studies are needed to determine the effect of diet on the endogenous formation of mutagens, such as nitrosamines and fecal and urinary mutagens, and to assess the carcinogenicity of such mutagens. Efforts to identify nitrosatable precursors and endogenously produced mutagens should be continued.
· Studies are needed to characterize the distribution of intake of such carcinogens and mutagens in foods as hydrazines in mushrooms, aflatoxins and other mycotoxins, polycyclic aromatic hydrocarbons, mutagenic flavonoids and glyoxals, and mutagens produced during cooking. The data should include the patterns and frequencies of
household and commercial cooking practices, cooking temperatures, and the duration of cooking for various types of food in which mutagens or carcinogens are produced during heating.
· Epidemiologic studies, including intervention trials when appropriate, should be conducted to determine whether consumption of foods containing high concentrations of nonnutritive inhibitors of carcinogenesis results in a lower incidence of cancer.
· Additional techniques for assessing the mutagenic effects of chemicals on human cells in vivo should be developed. Such techniques should be applied to diets believed to present a high or low risk for cancer in humans.
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