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14 Additives and Contam~ts ADDITIVES This section contains summaries of data on a few selected compounds that are added directly to foods, as well as for processing aids and some compounds that may migrate into foods in small amounts as a result of their use in packaging. Saccharin Saccharin has been used as a nonnutritive sweetener since 1907. In 1977, an estimated 2.2 million kilograms of saccharin and sodium saccharin were produced in the United States and an additional 1.3 million kilograms were imported (National Academy of Sciences, 1978~. During that year, approximately 2.9 million kilograms (~83% of the domestic and imported saccharin) were used in foods (U.S. Department of Agriculture, 1978~. Epidemiological Studies. The use of nonnutritive sweeteners has been studied primarily to determine their relationship to bladder cancer. Results from studies of diabetics did not indicate that there is a direct association between saccharin use and bladder cancer (Armstrong and Doll, 197S; Armstrong et al., 1976; Kessler, 1970~; however, diabetics are not generally representative of the general population in epidemiological studies of cancer incidence and mor- tality since they differ in several important respects. For example, diabetics as a group smoke less, and since smoking is associated with bladder cancer, less cancer at that site might be anticipated among these subjects (Armstrong and Doll, 197S; Christiansen, 1978~. Burbank and Fraumeni (1970) found no increase in mortality from bladder cancer in the United States following the widespread intro- duction of nonnutritive sweeteners. - ~~ ~ They examined mortality rates for this cancer after saccharin was introduced early in this century and after a 10:1 mixture of cyclamate:saccharin came into use during 1962. In England and Wales a cohort analysis of bladder cancer mortality from 1911 to 1970 provided no evidence of any disruption of mortality trends for either men or women corresponding to the introduction of saccharin (Armstrong and Doll, 1974~. However, time-trend studies generally cannot detect weak effects and can detect no effects for diseases with long latency periods, if only a short time has elapsed between exposure to the substances and the observation. The consumption of saccharin by bladder cancer patients and healthy controls has been compared in several case-control studies, although 304 14-1

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Additives and Contaminants 305 most of these studies were not originally designed to investigate the relationship between nonnutritive sweeteners and bladder cancer. In a case-control study based on responses to questionnaires from 74 female cases, 158 male cases, and an equal number of matched controls, Morgan and Jain (1974) observed that prolonged use of any nonnutritive sweetener was not associated with an increased risk in males and was associated with a reduced risk for females. In another study based on mailed questionnaires, Simon _ al. (1975) studied women only, and found no differences between the cases and controls in either saccharin or cyclamate use. Howe et al. (1977) conducted a case-control study of 480 male and 152 female sex-matched pairs. They observed that men who used nonnu- tritive sweeteners had a 60% increase in risk of bladder cancer and provided evidence of a dose-response relationship. On the other hand, there was no significant increase in risk for women. These preliminary findings were confirmed in a later study by the same investigators, who reanalyzed the data, controlling for potential confounding factors such as smoking and using a logistic regression model (Howe et al., 1980~. In a case-control study of 519 bladder cancer patients and twice as many controls, Kessler and Clark (1978) found no evidence of a link between nonnutritive sweetener consumption and bladder cancer. Miller _ al. (1978) studied 265 bladder cancer patients and 530 matched con- trols. They also found no significant risk associated with the regular use of nonnutritive sweeteners. Morrison (1979) found no association between current use of nonnutritive sweeteners and bladder cancer in 13 cases and 10,874 controls. Morrison and Buring (1980) evaluated the relationship between cancer of the lower urinary tract and the consumption of nonnutritive sweeteners in a case-control study of 592 patients and 596 controls. Overall, there was no increase in risk for lower urinary tract cancer among users of nonnutritive sweeteners. However, in a subgroup of nonsmoking women, there were elevated risks of 2.1 for use of sugar substitutes and 2.6 for use of dietetic beverages. Wynder and Stellman (1980) conducted a case-control study of 302 men and 65 women with bladder cancer and an equal number of matched controls. They also found no association between bladder cancer and the consumption of nonnutritive sweeteners or dietetic beverages. The National Cancer Institute (NCI) and the Food and Drug Adminis- tration (FDA) jointly sponsored a large scale case-control study in which 3,010 bladder cancer patients and 5,783 population controls were interviewed. This investigation was designed specifically to evaluate the relationship between nonnutritive sweetener consumption and bladder cancer. Subjects who reported ever having used nonnutritive sweeteners or artifically sweetened foods or beverages were found to have no in- crease in the risk of bladder cancer. However, white nonsmoking women 14-2

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306 DIET, NUTRITION, AND CANCER who had not been exposed to known bladder carcinogens such as azo dyes were found to have an increased risk of bladder cancer with increased nonnutritive sweetener consumption (relative risk of 2.7-3.0 in heavy users for at least 10 years and a suggested dose-response relationship). Users of both tabletop sweeteners and diet drinks,with a heavy use of at least one of the two, showed a relative risk of 1.5 (Hoover and Strasser, 1980~. The International Agency for Research on Cancer (1980) concluded, Although a small increase in the risk of urinary bladder cancer in the general population or a larger increase in some individuals consuming very high doses of saccharin cannot be excluded, the epidemiological data provide no clear evidence that saccharin alone, or in combination with cyclamates, causes urinary bladder cancer. There have also been some observations concerning consumption of saccharin and cancer at other sites, for example, pancreatic cancer. An increase in deaths from pancreatic cancer was found in cohort studies of diabetics (Armstrong _ al., 1976; Kessler, 1970~. Blot et _ . (1978) found a direct correlation of pancreatic cancer mortality by county in the United States with diabetes mellitus in women, but not in men, who consumed saccharin. In a case-control study, Wynder et al. (1973) found a direct association of pancreatic cancer with early-onset diabetes in women who used saccharin. Experimental Evidence: Carcinogenicity. The carcinogenicity of saccharin has been reviewed extensively (National Academy of Sciences, 1978~. The following discussion focuses on some recent data. There was no evidence of saccharin-induced carcinogenesis in a number of single-generation studies in which various doses of saccharin were fed to several strains of mice and rats (Furuya et al., 1975; Hamburger, 1978; National Institute of Hygienic Sciences, 1973; Roe et al., 1970; Schmahl, 1973) and to hamsters and rhesus monkeys (Althoff _ al., 1975; McChesney et al., 1977~. In a single-generation study, Wistar specific-pathogen-free (SPF) rats were fed saccharin at either 4 g/kg body weight (bw) daily in the diet for 2 years or saccharin containing 698 mg/kg o-toluenesulfonamide (OTS) at 2 g/kg bw in drinking water daily for the same period. The treated males in both groups developed more tumors than did the untreated controls, but there was no significant difference in the females (Chowaniec and Hicks, 1979~. In another single-generation study, Charles River CD rats fed 5% sodium saccharin (free of OTS) for their lifetime had a higher inci- dence of benign and malignant bladder tumors than observed in the untreated controls (D. L. Arnold et al., 1977, 1980~. Saccharin has also been tested in two-generation carcinogenicity bioassays in which parent animals (the Fo generation) are fed 14-3

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Additives and Contaminants 307 saccharin from weaning through pregnancy until their offspring are weaned. The offspring (F1 generation), already exposed to saccharin _ utero, are given the same diet as their parents for the rest of their lives. In one such study, there was no difference in the incidence of tumors in treated or control Swiss SPF mice in either generation (Kroes et al., 1977~. In three two-generation studies with Charles River and Sprague-Dawley rats (D. L. Arnold et al., 1977, 1980; Taylor and Friedman, 1974; Tisdel et al., 1974; U.S. Department of Health, Edu- cation, and Welfare, 1973a,~, the incidence of bladder tumors in treated male rats of the F1 generations given the highest dose was significantly higher than that in controls in all three studies and in the Fo males in one study (D. L. Arnold et al., 1977, 1980~. Saccharin (2 or 4 g/kg low/day in diet) increased the incidence of and decreased the latent period for tumor development in animals treated with N-nitroso-N-methylurea (NHU) (Chowaniec and Hicks, 1979; Hicks et al., 1978) or with N-~4~5-nitro-2-furyl)-2-thiazolyliforma- mide (FACET) (Cohen et al., 1979~. In several in vitro cell culture systems, saccharin also exhibited an activity similar to the tumor- promoting activity of tetradecanoylphorbol acetate (Trosko et al., 1980). Experimental Evil. Efforts to test saccharin for muta~ results. In the Ames Salmonella reverse mutation assay, saccharin of various degrees of purity was not mutagenic (Ashby et al., 1978; McCann, 1977; Poncelot et al., 1979~. Batzinger et al. (1977) reported that saccharin was weakly mutagenic to S. typhimurium TA98 and TA100 strains in a modified plate assay and that the urine of animals fed saccharin contained mutagens for TA98 and TA100 strains. Weak mutagenic effects were observed in the mouse lymphoma assay (Clive _ al., 1979~. Dominant lethal mutations were found in animals fed 1.72% sodium saccharin in the diet (Rao and Qureshi, 1972), and a dose-dependent increase in unscheduled DNA synthesis in fibroblasts from humans was reported by Ochi and Tonomura (1978~. Continuous exposure to saccharin following treatment of C3H/lOTl/ 2 cells with 3~ethylcholanthrene led to a significant increase in the number of transformed colonies (Mondal et al., 1978~. Saccharin also induces chromosome aberrations in mammalian cells (Abe and Sasaki, 1977; McCann, 1977; Yoshida et al., 1978) and sister chromatic exchanges in cells from humans (Wolff and Rodin, 1978~. Summary and Conclusions. The epidemiological data do not provide a clear indication of an association between the use of nonnutritive sweeteners and cancer, and the results of most studies of bladder can- cer have shown no association. Exceptions are the study by Howe et al. (1977), which showed a direct association in men, and those by Hoover 14-4

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308 DIET, NUTRITION, AND CANCER and Strasser (1980) and Morrison and Buring (1980), whose results suggested a possible effect in certain subgroups. Since the data regarding saccharin and pancreatic cancer are based on studies of diabetics, who as a group are not representative of the general population, no firm conclusions can be drawn. Experimental studies have provided sufficient evidence that saccharin alone, given at high doses, produces tumors of the urinary tract in male rats and can promote the action of known carcinogens in the bladder of rats. There is limited evidence of its carcinogenicity in mice. Cyclamates Until 1970, when cyclamates were banned from use in the United States (U.S. Food and Drug Administration, 1970), cyclamic acid, sodium cyclamate, and calcium cyclamate were used as nonnutritive sweeteners in carbonated beverages, in dry beverage bases, in diet foods, and in sweetener formulations. Sodium and calcium cyclamates were used pri- marily as a 10:1 cyclamate:saccharin salt mixture (Wiegand, 1978~. Epidemiological Evidence. Epidemiological data on cyclamates alone , . . are not adequate, because cyclamates were rarely used without saccharin. Thus, it was not usually possible to distinguish the consumption of cyclamate-containing mixtures from the consumption of saccharin. Experimental Evidence: Carcinogenicity. Swiss and Charles River CD mice receiving up to 5% sodium cyclamate for 18 months or 24 months, respectively, did not yield evidence that cyclamates are carcinogenic (Homburger, 1978; Roe et al., 1970~. When sodium cyclamate (99.5% pure) was administered in drinking water (6 g/liter, or 20-25 mg/mouse) to mice for their lifetime, there was no evidence of carcinogenesis in male and female C3H mice, but there was an increased incidence of lung tumors in RIII male and XVII female mice and of hepatocellular car- cinomas in (C3H x RIII)F1 male mice (Rudali et al., 1969~. Female SPF mice fed diets containing up to 7% sodium cyclamate for 80 weeks had a higher, but statistically insignificant increase in the incidence of lymphosarcomas than did the controls (Brantom et al., 1973~. Osborne Mendel rats fed sodium cyclamate at 0.4%, 2%, or 10% in their diet for 101 weeks had an increased incidence of transitional cell papillomas of the urinary bladder, although the number of animals examined histopathologically was small (Friedman et al., 1972~. Cycla- mate (1.0 g/kg low/day) fed for 2 years led to a slight increase in the incidence of bladder tumors in Sprague-Dawley rats (Hicks and Chowaniec, 1977; Hicks et al., 1978~. Lifetime studies in one generation of Syrian golden hamsters (Althoff et al., 1975) and rhesus monkeys (Coulston et al., 1977) and 14-5

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Additives and Contaminants 309 a six-generation study of Swiss SPF mice (Kroes et al., 1977) produced no evidence that sodium cyclamate is carcinogenic. Female Wistar SPF rats treated with 1.5 mg NMU and subsequently fed sodium cyclamate (containing 13 mg/kg cyclohexylamine) in diets at doses of 1, 1.5, or 2.0 g/kg low/day for their lifetime or up to 2 years had a significantly higher incidence of bladder cancer and a signifi- cant decrease in latent period (8 weeks vs. 87 weeks) compared to animals treated with NMU only and the untreated controls (Hicks et al., 1978). In another study, a single 2 mg dose of NMU was instilled into the urinary bladder of female Wistar rats before giving them a diet con- taining sodium cyclamate at 2% for 10 weeks and then at 4% for the rest of their lives. The overall incidence of urinary tract tumors was 70% in those given NMW and sodium cyclamate, 57Z in animals receiving NMW alone, and 65% in another control group given NMU and calcium carbonate (Mohr _ al., 1978~. Wistar weanling rats were fed a 10:1 mixture of sodium cyclamate: saccharin in the diet at doses of 0, 500, 1,120, or 2,500 mg/kg low/day for 2 years. After the 79th week, 50% of the survivors from all three treated groups were also fed cyclohexylamine hydrochloride, in addition to the cyclamate:saccharin diet. The animals consuming the diet con- taining the highest levels of cyclamate:saccharin (with and without added cyclohexylamine hydrochloride) were found to have a significantly higher number of urinary bladder cancers (9/25 males and 3/35 females) compared to the controls (0/35 males and 0/45 females). Of the tumor- bearing animals, three males and two females had received cyclohexyl- amine, indicating that cyclohexylamine hydrochloride is not carcinogenic (Oser _ al., 1975~. Experimental Evidence: Mutagenicity. There are no published . data on the ability of cyclamates alone to induce point mutations in microbial and mammalian cells. In two studies, cyclamates induced chromosome breaks in leukocytes from humans (Ebenezer and Sadasivan, 1970; Tokumitsu, 1971~. No increase in chromosome aberrations was observed in hamsters given oral doses of sodium cyclamate or cyclohexylamine sulfate (Machemer and Lorke, 1976~. Summary and Conclusions. There are no adequate epidemiological data on the effect of cyclamate alone since it was rarely consumed by humans in the absence of saccharin. The experimental data provide limited evidence for the carcinogenic- ity of cyclamates in mice and rats. In addition, there is evidence that cyclamates can promote the action of known carcinogens in the bladder. 14-6

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310 DIET, NUTRITION, AND CANCER Aspartame Aspartame, the methyl ester of the amino acids phenylalanine and aspartic acid, is approximately 180 times sweeter than sugar (Mazur, 1976~. In July 1981 the FDA approved its use as a sweetener or flavoring agent in certain foods (U.S. Food and Drug Administration, 1981~. Aspartame cannot be used in soft drinks because of its instability in liquids during storage. Epidemiological Evidence. Since aspartame has been on the market only since 1981 and in only a few countries (e.g., Belgium, France, and Canada), there are no epidemiological data regarding its association with cancer in humans. Experimental Evidence: ~ ~ Carcino~enicitY. A number of feeding studies have been conducted on mice and rats under the sponsorship of the G. D. Searle Co. to test the carcinogenicity of aspartame. In one of these studies, male and female Charles River mice received aspartame at O (control), 1.0, 2.0, or 4.0 g/kg low/day in their diet for 2 years. No tumors attributable to aspartame ingestion were reported (G. D. Searle and Co., 1974a). In another study, no statis- tically significant differences in the incidence of neoplasms were observed in the urinary bladders of control and treated mice 26 weeks after implantation of cholesterol pellets containing aspartame or its breakdown product diketopiperazine (DKP) (G. D. Searle and Co., 1973a). Male and female Sprague-Dawley rats fed aspartame in the diet at various levels for up to 2 years were observed for the incidence of brain tumors (G. D. Searle and Co., 1973b). After the study was com- pleted, the FDA appointed an independent board of inquiry to review the data. The board concluded that aspartame was a possible carcino- gen, based on three of the study's findings: The incidence of brain neoplasms in aspartame-fed rats was greater than that in controls, a possible dose response was observed when tumor incidence in the con- trols was compared with the two lower dose and the two higher dose treatment groups combined, and there was a decrease in the latent period for gliomas (U.S. Food and Drug Administration, 1980a). Investigators at the G. D. Searle Co. interpreted these data differently. They contended that statistical analysis using con- current instead of historical controls indicates that there was no significant increase in tumor incidence, that more appropriate sta- tistical tests show no dose response, and that the board of inquiry made errors concerning the time of death of certain rats (U.S. Food and Drug Administration, 1980a). In a follow-up study by the Searle group, rats were exposed in utero to aspartame at O (control), 2, and 4 g/kg bw and maintained on this diet for the duration of their lives (G. D. Searle and Co., 1974b). 14-7

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A`~t:ives and Contaminants 311 The incidence of brain tumors was: 4/115 (3.4%), 3/75 (4.0%), and 1/80 (1.3%), respectively, which indicated no statistically significant difference between the control and treated groups. Recently, Ishii et al. (1981) also found no evidence for carcino- genicity in chronic feeding studies with Wistar rats given aspartame or a mixture of aspartame and DKP. The FDA concluded that this study provides additional evidence favoring the safety of aspartame (U.S. Food and Drug Administration, 1981~. Groups of five male and female beagle dogs were fed aspartame at O (control), 1.0, 2.0, and 4.0 g/kg bw in their diet for more than 106 weeks. No evidence of neoplasia was observed in any of the treated or control groups (G. D. Searle and Co., 1973c). Experimental Evidence: Mutagenicity. Aspartame and DKP were negative in the Ames test with and without using the S9 fraction from rats (G. D. Searle and Co., 1978a,b,c). Similarly, no evidence of the mutagenicity of these compounds was observed in the host-mediated assay in rats and mice at doses ranging from 0.25 to 8.0 g/kg/day (G. D. Searle and Co., 1972a,b, 1974c). Aspartame and DKP (1 or 2 g/kg low/day) were also negative in the in viva dominant lethal assay in rats (G. D. Searle and Co., 1973d). Summary and Conclusions. Aspartame has been used as a sweetener , in Belgium and France only since 1981 e It has recently been approved for use in Canada and the United States. Consequently, there are no epidemiological data pertaining to its effects on human health. Aspartame appears to be negative in in vitro bacterial mutagenic- ity tests, in the host-mediated assay, and in dominant lethal tests in rats. It has been reported to be noncarcinogenic in chronic feeding studies in mice and dogs, most of which were conducted by G. D. Searle and Company. Although a board of inquiry appointed by the FDA con- cluded that aspartame may be neurooncogenic in rats, additional evi- dence led the FDA to conclude that aspartame is not carcinogenic in animals. Butylated Hydroxytoluene (BHT) and Butylated Hydroxyanisole (BHA) Butylated hydroxytoluene (BHT) and Butylated hydroxyanisole (BRA) are widely used as food additives, mainly because of their preservative and antioxidant properties. These compounds are included in the FDA's list of substances generally recognized as safe ((ERAS). Many studies have been conducted to test them for acute and chronic toxicity under a variety of experimental conditions, ranging from in vitro studies to in viva studies in animals (U.S. Food and Drug Administration, 1977a). Based on the evidence from these studies, the FDA in 1977 recommended that BHT be removed from the GRAS list and proposed interim regulations pending future studies. 14-8

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312 DIET, NUTRITION,AND CANCER Epidemiological Evidence. There are no epidemiological studies concerning the effects of BHT and BHA on human health. Experimental Evidence for BHT: Carcinogenicity. Male and female B6C3F1 mice were fed 0, 0.3%, or 0.6% BHT in the diet for 107 to 108 weeks. In female mice receiving the low dose, the incidence of alveo- lar/bronchiolar adenomas or carcinomas was significantly higher than in the controls, but there was no dose response (National Cancer Institute, 1979a). In a similar study of male and female Fischer 344 rats, the incidence of tumors in treated animals was not statisically different from that in controls (National Cancer Institute, 1979a). Experimental Evidence for BHT: Promoting Effects. Three groups of A/J mice were injected with urethan, 3-methylcholanthrene, or nitrosodi- methylamine and then given repeated injections of BHT. The treatment with BHT significantly increased the multiplicity of lung tumors induced by all three carcinogens (Witschi et al., 1981~. BHT administered orally increased the incidence of lung tumors in A/J mice pretreated with a single dose of urethan (Witschi, 1981~. When injections were begun as late as 5 months after the urethan was administered, they still produced an increase in the incidence of lung tumors. BHT does not appear to enhance lung tumor formation, even if given repeatedly prior to ure then administration. This suggests that BHT may be a tumor promoter (Witschi, 1981; Witschi et al., 1977~. BHT also appears to have some promoting activity in BALB77 mice (Clapp et _ ., 1974) and in male Sprague-Dawley rats treated with 2-aminoacetyl- fluorene (2-AAF) (Peraino et al., 1977~. Experimental Evidence for BHT: Mutagenicity. BHT inhibited cell-to-cell communication of mammalian cells in vitro--an indication of promoting activity (Trosko et al., 1982~. When BHT in concen- trations of 0-50 ug/ml were added to phytohemagglutinin-stimulated cultures of leukocytes from humans, it resulted in a dose-dependent decrease in cell survival, as well as in an uncoiling of the chromo- somes (Sciorra et al., 1974~. In the sister chromatic exchange assay, BHT was negative and it did not induce chromosome aberrations (Abe and Sasaki, 1977~. Experimental Evidence for BHA: Carcinogenicity. The administra- - tion of BHA had no significant effect on the tumor yield or tumor multiplicity in Swiss Webster mice injected with urethan and then given BHA in the diet (Witschi, 1981~. In other experiments, repeated intra- peritoneal 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~. Under different experimental conditions, BHA has been shown to inhibit the activity of a wide variety of carcinogens (see Chapter 15~. Experimental Evidence for BHA: Mutagenicity. BHA was positive in the sister chromatic exchange assay with Chinese hamster cells as in- dicator organisms; however, it did not induce chromosome aberrations in these cells (Abe and Sasaki, 1977~. 14-9

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Additives and Contaminants 313 Summary and Conclusions. BHT and BRA are used as antioxidant s and preservatives in many types of foods. There are no epidemiological studies concerning their effect on human health. At least one adequate bioassay to test the carcinogenicity of BHT has been conducted in each of two species, the mouse and the rat, without clear evidence of carcinogenicity under the conditions of the tests. Evidence for the enhancement of tumorigenesis by BHT is restricted to two experimental systems--carcinogen-induced lung tumors in mice and liver tumors in rats. The studies in mice have been repeated several times with other carcinogenic initiators. These studies provide evidence that BHT has a tumor-promoting effect, especially for ure then and 2-AAF. On the other hand, as discussed in Chapter 15, large amounts of BHT can inhibit neoplasia induced by a number of chemicals. There is no indication that BRA has any carcinogenic or tumor- promoting activity. Its ability to inhibit neoplasia is discussed in Chapter 15. Vinyl Chloride Containers made of polyvinyl chloride (PVC) are widely used for packaging and storing foods. Since the appearance of reports linking several fatal cases of a rare form of liver tumor with prolonged industrial exposure to vinyl chloride, considerable attention has been paid to the possible carcinogenicity and other toxic effects of the monomer vinyl chloride, of which PVC is composed (Creech and Johnson, 1974; Nicholson et al., 1975~. 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 (U.S. Consumer Product Safety Commission, 1974). Vinyl chloride has been detected in a variety of alcoholic drinks at levels ranging from 0.2 to 1 mg/liter (Williams, 1976a,b) and in vinegars at levels as high as 9.4 mg/liter (Williams and Miles, 1975~. It has also been found in products packaged and stored in polyvinyl chloride containers. For example, concentrations ranging from 0.05 to 14.8 mg/kg have been detected in edible oils (Rosli et al., 1975), 0.05 mg/kg has been detected in margarine and butter (Fuchs et al., 1975), and 10.0 ~g/liter is the highest concentration found in T-nished drinking water in the United States (U.S. Environmental Protection Agency, 1975a). Epidemiological Evidence. There have been no epidemiological studies on exposure to vinyl chloride as a food contaminant; however, 14-10

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314 DIET, NUTRITION, AND CANCER several investigators have studied the effect of occupational exposure. In the United States, Creech and Johnson (1974) were the first to re- port an association between inhalation exposure to vinyl chloride and hepatic angiosarcomas. In a cohort study of males who had been occupa- tionally exposed to vinyl chloride for at least 1 year, Tabershaw and Gaffey (1974) observed an excess of cancer of the digestive system, liver (mainly angiosarcoma), respiratory tract, and brain, as well as l~rmphomas. Nicholson et al. (1975) noted a 2.3-fold excess of cancer mortality among workers exposed for at least 5 years. Monson et al. (1974) reported a 50% excess of deaths due to all cancers in workers producing and polymerizing vinyl chloride. Several other studies have indicated an association between exposure to vinyl chloride and in- creased mortality from cancer at various sites (Duck and Carter, 1976; Fox and Collier, 1977; Waxweiler et al., 1976~. Experimental Evidence: Carcinogenicity. Male and female Sprague- Dawley rats receiving gastric incubations of vinyl chloride in doses up to 50 mg/kg bw developed mainly angiosarcomas and cancers of Zymbal's gland (Maltoni, 1977; Maltoni _ al., 1975~. In lifetime feeding studies with Wistar rats, Feron et al. (1975, 1981) observed that vinyl chloride monomer in doses ranging from 1.7 to 14.1 mg/kg bw induced hepatocellular carcinomas, hepatic angiosar- comas, pulmonary angiosarcomas, extrahepatic abdominal angiosarcomas, tumors of Zymbal's gland, abdominal mesotheliomas, and adenocarcinomas of mammary glands. Inhalation exposures to vinyl chloride produced cancers of the lung, mammary gland, and liver in mice (Maltoni, 1977~; cancers of Zymbal's gland, the liver, kidney, and brain in Sprague-Dawley rats (Maltoni et al., 1974~; and cancers of the liver, skin, and stomach in hamsters raltoni, 1977; Maltoni et al., 1974~. Experimental Evidence: Mutagenicity Tests and Other Short-Term Tests. Vinyl chloride vapors induced mutations in Ames Salmonella strains (Andrews et al., 1976; Bartsch et al., 1979), Escherichia cold (Greim et al., 1975), Schizosaccharomyces pombe (Loprieno et al., 1976), Drosophila melanogaster (Verburgt and Vogel, 1977), and mammalian cells (Huberman _ al., 1975~. They also induced gene conversions in yeast (Eckardt et al., 1981~. Male workers occupationally exposed to vinyl chloride were reported to have more chromosome aberrations than were observed in unexposed cohorts (Funes-Cravioto et al., 197S; Heath et al., 1977; Purchase et al., 1975~. Summary and Conclusions. Occupational exposure to vinyl chloride . is associated with increased incidence of cancer of the liver, brain, respiratory tract, and lymphatic system, but this evidence has been derived from studies of groups occupationally exposed to high doses of vinyl chloride. Similar carcinogenic effects were demonstrated in rats that ingested or inhaled large amounts of vinyl chloride. These results were later confirmed in mice and hamsters. 14-11

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A&~hves and Contaminants 347 Nagasaki, H., S. Tomii, and T. Mega. 1975. _ [In Japanese; English Title.] Factors on liver tumor in mice induced by benzene hexachloride (BHC) and technical polychlorinated biphenyls (PCBs). Nippon Eiseigaku Zasshi 30:134. Abstract 235. National Academy of Sciences. 1977. Drinking Water and Health, Volume lo Safe Drinking Water Committee, National Academy of Sciences, Washington, D. C. 939 pp. National Academy of Sciences. 1978. Saccharin: Technical Assessment of Risks and Benefits, Part I. Committee for a Study on Saccharin and Food Safety Policy, National Academy of Sciences, Washington, D. C. t250] pp. National Cancer Institute. 1976. Report on Carcinogenesis Bioassay of Technical Grade Chlordecone (Kepone). Carcinogenesis Program, Division of Cancer Cause and Prevention, National Cancer Institute, Bethesda, Md. [25] pp. National Cancer Institute. 1977a. Bioassay of Captan for Possible Carcinogenicity. NCI Carcinogenesis Technical Report Series No. 15. DHEW Publication No. (NIH) 77-815. PB-273 475. Carcinogenesis Program, National Cancer Institute, Bethesda, Md. 99 pp. National Cancer Institute. 1977b. Bioassay of Heptachlor for Possible Carcinogenicity. NCI Carcinogenesis Technical Report Series No. 9, DHEW Publication No. (NIH) 77-809. PB-271 966. Carcinogenesis Program, National Cancer Institute, Bethesda, Md. 111 pp. National Cancer Institute. 1977c. Bioassay of Lindane for Possible Carcinogenicity. NCI Carcinogenesis Technical Report Series No. 14. DHEW Publication No. (NIH) 77-814. PB-273 480. Carcinogenesis Program, National Cancer Institute, Bethesda, Md. 99 pp. National Cancer Institute. 1977d. Bioassay of Chlordane for Possible Carcinogenicity. NCI Carcinogenesis Technical Report Series No. 8. DHEW Publication No. (NIH) 77-808. PB 271-977. Carcinogenesis Program, National Cancer Institute, Bethesda, Md. 117 pp. National Cancer Institute. 1978a. Bioassay of Malathion for Possible Carcinogenicity. NCI Carcinogenesis Technical Report Series No. 24. DHEW Publication No. (NIH) 78-824. Carcinogenesis Testing Program, National Cancer Institute, Bethesda, Md. 102 pp. National Cancer Institute. 1978b. Bioassays of Aldrin and Dieldrin for Possible Carcinogenicity. NCI Carcinogenesis Technical Report Series No. 21. DHEW Publication No. (NIH) 78-821. Carcinogenesis Testing Program, National Cancer Institute, Bethesda, Md. 184 pp. 14-4 4

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348 DIET, NUTRITION, AND CANCER National Cancer Institute. 1978c. Bioassay of Dieldrin for Possible Carcinogenicity. NCI Carcinogenesis Technical Report Series No. 22. DHEW Publication No. (NIH) 78-822. Carcinogenesis Testing Program, National Cancer Institute, Bethesda, Md. 50 pp. National Cancer Institute. 1978d. Bioassays of DOT, TDE and p,p'-DDE for Possible Carcinogenicity. NCI Carcinogenesis Technical Report Series No. 131. Carcinogenesis Testing Program, National Cancer Institute, Bethesda, Md. [230] pp. National Cancer Institute. 1978e. Bioassay of Pentachloronitrobenzene for Possible Carcinogenicity. NCI Carcinogenesis Technical Report Series No. 61. Carcinogenesis Testing Program, National Cancer Institute, Bethesda, Md. [82] pp. National Cancer Institue. 1978f. Bioassay of Methoxychlor for Possible Carcinogenicity. NCI Carcinogenesis Technical Report Series No. 35. DHEW Publication No. (NIH) 78-835. Carcinogenesis Testing Program, National Cancer Institute, Bethesda, Md. [86] pp. National Cancer Institute. 1979a. Bioassay of Butylated Hydroxytoluene (BHT) for Possible Carcinogenicity. NCI Carcinogenesis Technical Report Series No. 150. NIH Publication No. 79-1706. Carcinogenesis Testing Program, National Cancer Institute, Bethesda, Md. 114 pp. National Cancer Institute. 1979b. Bioassay of Aldicarb for Possible Carcinogenicity. NCI Carcinogenesis Technical Report Series No. 136. NIH Publication No. 179-1391. PB 298-511. Carcinogenesis Testing Program, National Cancer Institute, Bethesda, Md. 106 pp. National Cancer Institute. 1979c. Bioassay of Diazinon for Possible Carcinogenicity. NCI Carcinogenesis Technical Report Series No. 137. NIH Publication No. 79-1392. PB-293 889. Carcinogenesis Testing Program, National Cancer Institute, Bethesda, Md. 96 pp. National Cancer Institute. 1979d. Bioassay of Malathion for Possible Carcinogenicity. NCI Carcinogenesis Technical Report Series No. 192. NIH Publication No. 79-174 8. PB-300 301. Carcinogenesis Testing Program, National Cancer Institute, Bethesda, Md. 72 pp. National Cancer Institute. 1979e. Bioassay of Methyl Parathion for Possible Carcinogenicity. NCI Carcinogenesis Technical Report Series No. 157. DHEW Publication No. (NIH) 79-1713. Carcinogenesis Testing Program, National Cancer Institute, Bethesda, Md. 112 pp. National Cancer Institute. 1979f. Bioassay of Parathion for Possible Carcinogenicity. NCI Carcinogenesis Technical Report Series No. 70. DHEW Publication No. (NIH) 79-1320. Carcinogenesis Testing Program, National Cancer Institute, Bethesda, Md. 104 pp. 14-4 5

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350 DIET, NUTRITION, AND CANCER Peraino, C., R. J. M. Fry, E. Staffeldt, and J. P. Christopher. 1977. Enhancing effects of phenobarbitone and butylated hydroxytoluene on 2-acetylaminofluorene-induced heptatic tumorigenesis in the rat. Food Cosmet. Toxicol. 15:93-96. Poncelet, F., M. Roberfroid, M. Mercier, and J. Lederer. 1979. Absence of mutagenic activity in Salmonella typhimurium of some impurities found in saccharin. Food Cosmet. Toxicol. 17:229-231. Pott, P. 1775. Cancer scroti. Pp. 63-68 in Chirurgical Observations. Hawes, Clarke, and Collins, London. Preston, B. D., J. P. Van Miller, R. W. Moore, and J. R. Allen. 1981. Promoting effects of polychlorinated biphenyls (Aroclor 1254) and polychlorinated dibenzofuran-free Aroclor 1254 on diethylnitrosamine- induced tumorigenesis in the rat. J. Natl. Cancer Inst. 66:509-515. Purchase, I. F. H., C. R. Richardson, and D. Anderson. 1975. Letter to the Editor: Chromosomal and dominant lethal effects of vinyl chloride. Lancet 2:410-411. Rao, M. S., and A. B. Qureshi. 1972. Induction of dominant lethals in mice by sodium saccharin. Indian J. Med. Res. 60:599-603. Rigdon, R. H., and J. Neal. 1969. Relationship of leukemia to lung and stomach tumors in mice fed benzo~a~pyrene. Proc. Soc. Exp. Biol. Med. 130:146-148. Roe, F. J. C., L. S. Levy, and R. L. Carter. 1970. Feeding studies on sodium cyclamate, saccharin and sucrose for carcinogenic and tumour- promoting activity. Food Cosmet. Toxicol. 8:135-145. Rdsli, M., B. Zimmerli, and B. Marek. 1975. [In German; English Summary.] Ruckstande von Vinylchlorid-Monomer in Speiseolen. Mitt. Geb. Lebensmittelunters. Hyg. 66:507-511. - Rudali, G., E. Coezy, and I. Muranyi-Kovacs. 1969. [In French.] Recherches sur ['action cancerigene du cyclamate de soude chez les souris. C. R. Hebd. Seances Acad. Sci. Ser. D. 269:1910-1912. Rurainski, R. D., H. J. Theiss, and W. Zimmenmann. 1977. [In Genman.] Uber das Vorkommen von naturlichen und synthetischen Ostrogenen im Trinkwasser. GWF Gas-Wasserfach:Wasser/Abwasser 118:288-291. Rustia, M. 1979. Role of hormone imbalance in transplacental carcinogenesis induced in Syrian golden hamsters by sex hormones. Natl. Cancer Inst. Monogr. 51:77-87. 14-4 7

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Alcoves and Contaminants 351 Rustia, M., and P. Shubik. 1976. Transplacental effects of diethyl- stilbestrol on the genital tract of hamster offspring. Cancer Lett. 1:139-14 6. Schmahl, D. 1973. [In German; English Summary.] Lack of carcinogenic effects of cyclamate, cyclohexylamine and saccharine in rats. Arzneim. Forsch. 23:1466-1470. Schwartz, L. 194 3. An outbreak of halowax acne ("~able rash") among electricians. J. Am. Med. Assoc. 122:158-161. Sciorra, L. J., B. N. Kaufmann, and R. Mater. 1974. The effects of butylated hydroxytoluene on the cell cycle and chromosome morphology of phytohaemagglutinin-stimulated leucocyte cultures. Food Cosmet. Toxicol. 12:33~4. Searle, G. D., and Co. 1972a. An Evaluation of Mutagenic Potential Em- ploying the Host-Mediated Assay in the Rat. P-T No. 1028H72. Final Report. G. D. Searle and Co., Skokie, Ill. 15 pp. Searle, G. D., and Co. 1972b. An Evaluation of Mutagenic Potential Employing the Host-Mediated Assay in the Rat. P-T No. 1029H72. Final Report. G. D. Searle and Co., Skokie, Ill. 15 pp. Searle, G. D., and Co. 1973a. A 26-Week Urinary Bladder Tumorigenicity Study in the Mouse by the Intravesical Pellet Implant Technique. P-T No. 10310T72. Final Report. G. D. Searle and Co., Skokie, Ill. Searle, G. D., and Co. 1973b. Two Year Toxicity Study in the Rat. P-T No. 838H71. Final Report. G. D. Searle and Co., Skokie, Ill. 104 PP Searle, G. D., and Co. 1973c. 106-Week Oral Toxicity Study in the Dog. P-T No. 855S270. G. D. Searle and Co., Skokie, Ill. Searle, G. D., and Co. 1973d. An Evaluation of the Mutagenic Potential in the Rat Employing the Dominant Lethal Assay. P-T No. 1007S72. G. D. Searle and Co., Skokie, Ill. 35 pp. Searle, G. D., and Co. 1974a. 104-Week Toxicity Study in the Mouse. P-T No. 984H73. Final Report. G. D. Searle and Co., Skokie, Ill. 295 PP Searle, G. D., and Co. 1974b. Lifetime Toxicity Study in the Rat. P-T No. 892H72. Final Report. G. D. Searle and Co., Skokie, Ill. 255 pp. Searle, G. D., and Co. 1974c. An Evaluation of Mutagenic Potential Employing the Host-Mediated Assay in the Mouse. P-T No. 1095S73. G. D. Searle and Co., Skokie, Ill. 23 pp. 14-4 8

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352 DIET, NUTRITION, AND CANCER Searle, G. D., and Co. 1978a. An Evaluation of Mutagenic Potential Employing the Ames Salmonella/Microsome Assay. Final Report. S.A. No. 13-77. G. D. Searle and Co., Skokie, Ill. Searle, G. D., and Co. 1978b. An Evaluation of Mutagenic Potential Employing the Ames Salmonella/Microsome Assay. Final Report. S. A. No. 13-78. G. D. Searle and Co., Skokie, Ill. Searle, G. D., and Co. 1978c. An Evaluation of the Mutagenic Potential Employing the Ames Salmonella/Microsome Assay. Final Report. S.A. 13-85. G. D. Searle and Co., Skokie, Ill. Simmon, V. F., D. C. Poole, and G. W. Newell. 1976. In vitro mutagenic studies of twenty pesticides. Toxicol. Appl. Pharmacol. 37:109. Abstract 42. Simmon, V. F., D. C. Poole, E. S. Riccio, D. E. Robinson, A. D. Mitchell, and M. D. Waters. 1979. In vitro mutagenicity and genotoxicity assays of 38 pesticides. Environ. Mutagenesis 1:142-143. Abstract Ca-9. Simon, O., S. Yen, and P. Cole. 1975. Coffee drinking and cancer of the lower urinary tract. J. Natl. Cancer Inst. 54:587-591. Simon, G. S., B. R. Kipps, R. G. Tardiff, and J. F. Borzelleca. 1978. Failure of kepone and hexachlorobenzene to induce dominant lethal mutations in the rat. Toxicol. Appl. Pharmacol. 45:330-331. Abstract 260. Snell, K. C., and H. L. Stewart. 1962. Pulmonary adenomatosis induced in DBA/2 mice by oral administration of dibenz~a,h~anthracene. J. Natl. Cancer Inst. 28:1043-1051. Soos, K. 1980. The occurrence of carcinogenic polycyclic hydrocarbons in foodstuffs in Hungary. Arch. Toxicol. Suppl. 4:446-448. Subcommittee on the Health Effects of Polychlorinated Biphenyls and Polybrominated Biphenyls. 1978. Final report of the Subcommittee on the Health Effects of Polychlorinated Biphenyls and Polybrominated Biphenyls of the DHEW Committee to Coordinate Toxicology and Related Programs. Environ. Health Perspect. 24:129-239. Suess, M. J. 1976. The environmental load and cycle of polycyclic aromatic hydrocarbons. Sci. Total Environ. 6:239-250. Tabershaw, I. R., and W. R. Gaffey. 1974. Mortality study of workers in the manufacture of vinyl chloride and its polymers. J. Occup. Med. 16:509-518. 14 -49

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