National Academies Press: OpenBook

Diet, Nutrition, and Cancer (1982)

Chapter: 14 Additives and Contaminants

« Previous: 13 Mutagens in Food
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 304
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 305
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 306
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 307
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 308
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 309
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 310
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 311
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 312
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 313
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 314
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 315
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 316
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 317
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 318
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 319
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 320
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 321
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 322
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 323
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 324
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 325
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 326
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 327
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 328
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 329
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 330
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 331
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 332
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 333
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 334
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 335
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 336
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 337
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 338
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 339
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 340
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 341
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 342
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 343
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 344
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 345
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 346
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 347
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 348
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 349
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 350
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 351
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 352
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 353
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 354
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 355
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 356
Suggested Citation:"14 Additives and Contaminants." National Research Council. 1982. Diet, Nutrition, and Cancer. Washington, DC: The National Academies Press. doi: 10.17226/371.
×
Page 357

Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

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

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

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

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

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

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

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

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

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

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

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

Ad~nves and Contaminants 315 Vinyl chloride is mutagenic in bacteria, yeast, Drosophila, and mammalian cells. It also has clastogenic effects on humans. Acrylonitrile Acrylonitrile is produced on a large scale in industry. Its occurrence 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. For example, in a preliminary analysis of three foods wrapped in acrylo- nitrile-based packaging materials (margarine, olive oil, and bologna), C. V. Breder (U.S. Food and Drug Administration, personal communica- tion, 1980) detected acrylonitrile in concentrations ranging from 13 to 49 ng/kg. Epidemiological Evidence. Exposure of the general public to acrylonitrile could occur through migration of the residual monomer in polymeric products in contact with food or potable water. The significance of such exposure has not yet been evaluated. However, a retrospective cohort study of 1,345 male employees possibly exposed to acrylonitrile at a DuPont textile plant indicated that there was a trend toward increased risk of cancer at all sites, especially the lung. The risk was greater as the duration and amount of exposure increased (O'Berg, 1980~. Experimental Evidence: Carcinogenicity. Rats receiving acrylo- nitrite in drinking water in doses of 100 or 300 mg/liter for 12 months developed stomach papillomas, tumors of the central nervous system, and carcinomas of Zymbal's gland (Norris, 1977~. In an inhalation study with acrylonitrile, rats developed tumors of the central nervous system and ear duct, as well as masses in the mammary region (Norris, 1977~. Experimental Evidence: Mutagenicity. Acrylonitrile induced mutations in the Ames test in Salmonella strains TA1535, TA1538, and TA78 (Milvy, 1978; Milvy and Wolff, 1977) and in E. cold (Venitt et al., 1977~. But chromosome aberrations in workers exposed to acrylo- nitrile for an average of 15.3 years did not exceed those in unexposed controls (Thiess and Fleig, 1978~. Summary and Conclusions. There is no information on the health effects resulting from the ingestion of small amounts of acrylonitrile monomer in the diet. Humans potentially exposed to acrylonitrile in a synthetic fiber plant were found to be at an increased risk of cancer, particularly of the lung, but there is no further information on this subject. In experiments in rats, ingestion or inhalation of large amounts of acrylonitrile enhanced tumors at several sites. This limited evidence, combined with the finding that acrylonitrile is mutagenic, suggests that acrylonitrile may be carcinogenic in humans. 14-12

316 DIET, NUTRITION, AND CANCER Diethylstilbestrol (DES) - Considerable attention has centered on the public health consequences of drug residues in animal tissues consumed by humans. Among the approximately 20 growth hormones commonly used in animal feed, attention has mainly focused on diethylstilbestrol (DES), whose residues have been monitored for many years following reports that DES was carcinogenic in animals (Fitzhugh, 1964; Jukes, 1974~. Until June 1978, DES was permitted for use by humans as a control for func- tional menstrual disorders; for prevention of postpartum breast en- gorgement; as therapy for estrogen deficiencies associated with the climacteric and other hormone-related conditions; as a morning-after pill; and as chemotherapy for prostate cancer and for breast cancer in postmenopausal women. Until 1979, when the use of DES was terminated, it was also permitted as a growth promoter for cattle and sheep under certain conditions delineated by the FDA (Code of Federal Regulations, 1978; U.S. Food and Drug Administration, 1979~. In 1972 and 1973, the U.S. Department of Agriculture detected DES residues in beef liver at levels of 2 and 0.5 ~g/kg, respectively (dukes, 1976; Mussman, 1975~. Since 1973 no residues of DES have been detected in 99.4% of a small number of beef livers sampled by methods that have a detection limit of 0.5 ~g/liter (Rurainski et al., 1977~. Epidemiological Evidence. There are no reports of epidemiological studies concerning the health effects of DES residues in food. Thera- peutic doses of DES during pregnancy have been associated with an in- crease in vaginal and cervical adenocarcinoma among the daughters of DES users, primarily in those between the ages of 10 and 30 years (Greenwald et al., 1973; Herbst and Cole, 1978; Herbst et al., 1972; Hill, 1973). Cases of breast cancer in men treated with DES for prostate cancer have been observed after the start of the treatment (Bulow et al., 1973~. Of 24 female patients treated with DES for 5 years or more for gonadal dysgenesis (Turner's syndrome), two developed endometrial car- cinoma (Cutler et al., 1972), but the risk of endometrial carcinoma in untreated patients is not known. Experimental Evidence: Carcinogenicity. DES fed to C3H female mice in concentrations ranging from 6.26 to 1,000 ~g/kg diet produced mammary carcinomas in increasing incidence with increased doses (Gass et al., 1964~. At the highest doses (500 and 1,000 ~g/kg diet), the latent period was reduced from 49 weeks to 31 weeks. Male C3H mice developed mammary carcinomas when fed DES at doses of 500 ~g/kg diet or more (Gass et al., 1964~. In C3H/An mice fed DES at O and 250 ~g/kg diet for 18 months, the incidence of mammary cancers was significantly higher than in the controls (Gass et al., 1974~. 14-13

Additives and Contaminants 317 Sprague-Dawley rats fed DES at 0.02 or 0.2 mg/kg bw in the diet daily for 2 years developed pituitary tumors (males only), some hepatomas (females only), and mammary tumors (males and females) (Gibson et al., 1967~. In the progeny of pregnant Syrian golden hamsters administered DES by intragastric tube, there was a high incidence of metaplastic, dysplastic, and neoplastic lesions in the genital tract (Russia, 1979; Rustia and Shubik, 1976~. Experimental Evidence: Mutagenicity and Other Short-Term Tests. DES was not mutagenic in the Ames test with and without metabolic activation (Glatt et al., 1979; McCann and Ames, 1976) and in E. cold (Fluck _ al., 1976~. It induced chromosome aberrations in Chinese hamster fibroblasts (Ishidate and Odashima, 1977) and in marine bone marrow cells in viva (Ivett and Tice, 1981~. In other studies, DES induced mutations in mouse lymphoma cells (Clive, 1977), unscheduled DNA synthesis in HeLa cells (Martin et al., 1978), and aneuploidy in viva in several strains of mice (Chrisman, 1974~. - Summary and Conclusions. There is sufficient evidence that DES used in therapeutic doses produces vaginal and cervical cancer in the female offspring of treated women. In animals, it produces mainly mammary tumors in various species. ENVIRONMENTAL CONTAMINANTS Environmental contaminants in food can be loosely divided into three categories: some trace metals and organometallic compounds, some natural and synthetic radioactive substances, and some natural and synthetic organic compounds. Only a few pesticides, two industrial chemicals, and some contaminants falling into the third category are discussed in this section. Pesticides 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. Despite extensive exposure of the general population to low levels of pesticides from numerous sources, especially foods and drinking water, very little reliable information is available about their effects on human health. Nevertheless, since many pesticides whose residues are present in food are known or suspected of being carcino- genic in some animal species, there is a basis for concern about their potential effects on human health. Although the use of several organo- chlorine compounds has been gradually suspended by the Environmental Protection Agency, some concern is still warranted because they have a propensity to persist in the environment, to accumulate in foods 14-14

318 DIET, NUTRITION, AND CANCER commonly consumed by humans (U.S. Department of Health, Education, and Welfare, 1969; U.S. Food and Drug Administration, 1980b), and to con- centrate in body tissues (International Agency for Research on Cancer, 1979). The general population is exposed to these compounds principally through food and drinking water (International Agency for Research on Cancer, 1979~. As demonstrated by the Market Basket Surveys conducted since the early 1960s by the FDA, the levels of pesticides in food are very low and they vary only slightly from region to region. The organo- chlorine compounds tend to accumulate in fat-containing foods such as meat, fish, poultry, and dairy products, whereas the organophosphates are generally more common in cereal products (U.S. Food and Drug Admin- istration, 1980b). This section focuses on only a few pesticides--primarily, the organochlorine insecticides and miticides, some organophosphates, and two carbamate insecticides. These compounds have been selected because most of them are monitored regularly through the Market Basket Surveys (U.S. Food and Drug Administration, 1980b), because they were or are used widely and, therefore, present a greater probability for human exposure, and because many of them, especially the cyclodienes and their epoxides, are believed to be potentially hazardous to human health (International Agency for Research on Cancer, 1974, 1979; National Academy of Sciences, 1977~. Epidemiological Evidence. Two cross-sectional studies were con- ducted on workers engaged in the manufacture of dichlorodiphenyltri- chloroethane (DDT). In one, 40 men exposed to an estimated 10 to 40 mg DDT daily, mainly through inhalation or dermal contact over 1 to 8 years, showed no evidence of neoplasia (Ortelee, 1958~. In the second, no cases of cancer or blood dyscrasia were reported among 35 workers exposed to 3 to 18 mg DOT daily for 11 to 19 years (Laws et al., 1967~. More than 30 cases of aplastic anemia associated with exposure to toxaphene, lindane, or benzene hexachloride have been reported (Inter- national Agency for Research on Cancer, 1974; West, 1967; U.S. Environ- mental Protection Agency, 1980~. Jedli~ka et al. (1958) described a family with two boys who developed leukemia 8 months after exposure to lindane in an agricultural distribution center. Infante et al. (1978) reported 14 cases of neuroblastoma over a 16-month period. Of these, five were in children who were unintentionally exposed pre- and postnatally to chlordane formulations. Wang and MacMahon (1979) reported that there was no overall excess in mortality from cancer and no significant excess in deaths due to lung cancer among 7,403 workers employed for 3 or more months in plants manufacturing chlordane and heptachlor. However, no definitive conclu- sions can be drawn because the population was small, and the period of follow-up was short. 14-15

Additives and Contaminants 319 In a case-control study of 60 subjects and 120 controls, Wang and Grufferman (1981) found no correlation between the disappearance data for various chlorinated hydrocarbons and mortality (during 1950-1975) from aplastic anemia among workers engaged in occupations associated with such exposure. Jager (1970) and Versteeg and Jager (1973) reported a follow-up study of 233 workers who were exposed to aldrin and dieldrin for as long as 17.5 years (average, 7.6 years). One death due to stomach cancer was reported among the 181 workers still employed by the firm at the time of the study in 1968. The EPA conducted a survey of 199 workers exposed to toxaphene for an average of 5.23 years between 1949 and 1977 (U.S. Department of Agricul- ture, 1977~. Among the 20 deaths that occurred, one was due to stomach cancer. Barthel (1976) reported a high incidence of lung cancer (11 cases versus 0.54 expected) among 316 farm workers exposed to various pesticides including DDT, toxaphene, lindane (~-benzene hexachloride), hexachloroben- zene (HCB), and parathion for 6 to 23 years. Whether cancer was asso- ciated with exposure to individual pesticides is difficult to determine because the investigator did not control for smoking, and the workers were exposed to various chemicals simultaneously or alternately. Experimental Evidence. Tables 14-1, 14-2, and 14-3 present the re- suits of carcinogenicity and mutagenicity tests for some organochlorine compounds, some organophosphates, and two carbamates. Only studies in which the chemical was administered orally have been included in the evaluation for carcinogenicity. For most organochlorine pesticides, the evidence for carcinogenic- ity is based on the production of parenchymal liver-cell tumors in mice. With the exception of methoxychlor, which has not been found to be mutagenic or carcinogenic, all other organochlorine compounds listed in Table 14-1 appear to be weakly carcinogenic in mice. Results from tests in rats indicate that toxaphene and Kepone (chlordecone) are carcinogenic and that heptachlor (with chlordane), hexachlorobenzene, and lindane may be carcinogenic. Hexachlorobenzene also causes cancer in hamsters. In bioassays conducted by the National Cancer Institute (1978a, 1979b,c,d,e), the organophosphates malathion, methyl parathion, and diazinon did not lead to an increase in tumor incidence in rats or mice (Table 14-2~. However, parathion resulted in an increased incidence of cortical tumors of the adrenal gland in Osborne Mendel rats (National Cancer Institute, 1979f). Parathion and diazinon were not mutagenic in bacterial tests, but studies have indicated that parathion induces chromosome abnormalities in guinea pigs (Dikshith, 1973) and that diazinon induces them in the lymphocytes of humans (Huang, 1973~. Aldicarb is a highly toxic compound, as indicated in Table 14-3, but it does not appear 14-16

320 to · ~ ~ _ Cut ~ 0 I: ~ 1 ~ ~ ~ 0 ~ ~ '- 0 a' ~ 0 ^ ~ ~ a, ~ ~ O ~ ~ ~ _ 0 ~ ^ ~ ^ ·~ - ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ '0 ~ 0 ~ a - 1 - ~ o ~ ~ ~ ~ ~ ~ ~ ~ ~ ~1~ °` $4 ~11~ o .- ~ o ° ~ ~ tlI O~ I, co ~ ~1 to ~ to tat ~ ~ a' 3 ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ' - ~ ~ ~ ~ ~ ~ ~ ~ _ - a^ ~ "^ ~ ~ ~ o ~ ~ V - = I ~l ~ ~ ~ ~ In ~ °` ~ ,= ~ .^ Z ~ C E ~ ~ ~ ~ ~ 1 ~ ~ ~ ~ ^ C) ~ ~ ~ ~ ~ ~ ~ ~ 0 ~ ~ ~ ~ ~ o ~ ~ ~ o ~ ~ '- ^ ~ ~ 0 ~ ~ ~ ~ C ~ ~ "U~ ~ ~ em ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ o ~ :~ 0 ~ C., 0 ~ ~ ~ - 0 ~ ~ ~ 0 ~ 0 ~ "1 ~ m~ o ~ "1 o~ ~ ~ ~ ~ c0~- "O ~ c~ ~ ql ~ q~ 0 a~ c~ a~ ~1o a~ ~ a" ~ c ~ 8 ~ ~ ~ ~ 8 ~ u ~ ~ ~ ~ ~ ~ 8 0 ~ ~ ~ 0 ~ ~ ~ ~ _ ~ ~ ~ c~ C ~ ~ ~ c~ C ~ ~ ~ ~ C ~ c~ ~ t ~ c~ C ~ . r~ c~ ~ ~ 0 0 c~ a V ~ O C ~ ~ ~ ~ N ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ O O. ~ ~ C: c. ~ —~ C.J ~ ~ ~ ~ ~ ~ ~ U ~ ~ u ~ ~ ~ C c) ~ ~ r' 3 u ~ ~ c) 3 ~ ~ ~ ~D ~ _' ~ C~ ~ C: ~ O ~ ~ ~ ~ C. c~ ~ a' u ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ u ~ ~ ~ u Z C ~ ~ ~ ~ - - 0 C ~ 0 ~ ~ ~ ^ ~ ~ ^ C ^~ ~ ~ ~ ~ ~ ~ 0 ~ ~ ~ ~ ~ ~ ~ 0 C ~ ~ ^ ~ ~ 0 o~ - ~ ~ C~ ~ s0 u C) S~ a~ c~ c) ~ ~ ~ O ~ c; ~ :~ ~ c; ~ ~ C ~ c~ ~ c~ ~ u c~ ~ ~ Eg 0 0 0 ~ n, ~ 0 ~ ~ 0 E" `: ~ ~ ~ ~ ~ ~ 7 ~ E ~ u tn 7 ~ cn ~ s~ C ~ ~ ~ 0 ~ ~ ^ ~ ~ C ~ S ~ ~ ~ 0 c, ~ ~ ~ ~ ~ ~ ~ 0 13 0 c~ ~ ~ 0 0 . qJ c~ ~ 7 ~ ·- ~ ~ ~ ~ s~ C ~ ~ 7 :~ u ~ ~ ~ t: ~s) ~ ~ s-~ ~ ~ ~~ c) ~ c ~ ~ ~ s" a' c ~ c~ ~ id ~ ~ C) ~ O O C) C ~ ~ 0 v C c~ ~ ~ ~ `: o a~ ~ a' ~ ~ oo ~ ~ o ~ ~o ~ ~ ~ o ~ ~ c ~o q ~ c oo ~ o~ 0 oo ~ ~ ~ 0 oo ~ ~ ~ e ~ ~ ~ ~ z s c a' ~ ~ ~ ~ s ~ ~ ~ ~ 7 C ce ~ ~ ~ ~ ~ ~ ~ cll 7 ~ C ~ :, ~ rC c~ C~ ~ U) C) ~ E~ ~ ~ c~ C) 0 ~ E~ :Z ~ C~ tn u ~ C~ u~ c~ ~ ~ ~ u~ ~c E3 ~ ° ~ c~ CO ^ ~ 0 - 1 C) a1 ~ 0 ~1 ·~ ~ {~~ ^ t_ I ~ ~ 0 cn mi e~~ u ~ ~ 0 ~ ~ ~ ~ ·— ^ a~ ~ ~ ~ u ~ C ^ — U 0 u~ 0 oo ~ ~ ~ ~ 0 u~ ~ ~ ~ ~ ~ ~ C ~ · O ~ ~ ~ o' a' ~ ~ ~ 1—~ 0 ~ ~ ~ ~ ~ C) ~ ~ 0 ~ 1— C~ Q-) ,, `,` u ~ ~ ~ U~ 70 ~ ~ ~ :> ~ O 13 S ~ E3 ~ ~ t. 0 0` ~ ~ 0 oo ~ ~ ~ ~ m 0 ~ ~ e 0 a ~ <~ . 0 s r4 ~ t: ~ ^ ~ · · ~ ~ _ ~ ~ ~ ~n ~ ~ ~ 5" 0 C ~ ~ · ^ ~ ~ 0 ~ ~ ~ 0 7~1 a ~ ~ ~ ~ ~ ~I: ~ - ' ~ g ~ ~ ~ ~ co ml~l ~ ~ N _1 al 1 0 ~ ~ ~ - ~ ~' S _ C 0 ~ ~ ~ ~! ~ _ 0 C C ~ U ~ ~ ~ ~ C ~ · U C ~ ~ U O ~ ~ C _d ~ ~u 0 ~ ~ ~ ~ =1= ~ ~ ~ c 0 ~ V E~ ~ O ~ ~ ~ ~ 7 ~ 3 O ~ ~ ~ `: ~ c0~ ~ O ~ ~ ~ S ~/ S C C ~ ~ ^ 0 ~ ~ C ~ <: ~ O ~ ~ ~ S _ c~ >c >~- a~ ~ ~a ~ c >~m ~a ~ c >~ ~ ~ ~ ~ c ~ 0 ~ c . ~ c c~ · o ~ 0 ~ ~ . - - ~ o ~ s" =: oO ~ ~ ~0 ~ ~ S ~ :^ ce ~ u ~ o o ml B ~ ~ ^ ~t 3 u ce o B ~ o ~ .^ V c~ ~ ~ ~ ~ s~ 0 ~ ~ a~ ~ c~ E~ t~ B ce S ~ ~ s c~ u~ ~ B ~o O ~ ~ to ~ oo c~ ~ ~ 0 0 0 c' E ~ ~ oo ~ u ~ u . oo ~ o0 · _ ~ Q, ~ x: ~ a: ~ c 0 ~ u O :~ ~ · C U, ~ ~ c' ~ ~ ~ ~ C · u, :; ~ z _ z _ ;~ c~ ~ ~ ~ _v~ =1q~ _ z 3 q~ ~ ~1 ~ Z ~ =1~ Z ~J ~ O E~ O U) :- ~ r~ ~ ~ ~ ~ u~ ~ C~ ~ 0 ~ O \0 ~D ~I h CO O u~ er) L~ ~ O C~ 1— 1~ u~ O _~ O ~ —I c~ tl ~ m~ ~ O O C~ C~ O O O O O O O O O _ —~ 00 0 0 0 0 ~ 00 00 0 00 0 000 O 3 · · ~ · ~ ~ ~ · ~ . . · ~ · ~ . · . ~ ~ ~ 000 0 00 ZOO 000 00 0 000 U ~ ~r~ :^ ~ 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 V ~ _ ~ ~ cr' u~ ~ ~ u~ r~ o' u~ ~ ~ u~ I— a' u~ l_ .— ~ 0~ ~ ~ r~ I_ ~ I_ ~ r_ t_ I_ ~ ~ [_ ~ f~ r_ I_ _~ ~ ~ ~ ~ ~ ~ ~ o~ a~ ~ a~ a~ ~ a~ a~ a~ o~ a o ,~:: — 1 ^ V t0 m~ ~ ~ c a `= ^ s _ ~ ~ ~ ~) _ ~ 1 S O c ~ ~ ~ P~ _ ~ v ~ c ~ c 3 ~ ~ C ~= ~ ~ ~3 ~ ~ ~ ~ O ~ O ~ S :^ S b0 ^ ~ ^ ~S O _ ~ t0 ~ ~ ~ S oO ~ C ~ O O V O a o~ 0 ~ ~ - ~ 0 E~ ~ E~ o o s~ o JJ _ 7 ~ ~ ~ S~ S O V O V V ~ c' · u~ ~ · C · ~ ~ C ~ 0 . . S~ <: O ~ ~ ~ ~ c~ ~ ~ O ~ Z 1 41 O ~ 1 1 X ~ a, 0 O ~ O O N ~ C —/ ~ ~ —~ C O ~c ~ ~ ~ a) ~ ~ V ~ ~ V ~ V~ ~ S C ct~ c~ S ~ ~ ~, Z C~ N 0 ~ E~ o. Pe~O _1 C ~ C-) X c~ ~ C S a, a ~ ~ := ~ v ~ c _ ~ ~ 14-18

c x o ~ E" J ., . . :~: 14-19 0 0 o o _ ~ C C C C~ eC 3 a~ c~ ~ O C) C oo ,! C~ ~ Z V C ~ t_ C ~ ~ 0= V ~ C 0 V C ~ ~ o oo ~ ~ ~ s~ ^ - CO ~ ~ ~ ~ v ~ 0 o ~ V~ C Z O o~ C^ a, ~ s0 o, 0^ O q V o o. - o _' ~C ~ ~ :^ 0 C ~ C 0 ~ ~ V V C) C~ C ~ al C O o Z C 1 ~ ~ V oo 0 o ~ V ~ C C C' · ~ .^ _1 1 ~ _I ~ ~ ~ ~ C ~ ~ o' ~ 0 Ps C ~ ~ ~ ~ C~ e0 ~ C ~ o~ ~ ~ _ o ~ ~ ^ O ~ C. ~ ~ o ~ · ~ V U. o ~ U. C. O _. ~ U) —~ ~ ~ C 3 J~ ~ (U V ~ ~ 0 O 4~ ~ O ~ ~ ~ ~ ~ ~ O 00 ~ ~ ~ ~ O 00 ~ ~ o . o' o :r: Z; 3 ~—1 ~ ~ C _ r~ co ~ ~ c~ c~ ~ ~ r~ O O O O ~ O O O O O O O · · · . . . 000 000 1 1 1 r~ t_ t_ a~ 1 1 1 U~ r~ ~ r~ ~ a~ ~ a' # V 4 ^C 0 · O V O ~ # ~ 0 # ·~ - C~ ~: r~ ~ V ~ 0 - e so ^ C~ # z o~ ~ ~ C 0 ~ ~ 0 t0 v 3— 0 V # Z C # 0 0 =" C ~ ~ ~ - 4 0 S" V ~ S # _ 0 .^ C) C ~ .` t0 or~ >^ ~ 3 U, ~ ~ 0 0 0e,1 #1— o _' C - 1. ~ ~ ~ ~ ~ ~ V O :^ 0 # 0 0 S4 ~ ~ 0 0 ~ ~ ql S O ~ ,~: ~ ~ ~ ~ V t~ )" ^ ~ :^ ¢11 0 1` e~ 0 ~ V C ~ 0\ C~ ~ ^ ~ ~ O ~ " - 0 0 V o' ~ # ~ ~ ~ ~ ~' O ~ 0= ~ # O O ^ - :~4 ~ ~ ~ ~ ~ ~ 0 ~ - _ V · - ' ~ ~ ~ :^ C Ll ~ ~ ~ ~ # O V s" # O 0 ~= ~ ~ ~ ~ ~ C _1 S :3 ~ oo # p. ~ ~ ~ V S ~ ~ O O O O 00 0 · · — O O O 1 1 1 U~ ~ o' |~ a' ~ o, _~ S~ ~ V ^ C) ~ ~ ~ # # 0 V ~ ~ ~ C~ O ~ C~ ~ _. al Pe=. ~ # ~ ~ # _. O S~ O V _~ # C ~ ~ 0 0 V ~ V Z ~ Z C 0 ·. 4 1 V~ 0 V C~ a~ ~ ~_ # - m ~ C~ # C 0 ~D V O C C ~ C _1 ~ ~ 54 C V ~ O ~ t0 ~ ~ 0 ~ 0 # # 0 # U) C) ~ ~ O ~ # 0 ^ C 0 · ~ ~ ~ V ~ ~ e~ 0 0 ~ - < <: ~ ~ ~ ~ C q~ C ~J .,1 — ~ ~ V J~ _1 0 $4 ~ 0 · ·^ V ~ OOS 3 r_ # ~ '_ # ~ C ~ · ~= ~ ~ 0` V 00 ~ ~ ~ ~ 0 0 t0 # U C # E~ 0 C ~ ^ O 0 V · ^ C - - ~ 0 ~ "~ - ~ ~ a~ 0 oo r~ ~ ~ ~ o ~ o' 0 c ~ ~ ~ "1 Z ~ ~ ~—~ ~ ~ V ~1 o ~C o (— ~ _' ~ C~ O O O O O O · . . . O O O ! ,, I i ~ ~ o~ ·_ ,~ ,_ 1 ~ o~ ~ _ # ~ ~o 0 C~ 0 0~0 Z V # 0 # ~ ~ 0 0 0 ~ ~ ~ _ 4d o ~ ~o C =` C V ~ - ~: 1 V 0 C o 0 o 0 ~ C ~ o 0 ~ C V ~ V C q4 o 0 ~ # ~ ~ V oo Ps V C a, U) s C o5 V s 0 ~ # ~ 0 0 ao ~o ~ C # ~ C # ~ o . 0 ~ o o 0 CO Z ~ ~o~ o 0 :^ C ~ U, o 0 V ~q # o ~ s" Z ~ # ~ c~ c ~ ~ o c s c' 321 c o C) C o o ~ ~ C) # o CO ~ 0 o P. ~ X # o N 0 C C t0 ~ O · S ~C 0 S V 0\ ~ 0 - S ~: 3 # O O ~ 0 O ~ ~ 3 N C C O a, b0 `0 S ~ C 0 ~ S V~ _~ 0 - o ~ O oD O ~3= Pc %_ ~ s" 0 ^ O a~ ~ C S ~ 0 0 0 - 1 C. S~ ~ - < 0 0 a, ~ 0 O O Ol4 - : O 00 ~ C ~ 0 0 ~ 3 ~ C (U ~S O C~ O O ~4 0 C O · ~n ~ ~ V X · ~ Ct —I J :> N 0o ~ ~ 0 ~ C. C~3 :^ _ ~ ~ - 0 ~ ~ O 0< 3 ~S ~ 0 C ~ ~ · :^ 0 ~ ~ C) ~ {0 :^ ~ ~ · ~ ~ 0 ~ CO a0 m S V o _ a 0 ~ 0 ~ . ,~ ~ # - ~ ~ · U U, ~ 0 O · V ~ ~ <: C ~ ~ 0 0 P. ~ ~ oo~ C V 0 V~ 0 0 s~ " - O <~: s. ~. ~ ~ 0a ~ r~ ~ ~ Z 0 q' ~ 0 a" ~ osaP3 ~ ~ 0 ~ a ~ z z a ~ ~ v ~ ~ - # 00 a'

322 U. a' e~ C) e~ CO CO o C~ 1 0 ~0 S~ ~ O ¢ ~0 U. o ~0 o erl C) S~ C: C) {0 ~ ~ :^ O ~ o :^ 4 O C) 00 O C el-4 _I C :,} e - . 1~4 63 C~ -; 0 :- ~ 0 eml ~ 00 4 x: ~ _% 3 _ 01 _ o 0 1 a, s~ ~ o o ~ C} e ~ ~ ~ ~ ~ so~ 0 ~ tO ~ e~ ~ O C ~ ~ e - . e~ ~ ~ Z ~ ~ _~ ^ CO a. Z ~ m ~o _ r~ ~ c; I~ ~ ~ CO e~ ~ ~d 0—~ ~ E!—I C~ ~ ~ ^ - e~ ~ 4~1 ~ 14 dU 4J ~ ~ ~ ~ ~ C' ~ ~ #! ~ ~ C) ~ ~ e~4 S~ I1J S ~ C ~ _. eC H4 C C) O so a erl erl ~ U. e~ ~ 0 ~ C) O ~ C} C O ~ ~ ~ - Z ~ C ~ e~4 CJ C,) ^= · ~ - 1= ~1 - 0 0 ~ - o ~ ~ ~ ~ ~ ~ ~ JJ · 1 ~ s s" ~ to c c ^ ~ ~ go ~ ~ ~ ~m u o ~ ~ ·- ~ El erl E3 0 00 - ~ ~ ~ ~ O Cm Z u, ~:1 ~ _I O O ~ O `0 ' - ~ ~ ~ == 0 00 J O O O · · · · · - O O O O O O 1 1 1 1 1 1 U~ r_ ~ 1_ ~ ~ C~ ~ a, S 4~ O ~ q' C O ~ C e~ O ~ ~ Z C 14 O O C) ~ 0` 0 C) O C ~ ~ V 4 C C) ~ ~ F' ~ ~ e~ ql ~ 0 000 C 0 ~ 4J O S" C ~ ~ C) ~ ~ C C~ ~ ~ C 0 1 ~ :^ ^ C. ~ ~ 0 · )" e~ L. t0 · 0 ~ t0 C) C C~ ~J ej~ O S ~ ~ =" "S ~ ~ 0 C) 0 a, ~ c~ ~ ~ 0 ~ 0 ~ "` U) , ~ ~ O C dJ )~ ~ E3 erl Se~ C ~ C~ O ~1 {0 ~ $4 i4 t0 C~ OO.C: ~ ~C C ~ ~ ~ ~ e—~ ~ _~ ~ O C) ·- ~ S ~ ~ e~ . - ~ 0 0 ~ ~ O O C~ ~ t0 ~ C0 0 0 0 e~l ~ C C 0` ~ e~ ~ ~ Z ~ ~ ~ V O _ aC C) 0 0 e~ - 4 40 CZ eP4 _ ~ :^ am a~ c~ ~ 0 erl 0 O - " C - ) e" C `0 ~ erl ~ ~D C ~ C e~ ~ b ' 0 00 ~ ~ ~ ~ a' Z b C) I e~ 0 O 0 C) O O ~ 0 · O Cz3 1 3 O O ~ C _4 b c' ~ ~ e - | ' ~ C) ~ C C ·- ~ _. - ^ 0 r~ 0` 0 C O 0` ~ O 0e b ~J ~ ~ ^ C) eO elo _1 C C b C ~C ~ ~ ~1 e' O q~ :~ O ~ ~ 3 _ C ~ _ \0 1_ O 0 0 ~D O 00 0 0 - 0 0= 0 0 0 . . ~ · . . O O Z O O O 1 1 1 1 1 1 r~ ~ u~ ~ ~ _ 1_ ~ I_ C'` ~ ~ Cr' 0` _t _t ~ 4 O O . ~ O ~ O ~: C JJ ~ ~ ~ N :~: ~ ~ 0 \0 C O C C 0 e" ~ _t O ~ ~ ~ 0_ ~ _~ ~ b b ~ ~— _I —1 ~ b O U) C ~ :^ C) —_I ~ C) It, ~ {0 0 · q, · 10 ·^ - 1 - ~ ~ ~ I ~ C~ C ~ ~ O ~ · C ~ 0 - 0 C O ~ O C - > - ^ O ~ 0 1 _~ ~ · b V U, ~ S ~ 0 ~ t0 00= 0 ~ ~ C ~ C ~ O O Z a, ~ ~rl ~ ~ C) oc 0 o e~ v N e~ 00 o ~C ~ ^ :~: 0` O ~ 3 0 er ~u dJ s ql C ~5 ~0 :^, b O S C) O b ^ b O S" O CO O ~3= s __. 0 0 0 0 <0 e~ _. ~ ~J 0 b ~ - : 0 0 O C O er O ~ `4 4 O 00 ~ 0 ~ ~ _ 00 _ 0 0 ~ ~ ~ O s~ O J `4 s" - cn c' X - ~ _ 0 0 a~ ~ 0 =3 :^ _ O ~ O ~: b ~4 ~ V) S ~ C ~ "4 0 :- ~ ~ 0 S ~ 0 - - 0 · . _. b a' ~ a, ql ~ c~ c~ ~ 0a ~ ~ co ~ ~ ~ ·= c, 0 v ~ 0 0 ~S: ~ b ~ ~ O c~ ~ OOZ 11 ~ ~1 q! cO ~ b n C. ~ 0 ~ 0 >O ~ ~o a ~ ~oz s 4~ 0 o x b 0 S S S 3 o 0 ~C o c~ S C S - S" O s4 S 00 S E JJ C C11 b 3 0 14-20

1 u] e~ C~ er1 ~n a, a) U C~ a, O ~ U) ¢ E~ 14-21 o u erl Cd e~ a, e~ C) ~ _ C}— ~ C C :^ C C C,) _ C ~ 00 ~ 0 a C ~ C V ~ s" E C~ ~ C. cn al a' V c oo 4 :~: ~ C~ c _ ~ 3 _ oo ~L ¢:) - ' 3 o~ _ ot ~ ~ O <~ ~ _1 :^ V ~ 0 s" P4 C~ . ~ V ^ ~ ~ oo -, C o ~ v e ~ ~ ~ 0 C C~ ~ ~ 0 ~ ~ ~ ~ ^0 C} rO t bo ~ ~ ~ C ~ ~ ~ c~ ~ c ~ ~ c) ~ - : c c ~ - ~ ~ ~ ~ o ~ x~ c) 0 e~ V _I V 34 ~ ~ e, - X o 0 ~ o E3 0 oo o 3= o ~ ~ _ ' ~ t. s~ p4 —_ $4 1 v ~ ~ ~ I—P: t) El 0 ~ ~ ~ ~ C o C~ ~ ~ ~ C. c ~ ~ u3 X ·^ c E1 `4 C. ~ O C~ -1 V e~ ~ ~D 0 ~ ~ Om C {0 1— a C O ~ ~ ~ ~ ~ 00 E! ^ ^C~ · E3 · =~ - o 0 ~ U] ~ U~ ~ V · ~ ~o ~ s~ o %4 :O ~ ~ C Y ~ Z 0 ~ _/ ~ `~ ~ m c _ ~ J o C ~¢ C ~ ^ 0 0 ~ V C} e~ ~ ~0 ' 0 ~ CO t0 ~ ~ _. O 4~ ~ Z 00 C ~ ~ C e" ~ ~ C E' I oo c, 1 ~ ~ V c c~ a' ~ . ~ ~ ~ o mIc ~ _ 0 ~ c El o C. o V ^ 3 ~ ~ ^" "u E3 ~ · ~ ~ O · o ~ ~ 0 ~ _' ~ ·^ ¢'C' a, "~ oO ^, _ C~ ~ U~ o C c~ ~ 1—~ ~ 0 ~ C a, ~ ~ m~ ~ ~ c~ ~ a03 ~0 - 0 ~ a- ~ ~ ^ - ~ ^ ~ 0 . ~ ~ c . C~ ~ · ~ ~ ~ ~ ~ · S ~I S 0 ~ I cd ~ ~ ~ ~ | N ~ ~ ~ ~ ~ ~ O C Z ~ ~ - ~ 0 ~ ~ ~ - C ·. 00^ t0m ~ · O O _ 0 ,C 3 · 0 C~ 0 ~0 r_ 0 C Cr' 3 O Eg El _' ~ ~o X ~: 0 v _I ~ C C) e'_' C V ~ _1 O a' ~0 CS ~ 0 1 C,, 1 - I El ~ 1 ~ 1 _I V 1 ;4 ,C ! C~ C~ ~0 en _I C O 0 JJ ~ ~S O Z q 0 . O 3 0 c C s" _I El C o :^ C 0 c 0 ~ ~ ~ CL e, - _' ~1 00 ~ .0 Z~ ~ :^ g ~ cn :^ _1 C ~ 0 m o ~ ~ o c -~ z ~ ~; s" ~5 c) ~: ~o 0 ~ ~ 0 c ~ s 0 ~ o ~ 0 0 to o L x c o N e~' 0 t0 Ei s~ ~ O S S :~: - ~^ 0 0 3 u~ c ~ ~ 0 S Ei ^ :^ 0 ~ ~ ~ S _1 N ~ CO ~ ~ S C) 00 ^~ 00= O ~ S~ S ~ O 4, ~ ~ E3 CL ~ ~ ^ O ~ :: c o 0 0 P o ~ 3 0 0 0 ~ O 0 a ~4 n, ~ oa ~ c ~ ~ 0 0 0= O c ~ S ~0 0 ,c ~ ~ O oS 0 · Ei cn C~ ~ · E1 3 El ~ >` 0 o C3 0 P. ~ Ei s o ~ ~ ~ X u, 3 ~ ~ o. u O 3 0= _ :>` O ~ ~ —I ~ 0 —~ 14 e~ 0 S ~ ~ S >,, {0 ~ -: == ~ c' S Ei ~ Y c' 0 0 0 0 0 u, ~ 0 t c~ ~ c; S c, S3 o 323

324 DIET, NUTRITION, AND CANCER to be carcinogenic in rats and mice. The data for carbaryl are inconclu- sive and do not permit an assessment of carcinogenicity. However, carbaryl is capable of reacting with nitrite under mildly acidic conditions (similar to those present in the human stomach) to produce N-nitrosocarbaryl, which is known to induce cancer in rats (Eisenbrand et al., 1976; Lijinsky and Taylor, 1976~. Although Ohshima and Bartsch (1981) have provided direct evidence that nitrosamines can be formed in the human stomach, such infor- mation should be interpreted with caution because the extent to which this reaction could occur endogenously would depend on a number of factors, including the differences in the concentration of the reactants, pH, and the presence of catalysts and blocking agents. The results of mutagenicity and related short-term tests for some organochlorine pesticides did not coincide with data from experiments to study carcinogenicity in animals. This disparity may indicate the limited value of mutagenicity tests for screening organochlorine compounds for potential adverse effects. Summary and Conclusions. Residues of a few organochlorine, organo- — q. phosphate, and carbamate pesticides are commonly detected in the diet, generally at levels that are one to two orders of magnitude below their Acceptable Daily Intake (ADI). Unlike the organophosphates and carba- mates, most of the organochlorine compounds are metabolized slowly and tend to accumulate in body tissues. The organochlorine compounds and the organophosphates have the potential to modify the activity of microsomal enzymes and to engage in synergistic interactions. Data from the few epidemiological studies that have been conducted permit no conclusion to be drawn about the carcinogenic risk to humans exposed to pesticides. The experimental data reviewed in this section indicate the following: · A number of the common organochlorine pesticides to which the general population is exposed cause cancer in mice and some in other animal species. O With the exception of parathion, the organophosphate pesticides discussed herein have not been found to be carcinogenic in laboratory animals. · Of the two carbamates, aldicarb does not appear to be carcingenic in rats or mice, and the data on the carcinogenicity of carbaryl are inconclusive. Carbaryl is capable of reacting with nitrite under mildly acidic conditions to produce carcinogenic N-nitroso compounds. Such nitrosation reactions have been shown to occur in the human stomach, but the degree of risk they pose to human health is not known. On the basis of studies in animals, and in the absence of adequate data from epidemiological studies, it appears that Kepone (chlordecone), 14-17

Additives and Contaminants 325 toxaphene, hexachlorobenzene, and, perhaps, heptachlor (with chlordane) and lindane present a carcinogenic risk to humans. However, it is rea- sonable to assume that the amounts present in the average U.S. diet do not make a major contribution to the overall risk of cancer for humans. Polychlorinated Biphenyls (PCB's) Polychlorinated Biphenyls (PCB's), which are complex mixtures of chlorinated hydrocarbons, have been used for industrial purposes for the past half century. With rare exceptions, commercial PCB's are contami- nated with low levels of toxic impurities such as Polychlorinated di- benzofurans and chlorinated naphthalenes. The effects of PCB's on health have been reviewed recently by the International Agency for Research on Cancer (1978) and the Subcommittee on the Health Effects of Polychlorinated Biphenyls and Polybrominated Biphenyls (1978~. Initial concern about the adverse health effects of various commercial PCB mixtures originated when chloracne and hepatic changes were observed among workers engaged in the production of these compounds (Schwartz, 194 3~. The gradual realization that PCB's are highly toxic and exceedingly persistent in the environment led the U.S. Environmental Protection Agency (1979) to suspend their manufacture and use in commerce. Because of the extreme stability and high potential of PCB's for assimilation in the food chain, the FDA has established limits for their levels in different foods (U.S. Food and Drug Administration, 1977b). For humans, the major source of exposure to low levels of PCB's is diet. Generally, PCB's have been found only in the flesh or prod- ucts of animals (e.g., fish, milk, eggs, and cheese) and in animal feed derived from animal products (e.g., fish meal) (Jelinek, 1981; Jelinek and Corneliussen, 1976~. Between 1969 and 1975 the levels of PCB's de- clined in all foods examined, except fish. Daily dietary intakes mea- sured between 1974 and 1977 indicated that PCB's had dropped to levels well below the tolerance levels in individual foods (U.S. Food and Drug Administration, 1980b). PCB's also tend to accumulate in the adipose tissue of humans, in milk, and in blood (Kutz and Strassman, 1976~. Epidemiological Evidence. During a 9-year period in Japan (1968- 1975), there were reports of more than 1,200 cases of Yusho disease (a disorder involving ocular, dermatological, and nervous symptoms) in humans who had consumed rice oil accidentally contaminated with Kanechlor 400 (a PCB) (Higuchi, 1976; Kuratsune et al., 1976~. Nine out of 22 (41%) of the deaths, which were reported as long as 5.5 years after the initial exposure, were due to malignant neoplasms (Kuratsune, 1976; Urabe, 1974~. However, the investigators did not compare this incidence with the rate of expected deaths from various neoplasms in the population. Bahn et al. (1976, 1977) reported two malignant melanomas among 31 workers (~ times the expected incidence) who had been heavily exposed to 14-22

326 DIET, NUTRITION, AND CANCER Aroclor 1254 (a PCB) and possibly other chemicals, and one melanoma among 41 others who had been less heavily exposed. Three other workers in the heavily exposed group were diagnosed as having four cancers at other sites, including two in the pancreas. Brown and Jones (1981) reported a retrospective study of 2,567 workers employed for at least 3 months in plants using PCB's. The total mortality from all causes and mortality from cancers were lower than expected, but were slightly, although not significantly, excessive (3 vs. 1.07 expected) for liver cancer. Experimental Evidence. A number of experiments have been conducted in laboratory animals to test the carcinogenicity of various PCB's. Table 14-4 summarizes the results of some experiments in which various compounds were administered orally to study their carcinogenicity, mutagenicity, or their ability to act as tumor-promoting agents. On the basis of data from the five experiments examined, it appears that Kanechlor 500 and Aroclor 1254 induce cancer in mice and that Aroclor 1260 is carcinogenic in rats. All three compounds have induced benign and malignant liver cell tumors in laboratory animals. From experiments in which PCB's were tested as promoting agents, it appears that Kanechlor 400 and 500 enhance hepatocarcinogenicity of 3-methyl-4-aminoazobenzene (3'- DMAB) and N-nitrosodiethylamine (NDEA) in rats and of lindane in mice, whereas Kanechlor 500 when administered to rats simultaneously with the carcinogen inhibited the hepatocarcinogenicity of 3'-DMAB, 2-AAF, and NDEA (Makiura _ al., 1974~. Aroclor 1221 and 1268 are mutagenic, and have been shown to induce microsomal activation in the Ames test (Wyndham et al., 1976~. A number of other PCB's, e.g., Aroclor 1254 (see Table 14-4), are negative in the dominant lethal assay in rats and do not induce chromosome aberrations in cultures of lymphocytes from humans. These findings are difficult to interpret for Aroclor 1254, which induces dose-related hepatocellular carcinoma in female rats and enhances NDEA-induced hepatocellular carcinoma in rats (Preston _ al., 1981~. Summary and Conclusions. PCB's are highly persistent in the environ- ment and have been detected in human tissues. They occur in fish, meat, and dairy foods in amounts that are well below the tolerance levels estab- lished by the FDA. Limited data from epidemiological studies suggest that exposure to high levels of PCB's may be associated with the development of malignant melanomas, but no conclusion can be drawn about the risk to humans from exposure to PCB-contaminated foods. Results of laboratory experiments indicate that some PCB's are carcinogenic in rodents, producing mostly tumors of the liver at doses much higher than those generally present in the average U.S. diet. Recent evidence indicates that some PCB's may act primarily as tumor-promoting agents. 14-23

327 U] - _. ~ ~ _ _' o :- _. o C ~ ~ To ~ ,1 o 0 al cat ~ Cat At: 1 ~ set ~ o ¢ V EN o o . - V ~ .,1 C 0 :^ do ~ ~ O c' En V Go ~ al :~: ~ o 14-24 0 At: 0 In C 0 sat a ,0 00 ^ a em ~ ~ 0 0 0 ~~ 0 ~ ~ ~ C =o ~ == E r_ ~ ~ C .— ~ ~ C) Cat o ~ ~ V ~ ^ _ ~ sat >= ^ ~ o en Cal c; Cut ^— Cal ~ ran · ~ ~ ~= ~ ~ o s~ s" ~ ~ ~ ~ ~ ~ ~ ~ o O c~ ~ ~ q' ~ C ~ ~ 1 ~ ~ o o ~ ~ ~ ~ a~ ~ a~ ^ C~ ~ v u ~ ~ ~ v ~Ic ~ VC ~ ~ 0 C ~ 0 ~ :^ ~ Y ~ ~ C ~ ~ c~ ~ P] ~ ~ S" cn S N :~; a~ t0 ~ ~ ·^ ~ S ~ V S ~ V V ~ ~ ~ 0 3 0 ~= a) 0 0 0 c = - 0 c.s ~ c C ~ ~ ~ ~ E o ~ ~ co I C ~ · C co r_ t; ~ _~ to as c~ ~ ~ ~ ~ ~ V ~ ~ 3 "= ~ ~ ~ ~ .- ~ ~ ~ .^z ~ ~ ~ ~ {U ^ a,, ~ ~ ~ O;~ 0 q' s C . 0 ~ S~ S ~ ~ S ~ s ~ V~ o ~t q~ ~ I_ ~— P9 V l— ~ ~ ~ o ~ ° ` - ~ ~ ~ ~ o ~ ~ o ~ 0 ~ ~ o ~ o ~ :~ c o ~ ~ 3 C n' ^ oo e ~ t., 411 ~ ~ Z ~ ~ · · 3 ~ ~ ~ ~ C ~ ~ ^ ~ ^ 1 - ^ ~ ^ V ~ o ~ U) ~ · V · - o ~ V · s~ o s" s ~ . - c: ~ c ~ c ~ c - 1 - c ~ c - 1 _' o ~ ~ ~ c~ ~ ~1 ~1 a~ a, ~1 ~ 4~ v ~ ~ ~ . - v ~ ~ ~ ~ ~ ~ v ~ ~ U" t~ 0 a, ~ 0 C s" a, ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ c v V ~ ~ V ~ ~ ~ ~ ~ V ~ V ~ ~ ~ ^ V ~ ~ ~ C ~ ~ 0 C C ~ ~ · C ~ ~ ~ ~ ~ ~ eC P4 ~ ~ ~ O ~ O ~ O ~ ~ O ~ ~ ~ S ~ O 00 S~ ~ ~ ~ ~ ~ ct ~ ~ ° S C cq ~ ~ ~ 1 C ^ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ s 0 ~ 0 ~ ~ ~ s ~ s ~ ~ ~ 4~1 ~ ~ c ~ oo oo O s" ~ ~ 0 ~ ~ ~ ~ ~ ~1 ~ ~ C ~ ·^ 0 ~ ~ ~ ~ ~ s ~ ~ ^Z ~ v ~ ~ ~ v 3 ~ ~ ~ ~ o ~ ·,4 0 ~ ~ ~ o ^ 0 E ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ o · ~ ~ 3 v 0 ~ u ~ S ~ v C) ~ ~ O ~ ~ ~ C ~ ~ ~ ~ C ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ^ ~ ~ ~ V V ~ ~ ~ ~ V C) ~ ~C ~ V ~ · · os a erl ~ ~ C ~ ~ C C C C ca C Z C C O S v ~ ~ o C S Z ~ V ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ 3 s" ~ ~ Ct V ~ ~ V ^ C ~ ~ ~ C · 1 _' 1 ~ C C ~ ~ 0 s~ :- C, C oo "~ ~ ~ 0 ~ ~ ~ ~ ~ ~ ~ ~ O s~ V V .O ~ 0 ~ ~ C e ~c ~" ~ ~o =- 0 ~ ~= 0 so ~ C :~: 0 s" ~ ~ ~ ~ C ~ - 0 ~ 0 ~ C ~ = - ^ ~ 0 0 ·- 0 ~ ~D O O .- :~ C S ~— ~ 3 ~ 3^ ~= o ~ o~ ~ ~ o o o o ~ 0 ~ ~ ~ o :^ ~ ~ ~ s~ $4 U~ 0 ~_ S ~ S ~ ~ C~ ^ v 0 ~ ~ a~ ~ ~ c · · m1 - ~ ~ 0 ^~ ~ o~ o 0 ~v C ~ C ~ ~ ~ 1 ~ ~ ~ o o ~ ~ ° '— ~ '°1 0 r~ co v ~ C ~ U~ C ~ o' c; ~ ~ ~ ~ - 18 C ~ C V ~10 C ~ ~ ~ ~/ ~ ~ ^ C 0 V ^ ~ o~ ~ ~ o o · 0 C o o . oo ~ C 0 ^ C 0 _1 C V ~ S ~ c cm c ~ ~ v 0 =0 - e :^ ~ 0 ~ ~ 0 ~ ~ ~ ~ ~ 0 ~ 3 ~ ~ c~ ~ ~ u o {~ S :~~ ~) s :£~ a- - a" ~ =~ - 0 · - ^~ 0 ·` 0 I_ CO a, C ~ C C ~ 0 ~ 0 0 C~ ~ ~ ~ 0 0 0 ~ ~ ~o " ~ ~ ~ .~ V 0 0 0 ~ to 00 s" ~ ~ ~ ~ ~ ~ 0 ~ ~ 0 ao O 0 0 S S S v C C C~ Cd V ~ ~ v ~ ~ v v ~ V a, ~ e e 0 ~ 0 0 0 C C C S" ~ S" ~ ~ ct E~ <: -¢ ~ Ct

328 DIET, NUTRITION, AND CANCER Polybrominated Biphenyls (PBB's) Polybrominated biphenyls (PBB's), which are chemically related to the PCB's, have been used as flame retardants in industrial processes. Like PCB's, PBB's persist in the environment and can accumulate in body fat. Epidemiological Evidence. Studies of a population accidentally - exposed to PBB's in Michigan in 1973 indicated that the exposure was associated with a number of adverse effects on health (Kay, 1977; Office of Technology Assessment, 1979~; however, because of the short interval between the time of exposure and the measurement of effects, these studies could provide no definitive information about the relationship between PBB's and cancer. Experimental Evidence. Sherman rats given a single oral dose of PBB's by Savage 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 PBB's or 12 divided doses by Savage. 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~. Recently, Aust has shown that PBB's are tumor promoters in rats (S. D. Aust, Michigan State University, personal communication, 1981~. The doses given in this in viva assay ranged from 1 to 100 mg/kg diet. PBB's did not induce mutations in the Ames test and in Chinese hamster uterine cells (Aust, personal communication, 1981~. When administered orally to mice at doses ranging from 50 to 500 mg/kg bw, they did not induce chromosome aberrations in bone marrow cells (Wertz and Ficsor, 1978~. Summary and Conclusions. These studies indicate that single doses or short-tenm treatment with PBB's can induce liver tumors in rats. There is some indication that the effect is dose-dependent, but the number of rats given the lower doses was small. Because of the lack of data from epidemiological studies, it is difficult to determine the significance of these findings for human health. PolYcYclic Aromatic Hydrocarbons (PAH's) Polycyclic aromatic hydrocarbons (PAH's) are organic compounds containing two or more benzene rings. To date, more than 100 of these compounds have been identified in the environment and in foods (Lo and Sandi, 1978; U.S. Environmental Protection Agency, 1975c). Of these, less than 20 have been shown to cause cancer in laboratory animals, and only five of these have induced cancer following oral administration: benzo~aipyrene (BaP), dibenz~a,hianthracene (DBA), benz~aJanthracene 14-25

Additives and Contaminants 329 (BA), 3 methylcholanthrene (3-MCA), and 7,12-dimethylbenz~aJanthracene (7,12-DMBA). Of these, 3-MCA and 7,12-DMBA are synthetic chemicals that do not occur normally in the diet. The major sources of the PAH contamination of food are curing smokes, contaminated soils, polluted air and water, and endogenous biosynthesis by plants and microorganisms. The methods with which foods are cooked or processed also affect the PAH content of the foods (Howard and Fazio, 1980; Lo and Sandi, 1978~. The contamination of foods by PAHts is widespread. These compounds have been detected in fresh meats, smoked fish and meats, grilled and roasted foods, leafy and root vegetables, vegetable oils, grains, plants, fruits, seafoods, whiskies, etc. Smoking of meat increases the total PAH burden (Howard and Fazio, 1980~. Similarly, hot air drying and roasting are potential sources of contamination of grain and coffee (Fritz, 1969~. Most foods contain very low levels of PAM's, but shellfish seem to concen- trate these compounds and are unable to metabolize them. Various PAM's, including BaP, benzanthracene, and chrysene, have been detected in Scotch, bourbon, and Japanese whiskies at extremely low levels, ranging from 0.03 to 0.08 ~g/liter (Masuda et al., 1966~. Leafy plants such as spinach, kale, and tobacco contain higher levels of BaP (Grimmer, 1968), and only a small fraction (~10%) appears to be removed by washing (Grimmer, 1968~. Although BaP constitutes only between 1% and 20Z of the total amount of carcinogenic PAM's in the environment, there is a great deal of infor- mation on the levels of that compound in various foods (Suess, 1976~. In contrast, the information on the levels of other carcinogenic PAM's is still fragmentary. Fritz (1971) estimated that the average annual intake of BaP in the German Democratic Republic ranged from 340 to 1,200 fig per person annually. In Hungary, it was calculated to be 290 to 612 ~g/per- son annually (Soos, 1980~. The main sources of ingested BaP were vege- tables and fruits, whereas the smoked foods contributed only a minor fraction of the total BaP intake. Although there is information concern- ing the levels of BaP in specific foods, such as oils and smoked meats, the total intake of BaP from all sources in the United States has not been reported. Epidemiological Evidence. Evidence concerning the association between cancer in humans (mainly cancer of the skin and lung) and exposure to PAM's derives from studies of humans exposed occupa- tionally to PAM's in soot from chimneys, coal tar, creasote oil, and other petroleum products (Butlin, 1892; Doll et al. 9 1972; Heller, 1930; Kennaway and Kennaway, 1947; Pott, 177557 There is little information concerning the relationship between ingestion of PAH-contaminated food and cancer in humans. In one study, Hajdu (1974) observed that the incidence of stomach cancer among the Vend population living in West Hungary is significantly higher than the incidence for the general Hungarian population. The Vend population 14-26

330 DIET, NUTRITION, AND CANCER routinely consumes home-smoked meat products that contain substantially higher BaP levels than found in samples of smoked food consumed in other parts of Hungary (Soos, 1980~. In another report, Dungal (1961) specu- lated that the high incidence of gastric cancer in the northwestern part of Iceland may be associated with the frequent consumption of smoked trout and smoked mutton, which were found to contain relatively high concentrations of PAH's. In Latvia, Voitalovich et al. (1957) reported that the incidence of gastrointestinal cancer over a 5-year period was significantly higher in a coastal region than in a nearby inland region. They attributed this difference to occupational exposures in the fishing industry (e.g., during the smoking of fish), frequent consumption of smoked fish, and poorly balanced diet. However, these investigators (Dungal, 1961; Soos, 1980; Voitalovich et al., 1957) did not take into consideration the potential effect of nitrite or N-nitroso compounds, which may also be present in such foods and which are also believed to be associated with gastric cancer. Experimental Evidence: Carcinogenicity and Mutagenicity. The PAM's exert their toxic, carcinogenic, and mutagenic effects only after being metabolized by the mixed-function oxidases of various tissues (Freudenthal and Jones, 1976~. Their carcinogenic activity varies from very weak to potent. Some of the PAM's have been shown to be carcinogenic to mice, rats, hamsters, rabbits, and monkeys when administered topically, orally, or parenterally (Freudenthal and Jones, 1976~. Many PAM's have also been found to be mutagenic. The discussion below is limited to those PAM's generally detected in foods and found to be carcinogenic when administered orally. Benzota~pyrene - The carcinogenicity of BaP in various animal species has been well established. A single 0.2 mg dose of BaP administered intragastrically produced forestomach tumors in mice (Peirce, 1961~. In other studies, mice fed a diet containing BaP at 250 mg/kg developed an increasing number of forestomach tumors as the duration of the experiment was ex- tended (Neal and Rigdon, 1967), and mice exposed for 140 days developed lung tumors and leukemia in addition to forestomach tumors (Rigdon and Neal, 1969~. In Sprague-Dawley rats, a single dose of 100 mg BaP resulted in the induction of mammary tumors (Hugging and Yang, 1962~. Hamsters fed BaP at 500 mg/kg diet 4 days/week for up to 14 months developed esophageal, intestinal, and stomach tumors (Chu and Malmgren, 1965~. BaP has been also shown to be mutagenic to Ames Salmonella strains (Hollstein et al., 1979; Nagao and Sugimura, 1978), to be genotoxic in the hepatocyte primary culture-DNA repair test (Tong et al., 1981), to induce mutations in the epithelial cells of the liver of rats (Tong et al., 1981), and to induce transformations in Syrian golden hamster embryo cells (Casto, 1979~. 14-27

Additives and' Contaminants 331 Dibenz [g,,hianthracene Dietary administration of DBA for 5 to 7 months (total dose, 9-19 mg/animal) resulted in the appearance of forestomach tumors in mice after 1 year (Larionov and Soboleva, 1938~. Mice receiving the compound at 0.2 mg/ml in an olive oil emulsion, which was substituted for their drinking water, received an average dose of 0.76 to 0.85 mg/day. Pulmonary adenomatosis developed in these animals after 200 days. In addition, females in this group developed mammary carcinomas (Snell and Stewart, 1962~. Administration of DBA by stomach tube to several strains of mice (total dose, 15 mg/mouse administered over 15 weeks) resulted in a significant increase in mammary carcinomas (Biancifiori and Caschera, 1962~. DBA was positive in the Ames test (McCann et al., 1975~. Treatment of hamster embryo cells with DBA increased the frequency of transforma- tions induced by the simian adenovirus SA7 (Casto, 1979~. Benz Ealanthracene Administration of 0.5 mg BA in mineral oil by stomach tube at intervals of 3 to 7 days induced papillomas of the forestomach in mice (Bock and King, 1959~. Mice receiving 15 doses of 1.5 mg BA each for 15 weeks by stomach tube developed lung adenomas, hepatomas, and forestomach papillomas (Klein, 1963~. BA has been shown to be mutagenic in the Ames test (Hollstein et al., 1979; McCann et al., 1975~. It was also positive in the prophage induc- tion test (Morreau _ al., 1976) and genotoxic in the hepatocyte primary culture-DNA repair test (Tong et al., 1981~. Summary and Conclusions. Low levels of many PAM's are present as contaminants in a variety of foods. Smoking and broiling of foods and the use of curing smokes contributes to the PAH content of foods. Of the more than 100 PAM's found in the environment, approximately 20 are carcinogenic in laboratory animals. Of the five PAM's found to be carcinogenic when administered orally, three (BaP, DBA, and BA) occur in the average U.S. diet. Occupational exposure of humans to PAM's is associated with an increased incidence of skin and lung cancer. There is no reliable information about the consumption of foods contaminated with low levels of PAM's and the development of human cancer. Some investigators have speculated that a high incidence of stomach cancer in Hungary and Iceland could be associated with consumption of smoked meat and fish, which are potential sources of PAM's and/or nitrosamines and their precursors, but this has not been conclusively demonstrated. However, since studies in animals have shown that PAM's are carcinogenic when administered orally, and occupational exposure to substances containing PAM's has been asso- ciated with skin and lung cancer, it would be prudent to minimize the dietary exposure to PAH's. 14-28

332 DIET, NUTRITION, AND CANCER OVERALL SUMMARY AND CONCLUSIONS Food Additives Nearly 3,000 substances are intentionally added to process foods in the United States. Another estimated 12,000 chemicals, such as vinyl chloride and acrylonitrile, which are used in food-packaging, are classified as indirect additives. Some additives, such as sugar, are consumed in large amounts by the general population. However, the annual per capita exposure to most of these substances constitutes a minute portion of the diet. Although the Food Safety Provisions and, in many cases, the Delaney Clause of the Federal Food, Drug, and Cos- metic Act prohibit the addition of known carcinogens to foods, only a small proportion of substances added to foods have been tested for carcinogenicity according to protocols that are considered acceptable by current standards. Moreover, except for the studies on nonnutritive sweeteners, very few epidemiological 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. Minute residues of a few indirect additives that are known either to produce cancer in animals, e.g., vinyl chloride and acrylonitrile, or to be carcinogenic in humans, erg., vinyl chloride, are occasionally detected in foods. There is no evidence suggesting that the increasing use of food additives has contributed significantly to the overall risk of cancer for humans. However, the lack of detectable effect may be due to the relatively recent use of these substances, to their lack of carcinogenicity, or to the inability of epidemiological techniques to detect the effects of additives against the background of common cancers from other causes. Therefore, no definitive conclusion can be reached until more data become available. Environmental Contaminants . Very low levels of a large and chemically diverse group of sub- stances--environmental contaminants--may be present in a variety of foods. The dietary levels of some of these substances are monitored by the FDA Market Basket Surveys. Many of these contaminants have been extensively tested for carcinogenicity. The results of standard chronic toxicity tests indicate that a number of environmental contaminants (e.g., some organochlorine pesti- cides, polychlorinated biphenyls, and polycyclic aromatic hydrocarbons) cause cancer in laboratory animals. There is no epidemiological evidence to suggest that these compounds individually make a major contribution to the risk of human cancer. However, the possibility that they may act synergistically and may thereby create a greater carcinogenic risk cannot be excluded. 14-29

Alcoves and Contaminants 333 REFERENCES Abe, S., and M. Sasaki. 1977. Chromosome aberrations and sister chromatic exchanges in Chinese hamster cells exposed to various chemicals. J. Natl. Cancer Inst. 58:1635-1641. Ahmed, F. E., R. W. Hart, and N. J. Lewis. 1977. Pesticide induced DNA damage and its repair in cultured human cells. Mutat. Res. 42:161-173. Althoff, J., A. Cardesa, P. Pour, and P. Shubik. 1975. A chronic study of artificial sweeteners in Syrian golden hamsters. Cancer Lett. 1:21-24. Andrews, A. W., E. S. Zawistowski, and C. R. Valentine. 1976. A comparison of the mutagenic properties of vinyl chloride and methyl chloride. Mutat. Res. 40:273-275. Andrianova, M. M., and I. V. Alekseev. 1970. [In Russian; English Summary.] On the carcinogenous properties of the pesticides Sevine, Maneb, Ciram and Cineb. Vopr. Pitan. 29~6~:71-74. Armstrong, B., and R. Doll. 1974. Bladder cancer mortality in England and Wales in relation to cigarette smoking and saccharin consumption. Br. J. Prev. Soc. Med. 28:233-240. Armstrong, B., and R. Doll. 1975. Bladder cancer mortality in diabetics in relation to saccharin consumption and smoking habits. Br. J. Prev. Soc. Med. 29:73-81. Armstrong, B., A. J. Lea, A. M. Adelstein, J. W. Donovan, G. C. White, and S. Ruttle. 1976. Cancer mortality and saccharin consumption in diabetics. Br. J. Prev. Soc. Med. 30:151-157. Arnold, D. L., C. A. Moodie, B. Stavric, D. R. Stoltz, H. C. Grice, and I. C. Munro. 1977. Letter to the Editor: Canadian saccharin study. Science 197:320. Arnold, D. L., C. A. Moodie, H. C. Grice, S. M. Charbonneau, B. Stavric, B. T. Collins, P. F. McGuire, Z. Z. Zawidzka, and I. C. Munro. 1980. Long-term toxicity of ortho-toluenesulfonamide and sodium saccharin in the rat. Toxicol. Appl. Pharmacol. 52:113-152. Arnold, D. W., G. L. Kennedy, Jr., M. L. Keplinger, J. C. Calandra, and C. J. Gala. 1977. Dominant lethal studies with technical chlordane, HCS-3260, and heptachlor:heptachlor epoxide. J. Toxicol. Environ. Health 2:547-555. 14-30

334 DIET, NUTRITION,AND CANCER Ashby, J., J. A. Styles, D. Anderson, and D. Paton. 1978. Saccharin: An epigenetic carcinogen/mutagen? Food Cosmet. Toxicol. 16:95-103. Ashwood-Smith, M. J., J. Trevino, and R. Ring. 1972. Mutagenicity of dichlorvos. Nature 240:418-420. Bahn, A. K., I. Rosenwaike, N. Herrmann, P. Grover, J. Stellman, and K. O'Leary. 1976. Letter to the Editor: Melanoma after exposure to PCB's. N. Engl. J. Med. 295:450. Bahn, A. K., P. Grover, I. Rosenwaike, K. O'Leary, and J. Stellman. 1977. Letter to the Editor: A reply to PCB's and melanoma. N. Engl. J. Med. 296:108. Barthel, E. 1976. [In German; English Summary.] High incidence of lung cancer in persons with chronic professional exposure to pesticides in agriculture. Z. Erkr. Atmungsorgane 146:266-274. Bartsch, H., C. Malaveille, A. Barbin, and G. Planche. 1979. Mutagenic and alkylating metabolites of halo-ethylenes, chlorobutadienes and dichlorobutenes produced by rodent or human liver tissues. Evidence for oxirane formation by P450-linked microsomal mono-oxygenases. Arch. Toxicol. 41:249-277. Bartsch, H., C. Malaveille, A.-M. Camus, G. Mart el-Planche, G. Brun, A. Eautefeuille, N. Sabadie, and A. Barbin. 1980. Validation and comparative studies on 180 chemicals with S. typhimurium strains and V79 Chinese hamster cells in the presence of various metabolizing systems. Mutat. Res. 76:1-50. Batzinger, R. P., S.-Y. L. 0u, and E. Bueding. 1977. Saccharin and other sweeteners: Mutagenic properties. Science 198:944-946. Biancifiori, C., and F. Caschera. 1962. The relation between pseudopregnancy and the chemical induction by four carcinogens of mammary and ovarian tumours in BALB/c mice. Brit. J. Cancer 16:722-730. Blot, W. J., J. F. Fraumeni, and B. J. Stone. 1978. Geographic correlates of pancreas cancer in the United States. Cancer 42:373-380. Bock, F. G., and D. W. King. 1959. A study of the sensitivity of the mouse forestomach toward certain polycyclic hydrocarbons. J. Natl. Cancer Inst. 23:833-840. Brantom, P. B., I. F. Gaunt, and P. Grasso. 1973. Long-term toxicity of sodium cyclamate in mice. Food Cosmet. Toxicol. 11:735-746. 14-31

Additives and Contaminants 335 Brown, D. P., and M. Jones. 1981. Mortality and industrial hygiene study of workers exposed to polychlorinated biphenyls. Arch. Environ. Health 36:120-129. Brzhesky, V. V. 1972. [In Russian; English Summary.] Study of mutagenic properties of Sevin, a carbamate insecticide. Genetika 8~6~:151-153. Bulow, H., H.-K. Wullstein, G. Bottger, and F. H. Schroder. 1973. [In German; English Summary.] Carcinomas of the breast under estrogen- treatment for prostatic carcinoma. Urologe A 12:249-153. Burbank, F., and J. F. Fraumeni, Jr. 1970. Synthetic sweetener consump- tion and bladder cancer trends in the United States. Nature 227: 296-297. Buselmaier, W., G. Rohrborn, and P. Propping. 1973. Comparative investigations on the mutagenicity of pesticides in mammalian test systems. Mutat. Res. 21:25-26. Abstract 9. Butlin, H. T. 1892. Three lectures on cancer of the scrotum in chimney sweeps and others. Lecture III.--Tar and paraffin cancer. Br. Med. J. 2:66-71. Cabral, J. R. P., P. Shubik, T. Mollner, and F. Raitano. 1977. Letter to the Editor: Carcinogenic activity of hexachlorobenzene in hamsters. Nature 269:510-511. Cabral, J. R. P., T. Mollner, F. Raitano, and P. Shubik. 1979. Carcino- genesis of hexachlorobenzene in mice. Int. J. Cancer 23:47-51. Casto, B. C. 1979. Polycyclic hydrocarbons and Syrian hamster embryo cells: Cell transformation, enhancement of viral transformation and analysis of DNA damage. Pp. 51-66 in P. W. Jones and P. Leber, eds. Polynuclear Aromatic Hydrocarbons. Ann Arbor Science Publishers, Ann Arbor, Mich. Chowaniec, J., and R. M. Hicks. 1979. Response of the rat to saccharin with particular reference to the urinary bladder. Br. J. Cancer 39: 355-375. Chrisman, C. L. 1974. Aneuploidy in mouse in embryos induced by diethy stilbestrol diphosphate. Teratology 9:229-232. Christiansen, J. S. 1978. Cigarette smoking and prevalence of micro- angiopathy in juvenile-onset insulin-independent diabetes mellitus. Diabetes Care 1:146-149. 14-32

336 DIET, NUTRITION,AND CANCER Chu, E. W., and R. A. Malmgren. 1965. An inhibitory effect of vitamin A on the induction of tumors of forestomach and cervix in the Syrian hamster by carcinogenic polycyclic hydrocarbons. Cancer Res. 25:884-895. Clapp, N. K., R. L. Tyndall, R. B. Cumming, and J. A. Otten. 1974. Effects of butylated hydroxytoluene alone or with diethylnitros- amine in mice. Food Cosmet. Toxicol. 12:367-371. Clive, D. 1977. A linear relationship between tumorigenic potency in viva and mutagenic potency at the heterozygous thymidine kinase _ ~ (TK ~/~) locus of L5178Y mouse lymphoma cells coupled with mammalian metabolism. Pp. 241-247 in D. Scott, B. A. Bridges, and F. H. Sobels, eds. Progress in Genetic Toxicology. Proceedings of the Second International Conference on Environmental Mutagens, Edinburgh. Elsevier/North-Holland Biomedical Press, Amsterdam, New York, and Oxford. Clive, D., K. O. Johnson, J. F. S. Spector, A. G. Batson, and M. M. M. Brown. 1979. Validation and characterization of the L5178Y/TK+/- mouse lymphoma mutagen assay system. Mutat. Res. 59:61-108. Code of Federal Regulations. 1978. Title 21, Section 556.190. Office of the Federal Register, National Archives and Records Service, General Services Administration, Washington, D.C. Cohen, S. M., M. Arai, J. B. Jacobs, and G. H. Friedell. 1979. Promoting effect of saccharin and DL-tryptophan in urinary bladder carcinogenesis. Cancer Res. 39:1207-1217. Coneva-Maneva, M., F. Kaloyanova, and A. Georgieva. 1969. [In Russian; English Summary.] Mutation action of Diazinone on lymphocytes of the human peripheral blood in vitro. Eksp. Med. Morfol. 8:132-136. Coulston, F., E. W. McChesney, and K.-F. Benitz. 1977. Eight-year study of cyclamate in rhesus monkeys. Toxicol. Appl. Pharmacol. 41:164-16S. Abstract 80. Creech, J. L., Jr., and M. N. Johnson. 1974. Angiosarcoma of liver in the manufacture of polyvinyl chloride. J. Occup. Med. 16:150-151. Cutler, B. S., A. P. Forbes, F. M. Ingersoll, and R. E. Scully. 1972. Endometrial carcinoma after stilbestrol therapy in gonadal dysgenesis. N. Engl. J. Med. 287:628-631. DeGiovanni-Donnelly, R., S. M. Kolbye, and P. D. Greeves. 1968. The effects of IPC, CIPC, Sevin and Zectran on Bacillus subtilis. Experientia 24:80-81. Degraeve, N., J. Gilot-Delhalle, J. Moutschen, M. Moutschen-Dahmen, A. Colizzi, M. Chollet, and N. Houbrechts. 1980. Comparison of the 14-33

Additives and Contaminants 337 mutagenic activity of organophosphorous insecticides in mouse and in the yeast Schizosaccharomyces pombe. Mutat. Res. 74 :201-202. Abstract 65. Deichmann, W. B., M. Keplinger, F. Sala, and E. Glass. 1967. Synergism among oral carcinogens. IV. The simultaneous feeding of four tumorigens to rats. Toxicol. Appl. Pharmacol. 11:88-103. Dikshith, T. S. S. 1973. In viva effects of parathion on guinea pig chromosomes. Environ. Physiol. Biochem. 3:161-168. Doll, R., M. P. Vessey, R. W. R. Beasley, A. R. Buckley, E. C. Fear, R. E. W. Fisher, E. J. Gammon, W. Gunn, G. O. Hughes, K. Lee, and B. Norman-Smith. 1972. Mortality of gas-workers--Final report of a prospective study. Br. J. Ind. Med. 29:394-406. Duck, B. W., and J. T. Carter. 1976. Response to letter. Lancet 2:195. Duggan, R. E., and P. E. Corneliussen. 1972. Dietary intake of pesticide chemicals in the United States (III), June 1968-April 1970. Pestic. Monit. J. 5:331-341. Dungal, N. 1961. The special problem of stomach cancer in Iceland. With particular reference to dietary factors. J. Am. Med. Assoc. 176: 789-798. Ebenezer, L. N., and G. Sadasivan. 1970. In vitro effect of cyclamates on human chromosomes. Q. J. Surg. Sci. 6:116-118. Eckardt, F., H. Muliawan, N. de Ruiter, and H. Kappus. 1981. Rat hepatic vinyl chloride metabolites induce gene conversion in the yeast strain D7RAD in vitro and in vivo. Mutat. Res. 91:381-390. Eisenbrand, G., D. Schmahl, and R. Preussmann. 1976. Carcinogenicity in rats of high oral doses of N-nitrosocarbaryl, a nitrosated pesticide. Cancer Lett. 1:281-284. Epstein, S. S. 1976. Carcinogenicity of heptachlor and chlordane. Sci. Total Environ. 6:103-154. Epstein, S. S., E. Arnold, J. Andrea, W. Bass, and Y. Bishop. 1972. Detection of chemical mutagens by the dominant lethal assay in the mouse. Toxicol. Appl. Pharmacol. 23:288-325. Feron, V. J., A. J. Speek, M. I. Willems, D. van BattuTn, and A. P. de Groot. 1975. Observations on the oral administration and toxicity of vinyl chloride in rats. Food Cosmet. Toxicol. 13:633-638. 14-34

33X DIET, NUTRITION, AND CANCER Feron, V. J., C. F. M. Hendriksen, A. J. Speek, H. P. Til, and B. J. Spit. 1981. Lifespan oral toxicity study of vinyl chloride in rats. Food Cosmet. Toxicol. 19:317-333. Fitzhugh, O. G. 1964. Appraisal of the safety of residues of veterinary drugs and their metabolites in edible animal tissues. Ann. N.Y. Acad. Sci. 111:665-670. Pluck, E. R., L. A. Poirier, and H. W. Ruelius. 1976. Evaluation of a DNA polymerase-deficient mutant of E. cold for the rapid detection of carcinogens. Chem.-Biol. Interact. 15 :219-231. Food and Agriculture Organization. 1978. Pesticide residues in food-- 1977. FAD Plant Prod. Prot. Paper 10 Rev. :41-42. Fox, A. J., and P. F. Collier. 1977. Mortality experience of workers to vinyl chloride monomer in the manufacture of polyvinyl chloride in Great Britain. Br. J. Ind. Med. 34 :1-10. Freudenthal, R., and P. W. Jones, eds. 1976. Carcinogenesis--A comprehensive survey. Volume 1. Polynuclear Aromatic Hydrocarbons. Chemistry, Metabolism, and Carcinogenesis. Raven Press, New York. 450 pp. Friedman, L., H. L. Richardson, M. E. Richardson, E. J. Lethco, W. C. Wallace, and F. M. Sauro. 1972. Toxic response of rats to cyclamates in chow and semisynthetic diets. J. Natl. Cancer Inst. 49:751-764. Fritz, W. 1969. [In German.] Zum LUsungsverhalten der Polyaromaten beim Kochen von Kaffee-Ersatzstoffen und Bohnenkaffee. Dtsch. Lebensm. Rundsch. 65:83-85. Fritz, W. 1971. [In German.] Umfang und Quellen der Kontamination unserer Lebensmittel mit krebserzeugenden Kohlenwasserstoffen. Ernaehrungaforschung 16:547-557. Fuchs, G., B.-M. Gawell, L. Albanus, and S. Slorach. 1975. [In Swedish; English Sun~ary.] Vinyl chloride monomer levels in edible fats. Var Foeda 17 :134-145. Funes-Cravioto, F., B. Lambert, J. Lindsten, L. Ehrenberg, A. T. Natarajan, and S. Osterman-Golkar. 1975. Letter to the Editor: Chromosome aberrations in workers exposed to vinyl chloride. Lancet 1:459. Furuya, T., K. Kawamata, T. Kaneko, O. Uchida, S. Horiuchi, and Y. Ikeda. 1975. Long-term toxicity study of sodium cyclamate and saccharin sodium in rats. Jpn. J. Pharmacol. 25(Suppl.~:55P-56P. Abstract. Gass, G. H., D. Coats, and N. Graham. 1964. Carcinogenic dose-response curve to oral diethylstilbestrol. J. Natl. Cancer Inst. 33:971-977. 14-35

Additives and Con tenants 339 Gass, G. H., J. Brown, and A. B. Okey. 1974. Carcinogenic effects of oral diethylstilbestrol on C3H mice with and without the mammary tumor virus. J. Natl. Cancer Inst. 53:1369-1370. Gibson, J. P., J. W. Newberne, W. L. Kuhn, and J. R. Elsen. 1967. Comparative chronic toxicity of three oral estrogens in rats. Toxicol. Appl. Pharmacol. 11:489-510. Glatt, H. R., Metzler, and F. Oesch. 1979. Diethylstilbestrol and 11 derivatives. A mutagenicity study with Salmonella typhimurium. Mutat. Res. 67:113-121. Green, S., K. A. Palmer, and E. J. Oswald. 1973. Cytogenetic effects of the polychlorinated biphenyls (Aroclor 1242) on rat bone marrow and spermatogonial cells. Toxicol. Appl. Pharmacol. 25:482. Abstract 113. Green, S., J.V. Carr, K. A. Palmer, and E. J. Oswald. 1975a. Lack of cytogenetic effects in bone marrow and spenmatogonial cells in rats treated with polychlorinated biphenyls (Aroclors 1242 and 1254~. Bull. Environ. Contam. Toxicol. 13:14-22. Green, S., F. M. Sauro, and L. Friedman. 1975b. Lack of dominant lethality in rats treated with polychlorinated biphenyls (Aroclors 1242 and 1254~. Food Cosmet. Toxicol. 13:507-510. Greenwald, P., P. C. Nasca, W. S. Burnett, and A. Polan. 1973. Prenatal stilbestrol experience in mothers of young cancer patients. Cancer 31:568-572. Greim, H., G. Bonse, Z. Radwan, D. Reichert, and D. Henschler. 1975. Mutagenicity in vitro and potential carcinogenicity of chlorinated ethylenes as a function of metabolic oxirane formation. Biochem. Pharmacol. 24:2013-2017. Grimmer, G. 1968. [In German.] Cancerogene Kohlenwasserstoffe in der Umge bung des Menschen. Dtsch. Apoth. Ztg.108:529-533. Guerzoni, M. E., L. Del Cupolo, and I. Ponti. 1976. [In Italian; English Summary.] Mutagenic activity of pesticides. Riv. Sci. Tecnol. Alimenti Nutr. Um. 6:161-165. Hajdu, G. 1974. lIn Magyar.] A "Vendvideken" elofordulo gyomorrak es a KUlonleges fustolesi mo~d osszefuggese. Medicus Universalis 7~6~:278- 289. Heath, C. W., Jr., C. R. Dumont, and R. J. Waxweiller. 1977. Chromosomal damage in men occupationally exposed to vinyl chloride monomer and other chemicals. Environ. Res. 14:68-72. 14-36

340 DIET, NUTRITION, AND CANCER Heller, I. 1930. Occupational cancers. J. Ind. Hyg. 12~5~:169-197. Herbst, A. L., and P. Cole. 1978. Epidemiologic and clinical aspects of clear cell adenocarcinoma in young women. Pp. 2-7 in A. L. Herbst, ed. Intrauterine Exposure to Diethylstilbestrol in the Human. American College of Obstetricians and Gynecologists, Chicago, Ill. Herbst, A. L., R. J. Kurman, R. E. Scully, and D. C. Poskanzer. 1972. Clear-cell adenocarcinoma of the genital tract ire young females. Registry Report. N. Engl. J. Med. 287:1259-1264. Hicks, R. M., and J. Chowaniec. 1977. The importance of synergy between weak carcinogens in the induction of bladder cancer in experimental animals and humans. Cancer Res. 37:2943-2949. Hicks, R.M., J. Chowaniec, and J. St.J. Wakefield. 1978. Experimental induction of bladder tumors by a two-stage system. Pp. 475-489 in T. J. Slaga, A. Sivak, and R. K. Boutwell, eds. Carcinogenesis--A Comprehensive Survey. Volume 2. Mechanisms of Tumor Promotion and Cocarcinogenesis. Raven Press, New York. Higuchi, K. 1976. Outline. Pp. 3-7 in K. Higuchi, ed. PCB Poisoning and Pollution. Kodansha Ltd., Tokyo; Academic Press, New York, San Francisco, and London. Hill, E. C. 1973. Clear cell carcinoma of the cervix and vagina in young women. Am. J. Obstet. Gynecol. 116:470-484. Hollstein, M., J. McCann, F. A. Angelosanto, and W. W. Nichols. 1979. Short-term tests for carcinogens and mutagens. Mutat. Res. 65:133-226. Homburg er, F. 1978. Negative lifetime carcinogen studies in rats and mice fed 50,000 ppm saccharin. Pp. 359-373 in C. L. Galli, R. Paoletti, and G. Vettorazzi, eds. Chemical Toxicology of Food. Elsevier/North-Holland Biomedical Press, Amsterdam, New York, and Oxford. Hooper, N. K., B. N. Ames, M. A. Saleh, and J. E. Casida. 1979. Toxaphene, a complex mixture of polychloroterpenes and a major insecticide, is mutagenic. Science 205:591-593. Hoopingarner, R., A. Samuel, and D. Krause. 1972. Polychlorinated biphenyl interactions with tissue culture cells. Environ. Health Perspect. 1:155-158. Hoover, R. N., and P. H. Strasser. 1980. Editorial: Saccharin: A bitter aftertaste? N. Engl. J. Med. 302:573-575. 14-37

Additives and Contaminants 341 Howard, J. W., and T. Fazio. 1980. Review of polycyclic aromatic hydrocarbons in foods. Analytical methodology and reported findings of polycyclic aromatic hydrocarbons in foods. J. Assoc. Off. Anal. Chem. 63:1077-1104. Howe, G. R., J. D. Burch, A. B. Miller, B. Morrison, P. Gordon, L. Weldon, L. W. Chambers, G. Fodor, and G. M. Winsor. 1977. Artificial sweeteners and human bladder cancer. Lancet 2:578-581. Howe, G. R., J. D. Burch, A. B. Miller, G. M. Cook, J. Esteve, G. Morrison, P. Gordon, L. W. Chambers, G. Fodor, and G. M. Winsor. 1980. Tobacco use, occupation, coffee, various nutrients, and bladder cancer. J. Natl. Cancer Inst. 64 :701-713. Huang, C. C. 1973. Effect on growth but not on chromosomes of the mammalian cells after treatment with three organophosphorus insecticides. Proc. Soc. Exp. Biol. Med. 142:36-40. Huberman, E., H. Bartsch, and L. Sachs. 1975. Mutation induction in Chinese hamster V79 cells by two vinyl chloride metabolites, chloro- ethylene oxide and 2-chloroacetaldehyde. Int. J. Cancer 16:639-644. Huggins, C., and N. C. Yang. 1962. Induction and extinction of mammary cancer. Science 137:257-262. Infante, P. F., S. S. Epstein, and W. A. Newton, Jr. 1978. Blood dyscrasias and childhood tumors and exposure to chlordane and heptachlor. Scand. J. Work Environ. Health 4 :137-150. Innes, J. R. M., B. M. Ulland, M. G. Valerio, L. Petrucelli, L. Fishbein, E. R. Hart, A. J. Pallotta, R. R. Bates, H. L. Falk, J. J. Cart, M. Klein, I. Mitchell, and J. Peters. 1969. Bioassay of pesticides and industrial chemicals for tumorigenicity in mice: A preliminary note. J. Natl. Cancer Inst. 42:1101-1114. International Agency for Research on Cancer. 1974. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Volume 5. Some Organochlorine Pesticides. International Agency for Research on Cancer, Lyon, France. 241 pp. International Agency for Research on Cancer. 1978. Pp. 37-103 in IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Volume 18. Polychlorinated Biphenyls and Polybrominated Biphenyls. International Agency for Research on Cancer, Lyon, France. International Agency for Research on Cancer. 1979. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Volume 20. Some Halogenated Hydrocarbons. International Agency for Research on Cancer, Lyon, France. 609 pp. 14-38

342 DIET, NUTRITION, AND CANCER International Agency for Reseach on Cancer. 1980. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Volume 22. Some Non-Nutritive Sweetening Agents. International Agency for Research on Cancer, Lyon, France. 208 pp. Ishidate, M., Jr., and S. Odashima. 1977. Chromosome tests with 134 compounds on Chinese hamster cells in vitro--a screening for chem- ical carcinogens. Mutat. Res. 48:337-353. Ishii, H., T. Koshimizu, S. Usami, and T. Fujimoto. 1981. Toxicity of aspartame and its diketopiperazine for Wistar rats by dietary administration for 104 weeks. Toxicology 21:91-94. Ito, N., H. Nagasaki, M. Arai, S. Makiura, S. Sugihara, and K. Hirao. 1973. Histopathologic studies on liver tumorigenesis induced in mice by technical polychlorinated biphenyls and its promoting effect on liver tumors induced by benzene hexachloride. J. Natl. Cancer Inst. 51:1637-1646. Ivett, J. L., and R. R. Tice. 1981. Diethylstilbestrol-diphosphate induces chromosomal aberrations but not sister chromatic exchanges in murine bone marrow cells in viva. Environ. Mutagenesis 3:445-452. Jager, J. W. 1970. Aldrin, Dieldrin, Endrin and Telodrin. An Epidem- iological and Toxicological Study of Long-Term Occupational Exposure. Elsevier, Amsterdam, London, and New York. 234 pp. Jedlicka, V., Z. He~manska, I. sm£da, and A. Kouba. l9S8. Paramyelo- blastic leukaemia appearing simultaneously in two blood cousins after simultaneous contact with gammexane (hexachlorcyclohexane). Acta Med. Scand. 161:447-451. Jelinek, C. 1981. Occurrence and methods of control of chemical con- taminants in foods. Environ. Health Perspect. 39:143-151. Jelinek, C. F., and P. E. Corneliussen. 1976. Levels of PCB's ~n the U.S. food supply. Pp. 147-154 in National Conference on Polychlori- nated Biphenyls, November, 1975. Chicago, Illinois. EPA-560/6- 75-004, Office of Toxic Substances, U. S. Environmental Protection Agency, Washington, D. C. Jukes, T. H. 1974. Estrogens in beefsteaks. J. Am. Med. Assoc. 229:1920-1921. Jukes, T. H. 1976. Diethylstilbestrol in beef production: What is the risk to consumers? Prev. Med. 5:438-453. 14-39

Additives and Contaminants 343 Kay, K. 1977. Polybrominated biphenyls (PPB) environmental contamination in Michigan, 1973-1976. Environ. Res. 13:74-93. Kennaway, E. L., and N. M. Kennaway. 1947. A further study of the incidence of cancer of the lung and larynx. Br. J. Cancer 1:260-298. Kessler, I. I. 1970. Cancer mortality among diabetics. J. Natl. Cancer Inste 44 :673-686. Kessler, I. I., and J. P. Clark. 1978. Saccharin, cyclamate, and human bladder cancer. No evidence of an association. J. Am. Med. Assoc. 240:349-355. Khera, K. S. 1974. Teratogenicity and dominant lethal studies on hexachlorobenzene in rats. Food Cosmet. Toxicol. 12:471~77. Kimbrough, R. D., and R. E. Linder. 1974. Induction of adenofibrosis and hepatomas of the liver in BALB/cJ mice by polychorinated biphenyls (Aroclor 1254~. J. Natl. Cancer Inst. 53:547-552. Kimbrough, R. D., R. A. Squire, R. E. Linder, J. D. Strandberg, R. J. Montali, and V. W. Burse. 1975. Induction of liver tumors in Sherman strain female rats by polychlorinated biphenyl Aroclor 1260. J. Natl. Cancer Inst. 55:1453-1459. Kimbrough, R. D., V. W. Burse, and J. A. Liddle. 1978. Persistent liver lesions in rats after a single oral dose of polybrominated biphenyls (FireMaster FF-1) and concomitant PBB tissue levels. Environ. Health Perspect. 23:265-273. Kimbrough, R. D., D. F. Groce, M. P. Korver, and V. W. Burse. 1981. Induction of liver tumors in female Sherman strain rats by polybrominated biphenyls. J. Natl. Cancer Inst. 66:535-542. Kimura, N. T., T. Kanematsu, and T. Baba. 1976. Polychlorinated bi- phenyl~s) as a promoter in experimental hepatocarcinogenesis in rats. Z. Krebsforsch. Klin. Onkol. 87:257-266. Klein, M. 1963. Susceptibility of strain B6AF1/J hybrid infant mice to tumorigenesis with 1,2-benzanthracene, deoxycholic acid, and 3-methylcholanthrene. Cancer Res. 23:1701-1707. Kroes, R., P. W. J. Peters, J. M. Berkvens, H. G. Verschuuren, T. de Vries, and G. J. van Esch. 1977. Long term toxicity and reproduction study (including a teratogenicity study) with cyclamate, saccharin and cyclohexylamine. Toxicology 8:285-300. 14-40

344 DIET, NUTRITION, AND CANCER Kuratsune, M. 1976. Epidemiologic studies on Yusho. Pp. 9-23 in K. Higuchi, ed. PCB Poisoning and Pollution. Kodansha Ltd., Tokyo; Academic Press, New York, San Francisco, and London. Kuratsune, M., Y. Masuda, and J. Nagayama. 1976. Some of the recent findings concerning Yusho. Pp. 14-29 in National Conference on Polychlorinated Biphenyls, November 1975. Chicago, Illinois. EPA-560/ 6-75-004, Office of Toxic Substances, Environmental Protection Agency, Washington, D. C. Kutz, F. W., and S. C. Strassman. 1976. Residues of polychlorinated biphenyls in the general population of the United States. Pp. 139-14 3 in National Conference on Polychlorinated Biphenyls, November 1975, Chicago, Illinois. EPA-560/6-75-004, Office of Toxic Substances, Environmental Protection Agency, Washington, 1). C. Larionov, L. T., and N. G. Soboleva. 1938. Gastric tumors experimentally produced in mice by means of benzopyrene and dibenzanthracene. Vestn. Rentgenol. Radial. 20:276-286. Laws, E. R., Jr., A. Curley, and F. J. Biros. 1967. Men with intensive occupational exposure to DDT. A clinical and chemical study. Arch. Environ. Health 15:766-775. Lijinsky, W., and H. W. Taylor. 1976. Carcinogenesis in Sprague-Dawley rats of N-nitroso-N-alkylcarbamate esters. Cancer Lett. 1:275-279. Lo, M.-T., and E. Sandi. 1978. Polycyclic aromatic hydrocarbons (polynuclears) in foods. Residue Rev. 69:35-86. Loprieno, N., R. Barale, S. Baroncelli, C. Bauer, G. Bronzetti, A. Cammellini, G. Cercignani, C. Corsi, G. Gervasi, C. Leporini, R. Nieri, A. M. Rossi, G. Stretti, and G. Turchi. 1976. Evaluation of the genetic effects induced by vinyl chloride monomer (VCM) under mammalian metabolic activation: Studies in vitro and in vivo. Mutat. Res. 40:85-95. Machemer, L., and D. Lorke. 1976. Evaluation of the mutagenic potential of cyclohexylamine on spermatogonia of the Chinese hamster. Mutat. Res. 40:24 3-250. Makiura, S., H. Aoe, S. Sugihara, K. Hirao, M. Arai, and N. Ito. 1974. Inhibitory effect of polychlorinated biphenyls on liver tumorigenesis in rats treated with 3~-methyl-4-dimethylaminoazobenzene, N-2- fluorenylacetamide, and diethylnitrosamine. J. Natl. Cancer Inst. 53:1253-1257. 14-41

Additives and Contaminants 345 Maltoni, C. 1977. Vinyl chloride carcinogenicity: An experimental model for carcinogenesis studies. Pp. 119-146 in H. H. Hiatt, J. D. Watson, and J. A. Winsten, eds. Origins of Human Cancer, Book A. Incidence of Cancer in Humans. Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. Maltoni, C., G. Lefemine, P. Chieco, and D. Carretti. 1974. Vinyl chloride carcinogenesis: Current results and perspectives. Med. Lav. 65:421-444. Maltoni, C., A. Ciliberti, L. Gianni, and P. Chieco. 1975. [In Italian.] Gli effetti oncogeni del cloruro di vinile somministrato per via vale mel ratto. Gli Ospedali delta Vita 2~6~:102-104. Marshall, T. C., H. W. Dorough, and H. E. Swim. 1976. Screening of pesticides for mutagenic potential using Salmonella typhimurium mutants. J. Agric. Food Chem. 24:560-563. Martin, C. N., A. C. McDermid, and R. C. Garner. 1978. Testing of known carcinogens and noncarcinogens for their ability to induce unscheduled DNA synthesis in HeLa cells. Cancer Res. 38:2621-2627. Masuda, Y., K. Mori, T. Hirohata, and M. Kuratsune. 1966. Carcinogenesis in the esophagus. III. Polycyclic aromatic hydrocarbons and phenols in whisky. Gann 57:549-557. Mazur, R. H. 1976. Aspartame--A sweet surprise. J. Toxicol. Environ. Health 2:243-249. McCann, J. C. 1977. Short-term tests. Pp. 91-108 in Cancer Testing Technology and Saccharin. Office of Technology Assessment, Congress of the United States, Washington, D. C. McCann, J., and B. N. Ames. 1976. Detection of carcinogens as mutagens in the Salmonella/microsome test: Assay of 300 chemicals: Discussion. Proc. Natl. Acad. Sci. U.S.A 73:950-954. McCann, J., E. Choi, E. Yamasaki, and B. N. Ames. 197S. Detection of carcinogens as mutagens in the Salmonella/microsome test: Assay of 300 chemicals. Proc. Natl. Acad. Sci. U.S.A. 72:5135-5139. McChesney, E. W., F. Coulston, and K.-F. Benitz. 1977. Six-year study of saccharin in rhesus monkeys. Toxicol. Appl. Pharmacol. 41:164. Abstract 79. Miller, C. T., C. I. Neutel, R. C. Nair, L. D. Marrett, J. M. Last, and W. E. Collins. 1978. Relative importance of risk factors in bladder carcinogenesis. J. Chronic Dis. 31:51-56. 14-42

346 DIET, NUTRITION, AND CANCER Milvy, P. 1978. Letter to the Editor. Mutat. Res. 57:110-112. Milvy, P., and M. Wolff. 1977. Mutagenic studies with acrylonitrile. Mutat. Res. 48:271-278. Mohn, G. 1973. Comparison of the mutagenic activity of eight organo- phosphorus insecticides in Escherichia colt. Mutat. Res. 21:196. Abstract 21. Mohr, U., U. Green, J. Althoff, and P. Schneider. 1978. Syncarcinogenic action of saccharin and sodium-cyclamate in the induction of bladder tumours in MNU-pretreated rats. Pp. 64-69 in B. Guggenheim, ed. Health and Sugar Substitutes. S. Karger, Basel, Munich, Paris, London New York, and Sydney. Mondal, S., D. W. Brankow, and C. Heidelberger. 1978. Enhancement of oncogenesis in C3H/lOTl/ 2 mouse embryo cell cultures by saccharin. Science 201:1141-114 2. Monson, R. R., J. M. Peters, and M. N. Johnson. 1974. Proportional mortality among vinyl-chloride workers. Lance t 2:397-398. Moreau, P., A. Bailone, and R. Devoret. 1976. Prophage Yinduction in Escherichia cold K12 envA uvrB: A highly sensitive test for potential carcinogens. Proc. Natl. Acad. Sci. U.S.A. 73:3700-3704. Morgan, R. W., and M. G. Jain. 1974. Bladder cancer: Smoking, beverages and artificial sweeteners. Can. Med. Assoc. J. 111:1067-1070. Morrison, A. S. 1979. Use of artificial sweeteners by cancer patients. J. Natl. Cancer Inst. 62:1397-1399. Morrison, A. S., and J. E. Buring. 1980. Artificial sweeteners and cancer of the lower urinary tract. N. Engl. J. Med. 302:537-541. Mussman, H. C. 1975. Drug and chemical residues in domestic animals. Fed. Proc. Fed. Am. Soc. Exp. Biol. 34 :197-201. Nagao, M., and T. Sugimura. 1978. Mutagenesis: Microbial systems. Pp. 99-121 in H. V. Gelboin and P. 0. P. Ts'o, eds. Polycyclic Hydrocarbons and Cancer, Volume 2. Molecular and Cell Biology. Academic Press, New York, San Francisco, and London. Nagasaki, H., S. Tomii, T. Mega, M. Marugami, and N. Ito. 1971. Letter to the Editor: Development of hepatomas in mice treated with benzene hexachloride. Gann 62:4 31. 14-43

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

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

Additives and Contaminants 349 National Cancer Institute. 1979g. Bioassay of Toxaphene for Possible Carcinogenicity. NCI Carcinogenesis Technical Report Series No. 37. DREW Publication No. (NIH) 79-837. Carcinogenesis Testing Program, National Cancer Institute, Bethesda, Md. 104 pp. National Institute of Hygienic Sciences. 1973. Chronic Toxicity Study of Sodium Saccharin: 21 Months Feeding in Mice. National Institute of Hygienic Sciences, Tokyo. Neal, J., and R. H. Rigdon. 1967. Gastric tumors in mice fed benzota)- pyrene: A quantitative study. Tex. Rep. Biol. Med. 25:553-557. Nicholson, W. J., E. C. Hammond, H. Seidman, and I. J. Selikoff. 1975. Mortality experience of a cohort of vinyl chloride-polyvinyl chloride workers. Ann. N.Y. Acad. Sci. 246:225-230. Nishizumi, M. 1976. Enhancement of diethylnitrosamine hepatocarcino- genesis in rats by exposure to polychlorinated biphenyls or phenobarbital. Cancer Lett. 2:11-15. Norris, J. M. 1977. Status Report on the 2 Year Study Incorporating Acrylonitrile in the Drinking Water of Rats. Health and Environ- mental Research. The Dow Chemical Company, Midland, Mich. [14] pp. O'Berg, M. T. 1980. Epidemiologic study of workers exposed to acrylonitrile. J. Occup. Med. 22:245-252. Ochi, H., and A. Tonomura. 1978. Presence of unscheduled DNA synthesis in cultured human cells after treatment with sodium saccharin. Mutat. Res. 54:224. Abstract 26. Office of Technology Assessment. 1979. Environmental Contaminants in Food. Office of Technology Assessment, Congress of the United States, Washington, D. C. 229 pp. Ohshima, H., and H. Bartsch. 1981. Quantitative estimation of endogenous nitrosation in man by monitoring N-nitrosoproline excreted in the urine. Cancer Res. 41:3658-3662. Ortelee, M. F. 1958. Study of men with prolonged intensive occupational exposure to DOT. Arch. Ind. Health 18:433-440. Oser, B. L., S. Carson, G. E. Cox, E. E. Vogin, and S. S. Sternberg. 1975. Chronic toxicity study of cyclamate: saccharin (10:1) in rats. Toxicology 4:315-330. Peirce, W. E. H. 1961. Tumour-promotion by lime oil in the mouse forestomach. Nature 189:497-498. 14-4 6

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

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

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

Alcoves and Contaminants 353 Tardiff, R. G., G. P. Carlson, and V. Simmon. 1976. Halogenated organics in tap water: A toxicological evaluation. Pp. 213-227 in R. L. Jolley, ed. The Environmental Impact of Water Chlorination. CONF-751096, UC-11,41,48. Oak Ridge National Laboratory, Oak Ridge, Tenn. Taylor, J. M., and L. Friedman. 1974. Combined chronic feeding and three-generation reproduction study of sodium saccharin in the rat. Toxicol. Appl. Phanmacol. 29:154. Abstract 200. Terracini, B., M. C. Testa, J. R. Cabral, and N. Day. 1973. The effects of long-term feeding of DDT to BALB/c mice. Int. J. Cancer 11:747-764. Thiess, A. M., and I. Fleig. 1978. Analysis of chromosomes of workers exposed to acrylonitrile. Arch. Toxicol. 41:149-152. Thorpe, E., and A. I. T. Walker. 1973. The toxicology of dieldrin (HEOD). II. Comparative long-term oral toxicity studies in mice with dieldrin, DDT, phenobarbitone, 6-BHC and y-BHC. Food Cosmet. Toxicol. 11:433-442. Tisdel, M. O., P. O. Nees, D. L. Harris, and P. H. Derse. 1974. Long- term feeding of saccharin in rats. Pp. 145-158 in G. E. Inglett, ed. Symposium: Sweeteners. AVI Publishing Company, Westport, Conn. Tokumitsu, T. 1971. Some aspects of cytogenetic effects of sodium cyclamate on human leucocytes in vitro. Proc. Jpn. Acad. 47:635-639. Tong, C., M. F. Laspia, S. Telang, and G. M. Williams. 1981. The use of adult rat liver cultures in the detection of the genotoxicity of various polycyclic aromatic hydrocarbons. Environ. Mutagenesis 3:477-487. Trosko, J. E., B. Dawson, L. P. Yotti, and C. C. Chang. 1980. Saccharin may act as a tumour promoter by inhibiting metabolic cooperation between cells. Nature 285:109-110. Trosko, J. E., L. P. Yotti, S. Warren, G. Tsushimoto, and C. C. Chang. 1982. Inhibition of cell-cell communication by tumor promoters. Pp. 565-585 in E. Hecker, W. Kunz, S. Marx, N. E. Fusenig, and H. W. Phielmann, eds. Carcinogenesis: A Comprehensive Survey. Volume 7, Carcinogenesis and Biological Effects of Tumor Promoters. Raven Press, New York. U.S. Consumer Product Safey Commission. 1974. Self-pressurized house- hold substances containing vinyl chloride monomer; classification as banned hazardous substance. Fed. Regist. 39:30112-30114. 14-50

354 DIET, NUTRITION, AND CANCER U.S. Department of Agriculture. 1977. Assessment of Toxaphene in Agriculture. USDA/State Assessment Team on Toxaphene, September 9, 1977. Coordinated by the Office of Environmental Quality Activities, U.S. Department of Agriculture, Washington, D. C. 633 pp. U.S. Department of Agriculture. 1978. Situation and Outlook. Sugar and Sweetener Report 3~5~:1-70. U.S. Department of Health, Education, and Welfare. 1969. Report of Secretary's Commission on Pesticides and Their Relationship to Environmental Health, Parts I and II. U.S. Department of Health, Education, and Welfare, Washington, D. C. 677 pp. U.S. Department of Health, Education, and Welfare. 1973a. Histo- pathologic Evaluation of Tissues from Rats Following Continuous Dietary Intake of Sodium Saccharin and Calcium Cyclamate for a Maximum Period of Two Years. Final Report, December 21, 1973. Project P-169-170. Division of Pathology, Food and Drug Administration, U. S. Department of Health, Education, and Welfare, Washington, D. C. U.S. Department of Health, Education, and Welfare. 1973b. Subacute and Chronic Toxicity and Carcinogenicity of Various Dose Levels of Sodium Saccharin. Final Report. Project P-169-170. Divison of Pathology, Food and Drug Administration, U.S. Department of Health, Education, and Welfare, Washington, D.C. U.S. Environmental Protection Agency. 1975a. Preliminary Assessment of Suspected Carcinogens in Drinking Water. Report to Congress. EPA-560/4-75-005. PB-25096. Office of Toxic Substances, U.S. Environmental Protection Agency, Washington, D. C. . Environmental Protection Agency. 1975b. Draft Report. Aspects of Pesticidal Uses of Carbaryl (Sevin) on Man and the Environment. Office of Pesticide Programs, U.S. Environmental Protection Agency, Washington, D. C. U.S. Environmental Protection Agency. 1975c. Scientific and Technical Assessment Report on Particulate Polycyclic Organic Matter (PPOM), EPA-600/6-75-001. March 1975. Office of Research and Development, U.S. Environmental Protection Agency, Washington, D. C. [95] pp. U.S. Environmental Protection Agency. 1979. Polychlorinated biphenyls (PCBs). Manufacturing, processing, distribution in commerce, and use prohibitions. Fed. Regist. 44 :31514-31568. U.S. Environmental Protection Agency. 1980. Summary of Reported Incidents Involving Toxaphene. Pesticide Incident Monitoring 14-51

Additives and Contaminants 355 System Report No. 316. Hazard Evaluation Division, Office of Pesticide Programs, U.S. Environmental Protection Agency, Washington, D. C. U. S. Food and Drug Administration. 1970. Revocations regarding cycla- mate-containing products intended for drug use. Fed. Regist. 35:13644-13645. U. S. Food and Drug Administration. 1977a. Polychlorinated biphenyls (PCB's). Unavoidable contaminants in food and food packaging materials; Reduction of temporary tolerances. Fed. Regist. 4 2:17487-17494. U. S. Food and Drug Administration. 1977b. Butylated hydroxytoluene. Use restrictions. Fed. Regist. 42:27603-27609. U. S. Food and Drug Administration. 1979. Diethylstilbestrol; With- drawal of approval of new animal drug applications; ComTnissioner's decision. Fed. Regist. 44 :54852-54900. U. S. Food and Drug Administration. 1980a. Aspartame: Decision of the Public Board of Inquiry, Department of Health and Human Services. Docket No. 75F-0355. 51 pp. U. S. Food and Drug Administration. 1980b. FDA Compliance Program Report of Findings, FY 77 Total Diet Studies - Adult (7320.73~. Food and Drug Administration, U.S. Department of Health, Education, and Welfare, Washington, D. C. U. S. Food and Drug Administration. 1981. Aspartame; Commisioner's Final Decision. Fed. Regist. 46:38283-38308. Urabe, H. 1974. [In Japanese; English Summary.] Foreward. Fukuoka Igaku Zasshi 65:1-4. Venitt, S., C. T. Bushell, and M. Osborne. 1977. Mutagenicity of acrylo- nitrile (cyanoethylene) in Escherichia colt. Mutat. Res. 45:283-288. Verburgt, F. G., and E. Vogel. 1977. Vinyl chloride mutagenesis in Drosophila melanogaster. Mutat. Res. 48:327-336. Versteeg, J. P. J., and K. W. Jager. 1973. Long-term occupational exposure to the insecticides aldrin, dieldrin, endrin, and telodrin. Br. J. Ind. Med. 30:201-202. 14-52

356 DIET, NUTRITION, AND CANCER Voitalovich, E. A., P. P. Deekoon, L. U. Deemarsky, and L. M. Shabad. 1957. [In Russian; English Summary.] Comparative study of malignant tumor frequency in Tookoom District of the Latvian SSR. Vopr. Onkol. 3:351-357. Wang, H. H., and S. Grufferman. 1981. Aplastic anemia and occupational pesticide exposure: A case-control study. J. Occup. Med. 23:364-366. Wang, H. H., and B. MacMahon. 1979. Mortality of workers employed in the manufacture of chlordane and heptachlor. J. Occup. Med. 21:745-748. Waxweiler, R. J., W. Stringer, J. K. Wagoner, J. Jones, H. Falk, and C. Carter. 1976. Neoplastic risk among workers exposed to vinyl chloride. Ann. N. Y. Acad. Sci. 271:40-4 8. Well, C. S., and C. P. Carpenter. 1965. Results of a Three-Generation Reproductive Study on Rats Fed Sevin in Their Diets. Report 28-53. Mellon Institute, Carnegie-Mellon University, Pittsburgh, Penn. 18 PP Well, C. S., and C. P. Carpenter. 1974. Aldicarb. Inclusion in the Diet of Rats for Three Generations and a Dominant Lethal Mutagenesis Test. Special Report 37-90. Carnegie-Mellon Institute of Research, Carnegie-Mellon University, Pittsburgh, Penn. 46 pp. Wertz, G. F., and G. Ficsor. 1978. Cytogenetic and teratogenic test of polybrominated biphenyls in rodents. 23:129-132. Environ. Health Perspect. West, I. 1967. Lindane and hematologic reactions. Arch. Environ. Health 15:97-101. Wiegand, R. G. 1978. Practical considerations for synthetic sweeteners: Past, present and future--Cyclamates. Pp. 263-267 in J. H. Shaw and G. G. Roussos, eds. Sweeteners and Dental Caries. Information Retrieval, Inc., Arlington, Va. Williams, D. T. 1976a. Gas-liquid chromatographic headspace method for vinyl chloride in vinegars and alcoholic beverages. J. Assoc. Off. Anal. Chem. 59:30-31. Williams, D. T. 1976b. Confirmation of vinyl chloride in foods by conversion to 1-chloro-1,2-dibromoethane. 59:32-34. J. Assoc. Off. Anal. Chem. Williams, D. T., and W. F. Miles. 1975. Gas-liquid chromatographic determination of vinyl chloride in alcoholic beverages, vegetable oils, and vinegars. J. Assoc. Off. Anal. Chem. 58:272-275. 14-53

Arrives and Contaminants 357 Witschi, H. P. 1981. Enhancement of tumor formation in mouse lung by dietary butylated hydroxytoluene. Toxicology 21:95-104. Witschi, H., D. Williamson, and S. Lock. 1977. Enhancement of urethan tumorigenesis in mouse lung by butylated hydroxytoluene. J. Natl. Cancer Inst. 58:301-305. Witschi, H. P., P. J. Hakkinen, and J. P. Kehrer. 1981. Modification of lung tumor development in A/J mice. Toxicology 21:37-45. Wolff, S., and B. Rodin. 1978. Saccharin-induced sister chromatic exchanges in Chinese hamster and human cells. Science 200:543-545. World Health Organization. 1958. Procedures for the Testing of Intentional Food Additives to Establish Their Safety for Use. Second Report of the Joint FAD/WHO Expert Committee on Food Additives. W.H.O. Tech. Rep. Ser. 144:1-19. World Health Organization. 1973. Safe Use of Pesticides. W.H.O. Tech. Rep. Ser. 513:1-54. Wynder, E. L., and S. D. Stellman. 1980. Artificial sweetener and bladder cancer: A case-control studye Science 207:1214-1216. Wynder, E. L., K. Mabuchi, N. Maruchi, and J. G. Fortner. 1973. Epidemiology of cancer of the pancreas. J. Natl. Cancer Inst. 50:645-667. Wyndham, C., J. Devenish, and S. Safe. 1976. The in vitro metabolism, macromolecular binding and bacterial mutagenicity of 4-chlorobiphenyl, a model PCB substrate. Res. Commun. Chem. Pathol. Pharmacol. 15:563- 570. Yoshida, S., M. Masubuchi, and K. Hiraga. 1978. Induced chromosome aberrations by artificial sweeteners in CHO-K1 cells. Mutat. Res. 54:262. Abstract 45. 14-54

Next: 15 Inhibitors of CarcinogenisisSection C - Patterns of Diet and Cancer »
Diet, Nutrition, and Cancer Get This Book
×
Buy Paperback | $125.00
MyNAP members save 10% online.
Login or Register to save!
Download Free PDF

Based on a thorough review of the scientific evidence, this book provides the most authoritative assessment yet of the relationship between dietary and nutritional factors and the incidence of cancer. It provides interim dietary guidelines that are likely to reduce the risk of cancer as well as ensure good nutrition.

  1. ×

    Welcome to OpenBook!

    You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

    Do you want to take a quick tour of the OpenBook's features?

    No Thanks Take a Tour »
  2. ×

    Show this book's table of contents, where you can jump to any chapter by name.

    « Back Next »
  3. ×

    ...or use these buttons to go back to the previous chapter or skip to the next one.

    « Back Next »
  4. ×

    Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

    « Back Next »
  5. ×

    To search the entire text of this book, type in your search term here and press Enter.

    « Back Next »
  6. ×

    Share a link to this book page on your preferred social network or via email.

    « Back Next »
  7. ×

    View our suggested citation for this chapter.

    « Back Next »
  8. ×

    Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

    « Back Next »
Stay Connected!