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OCR for page 202
L Alcohol
Estimates of per capita alcoholic beverage intake based on taxes
paid on alcohol purchases in various countries may be moderately or
extremely low. This is partly because alcoholic beverages purchased
either illegally or by special sanctions from U.S. government agencies
escape taxation, and thus, inclusion in the tax records from which the
estimates are drawn. Studies based on surveys are also prone to error
because consumers tend to underestimate their alcohol intake (DeLuca,
1981).
EPIDEMIOLOGICAL EVIDENCE
Specific Alcoholic Beverages
A number of reports implicate specific alcoholic beverages as risk
factors for cancers at certain sites. Using data on per capita intake
of various types of alcoholic beverages and standard mortality ratios
in the 46 prefectures of Japan, Kono and Ikeda (1979) found only
suggestive correlations for males between cancer of the esophagus and
intake of both whiskey and shochu; cancer of the rectum and wine intake;
and cancer of the prostate and shochu intake. There were no correlations
for females. Cook (1971) and Collis et al. (1972) ascribed the high
frequency of esophageal cancer in an African population to the consump-
tion of an alcoholic beverage prepared from maize. In the Normandy
region of France, people who consumed home-distilled apple brandy had
an increased risk of esophageal cancer, compared to nondrinkers (Tuyns
_ al., 1979~. Smoking enhanced this risk (Tuyns and Masse, 1973; Tuyns
_ el., 1977~. In a very early study, Lamy (1910) reported an associa-
tion between esophageal cancer and the consumption of absinthe by chronic
alcoholics in France. In China, where earlier records indicated that
esophageal cancer comprised approximately one-half of the gastrointesti-
nal tract cancers, pai-kan, a strong alcoholic beverage, was cited as an
etiological agent (Kwan, 1937; Wu and Loucks, 1951~.
Recently, Hoey et al. (1981) reported that the consumption of alcohol
(primarily red wine) increased the risk of adenocarcinoma of the stomach.
In this study, which was conducted in Lyon, France, patients with gastric
cancer consumed approximately 800 calories per day as alcohol compared to
400 calories per day for patients with other digestive diseases.
In a multi-ethnic population living in Hawaii, a direct association
was observed for beer consumption and eight cancer sites (including
tongue/mouth, pharynx, larynx, esophagus, stomach, pancreas, lung, and
kidney) (Hinds et al., 1980~. In the mainland United States, Breslow and
Enstrom '1974) and Enstrom (1977) demonstrated a statistically signifi-
cant association between per capita beer intake and colorectal cancer,
202
11-1
OCR for page 203
A]coho] 203
especially rectal cancer. Wynder and Shigematsu (1967) reported that a
group of 314 male colorectal cancer patients contained a significantly
higher proportion of beer drinkers than did one control group, but there
were no differences between the cases and a second control group. In a
study of 166 male bowel cancer patients in Great Britain, Stocks (1957)
demonstrated a significant association with beer drinking. Bjelke (1973)
reported a dose-response relationship for the risk of colorectal cancer
and the frequency of beer and liquor consumption in a prospective study
of 12,000 middle-aged Norwegian men. Dean et al. (1979) also reported a
direct association based on a cohort study in Dublin. Conversely, case-
control studies of bowel cancer in Finland, Kansas, and Norway by Pernu
(1960), Higginson (1966), and Bjelke (1971, 1973) showed no significant
relationship with beer drinking. Similarly, no associations were ob-
served in a correlational analysis by Hinds et al. (1980) or in a cohort
study by Jensen (1979~.
Using international data and estimates of ethanol intake from beer,
wine, and distilled spirits, Vitale et al. (1981) demonstrated a corre-
lation coefficient of 0.78 for beer drinking and colorectal cancer in 20
countries. Poor correlations were obtained for colon cancer and intake
of total ethanol, distilled spirits, or wine.
Thus, in certain populations throughout the world there appears to be
an association between consumption of strong, locally prepared alcoholic
beverages and esophageal cancer. There also appears to be a statistically
significant association between beer drinking and colorectal cancers in
certain countries but not in others. These associations with specific
beverage types suggest that the effects may be due to intake of other
contaminants in the beverages, rather than to consumption of ethanol per
_-
As noted above, epidemiological studies have linked the consumption
of alcoholic beverages to the development of cancers at various sites.
In an ideal study to examine this relationship, alcohol abusers and
"moderate" drinkers should be studied separately. In the abusers,
alcohol may play a modifying or contributing role in carcinogenesis by
inducing nutritional deficiency diseases that, in turn, may interact in
the process of carcinogenesis in the host. This effect of alcohol may be
different in moderate drinkers. However, because it is difficult to
determine alcohol intake with accuracy, the distinction between alcohol
abuse and moderate drinking in the studies described below is to some
extent arbitrary.
Total Alcoholic Beverages
An association between cancer at various sites and alcohol abuse has
been recognized for some time. In France, Piquet and Tison (1937)
observed that 95% of their patients with esophageal cancer were alcohol
abusers. In a study of 4,000 French patients, Schwartz and colleagues
11-2
OCR for page 204
204 DIET, NUTRITION, AND CANCER
showed a significant correlation between mean daily alcohol consumption
and frequency of cancers of the tongue, hypopharynx, and larynx (Schwartz,
1966; Schwartz et al., 1962, 1966~. A large majority of the individuals
with cancers at these sites were heavy drinkers. In a Finnish male cohort
study, chronic alcoholics were found to have excess morbidity from cancers
of the pharynx, esophagus, and lung (Hakulinen et al., 1974~. On the
basis of a literature survey, the World Health Organization (1964) con-
cluded that excessive consumption of alcoholic beverages was associated
with cancer of the mouth, larynx, and esophagus. Case-control studies
conducted in the United States have established that excessive consumption
of alcoholic beverages increases the risk of incurring cancer of the oral
cavity, excluding the lip, glottis and supraglottic region, larynx, and
esophagus (Bross and Coombs, 1976; Burch et al., 1981; Graham et al.,
1977; Kaminonkowski and Fleshier, 1965; Keller and Terris, 1965; Keller
et al., 1977; Moore, 1965; Rothman and Keller, 1972; Schottenfeld, 1979;
Schottenfeld _ al., 1974; Vincent and Marchetta, 1963; Wynder and Bross,
1961; Wynder et al., 1957a). Salient features of the earlier studies
have been summarized by Keller et al. (1977) in a report prepared for the
U.S. Congress.
Excessive alcohol consumption has also been linked with the develop-
ment of hepatomas (MacDonald, 1956~. Purtilo and Gottlieb (1973) noted
that by far the greatest number of hepatomas were hepatocellular carcino-
mas, which were found in 72% of the hepatoma patients studied. Approxi-
mately one-half of the 98 patients in this series were alcohol abusers.
The investigators suggested that chronic alcoholism contributed to the
development of hepatomas by inducing cirrhosis. Keen and Martin (1971)
suggested that aflatoxin consumed by African patients induced hepatomas
indirectly by first inducing cirrhosis. Vogel and his associates (1970)
found hepatitis-associated antigen (HAA) in African patients with hepato-
mas. Hepatitis B antigenemia has been frequently associated with hepato-
cellular carcinomas (Sherlock et al., 1970; Vogel et al., 1970; Wu and
Lam, 1979~. In general, hepatomas are found in individuals with cirrho-
sis. Thus, agents such as alcohol, hepatitis antigen, and aflatoxin,
which result in hepatic injury leading to cirrhosis, may contribute to
the development of hepatomas through this pathway. A number of etiolo-
gies have been proposed for the development of carcinomas through the
hepatocellular regeneration that accompanies cirrhosis (Lieber et al.,
1979).
There is a substantial amount of experimental evidence indicating
that aflatoxin is a carcinogen as well as a hepatotoxin (Rogers and
Newberne, 1971), but there is no direct evidence that hepatitis B virus
is oncogenic. (See Chapter 12 for a discussion of primary liver cancer
associated with exposure to hepatitis B viral infection.) No adequate
studies have been conducted to determine whether alcohol per se is
carcinogenic or cocarcinogenic in the develoment of hepatomas in the
absence of cirrhosis.
Lieber et al. (1979) reported that a small number of alcohol abu-
sers developed hepatocellular carcinomas in the absence of cirrhosis.
11-3
OCR for page 205
AIcoho] 205
Although other investigators (e.g., Keller, 1978) reported similar
findings, Lieber and colleagues suggested that the numbers were too small
to ascertain if the tumor incidence was significantly greater in alcohol
abusers than in moderate drinkers or nondrinkers. Additional studies are
required to evaluate fully the role of ethanol in hepatocarcinogenesis.
Other sites in the digestive tract where cancer has also been asso-
ciated with alcohol abuse include the gastric cardia (MacDonald, 1972)
and the pancreas (Burch and Ansari, 1968~.
Synergism Between Alcohol and Smoking
Alcohol consumers (especially abusers) are, more often than not,
smokers. Flamant _ al. (1964), assessing both variables, stressed the
interaction between alcohol consumption and smoking for cancers of the
oral cavity and the esophagus. Studies completed since then have con-
firmed these findings supporting an interactive role between tobacco and
alcohol in tumorigenesis of the oral cavity, the larynx, and esophagus
(Burch et al., 1981; Keller and Terris, 1965; Martinez, 1970; Pattern et
al., 1981, Rothman and Keller, 1972; Wapnick et al., 1972~. Avoidance of
tobacco and alcohol by males could effect a marked reduction of these
cancers (Rothman, 1980; Rothman and Keller, 1972~. Flamant et al. (1964)
suggested that alcohol abuse may be more important than smoking in the
development of esophageal cancer, but smoking is more closely allied to
cancers of the mouth and pharynx.
It is difficult to ascertain if moderate or heavy consumption of
alcohol (other than the beverages specified above) enhances the risk of
oral and upper respiratory tract cancer in nonsmokers. Synergistic
effects of alcohol and smoking have been observed in smokers consuming
45 ml or more of ethanol per day (Schottenfeld, 1979~. Cancer sites
correlating with past ethanol consumption more strongly than with ex-
posure to tobacco include the floor of the mouth, supraglottic region,
hypopharynx, and esophagus (Omerovic, 1976; Spala jkovic, 1976; Stevens,
1979~. Since alcohol consumption involves direct exposure of the sites,
Kissin (1975) suggested that ethanol exerts a direct local effect rather
than a systemic one. Geographic, ethnic, and dietary factors may also be
of some consequence in esophageal cancer (Pothe and Voigtsberger, 1976;
Sadeghi et al., 1977; Schwartz et al., 1966; Steiner, 1956~. A case-
control study conducted by Graham et al. (1977) introduced still another
variable. These investigators reported that the interaction of tobacco
and alcohol in cancers of the oral cavity was apparent only in individuals
with clinical evidence of inadequate dentition.
McCoy et al. (1979) noted that excessive ethanol consumption and
exposure to tobacco may act synergistically to affect the risk of cancer
of the upper alimentary and respiratory tracts. The much lower incidence
of cancer at these sites in nondrinkers and nonsmokers suggested to these
11-4
OCR for page 206
206 DIET, NUTRITION, AND CANCER
researchers that excessive alcohol consumption may augment other process-
es such as impaired nutritional status, which may be associated with the
development of cancer at these sites.
Estimated ethanol intake, independent of smoking, was associated with
a modest, but increased risk for cancers of the upper respiratory tract
(McCoy and Wynder, 1979; Rothman and Keller, 1972~. Williams and Horm
(1977) also observed that ethanol increased the risk for cancers at this
site when they controlled for smoking. A number of other reports have
indicated that there is a dose response between consumption of ethanol
(independent of the type of alcoholic beverage) and the risk of upper
respiratory tract cancer (Williams and Horm, 1977; Wynder and Stellman,
1977; Wynder _ al., 1957b). In general, these studies focused on mod-
erate to heavy consumers of ethanol.
Reports by Rothman (1980) and by Burch et al. (1981) indicate that
the risk for cancers of the oral cavity is slightly increased in smokers
reporting low to moderate consumption of ethanol (i.e., >12 to 45 ml, or
approximately 70 to 270 calories daily). However, because consumers tend
to underreport their ethanol intake (DeLuca, 1981), it is difficult to
interpret these findings.
Effect of Nutritional Status
Malnutrition may play a key role in the development of cancers of the
head and neck in alcohol abusers (Kissin and Kaley, 1974~. These indi-
viduals frequently suffer from malnutrition because they often consume
from 25% to 50% (or more) of their daily calories as alcohol. In the
absence of chronic alcoholism and smoking, malnutrition or nutritional
imbalance have been found frequently in individuals with cancer of the
oral cavity and respiratory tract (Kissin and Kaley, 1974~. For exam-
ple, an association between Plummer-Vinson (also called Paterson-Kelly)
syndrome and iron deficiency with esophageal cancer has been observed in
Swedish women (Wynder and Fryer, 1958; Wynder and Klein, 1965~. Since
the early 1950's, dietary supplementation with iron and vitamins has
markedly reduced the incidence of Plummer-Vinson syndrome as well as
esophageal cancer (Larsson et al., 1975~. Esophageal cancer in Iran
(Kmet and Mahboubi, 1972), Sweden (Jacobsson, 1961), and Puerto Rico
(Martinez, 1970) is more frequent among the malnourished. Experi-
mentallY induced deficiency of lipotropes, riboflavin, vitamin A, or
enhance carcino~en-induced tumors in labora-
zinc have been shown to ~
tory animals (Newberne and McConnell, 1980~.
EXPERIMENTAL EVIDENCE
Postulated Mechanisms of Action in Carcinogenesis
Possible mechanisms through which alcohol might contribute to the
risk of cancer of the head and neck are: alcohol acting as a carcinogen,
11-5
OCR for page 207
Alcohol 207
cocarcinogen, or promoter; alcohol acting as a solvent facilitating
transport of carcinogens across membranes; induction of microsomal
enzymes by alcohol leading to activation and/or metabolism of car-
cinogens; alcohol as a source of putative carcinogenic contaminants
in alcoholic beverages; alcohol-related nutritional deficiencies; and
alcohol abuse associated with immunosuppression. These have been dis-
cussed by Kissin and Kaley (1974), Vitale and Gottlieb (1975), McCoy
and Wynder (1979), Lieber et al. (1979), Schottenfeld (1979), and Vitale
_ al. (1981~.
There are only a few experimental data to indicate that alcohol
can act either as a carcinogen or cocarcinogen or that its solvent
properties facilitate the transport of carcinogens across cell mem-
branes. The relationship of alcohol-induced immunosuppression to
tumorigenesis in animals has not been explored, and the role of alco-
hol-related nutritional deficiencies to carcinogenesis in animals is
only in the preliminary stages of investigation.
Alcohol and Induction of Microsomal Enzymes
The chronic feeding of ethanol to laboratory animals can increase
the activity of the hepatic microsomal enzymes responsible for bioacti-
vation of procarcinogens (Rubin et al., 1970~. Polycyclic hydrocarbons,
e.g., benzotaipyrene, were activated to a greater extent when rats were
fed ethanol than when they were fed a control diet (Seitz et al., 1978~.
In contrast, Capel et al. (1978) reported a decrease in benzota~pyrene-
hydroxylase activity following chronic administration of ethanol. McCoy
_ al. (1979) demonstrated that ethanol fed to hamsters for 28 days in-
creased the hydroxylation rates of two cyclic nitrosamines, N-nitroso-
pyrrolidine and N-nitrosonornicotine, which are found in mainstream and
sidestream tobacco smoke. Enhanced mutagenicity of these hydroxylated
compounds was assessed with the Ames test. The enhanced activation of
both nitrosamines by ethanol provides some experimental evidence for the
synergistic effect of chronic alcohol abuse and smoking in the induction
of head and neck cancers. Microsomal activation of tobacco pyrolysate
has been observed in the rat lung, and activation of benzotaipyrene
occurs in cultures of small bowel tissue. The metabolic activation of
these procarcinogens was increased in tissues chronically exposed to
ethanol by injection (McCoy et al., 1979~.
Occurrence of Putative Carcinogens in Alcoholic Beverages
Certain congeners of alcoholic beverages, e.g., nitrosamines
(Li jinsky and Epstein, 1970) and fusel oil (Giber et al. , 1968), have
been demonstrated to produce tumors of the stomach and esophagus in
laboratory animals. Other putative carcinogens found in alcoholic
beverages include polycyclic hydrocarbons, such as phenanthrene,
fluoranthrene' benzanthracene, benzotaipyrene, and chrysene (Goff and
11-6
OCR for page 208
208 DIET, NUTRITION, AND CANCER
Fine, 1979; Masuda _ al., 1966), and asbestos fibers, which often leach
from filters into wines (Bignon et al., 1977; Gaudichet et al., 1978),
beer (Bile s and Emerson, 1968), and gin (Wehman and Plantholt, 1974~.
SUMMARY AND CONCLUSIONS
The effects of alcohol consumption on cancer incidence have been
studied in human populations. In some countries, including the United
States, excessive beer drinking has been associated with an increased
risk of colorectal cancer, especially rectal cancer. This observation
has not been confirmed in most case-control or cohort studies. There
is limited evidence that excessive alcohol consumption contributes to
hepatic injury and cirrhosis, which in turn may lead to the formation of
hepatomas. Excessive consumption of alcoholic beverages by smokers
appears to act synergistically in increasing the risk for cancer of the
mouth, larynx, esophagus, and the respiratory tract.
11-7
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Alcohol 209
REFERENCES
Bignon, J., M. Bientz, G. Bonnaud, and P. Sebastien. 1977. [In
French.] Letter to the Editor: Evaluation numerique des fibres
d'amiante dans des echantillons de vies. Nouv. Presse Med. 6:1148-
1149.
Biles, B., and T. R. Emerson. 1968. Examination of fibres in beer.
Nature 219:93-94.
Bjelke, E. 1971. Case-control study of cancer of the stomach, colon,
and rectum. Pp. 320-334 in R. L. Clark, R. C. Cumley, J. E. McCay,
and M. M a Copeland, eds. Oncology 1970. Volume 5: A. Environ-
mental Causes. B. Epidemiology and Demography. C. Cancer Educa-
tion. Yearbook Medical Publishers, Chicago.
Bjelke, E. 1973. Epidemiologic Studies of Cancer of the Stomach,
Colon, and Rectum; With Special Emphasis on the Role of Diet,
Volumes I-IV. Ph.D. Thesis, University of Minnesota. 1,746 pp.
Breslow, N. E., and J. E. Enstrom. 1974. Geographic correlations
between cancer mortality rates and alcohol-tobacco consumption in
the United States. J. Natl. Cancer Inst. 53:631-639.
Brass, I. D. J., and J. Coombs. 1976. Early onset of oral cancer
among women who drink and smoke. Oncology 33:136-139.
Burch, G. E., and A. Ansari. 1968. Chronic alcoholism and carcinoma
of the pancreas: A correlative hypothesis. Arch. Intern. Med.
122:273-275.
Burch, J. D., G. R. Howe, A. B. Miller, and R. Semenciw. 1981. To-
bacco, alcohol, asbestos, and nickel in the etiology of cancer of
the larynx: A case-control study. J. Natl. Cancer Inst.
67:1219-1224.
Capel, I. D., M. Jenner, M. H. Pinnock, H. M. Dorrell, and D. C.
Williams. 1978. The effect of chronic ethanol intake on the
growth and spread of some murine tumors. Oncology 35:224-226.
Collis, C. H., P. J. Cook, J. K. Foreman, and J. F. Palframan. 1972.
Letter to the Editor: Cancer of the oesophagus and alcoholic
drinks in East Africa. Lancet 1:441.
Cook, P. 1971. Cancer of the oesophagus in Africa: A summary and
evaluation of the evidence for the frequency of occurrence, and a
11-8
OCR for page 210
210 DIET, NUTRITION, AND CANCER
preliminary indication of the possible association with the con-
sumption of alcoholic drinks made from maize. Br. J. Cancer
25: 853-880.
Dean, G., R. MacLennan, H. McLaughlin, and E. Shelly. 1979. Causes
of death of blue-collar workers at a Dublin brewery, 1954-1973.
Br. J. Cancer 40: 581-589.
DeLuca, J. R., ed. 1981. Fourth Special Report to the U.S. Congress
on Alcohol and Health. National Institute on Alcohol Abuse and
Alcoholism, Public Health Service, U.S. Department of Health and
Human Services, Rockville, Md. 206 pp.
Enstrom, J. E. 1977. Colorectal cancer and beer drinking. Br. J.
Cancer 35: 674-683.
Flamant, R., O. Lasserre, P. Lazar, J. Leguerinais, P. Denoix, and
D. Schwartz. 1964. Differences in sex ratio according to cancer
site and possible relationship with use of tobacco and alcohol:-
Review of 65,000 cases. J. Natl. Cancer Inst. 32: 1309-1316.
audichet, A., P. Sebastien, G. Dufour, G. Bonnaud, M. Bientz,
J. Bignon, and J. Puisais. 1978. Asbestos fibers in wines:
Relation to filtration process. J. Environ. Pathol. Toxicol.
2: 417-425.
Gibel, W., G. P. Wildner, and K. Lobs. 1968. [In German; English
Summary.] Cancerogenic and hepatotoxic effects of fusel oil.
Arch. Geschwulstforsch. 32:115-125.
Goff, E. U., and D. H. Fine. 1979. Analysis of volatile N-nitros-
amines in alcoholic beverages. Food Cosmet. Toxicol. 17 :569-573.
Graham, S., H. Dayal, T. Rohrer, M. Swanson, H. Sultz, D. Shedd, and
S. Fischman. 19 77. Dentition, diet, tobacco, and alcohol in the
epidemiology of oral cancer. J. Natl. Cancer Inst. 59:1611-1618.
Hakulinen, F., L. Lehtimaki, M. Lehtonen, and L. Teppo. 1974. Cancer
morbidity among two male cohorts with increased alcohol consumption
in Finland. J. Natl. Cancer Inst. 52: 1711-1714.
Higginson, J. 1966. Etiological factors in gastrointestinal cancer
in man. J. Natl. Cancer Inst. 37: 527-545.
Hinds, M. W., L. N. Kolonel, J. Lee, and T. Hirohata. 1980. Associa-
tions between cancer incidence and alcohol/cigarette consumption
among five ethnic groups in Hawaii. Br. J. Cancer 41:929-940.
11-9
OCR for page 211
Alcohol 211
Hoey, J., C. Montvernay, and R. Lambert. 1981. Wine and tobacco:
Risk factors for gastric cancer in France. Am. J. Epidemiol.
113:668-674.
Jacobsson, F. 1961. The Paterson-Kelly (Plummer-Vinson) syndrome and
carcinoma of the cervical oesophagus. Pp. 53-60 in N. C. Tanner
and D. W. Smithers, eds. Neoplastic Disease at Various Sites,
Volume 4. Tumors of the Esophagus. E. and S. Livingstone, Ltd.,
Edinburgh and London.
Jensen, 0. M. 1979. Cancer morbidity and causes of death among Danish
brewery workers. Int. J. Cancer 23 :454063.
Kamionkowski, M. D., and B. Fleshier. 1965. The role of alcoholic
intake in esophageal carcinoma. Am. J. Med. Sci. 249 :696-700.
Keen, P., and P. Martin. 1971. Is aflatoxin carcinogenic in man?
The evidence in Swaziland. Trap. Geogr. Med. 23 :44-53.
Keller, A. Z. 1978. Liver cirrhosis, tobacco, alcohol and cancer
among blacks. J. Natl. Med. Assoc. 70 :575-579.
Keller, A. Z., and M. Terris. 1965. The association of alcohol and
tobacco with cancer of the mouth and pharynx. Am. J. Public Health
55:1578-1585.
Keller, M., D. M. Promisel, D. Spiegler, L. Light, and M. N. Davies,
eds. 1977. Alcohol and cancer. Pp. 53-67 in Second Special
Report to the U.S. Congress on Alcohol and Health. Public Health
Service, Department of Health, Education, and Welfare, Rockville,
Md.
Kissin, B. 1975. Epidemiologic investigations of possible biological
interactions of alcohol and cancer of the head and neck. Ann. N.Y.
Acad. Sci. 252:374-377.
Kissin, B., and M. M. Kaley. 1974. Alcohol and cancer. Pp. 481-511
in B. Kissin and H. Begleiter, eds. The Biology of Alcoholism.
Volume 3. Clinical Pathology. Plenum Press, New York and London.
Kmet, J., and E. Mahboubi. 1972. Esophageal cancer in the Caspian
littoral of Iran: Initial studies. Science 175:846-853.
Kono, S., and M. Ikeda. 1979. Correlation between cancer mortality
and alcoholic beverage in Japan. Br. J. Cancer 40:449-455.
Kwan, K. W. 1937. Carcinoma of the esophagus. A statistical study.
Chin. Med. J. (Peking) 52:237-254.
11-10
OCR for page 212
212 DIET, NUTRITION, AND CANCER
Lamy, L. 1910. [In French.] Etude de statistique clinique de 134
cas de cancer de l'oesophage et du cardia. Arch. Mall Appar. Dig.
Mall Nutr. 4 :451~7S.
Larsson, L.-G., A. Sandstrom, and P. Westling. 1975. Relationship of
Pl~mmer-Vinson disease to cancer of the upper alimentary tract in
Sweden. Cancer Res. 35:3308-3316.
Lieber, C. S., H. K. Seitz, A. J. Garro, and T. M. Warner. 1979.
Alcohol-related diseases and carcinogenesis. Cancer Res.
39:2863-2886.
Lijinsky, W., and S. S. Epstein. 1970. Nitrosamines as environmental
carcinogens. Nature 225:21-23.
MacDonald, R. A. 1956. Cirrhosis and primary carcinoma of the liver:
Changes in their occurrence at the Boston City Hospital, 1897-1954.
N. Engl. J. Med. 255:1179-1183.
MacDonald, W. C. 1972. Clinical and pathological features of adeno-
carcinoma of the gastric cardia. Cancer 29:724-732.
Martinez, I. 1970. Retrospective and prospective study of carcinoma
of the esophagus, mouth, and pharynx in Puerto Rico. Boll Asoc.
Med. P. R. 62:170-178.
Masuda, Y., K. Mori, T. Hirohata, and M. Kuratsune. 1966. Carcino-
genesis in the esophagus. III. Polycyclic aromatic hydrocarbons
and phenols in whisky. Gann 57:549-557.
McCoy, G. D., and E. L. Wynder. 1979. Etiological and preventive
implications in alcohol carcinogenesis. Cancer Res. 39:2844-2850.
McCoy, G. D., C. B. Chen, S. S. Hecht, and E. C. McCoy. 1979. Enhanced
metabolism and mutagenesis of nitrosopyrrolidine in liver fractions
isolated from chronic ethanol-consuming hamsters. Cancer Res.
39:793-796.
Moore, C. 1965. Smoking and cancer of the mouth, pharynx, and
larynx. J. Am. Med. Assoc. 191:283-286.
Newberne, P. M., and R. G. McConnell. 1980. Nutrient deficiencies
in cancer causation. J. Environ. Pathol. Toxicol. 3~4~:323-356.
Omerovic, V. H. 1976. [In Serbo-Croatian; English Summary.] Kronicni
alkololizam: Njegova korelacija sa karcinomom oro-farinska. Med.
Arh. 30:19-21.
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The Role of Nonnutnt:ive Dietary Constituents 223
TABLE B-2
Use of Some Food Additives (Nutritive and Nonnutritive)
in the United Statesa
Category
Thickeners/ stabilizers (hydrocolloids)
Flavors and enhancers
Emulsifiers (surfactants)
Approximate Quantity
(million kg/year)
195 - 215
132 - 145
123 - 136
Acidulants 82 - 91
Chemical leavening agents 80 - 91
Colors 36 - 39
Humectants 27 - 32
Nutritional supplements (vitamins)
Preservatives
Enzymes
Dietary sweeteners (nonnutritive)
Antioxidants
Sugar
Other
aAdapted from Jorgenson, 1980.
bData from U.S. Department of Agriculture
B-7
25 - 30
23 - 27
' 12
'2.3
2.3 - 3.6
9,000
'91
, 1980.
OCR for page 224
224 DIET, NUTRITION, AND CANCER
THE CARCINOGENICITY OF FOOD ADDITIVES AND CONTAMINANTS
-
Both additives and contaminants have been studied within the United
States and abroad. During the past two decades, these studies have
produced an immense body of literature on the health effects of food
additives. For example, the Select Committee on GRAS Substances (SCOGS)
has published 118 reports on 415 GRAS substances (Fisher and Allison,
1981), and the Flavor and Extracts Manufacturing Association (FEMA) has
compiled approximately 70 reports (Oser and Ford, 1979), which contain
the opinions of an FEMA expert committee on about 1,650 flavoring ingre-
dients used in foods. Since 1958 the FAD/WHO Joint Expert Committee on
Food Additives has prepared annual reports concerning the toxicity of
several hundred additives (World Health Organization, 1958-1980~. The
International Agency for Research on Cancer (1972-1981) has published 24
monographs, many of which evaluate the carcinogenic risk of selected
additives to humans. Before the 1970's, most reports concerned with the
safety of additives were based on data from tests of acute or subchronic
toxicity. These reports documented the general health effects of food
ingredients, but did not necessarily contain comments on carcinogenicity,
although they did identify substances found to be carcinogenic. More
chronic feeding studies have been conducted during the past decade.
However, the majority of food additives approved for use have not been
tested specifically for carcinogenicity or mutagenicity. Table B-3
summarizes the classes of chemicals tested from 1953 to 1973 in the
National Cancer Institute Carcinogenesis Bioassay Program (National
Cancer Institute, 1975~. Very few epidemiological studies have been
conducted to study the effect of food additives. This is probably
because of the difficulty of identifying populations with significantly
different exposures to specific additives, and because of lack of
sensitivity of epidemiological techniques to measure the effects of
exposure to low levels of chemicals.
Eighty-three of the 415 GRAS substances reviewed by SCOGS have been
tested by long-term feeding studies, but very few of these studies were
designed to test for carcinogenicity. A total of 513 GRAS substances
have been tested for mutagenicity and/or by long-term feeding studies.
Because SCOGS was restricted to evaluating each substance only for its
use as a GRAS substance, the determination of safety for many of the
compounds is based on one specific use of the compound. For example,
caffeine was evaluated for its use as an additive in cola beverages only,
not for total exposure from all dietary sources, such as from coffee and
tea (Fisher and Allison, 1981~.
Flavoring ingredients have been assessed by FEMA to determine their
safety for specific uses (Oser and Ford, 1979~; however, not all ingre-
dients have been tested for mutagenicity and carcinogenicity. Because
several food-coloring agents are suspected or known carcinogens, the
30 or more compounds currently approved for this use in the United
States have been studied extensively for carcinogenicity. Many pesti-
cides, heavy metals, and industrial chemicals have also been examined
B-8
OCR for page 225
The Role of Nonnutnhve Dietary Constituents 225
TABLE B-3
Categories of Compounds Bioassayed for Carcinogenicity
Between 1953 and 1973a
Category
-
Pharmaceuticals
Pesticides
Industrial chemicals (organic)
Metallic compounds
Natural food products
Food chemicals
Tobacco ingredients
Environmental agents (general)
Miscellaneous (structural analogues,
multiple uses)
aData from National Cancer Institute, 1975.
Percent of Total
Bioassayed
20 e8
17.4
15 e2
6~7
5~7
1~6
0.8
0.2
31.6
100.0
specifically for carcinogenicity and/or mutagenicity. Although many
naturally occurring contaminants have also been tested for mutagenicity
and a few for carcinogenicity, much less emphasis has generally been
placed on this class of substances.
Table B-4 lists examples of suspected or proven carcinogens in each
category of food ingredients. With the exception of saccharin, any direct
food additive known to cause cancer in animals or humans has been banned
from use in foods. For known carcinogens in some classes of additives,
especially contaminants of natural origin, the FDA establishes tolerable
levels. However, for residues of pesticides, the Environmental Protection
Agency establishes limits (Acceptable Daily Intakes) (U.S. Department of
Health and Human Services, 1980~.
B-9
OCR for page 226
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OCR for page 228
228 DIET, NUTRITION, AND CANCER
ASSESSMENT OF EFFECTS ON HUMAN HEALTH
-
Lack of adequate data on a large number of substances precludes a
comprehensive assessment of the risk to humans exposed to food additives
and contaminants. Therefore, Chapters 12, 13, 14, and 15 contain examples
of nonnutritive substances selected from Table B-4 to illustrate the car-
cinogenic potential of this vast group of substances. The selection of
these examples was determined by the extent to which humans are exposed
through the general diet and the reliability of the data pertaining to
these exposures.
Any assessment of the health effects of food additives and contami-
nants must take into consideration not only the extent to which humans
are exposed through the average diet, but also the wide range of exposure
for subgroups of the population, the wide range in the carcinogenic
potency of these compounds, and the potential for synergistic and/or
antagonistic effects of the numerous compounds that are present in the
average diet.
B-12
OCR for page 229
The Role of NonnutA~ve Dietary Constituents 229
REFERENCES
Cater, D. B. 1961. The carcinogenic action of carrageenin in rats.
Br. J. Cancer 15:607-614.
Code of Federal Regulations. 1981. Title 21, Parts 1-99, 100-169,
and 170-199. Office of the Federal Register, National Archives and
Records Service, General Services Administration, Washington, D. C.
Dickens, F., and H. E. H. Jones. 1961. Carcinogenic activity of a
series of reactive lactones and related substances. Br. J. Cancer
15:85-100.
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.
Fisher, K. D., and R. G. Allison. 1981. Food Additives as Candidates
for Carcinogenicity Testing. Paper prepared for the Committee on
Diet, Nutrition, and Cancer for its meeting of February 17-18,
1981. National Academy of Sciences, Washington, D. C. 36 pp.
[unpublished].
Gross, M. A., W. I. Jones, E. L. Cook, and C. C. Boone. 1967. Carcino-
genicity of oil of calamus. Proc. Am. Assoc. Cancer Res. 8:24.
Abstract 93.
Hirono, I., H. Mori, M. Haga, M. Fujii, K. Yamada, Y. Hirata,
H. Takanashi, E. Uchida, S. Hosaka, I. Ueno, T. Matsushima, K.
Umezawa, and A. Shirai. 1979. Edible plants containing carcino-
genic pyrrolizidine alkaloids in Japan. Pp. 79-87 in E. C. Miller,
J. A. Miller, I. Hirono, T. Sugimura, and S. Takayama, eds. Nat-
urally Occurring Carcinogens-Mutagens and Modulators of Carcino-
genesis. Japan Scientific Societies Press, Tokyo; University Park
Press, Baltimore, Md.
Hunter, B., J. Colley, A. E. Street, R. Heywood, D. E. Prentice, and
G. Magnusson. 1978a. Xylitol Tumorigenicity and Toxicity Study in
Long-Term Dietary Administration To Rats (Final Report). Huntingdon
Research Centre, Huntingdon, Cambridgeshire, England. Volumes 11-14
of Xylitol. F. Hoffman La Roche Company, Ltd., Basel, Switzerland.
2250 pp.
Hunter, B., C. Graham, R. Heywood, D. E. Prentice, F. J. C. Roe, and
D. N. Noakes. 1978b. Tumorigenicity and Carcinogenicity Study with
Xylitol in Long-Term Dietary Administration to Mice (Final Report).
Huntingdon Research Centre, Huntingdon, Cambridgeshire, England.
Volumes 20-23 of Xylitol. F. Hoffman La Roche Company, Ltd., Basel,
Switzerland. 1500 pp.
B-13
OCR for page 230
230 DIET, NUTRITION, AND CANCER
International Agency for Research on Cancer. 1973. IARC Monographs
on the Evaluation of the Carcinogenic Risk of Chemicals to Man.
Volume 3. Certain Polycyclic Aromatic Hydrocarbons and Heterocyclic
Compounds. International Agency for Research on Cancer, Lyon,
France. 271 pp.
International Agency for Research on Cancer. 1974a. IARC Monographs on
the Evaluation of the Carcinogenic Risk of Chemicals to Man. Volume
5. Some Organochlorine Pesticides. International Agency for Re-
search on Cancer, Lyon, France. 241 pp.
International Agency for Research on Cancer. 1974b. IARC Monographs
on the Evaluation of the Carcinogenic Risk of Chemicals to Man.
Volume 7. Some Anti-Thyroid and Related Substances, Nitrofurans and
Industrial Chemicals. International Agency for Research on Cancer,
Lyon, France. 326 pp.
International Agency for Research on Cancer. 1975. IARC Monographs
on the Evaluation of the Carcinogenic Risk of Chemicals to Man.
Volume 8. Some Aromatic Azo Compounds. International Agency for
Research on Cancer, Lyon, France. 357 pp.
International Agency for Research on Cancer. 1976a. IARC Monographs
on the Evaluation of the Carcinogenic Risk of Chemicals to Man.
Volume 10. Some Naturally Occurring Substances. International
Agency for Research on Cancer, Lyon, France. 353 pp.
International Agency for Research on Cancer. 1976b. IARC Monographs
on the Evaluation of the Carcinogenic Risk of Chemicals to Man.
Volume 12. Some Carbamates, Thiocarbamates and Carbazides.
International Agency for Research on Cancer, Lyon, France. 282 pp.
International Agency for Research on Cancer. 1977. IARC Monographs
on the Evaluation of the Carcinogenic Risk of Chemicals to Man.
Volume 13. Some Miscellaneous Pharmaceutical Substances.
International Agency for Research on Cancer, Lyon, France. 255 pp.
International Agency for Research on Cancer. 1978a. IARC Monographs
on the Evaluation of the Carcinogenic Risk of Chemicals to Man.
Volume 16. Some Aromatic Amines and Related Nitro Compounds--Hair
Dyes, Colouring Agents and Miscellaneous Industrial Chemicals.
International Agency for Research on Cancer, Lyon, France. 400 pp.
International Agency for Research on Cancer. 1978b. 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. 140 pp.
International Agency for Research on Cancer. 1979a. IARC Monographs
on the Evaluation of Carcinogenic Risk of Chemicals to Humans.
Volume 20. Some Halogenated Hydrocarbons. International Agency for
Research on Cancer, Lyon, France. 609 pp.
B-14
OCR for page 231
The Role of NonnutAhve Dietary Constituents 231
International Agency For Research on Cancer. 1979b. IARC Monographs
on the Evaluation of the Carcinogenic Risk of Chemicals to Humans.
Volume 21, Sex Hormones (II). International Agency for Research on
Cancer, Lyon, France. 583 pp.
International Agency for Research 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.
Jorgensen, D. J. 1980. The need of additives in industry. Pp. 652-677
in H. D. Graham, ed. The Safety of Foods. Second edition. AVI
Publishing Company, Westport, Conn.
Kraybill, H. F. 1976. Food chemicals and food additives. Pp. 245-318
in P. M. Newberne, ed. Trace Substances and Health: A Handbook.
Part 1. Marcel Dekker, New York and Basel.
Merrill, R. A. 1978. Regulating carcinogens in food: A Legislator Is
guide to the food safety provisions of the Federal Food, Drug, and
Cosmetic Act. Mich. Law Rev. 77:171-250.
National Academy of Sciences. 1972. A Comprehensive Survey of Industry
on the Use of Food Chemicals Generally Recognized as Safe (GRAS)
(Comprehensive GRAS Survey). A report prepared by the Subcommittee
on Review of GRAS List--Phase II. National Academy of Sciences,
Washington, D.C. 41 pp.
National Academy of Sciences. 1973. The Use of Chemicals in Food
Production, Processing, Storage, and Distribution. A report
prepared by the Committee on Food Protection, Food and Nutrition
Board. National Academy of Sciences, Washington, D.C. 34 pp.
National Academy of Sciences. 1978. 1975 Resurvey of the Annual
Poundage of Food Chemicals Generally Recognized as Safe (GRAS).
Committee on GRAS List Survey--Phase III. National Academy of
Sciences, Washington, D.C. 23 pp.
National Academy of Sciences. 1979. The 1977 Survey of Industry on
the Use of Food Additives. Volume 1, Description of the Survey;
Volume 2, Summarized Data; Volume 3, Estimates of Daily Intake.
Food and Nutrition Board, National Academy of Sciences, Washington,
D.C. 2,135 pp. Available from the National Technical Information
Service, Springfield, Va. as Publication No. PB 80-113418.
National Academy of Sciences. 1981. The Health Effects of Nitrate,
Nitrite, and N-Nitroso Compounds. Part 1 of a 2-Part Study by the
Committee on Nitrite and Alternative Curing Agents in Food.
National Academy Press, Washington, D.C. 544 pp.
B-15
OCR for page 232
232 DIET, NUTRITION, AND CANCER
National Cancer Institute. 1975. Survey of Compounds Which Have Been
Tested for Carcinogenic Activity. 1972-1973 Volume. National
Institutes of Health, U.S. Department of Health, Education, and
Welfare, Bethesda, Md. 1638 pp.
National Cancer Institute. 1979. Bioassay of Methyl Parathion for
Possible Carcinogenicity. NCI Carcinogenesis Technical Report
Series No. 157. DREW Publication No. (NIH) 79-1713. Carcinogenesis
Testing Program, National Cancer Institute, Bethesda, Md. 112 pp.
National Science Foundation. 1973. Chemicals and Health. Report
of the Panel on Chemicals and Health of the President's Science
Advisory Committee, September 1973. Science and Technology Policy
Office, National Science Foundation, Washington, D.C. 211 pp.
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. t14] pp.
(unpublished).
Oser, B. L., and R. A. Ford. 1979. Recent progress in the considera-
tion of flavoring ingredients under the food additives amendment.
12. GRAS substances. Food ~echnol. 33~7~:65-73.
Roberts, H. R. 1981. Food safety in perspective. Pp. 1-13 in H. R.
Roberts, ed. Food Safety. John Wiley & Sons, New York.
U.S. Department of Agriculture. 1980. Sugar and Sweetener Report 5~8~:
1-54.
U.S. Department of Health and Human Services. 1980. Food and Drug
Administration Acts. Federal Food, Drug, and Cosmetic Act, as
Amended January 1980; Public Health Service Act, Biological
Products; Radiation Control for Health and Safety Act; Fair
Packaging and Labeling Act. HHS Publication No. (FDA) 80-1051.
Food and Drug Administration, U.S. Department of Health and Human
Services, Rockville, Md. 169 pp.
U.S. Department of Health, Education, and Welfare. 1981. Toxicological
Principles and Procedures for Direct Food Additive Cyclic Review
U.S. Department of Health, Education, and Welfare, Washington, D.C.
(unpublished)
U.S. Food and Drug Administration. 1980. Compliance Program Report
of Findings. FY 77 Total Diet Studies--Adult (7320.73~. Bureau of
Foods, Food and Drug Administration, Washington, D.C. [33] pp.
B-16
OCR for page 233
The Role of Nonnutritive Dietary Constituents 233
U.S. Food and Drug Administration. 1981. Consumers participate in FDA's
priority setting process. FDA Consumer Update 18:1-3.
Witschi, H. P., P. J. Hakkinen, and J. P. Kehrer. 1981. Modification of
lung tumor development in A/J mice. Toxicology 21:37-45.
World Health Organization. 1958-1980. Reports of the Joint FAD/WHO
Expert Committee on Food Additives. World Health Organization
Technical Report Series (Twenty-four reports to date). World Health
Organization, Geneva, Switzerland.
World Health Organization. 1980. Evaluation of Certain Food Additives.
Twenty-Third Report of the Joint FAD/WHO Expert Committee on Food
Additives. WHO Tech. Rep. Ser. 648:1-45.
B-17
Representative terms from entire chapter:
alcoholic beverages
