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OCR for page 304
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
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Additives and Contaminants 305
most of these studies were not originally designed to investigate the
relationship between nonnutritive sweeteners and bladder cancer.
In a case-control study based on responses to questionnaires from 74
female cases, 158 male cases, and an equal number of matched controls,
Morgan and Jain (1974) observed that prolonged use of any nonnutritive
sweetener was not associated with an increased risk in males and was
associated with a reduced risk for females. In another study based on
mailed questionnaires, Simon _ al. (1975) studied women only, and
found no differences between the cases and controls in either saccharin
or cyclamate use.
Howe et al. (1977) conducted a case-control study of 480 male and
152 female sex-matched pairs. They observed that men who used nonnu-
tritive sweeteners had a 60% increase in risk of bladder cancer and
provided evidence of a dose-response relationship. On the other hand,
there was no significant increase in risk for women. These preliminary
findings were confirmed in a later study by the same investigators, who
reanalyzed the data, controlling for potential confounding factors such
as smoking and using a logistic regression model (Howe et al., 1980~.
In a case-control study of 519 bladder cancer patients and twice
as many controls, Kessler and Clark (1978) found no evidence of a link
between nonnutritive sweetener consumption and bladder cancer. Miller
_ al. (1978) studied 265 bladder cancer patients and 530 matched con-
trols. They also found no significant risk associated with the regular
use of nonnutritive sweeteners. Morrison (1979) found no association
between current use of nonnutritive sweeteners and bladder cancer in 13
cases and 10,874 controls.
Morrison and Buring (1980) evaluated the relationship between cancer
of the lower urinary tract and the consumption of nonnutritive
sweeteners in a case-control study of 592 patients and 596 controls.
Overall, there was no increase in risk for lower urinary tract cancer
among users of nonnutritive sweeteners. However, in a subgroup of
nonsmoking women, there were elevated risks of 2.1 for use of sugar
substitutes and 2.6 for use of dietetic beverages.
Wynder and Stellman (1980) conducted a case-control study of 302
men and 65 women with bladder cancer and an equal number of matched
controls. They also found no association between bladder cancer and
the consumption of nonnutritive sweeteners or dietetic beverages.
The National Cancer Institute (NCI) and the Food and Drug Adminis-
tration (FDA) jointly sponsored a large scale case-control study in
which 3,010 bladder cancer patients and 5,783 population controls were
interviewed. This investigation was designed specifically to evaluate
the relationship between nonnutritive sweetener consumption and bladder
cancer. Subjects who reported ever having used nonnutritive sweeteners
or artifically sweetened foods or beverages were found to have no in-
crease in the risk of bladder cancer. However, white nonsmoking women
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306 DIET, NUTRITION, AND CANCER
who had not been exposed to known bladder carcinogens such as azo dyes
were found to have an increased risk of bladder cancer with increased
nonnutritive sweetener consumption (relative risk of 2.7-3.0 in heavy
users for at least 10 years and a suggested dose-response relationship).
Users of both tabletop sweeteners and diet drinks,with a heavy use of
at least one of the two, showed a relative risk of 1.5 (Hoover and
Strasser, 1980~.
The International Agency for Research on Cancer (1980) concluded,
Although a small increase in the risk of urinary bladder cancer in the
general population or a larger increase in some individuals consuming
very high doses of saccharin cannot be excluded, the epidemiological
data provide no clear evidence that saccharin alone, or in combination
with cyclamates, causes urinary bladder cancer.
There have also been some observations concerning consumption of
saccharin and cancer at other sites, for example, pancreatic cancer.
An increase in deaths from pancreatic cancer was found in cohort
studies of diabetics (Armstrong _ al., 1976; Kessler, 1970~. Blot et
_ . (1978) found a direct correlation of pancreatic cancer mortality by
county in the United States with diabetes mellitus in women, but not in
men, who consumed saccharin. In a case-control study, Wynder et al.
(1973) found a direct association of pancreatic cancer with early-onset
diabetes in women who used saccharin.
Experimental Evidence: Carcinogenicity. The carcinogenicity of
saccharin has been reviewed extensively (National Academy of Sciences,
1978~. The following discussion focuses on some recent data.
There was no evidence of saccharin-induced carcinogenesis in a
number of single-generation studies in which various doses of saccharin
were fed to several strains of mice and rats (Furuya et al., 1975;
Hamburger, 1978; National Institute of Hygienic Sciences, 1973; Roe et
al., 1970; Schmahl, 1973) and to hamsters and rhesus monkeys (Althoff
_ al., 1975; McChesney et al., 1977~.
In a single-generation study, Wistar specific-pathogen-free (SPF)
rats were fed saccharin at either 4 g/kg body weight (bw) daily in the
diet for 2 years or saccharin containing 698 mg/kg o-toluenesulfonamide
(OTS) at 2 g/kg bw in drinking water daily for the same period. The
treated males in both groups developed more tumors than did the
untreated controls, but there was no significant difference in the
females (Chowaniec and Hicks, 1979~.
In another single-generation study, Charles River CD rats fed 5%
sodium saccharin (free of OTS) for their lifetime had a higher inci-
dence of benign and malignant bladder tumors than observed in the
untreated controls (D. L. Arnold et al., 1977, 1980~.
Saccharin has also been tested in two-generation carcinogenicity
bioassays in which parent animals (the Fo generation) are fed
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Additives and Contaminants 307
saccharin from weaning through pregnancy until their offspring are
weaned. The offspring (F1 generation), already exposed to saccharin
_ utero, are given the same diet as their parents for the rest of
their lives.
In one such study, there was no difference in the incidence of
tumors in treated or control Swiss SPF mice in either generation
(Kroes et al., 1977~. In three two-generation studies with Charles
River and Sprague-Dawley rats (D. L. Arnold et al., 1977, 1980; Taylor
and Friedman, 1974; Tisdel et al., 1974; U.S. Department of Health, Edu-
cation, and Welfare, 1973a,~, the incidence of bladder tumors in
treated male rats of the F1 generations given the highest dose was
significantly higher than that in controls in all three studies and
in the Fo males in one study (D. L. Arnold et al., 1977, 1980~.
Saccharin (2 or 4 g/kg low/day in diet) increased the incidence of
and decreased the latent period for tumor development in animals
treated with N-nitroso-N-methylurea (NHU) (Chowaniec and Hicks, 1979;
Hicks et al., 1978) or with N-~4~5-nitro-2-furyl)-2-thiazolyliforma-
mide (FACET) (Cohen et al., 1979~. In several in vitro cell culture
systems, saccharin also exhibited an activity similar to the tumor-
promoting activity of tetradecanoylphorbol acetate (Trosko et al.,
1980).
Experimental Evil. Efforts to test saccharin for
muta~ results. In the Ames Salmonella
reverse mutation assay, saccharin of various degrees of purity was not
mutagenic (Ashby et al., 1978; McCann, 1977; Poncelot et al., 1979~.
Batzinger et al. (1977) reported that saccharin was weakly mutagenic to
S. typhimurium TA98 and TA100 strains in a modified plate assay and
that the urine of animals fed saccharin contained mutagens for TA98 and
TA100 strains.
Weak mutagenic effects were observed in the mouse lymphoma assay
(Clive _ al., 1979~. Dominant lethal mutations were found in animals
fed 1.72% sodium saccharin in the diet (Rao and Qureshi, 1972), and a
dose-dependent increase in unscheduled DNA synthesis in fibroblasts
from humans was reported by Ochi and Tonomura (1978~.
Continuous exposure to saccharin following treatment of C3H/lOTl/ 2
cells with 3~ethylcholanthrene led to a significant increase in the
number of transformed colonies (Mondal et al., 1978~. Saccharin also
induces chromosome aberrations in mammalian cells (Abe and Sasaki, 1977;
McCann, 1977; Yoshida et al., 1978) and sister chromatic exchanges
in cells from humans (Wolff and Rodin, 1978~.
Summary and Conclusions. The epidemiological data do not provide
a clear indication of an association between the use of nonnutritive
sweeteners and cancer, and the results of most studies of bladder can-
cer have shown no association. Exceptions are the study by Howe et al.
(1977), which showed a direct association in men, and those by Hoover
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308 DIET, NUTRITION, AND CANCER
and Strasser (1980) and Morrison and Buring (1980), whose results
suggested a possible effect in certain subgroups. Since the data
regarding saccharin and pancreatic cancer are based on studies of
diabetics, who as a group are not representative of the general
population, no firm conclusions can be drawn.
Experimental studies have provided sufficient evidence that
saccharin alone, given at high doses, produces tumors of the urinary
tract in male rats and can promote the action of known carcinogens in
the bladder of rats. There is limited evidence of its carcinogenicity
in mice.
Cyclamates
Until 1970, when cyclamates were banned from use in the United
States (U.S. Food and Drug Administration, 1970), cyclamic acid, sodium
cyclamate, and calcium cyclamate were used as nonnutritive sweeteners
in carbonated beverages, in dry beverage bases, in diet foods, and in
sweetener formulations. Sodium and calcium cyclamates were used pri-
marily as a 10:1 cyclamate:saccharin salt mixture (Wiegand, 1978~.
Epidemiological Evidence. Epidemiological data on cyclamates alone
, . .
are not adequate, because cyclamates were rarely used without
saccharin. Thus, it was not usually possible to distinguish the
consumption of cyclamate-containing mixtures from the consumption of
saccharin.
Experimental Evidence: Carcinogenicity. Swiss and Charles River
CD mice receiving up to 5% sodium cyclamate for 18 months or 24 months,
respectively, did not yield evidence that cyclamates are carcinogenic
(Homburger, 1978; Roe et al., 1970~. When sodium cyclamate (99.5%
pure) was administered in drinking water (6 g/liter, or 20-25 mg/mouse)
to mice for their lifetime, there was no evidence of carcinogenesis in
male and female C3H mice, but there was an increased incidence of lung
tumors in RIII male and XVII female mice and of hepatocellular car-
cinomas in (C3H x RIII)F1 male mice (Rudali et al., 1969~. Female
SPF mice fed diets containing up to 7% sodium cyclamate for 80 weeks
had a higher, but statistically insignificant increase in the incidence
of lymphosarcomas than did the controls (Brantom et al., 1973~.
Osborne Mendel rats fed sodium cyclamate at 0.4%, 2%, or 10% in
their diet for 101 weeks had an increased incidence of transitional
cell papillomas of the urinary bladder, although the number of animals
examined histopathologically was small (Friedman et al., 1972~. Cycla-
mate (1.0 g/kg low/day) fed for 2 years led to a slight increase in
the incidence of bladder tumors in Sprague-Dawley rats (Hicks and
Chowaniec, 1977; Hicks et al., 1978~.
Lifetime studies in one generation of Syrian golden hamsters
(Althoff et al., 1975) and rhesus monkeys (Coulston et al., 1977) and
14-5
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Additives and Contaminants 309
a six-generation study of Swiss SPF mice (Kroes et al., 1977) produced
no evidence that sodium cyclamate is carcinogenic.
Female Wistar SPF rats treated with 1.5 mg NMU and subsequently
fed sodium cyclamate (containing 13 mg/kg cyclohexylamine) in diets at
doses of 1, 1.5, or 2.0 g/kg low/day for their lifetime or up to 2 years
had a significantly higher incidence of bladder cancer and a signifi-
cant decrease in latent period (8 weeks vs. 87 weeks) compared to
animals treated with NMU only and the untreated controls (Hicks et al.,
1978).
In another study, a single 2 mg dose of NMU was instilled into the
urinary bladder of female Wistar rats before giving them a diet con-
taining sodium cyclamate at 2% for 10 weeks and then at 4% for the rest
of their lives. The overall incidence of urinary tract tumors was 70%
in those given NMW and sodium cyclamate, 57Z in animals receiving NMW
alone, and 65% in another control group given NMU and calcium carbonate
(Mohr _ al., 1978~.
Wistar weanling rats were fed a 10:1 mixture of sodium cyclamate:
saccharin in the diet at doses of 0, 500, 1,120, or 2,500 mg/kg low/day
for 2 years. After the 79th week, 50% of the survivors from all three
treated groups were also fed cyclohexylamine hydrochloride, in addition
to the cyclamate:saccharin diet. The animals consuming the diet con-
taining the highest levels of cyclamate:saccharin (with and without
added cyclohexylamine hydrochloride) were found to have a significantly
higher number of urinary bladder cancers (9/25 males and 3/35 females)
compared to the controls (0/35 males and 0/45 females). Of the tumor-
bearing animals, three males and two females had received cyclohexyl-
amine, indicating that cyclohexylamine hydrochloride is not carcinogenic
(Oser _ al., 1975~.
Experimental Evidence: Mutagenicity. There are no published
.
data on the ability of cyclamates alone to induce point mutations in
microbial and mammalian cells. In two studies, cyclamates induced
chromosome breaks in leukocytes from humans (Ebenezer and Sadasivan,
1970; Tokumitsu, 1971~.
No increase in chromosome aberrations was observed in hamsters
given oral doses of sodium cyclamate or cyclohexylamine sulfate
(Machemer and Lorke, 1976~.
Summary and Conclusions. There are no adequate epidemiological
data on the effect of cyclamate alone since it was rarely consumed by
humans in the absence of saccharin.
The experimental data provide limited evidence for the carcinogenic-
ity of cyclamates in mice and rats. In addition, there is evidence
that cyclamates can promote the action of known carcinogens in the
bladder.
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310 DIET, NUTRITION, AND CANCER
Aspartame
Aspartame, the methyl ester of the amino acids phenylalanine and
aspartic acid, is approximately 180 times sweeter than sugar (Mazur,
1976~. In July 1981 the FDA approved its use as a sweetener or
flavoring agent in certain foods (U.S. Food and Drug Administration,
1981~. Aspartame cannot be used in soft drinks because of its
instability in liquids during storage.
Epidemiological Evidence. Since aspartame has been on the market
only since 1981 and in only a few countries (e.g., Belgium, France, and
Canada), there are no epidemiological data regarding its association
with cancer in humans.
Experimental Evidence: ~ ~
Carcino~enicitY. A number of feeding
studies have been conducted on mice and rats under the sponsorship
of the G. D. Searle Co. to test the carcinogenicity of aspartame. In
one of these studies, male and female Charles River mice received
aspartame at O (control), 1.0, 2.0, or 4.0 g/kg low/day in their diet
for 2 years. No tumors attributable to aspartame ingestion were
reported (G. D. Searle and Co., 1974a). In another study, no statis-
tically significant differences in the incidence of neoplasms were
observed in the urinary bladders of control and treated mice 26 weeks
after implantation of cholesterol pellets containing aspartame or its
breakdown product diketopiperazine (DKP) (G. D. Searle and Co., 1973a).
Male and female Sprague-Dawley rats fed aspartame in the diet at
various levels for up to 2 years were observed for the incidence of
brain tumors (G. D. Searle and Co., 1973b). After the study was com-
pleted, the FDA appointed an independent board of inquiry to review
the data. The board concluded that aspartame was a possible carcino-
gen, based on three of the study's findings: The incidence of brain
neoplasms in aspartame-fed rats was greater than that in controls, a
possible dose response was observed when tumor incidence in the con-
trols was compared with the two lower dose and the two higher dose
treatment groups combined, and there was a decrease in the latent
period for gliomas (U.S. Food and Drug Administration, 1980a).
Investigators at the G. D. Searle Co. interpreted these data
differently. They contended that statistical analysis using con-
current instead of historical controls indicates that there was no
significant increase in tumor incidence, that more appropriate sta-
tistical tests show no dose response, and that the board of inquiry
made errors concerning the time of death of certain rats (U.S. Food
and Drug Administration, 1980a).
In a follow-up study by the Searle group, rats were exposed in
utero to aspartame at O (control), 2, and 4 g/kg bw and maintained on
this diet for the duration of their lives (G. D. Searle and Co., 1974b).
14-7
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A`~t:ives and Contaminants 311
The incidence of brain tumors was: 4/115 (3.4%), 3/75 (4.0%), and 1/80
(1.3%), respectively, which indicated no statistically significant
difference between the control and treated groups.
Recently, Ishii et al. (1981) also found no evidence for carcino-
genicity in chronic feeding studies with Wistar rats given aspartame or
a mixture of aspartame and DKP. The FDA concluded that this study
provides additional evidence favoring the safety of aspartame (U.S.
Food and Drug Administration, 1981~.
Groups of five male and female beagle dogs were fed aspartame at O
(control), 1.0, 2.0, and 4.0 g/kg bw in their diet for more than 106
weeks. No evidence of neoplasia was observed in any of the treated or
control groups (G. D. Searle and Co., 1973c).
Experimental Evidence: Mutagenicity. Aspartame and DKP were
negative in the Ames test with and without using the S9 fraction from
rats (G. D. Searle and Co., 1978a,b,c). Similarly, no evidence of the
mutagenicity of these compounds was observed in the host-mediated assay
in rats and mice at doses ranging from 0.25 to 8.0 g/kg/day (G. D.
Searle and Co., 1972a,b, 1974c). Aspartame and DKP (1 or 2 g/kg
low/day) were also negative in the in viva dominant lethal assay in rats
(G. D. Searle and Co., 1973d).
Summary and Conclusions. Aspartame has been used as a sweetener
,
in Belgium and France only since 1981 e It has recently been approved
for use in Canada and the United States. Consequently, there are no
epidemiological data pertaining to its effects on human health.
Aspartame appears to be negative in in vitro bacterial mutagenic-
ity tests, in the host-mediated assay, and in dominant lethal tests
in rats. It has been reported to be noncarcinogenic in chronic feeding
studies in mice and dogs, most of which were conducted by G. D. Searle
and Company. Although a board of inquiry appointed by the FDA con-
cluded that aspartame may be neurooncogenic in rats, additional evi-
dence led the FDA to conclude that aspartame is not carcinogenic in
animals.
Butylated Hydroxytoluene (BHT) and Butylated Hydroxyanisole (BHA)
Butylated hydroxytoluene (BHT) and Butylated hydroxyanisole (BRA)
are widely used as food additives, mainly because of their preservative
and antioxidant properties. These compounds are included in the FDA's
list of substances generally recognized as safe ((ERAS). Many studies
have been conducted to test them for acute and chronic toxicity under a
variety of experimental conditions, ranging from in vitro studies to in
viva studies in animals (U.S. Food and Drug Administration, 1977a).
Based on the evidence from these studies, the FDA in 1977 recommended
that BHT be removed from the GRAS list and proposed interim regulations
pending future studies.
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312 DIET, NUTRITION,AND CANCER
Epidemiological Evidence. There are no epidemiological studies
concerning the effects of BHT and BHA on human health.
Experimental Evidence for BHT: Carcinogenicity. Male and female
B6C3F1 mice were fed 0, 0.3%, or 0.6% BHT in the diet for 107 to 108
weeks. In female mice receiving the low dose, the incidence of alveo-
lar/bronchiolar adenomas or carcinomas was significantly higher than
in the controls, but there was no dose response (National Cancer
Institute, 1979a). In a similar study of male and female Fischer 344
rats, the incidence of tumors in treated animals was not statisically
different from that in controls (National Cancer Institute, 1979a).
Experimental Evidence for BHT: Promoting Effects. Three groups of
A/J mice were injected with urethan, 3-methylcholanthrene, or nitrosodi-
methylamine and then given repeated injections of BHT. The treatment
with BHT significantly increased the multiplicity of lung tumors induced
by all three carcinogens (Witschi et al., 1981~.
BHT administered orally increased the incidence of lung tumors in
A/J mice pretreated with a single dose of urethan (Witschi, 1981~.
When injections were begun as late as 5 months after the urethan was
administered, they still produced an increase in the incidence of lung
tumors. BHT does not appear to enhance lung tumor formation, even if
given repeatedly prior to ure then administration. This suggests that
BHT may be a tumor promoter (Witschi, 1981; Witschi et al., 1977~. BHT
also appears to have some promoting activity in BALB77 mice (Clapp et
_ ., 1974) and in male Sprague-Dawley rats treated with 2-aminoacetyl-
fluorene (2-AAF) (Peraino et al., 1977~.
Experimental Evidence for BHT: Mutagenicity. BHT inhibited
cell-to-cell communication of mammalian cells in vitro--an indication
of promoting activity (Trosko et al., 1982~. When BHT in concen-
trations of 0-50 ug/ml were added to phytohemagglutinin-stimulated
cultures of leukocytes from humans, it resulted in a dose-dependent
decrease in cell survival, as well as in an uncoiling of the chromo-
somes (Sciorra et al., 1974~. In the sister chromatic exchange assay,
BHT was negative and it did not induce chromosome aberrations (Abe and
Sasaki, 1977~.
Experimental Evidence for BHA: Carcinogenicity. The administra-
-
tion of BHA had no significant effect on the tumor yield or tumor
multiplicity in Swiss Webster mice injected with urethan and then given
BHA in the diet (Witschi, 1981~. In other experiments, repeated intra-
peritoneal injections of BHA at high doses produced a slight, although
not statistically significant, increase in lung tumors in male A/J mice
(Witschi et al., 1981~. Under different experimental conditions, BHA
has been shown to inhibit the activity of a wide variety of carcinogens
(see Chapter 15~.
Experimental Evidence for BHA: Mutagenicity. BHA was positive in
the sister chromatic exchange assay with Chinese hamster cells as in-
dicator organisms; however, it did not induce chromosome aberrations in
these cells (Abe and Sasaki, 1977~.
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Additives and Contaminants 313
Summary and Conclusions. BHT and BRA are used as antioxidant s and
preservatives in many types of foods. There are no epidemiological
studies concerning their effect on human health.
At least one adequate bioassay to test the carcinogenicity of
BHT has been conducted in each of two species, the mouse and the
rat, without clear evidence of carcinogenicity under the conditions
of the tests. Evidence for the enhancement of tumorigenesis by BHT
is restricted to two experimental systems--carcinogen-induced lung
tumors in mice and liver tumors in rats. The studies in mice have
been repeated several times with other carcinogenic initiators.
These studies provide evidence that BHT has a tumor-promoting effect,
especially for ure then and 2-AAF. On the other hand, as discussed in
Chapter 15, large amounts of BHT can inhibit neoplasia induced by a
number of chemicals.
There is no indication that BRA has any carcinogenic or tumor-
promoting activity. Its ability to inhibit neoplasia is discussed
in Chapter 15.
Vinyl Chloride
Containers made of polyvinyl chloride (PVC) are widely used for
packaging and storing foods. Since the appearance of reports linking
several fatal cases of a rare form of liver tumor with prolonged
industrial exposure to vinyl chloride, considerable attention has been
paid to the possible carcinogenicity and other toxic effects of the
monomer vinyl chloride, of which PVC is composed (Creech and Johnson,
1974; Nicholson et al., 1975~.
PVC is classified as an indirect food additive by the FDA, whereas
the monomer, which may be present at low levels as a residue in PVC, is
regarded as a contaminant (U.S. Consumer Product Safety Commission,
1974).
Vinyl chloride has been detected in a variety of alcoholic drinks
at levels ranging from 0.2 to 1 mg/liter (Williams, 1976a,b) and in
vinegars at levels as high as 9.4 mg/liter (Williams and Miles, 1975~.
It has also been found in products packaged and stored in polyvinyl
chloride containers. For example, concentrations ranging from 0.05 to
14.8 mg/kg have been detected in edible oils (Rosli et al., 1975),
0.05 mg/kg has been detected in margarine and butter (Fuchs et al.,
1975), and 10.0 ~g/liter is the highest concentration found in T-nished
drinking water in the United States (U.S. Environmental Protection
Agency, 1975a).
Epidemiological Evidence. There have been no epidemiological
studies on exposure to vinyl chloride as a food contaminant; however,
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314 DIET, NUTRITION, AND CANCER
several investigators have studied the effect of occupational exposure.
In the United States, Creech and Johnson (1974) were the first to re-
port an association between inhalation exposure to vinyl chloride and
hepatic angiosarcomas. In a cohort study of males who had been occupa-
tionally exposed to vinyl chloride for at least 1 year, Tabershaw and
Gaffey (1974) observed an excess of cancer of the digestive system,
liver (mainly angiosarcoma), respiratory tract, and brain, as well as
l~rmphomas. Nicholson et al. (1975) noted a 2.3-fold excess of cancer
mortality among workers exposed for at least 5 years. Monson et al.
(1974) reported a 50% excess of deaths due to all cancers in workers
producing and polymerizing vinyl chloride. Several other studies have
indicated an association between exposure to vinyl chloride and in-
creased mortality from cancer at various sites (Duck and Carter, 1976;
Fox and Collier, 1977; Waxweiler et al., 1976~.
Experimental Evidence: Carcinogenicity. Male and female Sprague-
Dawley rats receiving gastric incubations of vinyl chloride in doses up
to 50 mg/kg bw developed mainly angiosarcomas and cancers of Zymbal's
gland (Maltoni, 1977; Maltoni _ al., 1975~.
In lifetime feeding studies with Wistar rats, Feron et al. (1975,
1981) observed that vinyl chloride monomer in doses ranging from 1.7
to 14.1 mg/kg bw induced hepatocellular carcinomas, hepatic angiosar-
comas, pulmonary angiosarcomas, extrahepatic abdominal angiosarcomas,
tumors of Zymbal's gland, abdominal mesotheliomas, and adenocarcinomas
of mammary glands.
Inhalation exposures to vinyl chloride produced cancers of the lung,
mammary gland, and liver in mice (Maltoni, 1977~; cancers of Zymbal's
gland, the liver, kidney, and brain in Sprague-Dawley rats (Maltoni et
al., 1974~; and cancers of the liver, skin, and stomach in hamsters
raltoni, 1977; Maltoni et al., 1974~.
Experimental Evidence: Mutagenicity Tests and Other Short-Term
Tests. Vinyl chloride vapors induced mutations in Ames Salmonella
strains (Andrews et al., 1976; Bartsch et al., 1979), Escherichia
cold (Greim et al., 1975), Schizosaccharomyces pombe (Loprieno et
al., 1976), Drosophila melanogaster (Verburgt and Vogel, 1977), and
mammalian cells (Huberman _ al., 1975~. They also induced gene
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Male workers occupationally exposed to vinyl chloride were reported
to have more chromosome aberrations than were observed in unexposed
cohorts (Funes-Cravioto et al., 197S; Heath et al., 1977; Purchase et
al., 1975~.
Summary and Conclusions. Occupational exposure to vinyl chloride
.
is associated with increased incidence of cancer of the liver, brain,
respiratory tract, and lymphatic system, but this evidence has been
derived from studies of groups occupationally exposed to high doses
of vinyl chloride. Similar carcinogenic effects were demonstrated in
rats that ingested or inhaled large amounts of vinyl chloride. These
results were later confirmed in mice and hamsters.
14-11
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A&~hves and Contaminants 347
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Representative terms from entire chapter:
bladder cancer