[CANCER RESEARCH35,3475-3480,November1975]

Potential Carcinogenicity of Food Additives and Contaminants'

Philippe Shubik
Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska 68105

Summary general principles of toxicology, which, of necessity, use

certain arbitrary guidelines. I mention this problem at the
The potential role in carcinogenesis of food additives and outset, since I believe it to be of central importance and
contaminants presents a complex problem in terms of likely to become more important as the effects of certain
assessing the risk to the general public. Long-term testing in agents in humans are questioned.
laboratory animals is still the most feasible method for Another key problem concerns the application of epide
determining potential carcinogenicity of various chemicals. miology in humans to inquiries into food additive carcinoge
The disadvantages encountered in the present methods of nicity. The general assumption has been that, because food
animal testing are discussed and a review is made of the additives are so widely distributed and carcinogenicity takes
current status of particular food additives and contaminants so long to make itself apparent in humans, the investigation
under scrutiny as possible carcinogens. It is suggested that, of such effects in population studies is all but impossible.
since it may not be possible to remove all carcinogenic That this is not the case has been demonstrated recently in
materials from the environment, methods to mitigate or studies undertaken into the potential carcinogenicity of
neutralize their harmful effects should be sought. Greater saccharin. In this instance we are fortunate to have popula
cooperation is called for among food technologists, tox tions to compare statistically which have been very differ
icologists, laboratory researchers, and epidemiologists in ently exposed. Imaginative epidemiologists have con
the decision-making process regarding the role of possibly structed impressive studies using diabetic populations and
carcinogenic additives and contaminants. a registry of bladder cancers created primarily to investi
gate occupational carcinogens. No doubt imaginative ex
Introduction
perimental design will be useful in the elucidation of the
possible effects in humans of many other intentional and
Since the end of World War II, the potential role of food
unintentional food additives. In diabetics there are other
additives, both intentional and unintentional, as potential
differences in diet that might be used. When the additive
carcinogens has received considerable attention. The rea
in question is a synthetic product or a manufactured
sons for this arise primarily from our rapidly changing
product derived from natural sources, there will be occu
environment and technology, resulting in the introduction of
pationally exposed groups, exposed usually to many times
many new agents in our daily lives, rather than from
the levels encountered in dietary use. An obvious example
knowledge that such materials have, indeed, caused increas
ing incidences of particular cancers. We have known for is DDT.2 In this case not only are the workers who are en
gaged in its manufacture exposed to high levels, but some
many years that chemical compounds can induce cancer in
agricultural users and crop dusters, for example, are (or
humans and that such findings are generally reproducible in
were) exposed to high levels. In addition, it is known that
animals. Toxicological testing has now been enlarged from
human populations in different parts of the world have
its scope of pre-World War II days to include routine
greatly varying levels of DDT in their fat. These statistics
evaluation for carcinogenicity. Unlike other manifestations
are available and have not been used adequately.
of toxicity encountered in routine tests, “carcinogenicity―
In the course of recent inquiries into the “significance― of
has been selected for special treatment and the toxicologist
fibers, possibly classifiable as “amphibole asbestos,―found
in the United States has been told by the Congress how to
in the water of Lake Superior, it became apparent that
use his findings. The Delaney Clause of the Food Additives
humans were exposed to vastly differing levels of various
legislation deprives the toxicologist of his usual prerogative
kinds of asbestos in many areas of the world, usually
to determine a rational approach to the control of a toxic
manifestation of a substance. In addition the issue of through drinking water. In many cases, this has obviously
carcinogenesis of “man-made―toxic materials has now been true for years. These differences can be used to clarify
become a “cause― and has a group of vociferous exponents, problems touched on tangentially by animal experiments
even among the oncologists, who have constituted them that are often so difficult to extrapolate.
selves as “the― authority and readily reject any minimal I start with these examples, which may seem to some to
deviation from this approach. represent a negative approach, in order to draw attention to
All this is very sad since, although caution is necessary in a changing situation that I believe has been overlooked as a
introducing new chemicals, particularly into our food result of the different natures of the initial problems posed.
supply, this should not require a gross departure from the Most toxicological evaluations of food additives are con
2 The abbreviations used are: DDT, l,l,l-trichloro-2,2-bis(p-chloro

1 Presented at the Conference on Nutrition in the Causation of Cancer, phenylethane); FDA, Food and Drug Administration; DES, diethylstilbes
May 19to 22, 1975,Key Biscayne,Fla. trol.

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cerned with new materials. Clearly, there is no way of These examples illustrate the complexity of the problem
determining the safety of such materials to humans except facing the toxicologist. It is not enough to consider the
by using laboratory toxicology methods, particularly long compound in its own right. It is important that tbe
term feeding studies in animals. Such studies are not easy toxicologist have the full cooperation of the food technolo
and I should like to discuss briefly some of the problems, gist. The mode of synthesis of potential impurities that arise
particularly rapid test methods, types of carcinogens, and from intermediaries or reactions is most important. Specifi
impurities. cations of food additives are of immense significance. They
are of course dealt with in the regulatory systems (WHO,
Problems of Studying New Materials FDA, Food and Agricultural Organization, etc.), but there
is often a hiatus where the toxicologist does not look into
Rapid Test Method. The most discussed rapid test this matter in depth. More frequent contacts between those
methods are mutagenicity testing in bacterial systems, involved are desirable. A thorough knowledge of the me
usually with mammalian liver microsomes added, and tissue tabolism of the test material is a prerequisite for the design
culture. There is a degree of correlation between results of a maximally effective test.
obtained with mutagenicity tests and those obtained in
whole animals. It is not a 1: I correlation and is reported to
vary from 65% to 75 or 80%. A carcinogen is not necessarily Additives
a mutagen in the whole system; nor is a mutagen necessarily
a carcinogen. Tissue culture presents similar problems and I should now like to discuss some of the additives,
has other disadvantages, particularly in limitations imposed intentional and unintentional, that have been found in one
by available cell types and ill-defined end points. Neither way or another to be carcinogenic and delineate some of
method can be used to classify a compound as a carcinogen their salient features.
potentially dangerous to humans. However, either might be Fluorenylacetamide. This proposed pesticide (also known
used as a prescreen for a manufacturer who is trying to as 2-acetylaminofluorene) represents a landmark in this
choose from a series of materials. field. It was tested for chronic toxicity by Wilson et a!. (20)
Types of Carcinogens. It is becoming increasingly more in 1941. It was found to have a wide range of carcinogenicity
apparent that carcinogens are dissimilar and that this term inducing a series of different malignant tumors in a variety
is much less specific than many have believed. Hormonal of organs of the rat. Since that time it has been found to
carcinogens and those compounds that induce bladder have a wide range of activity in a large number of species,
cancer at very low incidence rates, following induction of and much is known about the preliminary steps in its
bladder calculi, are 2 examples. The occurrence of hepato metabolism. It was never used as a pesticide and I believe
mas following administration of―enzyme inducers,― such as that it would be difficult to find anyone who would doubt
phenobarbital, DDT, and dieldrin (1,2,3,4, 10, lO-hexa the wisdom of the decision not to market this compound.
chloro-6,7-epoxy- I ,4,4a,5,6,7,8,8a-octahydro-exo- 1,4-endo Aramite. Aramite [2(p-tert-butylphenoxy)isopropyl-2-
5,8-dimethanonephthalene), is such an emotionally chloroethyl sulfite] is the classic example of some of the
charged area that I would rather not discuss it in depth at difficulties in this field. The compound was tested and found
this time. It is sufficient to say that these lesions cannot be to produce hepatomas in rats (12),. A committee of the
ignored. National Academy of Sciences was assembled and spent
Even the most superficial contemplation of the range of much time debating whether the hepatomas were regenera
carcinogens present in our environment reveals an enor tive nodules or benign or malignant neoplasms. They did
mous discrepancy in dose requirements. It ranges all the not arrive at a consensus and decided that the company in
way from the ;.tgdose requirements of aflatoxins to the large question should retest Aramite. Aramite was retested at
amount required with the aromatic amines, and intermedi considerable expense and produced the same lesions in rats
ate doses are well represented. Therefore, it would seem and cholangiocarcinomas in dogs. It was accordingly de
unreasonable from a toxicological standpoint to class all cided, perhaps because dogs were man's best friend, that
these varied agents together. Aramite was undoubtedly dangerous, and it was thereupon
Impurities. The problem of impurities and interacting banned.
products is being reported more frequently. There are Thiourea and Thioacetamide. These were at one time used
several categories involved. First, there are impurities that as fungicides. They produced both hepatomas and thyroid
may occur as a result of the manufacturing process used; an tumors in studies undertaken by the FDA, and both were
example of this is o-toluenesulfonamide in saccharin. Sec subsequently removed from the market. Thiourea and
ondly, there are those compounds that react with a food associated compounds have, of course, been administered to
constituent to give rise to a new compound of toxicological humans for years in the treatment of thyroid disease. It
significance. Many examples of this result from interactions would be rather nice .to know more about this. Naturally,
of secondary and tertiary amines and nitrites, or diethyl there is evidence available from the patients and, in general,
pyrocarbonate and alcohol. A third situation concerns the the compound would appear to be noncarcinogenic to
metabolic conversion, either by the animal or by bacteria in humans. I would have thought, however, that perhaps this
the gut of the animal, to another, perhaps more toxic, was a field for additional exploration by our colleagues in
compound, e.g., cyclamate —‘ cyclohexylamine. There are a epidemiology.
variety of similar instances familiar to the toxicologist but Aminotriazole. This was an offending substance, similar
not necessarily concerned with carcinogenesis. to thiourea, also inducing thyroid lesions. There was a great

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argument, still unsettled, about whether or not some of myself. With hindsight the importance of the study is
these were malignant. Aminotriazole (3-amino- I H- apparent. The next occurrencewas the overt demonstration
1,2,4-triazole) was the substance that caused removal of the of the carcinogencity of vinyl chloride in humans; it is
cranberries from the United States market over one sad known to cause hemangiosarcomas (rare tumors indeed and
Thanksgiving some years ago, and it has been unavailable rapidly fatal ones) in men apparently receiving relatively
ever since. large exposures. Since that time the compound has been
Isopropyl-N-phenylcarbamate. This is an anti-sprouting shown to be similarly carcinogenic in several animal species.
agent found to be an initiator of carcinogenesis when given I do not believe that control of the industrial hazard poses a
to animals whose skin was subsequently painted with croton great problem to the regulators. The widespread use of the
oil (16). This particular experiment, which was rather material in food packaging, on the other hand, requires
limited, was taken very seriously by our friends in The extrapolations that can only be made arbitrarily. In some
Netherlands and somehow or other it was banned there, but animal systems the dose required to induce neoplasms is
nowhere else. low, and surely this may be true for humans. It would seem
Maleic Hydrazide This compound, when injected into reasonable to be as prudent as possible.
newborn mice, produced tumors (3). However, such injec A major question now will be the relationship of these
tions must contain adequate amounts of hydrazine, which findings to the predictability of hazard from related com
occurs as a reaction product in maleic hydrazide, and it is pounds that find their way into the environment. A recent
impossible to obtain maleic hydrazide free from hydrazine. finding in the bioassay program of the National Cancer
Maleic hydrazide was used widely in agriculture by the Institute concerned the demonstration that trichloroethyl
tobacco industry. It was and is a difficult compound to ene induced hepatomas in mice. The biological result thus
regulate. far reported suggests similarities to DDT rather than to
vinyl chloride; however, further testing might change the
picture. The compound is widely used for dry cleaning and
Chlorinated Hydrocarbons
as an industrial solvent and can be a residue in foods. The
regulatory problem here is quite difficult, especially since
DDT, Aidrin, and Dieldrin. All of these produce hepato banning this compound may easily result in the substitution
mas in the mouse (15, 18). Studies in other species are rather of related, untested compounds.
hazy. The rat studies with some of these compounds would
appear to be equivocal. There is a negative study with DDT Nonnutritive Sweeteners
in the hamster; as a matter of fact, DDT is nontoxic in the
hamster. We are unable to get enough DDT into the Three compounds in this category, for some obscure
hamster even to cause a detectable effect. DDT, I personally reason, have absorbed as much funding for testing as was
happen to think, is one of the most useful compounds ever once the budget ofthe National Cancer Institute for a whole
invented by mankind, perhaps second, or even parallel to, year. Test after test has been performed with these particu
the antibiotics in lifesaving. This question of hepatoma lar agents.
induction in the mouse is very tricky and is currently Dulcin (p-Phenetylurea). This sweetener was demon
charged with emotion. I do not want to discuss it in depth, strated to induce hepatomas in a test (4) that was contra
but I mention the subject since some of you may not be dicted in a subsequent investigation (8). In this instance the
aware of the occurrence of hepatomas with aldrin (1,2,3,4, material was also toxic in other ways and no further energy
10, lO-hexachloro-l,4,4a,8,8a-hexahydro-exo-l,4-endo-5,8- was expended upon it. It was not deemed suitable for use
dimethanonaphthalene), dieldrin, and DDT and, more re following the initial report of carcinogenicity, and no
cently, with the solvent trichloroethylene, chloroform, and practical use was made of the subsequent negative studies.
with some other chlorinated hydrocarbons used in food. Saccharin and Cyclamates. There has been a succession of
Carbon tetrachloride (1, 2), which most people think of as experiments demonstrating that saccharin and cyclamates
being used in the cleaning industry, occurs as a low-level may indeed be carcinogenic. Epidemiologically, saccharin
residue in bread, and chloroform occurs as an additive in would seem to be given a clean bill of health, although all
toothpaste and cough mixtures. All thesecompounds pro the data have not yet been published. Cyclamates have
duce hepatomas, as does phenobarbital. These findings managed to become one of the curiosities of toxicology.
constitute an issue that must be resolved. We must dis Somehow over a period of years the usual mechanisms for
cover what this really means; possibly, there is an associa regulation of these materials have been by-passed, and
tion betweenenzyme induction and the occurrenceof these decisions have been made by a series of people who do not
tumors. usually take part in this aspect of control.
Vinyl Chloride. This chlorinated hydrocarbon appears to There is not the slightest doubt that compounds such as
be in a different biological class from those discussed thus cyclamate require extensive testing and that an error was
far. It would be most interesting to know how different it is made originally when cyclamate was allowed on the market
and more about mechanisms of the entire group. This in the United States without having been tested properly.
compound introduces a series of general problems for the Cyclamate was classified as a “generallyrecognized as
practical toxicologist. In an initial rat study vinyl chloride safe―material before it had been tested chronically in an
was shown to induce tumors ( 17); the study was not taken as animal system. I think a compound that might be ingested
seriously as was warranted, including, I must confess, by in as high a dose level as 3.5 g/day without doubt required

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thorough testing. If overt carcinogenicity had been discov Nevertheless, notwithstanding the exact nature of these
ered there would be no problem. It is when borderline experiments, serious consideration was given to the removal
results occur repeatedly that serious problems arise. For the of Tween 60 as a food additive. The compound has been fed
toxicologist, the saccharin-cyclamate issue is rather difficult and does not appear to produce tumors on its own, but there
because it raises, among other questions, the problem of is the suggestion that it allows carcinogens to penetrate
how extensive these tests really should be. Saccharin has more quickly. Those experiments are in the literature, but I
been found to produce tumors when given as 7.5% of the diet think are not too convincing that Tween 60 constitutes a
through 2 generations of the animals. Should one really do a hazard.
test like that? What are the implications? Should we ask Polyoxyethylene stearate (Myrj 45) (5) is a compound
people to test additives in 2 generations from now on? These that was used in a manner that I consider somewhat unde
and similar complicated questions face the toxicologist sirable. It was marketed as a product called Sta-Fresh and
every day. was added to bread to make it feel fresh. Myrj-45, when
fed to rats as one-fourth of their diet, resulted in the forma
Food Colors tion of bladder calculi and subsequently a certain number
of papillomas. The results were sent to the FDA. The FDA
For a variety of reasons the food colors have received assembled a very judicious committee, some of whom
special attention over the years and have, at times, played a decided that this was an inappropriate test, and Myrj-45 was
central role in the determination of basic principles for the allowed to remain on the market at a very low level.
elucidation of control measures for food additives. Some DES, of all carcinogens, may illustrate the complexity of
few years ago it was the fashion to test these substances by the issues best of all. In recent years it has been demon
s.c. injection; several food colors resulted in the induction of strated that some of the daughters of women who received
s.c. sarcomas. After much acrimonious discussion it was rather large doses of DES (6) to prevent threatened
generally accepted that such tests for food additives were abortion are developing carcinomas of the vagina. This is a
inappropriate and that the resultant sarcomas might be a terrible and terrifying occurrence. There has been consider
result of physical rather than chemical properties of the test able concern, perhaps most of all in the Congress, with the
materials. I believe this to have been an appropriate decision use of DES as a food additive for cattle. I am unable to
with the caveat that the induction of a sarcoma by a very discuss the economics of this situation in depth even though
small quantity of a test substance does, of course, indicate I come from a cattle-producing area. However, I must
an adverse effect requiring the toxicologist to carry out confess that I have been unable to understand the logic that
extensive additional tests. However, the general principle results in the elimination of this use of DES on the basis of
that food additives should be tested p.o. is obviously sound. the presence of ppb residues in beef liver when new
One of the 1st carcinogens to be used extensively in the therapeutic uses of the drug such as the “morning-after
laboratory was p-dimethylaminoazobenzene known previ pill―are approved, when extensive postmenopausal use of
ously as a food color, butter yellow. This compound is the drug is hardly discussed, and when there is no great
known primarily for its ability to induce hepatomas in the concern expressed about the indiscriminate use of more
rat, appears to be relatively limited in its carcinogencity to potent estrogens in “thepill―although these agents pro
the liver, and does not manifest equal activity in other duce similar effects in animal test systems. There is no
species tested. The presence of residues of the well-known great emphasis as far as I can tell applied to occupational
carcinogen 2-naphthylamine in Yellow OB and Yellow AB hazards from manufacturing these materials even though
resulted in control of these compounds. Red 2 still remains gynecomastia has been reported.
controversial not only as a possible carcinogen but as a There is a degree of illogic about all this that should be
teratogen. In this instance the problem of specifications considered since the matter arises in other situations,
plays a central role. perhaps in a less obvious manner. I cannot, obviously,
Auramine is a compound whose manufacture causes discuss this matter without stating my own position. I
cancer in man which seems to result from an as yet believe that the ppb residues of DES in beef liver are most
unidentified impurity. unlikely to pose a hazard to humans and that if they do it
would be small. This is a situation in which a benefit-risk
Additional Compounds analysis must be brought to bear upon the regulatory
decision. Insofar as the postmenopausal use of DES is
Next I shall mention a series of additional “problem concerned, it would seem again that the medical profession
children― to illustrate the complexity and confusion that should collect and collate data that will demonstrate the
may exist. The 1st compound, polyoxyethylene sorbitan usefulness and possible hazards in a proper manner. In view
monostearate or Tween 60 (14), is a well-known emulsifying of recent warnings that “thepill― is associated with an
agent used in numerous products and it is a promoting increase in fatal coronary artery thromboses in women over
agent. If you paint an animal on the skin once with a the age of4O, such a study should have a wide scope. I would
polycyclic hydrocarbon, you can follow this up by swamping have no doubt that the morning-after pill should not beused
the animal for the rest of its life with Tween 60; as a matter in view of the data on carcinoma of the vagina in young
of fact, the effective dose is approximately the weight of the women whose mothers received this drug in pregnancy and
animal. A mouse must be painted with 20 to 30 g of Tween in view of the availability of other methods for inducing
60 to produce skin papillomas and most of those regress. abortion. A major problem is the proper evaluation of the

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 Food Additives and Contaminants
effects of various versions of “the pill―which, it is now an earlier address (19), alluded to this matter very briefly.
agreed, induces hepatomas not only in rodents but appar Cancer associated with smoked fish in the Baltic States is
ently in a small proportion of women. The potential hazard often discussed and the Icelandic findings are similar. In this
from estrogens administered in these doses to such large instance, however, there are means of eradicating selected
populations cannot be overemphasized. It is astonishing carcinogens from some of these smoked foods. For exam
that we could have become so fragmented in our decision pie, by using liquid and condensed smoke, it is possible to
making; let us hope that it is not too late to rectify the produce foods that taste virtually the samç.The liquid
matter. smokes are made from wood smoke, condensed, and used in
Safrole was found originally to produce hepatomas in rats flavoring agents. In producing a substitute, the heating and
(9) and illustrates the danger of not looking into things in preserving processes would have to be replaced in some
detail in several species, since it was subsequently found to other way, but by using the substitute most of the polycyclic
produce tumors of the esophagus as well (10). I think that hydrocarbons could be removed. There are acceptable daily
we are well off without safrole. intakes set for foods such as these, as well as some standard
Korpássy (7) showed that tannic acid could induce liver procedures.
tumors in rodents. The extrapolation of this result to The essence of the story is that, if you can smoke a food
humans is difficult. There have been suggestions of an without producing these polycyclic aromatic hydrocarbons
association between hot tea drinking in Iran and cancer of and gain the same result, you might as well get rid of them.
the esophagus; but these have not been substantiated. Dr. There are, however, numerous other materials in these
Bogovski, formerly of International Agency for Research smoking fluids that the toxicologists haven't looked at.
on Cancer, has been undertaking experiments with tea in These factors are enormously complicated and they direct
rats, but I have not seen the results. In view of the com one to the fact that, despite all the attention given food
plexity of the chemistry of tannic acids, much additional additives, a minimal amount is being paid to cooking pro
work in this field would be needed before practical use cedures, of which smoking is one. The vast number of
could be made of this information. things that may occur in cooking constitute a Pandora's
Asbestos is used widely in the food industry. It is used for box just waiting to be opened by some fortunate young
filtering processes in making beer and for a variety of other scientist who is going to make a name for himself in the
processes in producing alcoholic beverages. As I understand future.
it, one of the highest asbestos contents is found in Italian There are clearly thousands of compounds that have not
vermouth. Again, I think that there are many ways of yet been tested. I think I can safely predict that in the next
looking at these problems epidemiologically and I would year or two items such as flavoring compounds, of which
concur with views expressed earlier in this session that the there are hundreds, will be found to be mutagenic by the
data on the effects of ingested asbestos are, at best, only droves. We won't know what to make of it and it will be a
suggestive. very difficult problem indeed.
The nitrosamines have been discussed in depth at this The next speaker, Dr. Schwartz (13), will deal with 2
conference, and I think there is little more to be said about elements of interest to me. One of these is the matter of
them. arsenic, which is a situation where everything is reversed, in
The findings that we were lucky enough to encounter with that there are epidemiological data but no animal data
inhibition of nitrosamines by vitamin C (I I) have some whatsoever. What we make ofthat, I don't know. Conceiva
general implications. The potential of being able to neutral bly, there is something else associated with the arsenic that
ize carcinogenic food additives or inhibit their formation, I has been looked at by the epidemiologist. It is, however, a
think, is an approach that must be looked into in detail. problem worthy of our attention and one that should be
There is no question in my mind that situations exist that sorted out.
indicate that it will not be possible to eliminate all The other matter concerns the excessive addition of iron
carcinogens. Accordingly, other ways must be found to deal to our diet, which deserves considerable attention, in view of
with this situation. The use of vitamin C appears to be one the facts that hemosiderosis is undoubtedly associated with
means of preventing formation of nitrosamines from nitrites an increased cancer risk in humans and that there are a
and seems, to some extent, to be practical. variety of iron derivatives that have been shown to pro
The presence of these very low levels of carcinogenic duce tumors in animals under certain circumstances. The
nitrosamines we now see (nitrosopyrrolidine in cooked association of iron as a carrier in the lungs is another
bacon, for example) has, I think, been dealt with very important consideration in this light. Currently, there is
wisely. The FDA, in such instances, has done nothing somewhat of a preoccupation with adding iron to numerous
drastic concerning these compounds, and I think that this is items including, as I discovered recently, black olives to
a reasonable approach. Were the quantities larger, on the make them shiny black. In California, ferrous glutonate is a
other hand, I would then say that action should be taken. In food additive used under these circumstances.
the end, it is essential that we behave like reasonable In conclusion, let me say that in spite ofthe harsh words I
toxicologists. Each one of these problems must be analyzed may have had to say about the Delaney Clause and the
in its own context and own right, and then a logical and philosophy surrounding it, much good has come as a result.
reasonable approach should be taken. At the time of the enactment of this legislation, we were lax
Last, I would like to mention the question of polycyclic indeed in our attitude towards compounds found to be
aromatic hydrocarbons in smoked foods. Dr. Weisberger, in carcinogenic in the laboratory. Some years ago I subscribed

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to the philosophy that all materials found to be carcinogenic Appearance in Young Women. New Engl. J. Med., 284: 878-881,
in the laboratory should be totally eliminated. Since that 1971.
time much research has been undertaken and many new 7. Korpássy, B. The Hepatocarcinogenicity ofTannic Acid. Cancer Res.,
facts have emerged making it clear that “carcinogens― 19:501-504,1959.
8. Lettrê, H., and Wrba, H. The Effect of the Sweetener Dulcin during
encompass a wide range of materials disimilar in their dose
Protracted Feeding.Naturwissenschaften,42: 217, 1955.
requirements, in their mode of action, and in their potential
9. Long, E. A., Nelson, A. A., Fitzhugh, 0., and Hansen,W. H. Liver
danger. They are not only man made but also occur as a Tumors Produced in Rats by Feeding Safrole. Arch. Pathol., 75:
result ofnaturally formed toxins. The practical nature of the 595-604,1963.
problem requires a broad approach that cannot be as 10. Long, E. L., and Jenner, P. M. EsophagealTumors Producedin Rats
limited as seemed possible 2 decades ago. We must beware by the Feeding of Dihydrosafrole. Federation Proc., 22: 275, 1963.
lest our rigidity born ofjustified anxiety makes us seem to 11. Mirvish, S. S., Wallcave, L., Eagen, M., and Shubik, P. Ascorbate
be extremists. Nitrite Reaction: Possible Means of Blocking the Formation of
Finally, it has been a great privilege to have been present Carcinogenic N-Nitroso Compounds. Science, 177: 65-68, 1972.
at a meeting largely devoted to epidemiology; cooperation 12. Oser, B. L., and Oser, M. 2-(p-tert-Butylphenoxy)isopropyl 2-Chloro
between the epidemiologist and the laboratory toxicologist ethyl Sulfite (Aramiter. II. Carcinogenicity. Toxicol. Appl. Phar
macol., 4: 70-88, 1962.
is of major importance and will, I believe, eventually solve
13. Schwartz, M. K. Role ofTrace Elements in Cancer. Cancer Res., 35:
most of the problems I have discussed today. 3481—3487, 1975.
14. Shubik, P. A Comparisonof Different Methodsof Skin Carcinogene
sis and Reflections on the Two Stage Hypothesis. Acta Unio. Intern.
References
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Potential Carcinogenicity of Food Additives and Contaminants
Philippe Shubik

Cancer Res 1975;35:3475-3480.

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