[CANCER RESEARCH 53. 6075-6076.
December 15, 1993]
Letters to the Editor
Correspondence re: A. M. Lynch et a/., Intra- and Interindividual Variability in Systemic Exposure in Humans to
2-Amino-3,8-dimethylimidazo[4,5-/]-quinoxaline
and 2-Amino-l-methyl-6-phenylimidazo-[4,5-6]pyridine,
Carcinogens Present in Cooked Beef. Cancer Res., 52: 6216-6223, 1992.
Much of cancer research is guided by established doctrines that are
infrequently reexamined in depth. This is true of the hypothetical
association between human cancer and nutrition. In a carefully written
review that makes every effort to distinguish between established fact
and unproven hypothesis, Doll and Peto (1) suggest that 35% of all
human cancer might be preventable by nutritional modification. A
more recent paper by Doll (2) states that "the 35% estimate remains
a reasonable guess." Even in the instance of the association between
The paper of Lynch et al. reports a first class investigation; how
ever, I feel the study should have been reported without any sugges
tion, other than speculation, that it had anything to do with cancer in
humans.
Philippe Shubik
Green College
Woodstock Road
Oxford OX2 6HG, United Kingdom
the fat content of the diet and cancer, Doll (2) concludes that there are
many weaknesses and inconsistencies in the evidence but that the
totality of the evidence "suggests" that there is a relationship between
fat consumption and the incidence of colorectal cancer.
In spite of these caveats, a recent publication by Lynch et al. (3)
states that "a substantial proportion of all human cancer is associated
with diet," quoting Doll and Peto (1) and Doll (2) in support. At the
least, the word "hypothesis" should have been used in regard to this
References
1. Doll, R., and Peto, R. The causes of cancer; quantitative estimates of avoidable risks
of cancer in the United States today. J. Nail. Cancer Insù 66: 1191-1308, 1981.
2. Doll, R. The lessons of life: keynote address to the nutrition and cancer conference.
Cancer Res. (Suppl.), 52: 2024-2029, 1992.
3. Lynch, A. M., Knize, M. G., Boobis, A. R., Gooderham, N. J., Davies, D. S., and
Murray, S. Intra- and interindividual variability in systemic exposure in humans
to 2-amino-3,8-dimethylimidazo[4,5-/]quinoxaline
and 2-amino-l-methyl-6-phenylimidazo[4,5-/>]pyridine, carcinogens present in cooked beef. Cancer Res., 52:
6216-6223, 1992.
assertion.
The paper of Lynch et al. is a study of considerable merit and will
doubtless provide an important basis for further investigations into
cancer prevention in humans. These comments are in no way intended
to be critical of this fine investigation. This letter is addressed to a far
more general problem that 1 believe is well illustrated by this paper.
Lynch et al. 's paper is presented in the context of (a) there is no
question but that diet is a proven significant factor in the origin of
human cancer, and (b) that heterocyclic amines such as those pro
duced in the cooking of meat are of particular importance. No mention
is made of the other carcinogenic compounds occurring under similar
circumstances but in much larger quantities, such as the polycyclic
aromatic hydrocarbons, or of the formation of nitrosamines. Drawing
our attention to the occurrence of 2-amino-l-methyl-6-phenylimidazo[4,5-o]pyridine in cigarette smoke illustrates a lack of perspec
tive of the relative risks involved. We are left with the impression that
the risk to humans from cooked meats is in the same range as the risk
from cigarette smoke. Equally, we are given an impression that
2-amino-l-methyl-6-phenylimidazo[4,5-£>]pyridine
may be just the
carcinogen we have been searching for in cigarette smoke all these
years.
There is certainly nothing wrong with scientists continuing to
search for carcinogens in our total environment. However, presenting
this material in an objective manner requires recognition of the ex
istence of the many confounding factors. Some years ago I took part
in a field trip to the Caspian littoral of Iran to search for causes of the
high incidence of esophageal cancer there. Our group included a
polycyclic hydrocarbon expert, a nitrosamine expert, and a fungal
toxin expert. Each evening we had a discussion in which each of our
experts would announce that they had found the culprit—a polycyclic
hydrocarbon, a nitrosamine, or a fungal toxin.
We have no evidence that the cooked meats in question are asso
ciated with human cancer and, if they were, it would be an insuperable
task to sort out which of the many identified carcinogenic compounds
were responsible. After all, this has not yet proved possible in the far
better circumscribed instance of lung cancer and cigarette smoke.
Reply
Like Dr. Shubik, we too are concerned that epidemiological rela
tionships not be interpreted as synonymous with cause and effect.
However, we take exception to the criticisms leveled at our recent
paper (1) by Dr. Shubik (2), although we acknowledge that the basis
of our differences is, in fact, semantic, rather than scientific.
We recognize that a causal relationship between the majority of
human cancers and diet has yet to be established. It was for this very
reason that we used the word "associated" to describe this relationship
in our paper (1). The term "associated" is defined in the Oxford
English Dictionary (1979 edition) as "combined circumstantially" and
"occurring in combination." It was in this sense that the word was
used in our paper. Hence, it is apparent that far from a hypothesis, an
association between diet and cancer has been established beyond
doubt, as reviewed by Doll (3). For Shubik to interpret our assertion
that such an association exists as "there is no question but that diet is
a proven significant factor in the origin of human cancer" misrepre
sents both our text
Not only is there
evidence has been
consumption of red
and meaning.
an association between diet and cancer, but recent
presented for an association between both the
meat (4-6) and the "doneness" of the meat (7) and
some forms of cancer in humans. During the cooking of meat, a
number of HA1 are formed from endogenous constituents. This group
of compounds accounts for almost all of the mutagenicity of cooked
meat (8). We therefore disagree with Shubik that other carcinogenic
compounds occur in much larger quantities, under similar circum-
Received 9/1/93; accepted 9/1/93.
1The abbreviation used is: HA, heterocyclic aromatic amines.
Received 5/18/93; accepted 10/12/93.
6075
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REPLY TO LETTER
stances. To date, all of the HA tested are carcinogenic (9) and some are
among the most potent primate carcinogens yet described (10). It is in
the light of such information that we, like a number of others, have
focused our attention on the HA. While accepting that HA have yet to
be established as causative agents in human cancer, this is clearly a
question worthy of investigation in humans. Information such as that
reported in our paper (1) is essential in any systematic study of HA in
humans.
Shubik is correct to point out that there are "many confounding
factors" in identifying causative agents in human cancer, and that the
human diet does not comprise HA alone. Not only are there other
carcinogens present but also compounds that can act as tumor pro
moters and as anticarcinogens. These must all be taken into account,
as should interindividual variability in the activity of the enzymes of
activation and detoxication. However, the existence of such confound
ing factors should not be allowed to preclude studies on the possible
role of individual chemicals naturally present in complex mixtures
which, with the application of modern analytical methods, may pro
vide important insights into the relationship between carcinogen ex
posure and tumorigenicity. We do not share Shubik's pessimism that
it would be "an insuperable task to sort out which of the many
identified carcinogenic compounds were responsible." While it is
increasingly apparent that extrapolation of data from studies of car
cinogens in animals to humans is fraught with pitfalls, it is possible to
design rational and informative prospective studies in humans to seek
answers to these questions.
If HA are shown unequivocally not to play a significant role in
human dietary-associated cancer, such a negative result will be as
important a finding as a positive one. Firstly, it would remove one
possible confounding factor in considering why diet is associated with
human cancer. Secondly, it would raise important questions on the
validity of current risk assessment procedures, based on the relation
ship assumed to exist between the carcinogenicity of genotoxins in
rodents, and acceptable risk in humans.
TO EDITOR
Anthony M. Lynch
Alan R. Boobis
Donald S. Davies
Stephen Murray
Nigel Gooderham
Department of Clinical Pharmacology
Hammersmith Hospital
London W12 ONN, United Kingdom
References
1. Lynch. A. M., Knize, M. G., Boobis, A. R., Gooderham, N. J., Davies, D. S., and
Murray, S. Intra- and inlerindividual variability in systemic exposure in humans to
2-amino-3,8-dimethylimidazo[4,5-/]quinoxaline
and 2-amino-1 -methyl-6-phenylimidazo[4.5-fc]pyridine, carcinogens present in cooked beef. Cancer Res., 52: 62166223, 1992.
2. Correspondence re: A. M. Lynch el al.. Intra- and interindividual variability in
systemic exposure in humans to 2-amino-3,8-dimcthylimidazo[4,5-/]quinoxaline
and
2-amino-l-methyl-6-phenylimidazo[4,5-o]pyridine,
carcinogens in cooked beef.
Cancer Res.. 52: 6216-6223, 1992. Cancer Res., 6075-6076, 1993.
3. Doll, R. The lessons of life: keynote address to the nutrition and cancer conference.
Cancer Res. (Suppl.), 52: 2024s-2029s, 1992.
4. Schiffman. M. H., and Felton. J. S. Letter to the Editor re: "Fried foods and (he risk
of colon cancer." Am. J. Epidemici., 131: 376-378, 1990.
5. Willet, W. C, Stampfer, M. J., Colditz, G. A., Rosner, B. A., and Speizer, F. E.
Relation of meat. fat. and fiber intake to the risk of colon cancer in a prospective study
among women. N. Engl. J. Med., 323: 1664-1672, 1990.
6. Norell, S. E., Ahlbom, A., Erwald, R., Jacobson, G., Lindberg-Navier, I.. Olin, R.,
Tornberg, B., and Wiechel, K. Diet and pancreatic cancer: a case-control study. Am.
J. Epidemiol., 124: 894-902, 1986.
7. Gerhardsson de Verdier, M.. Hagman, U., Peters, R. K., Steineck, G., and Overvick,
E. Meat, cooking methods and colorectal cancer: a case-referent study in Stockholm.
Int. J. Cancer, 49: 520-525, 1991.
8. Felton, J. S., Knize, M. G., Shen, N. H., Andresen, B. D., Bjeldanes, L. F., and Hatch,
F. T. Identification of the mutagcns in cooked beef. Environ. Health Perspect., 67:
17-24, 1986.
9. Ohgaki, H., Takayama, S., and Sugimura. T. Carcinogenicities of heterocyclic amines
in cooked food. Mutât.Res., 259: 399-410, 1991.
10. Adamson, R. H., Thorgeirsson, V. P., Snyderwine, E. G., Thorgcirsson, S. S., Reeves,
J., Dalgard, D. W., Takayama, S., and Sugimura, T. Carcinogenicity of 2-amino-3methyl-imidazo[4,5-/]quinoline
in nonhuman primates: induction of tumours in three
macaques. Jpn. J. Cancer Res., 81: 10-14, 1990.
6076
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1993 American Association for Cancer Research.
Correspondence re: A. M. Lynch et al., Intra- and Interindividual
Variability in Systemic Exposure in Humans to
2-Amino-3,8-dimethylimidazo[4,5-f]-quinoxaline and
2-Amino-1-methyl-6-phenylimidazo-[4,5- b]pyridine,
Carcinogens Present in Cooked Beef. Cancer Res., 52: 6216−
6223, 1992 −− Reply
Anthony M. Lynch, Alan R. Boobis, Donald S. Davies, et al.
Cancer Res 1993;53:6075-6076.
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