A cigarette placed almost unthinkingly on a pile of crystal powder led to the
discovery of cyclamate by a University of Illinois scientist in 1937. When the
scientist put the cigarette back in his mouth, he found that the powder, a
derivative of cyclohexylsulfamic acid, had a sweet and pleasant taste. In the
years that followed, the sweetener has endured both the sweet smell of success
and the bitter taste of rejection.
Cyclamate was introduced into beverages and foods in the early 1950's, and it
dominated the artificial sweetener market through most of the 1960s. But in
1968, the National Academy of Sciences (NAS) told FDA that, although consumption
of reasonable quantities of cyclamate probably posed no hazard to humans,
additional studies were needed to resolve various aspects of cyclamate's safety.
Further questions arose in 1969 after bladder tumors developed in rats and
mice that were fed a mixture of cyclamate and saccharin. That prompted FDA to
remove cyclamate from its GRAS list and to propose phasing it out of general
food use.
Its continued availability to diabetics was suggested, but after an NAS
medical advisory group concluded that cyclamate should not even be available as
a drug under medical supervision, FDA imposed a total ban effective Sept. 11,
1970.
Abbott Laboratories, North Chicago, Ill., the sole U.S. producer of
cyclamate, sought FDA's permission to re-market the artificial sweetener in
November 1973, for use only in special dietary foods and for specific
technological purposes. Abbott's petition included more than 400 toxicological
reports, all completed after 1970, with assessments of cyclamate's
carcinogenicity, mutagenicity (capability of producing genetic damage), and
metabolism. In March 1976, the National Cancer Institute told FDA that Abbott's
evidence did not establish or refute the cancer-causing potential of cyclamate.
FDA concurred and informed the company that its evidence did not demonstrate "to
a reasonable certainty" that cyclamate was safe for human consumption.
In effect, FDA was saying that the law placed the burden on the company to
prove cyclamate was safe before it could be sold, rather than on FDA to prove it
unsafe to keep it off the market. The 1958 Food Additives Amendment contains
"general safety" provisions that apply not only to carcinogenicity but to any
type of adverse health effect.
The fate of Abbott's 1973 petition was not resolved until Sept.4, 1980, when
then FDA commissioner Jere E. Goyan issued a final negative decision reaffirming
an earlier ruling by an administrative judge. In brief, Goyan's position was
that the safety of cyclamate had not been demonstrated, that it had not been
shown that cyclamate would not cause cancer and would not cause inheritable
genetic damage. Essentially, Goyan's decision was based on what the company's
evidence did not show. In saying that safety had not been adequately
demonstrated, Goyan did not say the product causes cancer. The Goyan decision,
in fact, noted that the evidence submitted, "does not conclusively establish
that cyclamate is a carcinogen."
Abbott filed again in 1982, asking FDA to permit expanded use of cyclamate
and its use in combination with other artificial sweeteners. Before its ban,
cyclamate generally was used in combination with saccharin. Industry spokesmen
say that combining artificial sweeteners enhances the sweetness of each,
increases a product's stability (or shelf life), mitigates the bitter aftertaste
of saccharin, and cuts costs. FDA said its review of the petition would include
59 new studies and other data supplied by Abbott.
The job of reviewing the information on carcinogenesis went to the Cancer
Assessment Committee of FDA's Center for Food Safety and Applied Nutrition. The
committee was to review the pertinent studies to determine whether cyclamate or
its primary metabolite, cyclohexylamine (which some scientists believe may be
more toxic than cyclamate itself), were potentially cancer-causing.
Noting that "current scientific thinking about carcinogenesis (had) undergone
considerable evolution in the past several years." the committee concentrated
its review on some 24 chronic feeding studies in which cyclamate or
cyclohexylamine was given to laboratory animals. Although some of the studies
preceded the 1970 ban, most were completed during the 1970's, before the 1980
Goyan decision. Particular emphasis was given by the FDA committee to the
evaluation of date that seemed to implicate cyclamate as a cause of tumors in
the urinary bladders of rats and in the lungs, liver and lymphoreticular tissues
of mice. Other studies indicated that consumption of cyclamate could cause
testicular atrophy and chromosome breakage, but the committee's evaluation was
limited only to whether cyclamate caused cancer.
The committee concluded, in a report issued in April 1984, that the evidence
did not indict cyclamate as a cancer-causing agent. Citing the studies with
mice, the report stated: "There exists no credible evidence for the
carcinogenicity of ingested cyclamate or cyclohexylamine on the basis of all
studies on these substances using mice as experimental subjects." On the key rat
studies, the committee also stated that there was "no credible case to be made
for the association between the administration of high dietary levels of
cyclamates and cancer of the bladder in rats. In addition, no neoplasms (tumors)
observed at any other sites (of the animals' bodies) were considered to be
induced by treatment with cyclamate."
At FDA's request, the National Academy of Sciences/National Research Council
then undertook an independent review of the carcinogenicity data. On June 10,
1985, the NAS panel of scientists issued a report that concluded that the
scientific evidence did not indicate that cyclamate or its major derivative,
cyclohexylamine, was carcogenic. However, the NAS committee recommended
repeating animal studies that suggested that cyclamate may act as a tumor
promoter - that is, as a substance that may cause the development of tumors when
used with a carcinogen. The NAS panel acknowledged, however, that scientists
were uncertain about how such findings might apply to humans. "If the findings
(of tumor promotion) are confirmed, uncertainty would still exist about the
assessment of risk of cyclamate use for humans...," the NAS report noted.
In the meantime, FDA continues its review of cyclamate, including resolution
of such safety issues as to whether cyclamate may cause genetic damage and
testicular atrophy.
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