Title: Alternative Sweeteners

Cyclamate 75
In 1976, the Temporary Committee of the National Cancer Institute that
was charged with reviewing the cyclamate data concluded ‘‘the present evidence
does not establish the carcinogenicity of cyclamate or its principal metabolite,
cyclohexylamine, in experimental animals’’ (54). On receipt of this report, the
Bureau of Foods of the U.S. FDA apparently concurred and reported to the Commissioner
that ‘‘we think the issue of the carcinogenicity of cyclamate is settled’’
(55). In 1977, the World Health Organization’s Joint Expert Committee on Food
Additives (JECFA) reached a similar conclusion, stating that ‘‘it is now possible
to conclude that cyclamate has been demonstrated to be non-carcinogenic in a
variety of species’’ (56). Nevertheless, carcinogenicity was a major issue in the
1980 decision of the FDA commissioner, who stated that ‘‘cyclamate has not
been shown not to cause cancer’’ and thus denied cyclamate food additive status
(10). However, some toxicological and statistical principles used in this decision
were subsequently challenged by the American Statistical Association (57) and
the Task Force of the Past Presidents of the Society of Toxicology (58).
After submission of the second Food Additive Petition for cyclamate in
1982, the Cancer Assessment Committee (CAC) of the U.S. FDA’s Center for
Food Safety and Applied Nutrition reviewed all the cyclamate data and concluded
that ‘‘there is very little credible data to implicate cyclamate as a carcinogen at
any organ/tissue site to either sex of any animal species tested,’’ that ‘‘the collective
weight of the many experiments . . . indicates that cyclamate is not carcinogenic,’’
and further that ‘‘no newly discovered toxic effects of cyclamate are
likely to be revealed if additional standardized studies were performed’’ (59). In
1985, the National Academy of Sciences reaffirmed the CAC conclusion stating
that ‘‘. . . the totality of the evidence from studies in animals does not indicate
that cyclamate or its major metabolite cyclohexylamine is carcinogenic by itself’’
(60). The NAS report, however, raised some concern about a possible role of
cyclamate as a promoter. This was largely predicated on two studies involving
direct exposure of the urinary bladder to cyclamate. One involved implantation
of a pellet containing cyclamate in the bladder of mice (61) and the other involved
intravesicular instillation of N-methyl-N-nitrosourea into the urinary bladder of
female rats, which were then given cyclamate in either their food or water (62).
At the request of the FDA, the Mitre Corporation evaluated these models and
concluded that ‘‘both types of direct bladder exposure studies, pellet implantation
and intravesicular catherization, are considered unsuitable for predicting human
carcinogenic risk’’ (63). Thus, once again, it would appear that the carcinogenicity
issue has been settled, at least from a scientific point of view, and that it
can be concluded that cyclamate and cyclohexylamine are not carcinogenic in
animals.
The possible association between cancer, particularly bladder cancer, and
the consumption of noncaloric sweeteners by humans has been extensively stud-