Title: Alternative Sweeteners

76 Bopp and Price
ied during the past 10–20 years. Since the widespread use of cyclamate in foods
and beverages was restricted to a relatively short time span in many countries,
these studies are more applicable to the assessment of the possible carcinogenicity
of saccharin than cyclamate. However, the cyclamate issue was specifically addressed
in some of the studies. The epidemiology studies with the noncaloric
sweeteners have been reviewed by others (64–66), and it has generally been
agreed that there is no conclusive evidence of an increased risk of bladder cancer
associated with the use of these sweeteners.
XIV. MUTAGENICITY
In the 1960s and 1970s, the mutagenic potential of cyclamate and cyclohexylamine
was evaluated in many different test systems, including the Ames test and
other microbial gene mutation assays, studies in Drosophila, in vitro cytogenetic
studies, in vivo cytogenetic studies with both somatic and germ cells, dominant
lethal tests, and others. Although there were instances of conflicting or discordant
results, the preponderance of evidence provided by this battery of tests suggested
that neither cyclamate nor cyclohexylamine represented a significant mutagenic
hazard (15, 67, 68). Nevertheless, in the 1980 decision the Commissioner of the
FDA still concluded that ‘‘cyclamate has not been shown not to cause heritable
genetic damage’’ (10).
In 1985 the NAS Committee evaluated the mutagenicity tests with cyclamate
and cyclohexylamine and found little evidence to conclude that either compound
was a DNA-reactive carcinogen (60). They, however, recommended that
additional tests for mammalian cell DNA damage, mammalian cell gene mutation
tests, and more definitive cytogenetic studies be conducted to complete and
strengthen the database for the two compounds. After consultation with the FDA,
both calcium cyclamate and cyclohexylamine were tested in the Chinese hamster
ovary HGPRT forward mutation assay, for unscheduled DNA synthesis in rat
hepatocytes, and in the Drosophila sex-linked recessive lethal assay (69). The
results of these three tests gave no evidence of any intrinsic genotoxicity from
either compound. In addition, dominant lethal and heritable translocation tests
were conducted in male mice given the maximal tolerated dose of calcium cyclamate
for 6 weeks because the sodium salt had been used in almost all the previous
studies with mammalian germ cells (70). The results of these two tests were
also negative, indicating that the calcium salt did not induce any transmissible
chromosomal aberrations in the germ cells of mice. Thus, these recent studies,
performed according to the currently accepted standards, confirm the previous
conclusions that cyclamate and cyclohexylamine are not mutagenic and do not
cause heritable genetic damage.