Safety evaluation of certain food additives - ipcs inchem

572 MISCELLANEOUS NITROGEN-CONTAINING SUBSTANCES (addendum)
spleen showed no significant differences from those of the controls. However, two
maternal deaths were recorded immediately after the treatment period (day 6) in
the group of rats treated with 50 mg benzyl isothiocyanate/kg bw. In pregnant rats
treated with benzyl isothiocyanate after fetal implantation, signs of toxicity were also
observed, typified by lethargy, ruffled fur, perinasal staining and hunched posture.
A dose-dependent decrease in body weights of the treated rats was recorded during
the treatment period. There were no significant differences in either the number of
fetal resorptions or the relative weights of liver, kidney and spleen compared with
the controls. One maternal death was recorded after the treatment period (day 14)
in the group treated with 50 mg benzyl isothiocyanate/kg bw. There were no
significant differences in the number of viable fetuses in the treatment group, and
external examination of viable fetuses did not reveal any important findings.
However, fetal weights in rats treated with 25 and 50 mg benzyl isothiocyanate/kg
bw, as well as the placental weights in all treatment groups, were significantly lower
than in the controls (Adebiyi et al., 2004).
(e) Anti-carcinogenesis studies
A variety of isothiocyanates have been studied for their ability to inhibit
carcinogenesis, which occurs mainly through blocking carcinogen metabolic
activation and enhancing carcinogen detoxication (Hecht, 2000; Conaway et al.,
2002; Thornalley, 2002). In co-carcinogenicity studies, administration of various
isothiocyanates prior to dosing with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
(NNK) inhibited the activation of the carcinogen by cytochrome P450 (CYP)
isoforms found in the rat lung (Smith et al., 1990; Guo et al., 1992, 1993). In a study
in rats, benzyl isothiocyanate, when administered simultaneously with N-butyl-N-(4hydroxybutyl)nitrosamine,
inhibited the urinary bladder carcinogenic effects of the
nitrosamine compound (Okazaki et al., 2002). Similarly, dietary administration of
phenethyl isothiocyanate or sulforaphane [()-1-isothiocyanate-4-(methylsulfinyl)butane]
reduced the incidences of NNK activation in rat lung and resulted in fewer
lung tumours (Morse et al., 1989; Boysen et al., 2003; Conaway et al., 2005).
However, rat liver tumour formation was not significantly affected, and, in general,
the inhibition by isothiocyanates of carcinogen-activating CYPs is isoform selective
and depends on the structure of the alkyl or aryl group attached to the isothiocyanate
functional group. 6-Phenylhexyl isothiocyanate, for instance, is the most potent
inhibitor of CYP2B1 (Conaway et al., 1996), whereas sulforaphane is a strong and
selective inhibitor of CYP3A4 (Mahéo et al., 1997).
A second mechanism for anti-carcinogenic activity may be the induction by
isothiocyanates of phase II enzymes, such as glutathione S-transferases and
quinone reductase, thus increasing the rate of carcinogen detoxication. In one study
in humans, numerous isothiocyanates were shown to increase glucuronidation
levels, resulting in increases of nicotinoid glucuronides excreted in the urine (Hecht
et al., 1999). As with CYP inhibition, the effectiveness and specificity of activation
are tissue specific and dependent upon the structure of the alkyl or aryl group
attached to the isothiocyanate functionality. For instance, phenethyl isothiocyanate
is an effective inducer of quinone reductase and glutathione S-transferase in the
liver, but not in the lung or nasal mucosa (Guo et al., 1992). Similarly, treatment with