IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

NAPHTHALENE 395
(1979) investigated the formation of glutathione conjugates using [ 14 C]naphthalene
given to female Spague-Dawley rats. After intraperitoneal injection of 100 mg/kg bw
[ 14 C]naphthalene, 65% of the water-soluble fraction of the radioactivity in urine was
identified as glutathione-derived conjugate (premercapturic acid) over a 72-h period.
Total recovery of radioactivity was 74% after 72 h, with 60% present in the urine and
14% in the faeces. 1,2-Dihydro-1,2-dihydroxynaphthalene (28%) and 1-naphthol (60%)
were the major metabolites in the ether-extractable fraction, which accounted for 6% of
the administered dose. Summer et al. (1979) found a dose-dependent increase in the urinary
excretion of mercapturic acid conjugates in male Wistar rats given 30, 75 or
200 mg/kg bw naphthalene by stomach tube but did not find any such increase in
chimpanzees (Pan troglodytes S.). A similar lack of a significant role for glutathione conjugation
in primates was observed in rhesus monkeys (Macaca mulatta) (Rozman et al.,
1982). [The Working Group noted that standards of naphthalene mercapturates were not
available in these studies and the analytical method employed may have underestimated
the amounts of mercapturates present in the urine samples.]
Horning et al. (1980) gave naphthalene (100 mg/kg bw) intraperitoneally to male
Sprague-Dawley rats and identified 21 oxygenated metabolites in the urine, all but one
being generated via epoxidation. Along with those identified in other studies, the total
number of known naphthalene metabolites was 31, excluding mercapturic acids, conjugates
and related compounds. Bakke et al. (1985) gave [ 14 C]naphthalene orally to male
Sprague-Dawley rats and found 4.6% of the 14 C dose as naphthols or their glucuronides
in the urine by 24 h. In addition, they found 1,2-dihydro-1-hydroxy-2S-(N-acetyl)cysteinylnaphthalene
(11, see Figure 1) (38.1%), 1,2-dihydroxynaphthalene (7, see
Figure 1) (4.9%), 1,2-dihydro-1,2-dihydroxynaphthalene glucuronide (23.9%), 1,2-dihydro-1-hydroxy-2-methylthionaphthalene
glucuronide (4.6%) and uncharacterized
metabolites (2.4%). Buonarati et al. (1990) showed that a consistent percentage of a dose
of either trans-1S-hydroxy-2S-glutathionyl-1,2-dihydronaphthalene or trans-1R-hydroxy-
2R-glutathionyl-1,2-dihydronaphthalene administered intravenously to male Swiss
Webster mice was eliminated as the corresponding diastereomeric mercapturic acid in the
urine. In contrast, a significant percentage of a dose of trans-1R-glutathionyl-2R-hydroxy-
1,2-dihydroxynaphthalene (14–25%, depending on the dose) was metabolized to
(2-hydroxy-1,2-dihydronaphthalenylthio)pyruvic acid. These observations indicate that
mercapturic acids generated by conjugation at the C2 position of the napththalene nucleus
can be used to assess the stereochemistry of naphthalene metabolism in vivo.
Pakenham et al. (2002) showed that 24–35% of an intraperitoneal dose of [ 14 C]naphthalene
was eliminated as mercapturates by both mice and rats at 24 h after dosing.
For both species, this percentage was the same over a wide dose range (3.12–200 mg/kg
bw). In contrast, after inhalation exposure, the amounts of mercapturic acid in mouse
urine were approximately twice those in rat urine at the same level of exposure. Over a
24-h period, approximately 100–500 μmol/kg bw mercapturates were eliminated in urine
of mice given intraperitoneal injections of 50–200 mg/kg bw naphthalene. In mice
exposed by inhalation to 1–100 ppm (5.24–524 mg/m 3 ) naphthalene for 4 h,