IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

Male Swiss Webster mice and male Sprague-Dawley rats were exposed to naphthalene
(0–110 ppm) [0–580 mg/m 3 ] for 4 h via whole-body inhalation (West et al., 2001).
Other groups of mice were given an intraperitoneal injection of 0, 50, 100, 200 or
400 mg/kg bw naphthalene. Inhalation exposure of rats to naphthalene did not result in
any detectable changes in the airway epithelial cells. In mice, exposure to naphthalene at
concentrations above 2 ppm [10.5 mg/m 3 ] resulted in a concentration-dependent increase
in Clara cell injury. At low concentrations, naphthalene caused injury in the proximal
airways, while at high concentrations, there was injury both in proximal airways and in
the more distal conducting airways. Parenteral exposure of mice to naphthalene caused
injury that was limited to the distal airways at low dose (≤ 200 mg/kg bw), while at
higher doses (> 300 mg/kg bw), the injury also included the proximal conducting airways.
The higher sensitivity of the distal airways was initially attributed to higher rates
of naphthalene metabolism (Buckpitt et al., 1995), but the results of West et al. (2001)
suggest that cells throughout the airways are equally sensitive and that sensitivity differences
between proximal and distal airways to naphthalene treatment may be due to
differences in the distribution of the compound, although there are no data to support this
suggestion. In conclusion, the pattern of injury after exposure to naphthalene is speciesspecific
and highly dependent on route of exposure.
The ability of naphthalene to cause oxidative stress was assessed in female Sprague-
Dawley rats (weighing 160–180 g) given vitamin E succinate for three days and then
administered 1100 mg/kg bw naphthalene as a single oral dose on day 4. Another group
of rats received naphthalene alone. Naphthalene induced oxidative stress as measured by
increased lipid peroxidation in mitochondria in liver and brain and reduction of glutathione
concentrations in these organs. The treatment also increased DNA single-strand
breaks in liver tissue, and induced an increase in membrane fluidity in liver and brain
microsomes, together with increases in the urinary elimination of malonaldehyde,
formaldehyde, acetaldehyde and acetone. These indices of oxidative stress were less
strong in the rats that had been pretreated with vitamin E succinate (Vuchetich et al.,
1996). [The Working Group noted the high dose used in this study.]
(b) In-vivo studies with multiple doses
NAPHTHALENE 405
Yamauchi et al. (1986) reported that daily administration of oral doses [number of
days not given] of 1 g/kg bw naphthalene to male Wistar rats (weighing 150–170 g)
resulted in increases in levels of serum and liver lipid peroxides, suggesting enhanced
lipid peroxidation. Oral administration of naphthalene in dose increments up to
750 mg/kg bw over nine weeks also enhanced lipid peroxidation and decreased the activity
of selenium-dependent glutathione peroxidase in the liver of male Blue-Spruce rats
(Germansky & Jamall, 1988).
Male albino rats (weighing 100–125 g) were administered 1 g/kg bw naphthalene
orally in refined groundnut oil daily for 10 days. Biochemical alterations in the liver,
kidney and eye were evaluated. Significant changes were observed only in the liver,
including increased liver weight, lipid peroxidation and aniline hydroxylase activity.