Toxicological Review for 2-Methylnaphthalene (CAS No. 91-57-6 ...

tissue from mice that were repeatedly exposed to dermal doses of a methylnaphthalene mixture (119
mg/kg methylnaphthalene mixture twice a week for 30 weeks) showed hyperplasia and hypertrophy of
type II pneumocytes in alveolar regions with proteinosis (Murata et al., 1992). Electron microscopic
examination showed that alveolar spaces were filled with numerous myelinoid structures resembling
lamellar bodies of type II pneumocytes (Murata et al., 1992). Associated with this extracellular
material were mononucleated giant cells (balloon cells) containing numerous myelinoid structures, lipid
droplets, and electron dense needle-like crystals. Murata et al. (1992) hypothesized that, in response
to a mixture containing 2-methylnaphthalene, type II pneumocytes produce increased amounts of
lamellar bodies due to hyperplasia and hypertrophy, and eventually transform into mononucleated giant
cells. The rupture of these cells is hypothesized to lead to the accumulation of the myelinoid structures
in the alveolar lumen. No in-depth ultrastructural studies of the pathogenesis of pulmonary alveolar
proteinosis from chronic exposure to 2-methylnaphthalene alone were available. However, Murata et
al. (1997) suggested that the adverse pulmonary effects detected by light microscopy following chronic
oral exposure to 2-methylnaphthalene alone were very similar to those detected following chronic
dermal exposure to the methyl-naphthalene mixture. These similarities suggest that the mode of action
(i.e., specific cellular targeting of type II pneumocytes in the alveolar region of the lung) prompted by
observations following exposure to the methylnaphthalene mixture are relevant to 2-methylnaphthalene.
Pulmonary alveolar proteinosis (also referred to as alveolar lipoproteinosis, alveolar
phospholipidosis, alveolar proteinosis, and pulmonary alveolar lipoproteinosis) is a disorder in humans
that is characterized by the accumulation of surfactant lipids and proteins in the alveoli. The condition
develops most commonly between the ages of 20-50 and more often in males then females (3:1,
respectively) and in smokers when compared to nonsmokers. The primary symptom associated with
this condition is dyspnea that may be accompanied with cough. Altered serum lactate dehydrogenase
(LDH) levels have been observed in few patients. Patients examined physically may appear normal,
but may have nonspecific pulmonary symptoms such as sporadic reduction in diffusing capacity to
modest reduction in vital capacity. In the majority of cases, pulmonary alveolar proteinosis is diagnosed
by the presence of a milky bronchiolar lavage fluid containing large amounts of granular acellular
eosinophilic proteinaceous material with abnormal foamy macrophages filled with periodic acid-Schiff
base (PAS) positive intracellular material. Upon examination of the bronchiolar lavage fluid by electron
microscopy, concentrically laminated phospholipid structures, known as lamellar bodies, may be
present and are used to confirm pulmonary alveolar proteinosis. Histopathologically, pulmonary
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