Chronic near lifetime toluene exposure in rodents does not replicate solvent abuse leukoencephalopathy in humans

Toluene is an organic solvent used in industry and as a substance of abuse. The latter situation may be associated with a leukoencephalopathy characterized by white matter atrophy, multifocal myelin loss, and macrophages that contain birefringent granular inclusions. To determine if rodents can develop the same white matter damage, we studied archived rodent brain samples from three near-lifetime toluene carcinogenicity experiments. Rats and mice were exposed to toluene via an inhalation chamber at 1200 ppm for 6.5 h daily, 5 days per week, for 103 weeks. Rats were exposed to toluene via oral gavage of 800 mg/kg, 4 days per week, for 104 weeks. In gavage-exposed brains, immunohistochemical staining was used to detect reactive astroglial and microglial changes, neuron populations, and cytochrome P450 upregulation. None of the white matter changes reported in human toluene abuse were identified in the rat or mouse brains. In a blinded analysis, a mild widespread increase in reactive microglia was detected in female rats that received toluene by gavage at 800 mg/kg. However, no significant differences were detected in neurons or astrocytes. Potential reasons for the absence of changes are discussed. We conclude that rodent studies designed to study carcinogenicity of toluene might not adequately model abuse exposure.