Methyl methacrylate toxicity in rat nasal epithelium: studies of the mechanism of action and comparisons between species

Female F344 rats exposed to 200 ppm methyl methacrylate for 6 h developed a lesion in the nasal olfactory epithelium which was characterised by degene ration and atrophy. The severity of the lesion was markedly reduced by pre- treatment of the rats with an intraperitoneal dose of 100 mg/kg bis-(p-nitr ophenyl)phosphate, an inhibitor of carboxylesterase enzymes, thus demonstra ting that the lesion is caused by the carboxylesterase mediated metabolism of methyl methacrylate to methacrylic acid, an irritant and corrosive metab olite. The distribution of the carboxylesterase in nasal tissues has been i nvestigated and the metabolism of methyl methacrylate to methacrylic acid h as been compared in rat, hamster and human nasal tissue fractions in vitro. Histocytochemistry showed that the carboxylesterases are heavily localised in the sustentacular cells and Bowman's glands of the rat olfactory region , but are more generally distributed in human olfactory epithelium. Consist ent with this, the enzyme activity in all three species was higher in fract ions prepared from olfactory tissue than from respiratory tissue, 3-fold in rat and human and 12-fold in the hamster. The maximum rates (V-max) of met abolism in rat and hamster olfactory tissue fractions were comparable, wher eas those in human olfactory tissue fractions were at least 13-fold lower. The rate of metabolism in rat olfactory tissue was also comparable to that in rat liver whereas in humans, the rate in olfactory tissue was 500-fold l ower than that in the liver. In respiratory tissues, the rate in humans was at least 6-fold lower than that in the rat. These results suggest that hum ans are significantly less sensitive than rodents to the nasal toxicity of methyl methacrylate (C) 2001 Elsevier Science Ireland Ltd. All rights reser ved.