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 degeneration 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-nitrophenyl)phosphate, an inhibitor of carboxylesterase enzymes, thus demonstrating that the lesion is caused by the carboxylesterase mediated metabolism of methyl methacrylate to methacrylic acid, an irritant and corrosive metabolite. The distribution of the carboxylesterases in nasal tissues has been investigated and the metabolism of methyl methacrylate to methacrylic acid has 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. Consistent with this, the enzyme activity in all three species was higher in fractions 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 metabolism in rat and hamster olfactory tissue fractions were comparable, whereas 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 lower 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 humans are significantly less sensitive than rodents to the nasal toxicity of methyl methacrylate.
Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, SK10 4TJ, Cheshire, UK.
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Mainwaring
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Foster
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Lund
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Green
D000818:Animals; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006651:Histocytochemistry; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008297:Male; D008647:Mesocricetus; D008689:Methacrylates / Q000378:metabolism; D020366:Methylmethacrylate / Q000378:metabolism / Q000633:toxicity*; D009297:Nasal Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009596:Nitrophenols / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity
D004791:Enzyme Inhibitors; D008689:Methacrylates; D009596:Nitrophenols; D020366:Methylmethacrylate; C008384:methacrylic acid; C002887:bis(4-nitrophenyl)phosphate; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase