Deposition of dibasic esters in the upper respiratory tract of the male and female Sprague-Dawley rat.
Inhalation exposure of the male and female rat to high concentrations of a mixture of the dibasic esters dimethyl succinate (DMS), dimethyl glutarate (DMG), and dimethyl adipate (DMA) results in mild olfactory toxicity. This response is thought to be due to the in situ formation of acidic metabolites via nasal carboxylesterases. The current study was designed to provide inhalation dosimetric information for these vapors. Deposition of DMS, DMG, and DMA was measured in the surgically isolated upper respiratory tracts (URT) of ketamine-xylazine-anesthetized male and female rats under constant velocity flow conditions at a flow rate of 100 ml/min. Deposition of acetone was measured in both genders for comparative purposes. URT deposition efficiencies in excess of 98.3% were observed for DMS, DMG, and DMA in animals exposed to each vapor individually. No gender differences in deposition efficiency were observed for these vapors or for acetone. Deposition of DMS, DMG, and DMA was also measured in animals exposed to all three vapors simultaneously. Deposition efficiency under simultaneous exposure conditions ranged between 97.3 and 98.5%. These values were slightly lower (about 1%) than those obtained under individual exposure conditions (p less than 0.0001). The reduced deposition efficiency may have resulted from competitive inhibition of nasal metabolism due to the simultaneous presence of all three carboxylesterase substrate vapors in nasal tissues. If so, inhalation of dibasic ester vapors would be expected to inhibit the uptake of other carboxylesterase substrate vapors without influencing uptake of vapors which are not substrates for this enzyme. Such was observed in studies using DMS, ethyl acetate (the substrate vapor), and isoamyl alcohol (the nonsubstrate vapor). Specifically, simultaneous exposure to DMS markedly inhibited uptake of ethyl acetate without altering uptake of isoamyl alcohol. Gender differences were not observed in URT deposition of any of the six vapors used in the current study, DMS, DMG, DMA, ethyl acetate, isoamyl alcohol, or acetone, suggesting that gender differences in URT deposition may not be widespread among vapors. The high URT deposition efficiencies of the dibasic esters are consistent with the olfactory toxicity resulting from inhalation exposure to these vapors.
Morris
J B
JB
Toxicology Program, School of Pharmacy, University of Connecticut, Storrs 06269.
Clay
R J
RJ
Trela
B A
BA
Bogdanffy
M S
MS
D000085:Acetates / Q000494:pharmacology; D000096:Acetone / Q000493:pharmacokinetics; D000272:Adipates / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D005260:Female; D005977:Glutarates / Q000493:pharmacokinetics* / Q000633:toxicity; D008297:Male; D000439:Pentanols / Q000493:pharmacokinetics; D051381:Rats; D011919:Rats, Inbred Strains; D012137:Respiratory System / Q000187:drug effects*; D012737:Sex Factors; D013386:Succinates / Q000493:pharmacokinetics* / Q000633:toxicity
D000085:Acetates; D000272:Adipates; D005977:Glutarates; D000439:Pentanols; D013386:Succinates; D000096:Acetone; C067353:dimethyl glutarate; C067354:dimethyladipate; C007650:ethyl acetate; C056451:dimethyl succinate; C029683:isopentyl alcohol