Influence of exposure route and oral dosage regimen on 1, 1-dichloroethylene toxicokinetics and target organ toxicity.
The objective of this investigation was to elucidate the effects of route of exposure and oral dosage regimen on the toxicokinetics (TK) of 1,1-dichloroethylene (DCE). Fasted male Sprague-Dawley rats that inhaled 100 or 300 ppm for 2 h absorbed total systemic doses of (10 or 30 mg/kg DCE, respectively. Other groups of rats received 10 or 30 mg/kg DCE by intravenous injection, bolus gavage (by mouth), or gastric infusion (g.i.) over a 2-h period. Serial microblood samples were taken from the cannulated, unanesthetized animals and analyzed for DCE content by gas chromatography to obtain concentration versus time profiles. Inhalation resulted in substantially higher peak blood concentrations and area under blood-concentration time curves (AUC(0)(2)) than did gastric infusion of the same dose over the same time frame at each dosage level, although inhalation (AUC(0)(infinity)) values were only modestly higher. Urinary N-acetyl-beta-D-glucosaminidase (NAG) and gamma-glutamyltranspeptidase (GGT) activities were monitored as indices of kidney injury in the high-dose groups. NAG and GGT excretion were much more pronounced after inhalation than gastric infusion. Administration of DCE by gavage also produced much higher Cmax and AUC(0)(2) values than did 2-h g.i., although AUC(0)(infinity) values were not very different. The 30 mg/kg bolus dose produced marked elevation in serum sorbitol dehydrogenase, an index of hepatocellular injury. Administration of this dose by inhalation and gastric infusion was only marginally hepatotoxic. These findings demonstrate the TK and target organ toxicity of DCE vary substantially between different exposure routes, as well as dosage regimens, making direct extrapolations untenable in health risk assessments.
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy and Interdisciplinary Toxicology Program, University of Georgia, Athens, Georgia 30602-2352, USA. bruckner@rx.uga.edu
J V
JV
Bruckner
C A
CA
White
S
S
Muralidhara
C
C
Hines
C E
CE
Dallas
D000118:Acetylglucosaminidase / Q000378:metabolism; D000280:Administration, Inhalation; D000284:Administration, Oral; D000818:Animals; D004000:Dichloroethylenes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012143:Respiratory Physiological Phenomena / Q000187:drug effects; D011503:Transglutaminases / Q000378:metabolism
D004000:Dichloroethylenes; C029297:vinylidene chloride; D011503:Transglutaminases; D000118:Acetylglucosaminidase