Influence of Exposure Route and Oral Dosage Regimen on 1, 1-Dichloroethylene Toxicokinetics and Target Organ Toxicity

Abstract

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 ϱ ) values were only modestly higher. Urinary N-acetyl-␤-D-glucosaminidase (NAG) and ␥-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 C max and AUC 0 2 values than did 2-h g.i., although AUC 0 ϱ 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.Home use of volatile organic chemical (VOC)-contaminated tap water commonly results in exposure by multiple routes. Previously, toxicity/carcinogenicity risk assessments focused primarily on the amount of chemical in the water ingested. It is now recognized that inhalation during showering and other water-use activities also contribute significantly to one's systemically absorbed dose (Weisel and Jo, 1996;Gordon et al., 2006). There is little information, however, on the relative quantities and toxicities of VOCs absorbed from different portals. Health risk assessments of ingested VOCs must often be conducted on the basis of inhalation toxicity data, with direct extrapolation from one route of exposure to another. In addition, oral cancer and noncancer studies of VOCs in rodents have usually used daily gavage dosing. The relevance of these single bolus data to human risks is questionable, as people typically consume contaminated water in small, divided doses over the course of the day.1,1-Dichloroethylene (DCE) was selected for the current study. It is used primarily as a chemical intermediate and in the production of polyvinylidene copolymers used to produce flexible films (e.g., Saranwrap, Velon) for food packaging. Environmental releases occur primarily by evaporation, although some DCE is released ...

NTP Technical Report on the Toxicology and Carcinogenesis Studies of Vinylidene Chloride (CASRN 75-35-4) in F344/N Rats and B6C3F1/N Mice (Inhalation Studies)

“…For urinary elimination of total radioactivity, the estimated half-lives for the first and second phases were 6 and 17 hours for both doses. Plasma toxicokinetics of vinylidene chloride in Sprague Dawley rats following gavage exposure showed a similar behavior to inhalation exposure 18 . The Cmax and AUC0-∞ following gavage exposure to 30 mg/kg were 8.9 mg/L and 233 μg•min/mL, respectively; the elimination half-life and bioavailability were 88 minutes and 46.5%, respectively.…”

“…An investigation of the plasma toxicokinetics of vinylidene chloride in Sprague Dawley rats showed that the Cmax and AUC0-∞, respectively, following inhalation exposure to 300 ppm were 2.8 mg/L and 279 μg•min/mL; the elimination half-life and bioavailability, respectively, were 50 minutes and 55.7% 18 .…”

Isotope method to identify and quantify organic pollutant biodegradation during natural attenuation monitoring

“…The research area was located near the chemical industry park. The groundwater had been polluted due to unreasonable discharge of wastewater containing benzene (BZ) and dichloroethylene (DCE), both of which are organic pollutants with the highest detection rate in the groundwater of this research area and both of which pose a threat to human health 22,23 . This study chose BZ and DCE as typical pollutant indicators.…”

“…The groundwater had been polluted due to unreasonable discharge of wastewater containing benzene (BZ) and dichloroethylene (DCE), both of which are organic pollutants with the highest detection rate in the groundwater of this research area and both of which pose a threat to human health. 22,23 This study chose BZ and DCE as typical pollutant indicators. By analyzing the 13 C isotopes of BZ and DCE and the fractionation of 13 C and 14 C isotopes in the total dissolved inorganic carbon (DIC), the natural attenuation capacity of organic pollutants in the groundwater of the study area was evaluated and the microbial degradation processes were quantitatively described.…”