Metabolic Basis for Nonlinearity in 1,3-Dichloropropene Toxicokinetics and Use in Setting a Kinetically-derived...

Area of Science:

• Toxicology
• Pharmacokinetics
• Risk Assessment

Background:

• 1,3-Dichloropropene (1,3-D) caused lung tumors in male mice but not female mice or rats in previous studies.
• This study investigated if metabolic clearance saturation at high doses caused the observed lung tumors in male mice.

Purpose of the Study:

• To determine the linearity of 1,3-D blood concentrations in mice during repeated inhalation exposure.
• To investigate the role of metabolic clearance saturation in 1,3-D-induced lung tumorigenicity in mice.

Main Methods:

• Mice were exposed nose-only to 1,3-D at concentrations ranging from 0 to 120 ppm for 6 hours/day, 7 days/week.
• Blood samples were collected at various time points during and after exposure to measure 1,3-D concentrations and determine area-under-the-curve.
• Glutathione (GSH) levels and minute volume were assessed to evaluate metabolic processes and respiratory function.

Main Results:

• Systemic exposure to 1,3-D became nonlinear at inhalation levels of 30 ppm and above.
• Significant depletion of GSH and decreased metabolic clearance of 1,3-D were observed at repeated exposure levels of 30 ppm and higher.
• Shifts in the ratio of cis- and trans-1,3-D isomers in blood also indicated nonlinear toxicokinetics well below 60 ppm.

Conclusions:

• The data suggest that the maximum kinetically derived dose for repeated 1,3-D exposure in mice should be at or below 30 ppm.
• The nonlinear toxicokinetics and GSH depletion at lower doses indicate that 1,3-D-induced lung tumors in mice may not be relevant for human health risk assessment.