Dosimetry by means of DNA and hemoglobin adducts in propylene oxide-exposed rats

Toxicol Appl Pharmacol. 2003 Sep 15;191(3):245-54. doi: 10.1016/s0041-008x(03)00253-9.

Abstract

The main purpose of the study was to establish the relation between exposure dose of propylene oxide (PO) and dose in various tissues of male F344 rats exposed to the compound by inhalation. The animals were exposed to 0, 5, 25, 50, 300, or 500 ppm PO in the air for 3 days (6 h/day) or 4 weeks (6 h/day, 5 days/week). Blood, nasal respiratory epithelium, lung, and liver were collected. 2-Hydroxypropylvaline (HPVal) in hemoglobin was quantified using the N-alkyl Edman method and gas chromatography/tandem mass spectrometry. 7-(2-Hydroxypropyl)guanine (7-HPG) in DNA was quantified using (32)P postlabeling. The levels of 7-HPG in DNA of nasal respiratory epithelium and lung increased linearly with concentration as measured both after 3 days and 4 weeks of exposure. Similarly, 7-HPG in liver DNA and HPVal in hemoglobin showed a linear increase with PO concentration in the 3-day exposure group, whereas a deviation from linearity was observed above 300 ppm in the 4-week exposure group. The new results confirm previous observations of a dose difference between tissues with the highest dose present in the nasal respiratory epithelium. The measured adduct levels were used for calculation of adduct increments and corresponding tissue doses per unit of external exposure dose. For this purpose, the buildup of adducts was modeled considering the different kinetics of formation and elimination of adducts with DNA and hemoglobin, respectively, and also considering the increasing body weight of the animals. The half-life of 7-HPG in vivo, as well as tissue doses, could be solved from DNA adduct data at the 3rd and 26th days. Within the range of concentrations where the dose-response curves for adduct formation are linear, the relationship between exposure dose and resulting tissue doses could be based equally well on adduct data from the short-term exposure as on adduct data from the prolonged exposure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogens / administration & dosage
  • Carcinogens / pharmacokinetics*
  • Carcinogens / toxicity
  • DNA Adducts / blood
  • DNA Adducts / metabolism*
  • Dose-Response Relationship, Drug
  • Epoxy Compounds / administration & dosage
  • Epoxy Compounds / pharmacokinetics*
  • Epoxy Compounds / toxicity
  • Guanine / analogs & derivatives*
  • Guanine / blood
  • Guanine / metabolism*
  • Hemoglobins / metabolism*
  • Inhalation Exposure
  • Liver / chemistry
  • Liver / metabolism
  • Lung / chemistry
  • Lung / metabolism
  • Male
  • Models, Biological
  • Rats
  • Rats, Inbred F344
  • Valine / analogs & derivatives*
  • Valine / blood
  • Valine / metabolism*

Substances

  • 7-(2-hydroxypropyl)guanine
  • Carcinogens
  • DNA Adducts
  • Epoxy Compounds
  • Hemoglobins
  • Guanine
  • 2-hydroxypropylvaline
  • Valine
  • propylene oxide