Characterization of glycidol-hemoglobin adducts as biomarkers of exposure and in vivo dose.
Hemoglobin adducts have been used as biomarkers of exposure to reactive chemicals. Glycidol, an animal carcinogen, has been reported to form N-(2,3-dihydroxy-propyl)valine adducts to hemoglobin (diHOPrVal). To support the use of these adducts as markers of glycidol exposure, we investigated the kinetics of diHOPrVal formation and its elimination in vitro and in vivo. Five groups of rats were orally administered a single dose of glycidol ranging from 0 to 75mg/kg bw, and diHOPrVal levels were measured 24h after administration. A dose-dependent increase in diHOPrVal levels was observed with high linearity (R(2)=0.943). Blood sampling at different time points (1, 10, 20, or 40days) from four groups administered glycidol at 12mg/kg bw suggested a linear decrease in diHOPrVal levels compatible with the normal turnover of rat erythrocytes (life span, 61days), with the calculated first-order elimination rate constant (kel) indicating that the diHOPrVal adduct was chemically stable. Then, we measured the second-order rate constant (kval) for the reaction of glycidol with N-terminal valine in rat and human hemoglobin in in vitro experiments with whole blood. The kval was 6.7±1.1 and 5.6±1.3 (pmol/g globin per μMh) in rat and human blood, respectively, indicating no species differences. In vivo doses estimated from kval and diHOPrVal levels were in agreement with the area under the (concentration-time) curve values determined in our earlier toxicokinetic study in rats. Our results indicate that diHOPrVal is a useful biomarker for quantification of glycidol exposure and for risk assessment.
R&D Safety Science Research, Kao Corporation, 2606 Akabane, Ichikai-Machi, Haga-Gun, Tochigi 321-3497, Japan. Electronic address: honda.hiroshi@kao.co.jp.
Hiroshi
H
Honda
Department of Materials and Environmental Chemistry, Environmental Chemistry Unit, Stockholm University, SE-106 91 Stockholm, Sweden.
Margareta
M
Törnqvist
R&D Safety Science Research, Kao Corporation, 2606 Akabane, Ichikai-Machi, Haga-Gun, Tochigi 321-3497, Japan.
Naohiro
N
Nishiyama
R&D Safety Science Research, Kao Corporation, 2606 Akabane, Ichikai-Machi, Haga-Gun, Tochigi 321-3497, Japan. Electronic address: kasamatsu.toshio@kao.co.jp.
Toshio
T
Kasamatsu
D000284:Administration, Oral; D000818:Animals; D015415:Biomarkers / Q000097:blood; D002273:Carcinogens / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D004912:Erythrocytes / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D016014:Linear Models; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D020005:Propanols / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D014633:Valine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics
D015415:Biomarkers; D002273:Carcinogens; D004852:Epoxy Compounds; D006454:Hemoglobins; C416044:N-(2,3-dihydroxypropyl)valine; D020005:Propanols; D014633:Valine; C004312:glycidol
Exposure assessment; Glycidol; Hemoglobin adducts; In vivo dose; Toxicokinetics