Sex differences in the toxicokinetics of inhaled solvent vapors in humans 2. 2-propanol.
The aim of this study was to evaluate possible sex differences in the inhalation toxicokinetics of 2-propanol vapor. Nine women and eight men were exposed on different occasions for 2 h during light physical exercise (50 W) to 2-propanol (350 mg/m3) and to clean air (control exposure). The level corresponds to the Swedish occupational exposure limit. 2-Propanol and its metabolite acetone were monitored up to 24 h after exposure in exhaled air, blood, saliva, and urine by headspace gas chromatography. Body fat and lean body mass were estimated from sex-specific equations using bioelectrical impedance, body weight, height, and age. Genotypes were determined by PCR-based assays for alcohol dehydrogenase and cytochrome P450 2E1 (CYP2E1). The CYP2E1 phenotype was assessed by the 2-h plasma 6-hydroxychlorzoxazone/chlorzoxazone metabolic ratio in vivo. The toxicokinetic profile in blood was analyzed using a one-compartment population model. The following sex differences were significant at the p = 0.05 level (Student's t test). The respiratory uptake was lower and the volume of distribution smaller in females. The women had a slightly shorter half-time of 2-propanol in blood and a higher apparent total clearance when corrected for body composition. However, women reached approximately four times higher 2-propanol levels in exhaled air at 10-min postexposure and onward. Acetone in blood was markedly higher in females than in males in the control experiment and slightly higher following exposure to 2-propanol. A marked sex difference was that of a 10-fold higher in vivo blood:breath ratio in men, suggesting sex differences in the lung metabolism of 2-propanol. The most marked sex difference was that of salivary acetone, for which an approximately 100-fold increase was seen in women, but no increase in men, after exposure to 2-propanol compared to clean air. The toxicokinetic analysis revealed no significant differences in toxicokinetics between subjects of different metabolic genotypes or phenotypes. In conclusion, the study indicates several sex differences in the inhalation toxicokinetics of 2-propanol. Most of these differences are consistent with anatomical differences between women and men. However, body build can not explain the sex differences in 2-propanol levels in expired air and acetone in saliva.
Ernstgård
Lena
L
Work Environment Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. Lena.Ernstgard@imm.ki.se
Sjögren
Bengt
B
Warholm
Margareta
M
Johanson
Gunnar
G
D019840:2-Propanol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000096:Acetone / Q000378:metabolism; D000280:Administration, Inhalation; D000328:Adult; D000426:Alcohol Dehydrogenase / Q000235:genetics; D019392:Cytochrome P-450 CYP2E1 / Q000145:classification / Q000235:genetics; D004247:DNA / Q000032:analysis; D005260:Female; D005838:Genotype; D006801:Humans; D019570:Inhalation Exposure; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D005082:Physical Exertion; D012463:Saliva / Q000378:metabolism; D012737:Sex Factors; D012997:Solvents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014835:Volatilization
D012997:Solvents; D000096:Acetone; D004247:DNA; D000426:Alcohol Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; D019840:2-Propanol