Single administration toxicokinetic studies of decalin (decahydronaphthalene) in rats and mice.
Decalin (decahydronaphthalene) is an industrial solvent known to cause alpha2u-globulin nephropathy in male rats. Studies were conducted using decalin (mixture of cis and trans isomers) to (1) characterize systemic elimination of decalin in rats and mice and (2) evaluate disposition of decalin, its metabolites, and kidney alpha2u-globulin in young and old rats of both sexes following a single 6-h whole-body inhalation exposure at up to 400 ppm decalin. Additionally, a separate group of young male F344/N rats were administered either cis- or trans-decalin iv at doses up to 20 mg/kg to assess disposition of each isomer, its metabolites, and kidney alpha2u-globulin. Decalin was eliminated from blood in a dose-dependent manner, regardless of sex, age, or species. C0 and AUC infinity increased supra-proportionally with exposure concentration. Mice were more efficient in eliminating decalin than rats at lower exposure concentrations, but nonlinear elimination kinetics were more noticeable at 400 ppm. Sex differences in blood decalin elimination were observed in rats; females had a consistently higher AUC infinity at all exposure concentrations. There was a dose-dependent increase in kidney decalin, decalone, and alpha2u-globulin in male rats exposed to decalin. Kidney alpha2u-globulin and decalone concentrations in old male rats were substantially lower than those in young males, but were similar to those observed in all (young and old) females. Compared to old males and all females, young male rats had significantly lower urinary decalol concentrations, but higher kidney decalin, decalone, and alpha2u-globulin concentrations. Administration of decalin to male rats as either the cis or trans isomer revealed that more cis -decalone is produced per unit dose as compared to trans-decalone, and that more trans-decalin accumulated in the kidney (as alpha2u-globulin-ligand complexes) compared to cis-decalin. These patterns of isomer-specific metabolism were also reflected in the cis/trans ratios of decalin in blood, as well as urinary decalol metabolites. The ratio of alpha2u-globulin to the total amount of decalin plus decalone measured in the male rat kidney was approximately 1.0. Therefore, alpha2u-globulin was a key factor in the accumulation of decalin and decalone in kidneys of young male rats, decalin and decalone were practically absent in all females and in old males.
Dill
Jeffrey A
JA
Battelle, Toxicology Northwest, Richland, Washington 99352, USA. dillj@battelle.org
Fuciarelli
Alfred F
AF
Lee
Kyeonghee M
KM
Mellinger
Kathleen M
KM
Chan
Po C
PC
Burka
Leo T
LT
Roycroft
Joseph H
JH
D000280:Administration, Inhalation; D000367:Age Factors; D000510:Alpha-Globulins / Q000652:urine; D000818:Animals; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D005260:Female; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009281:Naphthalenes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D012737:Sex Factors; D012997:Solvents
D000510:Alpha-Globulins; D009281:Naphthalenes; D012997:Solvents; C025500:alpha(2)-microglobulin; C007229:decalin