title: Determination of tissue partition coefficients for volatile tissue-reactive chemicals: acrylonitrile and its metabolite 2-cyanoethylene oxide.
abstract: Partition coefficients (PCs) are chemical-specific parameters used in physiologically based pharmacokinetic models to describe chemical solubility in tissues. Tissue:air PCs for volatile chemicals can be estimated using vial equilibration techniques in which the chemical concentration in the vial headspace is measured by gas chromatography after equilibrium is reached between the chemical in tissue and air. However, equilibrium would not be expected with tissue-reactive chemicals such as acrylonitrile (ACN) or its epoxide metabolite 2-cyanoethylene oxide (CEO). Active uptake of ACN was observed in rat blood due to reaction with blood sulfhydryl groups, while CEO reacted with all tissues examined (rat blood, muscle, fat, liver, and brain). The active uptake processes were first order as evidenced by a linear decrease in the log of the vial headspace concentrations over time. Linear extrapolation of the log of the apparent PC to zero time, where the contribution of the active uptake process is zero, yielded an estimated PC of 487 for ACN in blood. Equilibrium was achieved with ACN after treatment of blood with diethyl maleate to modify blood sulfhydryl groups, with a PC of 512 +/- 29 (mean +/- SE, n = 14). These PC estimates were verified by direct measurement of ACN concentrations in both the air and the blood (stabilized by acidification). The directly measured ACN blood:air PC was 437 +/- 8 (n = 8), which compared well with the estimated values. Treatment of tissues with diethyl maleate or 2,4-dinitrofluorobenzene did not abolish the active uptake of CEO. However, pretreatment of tissues with CEO itself abolished subsequent CEO uptake. The CEO blood:air PC estimates obtained from zero time extrapolation of four CEO concentrations (1672 +/- 139) and from CEO pretreatment (1658 +/- 137, n = 8) were in good agreement. These data indicate that tissue:air PCs for volatile reactive chemicals can be estimated by extrapolation of a first-order uptake process to zero time or at equilibrium following chemical modification of reactive groups in tissues.
authors.affiliation: Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709.
authors.forename: S K
authors.initials: SK
authors.lastname: Teo
authors.forename: G L
authors.initials: GL
authors.lastname: Kedderis
authors.forename: M L
authors.initials: ML
authors.lastname: Gargas
mesh_terms: D000181:Acrylonitrile / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D002273:Carcinogens / Q000493:pharmacokinetics*; D005027:Ethylene Oxide / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D051381:Rats; D011916:Rats, Inbred F344; D012995:Solubility; D014018:Tissue Distribution
chemical_list: D002273:Carcinogens; C033154:2-cyanoethylene oxide; D005027:Ethylene Oxide; D000181:Acrylonitrile