Toxicokinetic modeling of the combined exposure to toluene and n-hexane in rats and humans

被引:10
作者
Ali, N [1 ]
Tardif, R [1 ]
机构
[1] Univ Montreal, Fac Med, Dept Med Travail & Hyg Milieu, Montreal, PQ H3C 3J7, Canada
关键词
toluene; n-hexane; coexposure; toxicokinetic modeling; biological monitoring; metabolic interaction;
D O I
10.1539/joh.41.95
中图分类号
R1 [预防医学、卫生学];
学科分类号
1004 ; 120402 ;
摘要
We studied the toxicokinetic fate of toluene (TOL) and n-hexane (HEX) in rats exposed to mixtures of these solvents by inhalation during 4 hours. We developed and validated a physiologically based toxicokinetic (PBTK) model for this binary mixture in the rat, which after proper scaling, was used to predict the impact of combined exposure to TOL and HEX in humans, Simultaneous exposure to TOL (125-300 ppm) did not affect the kinetics of HEX (100 or 800 ppm) in blood in rats. Coexposure to HEX, however, increased the concentration of TOL in blood. Coexposure strongly reduced the urinary excretion of 2,5-hexanedione (HD) (up to 75% reduction for TOL 300 ppm + HEX 100 ppm) whereas the urinary excretion of HA and o-CR were reduced to a lesser extent (up to 28% reduction for TOL 200 ppm + HEX 100 ppm). Simulations of exposure to various TOL-HEX mixtures with the human PBTK model suggested that at concentration corresponding to their respective exposure limit values (TOL: 50 ppm; HEX: 50 ppm) coexposure during 7 hours would result in only slight effects on their respective kinetics. This study showed 1) that exposure indicators such as the blood concentration of unchanged TOL and HEX or the amount of their respective urinary metabolite(s) are not equally sensitive to the occurrence of a metabolic interaction and, 2) that such difference of sensitivity can be predicted a priori using a PBTK modeling approach.
引用
收藏
页码:95 / 103
页数:9
相关论文
共 26 条
[1]   Metabolic interaction between toluene, trichloroethylene and n-hexane in humans [J].
Baelum, J ;
Molhave, L ;
Hansen, SH ;
Vaeth, M .
SCANDINAVIAN JOURNAL OF WORK ENVIRONMENT & HEALTH, 1998, 24 (01) :30-37
[2]  
BAELUM J, 1985, ANN AM C IND HYG, V12, P305
[3]  
CHARESTTARDIF G, IN PRESS TOXICOLOGIC
[4]   Metabolism of n-hexane by rat liver and extrahepatic tissues and the effect of cytochrome P-450 inducers [J].
Crosbie, SJ ;
Blain, PG ;
Williams, FM .
HUMAN & EXPERIMENTAL TOXICOLOGY, 1997, 16 (03) :131-137
[5]  
ELLENHORN MJ, 1988, MED TOXICOL, P959
[6]   PARTITION-COEFFICIENTS OF LOW-MOLECULAR-WEIGHT VOLATILE CHEMICALS IN VARIOUS LIQUIDS AND TISSUES [J].
GARGAS, ML ;
BURGESS, RJ ;
VOISARD, DE ;
CASON, GH ;
ANDERSEN, ME .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 1989, 98 (01) :87-99
[7]   CHANGES OF NORMAL-HEXANE METABOLITES IN URINE OF RATS EXPOSED TO VARIOUS CONCENTRATIONS OF NORMAL-HEXANE AND TO ITS MIXTURE WITH TOLUENE OR MEK [J].
IWATA, M ;
TAKEUCHI, Y ;
HISANAGA, N ;
ONO, Y .
INTERNATIONAL ARCHIVES OF OCCUPATIONAL AND ENVIRONMENTAL HEALTH, 1983, 53 (01) :1-8
[8]  
Kaneko T., 1991, YAMANASHI MED J, V6, P127
[9]   Cytochrome P450 isozymes responsible for the metabolism of toluene and styrene in human liver microsomes [J].
Kim, H ;
Wang, RS ;
Elovaara, E ;
Raunio, H ;
Pelkonen, O ;
Aoyama, T ;
Vainio, H ;
Nakajima, T .
XENOBIOTICA, 1997, 27 (07) :657-665
[10]   INDUCTION OF CYTOCHROME-P450 ISOZYMES BY SIMULTANEOUS INHALATION EXPOSURE OF HENS TO N-HEXANE AND METHYL ISOBUTYL KETONE (MIBK) [J].
LAPADULA, DM ;
HABIG, C ;
GUPTA, RP ;
ABOUDONIA, MB .
BIOCHEMICAL PHARMACOLOGY, 1991, 41 (6-7) :877-883