A physiologically based pharmacokinetic (PB-PK) model for 1,2-dichlorobenzene linked to two possible parameters of toxicity.
A physiologically based pharmacokinetic (PB-PK) model was developed for 1,2-dichlorobenzene (1,2-DCB) for the rat. This model was adjusted for the human situation, using human in vitro parameters, including a Vmax and Km determined with human microsomes. For comparison, the Vmax and Km values from the rat were scaled allometrically to the human case. The model was used in two ways: (1) Acute hepatotoxicity was related to the amount of reactive metabolites (epoxides) formed in vitro. For rats, the hepatic concentration of epoxide metabolites in vivo after exposure to a toxic dose level (250 mg/kg bw) was predicted using in vitro parameters. For man, the dose level needed to obtain the same toxic liver concentration of reactive metabolites as in rat was predicted, assuming a concentration-effect relationship in the liver. It could be concluded that this concentration is not reached, even after induction of the oxidation step, due to saturation of metabolism and a concomitant accumulation of 1,2-DCB in fat. (2) Hepatotoxicity was related to depletion of glutathione (GSH) in the liver. In the model, the consumption of hepatic GSH by metabolism (based on in vivo and in vitro data) and normal turnover was described. In vivo validation was conducted by comparing the predictions of the model with the results of a GSH depletion study performed at two dose levels (50 and 250 mg/kg bw). Subsequently, the GSH consumption by 1,2-DCB metabolites was estimated for man using human in vitro metabolic data. GSH turnover in human liver was assumed to be the same as that in rat. It appeared that at a dose level of 250 mg/kg, hepatic GSH was completely depleted after 10 hr for man, whereas for the rat a maximum depletion of 75% was predicted, after 15 hr. The presented model provides a quantitative tool for evaluating human risk for two different toxicity scenarios, namely covalent binding of reactive metabolites and depletion of GSH.
Hissink
A M
AM
Toxicology Division, TNO Nutrition and Food Research Institute, Zeist, The Netherlands.
Van Ommen
B
B
Krüse
J
J
Van Bladeren
P J
PJ
D000284:Administration, Oral; D000818:Animals; D002722:Chlorobenzenes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007306:Insecticides / Q000493:pharmacokinetics / Q000633:toxicity; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D008954:Models, Biological; D051381:Rats; D017208:Rats, Wistar; D018570:Risk Assessment
D002722:Chlorobenzenes; D007306:Insecticides; C004726:2-dichlorobenzene; D005978:Glutathione