Pharmacokinetic factors and concentration-time threshold in m-dinitrobenzene-induced neurotoxicity

m-Dinitrobenzene is a multitarget toxicant. This study presents a concentra tion-time threshold model in m-dinitrobenzene (m-DNB)-induced neurotoxicity in F344 rats based on pharmacokinetic modeling and variable duration infus ions with neuropathological end points. Pharmacokinetic parameters for m-DN B were determined after giving a single i.v. dose of 10 mg/kg m-DNB. Time d ependency of the brain lesions was studied by either giving a single bolus i.v. dose of 30 mg/kg m-DNB or infusing this dose over 6, 12, or 24 h, or 2 , 4, 6, 8, or 14 days. The results show that the 6-day infusion, in which t he theoretical steady-state blood concentration was 2.0 mu M, caused brain damage, whereas the 8-and 14-day infusions, in which the steady-state blood concentrations were 1.5 and 0.8 mu M, respectively, did not induce apparen t brain damage. When this dose was infused over 6 h, the peak blood concent ration of m-DNB was 35 mu M and the time (T-m) for which m-DNB exceeded the 2-mu M concentration threshold was 18.8 h, but no brain damage was observe d. However, when the same total dosage was infused over periods of either 1 2 or 24 h, or 2, 4, or 6 days, the theoretical blood concentrations were fr om 21.9 to 2.0 mu M and the T-m was from 22.7 to 144 h, and brain damage wa s produced. Hence a T-m of 22.7 h was considered to be the time threshold f or m-DNB-induced brain damage. It is concluded that a high concentration al one does not result in m-DNB-induced neurotoxicity and that in addition to a concentration threshold, there also exists a time threshold. Both apparen tly need to be exceeded before neurotoxicity is seen. (C) 1999 Academic Pre ss.