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

m-Dinitrobenzene is a multitarget toxicant. This study presents a concentration-time threshold model in m-dinitrobenzene (m-DNB)-induced neurotoxicity in F344 rats based on pharmacokinetic modeling and variable duration infusions with neuropathological end points. Pharmacokinetic parameters for m-DNB were determined after giving a single i.v. dose of 10 mg/kg m-DNB. Time dependency 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 the theoretical steady-state blood concentration was 2.0 microM, caused brain damage, whereas the 8- and 14-day infusions, in which the steady-state blood concentrations were 1.5 and 0.8 microM, respectively, did not induce apparent brain damage. When this dose was infused over 6 h, the peak blood concentration of m-DNB was 35 microM and the time (T(m)) for which m-DNB exceeded the 2-microM concentration threshold was 18.8 h, but no brain damage was observed. However, when the same total dosage was infused over periods of either 12 or 24 h, or 2, 4, or 6 days, the theoretical blood concentrations were from 21.9 to 2.0 microM and the T(m) was from 22. 7 to 144 h, and brain damage was produced. Hence a T(m) of 22.7 h was considered to be the time threshold for m-DNB-induced brain damage. It is concluded that a high concentration alone does not result in m-DNB-induced neurotoxicity and that in addition to a concentration threshold, there also exists a time threshold. Both apparently need to be exceeded before neurotoxicity is seen.