DEVELOPMENT OF A MECHANISM-BASED DOSIMETRY MODEL FOR 2,4,4-TRIMETHYL-2-PENTANOL-INDUCED ALPHA-2U-GLOBULIN NEPHROPATHY IN MALE FISCHER-344 RATS

A mechanism-based dosimetry model was developed to describe 2,4,4-trim ethyl-2-pentanol (TMP-2-OH) dosimetry and renal alpha 2u-globulin (alp ha 2u) nephropathy in the male Fischer 344 rat. Experimental data were collected to estimate the chemical-specific parameters (metabolic con stants, tissue solubility, and oral absorption rate) necessary to desc ribe TMP-2-OH dosimetry in male rats. The concentrations of alpha 2u a nd TMP-2-OH were measured in male rats up to 64 hr after a single oral dose of TMP-2-OH (6, 60, or 600 mg/kg). The model predicted the time course behavior of TMP-2-OH and alpha 2u in the kidney, but overestima ted their renal concentrations by two or threefold. Simulations of ren al alpha 2u concentration were sensitive to changes in TMP-2-OH-alpha 2u-binding affinity and degradation rate of the TMP-2-OH-protein compl ex. In contrast, simulation of the concentration of TMP-2-OH in the ki dney was most sensitive to the amount of protein present. Oral absorpt ion of TMP-2-OH was dose dependent. The model predicted that alpha 2u and TMP-2-OH concentration in the kidney is sensitive to changes in th e rate of TMP-2-OH absorbed after oral administration. This model perm itted a more rigorous evaluation than has previously been possible of the combination of protein characteristics and chemical dosimetry requ ired for the accumulation of alpha 2u in the kidney of male rats. The behavior of the model is consistent with the qualitative aspects of th e alpha 2u hypothesis. However, further characterization of alpha 2u d istribution and renal hydrolysis will be required in order to fully ch aracterize the hypothesis at the quantitative level. (C) 1995 Society of Toxicology.