Target organ dose model for extrapolating animal toxicity data to human

抄録

An allometric (W^b) target organ dose model (TOD) with variable scaling exponent, b = br + (bo)(bm) – bi, is proposed for the extrapolation of animal toxicity to human. Instead of existing constant scaling exponent, this model takes into account associated chemical pathway interactions and incorporates components such as intake to entry organ (bi), route of transportation to target organ (br), mass of target organ (bo) and rate of metabolism at target organ (bm). This expression enables the a priori determination of b from known values of bi, br, bo, and bm. For forced intake [such as intragastric (ig), intraperitoneal (ip), intravenous (iv) or subcutaneous (sc) injections], bi = 0. Fitting toxicity data of nipradilol (target organ: respiratory system) yields br values of (1) 0.15 for ig; (2) 0.26 for ip; (3) 0.03 for iv; (4) 0.61 for sc and (5) 0.07 for absorption of systemic gases in the pulmonary region. With the values of br given herein and those of bi, br and bo from literature, the exponent b can be determined a priori and they compared well with those obtained from regression analysis of reported animal data; with student projects reporting model-b (a priori determined) and regression-b (from data) for CO, HCN or H₂S as 0.07 and 0.08; for HF as 0.33 and 0.28; for HCl as 0.33 and 0.33; for NH₃ as 0.33 and 0.16; for Cl₂ as 0.33 and 0.34; for monomethyl hydrazine as -0.043 and -0.045; and for the nerve gases as -0.155 and -0.179.