Abstract

An allometric target organ dose model (TOD-W^b) with variable scaling exponent, b = br + bo(bm) - bi, is proposed for the extrapolation of animal toxicity to human. The exponent b comprises four constituent parameters representing the intake mode 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. From nipradilol that target the respiratory system, the br values determined for intragastric (ig), intraperitoneal (ip), intravenous (iv), and subcutaneous (sc) injections were 0.15, 0.26, 0.03, and 0.61, respectively; from HF mouth breathing data, the br value is 0.07 for pulmonary absorption through inhalation (ih); and from actinomycin D data that target bone marrow through the ip-route, the bo value is 0.53. The model is tested with the parameter values obtained from literature; validating the a priori values determined in this paper with the empirical values measured. For ip-administration of OMPA and parathion, the a priori [3/4(bo) - 1] value and empirical value are -0.475 and -0.48; for nine alkylating agents, the values are -0.60 and -0.61; for ig-administration of NaCN, the [br + 3/4(bo) - 1] and empirical values are -0.1 and -0.092, respectively. The analysis of toxic gas inhalation data in student projects are also summarized herein. Consequently, values of these parameters can also be estimated by fitting known toxicity data to the TOD-W^b model.

Key words: Target organ dose model, allometric scaling, extrapolating human toxicity.