Abstract
An allometric target organ dose model (TOD-Wb) 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-Wb model. Key words: Target organ dose model, allometric scaling, extrapolating human toxicity.
Highlights
Dose-response remains fundamental to quantitative assessment of human toxicity
To ascertain whether the TOD-Wb model is able to explain the variation observed in the measured values, it is applied to literature toxicity data by comparing the empirical-b values to the a priori-b values determined with the model; which uses known values of bi, br, bo, and bm obtained from literature or estimated using toxicity data
Using Microsoft Excel, the empirical-b values for each different route of entry and transport can be determined from the respective slopes [slope = br + bo(bm) - bi - 1] and compared to the a priori-b values determined from the model
Summary
Dose-response remains fundamental to quantitative assessment of human toxicity. The ability to identify toxicologically equivalent doses for human from different animal species is a challenge and the use of animal toxicity data sets remain essential to interspecies scaling. The two main current approaches to extrapolation of animal toxicity to human using (1) physiologically based pharmacokinetic (PBPk) model and (2) constant exponent allometric (Wb) model have been well recognized and applied. The micro-scale PBPk model is knowledge and computation intensive, requiring detailed physiological.
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