Competing Mechanistic Hypotheses of Acetaminophen-Induced Hepatotoxicity Challenged by Virtual Experiments
Mechanism diversity mimics diversity of toxicity among genetically different mouse strains (A) Total Dead Hepatocytes (out of a total of 168,000) are plotted 24 hours after simulated oral APAP dosing using 64 plausibly biomimetic variants of MGNZ-Mechanism. Examples of the configuration used are shown in Supporting S3 Fig. Each variant represents a virtual mouse strain. Based on reported variability between mice in the same experiment, we specified that mean toxicity measurements for any variant that was within 20% (a judgment call) of mean values from MGNZ experiments (shaded green) could be determined experimentally indistinguishable. Inserts: Mechanistic consequences of changes to configurations are brought into focus by comparing Deaths per Zone rather than totals. (B) Shown are mean necrosis scores (left axis; n = 3–4/strain) data from Harrill et al.  along with one of the 64 Mouse Analog variants from A selected as described in the text. Their identifying Mechanism variant numbers are listed at the top.