Thresholds derived from common measures in rat studies are predictive of liver tumorigenic chemicals

Abstract

We hypothesized that typical tissue and clinical chemistry (ClinChem) end points measured in rat toxicity studies exhibit chemical-independent biological thresholds beyond which cancer occurs. Using the rat in vivo TG-GATES study, 75 chemicals were examined across chemical-dose-time comparisons that could be linked to liver tumor outcomes. Thresholds for liver weight to body weight (LW/BW) and 21 serum ClinChem end points were defined as the maximum and minimum values for those exposures that did not lead to liver tumors in rats. Upper thresholds were identified for LW/BW (117%), aspartate aminotransferase (195%), alanine aminotransferase (141%), alkaline phosphatase (152%), and total bilirubin (115%), and lower thresholds were identified for phospholipids (82%), relative albumin (93%), total cholesterol (82%), and total protein (94%). Thresholds derived from the TG-GATES data set were consistent across other acute and subchronic rat studies. A training set of ClinChem and LW/BW thresholds derived from a 38 chemical training set from TG-GATES was predictive of liver tumor outcomes for a test set of 37 independent TG-GATES chemicals (91%). The thresholds were most predictive when applied to 7d treatments (98%). These findings provide support that biological thresholds for common end points in rodent studies can be used to predict chemical tumorigenic potential.