Citation:

Corton, Jon, K. Korunes, J. Abedini, H. El-Masri, J. Brown, K. Friedman, Y. Liu, C. Martini, S. He, AND J. Rooney. Thresholds Derived from Common Measures in Rat Studies are Predictive of Liver Tumorigenic Chemicals. TOXICOLOGIC PATHOLOGY. Society of Toxicology, RESTON, VA, 48(7):857-874, (2020). https://doi.org/10.1177/0192623320960412

Impact/Purpose:

There is very little known about the potential for most chemicals currently in use to cause cancer in humans. These include over 140,000 substances registered by REACH (REACH, 2008), ~ 30,000 chemicals in widespread commercial use in the United States and Canada (Muir and Howard, 2006), and over 75,000 chemicals on the US EPA's Toxic Substances Control Act Inventory (USEPA, 2004). Determining the human carcinogenic potential of these chemicals remains a formidable challenge that relies primarily upon the 2-year rodent bioassay as the “gold-standard” to identify carcinogens. Only ∼1,500 chemicals in commercial use have been evaluated by the 2-year bioassay, due to the considerable resource expenditures required to assess a chemical in this manner (>800 rodents, histopathological analysis of more than 40 tissues, ~$2–4M USD) (Bucher and Portier, 2004, Gold et al., 2005, Waters et al., 2010). Further, the use of animal bioassay data for prediction of human cancer potential remains complex due to interspecies differences (Gottman et al 2001, Gold et al 1989, Haseman 2000) as well as the reproducibility of animal study results even in the most controlled conditions. This situation demands new, resource-efficient methods that identify the carcinogenic potential of environmental chemicals and pharmaceuticals in short-term exposures as well as methods that determine dose and exposure boundaries of human-relevant risk. A central premise of the AOP framework is that key events are required but not sufficient at a qualitative level to produce an AO. Progression beyond a MIE or KE depends on the level of molecular or cellular perturbation that can then propagate the chemical effects toward the AO (Conolly et al., 2017). This idea has led to increased interest in quantitative effect thresholds, or “molecular tipping points,” as a basis for adversity determinations using short-term data (Knudsen et al., 2015, Hill et al., 2017). A biological or effect threshold is one that is chemical-independent within a particular model system. It defines, for example, the level of receptor activation that may be needed for cancer to occur. This concept is critical for risk assessment, because thresholds would prescribe chemical-agnostic hazard levels that enable predictive evaluations using an AOP construct. While there are numerous examples of KE relationships within individual AOPs (Wittwehr et al., 2017, Edwards et al., 2016), neither the concept of chemical-independent biological thresholds or its application to AOPs have been widely investigated within toxicological or pharmacological sciences. In a previous study, we identified chemical-independent thresholds for gene expression biomarkers that predict activation of 6 of the major MIEs that lead to liver cancer in rodents. We found that these thresholds can be used to accurately predict liver cancer (Corton et al., 2019). In the present study, we hypothesized that many of the routine measures of a typical short-term rat exposure study also have chemical-independent thresholds beyond which tumors occur. To test this hypothesis, we examined LW/BW and ClinChem endpoints in a number of publicly-available databases including TG-GATEs, DrugMatrix, ToxRefDB, and National Toxicology Program (NTP) findings in Chemical Effects in Biological Systems (CEBS) at chemical doses with known liver tumor outcomes in 2-year bioassays. We found that many of the cc markers as well as LW/BW changes have measurable thresholds that are chemical- and study-independent. Furthermore, we found that these thresholds can be used to identify doses of chemicals predicted to cause liver tumors in long-term studies.

Description:

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.

URLs/Downloads:

Record Details: