Characterization of spontaneous and chemically induced cardiac lesions in rodent model systems: the national toxicology program experience

Induction of heart disease can be related to exposure to a number of agents, including environmental chemicals. Studies with laboratory rodents are commonly used to identify cardiotoxic agents and to investigate mechanisms of toxicity. This study was conducted to characterize spontaneous and chemically-induced rodent heart lesions. A retrospective light-microscopic evaluation was performed on the hearts of F344 rats and B6C3F1 mice from National Toxicology Program studies of six chemicals in which chemically-induced myocardial toxicity was present: oxymetholone, monochloroacetic acid, 3,3'-4,4'- tetrachoroazoxybenzene, diethanolamine, urethane, and methyl bromide. Two myocardial lesions were observed: cardiomyopathy (multifocal myofiber degeneration that could occur spontaneously or as a treatment effect) and degeneration (diffuse myofiber degeneration that was clearly related to treatment). Oxymetholone produced cardiotoxicity that was apparent as an increase in the incidence and average severity of cardiomyopathy. The remaining five chemicals produced degeneration, which appeared morphologically similar with each of the chemicals. Based on available information concerning possible mechanisms by which each of these chemicals may induce cardiotoxicity, this evaluation indicated it may be possible to place the chemicals into two main categories: (1) those that primarily affected the coronary vasculature with secondary effects on the myocardium (oxymetholone), and (2) those that had a direct toxic effect on the myocardial cells (the remaining five chemicals). Beyond this, however, light-microscopic findings did not indicate any specific mechanisms. Additional morphologic evaluations, such as electron microscopy or special histochemical or immunostains, may help identify specific subcellular sites of toxic damage, which in turn can indicate appropriate types of molecular mechanistic studies.