Chemical carcinogenesis and toxicity models: Matching complexity to objectives

Abstract

Mathematical models predicting tissue doses of chemical toxicants can be either highly complex or simple, depending upon the end results needed. As an example of a highly complex mathematical model, the Miller Model of the distribution of reactive gases in human and animal lungs is described. The Miller Model accounts for the convection, the radial and axial diffusion, and the chemical reactions of gases as an inhaled breath passes down the airways. The geometry and physiology of human and animal lungs are used to calculate the convection and diffusion likely in each generation or bifurcating series of airways commencing with the trachea and extending 24 generations in humans. The chemical reactivity of ozone, an air pollutant, is accounted for by simulating second-order chemical reactions with the fluid lining materials of the lung and tissue biological molecules. The flux of ozone into three compartments (pulmonary tissue, overlying liquid layer and capillary blood) in each generation of the lung is calculated to provide molecular doses of ozone reaching each region of the lung. These results of calculated molecular dose are then used to construct dose-response curves for a variety of biological endpoints.

A much simpler model is also described which recognizes the saturable or Michaelis-Menten type of kinetics controlling the removal of nickelous ion (nickel) from the lung. This model is used to calculate the chronic lung burden of the human lung for occupational, environmental and cigarette smoking exposure scenarios.

In both the complex Miller Model and the simpler nickel lung burden model, the results can be used to calculate molecular doses at the potential site of action of these environmental chemicals and to unify a wide variety of studies. The predictions made are more likely to be valid since multiple investigators using a variety of animal species have participated in generation of the primary data. As a methodology, mathematical modeling based on physiological, physicochemical and anatomical principles provides a means of eliminating non-scientific considerations from the important process of regulating and recognizing toxic or cancer causing chemicals in the human environment.