Non-linear pharmacokinetic parameters need to be considered in high dose/low dose extrapolation.

It is impossible to prove that any chemical, natural or man-made, cannot cause cancer in man. However, it is possible to estimate the relative degrees of risk associated with various agents. The precision of these estimations increases as experimental procedures elucidate the basic type of mechanism associated with carcinogenesis, the role of absorption, metabolism and distribution, and excretion in increasing or decreasing activity, and the dose dependency of metabolic pathways. We must constantly strive to make the most accurate risk estimations possible so that the complex issues of risk/benefit may be properly considered.