Those researching the cancer problem will be practicing a dramatically different type of science than we have experience over the past 25 years. Surely much of this change will be apparent at the technical level. But ultimately, the more fundamental change will be conceptual.1

Mesmerized by the dazzling advances in biomedical research via molecular biology, all traditional disciplinary fields of biomedicine have been transformed by the techniques of molecular biology. Even the interdisciplinary field of toxicology, once driven by examining the toxic effects of chemicals at the whole animal, physiological or tissue levels, is being overtaken by molecular/biochemical studies of these toxic chemicals. While, in principle, these detailed studies have provided some useful insights, they have not fully provided the kinds of answers promised. Will the sequencing of the complete human genome answer the question as to how all diseases are caused, thereby giving us the correct sequence of DNA to prevent or cure the disease? In all likelihood, it will not for the reason that the higher organism, such as a rat or human being, is the result of a cybernetic interaction between a hierarchy of molecular, biochemical, organelle, cellular, tissue, organ, organ systems, having unique genetic components constantly interacting with environmental factors.2 In other words, the whole is greater than the sum of its parts. One's linear sequence of nucleotides in their DNA is only one part of one's state of health or disease.

The Hanahan and Weinberg quote is meant to focus on the main thesis of this short review of mechanisms of toxicity. The word toxicity or even the field of toxicology means different things to different investigators. Originally, toxicity meant something is capable having a poisonous effect on an organism and toxicology meant a science to understand the method by which a toxicant or toxin might bring about the poisonous effect. Early methods to study the toxicity of chemicals on animals (birth defects, cancer, reproductive, neurological, behavioral effects, etc.), while providing some useful information on lethal doses, biologically toxic doses, could not provide a mechanistic understanding of the causes of these whole animal effects. With the advent of more reductionalistic approaches, cell-free, in vitro, biochemical, and molecular approaches were introduced into the field of toxicology to the point where many studies have disconnected the molecular levels with the whole animal levels.

It might be argued that the recent introduction of transgenic and knockout, knock-in animals have reunited the reductionalistic approaches with the holistic approaches.

Again, there is some truth in this statement; however, philosophically and experimentally, more effort will be needed to make the connection. Recall the amazement when the predicted p53 knock-out mouse survived and did not live up to the prediction; because p53 was so vital to live, an organism not having this gene should not have survived. What is missing today in understanding the connection between the genetic information at the DNA level and the state of health or disease at the whole animal level is the complex interaction of the quality and quantity of that genetic information with the environmental factors at each level and how the different levels effects those above and below it.

The working hypothesis of this challenge to the prevailing paradigm which shapes most of the subdisciplinary fields of toxicology is that the modulation of GJIC can contribute to a common cellular mechanism to teratogenesis, carcinogenesis, atherogenesis, immunomodulation, and reproductive- and neurotoxicities.

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