Metals must act intracellularly if any interaction or equilibration with nucleic acids or enzymes is to take place. Carcinogens too must exert their influence on a cellular level. Most carcinogenic hydrocarbons, azo dyes, or aromatic amines are sufficiently lipid-soluble to cross cell membranes, but how do metals penetrate these cell walls? By themselves, metals are unable to get into cells; they may be transported, however, as part of a chelate system. It is not yet known if a 1:1 or 1:2 metal: chelating agent is the more active form. Figure 3 shows pictorially how this process may come about.

For example, let us assume that the lipid-soluble carcinogenic chelating agent is able to penetrate the cell wall, bringing with it an abnormal metal which has been concentrated in that specific organ over a period of years. Within the cell an equilibration takes place between the chelating agent, Mg++, or Ca++, which may be interdependent, and the abnormal metal ion. The result is a mixture of free ions and complexed compounds. If the concentration (not total amounts) of magnesium ion is lowered beyond a threshold value with an insufficient amount being thus available for nucleic acid synthesis, and if the concentration of abnormal ion is sufficiently high, it is then possible that the abnormal metal may take the place of some magnesium in the lattice. This may result in an abnormal matrix.

Fig. 3. Transport of Metals Into Cells via Chelates

The replacing ion must be similar in size and shape to the essential trace element,* and must be more tenaciously held by the chelating agent. Zinc and magnesium both have coordination numbers of four, and both form tetrahedral complexes. The atomic radii of Mg and Zn are 0.65 A and 0.74 A respectively as bivalent. Calculated as univalent these values are now 0.82 A and 0.88 A. Thus it may be possible for one to replace the other. Two other similar metals are copper and nickel; both show coordination numbers of four and are square coplanar in configuration.

Nucleic acids which complex certain metals may also complex others if the binding conditions are met. A chelate may also combine with the nucleic acid (CVI). This may result in the new metal's influencing the formation of an altered "genetic recombinant." The mitotic apparatus can only reproduce that which is given to it, and thus the changed units are constantly resynthesized. The enzymes normally within the cells cannot function to prevent the formation of altered nucleic acid, and once these new units are made they cannot be degraded rapidly enough by the enzymes. The result is cancer.

The various "theories" of carcinogenesis can, in part, be explained by this postulation.

* A word of caution is important here. Most data for atomic radii of elements given in biological publications are taken from only one reference source, which uses crystallographic data based upon the assumption that the ions are spheres. Other values obtained differ, depending upon the physical state of the compound being measured. From crystals the atomic radius of Zn++ is given as 0.74 A; from vapor phase data the value is 0.62 A. Most ions under biological conditions are hydrated ions. These radii values may be of a completely different order of magnitude. For example, the K- crystal radius is 1.33 A; in water at 25° it is 1.20 A uncorrected, in water corrected 2.32 A, in methanol 2.78 A, in ethanol 3.45 A, in acetone 3.10 A. For biological studies, data on hydrated ions should be used for comparison.