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The Role of Trace Metals in Chemical Carcinogenesis: Asbestos Cancers

Consumer Protection and Environmental Health Service, Environmental Control Administration, Bureau of Occupational Safety and Health, USPHS, HEW, 1014 Broadway, Cincinnati, Ohio 45202

Evidence is presented in support of the hypothesis that, in the induction of asbestos cancer, trace metals play an active role; asbestos, a passive role as a metal carrier; and benzpyrene (BP) (or related polycyclic aromatic hydrocarbons) derived from the environment, a critical mediating role. In this hypothesis, the major determinant for carcinogenesis is the residence time of the unmetabolized BP in the lung. With unmetabolized BP as the carcinogen, any action (e.g., trace-metal inactivation) that slows metabolism increases residence time and, consequently, the carcinogenic risk.

By an in vitro procedure that utilized the microsomal fraction of homogenates of rat lungs to which a series of increasing concentrations of metals had been added, we found that metals in trace quantities can stimulate or inhibit the activity of BP hydroxylase. Activation or inhibition of this activity occurred, depending on the relative concentration of the metal added to the microsomal fraction.

All metals did not show the same activity pattern. Copper (Cu²⁺), magnesium (Mg²⁺), iron (Fe²⁺), zinc (Zn²⁺), nickel (Ni²⁺), and cobalt (Co²⁺) stimulated the BP hydroxylase enzyme significantly at low concentrations, as well as inhibiting the enzyme at higher concentration. Beryllium (Be²⁺), iron (Fe³⁺), and chromium (Cr⁶⁺) significantly inhibited the enzyme. No effect on the BP hydroxylase enzyme was demonstrable with arsenic (As³⁺), selenium (Se⁴⁺), and chromium (Cr³⁺). When the trace metals were extracted from chrysotile asbestos, and they were added to enzyme reaction mixtures, the enzyme activity was inhibited by approximately 73%. This inhibition of BP hydroxylase by the trace metals contained in chrysotile suggests that chrysotile has the potential of interfering with the detoxication of benzpyrene and thereby could contribute to carcinogenesis.

Further support is given the hypothesis by the independent finding of Selikoff that lung cancer occurs 3 times more frequently in asbestos workers who smoke; the decrease in lung BP hydroxylase, as well as copper, magnesium, and zinc with age; and the finding that patients with lung cancer had minimal activity levels of BP hydroxylase.

Received 11/19/68. Accepted 10/16/69.