Environment Industrial

Based predominately on epidemiological studies, only a small number of chemicals have been identified definitively as human carcinogens. For the most part, individuals exposed to high concentrations of these particular chemicals have exhibited an unusually high incidence of a specific tumor. There is increasing evidence that human cancers are causally associated with mutations in somatic cells. In vitro studies have shown that many of these chemicals form covalent adducts on DNA that alter DNA’s base-pairing properties. If these DNA modifications are not repaired, the altered DNA is copied at the time of cell replication, leading to misincorporations that produce mutagenesis (Loeb, 1989).  Included in the catalogue of human carcinogens are a number of metals that are ubiquitously present in our environment (Sunderman, 1986).  These metals form weak interactions with DNA and there is evidence that damage to DNA by transition metals is mediated by the generation of oxygen free radicals.  In this manuscript we will first summarize current concepts on the etiology of cancer by environmental agents and then consider in some detail the types of mutations caused by metal-generated oxygen free radicals.

In considering the spectrum of environmental agents that are classified as human carcinogens it is obvious that tobacco smoke is the most significant.  In the United States, cigarette smoking is responsible for some 30% to 40 of cancer deaths (Loeb et al., 1984) Cancer of the lung as a result of cigarette smoking is epidemic.  Until recently, the incidence of death from cancer of the lung in U.S. males had risen progressively for over forty years.  In the last ten years, the prevalence of cigarette smoking among males in the United States has declined from a high of 50% in 1965 to the current level of less than 30%.  As a result, after forty years of relentless increase in male lung cancer deaths, the rate has plateaued; in the 45-55 year old range there has been a significant decrease Figure 1. Unfortunately, the prevalence of smoking has not decreased among American females and currently cancer of the lung outranks cancer of the breast as the leading cancer-related cause of death in women in the United States.  In emerging industrialized countries, such as Thailand, the incidence of tobacco smoking is rapidly increasing.  If the experience in the United States is of any prognostic value, the lung cancer rate in Thailand will rapidly accelerate and lung cancer will soon become one of the leading causes of death.  Hopefully, Thailand can use the experience of the United States to curtail this epidemic.

Mutations and Cancer

A current model linking DNA damage to mutagenesis and carcinogenesis is presented with Figure 2.  In this model, random mutations result from DNA polymerase errors opposite unrepaired DNA damage.  Mutations found in key genes program changes in cells and initiate the carcinogenic process. These genes include oncogenes as well as genes involved in the maintenance of DNA replication fidelity (Loeb, L.A., 1989), and chromosomal segregation (Hartwell and Weinert, 1989).  DNA damage occurring in cells that do not divide, such as neurons, cannot be propagated to successive generations and thus is not associated with malignancy.  Also mutations do not result from an error-free DNA repair or from unrepaired DNA damage tat is copied during cell replication without a change in sequence.  A major factor linking DNA damage to mutagenesis is the copying of damaged DNA by DNA polymerases during each cell division cycle; DNA polymerases copy past the damaged DNA and insert non-complementary nucleotides opposite the site of damage.  In prokaryotes, SPS error prone DNA repair synthesis (Walker, 1984) can be induced by DNA damage, possibly to facilitate replication past DNA lesions, but it is uncertain whether such a response exists in human cells.  A few of the randomly distributed mutations would be in key genes that alter the growth properties of cells, allowing them to escape homeostatic mechanisms that regulate cell division and mutations in genes that might promote metastasis.  In this scheme, any process that increases the likelihood of division in cells containing DNA damage would also increase the likelihood of mutations and malignancy.  Stimuli for cell division could include increases in autocrine and paracrine growth factors, viruses, and regenerative stimuli brought about simply by the death of adjacent cells and tissues.  This model links unrepaired DNA damage to increased cell replication as causative factors in human cancer.