Cancer and Mutations
While the Tox Tutor focuses on the clinical stages, lets look at cancer at the sub-cellular level.
The nucleus of the cell has long strands of genetic material called DNA. These strands of DNA have only 4 main types of units, G, C, T, and A, but these four units are attached one to the other for millions of units. The order of these units determine what proteins the cell can make, and by controlling these proteins, DNA determines each cell's operation. All the somatic cells of the body have the same DNA, but the DNA is arranged within the cell so that only certain portions of the DNA are available at any given time. Cells will have very different functions, despite all having the same basic genetic program.
You can go back to Tox Tutor and look at basic cell physiology again. Here I'm going to simplify a great deal in order to make a few points that apply to risk assessment of chemicals that cause cancer.
The C, G, T, and A's are arranged in pairs, G with C and T with A. Each of these units has the same sugar and phosphate, but each has a characteristic "nitrogenous base" attached to a sugar molecule. These bases are toward the center of the molecule, and loosely bond with each other, but only if it is the "correct" base. The cartoon above shows some different configurations of the A, T, C, or G as block.
The bases all have nitrogen atoms in their molecular structure and three have oxygen as well. The nitrogen has an unbonded pair of electrons that is not very busy. If a molecule that was an "electrophile," that is, it craved electrons, wandered into the region of the nitrogenous bases, a chemical bond can form. If the intruder chemical becomes bonded, is called an adduct. It is not a coincidence that almost all of the (genotoxic) carcinogenic chemicals are electrophiles or are altered by the activation process into electrophiles.
Once an adduct is present, the cell can do several things with it. It might do nothing and the adduct will remain there harmlessly for the rest of the cell's life. Second, it might remain and somehow kill the cell or interfere with the cell's function. Neither is likely because in any given cell the vast majority of the DNA is not doing very much. Even if the cell died, it is likely just one of millions of cells performing the same function, so it's no big deal. If the adduct is in an active portion of the DNA, the cell is most likely to repair the DNA. Cells have several different mechanisms to repair DNA, either by removing the adduct or removing the entire patch of DNA.
If the adduct were not repaired and the cell was called upon to replicate, that is make two identical daughter cells, the adduct might cause the replication process to make a mistake. For example, if the cell was to put an A or T opposite a G, the genetic program of the daughter cells would be altered. (There was a newspeak movement to change the term "daughter" to "progeny" but it never caught on.) This fundamental change in the sequence of DNA in one of the daughter cells is called a mutation. Now what happens? Again, probably nothing. The vast majority of DNA is not functioning in the cell, so the mutation would not matter. Also, the altered pattern might still make the same protein output, because some of the sequences are redundant. Finally, the code might alter the protein, but often these rearrangements of the protein do not matter either.
However some of these mutations might matter a great deal. By altering certain proteins in certain way, it is possible for the cells replication machinery that is normally in tight control to some how slip out of control. This out-of-control replication is the sine qua non of cancer. Studies with colon cancer and other studies have indicated that it takes 6 to 8 key mutations to produce cancer. These events or "hits" at at the DNA level are what causes cancer. At the cellular level it does not matter how the hits happened, if they were caused by one chemical or several, or when they happened. (Besides chemical adducts, radiation, viruses and other agents might cause mutations as well).
A mutagen is a chemical that causes mutations. There are many in vitro tests of mutagenicity. There are many chemicals that cause mutations under these tests, but do not cause cancer in animal tests. A mutagen is not the same as a carcinogen, but all mutagens are suspect. Mutagen tests are very cheap compared with whole animal testing.
Now you know why the incidence of cancer increases with age. The mutations build up over the years. You also know why the averaging time for carcinogens is over a life time, the mutations could come at any time and be carried along through a lifetime.
In the table above you notice that it indicates a "promotion" phase that is not associated with mutations. A cell must go through a replication cycle with an unrepaired adduct (or other DNA damage) in order produce a mutation. Hence any substance that increased the rate of cell replication might promote the formation of mutations. There is a class of carcinogens called "epigenetic carcinogens" that seem to work by stimulating cell replication. Some of these are termed "cancer promoters" as opposed to the electrophilic chemicals that are referred to as "initiators." There are some carcinogens that are both initiators and promoters, these are sometimes called "complete carcinogens." Cigarette smoke is a complete carcinogen. Also there are some chemicals that act as promoters but do not themselves cause cancer.
In the past, the U.S. EPA and some other major health authorities have noted the above and advised that there is no threshold for carcinogens. The EPA and others have since backed up and today acknowledge that there may be threshold. The rational is that if a chemical or exposure is capable of causing a mutation, that mutation will add to the burden of mutations from other sources and thus increase the exposed individual's chances of cancer. More on the NEXT page.