What are carcinogens?

Chemicals and cancer: Certain chemicals are capable of causing cells in an organ of the body to grow uncontrollably. As early as a century ago, scientists knew of malignant growths produced by exposure to particular chemicals. The National Toxicology Program (NTP) produces a biennial Report on Carcinogens (RoC), which deals with carcinogenic compounds in humans, potential human exposure to these substances, and federal regulations of exposure limits to the chemicals. The introduction to the report defines a known carcinogen as a chemical for which there is sufficient evidence indicating a causal relationship between exposure and human cancer.

Definitive data on carcinogenicity is difficult to obtain, because there often is a need for multiple exposures to the substance and a long induction period before a tumor appears. Genetics, lifestyle, and ethnic factors are also important in the development of certain tumors. The National Toxicology Program employs a variety of approaches but considers two-year studies in rodents to be its primary method of determining what substances are carcinogens.

Development of cancer: Cancers seem to develop in stages showing substantial overlap and not progressing uniformly. Much research on the initiation stage has been devoted to the study of changes in deoxyribonucleic acid (DNA). Many carcinogenic chemicals have been shown to cause mutations. Bonding to a strand of DNA produces a mutation that might be replicated before it can be repaired. Such an error might be passed along to future generations. Most such mutations do not affect the cell, but if a protein associated with growth is involved, it might create the potential for future rapid cell growth. It is also believed that reactions between potential carcinogens and DNA do not occur in a random process but rather in the production of genes.

The way in which the promotion stage of cancer development proceeds is still obscure, but the nature of promoting substances provides clues. These compounds are believed to stimulate the production of multiple benign tumors. Their effect is reversible; with their withdrawal, the tumor disappears. They are, however, not able to produce the cancer by themselves.

At some point in the progression stage, another genetic change occurs that results in a selective growth advantage for the mutant cell. There are several ways in which such an event might take place: additional exposures to the original carcinogen, spontaneous mutation from replication enzymes, or changes in the genes caused by initiating mutations. The result is an irreversible change in the cell.

The malignant conversion stage produces a distinct growth advantage for the affected cell. There is evidence from rodent studies that genetics is an important factor in these late-stage changes as well as in the early development of the cancer. Experiments reveal protein synthesis, amplification of gene creation, and further DNA reactions at this stage in the tumor cell.

Testing for carcinogens: In testing to determine whether a substance is a carcinogen, scientists use animal testing and also test for mutagens, relying on the fact that nearly all carcinogenic molecules also produce mutations. However, there are significant problems involved. A direct effort along this line involves seeking a lethal mutation involving the X chromosome, which determines the sex of the offspring.

The realization that intermediate products from detoxification may be the cause of the initiation phase of cancer development has led to the development of tests involving bacteria and enzymes. These procedures greatly reduced cost (one-thousandth as much as mice) and time (two days compared with at least a year). It has become possible to test all new compounds for mutations and to conduct animal tests only on those showing positive results. All these approaches are actively being used by the National Toxicology Program.

Achieving a balance: Although carcinogenic chemicals are of concern, it is important to recognize the actual risk. Extensive studies conducted by the National Toxicology Program and the International Agency for Research in Cancer (IARC) show that only one-third of suspected chemicals are actually carcinogenic. Approximately 96 percent of human cancer results from naturally occurring carcinogens.

Intense study of such carcinogenic compounds shows that 95 percent involve only three types of chemicals:

• Alkylating agents: Transfer small fragments (CH3) to DNA





• Arylkylating agents: Transfer aromatic rings (C6H5) to DNA





• Arylhydroxylamines: Transfer amines, containing NH2, to DNA.

A common aspect of these materials is their ability to produce structures that have a deficiency of electrons. Such structures react rapidly with the electron-rich oxygen, sulfur, and nitrogen atoms of nucleic acids.

Perantoni, Alan O. “Carcinogenesis.” In The Biological Basis of Cancer, edited by Robert G. McKinnell et al. New York: Cambridge University Press, 1998.

Ruddon, Raymond W. “Causes of Cancer.” In Cancer Biology. 4th ed. New York: Oxford University Press, 2007.

Tomatis, Lorenzo, and James Huff. “Evolution of Research in Cancer Etiology.” In The Molecular Basis of Human Cancer, edited by William B. Coleman and Gregory T. Tsongalis. Totowa, N.J.: Humana Press, 2002.

U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program. Eleventh Report on Carcinogens. Research Triangle Park, N.C.: Author, 2005.

Yuspa, Stuart H., and Peter G. Shields. “Etiology of Cancer: Chemical Factors.” In Cancer: Principles and Practice of Oncology, edited by Vincent T. DeVita, Jr., et al. 6th ed. Philadelphia: Lippincott Williams & Wilkins, 2001.