Gen means birth or origin, as in the book of Genesis, which explains the origin of the Earth; “Muta” means change; “terato” means monster; and “carcino” means crab. Thus, all three “gens”-are physical or chemical agents that cause or originate malformations.
Mutagens cause changes (mutations) in the genetic material of cells. Teratogens cause irreversible, deleterious structural malformations in fetuses. Some congenital malformations are so severe they result in grossly deformed fetuses. Carcinogens cause cancerous tumors with a characteristically crablike appearance.
Mutagens, teratogens and carcinogens are similar in that each causes some form of mutation. Congenital malformations can be caused by mutations, which may occur in the parent germ cell (sperm or ovum), in the resulting embryo (mutagenic effect), or in some cells of a fetus after development has begun (teratogenic effect). Mutations in somatic (body) cells can cause certain cancers (carcinogenic effect). One hypothesis for determining the etiology of chemically induced cancer involves the concept of somatic mutation, which is based on the fact that several chemicals capable of causing cancer in animals also are capable of causing mutations in microorganisms.
Mutagens. The most significant mutagenic event is transmission of heritable effects through germ cells to the next generation. Germ cells are comprised of complex structures called chromosomes. Chromosomes are composed of molecules of deoxyribonucleic acid (DNA) and are contained in cell nuclei. A gene is the smallest unit of a germ cell considered to carry a genetic message; one gene exists for each characteristic. Genes are linked together in long chains to form chromosomes.
When sufficient evidence establishes a causal connection between human exposure to a chemical and heritable genetic effects, the substance is classified as a mutagen. Mutations may occur either in somatic (body) cells or germ (reproductive) cells. Somatic mutations are inherited by other somatic cells formed from a changed cell, but they are not inherited by offspring of organisms in which a somatic mutation resides. Chemicals that can produce this type of mutation are referred to as “genotoxic.” Although these agents do not damage future generations, they may initiate a biochemical rampage in cells of an affected organism. The result is a cancerous growth.
Recent studies show chemicals can cause mutations by generating rapid cell division, or mitogenesis. “A dividing cell is much more at risk of mutating,” explains Bruce Ames, a research scientist at the University of California, Berkeley. “These mutations can transform normal cells into cancer cells.” Non-genotoxic, or epigenetic, chemicals generally cause mutations only when administered in enormous doses. The best example is saccharin.
Saccharin is a synthetic, non-caloric sweetener developed in the 1960s. Scientists administered saccharin to 200 mice for 13 months. The mice developed sarcomas and carcinomas. However, the dosage given the test animals is equivalent to the amount of saccharin ingested by a human consuming about 800 cans of saccharin-sweetened soda a day for life.
When given to a test animal in large enough quantities, genotoxic chemicals, such as formaldehyde, and non-genotoxic chemicals, such as saccharin, can trigger cell mutations. These chemicals may pose no risk in lower doses. This dose-response relationship determines a substance’s relative toxicity. This premise is central to the study of toxicology.
Mutations are not rare. Everyone normally carries some mutated cells. The causes, nature and significance of such mutations are not well understood and open to speculation. All organisms have certain biochemical repair mechanisms to protect against mutations. The process is complex, but, in the simplest terms, errors in the genetic code (DNA) are identified and corrected by the repair systems. The fact that everyone carries some mutated cells indicates such systems are not fail-safe.
Teratogens. Teratogens are agents that cause abnormalities in developing organisms in the womb. When a fetal abnormality is manifested in progeny, the infant is born with a congenital defect, anomaly or malformation. Congenital abnormalities also may result from other factors. Human congenital abnormalities may stem from diseases mothers may have during the first trimester of pregnancy, particularly such viral diseases as German measles (rubella).
Hereditary abnormalities result from mutation and are expressed in the offspring of those who carry the associated train in their genes. Such nutritional factors as vitamin deficiencies or excesses also can interfere with normal fetal development, and maternal age at the time of conception is related to congenital anomalies. Finally, such physical factors as ionizing radiation also may cause malformations. X-rays, for example, are potent mutagens and teratogens.
For a teratogenic agent to produce a congenital abnormality, the agent must contact the developing organism. In the case of ionizing radiation, an embryo or fetus must be in the path of radiation. On the other hand, viruses or chemicals must be able to cross the placental barrier. A teratogen causes a malformation when it reaches a fetus during the critical phase of gestation when organs are developing. In humans, this stage occurs during the first trimester of pregnancy. The type of abnormality caused depends on which organ system is most rapidly developing at the time of exposure.
Few chemicals are known to be human teratogens. Among these are certain anti-cancer drugs and thalidomide, a drug used to combat nausea during pregnancy. Thalidomide causes an aberration by interfering with the fetal development of limbs, resulting in the hands being directly appended to the body at the shoulder.
Carcinogens. Carcinogens can cause malignant tumors. However, a distinction between benign and malignant tumors is not always possible. Nevertheless, the mark of carcinogenicity is an increase in malignant tumors. For a chemical to be considered a human carcinogen under expected conditions of exposure, it also must be genotoxic.
Studies show that up to 90 percent of all mutagens are carcinogens. The theory that mutation sets the stage for cancer development is based on the fact that many mutagenic physical and chemical agents also are carcinogenic. Mutations giving rise to cancer usually occur in somatic cells. If a change caused by such mutations is minor, it probably never will be discovered. However, if there is a major change, the cell may die.
If a mutated cells does not die but divides, and other similarly mutated cells are present, the cells may group together to form a benign or malignant tumor. Cancer experts generally agree that a minimum number of cells in close proximity must undergo mutation before a tumor can form.
Epigenetic chemicals, a second major category of carcinogens, may increase the mutation rate by some mechanism other than genetic-tissue or cellular damage. Saccharin is one example.
Mutagenic studies. Mutagens, teratogens and carcinogens are agents that cause chronic toxicity, the ability to cause illness or death after related exposures to low doses or after a latency period. For example, asbestos may cause mesothelioma, lung cancer or asbestosis; but these diseases typically are not manifested for 20 or more years after initial exposure and may never occur.
Because no single test can adequately predict mutagenic risk for humans, batteries of tests are run to evaluate the potential mutagenicity of chemicals. Mutagenicity studies employ a variety of other mammals, as well as animal tissues, insects or other lower animal forms, plants or microorganisms.
The most widely used mutagenicity test for preliminary screening of chemicals is the Ames test, named for its developer, Brice Ames. Used in more than 3,000 laboratories worldwide, it involves exposing bacterial cultures to suspect chemicals, then checking for mutations. More potent mutagens cause a higher incidence of change in the genetic material. The Ames test has unmasked a variety of potential carcinogens. However, relatively little is yet known about the “gen family.”
References
Alice M. Ottoboni, The Dose Makes the Poison. Berkeley, Calif.: Vincent Books, 1986.
Fifth Annual Report on Carcinogens. Research Triangle Park, NC: U.S. Department of Health and Human Services, 1989.
Woods, Michael, “A Lethal dose: How Must Is Safe?” The Toledo Blade, Dec. 17, 1990, p. 12.