Carcinogenesis

Cancer is "possibly the most dreaded toxic event and probably the hardest for which to provide reassuring safety precautions" (Williams and Burson, 1985). Normal cells respond to the presence of adjacent cells by ceasing to replicate. In cancer, the mechanisms limiting the growth of cells become damaged. The damaged cells grow uncontrollably, forming tissue masses called tumors (except in some cases, such as leukemia, the cancer of the white blood cells). This growth consumes the resources of the organism; impinges on nearby tissues, causing them to atrophy; and ultimately results in mortality. A great amount is understood about the causes and progresson of cancer, yet we are still far from having a complete understanding, or even from knowing enough to treat the disease effectively.

The Stages of Cancer Cancer progresses in distinct stages. The first step, which produces no symptoms, is a first mutation that predisposes the cell to cancer. This step is called initiation. In the second step, promotion, the first clinical manifestations begin with the formation of benign tumors. Finally, in progression, the tumors become malignant, which in turn can spread to other tissues to form secondary tumors. In the nomenclature of cancer, the suffix -oma is appended to a tissue name to denote a benign tumor; for example, hepatoma and osteoma are benign tumors of the liver and bone, respectively. Malignant tumors are described using either carcinoma or sarcoma, for mesothelial or epithelial tumors, respectively. Thus, names for the malignant tumors for liver and bone are hepatocellular carcinoma and osteosarcoma.

Benign tumors exhibit cellular differentiation and grow by expansion, causing adjacent tissues to atrophy. The tumor shows some differentiation and has a clear boundary. Benign tumor cells appear similar to normal cells under microscopic examination. Benign tumors are usually not fatal, except when they impinge on critical tissues such as in the brain. Brain tumors rarely become malignant because they are fatal before reaching that stage. Benign tumors do not inevitably progress to the next stage, although their clinical removal obviates that possibility.

Malignant tumors are undifferentiated. Instead of forming a discrete bounded structure as benign tumors do, they grow invasively into neighboring tissues. Malignant cells appear obviously deranged. They are capable of the process of metastasis, in which clumps of malignant cells migrate to other tissues through blood and lymph vessels, forming secondary tumors. This rapidly increases the growth of cancerous tissue and accelerates the progression of clinical symptoms, especially weakness, a large amount of weight loss, loss of various bodily functions, and pain.

What accounts for the observed stages of cancer? It is known that genetic damage is the root cause of cancer. The damage can be either mutations or aberrations. The latter include chromosome breakage, deletion of chromosome segments, or swapping of segments between chromosomes. Other evidence, however, suggested involvement of nongenotoxic agents. For example, when polynuclear aromatic hydrocarbons (PAHs) are applied to the skin of a mouse, cancer does not occur until followed by application of another chemical, such as phorbol esters from croton oil. It does not even matter if the second application is delayed for up to a year. Clearly, the PAH predisposes the skin cells to cancer, and the esters stimulate progression to other stages. Furthermore, the compounds that predispose were often found to be mutagenic, whereas the ones that only stimulate progression often were not.

Types of Carcinogens The knowledge that carcinogens act by different mechanisms led to a distinction in two types of carcinogens. The first type are called genotoxic carcinogens, which act either themselves or via metabolites to either damage DNA directly or impair the processes of repair or transcription. This is initiation, as defined above, and the chemicals are called initiators. Examples include nitrosamines, epoxides, and metals such as cadmium, chromium, or nickel. The direct-acting genotoxins are often electro-philic compounds that bind to DNA, similar to the action of mutagens. Others must be biotransformed to be genotoxic and are called precarcinogens. Most genotoxic environmental pollutants are in this category, including chlorinated hydrocarbons, aromatics such as benzene, and PAHs. The mechanism for carcinogenic metals, such as arsenic, chromium, and nickel, is not understood. They are thought to impair DNA replication or transcription by complexing with the DNA or associated proteins. Several nonchemical carcinogens act by changing the cellular DNA and therefore may be classified as geno-toxic. These include ionizing radiation and certain viruses.

The second type are called epigenetic carcinogens or promoters. They do not affect the DNA, but enhance the progression to cancer subsequent to initiation of genetic damage by the genotoxic carcinogen. Epigenetic carcinogens act by (1) encouraging cell division (promotion), (2) inhibiting intercellular communication, or (3) impeding mechanisms for destroying aberrant cells. Tobacco smoke contains both initiators and promoters.

Destruction of damaged cells is part of the function of the immune system, and immu-nosuppressant drugs used in organ transplants are known to cause cancer by inhibiting this function. One important group of pollutants that may act in this way is the dioxins. They seem not to be genotoxic, but are both strong promoters and highly immunosup-pressive. This is especially true for the form known as 2,3,7,8-tetrachlorodibenzodioxin (2,3,7,8-TCDD).

Intercellular communication normally helps limit cell growth. Cells send each other chemical signals that stop their division process when they are in contact. Cancer cells do not respond to these signals.

Many environmental pollutants are promoters, not initiators. Cell division can be stimulated a number of ways. Anything that kills or damages cells stimulates growth as part of the healing process. This can include chemical toxins which act by other means, and physical trauma such as burns, freezing, or possibly even mechanical injury. Even implanted foreign solid materials, such as asbestos, plastics, metal, and glass, can promote cancer. These are called solid-state carcinogens. A possible mechanism for this is that their presence stimulates fibrosis, connective tissue cell growth, as the organism attempts to encapsulate the foreign material. The more cell growth is stimulated, the greater the chance that any cell, previously initiated by a genotoxic carcinogen, will be activated; and the greater the chance of a transcription error causing an initiation.

Hormones are known to act as promoters. For example, estrogen administered to menopausal females increases the risk of endometrial cancer. The synthetic hormone diethylstilbestrol (DES) used to be given to pregnant women with high miscarriage risk to improve their chances of carrying the pregnancy to full term. Tragically, it has been found that daughters produced by those pregnancies are at a high risk of contracting cervical cancer in their late teens or early 20s. Testosterone, or more precisely its metabolite (dihydrotestosterone), promotes prostate cancer in men.

More important in an environmental context, many pollutants have been found to either mimic or influence hormones. The herbicide Amitrole (aminotriazole) inhibits an enzyme that uses iodine to form thyroxine. The pituitary responds to the low level of thyroxine by stimulating thyroid growth. This in turn, can lead to cancer of the thyroid.

A variety of anthropogenic compounds found in nature have been shown to mimic the hormone estrogen: xenoestrogens, endocrine disruptors, or environmental estrogens. These include the chlorinated pesticides atrazine, chlordane, DDT, endosulfan, kepone, and methoxychlor, as well as dioxins and some polychlorinated biphenyl (PCB) congeners. Several compounds associated with plastics are xenoestrogens as well: Bisphenol A is released by polycarbonates when heated. Nonylphenol is a softener for plastics used in packaging and in flexible plastic tubing. Phthalates are also plastic softeners that are commonly used in food packaging and which have been found in laboratory experiments to cause reproductive disorders.The xenoestrogenic properties of some of these materials were discovered when laboratory investigations were confounded by their presense. In one case, cultures of breast cancer cells grew more rapidly than expected because of contamination from laboratory plasticware. Possible xenoestrogenic effects have been observed in the environment as well. Male fish living near municipal sewer outlets were found to be producing a protein associated with females. Alligators hatched in Lake Apopka, Florida, following a spill of organochlorine insecticides had altered hormone levels and abnormally small penises.

Another type of epigenetic carcinogen is the cocarcinogens: These increase the concentration of an initiator by affecting absorption, biotransformation, or detoxification. For example, they may decrease detoxification by inhibiting enzymes or depleting detoxification substrates such as glutathione. Ferric oxide and asbestos may facilitate cellular uptake of genotoxics.

The distinction between genotoxic and epigenetic carcinogenesis may have significance in the risk assessment process. Specifically, the presence or absence of a toxic threshold, a level of exposure below which essentially no effect is found, may depend on the mechanism. This is discussed in Section 19.4.1.

Genetic Basis of Cancer A fairly detailed understanding of the causes of cancer progression is starting to emerge. Early in the twentieth century, the microscopic observation that tumors tended to have damaged chromosomes, plus the fact that susceptibility to some cancers could be inherited, led to the realization that genetic damage was the root cause of all cancers. In addition, the fact that daughters of a cancerous cell would continue to be cancerous if transplanted to another organism led to the one-hit hypothesis: Malignant cancer was caused by a single mutation to a critical gene.

Eventually, the one-hit hypothesis gave way to other facts. If a single gene caused cancer, and it was inherited, the cancer should develop immediately after birth. However, even in cases of inherited susceptibility, inception of cancer still takes some years. This implies that at least two changes are required, leading to the two-hit hypothesis. The fact that some cancers go through a series of stages with increasing virulence, and daughter cells from each stage maintain their characteristics when transplanted, imply that for such cancers even more than two mutations occur.

In recent years, the tools of genetic engineering have revealed many of the detailed steps involved for some cancers. The newer discoveries started with the examination of viruses that cause cancer. It was found that the viruses carried a mutated human gene that they inserted into the infected cell. The normal human gene was called a proto-oncogene, which is responsible for stimulating cell growth during gestation. Normally, this gene is turned off in adults. The proto-oncogene can be mutated into a more active form, called an oncogene. The oncogene sends growth signals despite the presence of signals that would tell other cells to stop. Thus, a single mutation is all that is necessary for the change to be expressed. This is called a dominant mutation or an activated mutation. Recall that a cell contains two copies of each gene. Only one mutation is necessary if the resulting gene produces a protein that causes the disease. However, although the presence of one or more oncogenes facilitates a cell's transformation into a cancer cell, by itself it is not potent enough to produce a malignancy.

Other genes, called tumor suppressor genes, code for proteins that inhibit cell replication. To produce cancer by damaging these genes, it would be necessary to mutate or delete both alleles, or else the undamaged copy would continue to produce the protein. This supported the two-hit hypothesis.

The further progression of changes was found by examining tumors at different stages and detecting genetic changes present. For example, colon tumors were studied because the malignant tumor could sometimes be found next to the benign tumor, or polyp, from which it had developed. The malignant tumor would always have all the mutations found in the benign tumor, plus additional ones. The results supported the theory of clonal evolution of cancer, which states that cancer progresses from a single cell that receives a single hit enabling it to replicate with less inhibition than normal cells; later, one of its daughter cells receives a second hit, which makes it replicate faster; and so on until enough hits occur to produce a malignant cell. Because each mutation causes the cells to replicate faster, the chance of further mutations is enhanced. The more replications, the greater the chance of an error.

In the case of colon cancer, the first hit was to a gene called APC, whose function is unknown. Then an oncogene called ras and two tumor suppressor genes, p53 and DCC, are mutated. The order of the last three apparently does not matter, although the ras mutation seems to occur first most often.

The gene p53 seems to be responsible for slowing cell division when DNA damage has occurred, presumably to allow time for DNA repair. Irradiation of a cell by ultraviolet light increases the amount of protein coded for by p53. It also may cause cell death when damage is too great. This can prevent mutations from being passed on. As a result, mutations to p53 can reduce these protective actions.

It may not be evident from this discussion that mutations and transcription errors are rare events. Cancer is common in humans only because cell growth and occasions for DNA repair occur with high frequency. Even without genotoxic chemicals in the environment, natural or not, radiation from cosmic rays and natural radionuclides in the body is probably responsible for the great majority of human cancers. It is estimated that each cell in our bodies must make tens of thousands of DNA repairs per day as a result of this radiation. Each human has up to 1014 cells. About 25% of all humans contract cancer in their lifetimes. Even if we assume that all of these cancers are caused by radiation damage and a 70-year lifetime, this would indicate that the probability of a single DNA repair resulting in cancer is about 10~25! This provides no consolation since the great number of repair events produces such a high risk at the individual level.

Several other factors at the genetic level reduce the risk of cancer. One is that the number of our 25,000 genes that are proto-oncogenes or tumor suppressor genes is very small. Also, many of the cellular mutations probably result in the death of the cell. Finally, a large portion of the DNA actually consists of introns, which are apparently not expressed.

Classification of Carcinogens Several U.S. federal agencies have developed classification systems for carcinogens based on the strength of the supporting evidence. For example, the U.S. EPA adopted the following classification system in 1986:

Group A: Human Carcinogen: Chemicals are placed in this group only if there is sufficient evidence from epidemiological studies to support a causal relationship between exposure to the chemical and cancer in humans.

Group B: Probable Human Carcinogen: This includes two subgroups:

Group B1: Agents for which there is "limited" epidemiological evidence for carcinogenicity in humans.

Group B2: Agents for which there is 'sufficient' evidence of carcinogenicity in animals but "inadequate evidence" or "no data" from epidemiological studies.

Group C: Possible Human Carcinogen: Includes agents with ''limited'' evidence of carcinogenicity in animals. Such limited evidence would include marginally statistically significant findings or finding of benign tumors caused by substances that are not mutagenic.

Group D: Not Classifiable as to Human Carcinogenicity: Includes agents for which there is inadequate evidence for human or animal carcinogenicity.

Group E: Evidence of Noncarcinogenicity for Humans: No evidence of carcinogenicity was found in at least two adequate animal tests in difference species or in both one animal test and one epidemiological study.

The International Agency for Research on Cancer (IARC) has a similar classification scheme used by many countries. Appendix C lists some substances classified as carcinogens by the U.S. EPA, along with their classification and levels of evidence. Group A is often called known human carcinogens. Only about 50 chemicals or substances have sufficient evidence associated with them to be placed in this classification. About 13 of these are of significant environmental concern:

In 1996 the U.S. EPA proposed a new set of guidelines for carcinogenic risk assessment in which they propose replacing the foregoing categories by three descriptors: known/likely, cannot be determined, and not likely.

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