51, 1–28. Benign liver tumors have regressed after withdrawal of oral contraceptives in women. Stem cell origin of cancer and differentiation therapy. These cells had undergone what Rous called initiation. Translocations between other chromosomes are associated with different forms of leukemia. These stem cells normally maintain Clara cell populations in the bronchioles and alveolar epithelial cells within the lung. Testing batteries, tier approaches, and decision-point analyses have been proposed to provide a basis for prioritizing chemicals in the testing queue and to provide a larger database for risk assessment. There is little evidence that there is direct interaction of endogenous hormones with DNA, although minimal DNA binding has been shown with some synthetic estrogens, and some hormones do bind to protein. Learn more about the topics in this list in the IARC monographs at https://monographs.iarc.fr/cards_page/publications-monographs/. Proto-oncogene and tumor suppressor gene mutation assays have become a popular tool for investigating tumor etiology in humans and rodents mainly because mutations tend to be chemical specific (see The Application of Toxicogenomics to the Interpretation of Toxicologic Pathology, Chapter 11). We are grateful to Dr Stephen Mastorides for his contributions to previous editions of the Handbook of Toxicologic Pathology, some of which remain with permission in this updated chapter. Conheim, J., 1875. While the maximum tolerated dose (MTD) concept has been retained in principle, it is applied more conservatively in setting the high dose. Similar multistage promotion has not yet been demonstrated in other experimental carcinogenesis model systems. Lung. Widespread and routine evaluation of chemicals for their carcinogenic potential began in earnest in the mid-1960s with the use of a standardized protocol for the “bioassay” program of the National Cancer Institute (NCI). A variety of activated oncogenes have been documented in rodent neoplasms. Carcinogenic, mutagenic and reprotoxic substances are often referred to as a group, due to the fact that a substance may present all three types of hazards but also due to similarities in classification and in legal approach. 8, 329–337. In contrast, 12-0-tetradecanoylphorbol-13-acetate is a potent skin and forestomach neoplasm promoter, but has no appreciable activity in the liver. Nature 414, 105–111. Since most of the multiple key events in chemical carcinogenesis have a non-linear dose–response relationship intrinsic to the mechanism involved, tumor development will likely show an overall threshold. Toxicity and hepatocarcinogenicity may occur when liver responses exceed adaptive changes or induced enzymes generate toxic metabolites (Table 5.5). DNA amplification has been shown to occur at the site of insertion of oncogenic retroviruses. Non-random chromosomal aberrations in animal neoplasms include trisomy 15 in T cell lymphoma of the mouse, trisomy 13 in mouse mammary adenocarcinoma, and trisomy 4 in ethylnitrosurea-induced neurogenic neoplasms in the rat. Health Perspect. Finally, reversing the order of administration by giving a known promoter prior to an initiator may prevent the expression of carcinogenic activity on the part of the initiator. Hypertrophy may be classified in a manner similar to how hyperplasia is classified. To fully characterize the toxicity of chemicals, modifications to the chronic rodent carcinogenicity study protocol have been selectively introduced by the NTP. 36 (Suppl. These findings in 1918 confirmed Percival Pott’s strong epidemiological observations in 1775 of increased rates of cutaneous scrotal cancer in chimney sweeps and demonstrated that chronic exposures were necessary for the induction of some cancers. Finally, there is no readily measurable threshold dose for maximum and minimum responses to initiators. 45, 872–877. Several radioactive substances are considered carcinogens, but their carcinogenic activity is attributed to the radiation, for example gamma rays and alpha particles, which they emit. Intercellular communication (sometimes referred to as metabolic cooperation, based on a popular assay for its measurement) is known to play an important role in the phenotypic expression of some transformed cells in vitro. Once there is binding to a specific membrane, cytosolic, or nuclear receptor, the receptor becomes activated and intracellular activity occurs that affects transcriptional or translational processes, resulting in the synthesis of specific proteins. Med. Anat. Similarly, bile acids, as modulated by fat consumption, are known promoters of rat liver carcinogenesis. “Short-term” or “medium-term” in vivo carcinogenesis animal models consist of an intact animal capable of chemical metabolism (activation and detoxification), complex tissue and hormonal interactions, and possessing repair mechanisms, all of which could influence the ultimate expression of carcinogenic responses to chemical exposure. The interval between initiation and promotion may be as long as 1 year in mouse skin-painting studies. Opin. Pathol. The judgment of whether a chemical poses a carcinogenic hazard should be made in light of the total evidence provided by all sources of available relevant information. These models are based on the theories of multistage carcinogenesis, and take into account initiation, proliferation, multiple genetic alterations, preneoplastic lesions, and the monoclonality of cancer development. Current studies have shown that many tumor-promoting agents inhibit gap junction intercellular communication associated with the aberrant expression of connexin and the loss of function of cell adhesion molecules. Benzo[a]pyrene, the most potent carcinogenic agent of tar, is present in the environment as a result of cigarette smoke and automobile exhaust fumes. Huff, J., Haseman, J., 1991. 217, 299–306. Moreover, it can take a long time for cancer to be detected. The limits of two-year bioassay exposure regimens for identifying chemical carcinogens. Lab. Cancer can be caused if a carcinogen damages a person’s DNA cells to the point of being irreparable. Sci. A number of observations have been made with respect to gene amplification and oncogenesis. For example, lung and colon cancers from people who smoke tend to have a specific mutation in the ras oncogene or p53 tumor suppressor gene (i.e., mostly a G to T nucleotide base substitution) and that this mutation is likely due to direct interaction of the carcinogen in smoke benzo[α]pyrene with DNA. However, in 70 “near-replicate” comparisons, good reproducibility of positivity, target site, and carcinogenic potency was found by comparing published studies done in rats, mice, or hamsters. In either case, the mechanism of cancer “induction” would be considered secondary. The idea that the growth of a solid tumor is driven by proliferation of cancer stem cells has profound implications for cancer therapy. Finally, cells must undergo additional changes in their progression to a malignant neoplasm. According to the mutational hypothesis, one or more point mutations are responsible for initial and/or critical steps in the neoplastic process. It also appears that pathways of chlordane-induced hepatocarcinogenesis progress independently of ras activation. Identification and expansion of human colon-cancer-initiating cells. High-dose selection relates to philosophic approaches to testing for toxicity and carcinogenicity. Aflatoxins 5. In an effort to consciously expand the original NCI “bioassay” and to make the test results more relevant for the interpretations being applied, considerable evolution has occurred in the design, conduct, and interpretation of long-term rodent carcinogenesis tests conducted under the auspices of the NTP. This capacity for autonomous growth remains latent for weeks, months, or years, during which time the initiated cell may be phenotypically indistinguishable from other parenchymal cells in that tissue. 52, 435–440. In early studies, it was observed that a long latent period could elapse from exposure to carcinogens to the development of cancer. The original NCI “bioassay” has evolved to the present day National Toxicology Program (NTP) 2-year and perinatal carcinogenicity study. Fortunately, the vast majority of such DNA damage is repaired prior to cell division by efficient cellular enzymatic systems. The new technologies will continue to contribute towards our improved understanding of human risks of disease and the betterment of human health. The existence of chalones has been debated. The current dogma is that cancer cells acquire resistance to chemotherapeutics as they evolve and undergo additional mutations; an alternative explanation to account for drug resistance is that the cancer stem cell population inherently possesses the ability to resist current therapies, and thus is able to contribute to disease progression or tumor reoccurrence. For example, because hypertension is a disease, then cardiac hypertrophy that occurs secondary to the hypertension can be considered pathologic. Five major classes of mammalian cyclins (termed A–E) have been described. Distinguishing progression from promotion is the presence of structural genomic alterations in the former and the absence of definable structural changes in the genome of the latter. A current example is the presence of ochratoxin A, a human carcinogen and nephrotoxin, in wines. In the normal cell, the growth deregulation caused by pRB inhibition can be counteracted by apoptotic cell death produced by normal p53. Cancer Res. Tu, S.M., Lin, S.H., Logothetis, C.J., 2002. Drug-induced gene amplification, possibly with an associated specific karyotypic change, is known to result in drug resistance due to an increase in the amount of gene product. For example, squamous metaplasia occurring in an area normally populated by ciliated respiratory epithelium represents a situation where fully specialized squamous epithelium provides protection against irritation. While it can be argued that activation of proto-oncogenes may be a necessary event in the genesis of some cancers, it is unlikely that a single point mutation associated with an activated oncogene is sufficient in and of itself for the development of all cancers. Therefore, it is essential to further advance our understanding of the intricate molecular mechanisms that govern chemical carcinogenesis. The non-mutational genetic hypothesis postulates that a genomic perturbation other than a mutation may lead to cancer. Allen, D.G., Pearse, G., Haseman, J.K., Maronpot, R.R., 2004. Cancer Res. In simple terms, Carcinogenic foods are the source of a substance called carcinogen. Cardiff, R.D., Anver, M.R., Boivin, G.P., Bosenberg, M.W., Maronpot, R.R., Molinolo, A.A., Nikitin, A.Y., Rehg, J.E., Thomas, G.V., Russell, R.G., Ward, J.M., 2006. Lessard, J., Sauvageau, G., 2003. Aluminum production 7. The current multistep model of carcinogenesis involves at least 80 cancer gene mutations or alterations, about a dozen of which are “drivers” of the cancer growth processes. Thus, a serious effort was undertaken to identify potential carcinogens using the mouse skin experimental model. (Hanahan and Weinberg, 2011). Relative to man, rodents infrequently develop prostate, colon, pancreatic, cervical, and uterine carcinomas, but develop lung, mammary, hematopoietic, and skin tumors at similar rates (Table 5.13). The development of intraneoplastic diversity may come about as a consequence of genetic change such as loss of polymorphic restriction fragments in DNA of malignant tumors or similar random processes such as additional genomic “hits” by genotoxic agents. Studies that are negative for carcinogenicity and were conducted with doses below the MTD leave doubt about the adequacy of the test. Environ. Similarly, complex formation of underphosphorylated pRB with the SV 40 large T antigen, the adenovirus EIA protein, and the papillomavirus E7 protein leads to pRB inactivation and cellular immortalization. Once again, the oncogene activation produced by the DMBA treatment was not sufficient to cause carcinoma development but required promotion by phorbol ester to obtain cancer. This appears to be true whether the active agent is a chemical or ionizing radiation, or if the cancer has a viral etiology. This is particularly true in skin initiation–promotion studies using phorbol esters as promoters, but is also seen in hyperplasia of hepatocytes following treatment with mitogenic agents such as phenobarbital. It has been shown that, similar to brain tumors, tumorigenic cells in small cell and non-small cell lung cancer in humans are a rare population of CD133-positive, undifferentiated cancer stem cells that are able to self-renew, grow indefinitely, and repopulate secondary transplanted hosts, whereas CD133- negative tumor cells are not. Direct acting carcinogens, which can cause cancer as is. Skin tumor promoters, such as phorbol esters, possibly inactivate the chalone receptor site, thereby switching off the mechanism of growth control in the affected cell(s). Ricci-Vitiani, L., Lombardi, D.G., Pilozzi, E., Biffoni, M., Todaro, M., Peschle, C., De Maria, R., 2007. Mod. There is epidemiological evidence suggesting that for some solvent-associated human leukemias, the exposure was associated with an increased risk of developing a tumor with ras activation. Toxicol. Risk assessment requires numerical estimates of human health risks, and numerous mathematical models have been developed based on animal bioassays, human exposure data, and epidemiology studies to predict a tumor response in a population. Christensen, J., Romach, E.H., Healy, L.N., Gonzales, A.J., Anderson, S.P., Malarkey, D.E., Cattley, R.C., Goldsworthy, T.L., 1999. It was generally not intended to be used for risk assessment, determining carcinogenic potency, identifying subtleties of chronic toxicity, determining the mechanism of observed carcinogenic responses, or establishing pathogenesis of lesions (see Carcinogenicity Assessment, Chapter 27). Cyclin D1 is overexpressed in many human cancers, including breast and non-small cell lung carcinomas, sarcomas, melanomas, B cell lymphomas, and squamous cell carcinomas of the head and neck. Arsenic and inorganic arsenic compounds 11. Stem cells and various neoplastic cells express telomerase, and have anti-apoptotic mechanisms, and increased membrane transporter activity (thus being able to efflux chemicals and chemotherapeutics from the intracellular compartment). Farrar, J.D., Katz, K.H., Windsor, J., Thrush, G., Scheuermann, R.H., Uhr, J.W., Street, N.E., 1999. The ratio between cell birth and counterbalancing cell death determines tumor growth. The classical skin tumor promoter, phorbol ester, causes amplification of specific genes in cultured cells. Identification of these brain tumor-initiating cells gives strong support for the cancer stem cell hypothesis as the basis for many solid tumors. It has been argued, however, that cancer is not blocked differentiation but rather represents a new state of differentiation conferring a selective growth advantage to the altered phenotype. In 1531, Paracelsus had described the “mala metallorum” among miners for silver and other metals, including uranium. As such, when intact, they have a function opposite to that of oncogenes and might effectively oppose the action of an oncogene. 70, 6–22. Pathol. The two-stage promotion model is based on the stimulation of basal cell hyperplasia (dark basal keratinocytes) in stage 1 of promotion followed by enhancement of cell proliferation in stage 2. Curr. Pathol. For example, the chemical induction of renal tumors in the male rat by some chemicals appears dependent on a pathway involving the deposition of α2u-globulin in the tubular epithelium;α2u-globulin is not found in humans. Cancer stem cells. Most notable is the association of the Philadelphia chromosome with the lymphoma/leukemia group of human diseases. Acid mists, strong inorganic 4. While the earliest evidence of cancer stem cells comes from studies in hematologic malignancies such as human acute and chronic leukemia and myeloma, multiple researchers have provided evidence for the existence of cancer stem cells in solid tumors, including brain, lung, colon, ovarian, pancreas and prostate tumors, as well as in breast cancer and melanoma, among others. A block of normal differentiation implies an alteration in normal gene expression. Bannasch, P., 1986. 116, 1439–1442. Malignant neoplasms grow rapidly and are characterized by local invasiveness. Based on this type of analysis, so far more than 100 agents have been classified as known human carcinogens by the International Agency for Research on Cancer (IARC) and the US Health and Human Services Annual Report on Carcinogens (ROC); virtually all are carcinogenic in animals (Table 5.1). 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