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5 Mechanisms of Carcinogenesis The public health effects resulting from reductions in exposures to various drinking water contaminants can be predicted with greater accuracy as the mechanisms underlying those effects become better understood. Among the possible chronic effects of concern to regulators faced with the task of estimating risk of such exposures, cancer ranks foremost. Carcinogenesis is a complex, multistep process that has been extensively reviewed by Becker (1981), Farber (1982), Farber and Cameron (1980), Slaga et al. (1980b), and Weinstein et al. (19841. This chapter provides an overview of principles that should be considered when assessing risk of exposure to drinking water. It is not intended to be comprehensive. THE MULTISTAGE THEORY OF CARCINOGENESIS Cancer is the product of a process involving complex interactions be- tween environmental and endogenous factors. It is usually manifested by the uncontrolled proliferation of cells that have sustained heritable alter- ations. The discovery that many carcinogens interact with DNA and thus alter the genotype, i.e., specific DNA sequencing of encoded information, is important to the development of the current theories of carcinogenesis. It has also been learned that the inheritance of a single mutation (i.e., a gene with altered DNA) may not be sufficient to produce cancer (Farber, 1982; Weinstein et al., 19841. In the human body, many millions of cells are at risk, and many of them can be shown to have DNA lesions; however, few cells give rise to malignant tumors. When DNA is damaged, the body responds with the cellular mechanisms of repair or eliminates the aberrant 139

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]40 DRINKING WATER AND HEALTH cell through immune-surveillance mechanisms. This process provides pro- tection against both exogenous and endogenous mutagens and carcinogens. Cellular mutation is often an early stage in a multistage process. Carcinogenesis has been experimentally demonstrated to be a multistage process in the cells of certain animal tissues, including skin, lung, liver, and bladder. This process is believed to occur in much of human tumor- igenesis as well. According to current theories, at least three such stages (initiation, promotion, and progression) are evident in many experimen- tally induced cancers (Farber, 1984a,b; Slaga, 1983; Weinstein et al., 19841. These stages are phenomenological, and their mechanisms of action are not well understood. The distinction between the stages has been defined experimentally. Each stage appears to be influenced by several exogenous and endogenous factors, such as age, sex, diet, metabolic activity, and the dose and type of xenobiotic substance to which the . . OrgaIllSm IS exposer . The early work of Rous and Kidd (1941), Berenblum (1941), and Mottram (1944) demonstrated that cancer could be induced in experimental animals in two steps: initiation and promotion. Subsequent studies in animals showed that sequential induction of cancer can occur in a number of tissues or organs. Epidemiological evidence on epithelial cancers col- lected by Armitage and Doll (1954) also suggested a multistage process in carcinogenesis. This was later supported by the toxicological studies of Boutwell (1964), Slaga et al. (l98Ob), and Van Duuren et al. (19731. Consequently, the initiation-promotion model has been generally accepted as being representative of tumor induction. initiation Initiators are mutagens that act either directly or indirectly by forming electrophilic species that interact with and modify DNA structure, or otherwise damage the DNA sequence, but do not by themselves induce tumor formation. Initiation is believed to cause a lesion that persists over a long period, as demonstrated by Van Duuren et al. (1975), who showed that mouse skin initiated more than 1 year before treatment with phorbol esters is still very susceptible to tumor induction. Thus, the initiation step is considered to be irreversible. In addition to demonstrating this, Boutwell (1964) showed that repeated doses of an initiator were additive in the number of tumors produced. Promotion A promoter is a substance that usually does not induce a carcinogenic response by itself but that results in a carcinogenic response when applied

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Mechanisms of Carcinogenesis 141 in multiple doses following a single, subcarcinogenic dose of an initiator. This temporal sequence of administration is only demonstrable in the laboratory; such distinctions are difficult to demonstrate in humans, who receive simultaneous environmental exposures to many types of chemicals. Some promoters can also show weak initiating activity at high doses. Unlike initiators, promoters do not form electrophilic species that interact with DNA. Some evidence indicates that promotion itself involves several stages and that it may be possible to characterize a promoter as a complete or a first- or second-stage promoter (Furstenberger et al., 1983; Slaga et al., 1980a). The effects of a first-stage promoter are thought to be re- versible; i.e., if promoter administration is terminated, a carcinogenic response is not produced. Administration of a second-stage promoter pro- duces irreversible effects. A compound capable of acting as both an initiator and a promoter in the same tissue is defined as a complete (whole) carcinogen. Most chem- icals that seem to have performed as initiators appear to be complete carcinogens. Progression The period during which ill-defined stages lead from benign tumor to malignant tumor is called progression. The transformation of neoplastic cells to a malignant tumor during this stage may involve several steps, such as oncogene activation (Weinberg, 1985), chromosome aberration (Weinstein et al., 1984), interaction between tumor cells and host defenses (Kripke and Morison, 1985), and various selection processes (OSTP, 1985~. Progression can be considered a dynamic process, since tumors may continue to increase in their degree of malignancy and heterogeneity (Weinstein et al., 19841. Cocarcinogenesis Cocarcinogenesis is the process by which two or more compounds, when administered concurrently, increase the risk of tumor development. In some cases, a cocarcinogen is not carcinogenic by itself, but enhances the carcinogenic potency of an initiator. In other cases, both compounds are carcinogenic by themselves, but together elicit a response that is greater than that expected on the basis of simple additivity. Cocarcinogens differ from promoters by definition because promoters are administered after initiators and are not usually carcinogenic alone. Some compounds may be both cocarcinogens and promoters. However, not all tumor promoters are cocarcinogens and not all cocarcinogens are tumor promoters, sug-

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|42 DRINKING WATER AND H"LTH gesting that promotion and cocarcinogenesis proceed by different mech- anisms. ONCOGENE ACTIVITY Oncogenes are naturally occurring genes that code for factors that reg- ulate, among other things, cellular growth. They have been identified in several human tumors as well as in spontaneous and xenobiotically induced tumors in animals. The most recent studies on the mechanisms of cell interactions in cancer induction have attempted to elucidate the role of oncogenes in carcinogenesis (Weinberg, 19851. In the last 4 years, such research has led to several key discoveries that strongly support the mul- tistage theory of carcinogenesis (Land et al., 1983; Slamon et al., 19841. Approximately 40 oncogenes have been discovered (Weinberg, 19851. Most of these have been operationally classified as immortalizing genes (myc type) and transforming genes (ras type). Recent studies have shown that rag-type oncogenes can be activated by chemical carcinogens and by ultraviolet light (Sukumar et al., 1983~. Immortalization of cells in culture has been carried out using chemical carcinogens, and these cells have been transformed and promoted by oncogene products and xenobiotic substances. Studies have shown that the DNA from chemically induced tumors contains active oncogenes, and recent research has demonstrated the potential importance of chromosome translocations in oncogene ac- tivation (Bishop, 1982; Land et al., 1983; Leder et al., 1983~. Immor- talization (presence of a myc-type oncogene) and transformation (presence of a rag-type oncogene) may be regarded as the biological counterparts of initiation and promotion. Recent findings have identified a third type of cancer gene (not yet classified) that may cause a cancer cell to metas- tasize (Bernstein and Weinberg, 19851. This finding of a unique oncogene in a metastatic tumor strongly supports the multistage model of carcino- genesis, since it indicates that different types of oncogenes may correspond to different stages of carcinogenesis. The literature on the specificity of oncogenes and their activation, their location in spontaneous and induced tumors, and the ability of transformed cells in culture (activated ras gene) to induce tumors in viva further in- dicates that tumor induction is indeed a multistage event. To reflect these experimental findings, risk modeling must consider at least three, if not more, stages in order to be consistent with the experimental and human evidence. In particular, the observation that certain promoting agents can induce chromosome aberrations (including translocations) and aneuploidy is of interest in view of the fact that both translocations and aneuploidy have been observed in certain animal and human neoplasms, such as Burkitt's

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Mechanisms of Carcinogenesis 143 lymphoma, retinoblastoma, and Wilms' tumor (Barrett et al., 1983; Cairns, 1981; Leder et al., 1983; Tsutsui et al., 1983; Yunis, 1983~. Increased risk of tumor development has also been observed in patients with con- genital aneuploidy, such as Down's syndrome (Windham et al., 19851. Recent research has illustrated the potential importance of chromosome translocations in oncogene activation (Bishop, 1982; Land et al., 1983; Leder et al., 19831. MODEL SYSTEMS Mouse Skin The mouse has served as an especially useful test animal, since tumor induction in its dorsal skin is relatively rapid and can easily be observed and quantitated without sacrificing the animal. For 30 years, up to the late 1960s, the mouse skin model was used almost exclusively for initi- ation-promotion studies in chemical carcinogenesis. For nearly 40 years, croton oil (an oil obtained from the seeds of Croton tiglium L.) was used as a promoting substance in mouse skin studies. The active component was identified in the late 1960s as phorbol myristate acetate (PMA) (Hecker, 1971; Van Duuren, 19691. Since that time, several PMA analogs have been synthesized. Although these PMA analogs have less promoting activity, they are important in studies designed to determine the mechanism of action of phorbol ester promoters (Boutwell, 19741. In addition to the phorbol ester tumor promoters, there are other classes of compounds with promoting activity in the mouse skin. Dihydroteleo- cidin B. a derivative of a natural product isolated from streptomyces, has strong promoting activity in this model (Fujiki et al., 1981), as do certain natural products other than the phorbol esters extracted from plants (Muf- son et al., 19791. Phenol and certain phenol derivatives were shown by Boutwell and Bosch (1959) to be weak promoters in skin, as are certain fatty acids and fatty acid methyl esters and long, straight-chain alkanes such as decane (C-10) and tetradecane (C-14) (Arffmann and Glavind, 1971; Van Duuren and Goldschmidt, 19761. Anthralin (1,8-dihydroxy-9- anthrone) was shown by Segal et al. (1971) to be a strong promoter in mouse skin, whereas detergents such as sodium lauryl sulfate and Tween 60 are weak promoters (Boutwell, 1964; Setala, 19601. A class of tumor promoters discovered recently are peroxides such as benzoyl peroxide, which is a moderately strong promoter in mouse skin (Slaga et al., 19811. Direct-acting alkylating agents such as iodoacetic acid and 1-fluoro-2,4- dinitrobenzene are weak to moderate promoters (Bock et al., 1969;.Gwynn and Salamon, 19531. Benzofe~pyrene, which is not a whole carcinogen in skin, is a moderate promoter in that tissue (Slaga et al., 1979), whereas

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]44 DRINKING WATER AND HEALTH 7-bromomethyl benz~ajanthracene is a complete carcinogen and also a strong promoter (Scribner and Scribner, 19801. Suganuma et al. (1984) have recently identified a new class of tumor promoters, aplasiatoxins, which are structurally unrelated to PMA. A number of chemicals that are tumor promoters in mouse skin are also cocarcinogens in mouse skin. The existence of cocarcinogenic substances was inferred from studies of carcinogenesis resulting from exposures to cigarette smoke condensate (CSC). Since the concentration of benzota~pyrene [B(a)P] in CSC and the dose delivered in CSC skin-painting experiments could not account for the observed tumor yield, it was surmised that other substances present in CSC enhanced the response to B(a)P (Hecht et al., 19811. Van Duuren and Goldschmidt (1976) showed that catechol (1,2- dihydroxybenzene), which is an abundant phenol in CSC, is a potent cocarcinogen in B(a)P-induced skin carcinogenesis. Thus when low car- cinogenic doses of B(a)P were applied to the skin repeatedly over a long period in the presence of catechol, the number of skin tumors increased significantly compared with the number induced by treatment with B(a)P without catechol. Treatment with catechol in the absence of B(a)P did not cause tumor induction. Van Duuren and Goldschmidt (1976) also showed that PMA is a cocarcinogen as well as a promoter. In addition to serving as a model system for identifying whole chemical carcinogens, initiators, and promoters, the mouse skin has been extremely useful for studying the mechanism of action of initiators and promoters since the early 1970s. At the tissue level, phorbol ester promoters cause hyperplasia and inflammation (Boutwell, 19641. Cellular responses ob- served within 24 hours after exposure include increased synthesis of DNA, RNA, and protein (Baird et al., 1971), increased phospholipid turnover (Rohrschneider and Boutwell, 1973), changes in cyclic nucleotide me- tabolism (Mufson et al., 1979), increases in protease activity (Troll et al., 1978), induction of ornithine decarboxylasea key enzyme in polyamine metabolism (O'Brien et al., 1975), and decreases in the activities of the antioxidant defense enzymes superoxide dismutase and catalase (Solanl~i et al., 1981~. Largely as a result of these studies, early investigations on the inhibition of promotion focused on substances that might reverse the tissue and biochemical responses caused by promoters. Thus antiinflam- matory compounds such as cortisol, dexamethasone, and fluocinolone acetonide were found to be effective promotion inhibitors (Berman and Troll, 1972; Schwartz et al., 1977), as were protease inhibitors (Troll et al., 19781. Vitamin A derivatives (Verma et al., 1979) and free-radical scavengers such as dimethyl sulfoxide (DMSO) (Loewengart and Van Duuren, 1977) were also effective promotion inhibitors. In the mouse skin, the two-stage initiation-promotion protocol results in the formation of a large number of papillomas, many of which progress

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Mechanisms of Carcinogenesis 145 to squamous cell carcinomas. Burns et al. (1976) identified two classes of papillomas one class that regressed after treatment with PMA was discontinued and another class that showed a decreased tendency to re- gress, i.e., a class of papillomas with autonomous growth. The greatest tendency to undergo malignant transformation occurred in the autonomous group. Klein-Szanto et al. (1983) have shown that the acquisition of ~y- glutamyltranspeptidase (GOT) and the loss of high-molecular-weight ker- atins appear to be good indicators of progression from benign to malignant tumor in mouse skin. Slaga et al. (1980a) demonstrated that the promotion phase in mouse skin can be subdivided into two stages. In the first stage, the initiated dorsal skin of mice is treated with a first-stage promoter such as PMA for 2 weeks. This treatment is followed by repeated treatments (18 weeks or longer) with a second-stage promoter (e.g., mezerein) (Slaga et al., 1980a,b). Treatment of initiated mouse skin with a first-stage promoter for 2 weeks without subsequent treatment with a second-stage promoter does not result in tumor induction, nor does treatment for a long time with a second- stage promoter without prior treatment with a first-stage promoter (Slaga et al., 1980a). In the two-stage promotion model, the complete promoter PMA is also a potent first-stage promoter. The weak promoter mezerein is a strong second-stage promoter, but the PMA analog 4-O-methyl-PMA, which is not a promoter in the two-stage carcinogenesis model, is a weak first-stage promoter (Slaga et al., 1980b). Furstenberger et al. (1983) have shown that the first stage of promotion was not reversible for at least 2 months when PMA was given as a first-stage promoter and was followed by 12-retinylphorbol-13-acetate (RPA). They also demonstrated that par- tial inversion can occur between initiation and the first stage of promotion. In their model, initiation with a subthreshold dose of dimethylbenzan- thracene (DMBA) could occur successfully up to 6 weeks after treatment with PMA. Rat and Mouse Liver This model system has in the past involved an invasive procedure (partial hepatectomy), followed by administration of the initiator [usually 2-ace- tylaminofluorene (2-AAF), diethylnitrosamine (DEN), or DMBA] and then by phenobarbital as the promoter. The interaction of phenobarbital with 2-AAF was first reported by Peraino et al. (1971), who established the promotional effect of phenobarbital in the liver. Recent results indicate that the rat and mouse liver models of carcinogenesis do not require use of the invasive technique and that dietary restriction of choline for less than 2 months after pretreatment with a cytochrome P450 modifier is sufficient to induce altered foci (Mylecraine, 19841.

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]46 DRINKING WATER AND HEALTH Recent evidence suggests that intraperitoneal pretreatment of Fischer 344 adult male rats with Q-naphthoflavone, a 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD)-type of P450 cytochrome inducer, enhances the pro- duction of altered foci by DEN (Mylecraine, 19841. A small percentage of these altered foci have been shown to progress to cancer (Williams and Weisburger, 19831. Mylecraine (1984) has shown that altered foci in rodent livers are enhanced when phenobarbital is injected intraperitoneally to the animals before initiators are administered. Thus, apart from in- creasing the production of reactive derivatives, some aspect of the pro- liferation induced by compounds known to induce one or more forms of cytochrome P450 may have an effect on the ability of the liver to respond to a carcinogen. Induction of uncontrolled cell replication is believed to be an important contributing factor in the process of cocarcinogenesis, but the role of proliferation in promotion is not entirely clear. Investigations of several organ systems indicate that cells in the process of normal replication are more susceptible to mutagenesis and carcinogenesis than are cells that are relatively dormant and replicate more slowly. For example, synchronized rat liver epithelial cells were shown to be most sensitive to mutation at the phosphoribosyltransferase locus by methyl methane sulfonate or by the gastric carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MUNG) during DNA synthesis (Tong et al., 19801. Following partial hepatectomy in the B6C3F~ mouse, Newberne et al. (1982) observed a small increase in spontaneous liver tumors. Rats given a single injection of dimethylnitro- samine 24 hours after undergoing partial hepatectomy (the peak time of DNA synthesis in the regenerating liver) developed hepatocellular carci- nomas, whereas nonhepatectomized rats did not (Craddock, 19711. How- ever, the lack of proportionality between the rate of cell division and induction of tumors in carcinogen-exposed rat livers indicates that there are modulating factors beyond the rate of cell division (Becker, 19794. J. M. Ward et al. (1984) have demonstrated that continuous, long-term exposure is not necessary for tumor promotion in the mouse liver. For example, di(2-ethylhexyl) phthalate administered after initiation with DEN resulted in the same significant increase in altered hepatic foci after 24 or 84 days of exposure. See next section, entitled Other Animal Systems, for further examples. Studies in which 2-AAF is administered serve as excellent examples of the complexity of multistage (and multiorgan) carcinogenicity. This com- pound behaves as a promoter in the mouse bladder but as an initiator in the liver of the same animal (Hughes et al., 19831. Further evidence for tissue specificity has been provided by studies demonstrating that liver tumors in rodents are not promoted by PMA or by other phorbol esters but, rather, by polyaromatic hydrocarbons (PAHs), polychlorinated bi-

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Mechanisms of Carcinogenesis 147 phenyls (PCBs), TCDD, and phenobarbital (Peraino et al., 1980; Pitot et al., 1980~. This finding is supported by evidence in humans for tissue- specific promotion by estrogens, cigarette smoking, and asbestos, the latter serving as a promoter of lung cancer development and as an initiator of mesothelioma (NRC, 1984, pp. 165-1991. Many inducers of hepatic cytochrome P450, e.g., phenobarbital, PCBs, dichlorodiphenyltrichloroethane (DDT), and TCDD, have been implicated as promoters in the rodent liver model. These agents may act as promoters through the generation of active oxygen molecules such as superoxide, hydroxyl radical, or peroxide, which may cause genetic effects, direct effects on the cell membrane through alteration of transport mechanisms, and immunotoxicity (see Kensler and Trush, 1984, for a review). Indeed, Dean et al. (1983a) have shown that 12-O-tetradecanoyl-phorbol-13- acetate (TPA) depresses cell-mediated immunity, T-cell function, and in viva tumor resistance. These responses are consistent with findings using other suspected promoters, e.g., diethylstilbestrol (DES), TCDD, and dimethylvinylchloride (DMVC) (Dean et al., 1983a). Other Animal Systems The discovery of experimental tumor promotion in other tissues, such as the bladder (Hicks, 1983; Verma et al., 1983), breast (Rogers, 1983; Wotiz et al., 1984), colon (Ready and Maeura, 1984; Rogers, 1983), lung (Witschi, 1983; Witschi et al., 1977), pancreas (Ohyama, 1985), and respiratory tract (Mossman et al., 1985), is relatively recent. Research in these areas has produced a great deal of information on possible mecha- nisms of carcinogenicity, including tissue specificity and a memory effect of promoters. Multistage carcinogenesis in the liver and skin has been more clearly defined (J. M. Ward et al., 1984) than in the lung, colon, brain, kidney, and thyroid. Estrogen-sensitive tissues (i.e., tissues with high levels of estrogen receptors) such as the endometrium, prostate, and breast appear to respond to estrogens and nonhormonal compounds that exhibit estrogen- like activity in a manner similar to the initiator-promoter (multistage) model (Baxter and Funder, 1979; Lippman and Allegra, 1978; McGuire et al., 1978; Wein and Murphy, 19731. Some promoters are active at only one site. However, others, such as 2-AAF, can act as an initiator in one tissue and a promoter in another (Hughes et al., 19831. Some agents can act as an initiator at one site, a promoter at another, and an inhibitor at a third. TCDD is an example of this phenomenon: in the mouse, it is a weak initiator in skin (DiGiovanni et al., 1977) and possibly in liver (Kociba et al., 19781; a promoter in liver (Pitot et al., 19801; and an inhibitor in skin (DiGiovanni et al., 1983)

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|48 DRINKING WATER AND H"LTH and possibly in the pituitary, uterus, mammary glands, pancreas, and adrenal gland (Kociba et al., 1978~. The effect of a promoter may vary, depending on the sequence of administration with the initiator. For ex- ample, when given to mice before an injection of urethan, the antioxidant butylated hydroxytoluene (BHT) will decrease the numbers of lung ad- enomas induced. When administered after urethan, BHT increases tumor yield (Malkinson and Beer, 19841. The sensitivities of different species and strains to promoter activity vary in many cases; mice are the most sensitive, forming multiple skin papillomas in response to an initiation- promotion regimen, as compared to less frequent basal cell carcinomas in rats and melanomas in hamsters (Slaga and Fischer, 1983~. In light of these observations, it may be desirable to test potential promoters and inhibitors of promotion in viva in several species and strains and in both sexes, to examine several organs for the response, and to administer the compounds in different sequences. Studies in Humans Evidence for multiple stages in human tumor promotion results from analysis of epidemiological data on several cancers. For example, epi- demiological data on cigarette smoking and lung cancer have been used to develop a simple multistage model in which the incidence rate is pro- portional to timer, where k is the slope of the log-log age-incidence curve and is believed to approximate the number of stages necessary for tumor development (Peso, 19771. Cessation of cigarette smoking reduces the risk of lung cancer, although not to the level of risk for nonsmokers (Doll, 1978), and is thus believed to affect the penultimate stage of lung cancer development (Peso, 19771. Cigarette smoke contains compounds capable of both initiating and promoting lung carcinogenesis. In another example, liver cancer in Africa appears to be linked to both aflatoxin Be exposure and hepatitis B virus infection (Linsell and Peers, 1977), each of which may affect different stages in liver cancer development. The risk of lung cancer for asbestos workers who smoke is 50 times greater than that of nonsmokers (NRC, 19841. Asbestos appears to be acting both as a pro- moter in the lung and as an initiator of mesothelioma (NRC, 1984, pp. 165-1991. Tumors of the endocrine organs are linked to hormone avail- ability; the hormones apparently exert a promoting effect (Day and Brown, 1980; Sivak, 19791. GENETIC TOXICITY Several contaminants in drinking water react chemically with DNA. A few of these are reviewed in Chapter 9. This genetic toxicity is of great

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Mechanisms of Carcinogenesis 149 concern since the information that controls the structure, function, and reproduction of cells is encoded in the DNA. Moreover, both theoretical considerations and experimental evidence indicate that alteration of the DNA is involved in at least one step in the complex process of carcino- genesis. Genotoxicity and, preferably, genetic toxicity are the general terms used to describe the niode of activity of an agent that itself or by way of its metabolites can interact with genetic material to induce heritable alterations in DNA sequence or chromosome number or structure in either somatic or germ cells. Mutagens are agents that can alter the primary base sequence of the DNA. Clastogenicity and aneuploidy refer to chromosome breakage or change in chromosome number, respectively. A distinction is sometimes made between genetic toxicants that act in different ways. In primary genetic toxicity, either the parent compound or its metabolite directly alters or binds to genetic material. For example, both methyl methane sulfonate (MMS) and B(a)P are primary genetic toxicants. MMS, however, is called a direct-acting agent because it interacts directly with DNA without the need for metabolic activation. In contrast, B(a)P is an example of a primary genetic toxicant that requires metabolic activation to exhibit genetic tox- icity. Secondary genetic toxicity refers to activity in which genotoxicity is a secondary result of the primary action of the agent. Examples of this type of toxicity are effects on the DNA polymerase, inhibition of DNA repair, induction of a physiological state that results in genetic toxicity, or forced cell proliferation, resulting in an increase in the frequency of spontaneous mutations. Some carcinogens are believed to act without affecting DNA. One example is DES, which can lead to a rare form of vaginal cancer in adolescent women who had been exposed transplacentally (Herbst et al., 1977~. DES may affect the differentiation of endocrine organs, leading to cancer later in life due to either hormonal imbalances or altered hormone receptor response (Weisburger and Williams, 1982~. Another example is asbestos, whose fibers do not seem to damage DNA directly (Fornace, 1982) or act as mutagens (Chamberlain and Tarmy, 1977) but which may transport PAHs (known initiators) into target cells because they adhere to asbestos fibers (Eastman et al., 19831. THE ROLE OF THE IMMUNE SYSTEM IN CARCINOGENESIS The immune system provides a major defense against invading micro- organisms and altered cells. It functions in overall host resistance to in- fections, in the maintenance of homeostasis, and in surveillance. against uncontrolled cell proliferation (Fidler, 1985~. The immune system pro- vides a natural defense against cancer. This conclusion is supported by

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Mechanisms of Carcinogenesis 157 that a threshold for cancer induction by a xenobiotic compound does not exist. Most laboratory evidence indicates that promoters need to be admin- istered continuously, or in large doses, implying that promoters should have discoverable thresholds (Hoer et al. 19831. A difficulty arises when the same chemical appears to behave both as an initiator with respect to one tissue and a promoter with respect to another tissue, raising questions of the importance not of the chemical but of the chemical-tissue interaction. Examples of this chemical-tissue interaction are asbestos, which is prob- ably a promoter with respect to lung cancer and an initiator with respect to mesothelioma in humans (NRC, 1984), and 2-AAF, which has pro- moting activity in both bladder and liver carcinogenesis in laboratory animals (Hughes et al., 1983~. In assessing cancer risk, projections from high animal doses to low- dose exposures of humans are driven more by the choice of the extrap- olation model than by the available data (Whittemore, 19801. Thus, further research, development, and validation of more sophisticated models are required. For example, models are needed to distinguish between re- sponses to lifetime exposures at relatively uniform increments of dose and those resulting from more erratic accumulation of doses that range from high to no dose for varying periods of time at irregular intervals. Studies of cohorts exposed to radiation or asbestos indicate that dose rate needs to be included in future dose-response models. When assessing the risk of exposure to carcinogens in drinking water, one should consider information on metabolism and pharmacokinetics. This information may be used to ascertain the validity of a linear dose- response assumption, which can misstate the risk because of inadequate information on metabolism. Determination of the biologically effective dose delivered to the target molecule (such as DNA) will allow a more realistic evaluation of risk. Because of the multistage nature of carcinogenesis, the concept of threshold dose, or no-observed-effect level, is not applicable as it is for other toxic effects. Instead, the multistage, no-threshold, low-dose ex- trapolation model described in Chapter 8 can be used to predict a finite excess risk of cancer at any low carcinogen dose. However, no model can unambiguously predict low-dose effects from data obtained at high doses. A major reason for this ambiguity is that at high doses, the behavior of an enzyme system responsible for the activation or detoxication of a carcinogen may often be governed by a set of parameters different from those that apply at low doses. Chapter ~ contains a more detailed discussion of risk assessment for carcinogens.

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