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Page 505

Appendix
H-2
Individual Susceptibility Factors

One way to categorize the many different factors that affect susceptibility to cancer is to divide them into qualitatively different classes along two strata—according to the prevalence of each factor in the human population and according to the degree to which the factor can alter susceptibility. Finkel (1987) noted that most of the factors that are very common (Table H-1) tend to confer only marginal increases in relative risk on those affected (less than a doubling of susceptibility). Many of the other predisposing factors, long recognized as conferring extremely high relative risks, also tend to be quite uncommon (see Table H-2).

However, several important determinants of cancer susceptibility might well be neither rare nor of minor importance to people, and some speculate that this might be quite important for societal risk assessment. This section discusses five factors that might be among the most significant.

Carcinogen Metabolism

Most chemical carcinogens require metabolic activation to exert their oncogenic effects, and the amount of carcinogen produced depends on the action of competing activation and detoxification pathways,. Interindividual variation in carcinogen metabolism is therefore an important determinant of cancer susceptibility.

Chemical carcinogens are metabolized by a wide variety of soluble and membrane-bound enzymes. Multiple forms of human cytochrome P450 (CYP) are involved in the oxidative metabolism of chemical carcinogens, such as poly-



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Page 505 Appendix H-2 Individual Susceptibility Factors One way to categorize the many different factors that affect susceptibility to cancer is to divide them into qualitatively different classes along two strata—according to the prevalence of each factor in the human population and according to the degree to which the factor can alter susceptibility. Finkel (1987) noted that most of the factors that are very common (Table H-1) tend to confer only marginal increases in relative risk on those affected (less than a doubling of susceptibility). Many of the other predisposing factors, long recognized as conferring extremely high relative risks, also tend to be quite uncommon (see Table H-2). However, several important determinants of cancer susceptibility might well be neither rare nor of minor importance to people, and some speculate that this might be quite important for societal risk assessment. This section discusses five factors that might be among the most significant. Carcinogen Metabolism Most chemical carcinogens require metabolic activation to exert their oncogenic effects, and the amount of carcinogen produced depends on the action of competing activation and detoxification pathways,. Interindividual variation in carcinogen metabolism is therefore an important determinant of cancer susceptibility. Chemical carcinogens are metabolized by a wide variety of soluble and membrane-bound enzymes. Multiple forms of human cytochrome P450 (CYP) are involved in the oxidative metabolism of chemical carcinogens, such as poly-

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Page 506 TABLE H-1 Examples of Common Predisposing Factors Predisposing Factor Mechanism Influencing Susceptibility to Cancer A. Temporal Factorsa   • Circadian rhythms   • Changing ingestion and inhalation characteristics during life   • Depression and stress   B. Nutritional Factorsb   • Vitamin A and iron deficiencies May increase susceptibility to carcinogenic hydrocarbons • Dietary-fiber intake Insufficient intake may increase residence time of carcinogens in contact with epithelium of digestive tract • Alcohol intake May affect susceptlbility through effect on liver C. Concurrent Diseasesc   • Respiratory tract infections and bronchitis May predispose lungs to cancer by disturbing pulmonary clearance or promoting scarring • Viral diseases, e.g., Hepatitis B May activate proto-oncogenes and cause liver necrosis and regeneration • Hypertension May increase the potential for DNA damage in peripheral lymphocytes aData from Fraumeni, 1975; Borysenko, 1987. bData from Calabrese, 1978. cData from Warren and Weinstock, 1987. cyclic aromatic hydrocarbons (PAHs). Interindividual variation by a factor of several thousand has been observed in placental aryl hydrocarbon hydroxylase (AHH) activity, which is catalyzed by CYP1A1; some of this variability is under direct genetic control, but variations also result from an enzyme induction process due to maternal exposure to environmental carcinogens, such as tobacco smoke. A genetic polymorphism in CYP1A1 in which an amino acid substitution in the heme-binding region of the protein increases catalytic activity of PAHs has been linked to enhanced susceptibility to squamous cell carcinoma of the lung in cigarette-smokers (Nakachi et al., 1991). Japanese with the suscepti-

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Page 507 TABLE H-2 Examples of Rare Predisposing Factorsa Predisposing Factor Mechanism Influencing Susceptibility to Cancer • Ataxia-telangiectasia Chromosomal fragility, causing sensitivity to agents that increase genetic recombination • Bloom's syndrome Hypermutability • Chediak-Higashi syndrome Depletion of "natural killer" cells that combat incipient malignancies • Down's syndrome trisomy 21 Tenfold excess leukemia risk • Duncan's disease Lymphoma in those infected by Epstein-Barr virus • Epidermodysplasia verruciformis Skin carcinoma associated with chronic infection with human papilloma virus • Familial polyposis coli Mutation in APC tumor suppressor gene leads to benign colonic growths that are predisposed to malignant transformation • Fanconi's anemia Possible deficiency of enzymes that scavenge active oxidizing species • Glutathione reductase deficiency Very high excess risk of leukemia • Hereditary retinoblastoma Predisposition to retinal cancer due to mutation of one allele of a tumor suppressor gene • Li-Fraumeni syndrome Germline mutation in the p53 tumor suppressor gene predisposes to multiple carcinomas and sarcomas • X-linked agammaglobulinemia Immune deficiency, predisposing to leukemia • Xeroderma pigmentosum Inability to repair some kinds of DNA damage, predisposing to skin cancer caused by ultraviolet radiation aData from Swift et al., 1991; Orth, 1986; Kinzler et al., 1991; Nishisho et al., 1991; Groden et al., 1991; Cleaver, 1968; Friend et al., 1986; Harris, 1989. ble genotype had an odds ratio of 7.3 (95% confidence interval, 2.1-25.1) at a low level of cigarette-smoking; the difference in susceptibility between genotypes was diminished at high levels of smoking, and that suggests that interindividual variation may be especially important for risk-assessment purposes when "low" exposures are involved. The frequencies of this and other genetic poly-

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Page 508 morphisms of enzymes involved in carcinogen metabolism may vary among ethnic groups. CYP2D6 activity is polymorphic and has been linked to lung-cancer risk (Ayesh et al., 1984; Caporaso et al., 1990). CYP2D6 hydroxylates xenobiotics, such as debrisoquine (an antihypertensive drug) and a tobacco-specific N-nitrosamine. A person's polymorphic phenotype is inherited in an autosomal recessive manner. The rate of 4-hydroxylation of debrisoquine varies by a factor of several thousand, and lung-, liver-, or advanced bladder-cancer patients are more likely to have the extensive-hydroxylator phenotype than noncancer controls. In a case-control study of lung cancer in the United States (Caporaso et al., 1990), the extensive-hydroxylator phenotype had a greater cancer risk (odds ratio, 6.1; 95% confidence interval, 2.2-17.1) than poor-hydroxylator phenotype. The increase in risk was primarily for histologic types other than adenocarcinoma. British workers who have the extensive-hydroxylator phenotype and who are exposed to high amounts of asbestos or PAHs have an increased risk of lung cancer (odds ratio, 18.4; 95% confidence interval, 4.6-74 and 35.3; 95% confidence interval, 3.9-317, respectively) (Table H-3) (Caporaso et al., 1989). CYP2D6 might activate chemical carcinogens in tobacco smoke, such as some N-nitrosamines, or perhaps inactivate nicotine, the addictive component of tobacco smoke, so as to decrease its steady-state concentration and lead to an increase in smoking. A person with the extensive-hydroxylator phenotype might thus be at greater cancer risk. Another hypothesis is that an allele of the CYP2D6 gene is in linkage disequilibrium with another gene that influences cancer susceptibility. The N-acetylation polymorphism is controlled by two autosomal alleles at a single locus in which rapid acetylation is the dominant trait and slow acetylation the recessive trait. Both slow acetylation and rapid acetylation of carcinogenic aromatic amines have been proposed as cancer risk factors. The slow-acetylator phenotype has been linked to occupationally induced bladder cancer in dye workers exposed to large amounts of N-substituted aryl compounds (Cartwright et al., 1982). The rapid-acetylator phenotype was more common in two of three studies of colon-cancer cases (Lang et al., 1986; Ladero et al., 1991; Ilett et al., 1987). Wide interindividual differences in enzymes that detoxify carcinogens are also found. For example, competing detoxifying enzymes are found at each step in the metabolic pathway of benzo[a]pyrene activation to electrophilic diol-epoxides. A recent study of several of the enzymes involved in benzo[a]pyrene metabolism confirmed previous observations by showing a more than 10-fold person-to-person variation in enzyme activities and presented indirect evidence that tobacco smoke induced many of these enzymes (Petruzzelli et al., 1988). Genetic control of the presumed detoxification of benzo[a]pyrene by conversion to water-soluble metabolites has also been reported (Nowak et al., 1988). Glutathione S-transferases (GST) are multifunctional proteins that catalyze

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Page 509 TABLE H-3 Examples of Internactions Between Inherited Cancer Predisposition and Environmental Carcinogens Candidate Gene Condition Examples of Cancer Site Environmental Carcinogens Odds Ratio (95% confidence interval) Reference XPAC Xeroderma pigmentosum Skin Sunlight ›1,500 Cleaver, 1968 Unknown Epidermodysplasia verruciformis Skin Sunlight and human papillomavirus (#30% of affected people) Orth, 1986 CYP2D6 Extensive-hydroxylator phenotype Lung Tobacco smoke; Asbestos; PAHa 6.1(2.2-17.1); 18.4 (4.6-74); 35.3 (3.9-317) Caporaso et al., 1990 Caporaso et al., 1989 Caporaso et al., 1989 YP1A1 Extensive-metabolic phenotypeb Lung Tobacco smoke 7.3 (2.1-25.1) Nokachi et al., 1991 Ha-ras Restriction-fragment length polymorphisms (rare alleles) Lungc Tobacco smoke 4.2(1.1-16) Sugimura et al., 1990 NAT2 Slow-acetylator phenotype (recessive inheritance) Bladder Aromatic amine dyes 16.7 (2.2-129) Cartwright et al., 198 NAT2 Rapid-acetylator phenotype (dominant inheritance) Colon Unknown 1.4 (0.6-3.6); 4.1 (1.7-10.3) Lang et al., 1986 Ilett et al., 1987 CYP1A1 Metabolic balance between Lungd Aromatic hydrocarbons 9.1(3.4-24.4) Hayashi et al., 1992 Seidegard et al., 1986 GSTI activation and detoxification       Hayashi et al., 1992 GSTI Metabolic balance between activation and detoxification Lunge Aromatic hydrocarbons 3.5(1.1-10.8) Seidegard et al., 1986 aPolycyclic aromatic hydrocarbon. bIncreased prevalence in Japanese. cNonadenocarcinoma lung cancer in African-Americans. dSquamous cell carcinoma in Japanese. eAdenocarcinoma.

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Page 510 the conjugation of glutathione to electrophiles, including the ultimate carcinogenic metabolite of benzo[a]pyrene, and are considered to be one means of detoxifying carcinogenic PAHs. The three isoenzymes of GST (-є, , and ) vary in their substrate specificity, tissue distribution, and activities among individuals. Expression of GST- is inherited as an autosomal dominant trait, and people with low GST- activity might be at greater risk of lung cancer caused by cigarette-smoking (Seidegard et al., 1986, 1990). In addition, an interaction between GST- and CYP1A1 genotypes has been observed (Hayashi et al., 1992). People with a homozygous deficient GST- genotype and a CYP1A1 genetic polymorphism in the heme-binding region of this cytochrome P450 enzyme have an increased risk of squamous cell carcinoma of the lung (odds ratio, 9.07; 95% confidence interval, 3.38-24.4) and adenocarcinoma of the lung (odds ratio, 3.45; 95% confidence interval, 1.10-10.8). DAN-Adduct Formation DNA adducts are one form of genetic damage caused by chemical carcinogens and might lead to mutations that activate proto-oncogenes and inactivate tumor-suppressor genes in replicating cells. The steady-state concentrations of the adducts depend on both the amount of ultimate carcinogen available to bind and the rate of removal from DNA by enzymatic repair processes. The genomic distributions of adduct formation and repair are nonrandom and are influenced by both DNA sequence and chromatin structure, including protein-DNA interactions that prevent electrophilic attack of the DNA by the active form of the carcinogen. Although the major DNA adducts are qualitatively similar for the chemical carcinogens so far studied in the in vitro models, quantitative differences have been found among people and among various tissue types. The differences due to interindividual variation and intertissue variation within an individual in formation of DNA adducts have a range of a factor of about 10-150 among humans. The interindividual distribution is generally unimodal (i.e., a curve with a single peak), and the variation is similar in magnitude to that found in pharmacogenetic studies of drug metabolism (Harris, 1989). DNA-Repair Rates DNA-repair enzymes modify DNA damage caused by carcinogens in reactions that generally result in the removal of DNA adducts. Studies of cells from donors with xeroderma pigmentosum have been particularly important in expanding understanding of DNA excision repair and its possible relationship to risk of cancer. The rate, but not the fidelity, of DNA repair can be determined by measuring unscheduled DNA synthesis and removal of DNA adducts; substantial interindividual variation in DNA repair rates has been observed (Setlow, 1983). The fidelity of DNA repair could also vary among people, and recent

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Page 511 advances in the identification of mammalian DNA-repair genes and their molecular mechanisms should soon provide an opportunity to investigate the fidelity of repair by excision. In addition to severe decreases in excision-repair rates in the cells of individuals with the recessive genetic conditions xeroderma pigmentosum cells, an approximately 5-fold variation among people in unscheduled DNA synthesis induced by UV exposure of lymphocytes in vitro has been found in the general population (Setlow, 1983). DNA repair might involve tens of enzymes and cofactors, and genetic polymorphisms of the genes encoding these repair enzymes could be responsible for the variation among both persons and groups. Interindividual variation has been noted in the activity of O6-alkyldeoxyguanine-DNA alkyltransferase; this enzyme repairs alkylation damage to O6-deoxyguanine. Wide variations (a factor of about 40) in this DNA-repair activity have been observed between persons in different types of tissues (Grafstrom et al., 1984; D'Ambrosio et al., 1984, 1987), and fetal tissues exhibit only about 20-50% as much activity as the corresponding adult tissues (Myrnes et al., 1983). A unimodal distribution of repair rates of benzo[a]pyrene diolepoxide-DNA adducts has been observed in human lymphocytes in vitro (Oesch et al., 1987). The interindividual variation was substantially greater than the intraindividual variation, and this suggests a role of inherited factors. The influence of those variations in DNA-repair rates in determining tissue site and risk of cancer in the general population remains to be determined. Synergistic Effects Of Carcinogens People who have been exposed to one type of carcinogen might be at increased risk of cancer when exposed, simultaneously or in sequence, to another type (Table H-4). Cigarette smokers, already at greater risk of lung cancer than nonsmokers, are at even greater risk if they are occupationally exposed to asbestos (Selikoff and Hammond, 1975; Saracci, 1977) or radon (Archer, 1985). Recently, a synergistic effect between hepatitis B virus and aflatoxin B1 in the risk of hepatocellular carcinoma has been described (Ross et al., 1992). Age Children exposed to carcinogens might be at higher risk of cancer than adults (NRC, 1993; ILSI, 1992). Studies of atomic-bomb survivors and persons irradiated for the treatment of cancer have found the risk of future cancers of breast, lung, stomach, thyroid, and connective tissues to be greater when exposure is at lower ages (Fry, 1989). On the other hand, the elderly may be at increased susceptibility to other carcinogenic stimuli, cue to diminished immune surveillance, exposure to multiple drugs, or simply to a larger accumulation of DNA damage that places some cells at high risk of initiation from one more "hit" to the genetic material.

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Page 512 TABLE H-4 Examples of Synergistic Effects Among Chemical, Physical, and Viral Carcinogens. Cancer Type Carcinogens Odds Ratio (95% Confidence Interval) Reference Liver Hepatitis B virus; + aflatoxin B1 exposure 4.8 (1.2-19.7) 60 (6.4-561.8) Ross et al., 1992 Esophagus Tobacco smoke; + alcoholic beverages 5.1 (-); 44.4 (-) Tuyns et al., 1977 Mouth Tobacco smoke; + alcoholic beverages 2.4 (-); 15.5 (-) Rothman and Keller, 1972 Lung Tobacco smoke; + occupational; asbestos exposure 8.1 (5.2-12.0) 92.3 (59.2-137.4) Selikoff and Hammond, 1975 Saracci, 1977 References Archer, V.E. 1985. Enhancement of lung cancer by cigarette smoking in uranium and other miners. Pp. 23-37 in Cancer of the Respiratory Tract: Predisposing Factors. Carcinogenesis—A Comprehensive Survey, Vol. 8, M.J. Mass, D.G. Kaufman, J.M. Siegfried, V.E. Steele, and S. Nesnow, eds. New York: Raven Press. Ayesh, R., J.R. Idle, J.C. Ritchie, M.J. Crothers, and M.R. Hetzel. 1984. Metabolic oxidation phenotypes as markers for susceptibility to lung cancer. Nature 312:169-170. Borysenko, J. 1987. Psychological variables. Pp. 295-313 in Variations in Susceptibility to Inhaled Pollutants: Identification, Mechanisms, and Policy Implications, J.D. Brain, B.D. Beck, A.J. Warren, and R.A. Shaikh, eds. Baltimore, Md.: The Johns Hopkins University Press. Calabrese, E.J. 1978. Methodological Approaches to Deriving Environmental and Occupational Health Standards. New York: Wiley Interscience. Caporaso, N.E., R.B. Hayes, M. Dosemeci, R. Hoover, R. Ayesh, M. Hetzel, and J. Idle. 1989. Lung cancer risk, occupational exposure, and the debrisoquine metabolic phenotype. Cancer Res. 49:3675-3679. Caporaso, N.E., M.A. Tucker, R.N. Hoover, R.B. Hayes, L.W. Pickle, H.J. Issaq, G.M. Muschik, L. Green-Gallo, D. Buivys, S. Aisner, J.H. Resau, B.F. Trump, D. Tollerud, A. Weston, and C.C. Harris. 1990. Lung cancer and the debrisoquine metabolic phenotype. J. Natl. Cancer Inst. 82:1264-1272. Cartwright, R.A., R.W. Glashan, H.J. Rogers, R.A. Ahmad, D. Barham-Hall, E. Higgins, and M.A. Kahn. 1982. The role of N-acetyltransferase phenotypes in bladder carcinogenesis: A pharmacogenetic epidemiological approach to bladder cancer. Lancet 2:842-846. Cleaver, J.E. 1968. Defective repair replication of DNA in xeroderma pigmentosum. Nature 218:652-656. D'Ambroiso, S.M., G. Wani, M. Samuel, and R.E. Gibson-D'Ambrosio. 1984. Repair of O6-methylguanine in human fetal brain and skin cells in culture. Carcinogenesis 5:1657-1661. D'Ambrosio, S.M., M.J. Samuel, T.A. Dutta-Choudhury, and A.A. Wani. 1987. O6-methylguanine-DNA methyltransferase in human fetal tissues: Fetal and maternal factors. Cancer Res. 47:51-55.

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