Chapter 16 Environmental Cancer 16.1 INTRODUCTION Cancer refers to any of a group of diseases characterized by uncontrolled growth and spread of abnormal cells. In the scientific or medical community, the term malignant neoplasm (tumor) is often used in place of cancer. Malignant tumors develop most commonly in major organs, such as the lungs, liver, stomach, intestines, skin, breasts, or pancreas, but they may also develop in lips, tongue, testes, or ovaries. Cancer may also develop in the blood-cell-forming tissues of the bone marrow (the leukemias) and in the lymphatic system or bones. In recent decades there has been growing concern about the possible effects of a large number of environmental toxicants on carcinogenesis. As noted in previous chapters, cancer incidence and mortality have increased dramatically over the past century. Researchers consider that there are two main reasons for the observed increase: the aging of the population, and an increase of carcinogens present in and released into the environment through human activities. Studies show that nearly 30% of the total mortality in many industrialized countries is attributed to cancer. In the U.S., can cer remains the number-two killer, accounting for nearly one fourth of all deaths. Despite the recent decline in the mortality rate, the total number of cancer deaths continues to rise as the elderly population increases. For example, the death toll in the U.S. in 1980 was 416,509, in 1995 it was 538,455, 1 and it is estimated to be 556,500 in 2003. 2 One of the most common characteristics of the development of a neoplasm in an organism is the long period of time between the initial application of a carcinogenic (cancer-causing) agent, or carcinogen, and the appearance of a neoplasm. The latency period varies with the type of carcinogen, its dosage, and certain characteristics of the target cells within the host. In humans, cancer may not be manifested until at least 10 or more years after an initial exposure to a carcinogen. 16.2 CAUSES OF CANCER Many factors can lead to cancer. These factors include: diet, smoking, alcohol, reproductive and sexual behavior, occupational hazard, geo graphical factors, and environmental agents. An estimate of the contribution of various agents or life styles to the cause of cancers is presented in Table 16.1. It is notable that [16:51 26/8/04 P:/CRC PRESS/4365 MING-HO.751 (1670)/4365-016.3d] Ref: 4365 MING-HO YU Chap-016 Page: 279 279-294 # 2005byCRCPressLLC diet and smoking account for approximately two thirds of all cancers. Smoking is particularly implicated in lung and bladder cancers. Although there are many theories concerning the causes of cancer, the fundamental principle underlying these theories is the alteration of the genetic material of the cell, the DNA. The various theories attempt to explain how this change is brought about. The DNA of a cancer cell is sligh tly different from that of a normal cell. This means that the sequence of the bases – adenine (A), guanine (G), thymine (T), and cytosine (C) – in a given strand of DNA is not the same as that of the bases in a normal cell. As mentioned in Chapter 15, these sequences dictate the sequences of the transcribed messenger RNA (mRNA), which in turn specify the kinds of proteins to be synthesized in a cell. Alteration in the DNA base sequence in cancer cells results in abnormal proteins. These new proteins influence the mechanisms of growth control in such a way that cell division continues indefinitely. As discussed in Chapter 15, several types of DNA damage can occur. The most common ones include: single- and double-strand breaks in the DNA backbone, formation of crosslinks between DNA bases and between DNA bases and proteins, and chemical addition to the DNA bases. These alterations can result from exposure to radiation and to chemical, biological, and genetic factors (Tab le 16.2). For example, ionizing radiations, such as x-rays and g- rays, can produce DNA single- and double-strand breaks and various forms of damage to bases. Ultraviolet (UV) light, which is a non-ionizing radiation, is capable of producing dimers. A variety of chemicals can cause DNA damage through base alterations. Alteration may be induced directly through formation of adducts, or indirectly through intercalation formed by a chemical between two bases. Many electrophilic chemicals can react with DNA, forming covalent additional products termed adducts. For example, alkylating agents can yield a reactive alkyl group that can react with base material, such as guanine, to produce an adduct. 280 Environmental Toxicology [16:51 26/8/04 P:/CRC PRESS/4365 MING-HO.751 (1670)/4365-016.3d] Ref: 4365 MING-HO YU Chap-016 Page: 280 279-294 Table 16.1 Speculative Proportion of Cancer Deaths Attributed to Various Factors Factor or class of factors Percent of all cancer deaths Diet 35 Tobacco 30 Reproductive and sexual behavior 7 Occupational hazards 4 Geophysical factors 3 Alcohol 3 Pollution 2 Industrial products 1 Medicine and medical procedures 1 Infection 10? Unknown ? Source: Adapted from USDHHS, The Surgeon General’s Report on Nutrition and Health, U.S. Government Printing Office, Washington, D.C., 1988. # 2005byCRCPressLLC 16.3 STAGES IN THE DEVELOPMENT OF CANCER It is generally accepted that the pathway leading to carcinogenesis includes three stages: init iation, promotion, and progression (Figure 16.1). 3 Initiation results from a simple mutation in one or more cellular genes that control key regulatory pathways of the cell. It requires cell division for the fixation of the process. Unlike promotion or progression, initiation is irreversible in a viable cell. 4 The efficiency of initiation is sensitive to xenobiotic and oth er chemical factors, and the stage can be altered by both endogenous and exogenous factors. For example, a variety of chemicals in different tissues can inhibit the metabolism of a procarcinogen to an ultimate carcinogen (see Section 16.6), thereby blocking the initiation process. Initiators may also produce trans- Environmental Cancer 281 [16:51 26/8/04 P:/CRC PRESS/4365 MING-HO.751 (1670)/4365-016.3d] Ref: 4365 MING-HO YU Chap-016 Page: 281 279-294 Table 16.2 General Classification of Carcinogenic Agents Class Example Radiation Ultraviolet and ionizing radiations Chemical Polycyclic aromatic hydrocarbons, aromatic amines and halides, benzene, vinyl chloride, aflatoxin B 1 , urethane, asbestos, certain metals, diet, and tobacco smoke Genetic Viruses Biological Transgenesis by enhancer–promoter–oncogene constructs FIGURE 16.1 Three stages of carcinogenesis. Source: Adapted from USDHHS, The Surgeon General’s Report on Nutrition and Health, 1988. # 2005byCRCPressLLC formed cells that can persist for the life-span of an individual without producing cancer. In such cases, the damaged gene in the transformed cells remains recessive because the damaged gene does not express an abnormal protein. Promotion results from the selective functional enhancement of signal transduction pathways induced in the initiated cell and its progeny by the continuous exposure to the promoting agent. 4 This stage involves gene activation, leading to the synthesis of the abnormal protein. Rapid cell division then occurs, which is accompanied by interruption of the organism’s normal functions or health. Promotion then leads to the express ion of the genetic changes as malignancy, which involves loss of control over cellular prolifera- tion. Examples of promoting agents include: saccharin, butylated hy droxyto- luene, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, see Chapter 13), and androgens and estrogens. In contrast to initiation, promotion is reversible. Therefore, if the promoting agent is withdrawn well before tumors are manifested, the appearance of tumors can be delayed or prevented. Furthermore, promotion may be continually modulated by various environ- mental factors, including frequency with which the promoting agent is administered, age and sex of the subject, hormonal balance, and composition and amount of diet. Research shows that many promoting agents exert their effects on the cell through mediation of receptor mechanisms. 5 Some chemicals act as both initiat ors and promoters. Benzo(a)pyrene is such a chemical. In small doses it initiates genetic damage, and in higher or repeated doses, it enhances promotion. Promoting agents involved in the onset of promotion do not cause cancer by themselves; they only have a specific impact on an initiated cell. Promotion is gradual, and some of the earlier steps are reversible. In the promotion stage, abnormal proliferation of the affected cell occurs, presumably because of a high concentration of growth factors or modified cell-surface receptors. If the damage to the gene is not drastic, most of the normal components of the cell will be produced and will be responsive to normal growth-inhibiting factors. Experiments with animals suggest that the time lapse between initiation and promotion is not critical. During the latter stage of promotion, however, cumulative genetic changes occur, leading to totally irreversible neoplastic transformation. Progression results from continuing evolution of an unstable karyotype. This stage usually develops from cells in the stage of promotion, but, in certain conditions, it may develop directly from normal cells. The critical molecular characteristic of this stage is karyotypic instability, and morphologically discernible changes in cellular or genomic structure occur. 4 Furthermore, benign or malignant tumors may be observed in this stage. The growth of altered cells is sensitive to environmental factors during the early phase of progression. 282 Environmental Toxicology [16:51 26/8/04 P:/CRC PRESS/4365 MING-HO.751 (1670)/4365-016.3d] Ref: 4365 MING-HO YU Chap-016 Page: 282 279-294 # 2005byCRCPressLLC 16.4 METASTASIS The most fearsome aspect of cancer is the spread of malignant cells from the primary site to other parts of the body – a process called metastasis. This is the late stage of the diseas e and is characterized by invasive activity and the appearance of a variety of cancer-cell types. Some of the cells that have the inherent ability to detach from the primary site eventually travel via the blood or lymph to start a secondary tumor at another site. Metastasis is the primary cause of the failure of treatment in cancer patients. The extent of the dissemination of the malignant cells is determined by the physiological condition of the host. During metastasis, continuous changes occur in the tumor, and the function and behavior of the tumor cells in the late stage are quite different from those in the early stage. Most frequently, the location of metastasis is in the organ or organs that are served by blood vessels from the original cancer site. Notably, growth and survival of a tumor require nourishment, which is provided by new blood vessels near the tumor site. 16.5 CLASSIFICATION OF CARCINOGENS Carcinogens are divided into two groups: Part A and Part B (based on a list prepared by the U.S. National Toxicology Program, see Appendix 3). Part A refers to those agents that are ‘‘Known to be a human carcinogen,’’ whereas Part B refers to those that are ‘‘Reasonably anticipated to be a human carcinogen.’’ Examples of carcinogens belonging to Part A include: aflatoxins, inorganic arsenic compounds, asbestos, benzene, beryllium, coal tars, dioxin, diethylstilbestrol, tobacco smoking, steroidal estrogens, nickel compounds, radon, vinyl chloride, and UV radiation (see Appendix 3, Part A). More than one hundred agents are included in Part B (see Appendix 3, Part B). As noted earlier, the basic changes in DNA that can lead to cancer, i.e., mutation, can be caused by many agents. These agents are generally divide d into four categories: radiation, chemical, biological, and genetic (Table 16.2). 3 Although mutation does not necessarily result in cancer, cancer occurs if the proteins that are produced following mutation affect cell ular growth-control mechanisms. The following section discusses in some detail the agents that can cause DNA damage. Emphasis is placed on radiation and chemical agents. 16.5.1 R ADIATION The process involved in radiation-induced DNA damage is complex and has received much attention over many years. As noted previously, ionizing radiation produces a wide variety of DNA lesions, including various base modifications, strand breaks, and DNA-protein crosslinks. 6 It was men tioned in Chapter 15 that absorption of short-wave UV radiation by DNA causes breakage in its strands, the opening of the rings of its bases, and the formation of thymine dimers. Environmental Cancer 283 [16:51 26/8/04 P:/CRC PRESS/4365 MING-HO.751 (1670)/4365-016.3d] Ref: 4365 MING-HO YU Chap-016 Page: 283 279-294 # 2005byCRCPressLLC UV radiation is the main cause of skin cancer. Increased UV radiation exposure– much of it is caused by sunbathing or tanning under a UV lamp – is the main contributing factor to the rising incidence of skin cancer worldwide. UV radiation induces formation of free radicals, especially reactive oxygen radicals. Of the three types of UV radiation (UV-A, -B, and -C), UV-B is the most harmful type. UV-B (which has a wavelength of 280 to 320 nm) is attenuated by the earth’s ozone layer. Several other factors modulate the amount of UV radiation to which people are exposed, including time of day, season, humidity, and distance from the equator. Skin cancer risk is also affected by skin type; fair skin that freckles or bumps easily is at more risk than very darkly pigmented skin. People who live in sunny climates and have red or blond hair and blue or light-col ored eyes are at especially high risk. Among the photochemical reactions that take place when UV-B penetrates the skin is mutation of the DNA in skin cells. Humans have repair enzymes that can correct this damage, but mutations accumulate as the individual ages. An individual’s lifestyle may also cause the repair system to eventually become overtaxed, resulting in skin cancer. Most researchers stress that the damage begins accumulating early – in childhood; by young adulthood about 50 % of lifetime sunlight exposure may have already accumulated. 16.5.2 C HEMICAL CARCINOGENS The association between exposure to chemicals and cancer incidence was first reported in 1775 by the English physician Percivall Pott, following the observation of scrotal cancer in chimney sweeps. 7 With an increase in European industrial development during the 19th century, high rates of skin cancer were observed among workers in the shale oil and coal tar industries. In 1915, a group of Japanese scientists conducted experiments in which they painted rabbits with coal tar and induced tumors. This led to the knowledge that the compounds contained in the coal tar could produce cancer in animals. Several groups of organic compounds have now been recognized as carcinogenic to laboratory animals. These include polycyclic aromatic hydro- carbons (PAHs), aromatic amines, aminoazo dyes, nitroso compounds, benzene, and vinyl chloride. 8 Many chemical agents that may be found in foods are also known to cause cancer. For example, aflatoxin B 1 , which causes liver cancer in several species of test animals, is produced by Aspergillus flavus found in contaminated peanut or cottonseed meal. There are also naturally produced substances that are carcinogenic. A number of inorganic substances have also been shown to induce cancer. These include some salts of arsenic (As), beryllium (Be), cadmium (Cd), chromium (Cr)(VI), nickel (Ni), and lead (Pb). It should be pointed out that some of these metals are essential nutrients for humans and animals. Trival ent Cr (Cr 3þ ) is one of these metals. As part of the glucose tolerance factor, Cr plays an important role in maintaining normal glucose metabolism in mammals. 284 Environmental Toxicology [16:51 26/8/04 P:/CRC PRESS/4365 MING-HO.751 (1670)/4365-016.3d] Ref: 4365 MING-HO YU Chap-016 Page: 284 279-294 # 2005byCRCPressLLC Several chlorinated hydrocarbons and other chemicals have been identified as carcinogenic. These include 2,4-D, DDE, hexachlorocyclohexane, poly- chlorinated biphenyls (PCBs), and polychlorinated dibenzo-p-dioxins (PCDDs) (see Chapter 13). 16.6 METABOLISM OF CHEMICAL CARCINOGENS As shown in Figure 16.1, chemical carcinogens are divided into two broad classes: direct carcinogens and procarcinogens. Direct carcinogens are usually electrophiles, such as H þ ,C þ ,N þ , and can react readily with nucleoph iles, such as proteins and nucleic acids. The main sites in these molecules where such reactions can occur are S, ¼N–, –C–OH, or –P–OH. Examples of cellular nucleophiles include some amino acids, such as methionine, cysteine, histidine, tryptophan, and tyrosine, and nucleic acid bases, such as adenine (N-1, N-3) and guanine (C-8, N-7, O-6). Procarcinogens are those agents that require biologic activation before becoming ultimate carcinogens. Compared with direct carcinogens, procarcinogens are relatively stable, and so many people may be environmentally or occupationally exposed to them. It is possible for people to ingest or absorb some procarcinogens, after which enzymes in the liver, lungs, or other organs convert them to their activated metabolites. It is thought that most, and probably all, chemical carcinogens are converted by metabolism into electrophilic reactants that exert their biological effects by covalent interaction with DNA. Some examples of these reactants are shown in Figure 16.2. Several of these chemicals are discussed in some detail in the following sections. The discussion will focus on free radicals, DDT, vinyl chloride, nitrosamine, ben zo[a]pyrene, and halogenated aromatic hydrocar- bons. 16.6.1 F REE RADICALS Reactive oxygen species, such as hydroxyl radicals (OH Á ), are produced during the enzymatic and chemical reactions of molecular oxygen in cells. Hydroxyl radicals are also produced when cells are exposed to ionizing radiation, tumor promoters, and chemical carcinogens. As mentioned earlier, reactive oxygen species can cause various lesions in DNA, by inducing damage to nucleic acids and altering their structures an d function. Oxygen-induced lesions of nucleic acids include strand breaks 9 and base modification products. Alternatively, the OH Á free radical, formed through the reaction between superoxide free radical (O 2 Á À ) and H 2 O 2 (Reaction 16.1), is unique and can induce breaks in the phosphodiester bonds. Both single- and double-strand breaks can occur. In addition, the free radical can abstract H-atoms from the DNA helix. 10 O 2 Á À þ H 2 O 2 ! O 2 þ HO À þ HO Á ð16:1Þ Environmental Cancer 285 [16:51 26/8/04 P:/CRC PRESS/4365 MING-HO.751 (1670)/4365-016.3d] Ref: 4365 MING-HO YU Chap-016 Page: 285 279-294 # 2005byCRCPressLLC 16.6.2 DDT DDT is one of the several pesticides that have been added to the long list of cancer-causing agents present in the en vironment. According to a report by the National Cancer Institute, women with high exposures to DDT may have a greater risk of developing breast cancer. Researchers at Mt. Sinai Hospital in New York City have found that women with blood levels of DDE (see Chapter 13) of 19 ng/ml have four times the risk of breast cancer compared with women with levels of 2 ng/ml. It is suggested that DDE may cause breast cancer in two ways: it may induce cytochrome P450 enzymes, thereby altering the metabolism of toxicants, or it may act as an estrogen mimic and as such may disrupt the endocrine system through interaction with estrogen receptors (see Chapter 14). 286 Environmental Toxicology [16:51 26/8/04 P:/CRC PRESS/4365 MING-HO.751 (1670)/4365-016.3d] Ref: 4365 MING-HO YU Chap-016 Page: 286 279-294 FIGURE 16.2 Some examples of chemical carcinogens. # 2005byCRCPressLLC 16.6.3 VINYL CHLORIDE Vinyl chloride, the common name for monochloroethene (CH 2 ¼CHCl), is one of the most widely manufactured organic chemicals in the U.S. Vinyl chloride is a gas at ambient temperature, with a boiling point of 14  C, and exhibits a low solubility in water. While the vinyl chloride monomer itself is rarely used, it is polymerized with itself and other organic compounds to form many products, making it a very important chemical to industry and to consumers. Among the many polymers that are derived from vinyl chloride, polyvinyl chloride (PVC) is the most common. PVC, as a solid material, is extremely adaptable and cost effective, and is used in numerous construction materials, home furnishings, packaging materials, automobile products, etc. Some examples of the products made of PVC are water pipes, raincoats, credit cards, wire coatings, and food packaging. PVC production involves three stages: synthesis of vinyl chloride monomer from petrochemicals and chlorine, polymerization of vinyl chloride into PVC resin, and PVC fabrication. Environme ntal contamination occurs from these processes, although the extent of it varies with each stage. The contamination includes emission of vinyl chloride into the atmosphere, and surface and groundwater contamination resulting from sludge and wastewater discharge. Vinyl chloride has been shown to be both mutagenic and carcinogenic. It is classified as a Part 1 carcinogen because sufficient evidence exists that the compound is carcinogenic to humans. This is highly important because only about 40 chemicals or chemical mixtures are classified as such. 11 Vinyl chloride causes liver cancer in both humans and laboratory animals. However, laboratory experiments with mice showed induction of not only liver can cer but also cancers of bone, skin, lung, brain, nephron, and mammary tissues. 11,12 In humans, vinyl chloride exposure may occur both occupationally and non- occupationally. Vinyl chloride is metabolized by the hepatic cytochrome P450 enzymes to the carcinogenic epoxide form. Studies show that this metabolite is an ultimate carcinogen. It reacts with DNA, causing it to change its function. In the liver, the active epoxide may be further converted to chloroethane aldehyde. A molecule of glutathione can conjugate the aldehyde and the resultant co njugate may then be excreted (Figure 16.3). 16.6.4 A LKYLATING AGENTS As noted in Chapter 15, alkylating agents are those chemicals that can react with DNA to produce alkylated DNA adducts. Several groups of organic compounds can be metabolized to alkylating agents. An example is N-nitroso compounds, which consist of nitrosamines and nitrosamides. Nitroso com- pounds are found in various types of food, particularly meat and meat products (e.g., fried and cured meat products) and cheese. Small amounts of the compounds have been shown to occur in beer, and tobacco smoke contains Environmental Cancer 287 [16:51 26/8/04 P:/CRC PRESS/4365 MING-HO.751 (1670)/4365-016.3d] Ref: 4365 MING-HO YU Chap-016 Page: 287 279-294 # 2005byCRCPressLLC varying amounts. Industrial exposure to N-nitrosamines accounts for another environmental source. Occupation or industrial activities that may lead to exposure include metal cutting and rolling, leather tanning, rubber manufac- ture, handling of hydraulic fluids, and producing or using amines in the chemicals industry. In these activities, exposure is mostly via air and skin. 13 The importance of nitrosamines as environmental carcinogens was first postulated in 1962. Subsequent studies demonstrated the endogenous forma- tion of such compounds from precursor amines and nitrite in vivo. The endogenous formation of N-nitroso compounds from precursor amines and nitrosating agents, particularly nitrite, is unique among the various chemical carcinogens. Nitrosat able amine precursors, such as secondary and tertiary amines, are natural constituents of food or contaminants of food, such as some pesticides that can be nitrosated. Nitrite is the most important nitrosating agent and is present in some food products. However, nitrite can also be formed from nitrate in saliva and possibly in the intestines. The pathway leading to the formation of an alkylating agent from dimethylamine is presented in Figure 16.4. The first step is nitrosation in which dimethylamine reacts with nitrite to form dimethylnitrosamine, a nitroso compound. Metabolism of dimethylnitrosamine leads to the formation of a CH 3 þ radical, which can react with DNA, resulting in methylated DNA. 288 Environmental Toxicology [16:51 26/8/04 P:/CRC PRESS/4365 MING-HO.751 (1670)/4365-016.3d] Ref: 4365 MING-HO YU Chap-016 Page: 288 279-294 FIGURE 16.3 Metabolism of vinyl chloride by the cytochrome P450 system. FIGURE 16.4 Activation mechanism of dimethylamine. # 2005byCRCPressLLC [...]... 2,3,7,8-Tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: Examination of the mechanism of toxicity, Annu Rev Pharmacol Toxicol., 22, 517, 1982 22 Stryer, L., Biochemistry, 3rd ed., W.H Freeman & Co., New York, 1988, p.694 # 2005 by CRC Press LLC [1 6:5 1 26/8/04 P:/CRC PRESS/4365 MING-HO.751 (167 0)/436 5-0 16. 3d] Ref: 4365 MING-HO YU Chap- 016 Page: 293 27 9-2 94 294 Environmental Toxicology. .. hematite mining (with exposures to radon) Source: IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Supplement No 4 (Updated) # 2005 by CRC Press LLC [1 6:5 1 26/8/04 P:/CRC PRESS/4365 MING-HO.751 (167 0)/436 5-0 16. 3d] Ref: 4365 MING-HO YU Chap- 016 Page: 291 27 9-2 94 292 Environmental Toxicology proteins As discussed in Chapters 13 and 14, the receptor is an intracellular protein... Press LLC [1 6:5 1 26/8/04 P:/CRC PRESS/4365 MING-HO.751 (167 0)/436 5-0 16. 3d] Ref: 4365 MING-HO YU Chap- 016 Page: 290 27 9-2 94 Environmental Cancer 291 PCDDs and some other halogenated aromatic hydrocarbons have been shown to be carcinogenic in rats and mice .16, 17 Hepatocellular carcinomas were produced in both species following dioxin exposure, but only female rats developed squamous cell carcinomas of the... and cancer 16. 8 REFERENCES 1 National Center for Health Statistics, 1997 2 American Cancer Society, Cancer Facts and Figures 2003, ACS, Atlanta, GA, 2003, p.4 3 U.S Department of Health and Human Services, The Surgeon General’s Report on Nutrition and Health, U.S Government Printing Office, Washington, D.C., 1988, 177 # 2005 by CRC Press LLC [1 6:5 1 26/8/04 P:/CRC PRESS/4365 MING-HO.751 (167 0)/436 5-0 16. 3d]... Comparison of potency of human carcinogens: Vinyl chloride chloromethylmethyl ether and bis(chloromethyl) ether, Environ Res., 49, 143, 1989 12 Moss, A.R., Occupational exposure and brain tumors, J Tox Environ Health, 16, 703, 1985 13 Preussmann, R., Eisenbrand, G and Spiegelhalder, B., Occurrence and formation of N-nitroso compounds in the environment and in vivo, in Emmelot, P and Kriek, E., Eds., Environmental. .. Fats and oils Cheese Alcohol beverage PAH content 2.6 to13.0 ng/m3 1.5 to 13.0 ng/m3 8.0 ng/l 1.2 ng/l 2.8 ng/l 0.07 mg/kg dry wt 1.10 mg/kg 137 mg/kg 35 mg/kg 26 mg/kg 12 mg/kg 0.10 mg/kg 36 mg/kg 46 mg/kg 9 mg/kg 2.4 mg/kg 0.09 mg/kg 66 mg/kg 1.70 mg/kg 0.08 mg/kg # 2005 by CRC Press LLC [1 6:5 1 26/8/04 P:/CRC PRESS/4365 MING-HO.751 (167 0)/436 5-0 16. 3d] Ref: 4365 MING-HO YU Chap- 016 Page: 289 27 9-2 94... (167 0)/436 5-0 16. 3d] Ref: 4365 MING-HO YU Chap- 016 Page: 292 27 9-2 94 Environmental Cancer 293 4 Pitot, H.C and Dragan, Y.P., Chemical carcinogenesis, in Klaassen, C.D., Ed., Casarett & Doull’s Toxicology, 6th ed., McGraw-Hill, New York, 2001, p.241 5 Pitot, H.C and Dragan, Y.L.P., Facts and theories concerning the mechanisms of carcinogenesis, FASEB J., 5, 2280, 1991 6 Le, X.C et al Inducible repair of thymine... ultimate carcinogen 15 How may DDE be related to carcinogenesis? 16 Explain the suggested mechanism by which dioxins act as a carcinogens 17 Explain the mechanism that mammalian systems possess for repairing DNA damage # 2005 by CRC Press LLC [1 6:5 1 26/8/04 P:/CRC PRESS/4365 MING-HO.751 (167 0)/436 5-0 16. 3d] Ref: 4365 MING-HO YU Chap- 016 Page: 294 27 9-2 94 ... 1,2,3,7,8,9Hexachlorodibenzo-p-dioxin for Possible Carcinogenicity DHHS Publication (NIH) 8 0-1 754, DHHS, Washington, D.C., 1980 17 National Toxicology Program (NTP), Bioassay of 2,3,7,8-Tetraclorodibenzo-pdioxin for Possible Carcinogenicity (Gavage Study), DHHS Publication (NIH) 8 2-1 765, DHHS, Washington, D.C., 1982 18 Kochiba, R.J and Schwetz, B.A., Toxicity of 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD), Drug... 27 9-2 94 290 Environmental Toxicology FIGURE 16. 5 Benzo[a]pyrene (BaP) and formation of BaP–guanine adduct disposal (open burning), wood burning, and forest and agricultural refuse burning BaP is found in most commercial motor oil, asphalt roofing and other construction materials, and tobacco smoke (Table 16. 4) Like most PAHs, BaP is ubiquitous in the environment, being found in air, water, soil, and food . HO Á ð1 6:1 Þ Environmental Cancer 285 [1 6:5 1 26/8/04 P:/CRC PRESS/4365 MING-HO.751 (167 0)/436 5-0 16. 3d] Ref: 4365 MING-HO YU Chap- 016 Page: 285 27 9-2 94 # 2005byCRCPressLLC 16. 6.2 DDT DDT is one of. pesticides. 290 Environmental Toxicology [1 6:5 1 26/8/04 P:/CRC PRESS/4365 MING-HO.751 (167 0)/436 5-0 16. 3d] Ref: 4365 MING-HO YU Chap- 016 Page: 290 27 9-2 94 FIGURE 16. 5 Benzo[a]pyrene (BaP) and formation of. adduct. 280 Environmental Toxicology [1 6:5 1 26/8/04 P:/CRC PRESS/4365 MING-HO.751 (167 0)/436 5-0 16. 3d] Ref: 4365 MING-HO YU Chap- 016 Page: 280 27 9-2 94 Table 16. 1 Speculative Proportion of Cancer