Environmental Life Cycle Costing - Chapter 15 (end) pptx

219 CHAPTER 15 Environmental Cancer 15.1 INTRODUCTION Cancer is any of a group of diseases characterized by uncontrolled growth and spread of abnormal cells. The term “malignant neoplasm (tumor)” is often used in place of cancer in the scientific or medical community. Most commonly, malignant tumors develop in major organs, such as the lungs, liver, stomach, intestines, skin, breasts, or pancreas, but they may also develop in lips, tongue, or the 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. As noted earlier, cancer incidence and mortality have increased dramatically over the last century. Researchers consider that there are two main reasons for this increase: the aging of the population and an increase in pollution from carcinogens present in and released into the environment through human activities. Indeed, nearly 30% of the total mortality in many industrialized countries is attributed to cancer. In the U.S., cancer 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, in the U.S. the toll in 1980 was 416,509; in 1995 it was 538,455; 1 and in 1999 it was estimated to be 564,100. 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 carcino- genic (cancer-causing) agent, or carcinogen, and the appearance of a neoplasm. The latency period varies with the type of carcinogen, its dosage, and certain character- istics of the target cells within the host. In humans, cancer may not be manifested until 10 or more years after an initial exposure to a particular carcinogen. LA4154/frame/C15 Page 219 Thursday, May 18, 2000 12:05 PM © 2001 by CRC Press LLC 220 ENVIRONMENTAL TOXICOLOGY 15.2 CAUSES OF CANCER Many factors can lead to cancer. Table 15.1 gives an estimate of the contribution of various agents or lifestyles to the cause of cancers. It is notable that 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 idea underlying these theories is the alteration of the genetic material, the DNA of the cell. The various theories attempt to explain how this change is brought about. The DNA of a cancer cell is slightly 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 a normal cell. As discussed in Chapter 14, these sequences dictate the sequence of the transcribed mRNA, which in turn specifies 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. 15.3 STAGES IN THE DEVELOPMENT OF CANCER Although the precise mechanisms involved in the causation of cancer are not known, many researchers consider the pathway leading to carcinogenesis to include three stages: initiation , promotion , and progression (Figure 15.1). 3 According to this view, carcinogenesis is initiated following an alteration of the genetic information, i.e., DNA of the cell. In other words, initiation occurs as a normal cell is transformed into a precancerous cell via alteration of the DNA molecule, and reflects a permanent and irreversible change in the initiated cell. The stage of initiation can be altered by both endogenous and exogenous factors. For example, a variety of chemicals in different tissues can inhibit the metabolism Table 15.1 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 ? Adapted from USDHHS, The Surgeon General’s Report on Nutrition and Health, U.S. Government Printing Office, Washington, DC, 1988. LA4154/frame/C15 Page 220 Thursday, May 18, 2000 12:05 PM © 2001 by CRC Press LLC ENVIRONMENTAL CANCER 221 of a certain chemical to an ultimate carcinogen, thereby blocking the initiation process. Furthermore, in humans there are corrective enzymes that can repair certain damage and reverse the adverse effects (see Section 15.7). Initiators can also produce transformed cells that may 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 is not expressing an abnormal protein. Promotion is the step involving gene activation to synthesize the abnormal pro- tein. Thus, rapid cell division occurs, and this is accompanied by the interruption of the organism’s normal function or health. Promotion then leads to the expression of genetic changes as malignancy, which involves loss of control over cellular prolif- eration. In contrast to initiation, promotion is considered to be reversible. Thus, if the promoting agent is withdrawn well before tumors are manifested, the appearance of tumors can be delayed or prevented. In addition, promotion may be continually modulated by various environmental factors, including the frequency with which the promoting agent is administered, age and sex of the experimental animals, 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. 4 Figure 15.1 Three stages of carcinogenesis. (Adapted from USDHHS, The Surgeon General’s Report on Nutrition and Health, U.S. Government Printing Office, Washington, DC, 1988.) LA4154/frame/C15 Page 221 Thursday, May 18, 2000 12:05 PM © 2001 by CRC Press LLC 222 ENVIRONMENTAL TOXICOLOGY Some chemicals act as both initiators and promoters. Benzo[a]pyrene, a product of incomplete combustion of carbonaceous material is such a chemical. In small doses it initiates genetic damage, and in higher or repeated doses, a promotion reaction ensues. The agents involved in the onset of promotion cause cancer not by themselves but only in an initiated cell. The artificial sweetener saccharin is an example of a promoter. Promotion is gradual; moreover, 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. Animal experiments suggest that the time lapse between initiation and promotion is not critical. During the later stage of promotion, however, cumulative genetic changes occur, leading to totally irreversible neoplastic transformation. Once a cell has been irreversibly modified, a cancer cell is born. It then multiplies to produce a large number of cancer cells, forming tumors. In the third stage, progression, neoplasm progresses to a malignant/cancerous state. During this stage, irreversible structural alterations occur in the genome of the neoplastic cell. These are related to the increased growth rate, invasiveness, metastatic capability, and biochemical changes in the malignant cell. 15.4 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 known as metastasis. Metastasis is the primary reason for 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 take place 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. The late stage of the disease is characterized by invasive activity and the appearance of a variety of cancer cell types. Some of the cells, which have the inherent ability to detach from the primary site, will eventually travel via the blood or lymph to start a secondary tumor in another site. Most frequently the location of metastasis is in the organ or organs that are served by blood vessels from the original cancer site. It is noted that growth and survival of a tumor require nourishment, which is provided by new blood vessels near the tumor site. 15.5 CLASSIFICATION OF CARCINOGENS The basic changes in the DNA, i.e., mutation, can be caused by many agents. These agents are generally classified into four categories: radiation, chemical, bio- logical, and genetic (Table 15.2). 3 Although mutation does not necessarily result in cancer, cancer occurs if the proteins that result from mutation affect cellular growth- control mechanisms. LA4154/frame/C15 Page 222 Thursday, May 18, 2000 12:05 PM © 2001 by CRC Press LLC ENVIRONMENTAL CANCER 223 15.5.1 Radiation The process involved in radiation-induced DNA damage is complex and has received much attention for many years. Ionizing radiation produces a wide variety of DNA lesions, including a large number of base modifications, strand breaks, and DNA-protein crosslinks. 5 It was mentioned in Chapter 14 that absorption of short- wave UV radiation by DNA causes breakage in its strand, the opening of the rings of its bases, and the formation of thymine dimers. Ultraviolet radiation from sunlight is the main cause of skin cancer. Increased UV radiation exposure — much of it caused by sunbathing or tanning under a UV lamp — is the main contributing factor to skin cancer, whose incidence is rising rapidly worldwide. Of the three types of UV radiation (UV-A, B, and C), UV-B ( λ = 280 to 320 nm) is the most harmful. UV-B is attenuated by Earth’s ozone layer. Several other factors modulate the amount of UV radiation to which people are exposed: time of day, season, humidity, and distance from the equator. Skin cancer risk also depends on the skin type; fair skin that freckles or bumps easily is more at risk than very dark-pigmented skin. People who live in sunny climates and have red or blond hair and blue or light-colored eyes are at especially high risk. Among the photochemical reactions that take place when UV-B penetrates the skin is muta- tion of the DNA in skin cells. Humans have repair enzymes that can correct this damage, but as the person ages, depending on the individual’s lifestyle, mutations accumulate, and the repair system will eventually be overtaxed, resulting in skin cancer. Researchers consider that the damage begins accumulating early — in childhood; by young adulthood about 50% of one’s lifetime sunlight exposure may have already accumulated. 15.5.2 Chemical Carcinogens The association between exposure to chemicals and cancer incidence was first reported in 1775 by the English physician Parcivall Pott, following the observation of scrotal cancer in chimney sweeps. 6 With an increase in European industrial development during the 19th century, high skin cancer rates 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 has led to the knowledge that the compounds contained in coal tar can produce cancer in animals. Several groups of organic compounds have now been recognized as carcinogenic to experimental animals. These include polycyclic aro- Table 15.2 General Classification of Carcinogenic Agents Class Example Radiations 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 LA4154/frame/C15 Page 223 Thursday, May 18, 2000 12:05 PM © 2001 by CRC Press LLC 224 ENVIRONMENTAL TOXICOLOGY matic hydrocarbons (PAHs), aromatic amines, aminoazo dyes, nitroso compounds, benzene, vinyl chloride, and others. 7 In addition to industrial carcinogens, a variety of chemical agents found in food can also 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. Various inorganic substances have also been shown to induce cancer. These include certain salts of As, Be, Cd, Cr 6+ , Ni, and Pb, as mentioned previously (Chapter 12). It is worth pointing out that some of the metals are essential nutrients for humans and animals. Trivalent chromium (Cr 3+ ) is one of these metals. As part of the glucose tolerance factor , Cr plays an important role in maintaining normal glucose metabolism in mammals. Figure 15.2 Some examples of chemical carcinogens. LA4154/frame/C15 Page 224 Thursday, May 18, 2000 12:05 PM © 2001 by CRC Press LLC ENVIRONMENTAL CANCER 225 In addition, several chlorinated hydrocarbons and other chemicals have been identified as carcinogenic. They include 2,4-D, DDE, hexachlorocyclohexane, PCBs, TCDD, and others. 15.6 METABOLISM OF CHEMICAL CARCINOGENS As shown in Figure 15.1, chemical carcinogens are normally divided into two broad classes: direct carcinogens and procarcinogens. Direct carcinogens are usually electrophiles, such as H + , C + , N + , and they can react readily with nucleophiles, such as proteins and nucleic acids. The main sites where such reactions can occur in these molecules are S, =N–, –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, on the other hand, are those requiring biologic activation. In contrast to direct carcinogens, procarcinogens are stable enough so that many people may be exposed environmentally or occupationally. Therefore, it is possible for some people to ingest or absorb some of the procarcinogens before enzymes in liver, lung, or other organs convert them to their activated metabolites. It is thought that most, and probably all, chemical carcinogens are, or are con- verted by metabolism into, electrophilic reactants that exert their biological effects by covalent interaction with DNA. Some examples of these reactants are shown in Figure 15.2. In the following sections, several of these examples are discussed in some detail. Our discussion will focus on free radicals, DDT, vinyl chloride, nitro- samine, benzo[a]pyrene (BaP), and halogenated aromatic hydrocarbons. 15.6.1 Free Radicals Certain free radicals, particularly oxygen free radicals, can damage nucleic acids, altering their structures and function. Oxygen-induced lesions of nucleic acids include strand breaks and base modification products. Superoxide has been shown to cause DNA strand breaks. 8 On the other hand, the OH · free radical, formed through the reaction between superoxide free radical (O 2 – · ) and H 2 O 2 (Equation 15.1), is unique and has been shown to be capable of abstracting protons from DNA, causing breaks O 2 – · + H 2 O 2 → O 2 + HO – + HO · (15.1) 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. 9 15.6.2 DDT DDT is one of the several pesticides that have been added to the long list of cancer-causing agents in the environment. According to a report by the National Cancer Institute, women with high exposures to DDT may have a greater risk of contracting breast cancer. Researchers at Mt. Sinai Hospital in New York City have LA4154/frame/C15 Page 225 Thursday, May 18, 2000 12:05 PM © 2001 by CRC Press LLC 226 ENVIRONMENTAL TOXICOLOGY found that women with blood levels of DDE of 19 ng/ml have four times the risk of breast cancer as women with 2 ng/ml. It is suggested that DDE, a stable metabolite of DDT (Chapter 13), may cause breast cancer in two ways: (a) it may induce cytochrome P450 enzymes, thereby altering the metabolism of toxicants; or (b) it may act as an estrogen mimic and, as such, may disrupt the endocrine system through interaction with estrogen receptors. 15.6.3 Vinyl Chloride Vinyl chloride (VC), the common name for monochloroethene (CH 2 =CHCl), is one of the most manufactured organic chemicals in the United States. VC is a gas at ambient temperature, with a boiling point of 14 ° C, and it exhibits a low solubility in water. While the VC monomer itself is rarely used, it is polymerized with itself and other organic compounds to form many products, thus making it a very important chemical to industry and to consumers. Among the many polymers that are derived from VC, 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, pack- aging materials, automobile products, and others. Some examples of products made of PVC are water pipes, raincoats, credit cards, wire coatings, and food packaging. The process involving PVC production includes three stages: synthesis of VC monomer from petrochemicals and chlorine; polymerization of VC into PVC resin; and PVC fabrication. Environmental contamination occurs in these processes, although the extent of the contamination varies with each stage. The contamination includes emission of VC into the atmosphere, and surface and ground water con- tamination resulting from sludge and wastewater discharge. Vinyl chloride has been shown to be both mutagenic and carcinogenic. It is classified as a Group 1 carcinogen because sufficient evidence exists that the com- pound is carcinogenic to humans. This is highly important since only about 40 chemicals or chemical mixtures are classified as such. 10 Vinyl chloride causes liver cancer in both humans and experimental animals. However, laboratory experiments with mice showed induction of not only liver cancer but also cancers of bone, skin, lung, brain, nephron, and mammary tissues. 10,11 In humans, the risk for VC exposure may occur both occupationally and nonoccupationally. Vinyl chloride is metabolized by the hepatic cytochrome P450 enzymes to the carcinogenic epoxide form. Studies show that this metabolite is an ultimate carcin- ogen, by reacting with DNA and causing the latter to change its function. In the liver, the active epoxide may be further converted to chloroethane aldehyde. A molecule of GSH can conjugate the aldehyde, and the resultant conjugate may then be excreted (Figure 15.3). 15.6.4 Alkylating Agents As noted in Chapter 14, alkylating agents are those chemicals that can react with DNA to form alkylated DNA adducts. Several groups of organic compounds can be metabolized to alkylating agents. An example is N-nitroso compounds that consist of LA4154/frame/C15 Page 226 Thursday, May 18, 2000 12:05 PM © 2001 by CRC Press LLC ENVIRONMENTAL CANCER 227 nitrosamines and nitrosamides. Nitroso compounds 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. Tobacco smoke also contains varying amounts of the compounds. Industrial exposure to N-nitro- samines accounts for another environmental source. Occupation or industrial activities that may potentially lead to exposure include metal cutting and rolling, leather tanning, rubber manufacture, hydraulic fluids handling, and producing or using amines in the chemical industry. In these activities, exposure is mostly via air and skin. 12 The importance of nitrosamines as environmental carcinogens was first postulated in 1962. Subsequent studies demonstrated the endogenous formation of such com- pounds 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. Nitrosatable 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 intestine. The pathway leading to the formation of an alkylating agent from dimethylamine is presented in Figure 15.4. The first step is nitrosation, in which dimethylamine reacts with nitrite to form dimethyl- nitrosamine, a nitroso compound. Metabolism of dimethylnitrosamine leads to the formation of a CH 3 + radical, which can react with DNA, resulting in methylated DNA. Figure 15.3 Metabolism of vinyl chloride by cytochrome P450 system. Figure 15.4 Activation mechanism of dimethylamine. 2 &\W3*6  +  & &+&O +  &&+&O&O¤&+  ¤&+2*6¤&+  &+2 9LQ\OFKORULGH9LQ\OFKORULGH HSR[LGH +  & +  & 1+ 12   + +  & +  2 +2+  & 11 2 +  & + +  & 11 2+&+2 + +  &1 12+ 2+ +  2 +  & 1 1 +  &1 1    &+  1  'LPHWK\ODPLQH 'LPHWK\OQLWURVDPLQH 'LD]RPHWKDQH  $ON\ODWLQJ DJHQW +  & 11 2 + LA4154/frame/C15 Page 227 Thursday, May 18, 2000 12:05 PM © 2001 by CRC Press LLC 228 ENVIRONMENTAL TOXICOLOGY 15.6.5 Polycyclic Aromatic Hydrocarbons Polycyclic aromatic hydrocarbons (PAHs) are a group of compounds composed of two or more fused aromatic rings. They are emitted into the environment through both natural and anthropogenic combustion processes. The two main sources of natural PAH production are volcanic eruptions and forest fires. Anthropogenic sources include fossil fuel combustion by automobiles and other transportation systems, petroleum refining processes, coking plants, asphalt production, industrial facilities that use fossil fuels, effluent disposal or oil spills, refuse burning, and others. PAHs are, therefore, widely distributed in our environment — air, soil, water, and sediment. They are of concern and represent major potential human hazards because of their possible contamination of food and drinking water supplies. For example, the carcinogenic PAH concentrations in various environmental media have been estimated to be as follows: outdoor air (2.6 to 13.0 ng/m 3 ), indoor air (1.5 to 13.0 ng/m 3 ); surface water (8.0 ng/L); ground water (1.2 ng/L); drinking water (2.8 ng/L); rural soil (0.07 mg/kg dry wt.); urban soil (1.10 mg/kg); road dust (137 mg/kg); charcoal-broiled or smoked beef (35 µ g/kg); pork (26 µ g/kg); poultry (12 µ g/kg); fish/shellfish (0.10 µ g/kg); smoked fish/shellfish (36 µ g/kg); green leafy vegetables (46 µ g/kg); grains (9 µ g/kg); fruits (2.4 µ g/kg); alcohol beverages (0.08 µ g/kg); fluid milk (0.09 µ g/kg); fats and oils (66 µ g/kg); and cheese (1.70 µ g/kg). 13 15.6.5.1 Benzo[a]pyrene Among the many PAHs, benzo[a]pyrene (BaP) (Figure 15.5) is probably the most widely known. Researchers have repeatedly shown the potent carcinogenic effect of BaP since the British doctor P. Pott reported in 1775 the relationship Figure 15.5 Formation of benzo[a]pyrene–guanine adduct. 0)2HQ]\PH 2 >2@ + 2+ 2+ + 2 + %D3 HSR[LGH %D3GLRO %D3GLRO HSR[LGH 1 1 1+ 2 1 1 + *XDQLQH +2 + 1 +2 +2 + 1 1 1 1+ 2 5 %D3 + +2 %D3JXDQLQHDGGXFW +2 1 5 LA4154/frame/C15 Page 228 Thursday, May 18, 2000 12:05 PM © 2001 by CRC Press LLC [...]... vivo, Science, 9, 592, 1976 15 National Toxicology Program (NTP), Bioassay of 1,2,3,6,7, 8- and 1,2,3,47,8,9Hexachlorodibenzo-p-dioxin for Possible Carcinogenicity, DHHS Publication (NIH) 8 0-1 754, DHHS, Washington, DC, 1980 16 National Toxicology Program (NTP), Bioassay of 2,3,7,8-Tetraclorodibenzo-p-dioxin for Possible Carcinogenicity (Gavage Study), DHHS Publication (NIH) 8 2-1 765, DHHS, Washington, DC,... LLC LA 4154 /frame/C15 Page 231 Thursday, May 18, 2000 12:05 PM ENVIRONMENTAL CANCER 231 11 Moss, A.R., Occupational exposure and brain tumors, J Tox Environ Health, 16, 703, 1985 12 Preussmann, R., Eisenbrand, G., and Spiegelhalder, B., Occurrence and formation of N-nitroso compounds in the environment and in vivo, in Environmental Carcinogenesis, Emmelot, P and Kriek, E., Eds., Elsevier/North-Holland... concentrations in 58 prepared meals averaged 0 .15 µg/kg, with a range of 0.005 to 1.17 µg/kg BaP can cause several forms of cancer, particularly cancers in the lung, intestine, kidney, and liver It has been reported that the ultimate carcinogenic form of BaP is benzo(a )-7 ,8-diol-9,10-epoxide.14 This active form of BaP is formed through cytochrome P450-dependent activation followed by several enzymatic... Washington, DC, 1982 17 Kochiba, R.J and Schwetz, B.A., Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), Drug Metab Rev., 13, 387, 1982 18 Shu, H.P., Paustenbach, D.J., and Murray, F.J., A critical evaluation of the use of mutagenesis, carcinogenesis, and tumor promotion data in a cancer risk assessment of 2,3,7,8-tetraclorodibenzo-p-dioxin, Regul Toxicol Pharmacol., 7, 57, 1987 19 Kimbrough, R.D et... Press LLC LA 4154 /frame/C15 Page 232 Thursday, May 18, 2000 12:05 PM 232 14 15 16 17 ENVIRONMENTAL TOXICOLOGY Explain how BaP can be converted into its ultimate carcinogen How may DDE be related to carcinogenesis? Explain the suggested mechanism involved in dioxin acting as a carcinogen Explain the mechanism that humans or animals possess for repairing DNA damage © 2001 by CRC Press LLC LA 4154 /frame/GLOSS... iodine-containing substance that is the chief active principle of the thyroid gland © 2001 by CRC Press LLC LA 4154 /frame/GLOSS Page 239 Thursday, May 18, 2000 12:16 PM GLOSSARY 239 TLV Threshold Limit Value TLV–TWA Time-weighted average threshold limit value The maximum timeweighted average concentration to which a healthy worker may be exposed for a normal 40-h work week up to 8 h a day over a working lifetime... 1260, J Natl Cancer Inst., 55, 1453, 1975 20 Poland, A and Knutson, J.C., 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 21 Stryer, L., Biochemistry, 3rd ed., W.H Freeman & Co., New York, 1988, 694 15. 9 REVIEW QUESTIONS 1 What is cancer? 2 What are the two most important causes of... essentially lost Invertase The enzyme that breaks down sucrose into glucose and fructose Isoenzymes (or isozymes) Enzymes that catalyze the same reaction but migrate differently on electrophoresis Itai-itai-byo Ouch-ouch-disease, caused by cadmium poisoning LC50 The median lethal concentration, the concentration that kills 50% of the test organisms, expressed as mg or ml (if liquid) per animal It is also the... considered reversible? 4 What is the fundamental idea underlying the many theories about the causes of cancer? 5 What is the main cause of skin cancer? 6 How does short-wave UV radiation affect DNA? 7 Which one is most harmful, UV-A, UV-B, or UV-C? 8 List five metals that can induce cancer 9 What is metastasis? How does it occur? 10 What are procarcinogens? 11 In what way does superoxide free radical affect... (AHH) activity It is generally accepted that the toxic activity of these chemicals is related to their interaction with a cellular receptor, the Ah © 2001 by CRC Press LLC LA 4154 /frame/C15 Page 230 Thursday, May 18, 2000 12:05 PM 230 ENVIRONMENTAL TOXICOLOGY receptor, which regulates the synthesis of a number of cellular proteins The receptor is an intracellular protein that binds to these biphenolic compounds . BaP is benzo(a )-7 ,8-diol-9,10-epoxide. 14 This active form of BaP is formed through cyto- chrome P450-dependent activation followed by several enzymatic steps. The result- ant BaP metabolite. 9, 592, 1976. 15. National Toxicology Program (NTP), Bioassay of 1,2,3,6,7, 8- and 1,2,3,47,8, 9- Hexachlorodibenzo-p-dioxin for Possible Carcinogenicity, DHHS Publication (NIH) 8 0-1 754, DHHS,. Viruses Biological Transgenesis by enhancer-promoter-oncogene constructs LA 4154 /frame/C15 Page 223 Thursday, May 18, 2000 12:05 PM © 2001 by CRC Press LLC 224 ENVIRONMENTAL TOXICOLOGY matic hydrocarbons