Environmental Life Cycle Costing - Chapter 15 (end) pptx

220 ENVIRONMENTAL TOXICOLOGY15.2 CAUSES OF CANCER Many factors can lead to cancer.. 15.3 STAGES IN THE DEVELOPMENT OF CANCER Although the precise mechanisms involved in the causation of

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As noted earlier, cancer incidence and mortality have increased dramaticallyover the last century Researchers consider that there are two main reasons for thisincrease: the aging of the population and an increase in pollution from carcinogenspresent in and released into the environment through human activities Indeed, nearly30% 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 ofcancer deaths continues to rise as the elderly population increases For example, inthe U.S the toll in 1980 was 416,509; in 1995 it was 538,455;1 and in 1999 it wasestimated 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 genic (cancer-causing) agent, or carcinogen, and the appearance of a neoplasm Thelatency 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 manifesteduntil 10 or more years after an initial exposure to a particular carcinogen

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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 andsmoking account for approximately two thirds of all cancers Smoking is particularlyimplicated in lung and bladder cancers

Although there are many theories concerning the causes of cancer, the fundamentalidea underlying these theories is the alteration of the genetic material, the DNA of thecell The various theories attempt to explain how this change is brought about TheDNA of a cancer cell is slightly different from that of a normal cell This means thatthe 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 inChapter 14, these sequences dictate the sequence of the transcribed mRNA, which inturn specifies the kinds of proteins to be synthesized in a cell Alteration in the DNAbase sequence in cancer cells results in abnormal proteins These new proteins influencethe 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 notknown, many researchers consider the pathway leading to carcinogenesis to includethree stages: initiation, promotion, and progression (Figure 15.1).3 According to thisview, 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 transformedinto a precancerous cell via alteration of the DNA molecule, and reflects a permanentand 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

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ENVIRONMENTAL CANCER 221

of a certain chemical to an ultimate carcinogen, thereby blocking the initiationprocess Furthermore, in humans there are corrective enzymes that can repair certaindamage and reverse the adverse effects (see Section 15.7) Initiators can also producetransformed cells that may persist for the life-span of an individual without producingcancer In such cases, the damaged gene in the transformed cells remains recessivebecause the damaged gene is not expressing an abnormal protein

Promotion is the step involving gene activation to synthesize the abnormal tein Thus, rapid cell division occurs, and this is accompanied by the interruption ofthe organism’s normal function or health Promotion then leads to the expression ofgenetic changes as malignancy, which involves loss of control over cellular prolif-eration In contrast to initiation, promotion is considered to be reversible Thus, ifthe promoting agent is withdrawn well before tumors are manifested, the appearance

pro-of tumors can be delayed or prevented In addition, promotion may be continuallymodulated by various environmental factors, including the frequency with which thepromoting agent is administered, age and sex of the experimental animals, hormonalbalance, and composition and amount of diet Research shows that many promotingagents 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.)

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Some chemicals act as both initiators and promoters Benzo[a]pyrene, a product

of incomplete combustion of carbonaceous material is such a chemical In smalldoses it initiates genetic damage, and in higher or repeated doses, a promotionreaction ensues

The agents involved in the onset of promotion cause cancer not by themselvesbut only in an initiated cell The artificial sweetener saccharin is an example of apromoter Promotion is gradual; moreover, some of the earlier steps are reversible

In the promotion stage, abnormal proliferation of the affected cell occurs, presumablybecause 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 cellwill be produced and will be responsive to normal growth-inhibiting factors Animalexperiments suggest that the time lapse between initiation and promotion is notcritical During the later stage of promotion, however, cumulative genetic changesoccur, 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 Theseare related to the increased growth rate, invasiveness, metastatic capability, andbiochemical changes in the malignant cell

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 incancer, cancer occurs if the proteins that result from mutation affect cellular growth-control mechanisms

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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 UVlamp — is the main contributing factor to skin cancer, whose incidence is risingrapidly 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 areexposed: time of day, season, humidity, and distance from the equator Skin cancerrisk 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 havered or blond hair and blue or light-colored eyes are at especially high risk Amongthe 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 thisdamage, but as the person ages, depending on the individual’s lifestyle, mutationsaccumulate, and the repair system will eventually be overtaxed, resulting in skincancer Researchers consider that the damage begins accumulating early — inchildhood; by young adulthood about 50% of one’s lifetime sunlight exposure mayhave already accumulated

Table 15.2 General Classification of Carcinogenic Agents

Biological Transgenesis by enhancer-promoter-oncogene constructs

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or cottonseed meal There are also naturally produced substances that are carcinogenic.Various inorganic substances have also been shown to induce cancer Theseinclude certain salts of As, Be, Cd, Cr6+, Ni, and Pb, as mentioned previously(Chapter 12) It is worth pointing out that some of the metals are essential nutrientsfor humans and animals Trivalent chromium (Cr3+) is one of these metals As part

of the glucose tolerance factor, Cr plays an important role in maintaining normalglucose metabolism in mammals

Figure 15.2 Some examples of chemical carcinogens.

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In addition, several chlorinated hydrocarbons and other chemicals have beenidentified 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 twobroad classes: direct carcinogens and procarcinogens Direct carcinogens are usuallyelectrophiles, 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 thesemolecules are S, =N–, –C–OH, or –P–OH Examples of cellular nucleophiles includesome 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 somepeople 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 verted by metabolism into, electrophilic reactants that exert their biological effects

con-by covalent interaction with DNA Some examples of these reactants are shown inFigure 15.2 In the following sections, several of these examples are discussed insome 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 includestrand breaks and base modification products Superoxide has been shown to causeDNA strand breaks.8 On the other hand, the OH· free radical, formed through thereaction between superoxide free radical (O2·) andH2O2 (Equation 15.1), is uniqueand has been shown to be capable of abstracting protons from DNA, causing breaks

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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 causebreast cancer in two ways: (a) it may induce cytochrome P450 enzymes, therebyaltering the metabolism of toxicants; or (b) it may act as an estrogen mimic and, assuch, may disrupt the endocrine system through interaction with estrogen receptors

15.6.3 Vinyl Chloride

Vinyl chloride (VC), the common name for monochloroethene (CH2=CHCl), isone 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 itselfand other organic compounds to form many products, thus making it a very importantchemical 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 costeffective, 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 VCmonomer 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 contaminationincludes 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 isclassified as a Group 1 carcinogen because sufficient evidence exists that the com-pound is carcinogenic to humans This is highly important since only about 40chemicals or chemical mixtures are classified as such.10 Vinyl chloride causes livercancer in both humans and experimental animals However, laboratory experimentswith 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 exposuremay occur both occupationally and nonoccupationally

Vinyl chloride is metabolized by the hepatic cytochrome P450 enzymes to thecarcinogenic 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 theliver, the active epoxide may be further converted to chloroethane aldehyde Amolecule 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 withDNA to form alkylated DNA adducts Several groups of organic compounds can bemetabolized to alkylating agents An example is N-nitroso compounds that consist ofLA4154/frame/C15 Page 226 Thursday, May 18, 2000 12:05 PM

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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 smokealso contains varying amounts of the compounds Industrial exposure to N-nitro-samines accounts for another environmental source Occupation or industrial activitiesthat may potentially lead to exposure include metal cutting and rolling, leather tanning,rubber manufacture, hydraulic fluids handling, and producing or using amines in thechemical 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 pounds from precursor amines and nitrite in vivo The endogenous formation of N-nitroso compounds from precursor amines and nitrosating agents, particularly nitrite,

com-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 importantnitrosating agent and is present in some food products However, nitrite can also beformed from nitrate in saliva and possibly in intestine The pathway leading to theformation of an alkylating agent from dimethylamine is presented in Figure 15.4 Thefirst step is nitrosation, in which dimethylamine reacts with nitrite to form dimethyl-nitrosamine, a nitroso compound Metabolism of dimethylnitrosamine leads to theformation of a CH3 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.

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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 throughboth natural and anthropogenic combustion processes The two main sources ofnatural PAH production are volcanic eruptions and forest fires Anthropogenicsources include fossil fuel combustion by automobiles and other transportationsystems, petroleum refining processes, coking plants, asphalt production, industrialfacilities that use fossil fuels, effluent disposal or oil spills, refuse burning, andothers PAHs are, therefore, widely distributed in our environment — air, soil, water,and sediment They are of concern and represent major potential human hazardsbecause of their possible contamination of food and drinking water supplies Forexample, the carcinogenic PAH concentrations in various environmental media havebeen estimated to be as follows: outdoor air (2.6 to 13.0 ng/m3 ), indoor air (1.5 to13.0 ng/m3); surface water (8.0 ng/L); ground water (1.2 ng/L); drinking water (2.8ng/L); rural soil (0.07 mg/kg dry wt.); urban soil (1.10 mg/kg); road dust (137mg/kg); charcoal-broiled or smoked beef (35 µg/kg); pork (26 µg/kg); poultry (12

µg/kg); fish/shellfish (0.10 µg/kg); smoked fish/shellfish (36 µg/kg); green leafyvegetables (46 µg/kg); grains (9 µg/kg); fruits (2.4 µg/kg); alcohol beverages (0.08

µg/kg); fluid milk (0.09 µg/kg); fats and oils (66 µg/kg); and cheese (1.70 µg/kg).13

15.6.5.1 Benzo[a]pyrene

Among the many PAHs, benzo[a]pyrene (BaP) (Figure 15.5) is probably themost widely known Researchers have repeatedly shown the potent carcinogeniceffect of BaP since the British doctor P Pott reported in 1775 the relationship

Figure 15.5 Formation of benzo[a]pyrene–guanine adduct.

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