These alterations can result from exposure to radiation and to chemical, biological, and genetic factors Table 16.2.For example, ionizing radiations, such as x-rays and g-rays, can produ
Trang 1Environmental 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., 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, the death toll in the
U.S in 1980 was 416,509, in 1995 it was 538,455,1and 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, geographical factors,
and environmental agents An estimate of the contribution of various agents or
life styles to the cause of cancers is presented inTable 16.1.It is notable that
Trang 2diet 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 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 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 (Table 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
Table 16.1 Speculative Proportion of Cancer Deaths Attributed to Various Factors
Factor or class of factors Percent of all cancer deaths
Reproductive and sexual behavior 7
Medicine and medical procedures 1
Source: Adapted from USDHHS, The Surgeon General’s Report on Nutrition and Health, U.S Government Printing Office, Washington, D.C., 1988.
Trang 316.3 STAGES IN THE DEVELOPMENT OF CANCER
It is generally accepted that the pathway leading to carcinogenesis includes
three stages: initiation, 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.4The efficiency of initiation is sensitive to xenobiotic and other 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-Table 16.2 General Classification of Carcinogenic Agents
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
F IGURE 16.1 Three stages of carcinogenesis.
Source: Adapted from USDHHS, The Surgeon General’s Report on Nutrition and Health, 1988.
Trang 4formed 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 expression of the genetic
changes as malignancy, which involves loss of control over cellular
prolifera-tion Examples of promoting agents include: saccharin, butylated
hydroxyto-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 initiators 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
Trang 516.4 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 disease 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 divided
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 cellular 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 RADIATION
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.6It was mentioned
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
Trang 6UV 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-colored 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 CHEMICALCARCINOGENS
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 B1, 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 Trivalent
Cr (Cr3þ) is one of these metals As part of the glucose tolerance factor, Cr
plays an important role in maintaining normal glucose metabolism in
mammals
Trang 7Several 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 Hþ
, Cþ , Nþ , and can react readily with nucleophiles, 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 inFigure 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, benzo[a]pyrene, and halogenated aromatic
hydrocar-bons
16.6.1 FREERADICALS
Reactive oxygen species, such as hydroxyl radicals (OH), 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 and function Oxygen-induced lesions of nucleic
acids include strand breaks9and base modification products Alternatively, the
OH free radical, formed through the reaction between superoxide free radical
(O2
) and H2O2 (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
O2 þH2O2!O2þHOþHO ð16:1Þ
Trang 816.6.2 DDT
DDT is one of the several pesticides that have been added to the long list of
cancer-causing agents present in the environment 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)
F IGURE 16.2 Some examples of chemical carcinogens.
Trang 916.6.3 VINYLCHLORIDE
Vinyl chloride, the common name for monochloroethene (CH2¼CHCl), 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 14C, 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 Environmental 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.11Vinyl chloride
causes liver cancer in both humans and laboratory 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.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 conjugate
may then be excreted (Figure 16.3)
16.6.4 ALKYLATINGAGENTS
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
Trang 10varying 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 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 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 CH3þradical,
which can react with DNA, resulting in methylated DNA
F IGURE 16.3 Metabolism of vinyl chloride by the cytochrome P450 system.
F IGURE 16.4 Activation mechanism of dimethylamine.