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Chemical factors
1. CHEMICAL FACTORS
• Environmental and lifestyle exposures are major
determinants of human cancer risk.
• Heritable factors also contribute to cancer risk, but
twin studies show that for the common cancers,
nongenetic risk factors are dominant, and the best
associations for genetic risks of sporadic cancers
indicate risks for specific genetic polymorphisms less
than 1.5-fold.Thus, for these common cancers,
chemical exposures can be mechanistically linked to
the carcinogenic process, and genetic susceptibilities
modulate that risk,
2. Continued….
• Most human cancer is not simply a genetically
determined sequela of aging, but rather the
manifestation of individual exposures (endogenous and
exogenous), superimposed on an individually
determined hereditary susceptibility.
• The experimental induction of tumors in animals and
neoplastic transformation of cultured cells by
chemicals, and the analysis of human tumors, have
revealed important concepts regarding the
pathogenesis of cancer and the consistency of
pathways impacted for cancer development
3. Mechanism of action
• Chemical carcinogens usually affect specific
organs, targeting the epithelial cells (or other
susceptible cells within an organ) and causing
genetic damage (genotoxic).
• Chemically related DNA damage and consequent
somatic mutations relevant to human cancer can
occur either directly from exogenous exposures
or indirectly by activation of endogenous
mutagenic pathways (e.g., nitricoxide and
oxyradicals).
4. Risk factors
• The most commonly occurring exposures that
increase cance risk are tobacco, alcohol,
ultraviolet light, diet, and reproductive factors
(e.g., sexual behavior and hormones).
• The risk of developing a chemically induced
tumor may be modified by nongenotoxic
exogenous and endogenous exposures and
factors (e.g., hormones, immunosuppression),
and by accumulated exposure to the same or
different genotoxic carcinogens
5. Etiology
• Chemically related DNA damage and
consequent somatic mutations relevant to
human cancer can occur either directly from
exogenous exposures or indirectly by
activation of endogenous mutagenic pathways
(e.g., nitric oxide and oxyradicals).
6. The Nature of Chemical Carcinogens:
Chemistry and Metabolism
• The National Toxicology Program lists over 200
chemical, physical and infectious agents as
known or probable.
• Most chemical carcinogens first undergo
metabolic activation by cytochrome P-450 or
other metabolic pathways so that they react
with DNA or alter epigenetic mechanism
7. Table 18.1 Known or Suspected Chemical Carcinogens in Humans
• Kidney Tobacco smoke, phenacetin — Renal cell cancer
• Bladder Tobacco smoke, 4-aminobiphenylbenzidine,
• 2-napthylamine phenacetin
• Magenta manufacture, auramine manufacture
Transitional cell cancer
• Prostat Cadmium — Adenocarcinoma
• Skin Arsenic, benzo(a)pyrene, coal tar
• and pitch, mineral oils, soots, Coal gasification,
• coke production
• cyclosporin A, PUVA
• Squamous cell cancer
• basal cell cancer
• Bone
• Marrow Benzene, tobacco smoke, ethylene Rubber workers Leukemia, lymphoma
• PUVA, psoralen-UV-A
• oxide, antineoplastic agents,
• cyclosporin A
• .
• a These carcinogen designations are determined by regulatory or review agencies based on public health
• needs. They do not imply proof of carcinogenicity in individuals. This table is not all inclusive.
• For additional information, the reader is referred to agency documents and publications.
• Genotoxic carcinogens may transfer simple alkyl or complexed (aryl) alkyl groups to specific sites on DNA bases.11,16
• These alkylating and aryl-alkylating agents include, but are not limited to, N-nitroso compounds, aliphatic
• epoxides, aflatoxins, mustards, polycyclic aromatic hydrocarbons, and other combustion products of fossil fuels
• and vegetable matter. Others transfer arylamine residues to DNA as exemplified by aryl aromatic amines,
8. • Kidney Tobacco smoke, phenacetin — Renal cell cancer
• Bladder Tobacco smoke, 4-aminobiphenyl,
• benzidine, 2-napthylamine,
• phenacetin
• Magenta
• manufacture,
• auramine
• manufacture
• Transitional cell
• cancer
• Prostate Cadmium — Adenocarcinoma
• Skin Arsenic, benzo(a)pyrene, coal tar
• and pitch, mineral oils, soots,
• cyclosporin A, PUVA
• Coal gasification,
• coke production
• Squamous cell cancer
• basal cell cancer
• Bone
• marrow
• Benzene, tobacco smoke, ethylene
• oxide, antineoplastic agents,
• cyclosporin A
• Rubber workers Leukemia, lymphoma
• PUVA, psoralen-UV-A.
• a These carcinogen designations are determined by regulatory or review agencies based on public health
• needs. They do not imply proof of carcinogenicity in individuals. This table is not all inclusive.
• For additional information, the reader is referred to agency documents and publications.
• Genotoxic carcinogens may transfer simple alkyl or complexed (aryl) alkyl groups to specific sites on DNA bases.11,16
• These alkylating and aryl-alkylating agents include, but are not limited to, N-nitroso compounds, aliphatic
• epoxides, aflatoxins, mustards, polycyclic aromatic hydrocarbons, and other combustion products of fossil fuels
• and vegetable matter. Others transfer arylamine residues to DNA as exemplified by aryl aromatic amines,
• aminoazo dyes, and heterocyclic aromatic amines. For genotoxic carcinogens, the interaction with DNA is not
• random, and each class of agents reacts selectively with purine and pyrimidine targets.3,11,16 Furthermore, targeting
• of carcinogens to particular sites in DNA is determined by nucleotide sequence, by host cell, and by selective DNA
• repair processes (see later discussion), making some genetic material at risk over others. As expected from this
• chemistry, genotoxic
9. GENOTOXIC CARCINOGENS
.
• Genotoxic carcinogens may transfer simple alkyl or complexed (aryl)
alkyl groups to specific sites on DNA bases.
• These alkylating and aryl-alkylating agents include, but are not
limited to, N-nitroso compounds, aliphatic epoxides, aflatoxins,
mustards, polycyclic aromatic hydrocarbons, and other combustion
products of fossil fuelsand vegetable matter. Others transfer
arylamine residues to DNA .
• For genotoxic carcinogens, the interaction with DNA is not random,
and each class of agents reacts selectively with purine and
pyrimidine targets.
• Furthermore, targeting of carcinogens to particular sites in DNA is
determined by nucleotide sequence, by host cell, and by selective
DNA repair processes, making some genetic material at risk over
others.
10. Continued………………
• Genotoxic carcinogens are potent mutagens,
particularly adept at causing base mispairing or
small deletions, leading to missense or nonsense
mutations.
• Others may cause macrogenetic damage such as
chromosome breaks and large deletions.
• In all cases, mutations detected in tumors
represent a combination of the effects of the
mutagenic change on the function of the protein
product and the functional alteration on the
behavior of the specific host cell type.
11. NON GENOTOXIC CARCINOGENS
• . Some chemicals that cause cancers in laboratory rodents are not
demonstrably genotoxic .In general, these agents are carcinogenic in
laboratory animals at high doses and require prolonged exposure.
Synthetic pesticides and herbicides fall within this group, as do a number
of natural products that are ingested
• The mechanism of action by nongenotoxic carcinogens is controversial,
and may be related in some cases to toxic cell death and regenerative
hyperplasia.
• Induction of endogenous mutagenic mechanisms such as DNA oxyradical
damage ,depurination, and deamination of 5-methylcytosine by exposure
to nongenotoxic carcinogens may contribute to carcinogenicity of these
agents
12. • Both genotoxic and nongenotoxic carcinogens
may alter gene expression through induction
of DNA or histone methylation or by other
nuclear mechanisms that influence the
transcriptome.
13. DNA Repair Protects the Host from
Chemical Carcinogens
• Multiple DNA repair defects in diverse pathways have been
identified in cancer-prone individuals, and repair-deficient
mammalian cells are susceptible to transformation by chemical and
physical carcinogens.
• The human cancer susceptibility genes
• BRCA1/2 and ATM participate in repair of carcinogen-induced DNA
double-strand breaks in pathways linked to homologous
recombination.
• Mutations in genes encoding a separate family of genes involved in
homologous recombination, RecQ helicases, underlie two cancer-
prone inherited diseases,
• Bloom and Werner syndromes,characterized by DNA
rearrangements. Cells from these patients are particularly sensitive
to genotoxic chemic
14. Genetic Susceptibility to Chemical
Carcinogenesis
• Genetically determined differences in the
affinity for the aryl hydrocarbon hydroxylase
(Ah) receptor or other differences in metabolic
processing of carcinogens is one modifier that
has a major impact on experimental and
human cancer risk.
• In humans, the determination of genetic
susceptibility can be assessed by phenotyping
or genotyping methods
15. TYPING
• Phenotypes generally represent complex genotypes. Examples of
phenotypes include the assessment of DNA repair capacity in cultured
blood cells, mammographic breast density, or the quantitation of
carcinogen-DNA adducts in a target Phenotypes generally represent
complex genotypes.
• Examples of phenotypes include the assessment of DNA repair capacity in
cultured blood cells, mammographic breast density, or the quantitation of
carcinogen-DNA adducts in a target organ.
• Highly penetrant cancer-susceptibility genes cause familial cancers, but
account for less than all cancers. Low-penetrant genes cause common
sporadic cancers, which have large public health consequences
16. Genetic polymorphism (e.g., single nucleotide polymorphisms) is
defined as a genetic variant present in at least
1% of the population
• Genes under study are from pathways that affect
behavior, activate and detoxify carcinogens, affect
DNA repair, govern cell-cycle control, trigger
apoptosis, effect cell signaling, and so forth.
. Virtually every cancer type has been examined for
associations with genetic susceptibilities, and
although there are many associations that have
not been replicated, there is some consistency for
cancers of the lung, breast, prostate, and colon.
17. Molecular Epidemiology, Chemical Carcinogenesis, and
Cancer Risk in
Human Populations
• Molecular epidemiology is the application of biologically based
hypotheses using molecular and epidemiologic methods and
measures.
• An important goal has been to identify cancer risk based on gene-
environment interactions.
• In humans, the best evidence that exists for how cancer develops is
that of a genetic disease through multiple DNA-damaging events
(e.g., mutations and alterations in genexpression through
hypermethylation of promoter sequences)
• Two fundamental principles underlie current studies of molecular
epidemiology. First, carcinogenesis is a multistage and behind each
is list of genetic events.
• Second, wide interindividual variation in response to carcinogen
exposure and other carcinogenic processes indicate that the human
response is Non homogeneous.
18. Biomarkers of Cancer Risk
• The evaluation of dose and risk estimates in
epidemiologic studies can include four
components, namely, external exposure
measurements, internal exposure measurements,
biomarkers estimating the biologically effective
dose,and biomarkers of harm.
• The latter three measurements are biomarkers
that improve on the first by quantify in exposure
at the cellular level to characterize low-dose
exposures in low-risk populations providing
relative contribution of carcinogen and its burden
19. Biomarkers
• Chemicals cause genetic damage in different
ways, namely the formation of carcinogen-
DNA adducts leading to base mutations, or
gross chromosomal changes.
• The level of DNA damage is the biologically
effective dose in a target organ, and reflects
the net result of carcinogen exposure,
activation, lack of detoxification, lack of DNA
repair, and lack of programmed cell death.
20. No single biomarker has been
considered to be sufficiently validated
for use
• Important considerations for the assessment of
biomarkers include sensitivity, specificity
reproducibility, accessibility for human use, and
whether it represents a risk measured in a target organ
or surrogate tissue.
• Exposure can occur through endogenous formation of
N-nitrosamines from nitrates in food or directly from
dietary sources, cosmetics, drugs, household
commodities, and tobacco smoke.
• Endogenous formation occurs in the stomach from the
reaction of nitrosatableamines and nitrate, used as a
preservative, which is converted to nitrites by bacteria
21. The N-nitrosamines undergo
metabolic activation by cytochrome P-450s (CYP2E1, CYP2A6,
and CYP2D6) and form DNA adducts.
• Biomarkers are available to assess N nitrosamine
exposure from tobacco smoke (e.g., urinary
tobacco-specific nitrosamine levels)or DNA,
including in target organs such as the lungs.
Aromatic amines are another class of human
carcinogens.
• Aryl aromatic amines have been implicated in
bladdercarcinogenesis, especially in
occupationally exposed cohorts.
,
22. Phenotyping assays - represent the lifetime response of a
person's exposure to endogenous and
exogenous chemical exposures
• Examples include carcinogen-DNA adduct studies
,mammographic breast density(6 fold risk with breast
cancer and related to exogenous estrogen and alcohol)
• Emerging technologies using the omics approaches
(genomics, measuring heritable variation, somatic
mutations,and copy number; transcriptomics,
measuring mRNA and microRNA expression;
epigenomics; proteomics,measuring proteins; and
metabolomics, measuring small metabolites) are
increasingly being applied to chemical carcinogenesis
and human cancer risk studies
23. Polyclic Aromatic Hydrocarbons as A Model for
Gene-Environment
Interaction
• Polycyclic aromatic hydrocarbons (PAHs) are large
aromatic (three or more fused benzene rings)
compounds that are from a class of more than 200
chemicals and are ubiquitous. Formed from
overcooking foods, fireplaces, charcoal barbeques,
burning of coal and crude oil, tobacco smoke, and in
various occupational settings.
• In order for PAHs to exert their toxic effect, they must
undergo metabolic activation via cytochromes P-
4501A1 and P-4503A4 to form DNA adducts, orare
excreted via pathways involving the glutathione-S-
transferase genes.
24. PAH……………………
• PAHs are associated with an increased risk of lung and
skin cancer in the occupational setting.
• Benzo(a)pyrene is among the most commonly studied
PAH.
• It is classified as a known human carcinogen by the
International Agency for Research on Cancer, and a
suspected human carcinogen by the American
Conference of Governmental Industrial Hygienists.
• It should be noted that other PAHs are considered as
lesser classifications, and about 45 have not been
shown to be carcinogenic or classified as group 3
25. • PAH exposure is causally associated with lung
cancer from inhalation exposures in the
workplace, such as for aluminum, steel, coke
oven, stokers, and asphalt.
• Exposure to PAHs via other routes such as diet
and skin absorption is not associated with lung
cancer,even though the dietary contribution of
PAHs to total body burden may be sizeable.
• Skin cancer is the next most commonly
associated cancer with PAH exposure
For
dietary exposures, increased intake of charcoal-broiled meat was shown to
increase PAH adducts in the DNA of
white blood cells.93 But the evidence for a clear association of dietary PAH,
adducts, mutations, and cancer is lacking
26. Various biomarkers of exposure have been
developed for assessing PAH exposure
• These include measuring DNA adducts, protein
adducts, and urinary 1-hydroxypyrene; only the
latter is a validated biomarker of exposure and no
adducts have been validated as biomarkers of
cancer risk.
• A validatedbiomarker of cancer risk has not been
achieved. Examples include polymorphisms in the
CYP1A1, CYP3A4 glutathione transferase mu, and
DNA repair genes.