CHEMICAL CARCINOGEN

1. CHEMICAL
CARCINOGENESIS
MODERATOR : DR MEKHALA RAO
PRESENTER : K HARI KRISHNA

3. Introduction :
Carcinogenesis or oncogenesis or tumorigenesis
- normal cells are transformation into cancer cells.
Carcinogens :
- Agents that cause cancer.
Types:
Physical carcinogens:
These include radiation from the sun, X-rays, and other radioactive materials.
Chemical carcinogens:
These substances include hydrocarbons, industrial wastes, benzene,
Aromatic amines etc
Biological carcinogens:
These include infections from certain viruses, bacteria, or parasites.

4. CHEMICAL CARCINOGENS :
• Chemical carcinogens have :
Highly reactive electrophile groups that directly damage DNA
leading to mutations
eventually cancer

5. How do carcinogens enter the body?
• Skin absorption: Many solvents and other chemicals go
directly through the skin.
• Ingestion : Swallowing of a carcinogen.
• Inhalation : Breathing gases, fumes and vapors is the most
common form of exposure.

6. Multi-step theory
According to this theory, chemical carcinogenesis is a multi-step process.
• In chemical carcinogenesis, there are 2 steps occur in sequence –
Initiation and promotion.
• Many tumors arise from combination of activation of growth
promoting oncogenes and inactivation of growth-suppressing anti-
oncogenes.
• Chemical carcinogens undergo metabolic activation by cytochrome
P450 or other metabolic pathway and react with DNA or alter epigenetic
mechanism .

7. Multi-step theory
• Cytochrome P450 aids in the oxidation and detoxification of xenobiotics
such as drugs and carcinogens.
• DNA is considered the ultimate target for most carcinogens to cause
mutations or gross chromosomal changes.
• Formation of DNAAdducts occurs by binding of chemicals to DNA
• Carcinogen - DNAAdducts leads to base mutation or gross chromosomal
changes.
• It can cause base substitution , deletion , insertion during DNA
replication .

8. Sequential changes in chemical carcinogenesis

9. Initiation of carcinogenesis
Initiation:-
• Results from exposure of sufficient dose of carcinogenic agent usually
genetic and is introduced into target cell.
• Causes permanent DNA damage.
• Essentially irreversible and has memory.
• Occurs rapidly after carcinogen exposure
• Alone does not result in tumor formation
• Undergoes mutations and induce proliferation but not differentiation.
• Carcinogen altered cell must undergo atleast one cycle of
proliferation so that change in DNA becomes fixed or
permanent.

10. Chemical carcinogens acting as initiators of
carcinogenesis can be grouped into 2 categories :
• Direct-acting agents
• Indirect-acting agents

11. Direct acting carcinogens
• They do not require metabolic conversion to become carcinogenic.
• Weak carcinogens
• These agents have cured, controlled or delayed recurrence for certain
types of cancers.
• Example: Alkylating agents, Acylating agents.

12. Indirect acting Carcinogens
• They are not active until converted to ultimate carcinogen by
endogenous metabolic pathways.
• Most chemical carcinogens act indirectly and require metabolic
activation for conversion into ultimate carcinogens.
• Examples: Aromatic amines, Azo dyes, Polycyclic aromatic
hydrocarbons, Natural plant and microbial products.

14. Promotion of carcinogenesis
• Promotion is the process whereby an initiated tissue or organ develop
focal proliferation (altered differentiation).
• Promoter : is a substance which doesn’t damage DNA but enhance
growth of tumor induced by genotoxic carcinogens.
• This leads to proliferation and clonal expansion of Intiated mutated cells
• Leading to formation of cancerous subclones (paraneoplastic) of initiated
cell to undergo additional mutation forming malignant neoplasm.

15. Promotion of carcinogenesis
Promotion :
1) Reversible
2) Acts only after exposure to an initiating agent
3) Requires repeated administration of a promoter
4) Non-carcinogenic
5) Application of promoter’s do not affect DNA directly.
6) Effictiveness depends on its concentration in target tissue.
Example : skin cancer in mice can be induced by application of benzo
alpha pyrene (initiator) followed by phorbol ester from cotton oil
(promoter)

16. Contrasting features of initiator and promoter
genes
Feature Initiator carcinogens Promoter carcinogens
1. Mechanism Induction of mutation Not mutagenic
2. Dose Single for a short time Repeated dose exposure
for a long time
3. Response Sudden response Slow response
4. Sequence Applied first then followed
by promoter
Applied after prior
exposure to initiater
5. Effectivity Effective alone if exposed
in large dose
Not effective alone

17. METABOLIC ACTIVATION:

18. AMES TEST
• A semi-quantitative biological assay that uses bacteria to evaluates a chemical’s
ability (potential) to induce mutations in Salmonella tiphymurium in a culture
medium improved with microsomatic enzymes to cause mutations in DNA.
• Ames test is frequently used to evaluate the carcinogenic potential of chemical
carcinogenes. Most mutagenic chemicals are carcinogenic.

19. Carcinogenic Chemicals
in our daily life.

20. Naturally occuring carcinogens
• Produced by plants and micro-organisms.
• Mycotoxin produced by Aspergillus flavus present on stored
corn, rice and peanuts – hepatocarcinogen producing
hepatocellular carcinoma.
• Aflatoxin and Hepatitis B virus collaborate in the production
of Hepatocellular carcinoma.

21. Nitrosamines and Amides
• Nitro stable amines and nitrate used as a food preservative
which is converted to nitrites by bacteria in stomach producing
Esophageal and gastric carcinoma.

22. Aromatic amines and Azo dyes
• “Ultimate carcinogen” formed by action of cytochrome P-450
oxygenase systems.
• Beta-naphthalamine after absorption, hydroxylated in active form
then detoxified by conjugation with glucoronic acid in liver, when
excreted in urine, nontoxic conjugate is split by urinary
glucoronidase – release of electophilic reactant causing Bladder
carcinoma.

23. Metals
• Arsenic - Skin and prostate cancer
• Cadmium - Lung and prostate cancer
• Chromium - lung cancer
• Nickel - Lung and Nasal cancer
• Cobalt - skin and lung cancer
• Mercury - Kidney cancer
• Aluminium - Breast cancer

24. Polycyclic aromatic hydrocarbons
• Derived from coal tar.
• Require metabolic activation
• Painted on the skin – Skin cancer
• Injected subcutaneusly – Sarcomas
• Combustion of tobacco – lung and bladder cancer
• Smoked meats - hepatic angiosarcoma

25. Formaldehyde
• Colorless, strong smelling, flammable chemical
Uses :
• Preservative in mortuaries and
medical laborateries.
• Plywood and particlewood industry
• Fungicide, germicide and disinfectant

26. How are people exposed to formaldehyde?
• By inhaling formaldehyde gas or vapor from the air
• By absorbing liquids containing formaldehyde through the skin.
Cancers associated with exposure to formaldehyde
• Myeloid leukemia
• Cancers of paranasal sinuses
• Cancer nasal cavity
• Carcinoma nasopharynx

27. Microwave Popcorn
• The Microwave Popcorns contain Perfluorooctanoic acid (PFOA)
and which is a likely carcinogen.
• Inhalation of vapour of artificial butter present in it which contains
dangerous chemicals and can cause kidney and lung cancers.
• Perfluorooctanoic acid (PFOA) - other uses are - in food wrappers,
candy wrappers, microwave wrappers.

28. Fruit Ripening agents (Carcinogens)
• Artificial ripening of fruits and vegetables has become essential
practice.
• The most commonly used chemical for artificial ripening is Calcium
Carbide (CaC2).
• Calcium Carbide is colourless when pure, but greyish-white to black
in colour otherwise, with garlic like odour.

29. Professions and industries associated with
high risk of cancer
Aluminium industry Polycyclic aromatic
hydrocarbons(PAH)
Lung and bladder cancer
Coal industry Polycyclic aromatic
hydrocarbons(PAH)
Lung, bladder, skin and
scrotum cancer
Shoe making Benzene Lympomas, leukemias
Furniture making Wood dust Nasopharyngeal cancer
Fuchsin dye production Fuchsin, ortho-toluidine Bladder cancer
Rubber industry Aromatic amines, solvents Lung, colon, stomach, bladder,
prostatic cancer, leukemia