PHYSICAL AND CHEMICAL

CARCINOGENIC AGENTS
Presented by, SHASHANK M
1st MSc Biotechnology
Dept. Of Biosciences
Mangalore University
 CONTENTS
▪ INTRODUCTION
▪ PHYSICAL CARCINOGENIC AGENTS
▪ CHEMICAL CARCINOGENIC AGENTS
▪ SUMMARY
▪ REFERENCES
 INTRODUCTION
• Cell- The unit of life
• Self reproduction- characteristics of cells.
• Defect in cell cycle regulation are a common cause of the abnormal proliferation of
cancer cells.
• Cell death and cell proliferation are balanced throughout the life cycle of
multicellular organisms.
• Abnormalities of cell death results in illness including cancer , autommune disease
and neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease.
• Cancer is defined as uncontrolled cell division which produces excess of
abnormal tissue. This excess of abnormal tissue form a tumor or a neoplastic
growth.
• The study of cancer is called oncology.
• A person who specialised in this field is called. Oncologist.
• The term cancer was first coined by Hippocrates in 5th century B.C
 CARCINOGENIC AGENTS
• Substances or external agents which cause cancer are called carcinogens.
• Carcinogens may occur naturally in the environment or may be generated by humans.
• Carcinogens have been identified both by studies in experimental animals and by
epidemiological analysis of cancer frequencies in human population.
Example: The high incidence of lung cancer among cigarette smokers.
• Radiation, chemicals and biological agents have been found to induce cancer in both
experimental animals and humans.
• The process of transformation of normal cells into malignant cell which repeatedly
divides to become a cancer is known as carcinogenesis.
• Carcinogens interact with DNA in cells interfering normal cellular functions
• This results in tumours, which have the ability to metastasize .cause
dysfunction of tissues ,organ failure and death.
Mechanisms;
i. Alteration in DNA –forming DNA adducts and DNA strand breaks .
ii. non genotoxic mechanisms – immunosuppression and induction of tissue
specific inflammation.
 HISTORY

• First ever evidence of cause of neoplasia from observations of Sir Percival Pott in
1755
• That there was higher incidence of cancer of scrotum in chimney sweeps in
London than in general population.
• First successful experimental induction of cancer was produced by two Japanese
scientists Yamagiwa and Ichikawa in 1914.
• In rabbits skin by repeatedly painting coal tar.
• Carcinogenic agents are of three types
1. Physical carcinogenic agents
2. Chemical carcinogenic agents
3. Biological carcinogenic agents
• The various carcinogens may be exogenous or endogenous.
• Physical and chemical carcinogens are exogenous
• Exogenous carcinogens: All the type of physical chemical and biological agents that
can cause cancer after having penetrated into the organism by respiratory, digestive,
cutaneous or other possible contamination routes.
• Endogenous carcinogens: Carcinogens that cause malignant transformation include a
broad group of factors from within the body.
 CLASSIFICATION

IONIZING Eg: X- Ray, Nuclear

RADIATION radiation
RADIATION
NON IONIZING Eg: UV rays, Visible
light, IR, Microwaves,
RADIATION Radio waves
PHYSICAL
Eg: Mechanical,
Burns, Surgical
NON RADIATION implants, Foreign
bodies
Eg: Anti- cancer drugs
ALKYLATING - Cyclophosphamide,
AGENTS Busulfan, Nitrosourea
CARCINOGENIC DIRECT ACTING
AGENTS ACYLATING
Eg: Acetyl imidazole
AGENTS
CHEMICAL
Eg: Polycyclic aromatic
INDIRECT ACTING hydrocarbons,
Aromatic amines , Azo
dyes , Cigarette smoke

Eg: Viruses, Bacteria ,

BIOLOGICAL Parasitic organisms
 PHYSICAL CARCINOGENS
• Physical agents which cause cancer are called physical carcinogens.
• Radiation (natural and artificial) ,X- rays, nuclear fission products are main physical
carcinogens.
• Two major groups are : Radiation and Non radiation
RADIATION
• It’s energy travelling in the form of
1. Waves – Gamma and electromagnetic radiations
2. Atomic particles- alpha and beta particles
• The affect in mechanism and amount of DNA damage depends on the rate at which
the energy released by the particular radiation source.
• Radiations are of two types: Ionizing radiation and non- ionizing radiation.
 1] IONIZING RADIATION

• Produced from natural and artificial sources

• X- Ray, nuclear radiation has enough energy to ionize; that is removal of an
electron from an atom
• Capacity to change the chemical composition of DNA.
• Include α- particles, β- particles and γ rays
• Examples: X- ray, Gamma ray, cosmic ray
• Incidence of malignancy is higher amongst radiologists due to long period
exposure of X ray
• These radiation lead to the formation of an ion or highly reactive free radical and
water derived free radicals.
• Ionization of atoms comprising of DNA
• Interact with water molecules generating dangerous intermediates called
Reactive Oxygen Species (ROS).
• Since the electrons are stripped away bonds break, individual bases are lost and
trigger single or double strand breaks in DNA double helix.
• X- ray most serious cancer hazard , they penetrate enough through skin and reach
internal organs
• Radiation used for treatment can cause cancer.
• Radioactive materials inhaled or ingested accidentally may produce carcinoma.
• Miners and persons handling radioactive chromium or uranium have higher
incidence of lung cancer.
• Workers engaged in preparing watch dials with luminous paint containing
radioactive materials develop osteogenic sarcomas of bones.
• Exposure to atomic radiations increases the incidence of malignancy , whole
population may affected.
• Most horrifying example is cancer occurred in Japan after the atomic bombs
were exploded over Hiroshima and Nagasaki 1945.
• The massive radioactive fall caused lukemia, lymphomas, breast, uterus and
gastrointestinal tract cancer.
 2] NON IONIZING RADIATION
• Does not have enough energy to remove electrons from atoms and molecules.
• Examples, UV rays, visible light, Infrared, Microwave, Radio waves.
Ultraviolet Radiation (UV):
• It is known to induce skin cancer.
• 3 type
a. UV A ; 320- 380 nm
b. UV B; 290-320nm
c. UV C; 200-290nm
a. UV A
• These radiation cause free radical mediated damage.
• Water fragmented generates electron seeking ROS thereby DNA damage.
E.g. ; oxidation of bases
• Transition occurs G T
b. UV B
• UV-B radiations are absorbed by the conjugated double bonds in rings of
nitrogenous bases of DNA.
• UV-B forms
i. Cyclobutane pyrimidine dimers
ii. Pyrimidine pyrimidone products
• These induce transition TC TT , CC TT
• The DNA damage because of this can lead to
⮚ p53 protein accumulates , this trigger apoptosis leading to sunburn.
⮚if UV induce mutation inactivate p53 genes, cells with damaged DNA no longer self
destruct ,cancer may arise from the uncontrolled proliferation of this mutant cells.
 Other examples for physical carcinogens
• Farmers exposed to direct sunlight over long period of time results skin cancer
(Farmer’s cancer).
• Such carcinomas are also known as occupational or social carcinomas.
• Fair skinned people exposed to sunlight may develop skin cancer, especially in
tropical regions where sunlight is very intense.
• Heat induces necrosis and regeneration. Examples are met with,
• In hypertrophied scars (keloids) following burns especially if subjected to chronic
irritation.
• Carcinomas supervening on scars are called Marjolin’s ulcer. Majority , they are
squamous cell carcinomas
• Kangri cancer met within Kashmir valley where people use specially designed
baskets called kangri containing live charcoals under the cloths directly in touch
with skin to ward of excessive cold.
• Tumors are seen over the skin of chest and abdominal wall.
• Chhota cancer seen in natives of South India , who have practice of smoking with
lighted end of cigar inside the mouth.
• Very hot food causes death of surface cells. Which when replaced may turn out to
be cancerous.
• Raw tobacco in the cheeks for long period may also cause cancer.

Kangri
 CHEMICAL CARCINOGENS

• Many chemical compounds have been identified as carcinogens.

• Chemical carcinogens are extremely diverse structure.
• Include both natural and synthetic products.
• All chemical carcinogens are highly relative electrophile (have electron
deficient atom) that react with electron rich atoms in RNA , cellular proteins
and mainly DNA.
• Many carcinogens have no requirement for promoting agents.
• Categorized into two groups:
a] Direct acting
b] Indirect acting carcinogens
 a] Direct acting carcinogens:
• These chemical carcinogens do not require metabolic
activation.
• They are grouped into
1. Alkylating agents
2. Acylating agents
Mustard gas (world war 1)
1. Alkylating agents:
• These agents act directly on DNA, resulting in its cross linking and causing breaking of DNA
strand.
• Includes various anticancer drugs
• Eg: Cyclophosphamide, Busulfan, Nitrosourea
Mustard gas – Chemical warfare agent: Sulphur mustard is used in world war 1 by German
soldiers
Vinyl chloride- Production of plastic
Ethyleneoxide- Production of anti-freeze and other products
2] Acylating agents:
• Important class of highly reactive electrophilic agents.
• Interfere with normal biological reactions because of their high chemical
reactivity towards biochemical substances.
• Eg: Acetyle imidazole, Benzoyl chloride

b] Indirect acting carcinogens:

• These are chemical substances that require metabolic activation to become a
potent carcinogen.
• Most of the chemicals fall into this category
• Examples are as follows,

Polycyclic aromatic hydrocarbons:

⮚ Largest group of chemical carcinoges.
Benzo(α)pyrene
⮚ Main sources of these hydrocarbons are tobacco, fossil fuel ( coal soot, coal tar,
mineral oil)
⮚ Industrial and atmospheric pollutants
⮚ Eg: Benzanthrene and Benzo(α)pyrene
⮚ Direct contact is associated with high incidence of skin cancer
⮚ Smoking- lung cancer
7,12 dimethyl benz
⮚ Oral cancer is common in prople chewing tobacco. (α) anthracene
⮚ Long term exposure of polycyclic aromatic hydrocarbons caused cancer in
laboratory animals
Aromatic amines and azo dyes:
⮚ Organic molecules that possess amino group (-NH2) attached to the carbon
backbone containing one or more benzene rings are called aromatic amines.
⮚ Many aromatic amines have been reported to potent mutagenic, carcinogenic
and hemotoxic agents.
⮚ Β- naphthylamine in aniline dyes and rubber industry cause bladder cancer.
⮚ Azo dye used for colouring foods ( Butter yellow for colouring butter and
margarine used for colouring cherries) cause liver cancer.
⮚ Some other examples are: 2- naphthylamine, 4-amino biphenyl, 2- acetyl
amino purine.
⮚ Amino azo compounds: 4- dimethyl amizo biphenyl, 6- amizo toluene
Naturally occurring compounds:
⮚ These carcinogens are derived from plants and microbes.
⮚ Actinomycin D, Mitomycin, Aflatoxin B are examples
Aspergillus flavus
⮚ Aflatoxin B causes liver cancer, it derived from the fungus Aspergillus flavus -
grows in stored grains and plants.
⮚ They cause hepatocellular carcinoma.
⮚ Aflatoxin B1 forms DNA adducts that rapidly denatures and excreted in urine.
⮚ TP53mutation spectrum,mutation induced by Aflatoxin B1 leads to liver cancer
and it is common in China, Taiwan, Korea and sub Sahara Africa.
Miscellaneous substances:
⮚ Nitroso compounds Vinyl chloride, Asbestos, Arsenic compounds and
metals (nickel, mercury, lead, cobalt and chromium) cause cancer in
different parts of the body.
Asbestos:
⮚ Fibrous silicate mineral, have insulating property
⮚ It has ability to cause cancer related to crystal structure and size of
microscopic fibres it forms cause lung cancer and mesothelioma.
Arsenic:
⮚ The international agency for research on cancer (IARC) has classified
arsenic and arsenic compounds as carcinogenic to humans.
⮚ It cause cancer in the skin, urinary bladder and kidney.
Tobacco smoke:
⮚Causes cancer in lung, bladder, renal pelvis, oral cavity,oropharynx,
hypopharynx, liver , stomach, uterine cervix, tongues, bone marrow, ovary
etc.
⮚Most of these compounds are genotoxic, induce smoking related DNA
adducts.
⮚Its complex mixture has more than 4000 identified chemicals of which 60
are carcinogenic.
⮚Mutational signatures
Alcohol:
⮚ Cause cancer in oral cavity, pharynx, oesophagus and breasts, liver, pancreas.
⮚ Genotoxic mechanisms induce metabolism of ethanol to acetaldehyde.
⮚ Generation of Ros, effect on hormone level and folate metabolism and
inducing cirrhosis.
Nitrosamine and Nitrosamides:
⮚ Nitroso compounds Dimethyl nitrousamine
Methyl nitrosurea
⮚ Tobacco, preservative nitrite react with amine in fish,
meats, during smoking these are formed.
⮚ Procarcinogens are chemical substances that become carcinogenic only after
they are altered by metabolic processes
⮚ Example: Nitrates and nitrite in stomach (taken in by diet) converted to
nitrosamine.
 SUMMARY
• Cancer is a disease due to the malfunctioning of the pathways necessary to the life
of a multicellular organism , abnormal cells proliferate in an uncontrolled fashion
and spread through the body
• Carcinogens are substances or exposures that can cause cancer .
• Carcinogens are chemical ,physical and biological.
• Physical carcinogens, ionizing radiation being the most dangerous causing
mutations .
• Chemical carcinogens can be natural as well as synthetic.
• Among the chemical carcinogens tobacco smoke causes the most cancer death
followed by Asbestos the 2nd most lethal commercial product.
• Current lifestyle makes us expose to many carcinogens but most of them are weak
carcinogens and the most potent ones should largely to be avoided by people.
 REFERENCES
1. Cooper, Geoferry M. The cell: A molecular approach. Eighth Edition. New York, Sinauer
Associates an imprint of Oxford University Press, 2019.
2. Gupta, M.L, Jangir, M.L. Cell biology: Fundamentals and Applications. Agrobios ( India)
Agro House, 2004.
3. Johnson, Alexander, Lewis, Julian, Bruce, Alberts, David Morgan, Martin Raff, Keith
Roberts, Peter Walter. Molecular Biology of the Cell,6th edition, Garland Science, Tylor
and Francis group. LLC, New York,2015
4. Kleinsmith, Lewis J., Valerie, M. Kish. Principles of cell and molecular biology,2nd
edition, Harpercollins college publishers,1995.
5. Ruddon, Raymond W. Cancer biology. Oxford University Press,2007
6. Oliveira, Paula A.et al. Chemical carcinogenesis. Anias da academia brasileira de ciencias
79 ,2007: 593-616.
THANK YOU