CARCINOGENIC CHEMICALS

Jonathan S. Viernes
 Direct-Acting Alkylating Agents

These agents are activation-dependent and they

are weak carcinogens
Therapeutic agents (cyclophosphamide,
chlorambucil, busulfan and melphalan) fall in this
category
These are used as anti-cancer drugs but have
been documented to cause: (1) lymphoid
neoplasms; (2) leukemia and other forms of
cancer
 Direct-Acting Alkylating Agents
Cyclophosphamide a powerful immuno-
suppressive agent and used in the treatment of
immunologic disorders including rheumatoid
arthritis and Wegener granulomatosis
Judicious use of direct-acting alkylating agents is
indicated
Mechanism of action: these drugs exert their
therapeutic effects by interacting with and
damaging DNA
Note: This mechanism of action of these drugs
render them carcinogenic
 Polycyclic Aromatic Hydrocarbons
These drugs represent the most potent carcinogens
They require metabolic activation and can induce
tumors in a wide variety of tissues and species:
Causes skin cancer if painted on the skin
Induces sarcomas if injected subcutaneously
Causes cancer locally if introduced into a
specific organ
 Polycyclic Aromatic Hydrocarbons

PAC are produced in the combustion of tobacco

and are thought to contribute to the causation of
lung and bladder cancers
PAC are also produced from animal fats in the
process of broiling meats and are present in
smoked fish and meats
 Aromatic Amines and Azo Dyes

The carcinogenecity of these chemicals is

exerted mainly in the liver
Note: The ultimate carcinogen is formed by the
action of the cytochrome P-450 oxygenase
systems in the liver
Hepatocellular carcinomas are induced if
acetylaminolfuorene and the azo dyes are fed to
rats
 Aromatic Amines and Azo Dyes
-napthylamine was responsible for a 50-fold
increased incidence of bladder cancer in heavily
exposed workers in aniline and dye rubber
industries

Detoxifed by When exreted, the

Hydroxylated conjugation
Absorption non-toxic
into active with conjugate is split
form glucoronic and electrophillic
acid reactant is
released again
 Aromatic Amines and Azo Dyes

Humans have urinary glucoronidase

Some Azo dyes were developed as food
coloring:
Butter yellow
Scarlet red
 Naturally Occurring Carcinogens

Aflatoxin B1 a potent hepatic carcinogen that

is produced by Aspergillus flavus that thrive on
improperly stored rice, corn and peanuts

Aflatoxin and HBV are responsible for the

causation of hepatocellular carcinoma
 Nitrosamines and Amides

There is a possibility that these carcinogens are

formed in the GI tract of humans
Note: They may contribute to the causation of
gastric carcinoma
They are derived from the stomach from the
reaction of nitrostable amines and nitrate used
as a preservative, which is converted by nitrites
by bacteria
 Miscellaneous Agents

Chromium, nickel and other metals causes

lung cancer if these metals are volatilized and
inhaled
Skin cancer is also associated with arsenic
Insecticides (aldrin, dieldrin and chlordane and
the polychlorinated biphenyls) are carcinogenic
in animals
 Promoters of Chemical
Carcinogenesis
Certain promoters may contribute to cancers in
humans
Note: Promoters are as important as initiating
chemicals in carcinogenesis because cells
initiated by environmental carcinogens are
innocuous unless subjected to repeated assault
by promoters
Tumor promotion may occur after exposure to
exogenous agents (cigarette smoking or viral
infections) that cause tissue damage and reactive
hyperplasia
 Promoters of Chemical
Carcinogenesis
Endogenous promoters (hormones and bile salts)
are hard to control.
Estrogen serve as tumor promoters in animals
Notes:
1. Prolonged use of diethyl stilbestrol is
implicated in the production of postmenopausal
endometrial carcinoma and in the causation of
vaginal cancer in offspring exposed in utero
 Promoters of Chemical
Carcinogenesis
2. Intake of high levels of dietary fat has been
associated with increased risk of colon cancer
* due to the increase of the synthesis of bile
acids (bile acids are promoters in experimental
models of colon cancer)
3. Alcohol consumption increases the risk of
development of cancers of the mouth, pharynx
and larynx by more than ten fold
 Major Chemical Carcinogens
Direct Acting Carcinogens Polycyclic and Heterocyclic Aromatic
Hydrocarbons
Alkylating agents
Benz(a)anthracene
-propiolactone
Benzo(a)pyrene
Dimethyl sulfate
Dibenz(a,h) anthracene
Diepoxybutane
3-Methylcholanthrene
Anticancer drugs
7,12-Dimethylbenz(a)anthracene
Acylating Agents
Aromatic Amines, Amides and Azo Dyes
1-Acetyl-imidazole
2-Naphthylamine
Dimethylcarbamyl chloride
Benzidine
Procarcinogens that Require
Activation 2-acetylaminofluorence
Dimethylaminoazobenzene (butter yellow)
 Major Chemical Carcinogens
Natural Plant and Microbial Products
Aflatoxin B1
Griseofulvin
Cycasin
Safrole
Betel Nuts
Others
Nitrosamine and amides
Vinyl chloride, nickel, chromium
Insecticides, fungicides
Polychlorinated biphenyls