Carcinogenic Chemicals In Humans Notes

Carcinogenic Chemicals In Humans

The list of diverse chemical compounds which can produce cancer in experimental animals is a long one but only some of them have sufficient epidemiological evidence in human neoplasia.

Depending upon the mode of action of carcinogenic chemicals, they are divided into 2 broad groups:

1. Initiators and
2. Promoters.

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Initiator Carcinogens

Chemical carcinogens that can initiate the process of neoplastic transformation are further categorised into 2 subgroups

1. Direct-acting and
2. Indirect-acting carcinogens or procarcinogens.

1. Direct-Acting Carcinogens

These chemical carcinogens do not require metabolic activation and fall into 2 classes:

1. Alkylating agents:  This group includes mainly various anti-cancer drugs (for example, Cyclophosphamide, chlorambucil, busulfan, melphalan, nitrosourea), β-propiolactone, and epoxies. They are weakly carcinogenic and are implicated in the etiology of lymphomas and leukemias in human beings.
2. Acetylating agents:  The examples are acetyl imidazole and dimethyl carbamyl chloride.

2. Indirect-Acting Carcinogens (Procarcinogens):

These are chemical substances that require prior metabolic activation before becoming potent ‘ultimate’ carcinogens. This group includes the vast majority of carcinogenic chemicals. It includes the following 4 categories:

1. Polycyclic aromatic hydrocarbons: These comprise the largest group of common procarcinogens which, after metabolic activation, can induce neoplasia in many tissues in experimental animals and are also implicated in a number of human tumors.
   • They cause different effects by various modes of administration for example:
     • Topical application may induce skin cancer
     • Subcutaneous injection may cause sarcomas
     • Inhalation produces lung cancer, and
     • When introduced in different organs by parenteral/metabolizing routes may cause cancer of that organ.
   • The main sources of polycyclic aromatic hydrocarbons are:
     • Combustion of tobacco
     • Tobacco chewing
     • Smoke
     • Fossil fuel (for example, Coal), Soot
     • Tar
     • Mineral oil
     • Smoked animal foods
     • Industrial and Atmospheric pollutants.
   • Important chemical compounds included in this group are:
     • Anthracenes (benza-, dibenza-, dimethylbenza-)
     • Benzapyrene and Methylcholanthrene.
   • The following Examples have evidence to support the etiologic role of these substances:
     • Smoking and lung cancer There is a 20-fold higher incidence of lung cancer in smokers of 2 packs (40 cigarettes) per day for 20 years.
     • Skin cancer Direct contact of polycyclic aromatic hydrocarbon compounds with the skin is associated with higher incidence of skin cancer.
     • For example, the natives of Kashmir carry an earthen pot containing embers, the kangri, under their clothes close to the abdomen to keep themselves warm; skin cancer of the abdominal wall called kangri cancer is common among them.
     • Tobacco and betel nut chewing and cancer oral cavity Cancer of the oral cavity is more common in people chewing tobacco and betel nuts. The chutta is a cigar that is smoked in South
     • India (in Andhra Pradesh) with the lighted end in the mouth (i.e. reversed smoking) and such individuals have higher incidence of cancer of the mouth.
2. Aromatic amines and tie-dyes:  This category includes the following substances implicated in chemical carcinogenesis:
   • β-naphthylamine in causing bladder cancer, especially in aniline dye and rubber industry workers.
   • Benzidine in the induction of bladder cancer.
   • Azo-dyes used for coloring foods (for example, Butter and margarine to give them yellow color, scarlet red for coloring cherries etc) in the etiology of hepatocellular carcinoma.
3. Naturally-occurring products:
   • A few important chemical carcinogens derived from plant and microbial sources are antitoxin B1, actinomycin D, antimycin C, parole and betel nuts.
   • Aflatoxin B1 is derived from the fungus, Aspergillus Flavius, that grows in stored grains and plants and is implicated in etiology of hepatocellular carcinoma, especially when the patient has concomitant hepatitis B viral infection.
4. Miscellaneous:   A variety of other chemical carcinogens having a role in the etiology of human cancer are as under:
   • Nitrosamines and nitrosamides are involved in gastric carcinoma. These compounds are actually made in the stomach by nitrosylation of food preservatives.
   • Vinyl chloride monomer derived from polyvinyl chloride (PVC) polymer in the causing haemangiosarcoma of the liver.
   • Asbestos in bronchogenic carcinoma and mesothelioma, especially in smokers.
   • Arsenal compounds in causing epidermal hyperplasia and basal cell carcinoma.
   • Metals like nickel, lead, cobalt, chromium etc in industrial workers cause lung cancer.
   • Insecticides and fungicides ( for example, Aldrin, Dieldrin, Chlordane) in carcinogenesis in experimental animals.
   • Saccharin and cyclamens in cancer in experimental animals.

Promoter Carcinogens

Promoters are chemical substances that lack the intrinsic carcinogenic potential but their application subsequent to initiator exposure helps the initiated cell to proliferate further.

These substances include formal esters, phenols, certain hormones, and drugs.

1. Phobos’s esters The best-known promoter in experimental animals is TPA (tetradecanoylphorbol acetate) which acts by signal-induction protein activation pathway.
2. Hormones Endogenous or exogenous estrogen excess in promotion of cancers of the endometrium and the breast, prolonged administration of diethylstilbestrol in the etiology of postmenopausal endometrial carcinoma and in vaginal cancer in adolescent girls born to mothers exposed to this hormone during their pregnancy.
3. Miscellaneous for example, Dietary fat in cancer of the colon, cigarette smoke and viral infections, etc.

Tests For Chemical Carcinogenicity

There are 2 main methods of testing chemical compounds for their carcinogenicity:

1.  Experimental Induction: The traditional method is to administer the chemical compound under test to a batch of experimental animals like mice or other rodents by an appropriate route for example, painting on the skin, giving orally or parenterally, or by inhalation.
   • The chemical is administered repeatedly, the dose varied, and promoting agents are administered subsequently.
   • After many months, the animal is autopsied and results obtained.
   • However, all positive or negative tests cannot be applied to humans since there is sufficient species variation in susceptibility to a particular carcinogen.
   • Besides, the test is rather prolonged and expensive.
2. Tests For Mutagenicity:( Ames’ Test):  A mutagen is a substance that can permanently alter the genetic composition of a cell.
   • Ames’ test evaluates the ability of a chemical to induce mutation in the mutant strain of Salmonella typhimurium that cannot synthesize histidine.
   • Such strains are incubated with the potential carcinogen to which liver homogenate is added to supply enzymes required to convert procarcinogen to ultimate carcinogen.
   • If the chemical under test is mutagenic, it will induce mutation in the mutant strains of S. typhimurium in the form of a functional histidine gene, which will be reflected by the number of bacterial colonies growing on histidine-free culture medium.
   • Most of the carcinogenic chemicals tested positive in Ames’ test are carcinogenic in vivo.