A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved
in causing cancer.
This may be due to the ability to damage the genome or to the disruption of cellular metabolic
processes.
Several radioactive substances are considered carcinogens, but their carcinogenic activity
is attributed to the radiation, for example gamma rays and alpha particles, which they
emit.
Common examples of non-radioactive carcinogens are inhaled asbestos, certain dioxins, and
tobacco smoke.
Although the public generally associates carcinogenicity with synthetic chemicals, it is equally likely
to arise in both natural and synthetic substances.
Carcinogens are not necessarily immediately toxic, thus their effect can be insidious.
Cancer is any disease in which normal cells are damaged and do not undergo programmed
cell death as fast as they divide via mitosis.
Carcinogens may increase the risk of cancer by altering cellular metabolism or damaging
DNA directly in cells, which interferes with biological processes, and induces the uncontrolled,
malignant division, ultimately leading to the formation of tumors.
Usually, severe DNA damage leads to apoptosis, but if the programmed cell death pathway is
damaged, then the cell cannot prevent itself from becoming a cancer cell.
There are many natural carcinogens.
Aflatoxin B1, which is produced by the fungus Aspergillus flavus growing on stored grains,
nuts and peanut butter, is an example of a potent, naturally occurring microbial carcinogen.
Certain viruses such as hepatitis B and human papilloma virus have been found to cause cancer
in humans.
The first one shown to cause cancer in animals is Rous sarcoma virus, discovered in 1910
by Peyton Rous.
Other infectious organisms which cause cancer in humans include some bacteria and helminths.
Dioxins and dioxin-like compounds, benzene, kepone, EDB, and asbestos have all been classified
as carcinogenic.
As far back as the 1930s, industrial smoke and tobacco smoke were identified as sources
of dozens of carcinogens, including benzo[a]pyrene, tobacco-specific nitrosamines such as nitrosonornicotine,
and reactive aldehydes such as formaldehyde—which is also a hazard in embalming and making plastics.
Vinyl chloride, from which PVC is manufactured, is a carcinogen and thus a hazard in PVC production.
Co-carcinogens are chemicals that do not necessarily cause cancer on their own, but promote the
activity of other carcinogens in causing cancer.
After the carcinogen enters the body, the body makes an attempt to eliminate it through
a process called biotransformation.
The purpose of these reactions is to make the carcinogen more water-soluble so that
it can be removed from the body.
But these reactions can also convert a less toxic carcinogen into a more toxic carcinogen.
DNA is nucleophilic, therefore soluble carbon electrophiles are carcinogenic, because DNA
attacks them.
For example, some alkenes are toxicated by human enzymes to produce an electrophilic
epoxide.
DNA attacks the epoxide, and is bound permanently to it.
This is the mechanism behind the carcinogenicity of benzo[a]pyrene in tobacco smoke, other
aromatics, aflatoxin and mustard gas.
Radiation
CERCLA identifies all radionuclides as carcinogens, although the nature of the emitted radiation,
its consequent capacity to cause ionization in tissues, and the magnitude of radiation
exposure, determine the potential hazard.
Carcinogenicity of radiation depends of the type of radiation, type of exposure, and penetration.
For example, alpha radiation has low penetration and is not a hazard outside the body, but
emitters are carcinogenic when inhaled or ingested.
For example, Thorotrast, a suspension previously used as a contrast medium in x-ray diagnostics,
is a potent human carcinogen known because of its retention within various organs and
persistent emission of alpha particles.
Not all types of electromagnetic radiation are carcinogenic.
Low-energy waves on the electromagnetic spectrum including radio waves, microwave radiation,
infrared radiation and visible light are thought not to be, because they have insufficient
energy to break chemical bonds.
Evidence for carcinogenic effects of non-ionizing radiation is generally inconclusive, though
there are some documented cases of radar technicians with prolonged high exposure experiencing
significantly higher cancer incidence.
Higher-energy radiation, including ultraviolet radiation, x-rays, and gamma radiation, generally
is carcinogenic, if received in sufficient doses.
Low level ionizing radiation may induce irreparable DNA damage leading to pre-mature aging and
cancer.
Substances or foods irradiated with electrons or electromagnetic radiation are not carcinogenic.
In contrast, non-electromagnetic neutron radiation produced inside nuclear reactors can produce
secondary radiation through nuclear transmutation.
Carcinogens in prepared food
Cooking food at high temperatures, for example grilling or barbecuing meats, can lead to
the formation of minute quantities of many potent carcinogens that are comparable to
those found in cigarette smoke.
Charring of food resembles coking and tobacco pyrolysis, and produces similar carcinogens.
There are several carcinogenic pyrolysis products, such as polynuclear aromatic hydrocarbons,
which are converted by human enzymes into epoxides, which attach permanently to DNA.
Pre-cooking meats in a microwave oven for 2–3 minutes before grilling shortens the
time on the hot pan, and removes heterocyclic amine precursors, which can help minimize
the formation of these carcinogens.
Reports from the Food Standards Agency have found that the known animal carcinogen acrylamide
is generated in fried or overheated carbohydrate foods.
Studies are underway at the FDA and European regulatory agencies to assess its potential
risk to humans.
Carcinogens in cigarettes
Mechanisms of carcinogenicity Carcinogens can be classified as genotoxic
or nongenotoxic.
Genotoxins cause irreversible genetic damage or mutations by binding to DNA.
Genotoxins include chemical agents like N-nitroso-N-methylurea or non-chemical agents such as ultraviolet
light and ionizing radiation.
Certain viruses can also act as carcinogens by interacting with DNA.
Nongenotoxins do not directly affect DNA but act in other ways to promote growth.
These include hormones and some organic compounds.
Classification of carcinogens International Agency for Research on Cancer
The International Agency for Research on Cancer is an intergovernmental agency established
in 1965, which forms part of the World Health Organization of the United Nations.
It is based in Lyon, France.
Since 1971 it has published a series of Monographs on the Evaluation of Carcinogenic Risks to
Humans that have been highly influential in the classification of possible carcinogens.
Group 1: the agent is definitely carcinogenic to humans.
The exposure circumstance entails exposures that are carcinogenic to humans.
Group 2A: the agent is probably carcinogenic to humans.
The exposure circumstance entails exposures that are probably carcinogenic to humans.
Group 2B: the agent is possibly carcinogenic to humans.
The exposure circumstance entails exposures that are possibly carcinogenic to humans.
Group 3: the agent is not classifiable as to its carcinogenicity to humans.
Group 4: the agent is probably not carcinogenic to humans.
Globally Harmonized System The Globally Harmonized System of Classification
and Labelling of Chemicals is a United Nations initiative to attempt to harmonize the different
systems of assessing chemical risk which currently exist around the world.
It classifies carcinogens into two categories, of which the first may be divided again into
subcategories if so desired by the competent regulatory authority:
Category 1: known or presumed to have carcinogenic potential for humans
Category 1A: the assessment is based primarily on human evidence
Category 1B: the assessment is based primarily on animal evidence
Category 2: suspected human carcinogens U.S. National Toxicology Program
The National Toxicology Program of the U.S. Department of Health and Human Services is
mandated to produce a biennial Report on Carcinogens.
As of June 2011, the latest edition was the 12th report.
It classifies carcinogens into two groups: Known to be a human carcinogen
Reasonably anticipated to be a human carcinogen American Conference of Governmental Industrial
Hygienists The American Conference of Governmental Industrial
Hygienists is a private organization best known for its publication of threshold limit
values for occupational exposure and monographs on workplace chemical hazards.
It assesses carcinogenicity as part of wider assessment of the occupational hazards of
chemicals.
Group A1: Confirmed human carcinogen Group A2: Suspected human carcinogen
Group A3: Confirmed animal carcinogen with unknown relevance to humans
Group A4: Not classifiable as a human carcinogen Group A5: Not suspected as a human carcinogen
European Union The European Union classification of carcinogens
is contained in the Dangerous Substances Directive and the Dangerous Preparations Directive.
It consists of three categories: Category 1: Substances known to be carcinogenic
to humans.
Category 2: Substances which should be regarded as if they are carcinogenic to humans.
Category 3: Substances which cause concern for humans, owing to possible carcinogenic
effects but in respect of which the available information is not adequate for making a satisfactory
assessment.
This assessment scheme is being phased out in favor of the GHS scheme, to which it is
very close in category definitions.
Safe Work Australia Under a previous name, the NOHSC, in 1999
Safe Work Australia published the Approved Criteria for Classifying Hazardous Substances
[NOHSC:1008(1999)].
Section 4.76 of this document outlines the criteria for classifying carcinogens as approved
by the Australian government.
This classification consists of three categories: Category 1: Substances known to be carcinogenic
to humans.
Category 2: Substances that should be regarded as if they were carcinogenic to humans.
Category 3: Substances that have possible carcinogenic effects in humans but about which
there is insufficient information to make an assessment.
Procarcinogen A procarcinogen is a precursor to a carcinogen.
One example is nitrites when taken in by the diet.
They are not carcinogenic themselves, but turn into nitrosamines in the body, which
are carcinogenic.
Common carcinogens Occupational carcinogens
Occupational carcinogens are agents that pose a risk of cancer in several specific work-locations:
Others Gasoline
Lead and its compounds Alkylating antineoplastic agents
Other alkylating agents Ultraviolet radiation from the sun and UV
lamps Alcohol
Other ionizing radiation Major carcinogens implicated in the four most
common cancers worldwide In this section, the carcinogens implicated
as the main causative agents of the four most common cancers worldwide are briefly described.
These four cancers are lung, breast, colon, and stomach cancers.
Together they account for about 41% of worldwide cancer incidence and 42% of cancer deaths.
Lung cancer Lung cancer is the most common cancer in the
world, both in terms of cases and deaths.
Lung cancer is largely caused by tobacco smoke.
Risk estimates for lung cancer in the United States indicate that tobacco smoke is responsible
for 90% of lung cancers.
Other factors are implicated in lung cancer, and these factors can interact synergistically
with smoking, so that total attributable risk adds up to more than 100%.
These factors include occupational exposure to carcinogens, radon and outdoor air pollution.
Tobacco smoke is a complex mixture of more than 5,300 identified chemicals.
The most important carcinogens in tobacco smoke have been determined by a “Margin
of Exposure” approach.
Using this approach, the most important tumorigenic compounds in tobacco smoke were, in order
of importance, acrolein, formaldehyde, acrylonitrile, 1,3-butadiene, cadmium, acetaldehyde, ethylene
oxide and isoprene.
Most of these compounds cause DNA damage by forming DNA adducts or by inducing other alterations
in DNA.
DNA damages are subject to error-prone DNA repair or can cause replication errors.
Such errors in repair or replication can result in mutations in tumor suppressor genes or
oncogenes leading to cancer.
Breast cancer Breast cancer is the second most common cancer
[(1.4 million cases, 10.9%), but ranks 5th as cause of death].
Increased risk of breast cancer is associated with persistently elevated blood levels of
estrogen.
Estrogen appears to contribute to breast carcinogenesis by three processes; the metabolism of estrogen
to genotoxic, mutagenic carcinogens, the stimulation of tissue growth, and the repression of phase
II detoxification enzymes that metabolize ROS leading to increased oxidative DNA damage.
The major estrogen in humans, estradiol, can be metabolized to quinone derivatives that
form adducts with DNA.
These derivatives can cause dupurination, the removal of bases from the phosphodiester
backbone of DNA, followed by inaccurate repair or replication of the apurinic site leading
to mutation and eventually cancer.
This genotoxic mechanism may interact in synergy with estrogen receptor-mediated, persistent
cell proliferation to ultimately cause breast cancer.
Genetic background, dietary practices and environmental factors also likely contribute
to the incidence of DNA damage and breast cancer risk.
Colon cancer Colorectal cancer is the third most common
cancer [1.2 million cases, 608,000 deaths].
Tobacco smoke may be responsible for up to 20% of colorectal cancers in the United States.
In addition, substantial evidence implicates bile acids as an important factor in colon
cancer.
Twelve studies indicate that the bile acids deoxycholic acid and/or lithocholic acid induce
production of DNA damaging reactive oxygen species and/or reactive nitrogen species in
human or animal colon cells.
Furthermore 14 studies showed that DCA and LCA induce DNA damage in colon cells.
Also 27 studies reported that bile acids cause programmed cell death.
Increased apoptosis can result in selective survival of cells that are resistant to induction
of apoptosis.
Colon cells with reduced ability to undergo apoptosis in response to DNA damage would
tend to accumulate mutations, and such cells may give rise to colon cancer.
Epidemiologic studies have found that fecal bile acid concentrations are increased in
populations with a high incidence of colon cancer.
Dietary increases in total fat or saturated fat result in elevated DCA and LCA in feces
and elevated exposure of the colon epithelium to these bile acids.
When the bile acid DCA was added to the standard diet of wild-type mice invasive colon cancer
was induced in 56% of the mice after 8 to 10 months.
Overall, the available evidence indicates that DCA and LCA are centrally important DNA-damaging
carcinogens in colon cancer.
Stomach cancer Stomach cancer is the fourth most common cancer
[990,000 cases, 738,000 deaths].
Helicobacter pylori infection is the main causative factor in stomach cancer.
Chronic gastritis caused by H. pylori is often long-standing if not treated.
Infection of gastric epithelial cells with H. pylori results in increased production
of reactive oxygen species.
ROS cause oxidative DNA damage including the major base alteration 8-hydroxydeoxyguanosine.
8-OHdG resulting from ROS is increased in chronic gastritis.
The altered DNA base can cause errors during DNA replication that have mutagenic and carcinogenic
potential.
Thus H. pylori-induced ROS appear to be the major carcinogens in stomach cancer because
they cause oxidative DNA damage leading to carcinogenic mutations.
See also
References
External links U.S. National Toxicology Program's Report
on Carcinogens CDC – Occupational Cancer – Carcinogen
List – NIOSH Safety and Health Topic Recognized Carcinogens
American Cancer Society Database of Rodent Carcinogens
Comparing Possible Cancer Hazards from Human Exposures to Rodent Carcinogens