How Is a Chemical Determined to Be Carcinogenic (Cancer-Causing)?

Carcinogen is a word we encounter increasingly in everyday life. It derives from "carcinoma" (cancer) and "genesis" (formation), and means cancer-causing (the incorrect Turkish expression "kanserojen" is often used). Various observations and experiments are used to classify a substance as carcinogenic. These examine its effects in the body, and classifications are made according to the results.

A carcinogen need not be a substance: "anything" causing cancer can be classified as carcinogenic. For example, smoking and alcohol are widely known carcinogens, while obesity and certain viruses and bacteria are also well-known carcinogens.

Genotoxic and Non-Genotoxic Carcinogens

Carcinogens interact with DNA to initiate and support cancer development. For cancer to develop, DNA damage / genetic changes / mutations must occur and accumulate.

Chemical carcinogens causing DNA damage are called genotoxic substances. Alongside these, a smaller proportion consists of nongenotoxic (non-genotoxic) chemical carcinogens. Rather than directly causing DNA damage, nongenotoxic carcinogens act through various mechanisms, including tumor promotion and suppression of the immune system . Explaining the role of nongenotoxic chemicals in cancer is therefore more difficult than explaining that of genotoxic chemicals.

Carcinogens have toxicological (harmful) effects that enable them to trigger cancer. The 24 toxicological points most commonly affected by carcinogens are listed below:

• DNA damage,
• oxidative stress,
• protein addition (increased production), 
• chromosomal effects,
• gene mutations,
• epigenetic effects,
• changes in gene production,
• alternative cell growth pathways being used,
• metabolic effects,
• sensitivity,
• immune system effects,
• chronic inflammation,
• cell death, 
• chronic irritation (which may lead to inflammation), 
• cell cycle,
• DNA repair,
• receptor effects,
• hormonal effects,
• angiogenesis (formation of new blood vessels by the tumor),
• telomere length changes,
• differences in communication between adjacent cells, 
• Bystander effect,
• cell immortalization and 
• effects on ADME (absorption, distribution and elimination of a substance) are the most important effects enabling cancer formation.

These toxic effects of carcinogens are also closely related to The 10 Hallmarks of Cancer .

These effects also give carcinogens characteristic properties, such as receptor-mediated actions and triggering chronic inflammation. Characteristic properties are used to classify toxicological effects. When a substance is considered for classification as carcinogenic, its effects are observed. If its association with cancer is demonstrated, it is classified as carcinogenic.

When investigating whether a chemical is carcinogenic, experimental animal tests, tests performed outside animal and human cells (in vitro), and epidemiological studies are examined.

The Importance of Epidemiological Studies in Determining Whether Something Is Carcinogenic

Epidemiology is the science studying the distribution and frequency of a disease and the factors affecting it. Epidemiological studies are used in many health studies today. In the 1850s, John Snow investigated the homes of people who died of cholera in London and observed that cholera spread through water. This discovery reduced deaths from cholera and laid the foundations of epidemiology. The first epidemiological study of chemicals was conducted in the 1950s by Richard Doll and Andrew Hill. They examined the association between smoking and lung cancer, investigating how many times per day patients with lung cancer had smoked in the past. They observed that tobacco smoke increased the risk of lung cancer. Thus, smoking/tobacco smoke was understood to be carcinogenic.

Epidemiological studies are divided into 2 types: observational and experimental

Observational epidemiological research is also divided into 2 types: descriptive and analytical. Descriptive studies investigate disease extent and the affected population, formulate hypotheses about suspected causes, and compare with other diseases. They examine case reports and individual factors such as age, sex, ethnicity, occupation, habits, region of residence, socioeconomic status and time. Analytical studies aim to prove hypotheses proposed in descriptive research. Hypothesis testing includes association studies of similar diseases caused by the substance under investigation, case-control studies for definitive results, and cohort studies explaining the association with any disease that may cause the disease under investigation. Analytical research also includes cross-sectional studies (prevalence studies) determining the frequency of a disease-related event in a population at a given time. Experimental research examines results obtained through clinical trials, field studies and community screening.

Advances Through Molecular Epidemiology

Conventional epidemiological research has contributed greatly to cancer research. With developing technology, conventional epidemiology is now joined by molecular epidemiology . Molecular epidemiology identifies and classifies an agent at the molecular level. It plays a particularly important role in studying diseases occurring at the cellular level, such as mechanisms of carcinogen action and infectious diseases caused by viruses. Investigating cancer risks and learning that DNA damage may lead to cancer have been made possible through molecular epidemiology. It has also developed biomarkers enabling understanding of genes such as tumor suppressor and repair genes in the chemical-cancer relationship. Conventional epidemiology does not examine cancer’s cellular changes, whereas molecular epidemiology examines it at the cellular level from beginning to end. Molecular epidemiology has developed 3 main types of biomarkers: exposure biomarkers showing chemical exposure and biologically effective dose; effect biomarkers including early clinical manifestations and structural and functional changes such as genotoxic DNA damage; and individual susceptibility biomarkers concerning enzymes affecting cancer and those responsible for these enzymes. These biomarkers enable more definitive conclusions about carcinogens and more sensitive carcinogen classifications.

Classification of Carcinogens

After epidemiological studies, substances are classified for carcinogenicity. The International Agency for Research on Cancer (IARC), affiliated with the World Health Organization, studies cancer causes and mechanisms and shares its findings. When a substance is thought to be associated with cancer, IARC examines all studies, experiments and findings concerning it. If the review concludes that the substance is carcinogenic, it is assigned to one of 3 groups.

These 3 groups are:

• Group 1: Carcinogenic to humans. In this group, 107 agents have been identified.
• Group 2A: Probably / very likely carcinogenic to humans. In this group, 58 agents have been identified. For substances classified as Group 2A carcinogens, there is sufficient scientific evidence of carcinogenicity in animals but limited evidence in humans.
• Group 2B: Possibly carcinogenic to humans. In this group, 249 agents have been identified.

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Smoking (tobacco smoke), obesity, arsenic, excessive processed meat consumption, and hepatitis B and C viruses are examples of Group 1 carcinogens. Sufficient evidence has been obtained for carcinogens in this group in both animal and human studies. Night-shift work, excessive red meat consumption, nitrate and nitrite are Group 2A carcinogens, with limited evidence in humans and sufficient evidence in animals. Group 2B includes substances such as caffeic acid, cell phones and phenytoin (an epilepsy drug). In this group, evidence of carcinogenicity in humans is very limited or conflicting, while sufficient evidence in animals has not been obtained.

Related Topic:

• The Most Common Carcinogens in Foods – Potential Cancer-Causing Agents