Carcinogens seem to be in everything, but what are they??

A carcinogen is an agent that has the capacity to cause cancer in humans. The agent can be of a chemical nature (e.g. drugs), physical nature (e.g. UV rays), or biological nature (e.g. viruses). While there are many organizations that have lists of carcinogens, I am going to talk about how carcinogens are defined by the US government. It is a rather complex process that involves input from multiple individuals and a comprehensive review of the science.


Report on Carcinogens

The Report on Carcinogens (RoC) is a public health report prepared by the National Toxicology Program (NTP) which provides a list of known or reasonably anticipated human carcinogens. This report is mandated by congress and summarizes the evidence of carcinogenicity, common causes of exposure, and current regulations for each agent. The process of preparing the RoC starts by accepting suggestions from the public, which can include adding an agent to the list, reclassification of an agent already on the list, or the removal of an agent from the list. Each agent then undergoes a scientific evaluation of its carcinogenicity and many rounds of review from those within the department, other agencies, non-government experts, and the general public. Before the RoC can be released, it must be approved by the Secretary of Health and Human Services.


In the RoC, an agent can be classified as either a known human carcinogen or reasonably anticipated human carcinogen. The classification is based on the type of evidence found in peer reviewed studies.


Known Carcinogens

An agent is classified as a known carcinogen when it satisfies 2 criteria:

1. Evidence of carcinogenicity is from studies in humans, and

2. Evidence indicates a causal relationship between exposure to the agent and cancer.

In the latest RoC, released in 2016, there are 62 known carcinogens. These include some of the more well-known carcinogens like tobacco products, UV rays, alcohol consumption, and hepatitis viruses. An interesting agent on this list was Tamoxifen, one of the most popular drugs to treat breast cancer. Although in breast tissue, Tamoxifen inhibits estrogen activity, in the uterus it promotes estrogen activity which can promote cancer in the lining of the uterus (endometrial cancer).

Another anti-cancer drug on the list was Melphalan, which is used to treat many types of cancers, but increases the risk of leukemia. Melphalan provides its anti-oncogenic activity through DNA damage by adding these small molecules called alkyls to the DNA. The DNA damage occurs in both cancer and normal cells, but cancer cells proliferate faster and with less DNA repair, so Melphalan should be more toxic to the cancer cells. However, the DNA damage can happen in cells that divide frequently like those in the bone marrow. The DNA damage can then cause mutations that could lead to cancer, which explains the association between Melphalan treatment and leukemia (cancer of the bone marrow).

Reasonably Anticipated Carcinogens

There are 186 agents listed as reasonably anticipated carcinogens in the latest RoC. The agents in this category have not met either or both criteria required to be a known carcinogen. However, there is still some evidence suggesting that it might be carcinogenic. This evidence can come in 3 different forms:


1. Limited evidence of carcinogenicity from studies in humans

Because evidence is limited, other explanations besides causation cannot be ruled out. This is the classic “correlation does not mean causation” issue, where studies have shown a correlation between exposure to this agent and cancer. However, the correlation could be due to chance, bias, or confounding factors, and the evidence is not strong enough to disprove otherwise. An agent that falls into this category is Chloramphenicol, which is a drug used to treat severe bacterial infections, but can also cause serious and potentially fatal anemia, or lack of sufficient healthy red blood cells to carry oxygen to the body's tissues. While there have been some studies showing that children with cancer were more likely to have previously taken chloramphenicol than healthy children, there are no studies that show a causal link.


2. Sufficient evidence of carcinogenicity in animal models

It seems logical that if an agent is carcinogenic in another animal, it must also be carcinogenic in humans. However, that is not always the case and it may be that these agents act through mechanisms that do not occur in humans. For example, Basic Red 9 Monohydrochloride, (a dye used in biological staining, textile manufacturing, and printer ink) is considered potentially carcinogenic. This substance ended up on the list due to studies on rodents that showed oral injection and/or subcutaneous (under the skin) injection of the dye caused tumors. However, this is not how humans get exposed to this chemical, no one is swallowing large amounts of it nor is anyone injecting it into their blood. The main route of exposure is through the skin and/or inhalation. A more accurate model of the dye’s carcinogenicity would be to expose animals through routes experienced by humans: inhalation and dermal contact.


3. Evidence shows mechanisms of carcinogenesis

While there may be no evidence of carcinogenicity in human or animals, “there is convincing, relevant information that the agent acts through mechanisms indicating it would likely cause cancer in humans”. For example, there is no direct evidence of carcinogenicity for diazoaminobenzene, but it has been shown that human tissues convert it to benzene, which is a known human carcinogen, and that the benzene (at least in rodents) was distributed throughout the body. In addition, diazoaminobenzene has been shown to cause DNA damage. So, there are factors that would indicate dazaominobenzene would be carcinogenic, but no studies even showing a correlation between its exposure and cancer.


Takeaways

Determining the carcinogenicity of an agent is very complicated. The process requires scientists and regulators to deal with nuances, apparent contradictions, confounding factors, and conflicting results. It is incumbent on both science communicators and health professionals to do their due diligence in both understanding and communicating the evidence of carcinogenicity.