Reasonably anticipated carcinogens

DEFINITION: Chemical compounds similar chemically to those that have shown carcinogenicity are labeled “reasonably anticipated carcinogens” by the National Toxicology Program of the US Department of Health and Human Services.

Describing cancer: Cancer has been studied intensely for a long time, yet some of its causes remain elusive and uncertain. There is much evidence that when certain chemical compounds are introduced to the human body, the probability of a tumor forming is increased; such compounds are known as carcinogens. Scientists use several methods to gather evidence about a chemical's carcinogenicity before allowing general use.

A central difficulty with methods of studying cancer is that a specific chemical introduced by a particular route does not always produce a tumor. Therefore, carcinogenicity is defined as the increased risk of producing a tumor. Because the primary interest of such studies is tumors produced in human beings, there is a species problem. It is very difficult to show that susceptibility to increased rates of tumor production in test animals predicts a similar outcome in humans. The National Toxicology Program (NTP) uses animal testing in its basic studies. Research conducted with bacteria also shows great promise.

Such complications have resulted in the creation of a rather limited list of carcinogenic chemicals. It pays to take a conservative position in public health, so there is a much longer list of suspected carcinogens.

The National Toxicology Program issues a biennial Report on Carcinogens (RoC) in which compounds may be labeled “reasonably anticipated carcinogens” if they meet one of the following criteria:

• There are limited studies in humans.
• Sufficient animal studies exist.
• A structural relationship to a known carcinogen exists.

Carcinogens and suspected carcinogens: Even known carcinogens may not cause cancer in every case. The many factors involved in the development of cancer in humans, such as exposure amount and genetics, mean that substances listed as reasonably anticipated carcinogens are not proven to cause or not cause cancer but are connected to enough evidence to justify their listing. Official listings by the National Toxicology Program, the International Agency for Research on Cancer (IARC), or other groups are based on the best available scientific consensus. Most known carcinogens belong to three general types of compounds, and the structure-activity relationship, which states that a set of atoms arranged in a particular pattern will often lead to very similar chemical behavior, is an important tool for categorizing suspected substances.

The chief cancer-causing molecules predominantly display one of the following chemical structural types: polycyclic aromatic hydrocarbons, aromatic amines, or alkylating agents.

Polycyclic aromatic hydrocarbons: As their name suggests, polycyclic aromatic hydrocarbons are composed only of atoms of the elements carbon and hydrogen, and the carbon atoms are linked together in a ring or cycle. The simplest chemical in this class is the known carcinogen benzene, which has a single ring of six carbon atoms. Molecules of four or more benzene rings fused by sharing two carbon atoms are quite common.

Aromatic amines: As with hydrocarbons, aromatic amines generally have the six-carbon atom ring, but a nitrogen atom attached to that ring. The most common example is 2-naphthylamine. This compound has two benzene rings attached to each other and an ammonia-like nitrogen atom containing two hydrogen atoms attached to the second carbon atom.

Alkylating agents: Although the first two categories of carcinogenic compounds are characterized by their structure, alkylating agents share a common chemical function. An alkyl group is a fragment of a molecule that is of high energy and, therefore, reacts rapidly. One of the most common is the methyl group, composed of a single carbon atom and three hydrogen atoms. A methylating agent is a molecule that can transfer such a reactive fragment during a chemical reaction. Many compounds can perform this function, but one of the most active subgroups is that of the nitrosamines, for example, N-nitrosodimethylamine. Like the aromatic amines, there is a nitrogen atom, but in place of the two hydrogen atoms, there are two methyl groups. The aromatic ring is replaced by a second nitrogen atom connected to an oxygen atom.

A summary of suspected carcinogens: Some examples of probable carcinogens based on chemical structure but lacking sufficient studies to warrant listing as known carcinogens include:

• Dimethyl sulfate, like N-nitrosodimethylamine, has two methyl groups available to be transferred. The new compound has a sulfur atom and four oxygen atoms in place of the carcinogen's nitrogen and oxygen atoms.
• Benzo[a]pyrene has five benzene rings, all sharing two or more carbon atoms.
• Other examples of reasonably anticipated carcinogens, according to the Centers for Disease Control and Prevention, include: Acrylamide, cobalt, DDT, and formaldehyde.

Bear in mind that while these compounds are suspected of being carcinogenic and proper safeguards are needed when they are used, many examples show that compounds with similar structures have very different, or no, carcinogenic properties. 

Bibliography

Centers for Disease Control and Prevention. “Reasonably Anticipated to be a Human Carcinogen.” Agency for Toxic Substances and Disease Registry, 14 Aug. 2018, www.cdc.gov/TSP/substances/ToxChemicalListing.aspx?toxid=24. Accessed 25 June 2024.

DeVita, Vincent T., Jr., Theodore S. Lawrence, and Steven A. Rosenberg, editors. Cancer: Principles and Practice of Oncology. 9th ed., Philadelphia: Lippincott, 2011.

“15th Report on Carcinogens.” National Toxicology Program, 21 June 2021, ntp.niehs.nih.gov/whatwestudy/assessments/cancer/roc. Accessed 25 June 2024.

“IARC Publications Website - IARC Monographs on the Identification of Carcinogenic Hazards to Humans.” IARC Publications, publications.iarc.fr/Book-And-Report-Series/Iarc-Monographs-On-The-Identification-Of-Carcinogenic-Hazards-To-Humans. Accessed 25 June 2024.

“Known and Probable Human Carcinogens.” American Cancer Society, 25 Mar. 2024, www.cancer.org/cancer/risk-prevention/understanding-cancer-risk/known-and-probable-human-carcinogens.html. Accessed 25 June 2024.

Perantoni, Alan O. “Carcinogenesis.” The Biological Basis of Cancer. 2nd ed., Edited by Robert G. McKinnell, et al. New York: Cambridge UP, 2006, pp.80–125.

Ruddon, Raymond W. Cancer Biology. 4th ed. New York: Oxford UP, 2007.

Tomatis, Lorenzo, and James Huff. “Evolution of Research in Cancer Etiology.” The Molecular Basis of Human Cancer. Edited by William B. Coleman and Gregory T. Tsongalis. Totowa.: Humana, 2002, pp. 189–203.