IARC Monographs Meeting 128: Acrolein, Crotonaldehyde, and Arecoline
QUESTIONS AND ANSWERS (Q&A)

Acrolein is a reactive aldehyde. It is a chemical with a high production volume that is used as a reactive intermediate and in the manufacture of numerous chemical products, and as a herbicide in recirculating water systems. Tobacco smoke is a major source of exposure in the general population. Acrolein is also formed during combustion of fuels, wood, and plastics, and is present in ambient air pollution and vapour from electronic cigarettes.

Acrolein was classified as probably carcinogenic to humans (Group 2A) on the basis of sufficient evidence of carcinogenicity in experimental animals and strong mechanistic evidence.

• Sufficient evidence for the carcinogenicity of acrolein in experimental animals was demonstrated in two rodent species: acrolein increased the incidence of malignant neoplasms in mice and increased the incidence of the combination of benign and malignant neoplasms in rats.
• There was strong evidence that acrolein exhibits multiple key characteristics of carcinogens: acrolein is electrophilic; it is genotoxic; it alters DNA repair or causes genomic instability; it induces oxidative stress and chronic inflammation; it is immunosuppressive; and it alters cell proliferation, cell death, or nutrient supply. The strong evidence was primarily from studies in human primary cells and studies in experimental systems, supported by studies on DNA adducts in humans.
• There was inadequate evidence in humans regarding the carcinogenicity of acrolein.

Acrolein is present in smoke from cigarettes and vapour from electronic cigarettes. It is formed during combustion of fuels, wood, and plastics, and is present in ambient air pollution. In kitchens, there are measurable amounts of acrolein in the air during high-temperature roasting and deep-fat frying. Acrolein also forms endogenously (i.e. within the body). Firefighters are exposed occupationally.

Tobacco smoking cessation is an important way for people to reduce their exposure to acrolein. Exposure to acrolein could also be reduced by avoidance of electronic cigarette use, because acrolein is present in the vapour from electronic cigarettes.

Crotonaldehyde is a reactive aldehyde. It is a chemical with a high production volume that is widely used for synthesizing chemical agents used in various industries, including pharmaceuticals, rubber, chemicals, leather, and food and agriculture. Crotonaldehyde is also found in tobacco smoke and in cooking oils heated to a high temperature.

Crotonaldehyde was classified as possibly carcinogenic to humans (Group 2B) on the basis of strong mechanistic evidence.

• There was strong evidence that crotonaldehyde exhibits multiple key characteristics of carcinogens: crotonaldehyde is electrophilic; it is genotoxic; it induces oxidative stress; and it induces chronic inflammation. This strong evidence was from studies in human primary cells and in various experimental systems.
• There was limited evidence of carcinogenicity in experimental animals.
• There was inadequate evidence in humans regarding the carcinogenicity of crotonaldehyde.

Tobacco smoke is a major source of exposure to crotonaldehyde in the general population. Crotonaldehyde is also formed during combustion of vehicle fuels and wood, and during thermal treatment of foodstuffs. It is found in cooking fires, ambient air pollution, and vapour from electronic cigarettes, as well as in some foods, including cooking oils heated to a high temperature. Crotonaldehyde is also formed endogenously (i.e. within the body). Occupational exposures to crotonaldehyde occur among firefighters and workers in coke ovens, aldehyde manufacture, garages, and toll booths.

These compounds were both previously evaluated by the Working Group in 1995 as not classifiable as to its carcinogenicity to humans (Group 3). An IARC Advisory Group of independent experts ² recommended that these compounds be re-evaluated with high priority. A recent high-quality animal bioassay was available for acrolein, and new mechanistic evidence was available for both acrolein and crotonaldehyde.

(² Marques MM, Berrington de Gonzalez A, Beland FA, Browne P, Demers PA, Lachenmeier DW, et al.; IARC Monographs Priorities Group. Advisory Group recommendations on priorities for the IARC Monographs. Lancet Oncol, Published online 18 April 2019; https://doi.org/10.1016/S1470-2045(19)30246-3

Arecoline is the primary active ingredient of the areca nut. Areca nut has been classified as carcinogenic to humans (Group 1).

Arecoline was classified as possibly carcinogenic to humans (Group 2B) on the basis of strong mechanistic evidence.

• There was strong evidence that arecoline exhibits multiple key characteristics of carcinogens: arecoline is electrophilic; it is genotoxic; it alters DNA repair or causes genomic instability; and it induces oxidative stress. The strong evidence was from studies in human primary cells and in various experimental systems.
• There was limited evidence of carcinogenicity in experimental animals.
• There was inadequate evidence in humans regarding the carcinogenicity of arecoline.

Areca nut is widely cultivated in Asia. It has been estimated that more than 10% of the world’s population, primarily in south-eastern Asia, chews areca nut for its mild psychoactive effects. Arecoline has been used medicinally as an anthelmintic, and it is still applied in the form of areca nut preparation and as an ingredient in traditional Chinese and Ayurveda medicines. Arecoline is readily absorbed and can be detected in saliva, blood, urine, hair, and breast milk after exposure.

An IARC Advisory Group of independent experts² recommended that arecoline be evaluated with high priority, on the basis of the available mechanistic evidence.

(² Marques MM, Berrington de Gonzalez A, Beland FA, Browne P, Demers PA, Lachenmeier DW, et al.; IARC Monographs Priorities Group. Advisory Group recommendations on priorities for the IARC Monographs. Lancet Oncol, Published online 18 April 2019; https://doi.org/10.1016/S1470-2045(19)30246-3

Areca nut is a complex mixture, and the carcinogenic components of this mixture have not been identified. Arecoline is the primary active ingredient of the areca nut, and can be detected in saliva, blood, urine, hair, and breast milk of areca-nut users. Arecoline has also been applied directly in traditional medicines. In terms of properties, arecoline is an alkaloid that has been compared to nicotine. Like nicotine, arecoline acts on the nicotinic acetylcholine receptor; however, arecoline is also a partial agonist of other receptors, including the muscarinic acetylcholine receptors.

This evaluation is important because it adds to the understanding of how areca nut causes cancer. It has been estimated that more than 10% of the global population, primarily in south-eastern Asia, chews areca nut for its mild psychoactive effects. This evaluation indicates that arecoline is possibly carcinogenic to humans (Group 2B).

The studies evaluated came primarily from mechanistic investigations in laboratories around the world, including in south-eastern Asia, where areca-nut use is prevalent.

For more information about the IARC Monographs Programme and classifications, see:

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