The role of acetaldehyde outside ethanol metabolism in the carcinogenicity of alcoholic beverages: Evidence from a large chemical survey

Abstract

Acetaldehyde is a volatile compound naturally found in alcoholic beverages, and it is regarded as possibly being carcinogenic to humans (IARC Group 2B). Acetaldehyde formed during ethanol metabolism is generally considered as a source of carcinogenicity in alcoholic beverages. However, no systematic data is available about its occurrence in alcoholic beverages and the carcinogenic potential of human exposure to this directly ingested form of acetaldehyde outside ethanol metabolism. In this study, we have analysed and evaluated a large sample collective of different alcoholic beverages (n = 1555). Beer (9 ± 7 mg/l, range 0–63 mg/l) had significantly lower acetaldehyde contents than wine (34 ± 34 mg/l, range 0–211 mg/l), or spirits (66 ± 101 mg/l, range 0–1159 mg/l). The highest acetaldehyde concentrations were generally found in fortified wines (118 ± 120 mg/l, range 12–800 mg/l). Assuming an equal distribution between the beverage and saliva, the residual acetaldehyde concentrations in the saliva after swallowing could be on average 195 μM for beer, 734 μM for wine, 1387 μM for spirits, or 2417 μM for fortified wine, which are above levels previously regarded as potentially carcinogenic. Further research is needed to confirm the carcinogenic potential of directly ingested acetaldehyde. Until then, some possible preliminary interventions include the reduction of acetaldehyde in the beverages by improvement in production technology or the use of acetaldehyde binding additives. A re-evaluation of the ‘generally recognized as safe’ status of acetaldehyde is also required, which does not appear to be in agreement with its toxicity and carcinogenicity.

Introduction

Acetaldehyde (ethanal, CH₃CHO) is a potent volatile flavouring compound found in many beverages and foods (Liu and Pilone, 2000). Acetaldehyde at low levels gives a pleasant fruity aroma, but at high concentrations it possesses a pungent irritating odour (Miyake and Shibamoto, 1993). In alcoholic beverages, acetaldehyde may be formed by yeast, acetic acid bacteria, and coupled auto-oxidation of ethanol and phenolic compounds (Liu and Pilone, 2000). Acetaldehyde is extremely reactive and readily binds to proteins, specifically to the peptide glutathione or to individual amino acids to generate various flavour compounds (Liu and Pilone, 2000, Miyake and Shibamoto, 1993).

According to the International Agency for Research on Cancer (IARC), there is sufficient evidence in animals to demonstrate carcinogenicity of acetaldehyde and therefore it is possibly carcinogenic to humans also (Group 2B) (IARC, 1999). In a recent IARC meeting, acetaldehyde was discussed in the context of the carcinogenicity of alcoholic beverages. The IARC working group agreed that substantial mechanistic evidence in humans deficient in aldehyde dehydrogenase (ALDH) indicates that acetaldehyde derived from the metabolism of ethanol in alcoholic beverages contributes to causing malignant oesophageal tumours (Baan et al., 2007, IARC, in press). Acetaldehyde is able to cause point mutations or to form covalent bonds with DNA, leading to carcinogenesis (Cheng et al., 2003, Fang and Vaca, 1997, Hecht et al., 2001, Noori and Hou, 2001, Wang et al., 2000). Recent experimental evidence shows that acetaldehyde can form mutagenic adducts in cellular concentrations of 100 μM and above (Theruvathu et al., 2005). This is in accordance with findings in man, which show that salivary acetaldehyde concentrations after a moderate dose of alcohol range between 18 and 143 μM within 40 min of alcohol ingestion (Homann et al., 1997a). The mutagenic and carcinogenic changes caused by acetaldehyde can already occur with an acetaldehyde concentration from 40 to 200 μmol/l (Homann et al., 1997a, Salaspuro et al., 2002).

Furthermore, acetaldehyde interferes with DNA repair mechanisms by inhibiting repair enzymes (Espina et al., 1988). Additionally, genetic epidemiological studies provide strong evidence that the heterozygous genotype (ALDH2∗1/∗2) contributes substantially to the development of oesophageal cancer related to alcohol consumption, with up to a 12 fold increase in risk for heavy drinkers in comparison to carriers of the homozygous ALDH2∗1/∗1 genotype (which encodes the active enzyme) (Lewis and Smith, 2005).

ALDH deficient humans have higher levels of acetaldehyde in their blood (Mizoi et al., 1979) and saliva (Väkeväinen et al., 2000) after drinking alcohol, and according to a recent study higher levels of acetaldehyde-related DNA adducts have been measured in their lymphocytes (Matsuda et al., 2006). After ingestion of a moderate dose of alcohol, salivary acetaldehyde concentrations are 2–3 times higher among ALDH2-deficient subjects than in those with the normal ALDH2 enzyme, which is associated with a remarkably increased risk for digestive tract cancers (Salaspuro, 2003b, Väkeväinen et al., 2000).

In addition to acetaldehyde metabolism in the gastrointestinal tract and in the liver, the oral and colonic bacterial flora may considerably contribute to an accumulation of acetaldehyde (Homann et al., 1997a, Homann et al., 1997b, Homann, 2001, Jokelainen et al., 1996a, Jokelainen et al., 1996b, Kurkivuori et al., 2007, Salaspuro, 2003a, Väkeväinen et al., 2000, Väkeväinen et al., 2001). For this reason, poor dental status or lacking oral hygiene are associated with a higher risk for cancer of the upper gastrointestinal tract (Homann et al., 2000a, Homann et al., 2000b, Homann et al., 2001). In addition, chronic alcohol abuse may lead to atrophy of the parotid glands and reduced saliva flow, which aids local acetaldehyde accumulation (Salaspuro, 2003b).

In summary, the IARC working group confirmed that alcoholic beverages are ‘carcinogenic to humans’ (Group 1) and concluded that the occurrence of malignant tumours of the oral cavity, pharynx, larynx, oesophagus, liver, colorectum, and female breast is causally related to alcohol consumption (Baan et al., 2007, IARC, in press).

During the IARC meeting, an absence of information about acetaldehyde outside ethanol metabolism was noted. There are indications that consumption of spirits with exceptionally high concentrations of acetaldehyde might lead to an increased risk for cancer of the oesophagus (Linderborg et al., 2008). However, there are no systematic and actual data available about the occurrence of acetaldehyde in alcoholic beverages to evaluate its carcinogenic potential.

In this study, we collected novel data on the acetaldehyde content of a large collection of different alcoholic beverages (over 1500 samples). The data was statistically evaluated to find differences between sub-groups (i.e. beer, wine, fortified wine and spirits), as well as to estimate the typical ingested amount of acetaldehyde and its possible concentrations in saliva after ingestion. Finally, we provide a risk analysis for acetaldehyde outside ethanol metabolism and propose intervention measures.