Alcohol beverages: update on information
published between 1995-2000
COM statement COM/00/S5 - December 2000
Introduction
1. In 1995 the COM gave detailed consideration to the mutagenicity of ethanol,
acetaldehyde and alcoholic beverages. This was to provide input to the Government
Interdepartmental Working Group reviewing overall advice on this topic.
The Committee on Carcinogenicity (COC) also carried out a detailed review
of the available data, mainly from epidemiology studies on the carcinogenicity
of alcoholic beverages. The advice from these Committees was considered
by the Interdepartmental Working Group when drawing up their Report on Sensible
Drinking published in December 1995(1). The main conclusions reached were:
The COC concluded that the epidemiological evidence supported the view
that drinking alcohol causes a dose-related increase in the risk of
squamous carcinomas of the upper aerodigestive tract as a whole, and
for cancers of the oral cavity, pharynx, larynx and oesophagus.
The COM agreed that the consumption of alcoholic beverages does not
present any significant concern with respect to their mutagenic potential.
2. With regard to the COC conclusions on the particularly important topic
of the association between alcohol and breast cancer, the Committee felt
that while there was no decisive evidence that breast cancer is causally
related to drinking alcohol, the potential significance for public health
of a weak causal association between alcohol and breast cancer was such
that they recommended that this matter be kept under review.
3. The COC has recently finalised its review of the published literature
from 1995-1999 on alcohol and breast cancer. The COC concluded:
i) There is an association between drinking alcoholic beverages and
increased risk of breast cancer. It is difficult to resolve whether
this is causal. The magnitude of the observed association is small (ie
the relative risk is modest and, even for heavy drinkers, rarely in
excess of 3) and within the range where it is difficult to exclude bias
and/or confounding as explanations for the observed results in epidemiological
studies. It is difficult to derive a quantitative relationship from
the dose-response data available in the literature.
ii) Further epidemiological studies have been published since 1995.
There is a need for further systematic review of the epidemiological
literature to assess fully the influence of bias, confounding and effect
modification. This will contribute to a conclusion on causality and
population attributable risk associated with drinking alcoholic beverages.
iii) Studies of possible mechanisms provide evidence for a plausible
basis for the causation of breast cancer by consumption of alcohol.
Alcohol increases blood levels of oestrogens and in particular oestradiol
in both pre menopausal and postmenopausal women. These data suggested
a similar mechanism to other known breast cancer risk factors.
iv) The COM should be asked to update its opinion of 1995 on the mutagenicity
data on alcohol.
4. This statement details the conclusions reached by the COM with regard
to the published information on ethanol, acetaldehyde and alcoholic beverages
from 1995 to February 2000, and whether there was any need to modify the
conclusions drawn in 1995. The Committee recalled that alcoholic beverages
contain small amounts of a significant number of volatile and non-volatile
organic compounds formed during production, storage and maturation. The
Committee reaffirmed its view that it was not essential nor practical
to review these constituents individually for their mutagenic potential.
5. The conclusions reached with regard to the mutagenic potential of ethanol,
acetaldehyde and alcoholic beverages are given below. A discussion of
one recent hypothesis (1) that alcohol might induce breast cancer via
the production of reactive oxygen species (ROS) is also included (2).
Mutagenicity of ethanol
6. The Committee noted that there were no new in-vitro mutagenicity
studies with ethanol. No conclusions could be drawn regarding the in-vitro
investigations of effects of ethanol in the pre-implantation development
of mouse oocytes injected with spermatozoa stored in 70% ethanol (3).
7. The Committee reaffirmed its previous conclusions with regard to the
mutagenicity data on ethanol, namely: negative results have been obtained
in a wide range of in-vitro tests and in in-vivo tests including
those for effects on germ cells; it was concluded that there was no evidence
that ethanol induces germ cell mutation in-vivo.
Mutagenicity of acetaldehyde
8. The committee agreed that the most recent experiments using human lymphoma
cells had confirmed earlier studies that acetaldehyde induces protein-DNA
cross links, but only at concentrations which resulted in cell death.
In addition acetaldehyde induced HPRT mutations in human T cells (5).
Members agreed that no conclusions could be drawn from the finding of
acetaldehyde DNA adducts in peripheral white blood cells of alcoholics
in view of lack of control for the effects of smoking by alcoholics in
the study group and the well known abnormalities in metabolism in alcoholics
(6).
9. The Committee reaffirmed its previous conclusions with regard to acetaldehyde.
The available data show that acetaldehyde includes chromosome aberrations
in mammalian cells in the absence of an exogenous metabolising fraction.
There is some evidence to show that covalent binding (DNA-protein cross
links) in the nasal mucosa of rats exposed to high levels of acetaldehyde
by inhalation.
The mutagenic profile of acetaldehyde is very similar to that of formaldehyde.
The compound has direct acting mutagenic potential in-vitro, but
would only be expected to have the potential of in vivo activity at sites
where it is not rapidly metabolised to acetic acid. The COC has concluded
that the observation of tumours in animals exposed to high inhalation
doses of acetaldehyde is not relevant to drinking alcohol(1).
Mutagenicity of Alcoholic Beverages
10. The Committee recalled that in 1995, considerable weight had been
attached to one study from the Medical Research Council's Cell Mutation
Unit, who has examined hprt mutant frequency in circulating T-lymphocytes
of normal adults and the relationship with alcohol intake (7). The study
showed that alcohol intake in 143 people over the range of 0-56 units/week
(1 unit - 8g ethanol) had no effects on hprt mutant frequency.
Less weight had been placed on studies which examined the mutagenicity
of concentrated extracts of wines and sprits in bacteria (1), and the
significance of such data was felt to be questionable. There were no adequate
in-vivo mutagenicity studies of alcoholic beverages available in
1995 or for the current review.
11. Since 1995 two further studies of the relationship between hprt mutant
frequency in lymphocytes obtained from individuals for whom information
on drinking patterns were available (8,9). There was no association between
hprt mutant frequency and alcohol ingestion in these studies, thus confirming
the results of the earlier MRC investigation.
The Reactive Oxygen Species hypothesis of alcohol induced breast cancer
12. Members reviewed the hypothesis published by Wright et al (2). Wright
and colleagues had noted the finding that alcohol metabolism is known
to produce reactive oxygen species (ROS) and mammary tissue contains the
necessary metabolising enzymes to produce ROS from alcohol. In addition,
Wright and colleagues noted two further observations which supported their
hypothesis, namely that breast cancer is associated with higher levels
of hydroxyl modified DNA and iron which has been proposed to catalyse
the formation of ROS accumulated with time in breast tissue. Members agreed
that there was evidence that ethanol and its metabolites induced the formation
of free radicals in-vitro, but the evidence in-vivo was
conflicting. Members commented that the observations reported by Wright
and colleagues might be a result of tumour progression rather than an
initiator of cancer. In addition it was noted that co-administration of
iron and alcohol to rats in the initiation phase of a two stage model
for hepatocarcinogenesis(10) did not result in any genotoxic effects.
Overall, the COM concluded that there was insufficient evidence to support
the Wright et al hypothesis regarding breast cancer.
Overall Conclusion
The Committee reaffirmed its 1995 conclusion that consumption of alcoholic
beverages does not present any significant concern with respect to their
mutagenic potential.
November 2000
References
1. Department of Health (1995). Sensible Drinking. The report of an Inter-Departmental
Working Group.
2. Wright RM, McManaman JL and Repine JE (1999). Alcohol-induced breast
cancer: a proposed mechanism. Free Radical Biochemistry and Medicine,
26, 347-354.
3. Taleno H, Wakayama T, Ward WS and Yanagimachi R (1998). Can alcohol
retain the reproductive and genetic potential of sperm nuclei? Chromosome
analysis of mouse spermatozoa stored in alcohol. Zygote, 6, 233-238.
4. Costa M, Zhitkovich A, Harris M, Paustenbach D and Gargas M (1997).
DNA-protein cross-links produced by various chemicals in cultured human
lymphoma cells. Journal of Toxicology and Environmental Health, 50, 433-449.
5. Lambert B, Adersson B, Bastlova T, Hou S-M, Hellgren D and Kolman A
(1994). Mutations in the hypoxanthene phosphoribosyl transferase gene
by three urban air pollutants: acetaldehyde, beinzo (a) pyrene diolepoxide,
ethylene oxide. Environmental Health Perspectives, 102, 135-138
6. Fang JL and Vaca CE (1997). Detection of DNA adducts of acetaldehyde
in peripheral white blood cells of alcohol abusers. Carcinogenesis 18,
627-632.
7. Cole J and Green HHL (1995). Absence of evidence for mutagenicity of
alcoholic beverages: an analysis of hprt mutant frequencies in 153 normal
humans. Mutagenesis, 10, 449-452
8. Branda RF and Albertini RJ (1995). Effects of dietary components on
hprt mutant frequencies in human T-lymphocytes. Mutation Research, 346,
121-127
9. Barnette YA, Warnock CA, Gillespie ES, Barnett CR and Livingstone BE
(year?). Effect of dietary intake and lifestyle factors in in-vivo
mutant frequency at the hprt gene locus in healthy subjects. Mutation
Research, 431, 3-5-315.
10. Stahl P, Olsson J, Svoboda P, Hulcrantz R, Harms-Ringdahl M and Ericksson
LC (1997). Studies on genotoxic effects of iron overload and alcohol in
an animal model of hepastrocarcinogenesis. Journal of Hepatology, 27,562-571.
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