Lachenmeier et al. BMC Cancer 2010, 10:266
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RESEARCH ARTICLE
Open Access
Cancer risk assessment of ethyl carbamate in
alcoholic beverages from Brazil with special
consideration to the spirits cachaça and tiquira
Dirk W Lachenmeier1†, Maria CP Lima2*†, Ian CC Nóbrega3†, José AP Pereira3, Florence Kerr-Corrêa
Fotis Kanteres4,5†, Jürgen Rehm4,6,7
2†
,
Abstract
Background: Ethyl carbamate (EC) is a multi-site carcinogen in experimental animals and probably carcinogenic to
humans (IARC group 2A). Traces of EC below health-relevant ranges naturally occur in several fermented foods and
beverages, while higher concentrations above 1 mg/l are regularly detected in only certain spirits derived from
cyanogenic plants. In Brazil this concerns the sugarcane spirit cachaça and the manioc (cassava) spirit tiquira, which
both regularly exceed the national EC limit of 0.15 mg/l. This study aims to estimate human exposure in Brazil and
provide a quantitative risk assessment.
Methods: The human dietary intake of EC via alcoholic beverages was estimated based on WHO alcohol
consumption data in combination with own surveys and literature data. This data comprises the EC contents of
the different beverage groups cachaça, tiquira, other spirits, beer, wine, and unrecorded alcohol (as defined by the
WHO; including alcohol which is not captured in routine government statistics nor taxed). The risk assessment was
conducted using the margin of exposure (MOE) approach with benchmark doses obtained from dose-response
modelling of animal experiments. Lifetime cancer risk was calculated using the T25 dose descriptor.
Results: Considering differences between pot-still and column-still cachaça, its average EC content would be 0.38
mg/l. Tiquira contained a considerably higher average EC content of 2.34 mg/l. The whole population exposure
from all alcoholic beverages was calculated to be around 100 to 200 ng/kg bw/day, with cachaça and unrecorded
alcohol as the major contributing factors. The MOE was calculated to range between 400 and 2,466, with the
lifetime cancer risk at approximately 3 cases in 10,000. An even higher risk may exist for binge-drinkers of cachaça
and tiquira with MOEs of up to 80 and 15, respectively.
Conclusions: According to our risk assessment, EC poses a significant cancer risk for the alcohol-drinking
population in Brazil, in addition to that of alcohol alone. Model calculations show that the implementation of the
0.15 mg/l limit for cachaça would be beneficial, including an increase of the MOE by a factor between 3 to 6. The
implementation of policy measures for tiquira and unrecorded alcohol also appears to be advisable.
Background
According to epidemiological findings, the consumption
of alcoholic beverages is causally related to the occurrence of malignant tumours of the oral cavity, pharynx,
larynx, oesophagus, liver, colorectum, and female breast;
this includes a classification as “carcinogenic to humans”
* Correspondence: mclima@fmb.unesp.br
† Contributed equally
2
Departamento de Neurologia, Psicologia e Psiquiatria, Botucatu Medical
School UNESP, São Paulo State University, CP 540 - Distrito Rubiao Junior,
18618-970 Botucatu, São Paulo, Brazil
(group 1) by the IARC [1]. Because the carcinogenicity
was generally noted with different types of alcoholic
beverage, and in view of the carcinogenicity of ethanol
in animals, the IARC also classified ethanol in alcoholic
beverages as “carcinogenic to humans” (group 1) [1].
The major mechanism appears to be the metabolism of
ethanol to acetaldehyde, which was proven by geneticepidemiological evidence as a risk-factor for alcoholrelated oesophageal and head and neck cancers, and
© 2010 Lachenmeier et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License http://creativecommons.org/licenses/by/2.0, which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
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acetaldehyde associated with alcohol consumption was
also recently upgraded to group 1 by the IARC [2].
While there is consensus that ethanol along with acetaldehyde are the major carcinogenic factors in alcoholic
beverages, other constituents and contaminants may
additionally contribute to the carcinogenicity, especially
in unrecorded alcohol that is not quality controlled [3].
From the range of possible carcinogenic substances in
alcoholic beverages (e.g. lead, nitrate, certain pesticides
and mycotoxins), EC (ethyl carbamate, urethane,
C2H5OCONH2, CAS # 51-79-6) is the most likely candidate for causing additional carcinogenicity, and has been
judged as a probable health risk for regular drinkers of
certain types of alcoholic beverages (see below) [4,5].
EC is a recognized genotoxic carcinogen, with widespread occurrence in fermented foods and beverages
[6-11]. In rodents, EC has been demonstrated to cause
dose-dependent increases in liver, lung, and harderian
gland adenoma or carcinoma, and hemangiosarcoma of
the liver and heart (both sexes), mammary gland and
ovarian tumours (females), and squamous cell papilloma
as well as carcinoma of the skin and forestomach
(males). The increase in hepatocellular tumours was
found to occur in a relatively linear manner and was
attributed to the formation of 1, N6-ethenodeoxyadenosine in hepatic DNA coupled with an increase in cell
replication. Lung alveolar/bronchiolar and harderian
gland adenoma or carcinoma also increased in a relatively linear manner, suggesting a genotoxic mechanism
for tumour induction [12]. In 2007, the IARC upgraded
its classification of EC to group 2A (probably carcinogenic to humans) [13]. This reflects mounting evidence
regarding the metabolic pathways of the activation of
EC, wherein the formation of proximate DNA-reactive
carcinogens, hypothesized to play a major role in ECinduced carcinogenesis in rodent cells, is also likely to
occur in humans due to significant similarities with
rodents [13]. Limited evidence from the human administration of EC has shown that it can in fact cause liver
disease, specifically hepatic angiosarcoma [14].
While the concentration of EC in foods and most beverage groups is very low and not seen as a public health
risk [4,5], concerns about the presence of this substance
in alcoholic beverages began in 1985, when comparably
high levels were detected by Canadian authorities in
imported alcohol products [15]. Canada proceeded to
establish an upper limit of 0.15 mg/l for EC in distilled
spirits [4]. The rationale for the Canadian limit was
based on a VSD of 0.3 μg/kg, a level that, in combination with a daily intake of 125 g distilled spirits, would
not result in an increased incidence of cancer greater
than one in a million [15]. The VSD was extrapolated
from the daily dose required to produce tumours in 50%
of the exposed animals over a standard lifetime and
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adjusted for background incidence. The same 0.15 mg/l
limit is currently being established in Brazil for cachaça,
to be enacted in June 2010 [16]. In this context, our
team recently detected that 70% of the analyzed products from Paraíba State, Brazil, exceeded this limit [17].
The relatively high incidence for EC contamination was
confirmed in a second survey by our group, in which
55% of all samples were above 0.15 mg/l [18].
International risk assessments of EC in alcoholic beverages have found that exposure levels may exceed
acceptable thresholds. For example, the JECFA [5] estimated the MOE, the risk assessment approach also preferred by the EFSA, as being 3,800 in certain alcoholic
beverages. The MOE approach has been advised by the
JECFA and EFSA as the best approach for assessing substances that are both genotoxic and carcinogenic. The
MOE is defined as the ratio between the point on the
dose response curve which characterizes adverse effects
in animal studies, and the estimated human intake of
the same compound. Clearly, the lower the MOE, the
larger the risk for humans. A threshold of 10,000 is
often used to define public health risks. In this framework, 3,800 is a value of concern, necessitating mitigative measures, namely lowering the concentration of the
substance. The EFSA also recently confirmed the JECFA
evaluation, noting that the MOE for high consumers of
fruit spirits was less than 600, indicating an even greater
public health concern [4]. The JECFA evaluation was
based on data from the USA, the UK and Japan,
whereas the EFSA evaluated data from Europe and
North America. Evidence in the international literature
(as summarized in Ref. [13]), which is generally
restricted to European-style alcoholic beverages, indicates that the EC problem may be limited to certain
fruit spirits (mainly stone-fruit spirits). Only recently,
the mentioned studies from Brazil pointed to the fact
that EC in the sugarcane spirit cachaça may be as problematic as from European fruit spirits, due to the cyanogenic nature of sugarcane materials, with hydrogen
cyanide suspected as a major precursor of EC formation
in both stone-fruit spirits and cachaça [18]. Another
Brazilian spirit described to contain comparably high
contamination levels of EC is tiquira, a product derived
from manioc/cassava (Manihot esculenta Crantz) fermentations [19,20]. Tiquira also contains hydrogen cyanide and other nitrogen compounds discussed as
precursors of EC formation [21,22].
Due to the limited presence of cachaça and complete
market absence of tiquira in Europe and North America,
neither the JECFA nor the EFSA have considered these
two types of spirits in their risk assessments. In Brazil,
however, where cachaça is the major spirit of consumption (while tiquira consumption is concentrated in the
States of Maranhão and Piauí [23]), a quantitative
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population-based risk assessment is needed. This is even
more pertinent, as critical opinions are currently being
voiced against the implementation of the EC limit for
cachaça in 2010. This article will be the first to provide
a quantitative population-based risk assessment using
the MOE model established by the JECFA and EFSA.
Additionally, we will calculate the lifetime cancer risks
for consumers of cachaça, tiquira and beer using the
T25 method. Our risk assessment will also be used to
evaluate the effectiveness of the 0.15 mg/l limit to protect consumers of alcoholic beverages from additional
cancer risks above the risk of ethanol and/or acetaldehyde in alcoholic beverages alone [1].
Methods
Literature research
The literature search was conducted by researchers
with qualifications in food science, chemistry, toxicology, epidemiology and cancer risk assessment. Data
on the occurrence of EC in Brazilian cachaça were
obtained by a computer-assisted literature search
using the key words ‘ethyl carbamate’ or ‘urethan(e)’
and ‘cachaça’, ‘tiquira’, ‘Brazil’ or ‘Brazilian’. Benchmark doses and toxicological dose descriptors were
obtained by searching with the key words ‘ethyl carbamate’ or ‘urethan(e)’ and ‘margin of exposure’,
‘MOE’, ‘benchmark dose’, ‘BMD’, ‘BMDL’, ‘BMDL10’
or ‘T25’. Searches in English and Portuguese were
carried out in July 2009, in the following databases:
PubMed (U.S. National Library of Medicine, Bethesda,
MD), Web of Science (Thomson Scientific, Philadelphia, PA), and SciELO - Scientific Electronic Library
Online (FAPESP - BIREME, São Paulo SP - Brazil).
Efforts were made to include all available studies; this
was accomplished by a hand search of the reference
lists of all articles for any relevant studies not
included in the databases. The references, including
abstracts, were imported into Reference Manager
V.12 (Thomson Reuters, Carlsbad, CA) and the relevant articles were manually identified and purchased
in full text. We did not identify any article, which was
available as abstract only or which we were not able
to obtain in full text. No unpublished study was identified. If raw data on EC were not present in the article, the corresponding authors were contacted by
e-mail with a request for the data.
Sampling of cachaça in Pernambuco State
Duplicate samples of 33 brands of cachaças (n = 66)
produced in Pernambuco State, the second major Brazilian state in terms of production and consumption of
cachaça [24], were obtained from retail outlets in Recife,
Pernambuco’s capital, between February and March
2009. Information on the distillation methods (pot still
Page 3 of 15
or column still) was obtained from local inspecting
authorities or by visiting distilleries. EC measurements
were conducted according to Nóbrega et al. [17].
Survey of drinking behaviours for individual-based
exposure assessment
In order to assess individual exposure scenarios, drinking behaviours and patterns were investigated. The
focus was set on lower socioeconomic class for which
cachaça, mainly the industrial/column still type, is the
typical drink due to its relatively lower price compared
to other types of alcoholic beverages [25-28]. For this
reason, 17 cachaça selling bars in 5 different low socioeconomic neighbourhoods in Recife were visited in
August 2009. This included questioning of patrons
regarding typical consumption behaviour and volumetric
measurement of common drink sizes. The standard
glass size for cachaça was a 190 ml ‘copo americano’
glass. Customers usually ordered cachaça by single shot
or by ‘quartinho’. The single shot size varied from 50-80
ml, with the quartinho size approximately 170 ml (an
almost full copo americano glass). Prices for the most
consumed brands ranged between US$ 0.25-0.50 for a
single shot, and US$ 0.75-1.00 for a quartinho shot.
Typical consumption patterns included the ingestion of
1-4 shots per drinking occasion (i.e. 50-320 ml) on a
weekend basis (i.e. on each Friday, Saturday and Sunday). Daily consumers of cachaça typically consumed 12 single shots (i.e. 50-160 ml). Binge drinkers would
consume 1-4 quartinhos per drinking occasion (i.e., 170680 ml). The frequency of such binge-drinking sessions
was once or twice a week.
The consumption of cachaça was often followed by
that of beer. Beer was commonly served in 600 ml bottles, with typical consumption patterns including 1-3
bottles per drinking occasion (600-1800 ml). Binge drinkers would consume 3-6 bottles per drinking occasion
(1800-3600 ml).
Approach for risk analysis
The risk analysis was conducted according to the harmonised approach of the EFSA for the risk assessment
of substances that are genotoxic and carcinogenic [29].
As discussed, the EFSA has developed and recommends
an approach known as the MOE. This approach uses
the doses of substances that have been observed to
cause low but measurable harmful responses (i.e. cancer
incidences in this context) in animals as reference point
values and, taking into account differences in consumption patterns, compares them with relevant substance
specific dietary intake estimates in humans. The BMD,
derived from animal cancer data by mathematical modelling within the observed range of experimental data, is
recommended as a standardized reference point. To
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obtain the MOE, the Benchmark Dose Lower Confidence Limit (BMDL) of 10% was taken. The BMDL is
an estimate of the lowest dose that is 95% certain to
cause no more than a 10% cancer incidence in rodents.
In general, BMDLs are used as the statistical lower confidence limits of benchmark doses to derive “safe” exposure levels [30]. MOEs were calculated by dividing the
reference point, i.e. the BMDL, by the estimated human
intakes.
Calculation of lifetime cancer risk
While the MOE method is preferred by JECFA and
EFSA for risk assessment analysis, the resulting values
are dimensionless, with the ratio between rodent carcinogenic dose and human intake not easily interpreted.
Thus for a second, more descriptive indicator, we calculated the lifetime cancer risk using the T25 method [31].
The T25 dose descriptor corresponds to the dose representing a 25% incidence of tumours, after correction for
spontaneous incidence. The basic difference between the
determination of the BMD and the T25 calculation, is
that the BMD is accomplished through dose-response
modelling that considers all available information on the
dose response curve, whereas the T25 is calculated from
a single data point [29]. For further details on the T25
calculation see Dybing et al. [32].
Population-based dietary intake assessment and exposure
scenarios
The EFSA harmonized approach has also been used for
the dietary intake assessment analysis [29]. Data on
alcohol consumption for the groupings of beer, wine,
spirits and unrecorded alcohol were obtained from the
WHO GISAH [33] based on data from the FAO as well
as other sources (e.g. country records) [34,35] for the
year 2003 for populations older than 15. The data on
unrecorded alcohol consumption were based on the
estimated volume for the years after 1995 and populations older than 15 [36].
The distribution of beverage groups in the spirits category was taken from a national survey carried out in
Brazil [37]. Consumption of tiquira was estimated based
on data from the IBGE, which stated the annual tiquira
consumption at 640,000 l [38].
The EC content of the alcoholic beverages was estimated based on data from our literature review (see
above). Special exposure scenarios were developed for
light, moderate and heavy drinkers of cachaça and
tiquira with comparison to beer drinkers. For these calculations, we used the typical drink sizes from the
WHO GENACIS study [39,40], of 50 ml for spirits
(cachaça, tiquira) and 350 ml for beer, as well as data
from our survey in Pernambuco (see above).
Page 4 of 15
Results
Occurrence of ethyl carbamate in alcoholic beverages of
the Brazilian market
The literature review identified 16 studies on the occurrence of EC in alcoholic beverages available in Brazil.
Thirteen of the studies included data on cachaça
[4,17-19,41-49], four studies researched tiquira
[19,41,47,50], one was about grape wine including sparkling wines [51], and one on orange press-liquor spirit
[52]. There were limited analytical results on other beverages on the Brazilian market (e.g. whisky, fruit spirit,
or grappa) [19,41]. The studies are summarized in Table
1; we also include the new results from our analysis on
EC in 33 cachaça brands from Pernambuco.
For the purposes of our risk assessment, we summarized the single studies into an overall mean, median,
and percentiles. The results of this meta analysis for the
different classes of alcoholic beverages are presented in
Table 2. According to the EFSA criteria [29], we provide
scenarios for average content as well as the percentiles
in all cases.
The meta analysis aimed to only include products
available to the typical consumer, therefore we excluded
the study on orange press liquor, which is currently not
commercially available [52]. We also excluded studies
that did not present the raw results but only averages
[44,49,51]. Although the studies of Bruno et al. [45] and
Reche and Franco [48] contain results of distillate fractions sampled in distilleries, we decided to include these
studies with the aim of making the estimates more
stable with the inclusion of more data.
For cachaça, it became quickly evident that it was problematic to simply average over all values, as the two
major categories of cachaça - pot still and column still
cachaça - appear to have significant differences in their
EC contents. From the 13 studies on cachaça, three provided differentiated data on column still cachaça
[18,45,48], and five provided data on pot still cachaça
[17,18,45,46,48]. Our own results from Pernambuco also
differentiated the two types. The rest of the studies gave
no information on cachaça type and could not be used
for meta analysis on type.
In total, we gathered 275 results on pot still cachaça
(average 0.38 mg/l) and 101 results on column still
cachaça (average 0.49 mg/l). Column still cachaça had a
higher average EC content than pot still (t-test, p =
0.048). Including all analytical data from all selected studies, we had a total of 536 analytical results, with an
average of 0.38 mg/l. However, this form of data summarization could lead to bias towards lower EC contents, as considerably more results on pot still than on
column still cachaça were available. To avoid this bias,
we also conducted a weighting according to production
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Table 1 Literature data on ethyl carbamate in recorded and unrecorded alcoholic beverages from the market and
from experimental studies
Ethyl carbamate [mg/l]
Production
origin
N
Mean
95th
99th
Maximum Percentage
Median 90th
percentile percentile percentile
above 0.15
Farah Nagato Recorded, column/pot
et al. [41]
still, Brazilian market
São Paulo
State, Brazil
13
0.33
0.24
0.68
0.95
1.14
1.20
69%
Boscolo [49]
Recorded, Brazilian
market
Different
states, Brazil
84
0.90
-a
-
-
-
5.5
87%
AndradeSobrinho
et al. [19]
Recorded, column/pot
still, Brazilian market
Different
states, Brazil
126 0.77 (pot still: 0.479
0.63; column
still: 0.93)
-
-
-
5.70
79%
Lelis [42]
Recorded, un-recorded Different
column/
states, Brazil
Pot still, Brazilian market.
75
0.38 (pot still: 0.36
0.40; column
still: 0.29)
0.63
0.83
0.91
0.95
87%
Baffa Júnior
et al. [43]
Recorded, Brazilian
market
Minas Gerais 22
State, Brazil
1.20
0.60
1.67
1.96
10.19
12.38
77%
EFSA 2007
[4]
Recorded, European
market
No data
19
0.229
0.11
-
0.478
-
0.73
-
Barcelos
et al. [44]
Pot still, experimental
Minas Gerais 52
State, Brazil
0.243
-
-
-
-
0.643
-
Bruno et al.
[45]
Recorded, column/
pot still, experimental,
Brazilian market
Rio de
Janeiro
State, Brazil
0.17 (pot still: 0.10
0.11; column
still: 0.31)
0.42
0.60
0.68
0.71
44%
Labanca
et al. [46]
Recorded, pot still
Brazilian market,
Minas Gerais 69
State, Brazil
0.89
0.79
1.78
2.10
2.42
2.61
93%
Andrade
Sobrinho
et al. [47]
Recorded, Sampling
2002
Sao Paulo
State, Brazil
108 0.14
0.07
0.29
0.55
1.23
1.39
27%
Andrade
Sobrinho
et al. [47]
Recorded, sampling
2004
Different
36
States, Brazil
-
0.108
-
-
-
0.46
33%
Andrade
Sobrinho
et al. [47]
Recorded, Brazilian
market, sampling 2005
Brazil
41
-
0.163
-
-
-
1.16
58%
Andrade
Sobrinho
et al. [47]
Recorded, sampling
2006
Different
34
States, Brazil
-
0.085
-
-
-
0.646
24%
Andrade
Sobrinho
et al. [47]
Recorded, Brazilian
market,
sampling 2006
Brazil
35
-
0.138
-
-
-
1.67
49%
Nóbrega
et al. [17]
Recorded, pot still
Brazilian market
Paraíba
State, Brazil
25
0.22
0.20
0.40
0.42
0.63
0.70
68%
Lachenmeier
et al. [18]
Recorded, un-recorded,
column/
pot still, European/
Brazilian markets
Different
42
States, Brazil
0.27 (pot still: 0.18
0.15; column
still: 0.37)
0.55
0.68
1.27
1.54
56%
Reche and
Franco [48]b
Pot still, experimental
Brazil
73
0.11
0.05
0.24
0.29
0.83
1.29
15%
Reche and
Franco [48]b
Column still,
experimental
Brazil
42
0.42
0.41
1.79
2.10
2.93
3.37
83%
This study
Recorded, column/
pot still Brazilian market
Pernambuco 33
State, Brazil
0.18 (pot still: 0.19
0.06; column
still: 0.30)
0.33
0.39
0.49
0.53
55%
Maranhão
State, Brazil
3.51
6.01
7.95
9.75
10.2
100%
Beverage
Sample/Sampling
group/Study characterization
1. Cachaça
34
2. Tiquira
Boscolo et al. No data
[50]
12
3.26
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Table 1 Literature data on ethyl carbamate in recorded and unrecorded alcoholic beverages from the market and
from experimental studies (Continued)
Farah Nagato No data
et al. [41]
Maranhão
State, Brazil
1
0.80
-
-
-
-
-
-
AndradeSobrinho
et al. [19]
No data
Maranhão
State, Brazil
37
2.35
1.80
5.36
6.10
8.60
10.00
100%
Andrade
Sobrinho
et al. [47]
No data
Maranhão
State, Brazil
45
2.06
1.51
4.67
6.01
8.41
10.2
98%
Farah Nagato Whisky/Fruit spirit,
et al. [41]
Brazilian market
Scotland/
Brazil.
2
0.7 (Scotch),
1.41 (Fruit
spirit)
-
-
-
-
-
-
AndradeSobrinho
et al. [19]
Grappa, Italian/
Brazilian markets.
Italy and
Brazil
6
0.02
0.01
0.05
0.06
0.07
0.07
AndradeSobrinho
et al. [19]
Whisky, Brazilian market
USA and
Scotland
19
0.14
0.10
0.22
0.35
0.39
0.40
26%
Francisquetti
et al. [51]
Wines including
R. Grande
sparkling wines, Brazilian do Sul St,
market
Brazil
124 0.004 to
0.019
-
-
-
-
0.07
0%
Ferreira et al.
[52]
Orange press liquor
spirit, experimental, not
commercially available
10
-
-
-
-
-
0%
3. Other Beverages
a
b
c
Brazil
n.d.c
Values marked as (-) not calculable because raw data is not available
Values were reported in g/hl of pure alcohol. Own recalculation to mg/l assuming an average alcoholic strength of 40% vol.
not detectable
amount (Table 2). According to the Cachaça Official
Guide [53], Brazilian production consists of 38% pot still
(artisanal) and 62% column still (industrial) cachaça.
We, therefore, used this percentage for weighting the
total of 376 cachaças with known production methodology. The average content for the calculation with
weighting was 0.45 mg/l.
To evaluate the potential effectiveness of the Brazilian
0.15 mg/l limit for cachaça, we also included a hypothetical calculation in Table 2, in which all samples with
EC contents higher than the limit were set to 0.15 mg/l.
The meta analysis for tiquira resulted in 95 samples
with an average content of 2.34 mg/l. For all other alcoholic beverages, the sample numbers were too low to
derive an overall mean for the Brazilian market. There
were no studies available for beer. It is, however, known
from international studies, that beer and wine contain
only very low concentrations of EC. Moreover, no significant geographical differences were found for beer
and wine. We therefore decided to use the international
average values (e.g. as published by EFSA [4]) to evaluate the missing groups in Brazil (Table 3).
Finally, as significant unrecorded consumption occurs
in Brazil, we also estimated the EC content in unrecorded alcoholic beverages. Considering the high likelihood that the majority of unrecorded consumption
would be in the form of artisanally produced cachaça (i.
e. pot still cachaça), we chose to use the contents of pot
still cachaça for the category of unrecorded alcohol. The
appropriateness of using the values of recorded pot still
cachaça for unrecorded cachaça was also confirmed by
two studies in the literature. Our own recent study
included one sample of unrecorded cachaça, which had
an EC content of 0.47 mg/l [18]. The study of Lelis [42]
compared 27 unrecorded with 48 recorded cachaça samples. The average contents were 0.42 mg/l for unrecorded and 0.36 mg/l for recorded. Due to the relatively
high standard deviations (Figure 1), no significant differences between both collectives could be proven (p =
0.236, own t-test calculation with data from Lelis [42]).
The averages for these limited surveys of unrecorded
cachaça therefore appeared to be in reasonable agreement with our meta analysis for pot still cachaça, and
justified the use of this data for exposure estimation,
until more comprehensive surveys on unrecorded alcohol are available.
Exposure assessment
As the occurrence data in tables 2 and 3 show, the EC
contents in beverages on the Brazilian market significantly depend on beverage type. The highest average
contents were found in tiquira, by almost a factor of 5
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Table 2 Meta analysis on the ethyl carbamate occurrence in Brazilian spirits
Ethyl carbamate [mg/l]
95th
99th
Mean Median 90th
percentile percentile percentile
Type of beverage
Data sources
N
Pot still cachaça
[17,18,42,45,46,48],
this study
275 0.38
0.21
0.96
1.32
2.21
Column still cachaça
[18,42,45,48],
this study
101 0.49
0.32
1.01
1.68
2.30
All types cachaça (without weighting for distillation type)
[17,18,41-43,45-48],
this study
536 0.38
0.19
0.91
1.34
2.22
All types cachaça (with weighting according to production
amount: 38% pot and 62% column still)
[17,18,45,46,48],
this study
376 0.45
0.28
0.99
1.54
2.26
Regulated cachaça (hypothetical distribution after full
implementation of 0.15 mg/l limit)a
All types cachaça,
see above
536 0.11
0.15
0.15
0.15
0.15
Tiquira
[19,41,47,50]
95
1.72
5.44
6.10
10.20
a
2.34
To derive this hypothetical distribution, all samples with concentrations above the limit were set to 0.15 mg/l
or more than in cachaça. All other types of alcoholic
beverages generally showed contents of less than 0.15
mg/l. For this reason, the population based exposure
assessment separately considered the consumption of
the different kinds of beverages. Table 4 shows our estimation on the annual consumption of the different categories, based on the WHO GISAH data [33] along with
results from a national survey on spirit type consumed
in the previous year [37]. The EC exposure due to alcoholic beverage consumption (Table 5) was calculated
with the combined data from tables 2, 3, 4.
The highest exposures arose from cachaça (60 -70 ng/
kg bw/day on average) and unrecorded alcohol (50-130
ng/kg bw/day on average). The total exposure from all
alcoholic beverages was calculated to be around 100-200
ng/kg bw/day on average.
Derivation of toxicological dose descriptors for ethyl
carbamate
EC. The basis for all four evaluations was the 2004 NTP
2-year rodent bioassay [56] that contains data meeting
the criteria for the modelling of the dose-response relationship for lifetime exposure to EC [5]. The BMDL
value for EC obtained by the JECFA for the incidence of
alveolar and bronchiolar neoplasms (the most sensitive
endpoints) in male and female mice was found to be 0.3
mg/kg bw/day [5]. Similar results for dose-response
modelling were published in the other studies [54,55].
The EFSA chose the same internationally established
BMDL value of 0.3 mg/kg bw/day for their risk assessment of EC [4]. We also chose to use this internationally established value as the basis for our risk evaluation
in Brazil.
Neither the JECFA nor EFSA published a T25 value
for EC. However, O’Brien et al. [54] and Schlatter et al.
[55] calculated the T25 dose descriptor from the same
NTP data. The lowest dose group with a significantly
The literature search revealed two international risk
assessments by the JECFA [5] and EFSA [4], as well as
articles by O’Brien et al. [54] and Schlatter et al. [55]
that contained data on toxicological dose descriptors for
Table 3 Ethyl carbamate occurrence in European-style
alcoholic beverages from large international samplings
(data from EFSA [4])
Ethyl carbamate [mg/l]
Type of beverage
Mean
Median
95th percentile
Beer
0.005
0.005
0.006
Wine
0.007
0.005
0.078
Spirits (excluding fruit spirits)
0.094
0.022
0.390
- Whisky
0.040
0.030
0.106
- Rum
0.017
0.012
0.045
- Vodka
0.008
0.005
0.017
- Brandy
0.078
0.045
0.345
Figure 1 Distribution of ethyl carbamate in recorded and
unrecorded cachaça samples (data from Lelis [33]). No
statistically significant differences between both collectives could be
proven.
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Table 4 Annual per capita consumption of alcoholic beverages in Brazil
Type of
beverage
Annual per capita
consumption [Litres of
pure alcohol]a
Distribution in spirits
category according to
national surveyb
Distribution in spirits
category, own
estimationc
Annual per capita consumption of
spirits, own estimation [Litres of pure
alcohol]d
Beer
3.41
Wine
0.29
Spirits all
2.06
- Cachaça
(no data)
66%
66%
1.36
- Whisky
(no data)
24%
8.9%
0.18
- Rum
(no data)
13%
4.8%
0.10
- Vodka
(no data)
28%
10.3%
0.21
- Brandy
(no data)
23%
8.5%
0.17
- Other
(no data)
4%
1.5%
0.03
- Tiquira
(no data)
(no data)
(less than 1%)
0.003
Unrecorded 3.00
a
Data from WHO GISAH for 2003 for population older than 15 [33]
Data from a national survey on types of spirits consumed in the previous year [37]. The total is not 100% because of overlapping.
c
Estimation was necessary to come to a total 100%. This was conducted on the basis of a 66% cachaça consumption. The rest of 34% was distributed according
to the percentages from the national survey [37].
d
Calculated from the total spirits consumption of 2.06 l according to WHO GISAH [33] using the estimated distribution. The estimation for tiquira was based on
annual consumption of 640.000 l from IBGE [38].
b
increased tumour incidence was 1.2 mg/kg bw/day in
male mice. At this dose, the cancer incidence increased
by 30.2% compared to the control group. This lead to a
T25 value of 1.0 mg/kg bw/day. The human dose
descriptor HT25 could then be calculated from the T25
by dividing the animal dose data with the appropriate
scaling factor. The scaling factor, calculated according
to Sanner et al. [31] with data of the animal weights
from NTP [56], was 6.3 leading to a HT25 of 0.16 mg/
kg bw/day.
Risk characterization
The exposure data from Table 5 was used to characterize risk using the MOE calculated from the BMDL
(Table 6) and the lifetime cancer risk calculated with
the T25 method (Table 7). As noted above, the threshold of 10,000, generally used for characterizing a public
health risk, was used in our analysis (see discussion
below).
In the case of EC, the MOEs were below the 10,000
threshold for cachaça with the exception of the median
Table 5 Exposure with ethyl carbamate from alcoholic beverages in Brazil
Scenario 1 for cachaça all types
without weighting
Scenario 2 for cachaça all types
with weighting
Mean
Median
95th percentile
Beer
17.3
17.3
20.8
(similar to scenario 1)
Wine
0.77
0.55
8.61
(similar to scenario 1)
Cachaça
59.0
29.5
208.0
Whisky
0.82
0.62
2.18
(similar to scenario 1)
Rum
0.19
0.14
0.51
(similar to scenario 1)
(similar to scenario 1)
Vodka
0.19
0.12
0.41
(similar to scenario 1)
(similar to scenario 1)
Brandy
1.51
0.87
6.70
(similar to scenario 1)
(similar to scenario 1)
Other
0.32
0.08
1.34
(similar to scenario 1)
(similar to scenario 1)
Tiquira
0.80
0.59
2.09
(similar to scenario 1)
(similar to scenario 1)
EC exposure
Mean
69.9
Median
43.5
95th percentile
Hypothetical scenario 3 for regulated
cachaça (including regulated unrecorded
cachaça)
239.1
(similar to scenario 1)
Mean
Median
95th percentile
(similar to scenario 1)
(similar to scenario 1)
17.1
23.3
23.3
(similar to scenario 1)
Unrecorded
130.1
71.9
452.1
37.7
51.4
51.4
Total alcohol
211.1
121.7
702.7
221.9
135.7
733.7
76.7
94.9
117.3
Total plus other foodsa
227.8
138.4
719.4
238.6
152.4
750.4
93.4
111.6
134.0
Calculated as ng/kg bw/day (calculated for a 60 kg person)
a
an exposure of 16.7 ng/kg bw/day is assumed for other foods by EFSA based on an international JECFA estimate, see [4,5] for details.
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Table 6 Margin of Exposure (MOE) for ethyl carbamate in different exposure scenarios
Scenario 1 for cachaça all types
without weighting
EC exposure
Mean
Median
95th percentile
Scenario 2 for cachaça all types
with weighting
Mean
Median
95th percentile
Hypothetical scenario 3 for regulated
cachaça (including regulated unrecorded
cachaça)
Mean
Median
95th percentile
Beer
17340
17340
14450
(similar to scenario 1)
(similar to scenario 1)
Wine
388374
543724
34854
(similar to scenario 1)
(similar to scenario 1)
Cachaça
Whisky
5085
10170
1442
365000
486667
137736
4294
(similar to scenario 1)
6901
1255
17567
(similar to scenario 1)
12882
12882
Rum
1545882
2190000
584000
(similar to scenario 1)
(similar to scenario 1)
Vodka
1564286
2502857
736134
(similar to scenario 1)
(similar to scenario 1)
Brandy
198190
343529
44808
(similar to scenario 1)
(similar to scenario 1)
Other
931915
3981818
224615
(similar to scenario 1)
(similar to scenario 1)
Tiquira
374359
509302
143607
(similar to scenario 1)
(similar to scenario 1)
Unrecorded
2305
4171
664
7964
5840
Total alcohol
1421
2466
427
1352
(similar to scenario 1)
2212
409
3913
3161
5840
2559
Total plus other foods
1317
2168
417
1257
1969
400
3213
2688
2240
Calculated with BMDL of 0.3 mg/kg bw/day (MOE = BMDL/Exposure).
exposure for scenario 1 (calculation without weighting).
Notably, the values for the hypothetical scenario of
regulated cachaça were above 10,000. For unrecorded
alcohol, all scenarios were below 10,000. The cumulative
exposures from all groups of alcoholic beverages and
other foods resulted in levels below 10,000 with MOE
values ranging between 400 and 2,466.
According to the T25 method, if average values for EC
concentration in the beverages were assumed, the cancer risk was approximately 3 cases per population of
10,000. This risk went as high as 1 case per population
of 1000, if alcoholic beverages with extremely high levels
of EC were to be consumed on a daily basis (95th
percentile). However, we think that this latter scenario,
which is almost approaching the risk of ethanol in alcoholic beverages itself (in the extreme case up to 1:100
for females drinking more than 100 g on average for all
alcohol-attributable cancers combined based on a different approach [57]), overestimates the risk of EC, as it is
relatively unlikely that highly contaminated alcohol is
consumed on a daily basis. In light of the epidemiological evidence regarding alcoholic beverage consumption,
we think that an average risk in the range of 10 -4 is
probable. The estimation of a risk in the range of 10-4 is
based on indirect reasoning. For if the risk was higher it
would be expected to result in markedly elevated cancer
Table 7 Lifetime cancer risk of ethyl carbamate in different whole population exposure scenarios
Scenario 1 for cachaça all types
without weighting
EC exposure
Beer
Mean
Median
95th percentile
2.7E-05
2.7E-05
3.2E-05
Wine
1.2E-06
8.6E-07
1.3E-05
Cachaça
9.2E-05
4.6E-05
3.3E-04
Whisky
1.3E-06
9.6E-07
3.4E-06
Scenario 2 for cachaça all types
with weighting
Mean
Median
95th percentile
Hypothetical scenario 3 for regulated
cachaça (including regulated unrecorded
cachaça)
Mean
(similar to scenario 1)
6.8E-05
95th percentile
(similar to scenario 1)
(similar to scenario 1)
1.1E-04
Median
(similar to scenario 1)
3.7E-04
2.7E-05
(similar to scenario 1)
3.6E-05
Rum
3.0E-07
2.1E-07
8.0E-07
(similar to scenario 1)
(similar to scenario 1)
Vodka
3.0E-07
1.9E-07
6.4E-07
(similar to scenario 1)
(similar to scenario 1)
Brandy
2.4E-06
1.4E-06
1.0E-05
(similar to scenario 1)
(similar to scenario 1)
Other
5.0E-07
1.2E-07
2.1E-06
(similar to scenario 1)
(similar to scenario 1)
Tiquira
1.3E-06
9.2E-07
3.3E-06
(similar to scenario 1)
Unrecorded
2.0E-04
1.1E-04
7.1E-04
(similar to scenario 1)
Total alcohol
3.3E-04
1.9E-04
1.1E-03
3.5E-04
2.1E-04
Total plus other foods
3.6E-04
2.2E-04
1.1E-03
3.7E-04
2.4E-04
Calculated with HT25 of of 0.16 mg/kg bw/day (Lifetime cancer risk = Exposure/HT25·0.25).
3.6E-05
(similar to scenario 1)
(similar to scenario 1)
5.9E-05
8.0E-05
8.0E-05
1.1E-03
1.2E-04
1.5E-04
1.8E-04
1.2E-03
1.5E-04
1.7E-04
2.1E-04
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rates for regions with high EC exposure (e.g. the tiquiraconsuming states of Maranhão and Piauí, Northeast
Brazil) compared to regions with the same per capita
consumption but lower EC exposure, which until now
has not been the case.
In addition to this whole population estimate, we provide individual risk assessments for daily drinkers of
cachaça, tiquira and beer (Figure 2). For one drink per
day, the average EC exposure would be 0.4 μg/kg bw/
day (cachaça), 1.95 μg/kg bw/day (tiquira) or 0.03 μg/kg
bw/day (beer). The MOE for these exposures are 800
(cachaça), 154 (tiquira) and 10,286 (beer). The corresponding lifetime cancer risks would be 5.9E-04
(cachaça), 3.0E-03 (tiquira) and 4.6E-05 (beer).
For cachaça, we also provide a more detailed evaluation showing the MOE resulting from different drinking
scenarios (once a year to once daily) as well as for different numbers for drinks per occasion (Figure 3).
MOEs below 10,000 were calculated for cachaça consumers drinking more than 1 drink per week or more
than 2 drinks on two occasions per month.
Discussion
Limitations of the risk assessment
The first and major limitation of this risk assessment is
the extrapolation step from animal to human data. In
this, it may be especially scrutinized that the incidence
of alveolar and bronchiolar adenoma or carcinoma were
used as critical responses for obtaining the toxicological
dose descriptors [5]. These sites are not considered to
be alcohol-associated in human epidemiology [1]. However, the JECFA noted that the ranges of BMDL values
of other cancer sites are in the same range as those of
the alveolar and bronchiolar adenoma or carcinoma [5],
Figure 2 Lifetime cancer risk calculated with the T25 method
for consumers of different alcoholic beverages in Brazil (Mean
with 95th percentile as error bar are shown).
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and we agree that for precautionary reasons the conservative lower end of the range of values should be used.
As a multi-site carcinogen, it is interesting and relevant
that EC was proven in rodents and non-human primates
to induce tumours in the liver, which is also a proven
site of carcinogenicity of alcoholic beverages in general
[1]. EC also induces squamous cell papilloma or carcinoma in the forestomach of mice, which contain comparable tissues to the mouth and oesophagus of
humans, which are also known sites for the carcinogenicity of alcoholic beverages in general, likely impacted by
the ethanol-acetaldehyde pathway [1]. Animal experiments point to complex interactions between ethanol
and EC, e.g. in decreased first-pass hepatic clearance
[12]. However, no consistent trend of the co-administration of ethanol on the carcinogenicity of EC has been
found [5]. Nevertheless, there remains the possibility
that the effects of both agents are additive. We also cannot exclude the possibility of synergistic effects as seen
with the combined risk of alcohol and tobacco consumption [1,58,59]. Interactions with acetaldehyde, a
further carcinogen directly contained in alcoholic beverages and formed during ethanol metabolism must also
be considered [60]. However for our quantitative risk
assessment, the current state of knowledge did not allow
for the consideration of the interactions of EC with
ethanol and other substances.
The second limitation concerns the occurrence data of
EC in foods and beverages in Brazil. Despite the considerable knowledge on cachaça, there were few studies on
other beverages and no studies on other fermented
foods. Therefore, our risk assessment contains data
extrapolated from international surveys conducted in
other countries. We therefore cannot exclude the possibility that other beverages or foods might contain higher
concentrations of EC, in which case we may have underestimated the risk. In the current evaluation, the major
contributing factors to EC exposure were cachaça and
unrecorded alcohol, while the other exposures could be
quantitatively neglected. Therefore, we would currently
exclude the possibility of having overestimated the risk.
For cachaça itself, we have the problem that the market is so large, that even the 500 samples we have considered in our meta analysis may appear to be quite
small a number. However, during our calculations it
became evident that the inclusion or exclusion of single
studies led to only minor changes in the overall averages
(only on the second decimal place), as such we think we
have reached a very stable estimate of the current situation. This also appears to justify the inclusion of studies
sampling distillates and not products bottled and sold to
the final consumer. A larger problem was the differences
between the different categories of cachaça, which we
think we have adequately addressed by using different
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Figure 3 Margin of Exposure calculated using the BMD-method for different exposure scenarios of cachaça consumption in Brazil
(calculated for all types cachaça with weighting, mean with 95th percentile as error bar are shown).
calculation approaches (e.g. with and without weighting
of the distillation type). In total, the differences between
the averages of the calculation methods remained relatively small (i.e. 0.1 mg/l). In the population based risk
assessments, the differences that arose in the MOE
values (e.g. MOE 5058 without weighting, 4294 with
weighting) were not relevant for the interpretation, as
both values were significantly below the threshold of
10,000 (see below).
All factors considered, the mentioned limitations were
not as grave as to completely prohibit a risk assessment
of EC. It is in fact on the contrary, as the same limitations generally apply to the assessments of the international agencies EFSA and JECFA, whose approaches we
specifically followed.
Risk of ethyl carbamate for the Brazilian population
Our risk assessment comes to the conclusion that EC
may pose a health risk for the alcohol-drinking population in Brazil. MOEs can be used by risk managers for
setting priority, with a small MOE representing a higher
risk than a larger one. In general, a MOE of 10,000 or
higher, if based on a BMDL from an animal study,
would be considered a low public health concern and
subsequently a low priority for risk management actions
[29]. The MOEs for cachaça or unrecorded alcohol
alone are below 10,000. If we look at the cumulative
exposure from all sources, this leads to MOEs around
1,300 and lifetime cancer risks in the 1:10,000 range.
These are considerably higher risks than what the EFSA
has calculated for Europe, where the MOE for the overall population would be in the range of 9,090 to 5,450.
Even these values for Europe were considered as health
relevant by EFSA. The difference between Europe and
Brazil derives from the fact that the preferred alcoholic
beverages in Europe have relatively low contents of EC,
while in Brazil the preferred alcoholic beverages with
the exception of beer contain comparably high concentrations of EC.
Risk for individual drinkers
On an individual scale, the highest risks arose for regular drinkers of EC contaminated beverages (e.g. compare
cachaça and beer in Figure 2). The health relevant range
was reached even for moderate drinkers of 1 drink of
cachaça per day (MOE 800), as well as for binge drinkers that drink more than three drinks on one occasion
per month (MOE 8267). From our survey in Pernambuco, the binge drinkers that consumed quartinhos on a
daily basis appeared to be at highest risk, e.g. one quartinho (170 ml) per day would correspond to a MOE of
235, and the maximum amount observed of four quartinhos (680 ml) would lead to a MOE of 59. In terms of
drinking patterns and prevalence, it should be noted
that a survey carried out in Bahia’s capital (Salvador)
showed the prevalence of high-risk drinking at 6.9%
[25]. A recent national survey found that of the total
sample (including those who were abstinent) 28%
reported at least one occasion of binge drinking in the
12 months prior to the interview [27].
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Similar to the results on a population scale, the risks
for individual drinkers in Brazil appeared to be higher
than the ones in Europe from the EFSA study, which
stated MOEs of 4620 to 8110 for consumers of alcoholic
beverages in general, and specifically MOEs of 3000 to
17,600 for consumers of beer (1000 ml daily), and a
MOE of 5000 for consumers of spirits (125 ml daily).
An interesting finding of this study is the fact that
tiquira consumers were at an even higher risk than consumers of cachaça. Tiquira appears to be the spirit with
the highest EC contamination worldwide. Even stone
fruit spirits that were thus far considered as the beverage group highest in EC, usually contain less than 1 mg/
l of EC and only very seldom more than 1.5 mg/l [11].
The EFSA calculated a MOE of 540 for individual consumers of fruit spirits at the 95th percentile (i.e. 125 ml
daily). Our corresponding calculation for individual consumers of tiquira lead to a MOE of 154 for one drink
per day and up to a MOE of 15 for ten drinks per day.
Therefore, the MOE has almost reached unity meaning
that the human exposure (which is ranging between 2
to 20 μg/kg bw/day) has almost reached the dose that
may cause a 10% cancer incidence in experimental
animals.
In evaluating these risks, we should again mention and
take into consideration that EC is not the only compound from alcoholic beverages, which may cause cancer in humans [1]. The IARC has concluded that
consumption of alcoholic beverages is carcinogenic to
humans (see introduction) [1]. Based on these assessments, it was estimated that alcohol caused almost
500,000 cancer deaths worldwide in 2004 [61]. The
main pathway is probably acetaldehyde [60] and as has
been discussed EC may also play a significant role.
Policy implications
In light of the proven public health risk of EC in
cachaça signified by MOE values below 10,000, it is
commendable that Brazil has implemented a legislative
limit for cachaça. Table 6 shows that the full implementation of this limit would lead to MOE values above
10,000 for cachaça alone. Therefore, the policy appears
to be toxicologically founded and effective if it can be
implemented and enforced. Although there is no information about the association between liver cancer and
cachaça available, a case-control study carried out in
Brazilian cities showed that consumption of cachaça had
a high risk for cancers of the upper aerodigestive tract
[62]. It is with great likelihood that EC contributed to
this risk.
A major problem here is the large consumption of
unrecorded alcohol (which we assume to be in the form
of illegally-produced and artisanally-produced pot-still
cachaça). This consumption is so high that even
Page 12 of 15
assuming unrecorded producers also apply measures to
bring the EC content to the limit of 0.15 mg/l, it would
still not effectively bring the MOE of unrecorded alcohol
above 10,000. Moreover, in the cumulative assessment
of all alcoholic beverages and other foods, the full
implementation of the limit for both cachaça and unrecorded alcohol also does not appear to be sufficient for
bringing the exposure to a level outside of the healthrelevant range of 10,000. However, it would at least
increase the MOE by a factor of 3-6 and therefore provide a quantifiable increased safety measure for the Brazilian population. We therefore recommend that the
limit should be enacted as planned in June 2010, and
that opposing opinions from the alcohol industry be
overruled due to significant and demonstrable public
health risk.
The problem of EC contamination of unrecorded alcohol also strengthens the point that alcohol policy not
neglect this type of consumption [63]. The Brazilian
Beverage Association estimated that approximately 50%
of all spirits consumed in Brazil were unrecorded in
1984 [64]. According to a more recent WHO estimation, 59% of spirits and 34% of total alcohol consumption is unrecorded (see table 4). Here we have the
additional danger that cachaça producers unable to
meet the EC limit simply move to the unrecorded market, a situation which is already compounded by the
relatively high taxation of spirits in Brazil compared to
other middle income countries [65]. In some areas of
Brazil, it has been estimated that only about 10% of all
distilleries are registered [66]. Indeed, there is scant
information regarding unrecorded alcohol consumption
and this issue demands further investigation [3].
It must also be appreciated that from a quantitative
standpoint the real risk factor of alcoholic beverages is
of course not EC, but ethanol or its metabolite acetaldehyde, which when combined have a risk of at least one
order of magnitude higher (i.e. 10-3-10-2) [57]. For comparison, the MOE for ethanol in alcoholic beverages was
judged to be 3 (for an exposure of 22.8 ml ethanol) [67].
Naturally, scientifically proven effective measures for
reducing alcohol consumption itself [68,69] would also
simultaneously lead to a reduced EC exposure. We
think that both measures - mitigation of the EC problem as well as alcohol policy measures - should go
hand in hand.
Regarding policy, we also advise the implementation
of mitigative measures and possibly a limit for tiquira,
as this beverage may be problematic for a sub-group of
the population.
Conclusions
The case of EC contamination in alcoholic beverages
from Brazil, particularly in cachaça and tiquira, is
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extremely relevant, as we have found a considerably
higher exposure than in studies conducted in Europe [4]
or Central America [70]. In our opinion the scientific
evidence is sufficient grounds for the strict enforcement
of the maximum limit for EC in cachaça, and the implementation of such an effort for tiquira. Priority research
should also be conducted for gaining better knowledge
on the formation mechanisms and strategies for EC
reduction in these beverages as well as for investigating
other popular Brazilian alcoholic beverages (e.g. Brazilian vodkas and rums) that may also contain EC.
Furthermore, measures that are applicable in small-scale
artisanal distilleries should be developed and distilleries
(including the unrecorded producers) should be made
aware about the risk and possibly receive mitigative
measures.
From an epidemiological point of view, it may be sensible to study cancer incidences of ethanol, acetaldehyde
and EC related cancer sites prior to the implementation
of the cachaça limit and in the following years. This
would also provide an excellent case for studying the
effectiveness of food policy measures regarding carcinogenic contaminants as well as the validity of risk evaluations using the MOE approach.
However, first and foremost, the safety of consumers
should be improved by taking the appropriate means to
reduce known risk factors such as EC from beverages.
The current knowledge clearly is sufficient to necessitate
intervention, given the precautionary principle of public
health.
List of abbreviations
BMD: benchmark dose for a benchmark response of 10%;
BMDL/BMDL10: Benchmark Dose Lower Confidence Limit for a
benchmark response of 10% (The BMDL is an estimate of the lowest
dose that is 95% certain to cause no more than a 10% effect); EC:
ethyl carbamate; EFSA: European Food and Safety Authority; FAO:
Food and Agriculture Organization; GISAH: Global Information System on
Alcohol and Health; HT25: human tumorigenic dose 25%, which is
converted from the T25 by dividing it with the appropriate scaling factor
for interspecies dose scaling based on comparative metabolic rates;
IARC: International Agency for Research on Cancer; IBGE: Instituto
Brasileiro de Geografia e Estatistica; JECFA: Joint FAO/WHO Expert
Committee on Food Additives; MOE: margin of exposure; NTP: National
Toxicology Program; T25: tumorigenic dose 25% (chronic dose of a
carcinogen that leads in experimental animals to a tumour incidence
of 25%); VSD: virtually safe dose; WHO: World Health Organization.
Acknowledgements
ICCN and JAPP are indebted to the Brazilian Government through CNPq and
MAPA (Project No. 578384/2008-6) for providing financial support.
Author details
1
Chemisches und Veterinäruntersuchungsamt (CVUA) Karlsruhe,
Weissenburger Strasse 3, D-76187 Karlsruhe, Germany. 2Departamento de
Neurologia, Psicologia e Psiquiatria, Botucatu Medical School UNESP, São
Paulo State University, CP 540 - Distrito Rubiao Junior, 18618-970 Botucatu,
São Paulo, Brazil. 3Universidade Federal Rural de Pernambuco, Programa de
Pós-graduação em Ciência e Tecnologia de Alimentos, CEP 52171-900,
Recife, PE, Brazil. 4Centre for Addiction and Mental Health (CAMH), 33 Russell
Street, Toronto, ON, M5 S 2S1, Canada. 5Faculty of Health, Medicine and Life
Page 13 of 15
Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The
Netherlands. 6Dalla Lana School of Public Health, University of Toronto, 55
College Street, Toronto, ON, M5T 3M7, Canada. 7Epidemiological Research
Unit, Institute for Clinical Psychology and Psychotherapy, TU Dresden,
Chemnitzer Strasse 46, 01187 Dresden, Germany.
Authors’ contributions
DWL developed conception and design of the study, drafted the first
version of the manuscript, organized data acquisition, and performed the
meta analysis, MOE and T25 calculations. MCPL and FKC collected the
alcohol consumption and exposure data for Brazil. ICCN conducted the
literature review on EC in cachaça and provided EC occurrence and
exposure data. ICCN and JAPP conducted analyses and provided original
data on occurrence of EC in cachaça samples from Pernambuco State.
MCPL, FKC and ICCN contributed to the interpretation of findings with their
local knowledge about the specific situation in Brazil and revised the
manuscript accordingly. FK participated in drafting and revising the
manuscript and provided language editing. JR conceived of the study,
provided the original contact between the members of the international
research team, participated in the design and coordination of the study and
helped to draft the manuscript. All authors read and approved the final
manuscript.
Competing interests
The authors declare that they have no competing interests.
Received: 24 September 2009 Accepted: 8 June 2010
Published: 8 June 2010
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Pre-publication history
The pre-publication history for this paper can be accessed here:
http://www.biomedcentral.com/1471-2407/10/266/prepub
doi:10.1186/1471-2407-10-266
Cite this article as: Lachenmeier et al.: Cancer risk assessment of ethyl
carbamate in alcoholic beverages from Brazil with special consideration
to the spirits cachaça and tiquira. BMC Cancer 2010 10:266.
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