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CancerMail from the National Cancer Institute
CANCER FACTS National Cancer Institute National Institutes of Health
Coffee is a common beverage made from the roasted and ground berries
of the small evergreen tree of the genus Coffea. Several large-scale
studies have been conducted to determine whether there is an
association between coffee intake and cancer risk. Most of them have
not found an increased incidence of cancer among people who drink
Coffee contains caffeine, a mild stimulant also found in other popular
drinks such as soft drinks and tea. Research into a possible link
between caffeine and cancer has been inconclusive.
Studies have also been conducted to evaluate the possible risk of
cancer from decaffeinated coffee. Trichloroethylene, a solvent once
used to decaffeinate coffee, was tested by the National Cancer
Institute (NCI) in 1976 and shown to cause liver tumors in mice. The
NCI later conducted an epidemiologic study of civilian workers exposed
to trichloroethylene while engaged in aircraft maintenance at a United
States Air Force Base. In reviewing this and other epidemiologic
studies, the International Agency for Research on Cancer concluded
that evidence for the risk of cancer from trichloroethylene in humans
Since the 1970s, coffee companies have switched to other solvents such
as methylene chloride (dichloromethane), ethyl acetate, or other types
of processing to decaffeinate coffee. However, because methylene
chloride is now strongly suspected to cause cancer in humans, most
coffee producers no longer use it. Companies that produce coffee may
be contacted to learn about their decaffeination method.
Additional information about decaffeinating solvents can be obtained
from the U.S. Food and Drug Administration (FDA) Center for Food
Safety and Applied Nutrition at 200 C Street, SW., Washington, DC
20204; or from the FDA's Office of Consumer Affairs toll-free
information line at 1-888-INFO-FDA (1-888-463-6332). The FDA Web site
is located at Http: //www.fda.gov on the Internet.
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The maximum acceptable concentration (MAC) for dichloromethane in
drinking water is 0.05 mg/L (50 µg/L).
Identity, Use and Sources in the Environment
Dichloromethane (methylene chloride) is a highly volatile, colourless
liquid that is completely miscible with a variety of lipophilic
solvents and is appreciably soluble in water (0.02 g/mL at 20°C).1 It
is used extensively as an industrial solvent, for paint stripping, as
a degreasing agent and as an aerosol propellant.2 Dichloromethane is
not manufactured in Canada, but approximately 11 kilotonnes were
imported annually between 1980 and 1984, principally from the United
About 85% of the dichloromethane produced in the United States is
estimated to be lost to the environment (and hence to the drinking
water supply) via sewage treatment, whereas only a small fraction is
lost as fugitive emissions to the atmosphere.2
Dichloromethane was detected in 30 to 53% of potable water samples
taken from 30 treatment facilities across Canada.4 Mean concentrations
ranged from 6 to 10 µg/L, with a maximum of 50 µg/L recorded in
several instances. The total amount that would be ingested daily by
drinking 1.5 L of water containing 8 µg/L dichloromethane is 12.0 µg.
Because dichloromethane is a volatile compound, there is a potential
for its release from tap water to indoor air.
Available information on the presence of dichloromethane in foods is
limited to decaffeinated tea (0.5 to 16 µg/g), decaffeinated coffee
(0.5 to 4 µg/g) and spice oleoresins (10 to 83 µg/g).5-7
Dichloromethane is used as an extraction solvent in the preparation of
these foods, and the estimated intake by humans from these sources is
considered to be very small. The usual background concentration of
dichloromethane in ambient air is no more than 50 ppt (180 ng/m3).
Near industrial sources, concentrations range from 7.1 to 14.3 ppb (26
to 51 µg/m3), averaged over one year.2
Analytical Methods and Treatment Technology
Dichloromethane is detected by a purge and trap gas chromatographic
procedure.8 The practical quantitation limit (PQL) (based on the
ability of laboratories to measure dichloromethane within reasonable
limits of precision and accuracy) is 5 µg/L.9,10
Removal of volatile chlorinated aliphatic hydrocarbons similar to
dichloromethane by packed tower aeration and granular activated carbon
adsorption is estimated to be 90 to 99% effective.8 It would appear
that, using advanced technology, a reduction to concentrations of
dichloromethane below 1 µg/L is feasible.
Pharmacokinetic studies with dichloromethane have demonstrated
efficient uptake via the lung, some 55% being retained after
inhalation of air containing between 250 and 750 ppm (900 and 2700
mg/m3).11,12 Dichloromethane is also efficiently absorbed from the
gastrointestinal tract from oil or aqueous solution,13 although dermal
absorption is slow and relatively inefficient in humans.14
Dichloromethane is rapidly and efficiently distributed to various
organs and tissues. It crosses the blood-brain barrier, affecting
neurological functions,15 crosses the placental barrier16 and is
sequestered by body fat.12 Metabolism proceeds via two major metabolic
pathways. The predominant pathway at low doses involves a saturable
P-450 microsomal oxidation producing carbon monoxide. The other is a
cytosolic glutathione-dependent pathway, leading to the formation of
carbon dioxide.17,18 The mixed-function oxidase pathway is saturable
when concentrations of about 500 ppm (1800 mg/m3) in air are inhaled,
whereas the cytosolic pathway shows no signs of saturation at
concentrations up to 10 000 ppm (36 000 mg/m3) in air.19 After
administration by various routes, the elimination of dichloromethane
from the blood is dose-dependent and follows a two- or
three-compartment mathematical model.13,19-21
Health effects induced by dichloromethane have been studied in humans
exposed to concentrations up to about 800 ppm (2880 mg/m3) in air.
Exposure to 868 ppm (3125 mg/m3) induced signs of neurotoxicity,
including feelings of "light-headedness," difficulties with speech
articulation and hand-eye co-ordination impediments.
Carboxyhaemoglobin levels also increased.15 Chronic exposures to
dichloromethane do not produce any demonstrable irreversible effects
at concentrations up to about 500 ppm (1800 mg/m3).22 In one case of
excessive chronic exposure (300 to 1000 ppm, or 1080 to 3600 mg/m3,
over three years), bilateral temporal lobe degeneration was ascribed
either to the neurotoxic effects of dichloromethane or to increased
carboxyhaemoglobin levels.23 The results of epidemiological studies,
designed (in part) to examine the carcinogenic potential of
dichloromethane, have been negative because of the limitations of
these studies (e.g., insufficient exposure to provide the statistical
power to detect a significant carcinogenic effect,24 or the lack of a
latency period sufficient for the development of site-specific
cancer). Precise conclusions cannot, therefore, be drawn.22
Acute inhalation exposures of animals to concentrations of 500 to 1000
ppm (1800 to 3600 mg/m3) indicate that the central nervous system is
the primary target for dichloromethane.25 Cardiovascular effects are
seen after a five-minute exposure to 5000 ppm (18 000 mg/m3), and
concentrations of 15 000 ppm (54 000 mg/m3) for six hours are lethal
to rats and mice.26-28 Chronic exposures to high concentrations (>5000
ppm or 18 000 mg/m3) result in hepatic and renal effects. Deaths are
usually caused by pulmonary congestion.18,29 Dogs exposed to 10 000
ppm (36 000 mg/m3) for four hours per day, five days per week for
eight weeks, showed centrilobular congestion and fatty degeneration of
the liver, as well as effects on the central nervous system.29
The results of a number of carcinogenicity bioassays of
dichloromethane are equivocal and do not permit a clear conclusion
regarding the carcinogenic potential of this compound. These studies,
conducted by Dow Chemical U.S.A., the National Coffee Association, the
National Toxicology Program (NTP) (gavage, in mice) and Theiss and his
co-workers (intraperitoneal, in mice), have been extensively reviewed
in the United States.2
The best-designed and most definitive study is the recent NTP
inhalation study in rats and mice.30 In this study, groups of 50
F344/N male or female rats were exposed, by inhalation, to
concentrations of 0, 1000, 2000 or 4000 ppm (0, 3600, 7200 or 14 400
mg/m3) of dichloromethane for six hours per day, five days per week
for 102 weeks. The incidence of fibroadenomas or fibroadenomas and
adenomas combined was significant for the high-dose males and showed a
significant positive trend with increasing dose for the females.
Mesotheliomas of the tunica vaginalis and other organs occurred in
male rats with a significant dose-related trend. Mononuclear cell
leukaemia in male and female rats also occurred with significant
In a parallel (NTP) study, groups of 50 B6C3F1 male and female mice
were exposed to 0, 2000 and 4000 ppm (0, 7200 and 14 400 mg/m3) of
dichloromethane for six hours per day, five days per week for two
years. Alveolar or bronchiolar adenomas, alveolar or bronchiolar
carcinomas of the lung or the two combined occurred with significant
positive trends in both males and females. Hepatocellular adenomas or
carcinomas, as well as the two combined, occurred with significant
positive trends in both male and female mice.
Dichloromethane is a weak mutagen in three strains of Salmonella31 and
causes gene conversions, mitotic recombination and reverse mutations
in the yeast Saccharomyces cerevisiae.32 Embryotoxicity and minor
increases in skeletal abnormalities were apparent in rats and mice
exposed to concentrations above 1000 ppm (3600 mg/m3), seven hours per
day, on days 6 to 15 of gestation.33
Classification and Assessment
The evidence for the carcinogenicity of dichloromethane is inadequate
in humans, but evidence from animal studies (both sexes of two
species) is sufficient to classify it in Group II -- probably
carcinogenic to man.
Using a physiologically based model, Andersen and his colleagues
calculated the delivered "internal" dose to specific organs and
tissues after administration by any route, not only of dichloromethane
per se but also of its two major metabolites.34,35 They pointed out
that dichloromethane is not genotoxic and that the mixed-function
oxidase pathway, which proceeds via a putative formyl chloride
intermediate, probably does not induce tumours and may be regarded as
a detoxification pathway. There is good supporting evidence that the
glutathione-S-transferase pathway, yielding S-chloromethyl
glutathione, does result in tumour formation. Because the
physiological blood flow, organ mass and volume parameters in rodents
and man are known with reasonable certainty and the
glutathione-S-transferase activities in man and several animal species
are also known for specific organs, the empirical methods for species
extrapolation used by the U.S. Environmental Protection Agency are not
necessary. Further, the kinetics for both the mixed-function oxidase
and cytosolic metabolism are known. The Andersen methodology allows
the calculation of the actual dose of active metabolite delivered to
the tumour-susceptible organs (the lung and the liver) in the rodent
species used in the NTP carcinogenicity bioassay30 for any exposure
Using the physiologically based pharmacokinetic model methodology to
calculate the surrogate delivered dose to the liver* and selecting the
liver adenoma and carcinoma response in female mice in the robust
linear extrapolation model, one can calculate that the unit lifetime
risk associated with the ingestion of 1 µg/L dichloromethane in
drinking water is 1.7 × 10-9. The estimated concentrations in drinking
water corresponding to lifetime risks of 10-5, 10-6 and 10-7, based on
the model described above,** are 5900, 590 and 59 µg/L, respectively.
Because dichloromethane has been classified in Group II (probably
carcinogenic to man), the maximum acceptable concentration (MAC) is
derived based on consideration of available practicable treatment
technology and estimated lifetime cancer risks. Because the MAC must
also be measurable by available analytical methods, the PQL is also
taken into consideration in its derivation.
A MAC of 0.05 mg/L (50 µg/L) for dichloromethane was established,
therefore, on the basis of the following considerations:
(1) The estimated unit lifetime risk associated with the ingestion of
1 µg/L dichloromethane in drinking water is 1.7 × 10-9 (based on
hepatocellular adenomas or carcinomas in female mice). Therefore, the
estimated lifetime risk associated with the ingestion of drinking
water containing 50 µg/L dichloromethane (i.e., 8.5 × 10-8) is within
a range that is considered to be "essentially negligible."
(2) Although it is unlikely that dichloromethane concentrations are
reduced significantly during conventional drinking water treatment
processes, concentrations in Canadian drinking water supplies are
generally considerably less than 50 µg/L. It is likely that
concentrations of dichloromethane below 1 µg/L can be achieved by
packed tower aeration and granular activated carbon adsorption.
(3) The PQL (based on the ability of laboratories to measure
dichloromethane within reasonable limits of precision and accuracy) is
* The sum of the adenomas and carcinomas of the liver (counting each
mouse no more than once) is selected because female mice gave the
higher risk estimate (i.e., are more sensitive) and there were
"suggestively positive findings" of liver tumours in the mice of the
National Coffee Association drinking water study.
** Average adult body weight = 70 kg; average daily intake of drinking
water = 1.5 L.
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