5006
SNARL For Trichloroethylene
Health Effects Branch, Criteria and Standards Division
Office of Drinking Water
U.S. Environmental Protection Agency
Washington, D.C. 20460
The Office of Drinking Water has reviewed the current literature
on the health effects of trichloroethylene. Both data from
animal tests and some studies from high level exposure in
humans were used as basis for extrapolating to levels in
drinking water that would result in negligible risks to the
general human population. When considering toxicity that
does not include the risk of cancer, we generally use a
child weighing 10 kg (22 pounds) and drinking one liter of
water per day as the basis for calculations of short exposure
(acute) toxicity and longer exposure (chronic) toxicity.
These levels are derived using safety factors from classical
toxicology and a logic similar to that used by the National
Academy of Sciences in "Drinking Water and Health." When
considering the possible cancer risk, where it is assumed
that there is some risk at any level of exposure, and that
the risk increases as the lifetime exposure increases, we
use the 70 kg (154 pounds) adult living 70 years who drinks
two liters of water as the base, and calculate the excess
cancer risk above the normal background according to a
mathematical model developed by the National Academy of
Sciences in "Drinking Water and Health," and based on animal
tests conducted by the National Cancer Institute.
The drinking water levels that we have calculated providing
a margin of safety from likely toxic effects in humans
(assuming that 100% of the exposure is from drinking water.)
were related to the length of time that water is being
consumed, and range from short-term emergency levels to
long-term chronic exposure. We have separately computed the
potential additional cancer risk.
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The computed drinking water guidance levels for effects
excluding cancer risks are as follows:
Time Concentration
1 ay
10 days __ __ 0.2 me/1 (200 ug/1)
Chronic (long-term) 75 ug/1
The computed excess lifetime cancer risks from the NAS model
at various exposures assuming the 70 kg adult drinking two
liters of water per day for 70 years at the indicated concen-
tration are as follows:
Concentration Excess Risk
4.5 ug/1 one in 1,000,000
45 ug/1 one in 100,000
75 ug/1 approximately two in 100,000
The development of a SNARL for trichloroethylene does not
condone its presence in drinking water, but rather provides
useful information to guide control priorities in cases
where it is found as a contaminant. Human exposure to
contaminants in drinking water such as trichloroethylene
should be reduced to the extent feasible, to avoid the
unnecessary risks from their presence as adulterants. The
applicable treatment technologies include aeration and
granular activated carbon.
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NOV 2 6 1979
SNARL For Trichloroethylene
Health Effects Branch, Criteria and Standards Division
Office of Drinking Water
D.S. Environmental Protection Agency
Washington, D.C. 20460
In the absence of a formal drinking water standard for
trichloroethylene, the Office of Drinking Water has estimated
a suggested no adverse response level (SNARL) following the
state-of-the-art concepts in toxicology for non-carcinogenic
risk for short and long term exposures. For carcinogenic
risk a range of risk estimates are provided for life-time
exposures using a model and computations from the National
Academy of Sciences Report: Drinking Water and Health
(1977). However, SNARLS are given on a case-by-case basis
in emergency situations such as spills and accidents. The
SNARL calculations for short-term and chronic exposures
ignore the possible carcinogenic risk that may result from
those exposures. In addition SNARLS usually do not consider
the health risk resulting from possible synergistic effect
of other chemicals in drinking water, food and air.
I. General information and health effects
Trichloroethylene is used primarily as a metal degreasing
agent. It is also used, however, in dry-cleaning as a
solvent, and in refrigerants, and fumigants. Trichloroethylene
is slightly soluble in water.
Trichloroethylene, like other halogenated hydrocarbons
at high dose levels, has been reported to produce liver and
kidney ..damage ..and ..central .nervous system disturbances .in .. .
mammals, including humans. These effects have been observed
as a result of short-term exposures and the intensity of the
response was dependent upon the dosage levels. Salvini et
al» (Brit. J. Med. 1971. 28::293) observed psychophysiologTcal
changes in human volunteers in a controlled inhalation study
using trichloroethylene at as low a level as 110 ppm for two
four-hour periods.
Long-term exposures of mice to trichloroethylene produced
carcinogenic effects in both male and female animals (National
Cancer Institute, 1976). In addition to the carcinogenic
effect, trichloroethylene has been reported to be mutagenic
in microorganisms, transforms cultured mammalian cells to
carcinogenic cells, and binds with tissue macromolecules,
thus supporting the carcinogenic potential of trichloroethylene,
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There has been some controversy over the current evidence
linking trichloroethylene and carcinogenicty in animal
studies. Although the NCI bioassay was positive, others
have argued that the effects may have been due to contaminants
(epichlorohydrin and epoxybutane) in the tested trichloroethylene,
NCI has agreed to retest. The NAS in its 1979 report,
however, recognizing the issue, accepted the NCI result and
computed a risk value based upon carcinogenic potential.
Recent studies on the metabolism and elimination of
trichloroethylene in rats and human volunteers reveal that
the metabolites of trichloroethylene, namely trichloroethanol
and trichloroacetic acid, are not. immediately eliminated
from the body. Trichloroethanol was found to have a half-
life of 12 hours in human volunteers. This would mean that
repeated daily exposure to trichloroethylene via drinking
water would result in some accumulation of trichloroethanol
in the body. Moreover, the metabolite trichloroacetic acid
has been reported to bind to plasma proteins. This property
of trichloroacetic acid may result in interaction with drugs
and chemicals having similar properties, thereby resulting
in toxic effects. (Ertle £t^al. Arch. Toxicol. 29, 171-188,
1972.)
II. SNARL Development
Trichloroethylene is a carcinogen in mice, and also
causes non-carcinogenic bioeffects. One-day, 10-day and
chronic SNARL values based on non-carcinogenic bioeffects
are computed incorporating appropriate factors of safety.
Estimates of concentrations projected to increase the lifetime
cancer risk by one in 100,000 and one in a 1,000,000 are
also provided using the NAS model.. The non-carcinogenic
SNARL recommendations are made considering the child and
other possibly sensitive members of the population.
Using a study where human volunteers were exposed via
inhalation to 110 ppm (590 mg/m > of trichloroethylene for
an 8-hour period where psychophysiological symptoms were
observed, a one-day SNARL value of 2 mg/1 could be calculated
for the child.
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(590 n>8/m3)(8 m3/day)(0.30) x J_ = 2.02 mg/1
(1 I/day)(100 uncertainty factor) 7
where: 1/7 = child/adult body weight ratio
0.30 = absorption factor
1 I/day = child daily water consumption
100 = uncertainty factor via 10 factor because
a human experiment was used and 10 factor
because data did not specify the no observed
adverse effect level
To calculate a SNARL for 10 days metabolic and pharmacokinetics
data are required. Since that data is not available a
conservative method would be to divide the one-day SNARL of
2 mg/1 by 10 whereby the 10-day SNARL value would become
approximatley 200 ug/1.
Since the one-day and 10-day SNARL values are determined
for emergencies and spills for a short period of time, it
should be assumed that drinking water would be the primary
or sole source of human intake of trichloroethylene. This
is in opposition to that for a chronic SNARL where a lesser
contribution from drinking water may be appropriate.
Therefore, a relative source contribution factor has not
been incorporated into the suggested one-day and 10-day
SNARL values of 2 mg/1 and 0.2 mg/1, respectively.
The NAS (1979) has computed a one-day SNARL of 105 mg/1
and 15 mg/1 for the seven-day SNARL. Their calculations
were based upon the observation of intoxication of adults
and the application of uncertainty factors. Our calculations,
however, were based upon psychophysiological parameters and
extrapolated to the child with the appropriate uncertainty
factors.
The NAS chose to work with uncontrolled case histories
where trichloroethylene was accidentally ingested. The
study which the Office of Drinking Water chose to evaluate
and extrapolate, while being an inhalation study, was conducted
under controlled conditions.
A longer exposure SNARL for trichloroethylene, can be
calculated using a study by Kimmerle and Eben entitled
"Metabolism, Excretion and Toxicology of Trichloroethylene
after Inhalation." This study evaluated the subacute exposure
to trichloroethylene via inhalation in adult rats for some
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14 weeks following exposure to 55 ppm (300 mg/tn3), five days
a week. Indicies of toxicity include hematological investigation,
liver and renal function tests, blood glucose and organ/body
weight ratios. Liver weights were shown to be elevated
while the other test values were not different from controls.
The elevated liver weights could be interpreted to be the
result of hydropic changes or fatty accumulation. The no-
observed-effect level was not identified.
Using the method of Olsen and Gehring (1976) whereby
the lung-whole body ratios for humans (adults) and rats
(adults) are assumed to be roughly equivalent, the total
dose of trichloroethylene to the child can be determined and
a longer term SNARL can be calculated to be approximately 75
ug/1 when the principal source of trichloroethylene is
assumed to be from drinking water.
(300 mg/m3) 8 m3/day (5)(1)(0.30) = 73.5 ug/1
(1 I/day) (7)(7) (1000)
Where:
55 opm (5.46) = 300 mg/m minimum effect level
8m = according to Olsen/Gehring
5/7 = fraction converting from 5 to 7-day exposure
1/7 = child/adult body weight ratio
0.30 = absorption rate
1 I/day = child consumption per day
1000 = uncertainty factor due to animal study
where minimal effect was reported
In cases where other sources of exposure are prevalent
and, for example, drinking water Ls assumed to account for
a portion of the total exposure, say 20%, of the trichloroethylene
intake, then the SNARL value would become 15 ug/1. By-and-
large, however, the 75 ug/1 SNARL would be assumed to be
appropriate under normal circumstances in the absence of
other major sources of TCE.
A chronic SNARL approximately equivalent to the SNARL
of 75 ug/1 can be justified on the basis that (1) long-term
exposure to low doses of trichloroethylene probably does not
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bioaccumulate much more over a lifetime than in 3-6 months,
and (2) the SNARL was calculated for the child and not the
adult thus providing a somewhat larger safety margin.
Since trichloroethylene is considered a carcinogen, at
least for mice, and using the risk estimates generated by
the National Academy of Sciences (NAS), it is possible to
identify that range of trichloroethylene concentrations that
would increase the risk of one excess cancer per 10 or
10 people exposed over a lifetime. From the NAS model it
is estimated that consuming 2 I/day over a lifetime having a
trichloroethylene concentration of 4.5 ug/1 or 45 ug/1 would
increase the risk by one excess cancer/million exposed .or
one excess cancer/100,000 exposed, respectively. This is
the range of risks where many EPA regulatory values for
other carcinogens have been.
These risk extrapolations were based on an assumption
that there is no threshold level for carcinogens. The
state-of-the-art at the present time is such that no experimental
tools can accurately define the absolute numbers of excess
cancer deaths attributable to trichloroethylene in drinking
water. Due to the biological variability and a number of
assumptions required, each of the risk estimating procedures
lead to a different value. There is wide variation among
these estimates and also in their interpretation. For this
reason we report the results of the NAS risk computations,
which is a conservative approach, as a range of values in
the one in one hundred thousand to one in one million incremental
risk (risk above background) for a carcinogen. The NAS risk
estimates are based on the multistage model concept. "At
low dose the multistage model is often mathematically equivalent
to the linear or single hit model. Therefore, its use for
extrapolation is consistent with the conservative linear
risk estimation. If the precise mechanism of carcinogenesis
is represented by a threshold or log-normal dose response
relationship, the multistage model may considerably over
estimate the risk at low dose levels. However, this possibility
cannot be reasonably quantified." (NAS-1979)
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