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Appendixes
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1
Chloroform
Hector D. Garcia, Ph.D.
NASA-Johnson Space Center Toxicology Group
Habitability ancI Environmental Factors Branch
Houston, Texas
PHYSICAL AND CHEMICAL PROPERTIES
Chloroform is a nonflammable, clear, colorless, volatile and mobile, highly
refractive, dense liquid with a characteristic pleasant, non-irr~tating odor
and a slight, sweet taste (see Table 1-1) (ATSDR 1997~.
OCCURRENCE AND USE
Chloroform is used as an extractant or solvent for fats, oils, greases,
resins, lacquers, rubber, alkaloids, gums, waxes, gutta-percha, penicillin,
vitamins, flavors, floor polishes, and adhesives. It is also used as a raw
material in the chemical industry for the manufacture of chlorodifluoro-
methane (Freon 22), resins, and plastics; as a pharmaceutical solvent; as a
dry cleaning spot remover; and as an intermediate in the manufacture of
dyes and pesticides (ATSDR 1997; ACGIH 1991~. In the past, chloroform
was used as a general anesthetic, in fire extinguishers, and as a flavoring
agent in toothpastes and cough syrups (ACGIH 1991~. Trace amounts of
chloroform are present in drinking water and in wastewater from sewage
treatment plants as a by-product of chlorine treatment to kill bacteria. Trace
levels of chloroform are also found almost ubiquitously in the environment.
11
OCR for page 12
12
Spacecraft Water Exposure Guidelines
TABLE 1-1 Physical and Chemical Properties of Chloroform
Formula CHC13
Chemical name Trichloromethane
Synonyms Chloroform, trichloroform, formyl bichloride,
Cl methenyl chloride, methenyl bichloride, methane tri-
chloride, methyl bichloride, NCI-C02686, Freon 20,
~ R-20, TOM
Cl C H
Cl
CAS registry no. 67-66-3
Molecular weight 1 19.38
Boiling point
Melting point
Liquid density
61.3°C
-63.2°C
1.485 g/cc
Vapor density 4.36 (air = 1)
Vapor pressure 159 tort at 20°C
Solubility 1 mL dissolves in 200 mL water at 25°C
Odor threshold 2.4 ppm (water); 85 ppm (vapor)
Miscible with alcohol, benzene, ether, petroleum ether, carbon tetrachloride,
carbon disulfide, and oils.
Chloroform was detected in the space shuttle atmosphere in six of 27 mis-
sions at levels of 0.002-0.03 milligrams per cubic meter (mg/m3) (Huntoon
1987; Huntoon 1993) and, in more recent missions, in about 10% of air
samples at concentrations in the range of 0.01-0.1 mg/m3 (James et al.
1994~. Small amounts of chloroform are sometimes carried on board the
space shuttle as part of mid-deck or module experiments. Drinking water on
the International Space Station (ISS) will not be chlorinated, but will be
iodinated or treated with silver to kill bacteria. It will be generated from
recycled hygiene water, urine, and humidity condensate, and supplemented
by water from the shuttle or the Russian Progress spacecraft. Thus, it is
expected that traces of chloroform may be found occasionally in spacecraft
drinking water under normal conditions.
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Chloroform
13
PHARMACOKINETICS AND METABOLISM
Considerable data are available on the uptake, metabolism, and elimina-
tion of chloroform in several species. The weight of evidence indicates that
chloroform is rapidly distributed throughout the body and that its toxic
effects have a threshold that is dependent on the dose rate.
Absorption
Chloroform is rapidly absorbed through the gastrointestinal tract from
foodstuffs and drinking water (EPA 1985~. The composition and volume
of the vehicle in which it is dissolved may affect the rate of absorption of
orally administered chloroform. In female B6C3F, mice, the absorption and
tissue dosimetry in blood, liver, and kidneys of a single dose of chloroform
administered by gavage was increased in aqueous gavage vehicles com-
pared with corn oil, but in male F-344 rats, the gavage vehicle had minimal
effects (six et al. l 997~. The absorption rate of chloroform in corn oil was
decreased at dosing volumes of 10 milliliters per kilogram (mL/kg) com-
pared with 2.5 mL/kg in both rats and mice. In aqueous 2% emuIphor, a
large volume of liquid was observed in the stomachs of mice at sacrifice,
but not in those of rats.
Rate constants for gavage absorption were reported by CorIey et al.
(1990) to be Kas~hr~~), corn oil = 0.6; Kas~hr~~), water= 5.0. Absorption of
chloroform through the skin is significant (329 ~mol/min/cm2 of skin ex-
posed to the liquid) (EPA 1985~.
Distribution
In humans (Smith et al. 1973) and animals (Cohen 1971; Brown et al.
1974a), chloroform absorbed either by inhalation or orally is distributed to
all tissues with relative tissue concentrations of body fat > brain > liver >
kidneys > blood, as expected due to the lipophilic nature of chloroform.
Partition coefficients in humans were reported by CorIey et al. (1990) as
follows: blood/air = 7.43; liver/air = 17.0; kidney/air = 11.0; fat/air = 280;
rapidly perfused tissues/air = 17.0; slowly perfused tissues/air = 12.0.
In mouse studies, the relative distribution among the organs was de-
pendent on the route of administration, the time between dosing and mea-
surement, end the metabolism and covalent birding of metabolites to cellu-
OCR for page 14
14
Spacecraft Water Exposure Guidelines
tar macromolecules (Taylor et al. 1974; Brown et al. 1974a). The highest
levels were seen in the liver after oral dosing, probably due to a first-pass
effect in which most of the chloroform is metabolized by the liver before
reaching the general blood circulation.
Excretion
Chloroform was detected in the exhaled air of volunteers exposed to a
normal environment, to heavy automobile traffic, or to 2 hours (h) in a dry-
cleaning establishment (Gordon et al. 1988~. Higher chloroform levels in
the breath corresponded to higher exposure levels. The calculated biologic
half-time for chloroform in breath was 7.9 h.
Excretion of radioactivity in mice and rats was monitored for 48 h
following exposure to ~4C-labeledtracer chloroform in chloroform at 10, 89,
and 366 parts per million (ppm) in mice or 93, 356, and 1,041 ppm in rats
(CorIey et al. 1990~. In this study, 92-99% of the absorbed radioactivity
was recovered in mice, and 58-98°/O was recovered in rats; percent recovery
decreased with increasing exposure. Ofthe total radioactivity absorbed, the
percentages recovered as exhaled ~4C-labeled carbon dioxide were 80-85°/O
for mice and 48-85°/O for rats. After exposure, the fractions recovered as
~4C-labeled chloroform were 0.4-~°/O for mice and 2-42% for rats. The
fractions recovered as urinary and fecal metabolites were S-11% and 0.6-
1.4%, respectively, for mice and 0.1% and 0.6%, respectively, for rats. A
4-fold increase in exposure concentration was followed by 50- and 20-fold
increases in the amount of exhaled, unmetabolized chloroform in mice and
rats, respectively. This indicates that the higher concentrations exceeded
the capacity of the body to metabolize chloroform.
Metabolism
The metabolism of chloroform has been studied extensively and is
understood fairly well. In humans, approximately 50°/O of an oral dose of
0.5 g chloroform was metabolized to carbon dioxide (Fry et al. 1972~. Me-
tabolism was dose dependent, decreasing with higher exposure. A first-pass
effect was observed after oral exposure (Chiou 1975~. Approximately 38°/O
of the dose was converted in the liver, and < 17% was exhaled unchanged
from the lungs.
In a physiologically based pharmacokinetic (PBPK) modeling study of
chloroform, CorIey et al. (1990) derived in viva metabolic rate constants
OCR for page 15
Chloroform
15
(VmaxC = 15.7 mg/hL/kg, Km = 0.448 mg per liter [L]) for humans on the
basis of experimental results obtained in rats and mice exposed to chioro-
form by inhalation and enzymatic studies in human tissues in vitro. The
order of activity of liver microsomes was hamster > mouse > rat > human.
Microsomes obtained from the kidneys of the various species were less
active than those obtained from the livers. Virtually no activity could be
detected from the three samples of human kidney tissues available; there-
fore, for the PBPK model, Coriey et al. (1990) assumed that activity in
human kidney was present at the limit of detection. Their results predicted
that the "delivered doses" of chloroform, defined as the milligram equiva-
lents of phosgene bound to macromolecules per liter of liver tissue per day,
were about 10-fold lower in humans than in mice and about 5-fold lower in
humans than in rats exposed to the same concentrations of chloroform in
drinking water. They assume that equivalent levels of macromolecular
binding produce equivalent toxicities in target tissues. The relative sensitivi-
ties of the three species (mouse > rat > human) predicted by the Coriey et
al. (1990) PBPK model differ markedly from those predicted by the default
assumptions used by EPA. In the absence of experimental data, EPA as-
sumes that equal concentrations in the air or water produce a 10-fold greater
risk in humans than in the most sensitive tested species (mice). The Coriey
et al. data show that humans should have a 10-fold lower risk than mice
exposed at equal chloroform concentrations.
Chloroform can be metabolized both aerobically and anaerobically as
shown below (Figures 1 - 1 and 1 -2~. The production of CO2 by the aerobic
pathway accounts for up to 85°/O of administered chloroform in mice, 65%
in rats, and lesser amounts in humans (50°/O) and squirrel monkeys (28%)
(Brown et al. 1974a; Taylor et al. 1974~. In mice, Brown et al. (1974a)
found greater levels of radiolabeled chloroform in the kidneys of male mice
than in females. Similarly, Culliford and Hewitt (1957) found that chloro-
form accumulated and metabolized in the renal cortex of males to a greater
extent than in females; however, the results may have been influenced by
testosterone levels. This effect was not observed in any other species.
These species and gender differences in metabolism, distribution, and bind-
ing point out the limitations and difficulties in extrapolating studies in lower
animals to humans.
Metabolism studies by Pohl (1979) and Stevens and Anders (1981)
indicated that chloroform was exhaled from the lungs or was converted to
phosgene (Pohl 1979; Stevens end Anders 1981) in the river end kidneys by
cytochrome P-450 (Branchflower et al.1984; Smith and Hook 1984~. Phos-
gene may react with cellular elements, inducing cytotoxicity to lipids and
proteins ofthe endoplasmic reticulum proximate to the cytochrome P-450.
OCR for page 16
16
Spacecraft Water Exposure Guidelines
In phenobarbital-pretreated Sprague-Dawley rats, chloroform treatment
yielded a covalent abduct to a single phospholipid, identified as phospha-
tidylethanolamine, in liver mitochondria (Guastedisegni et al. l 998~. It was
further demonstrated that chloroform can induce lipid peroxidation and
inactivation of cytochrome P-450 in rat liver microsomes under aerobic
conditions (DeGroot and Noll 1989~. This mechanism may also contribute
to chloroform-induced hepatotoxicity in rats, although phosgene and other
active metabolites are primarily responsible. The conversion of chloroform
to reactive metabolites occurs in nuclear preparations as well as in micro-
somes (Gomez and Castro 1980~. Covalent binding of chloroform to lipids
can occur under anaerobic and aerobic conditions, although binding to
protein occurs only under aerobic conditions (Testai et al. 1987~.
Covalent binding of chloroform metabolites to microsomal protein in
vitro was increased by microsomal enzyme inducers and prevented by
glutathione (GSH) (Brown et al. 1974b). It was proposed that the reaction
of chloroform metabolites with GSH might act as a detoxifying mechanism.
Phosgene may combine with two molecules of GSH to form diglutathiony!
dithiocarbonate, which is further metabolized in the kidneys (Sipes et al.
1977; Wolfet al. l977~. Chloroform doses that caused liver GSH depletion
produced liver necrosis (Docks and Krishna 1976~. Furthermore, chioro-
form has been found to be more hepatotoxic in fasted animals, possibly due
to decreased GSH content in the liver (Brown et al. 1974b; Docks and
Krishna 1976; Wang et al. 1995~.
Evidence that chloroform is metabolized at its carbon-hydrogen bond
is provided by experiments that used the deuterated derivative of chioro-
form (McCarty et al. 1979; Poh! et al. 1980; Branchflower et al. 1984~.
Deuterated chloroform is one-half to one-third as cytotoxic as chloroform,
and its conversion to phosgene is much siower. The results confirmed that
the toxicity of chloroform to the liver and kidneys is due primarily to its
metabolites (ATSDR 1997~.
The final product of the aerobic metabolic pathway of chloroform is
carbon dioxide (Fry et al.1972; Brown et al.1974a), which is mostly elimi-
nated through the lungs, but some is incorporated into endogenous metabo-
lites and excreted as bicarbonate, urea, methionine, and other amino acids
(Brown et al. 1974a). Inorganic chloride ion is an end-product of chioro-
form metabolism found in the urine (Van Dyke et al. 1964~. Carbon mon-
oxide was a minor product of the anaerobic metabolism of chloroform in
rats in vitro (Ahmed et al. 1977) and in vivo (Anders et al. 1978; ATSDR
1997~.
OCR for page 17
Chloroform
Cl
P-450, 0
2
H C C I NADPH
I M c oso es
Cl 1 r m
Acce pto r
H
H—C C
S N
`' / H
C'
11
o
2-Oxathiazolid ine-
4-Carboxylic acid
Cl
HO-C-CI
Cl
Macromolecule O
11
CO < C
-H C1
'jY
O\ ~
~C—O -H
.~.0~ Cl Cl
Phosoene
+H2O
2HCl ~ CO2
G lutath ione
Conjugates?
FIGURE 1-1 Major pathway (aerobic). Source: Redrawn from ATSDR 1997.
C I Anaerobic
H C C I Reduce~ > P-450-Fe :C C 12 ~ H C I
C I M icroso m es
+H2O
P-450-Fe++ C O <
CO ~ 2HCI
FIGURE 1-2 Minor pathway (anaerobic). Source: Redrawn from ATSDR 1997.
17
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18
Spacecraft Water Exposure Guidelines
A recent in vitro study of hepatic microsomes in mice indicated that a
reductive pathway might play an important role in chloroform hepatotoxic-
ity (Testai et al. 1990~. It was demonstrated that radical chloroform metabo-
lites bind to macromolecules (i.e., proteins, lipids), and the process can be
inhibited by reduced GSH (ATSDR 1997).
Interspecies differences in the rate of chloroform conversion were ob-
served in mice, rats, and squirrel monkeys. The conversion of chloroform
to carbon dioxide was highest in mice (85°/O) and lowest in squirrel mon-
keys (28%) (Brown et al. 1974a). Similarly, because of the lower relative
rates of chloroform metabolism, ventilation, and cardiac output (per kilo-
gram body weight) in the larger species, physiologically based pharmaco-
kinetic (PBPK) calculations indicated that exposure to equivalent concen-
trations of chloroform vapor would lead to a lower delivered dose of active
metabolites in humans compared with rats; rats would have a lower deliv-
ered dose than mice (Coriey et al. 1990; ATSDR 1997~.
TOXICITY SUMMARY
Although high concentrations of inhaled chloroform vapor have pro-
nounced effects on the central nervous system (CNS), most of which are
reversible upon cessation of exposure, there are no reports of CNS effects
resulting from exposure to chloroform in drinking water. This is true even
at concentrations high enough to render the water unpalatable to very thirsty
rodents. This lack of CNS effects is due to a first-pass effect in which most
of the chloroform is metabolized by the liver before reaching the general
blood circulation. Other reported effects of exposure to high vapor concen-
trations include cardiac arrhythmias, immune system depression, and, in
rats, nasal lesions. None of these effects have been reported for oral expo-
sures. Short-term exposure to high levels by various routes, including oral,
causes liver necrosis and kidney degeneration. Long-term exposure to levels
high enough to cause cytotoxicity may lead to liver or kidney cancer.
Acute Toxicity (<1 d)
Hepatotoxicity
The liver has been shown to be the primary toxicity target of ingested
chloroform in humans. Ingestion of chloroform at approximately 3,755
mg/kg produced jaundice, liver enlargement and tenderness, increased
OCR for page 19
Chloroform
19
levels of serum glutamic oxaloacetic transaminase (SGOT), serum glutamic
pyruvic transaminase (SGPT), and lactate dehydrogenase activities, and
increased bilirubin levels in an individual who died of chloroform poisoning
(Pierso! et al. 1933~. Autopsy revealed fatty degeneration and extensive
centrilobular necrosis.
The hepatotoxicity of chloroform is believed to be due to the production
of reactive chloroform metabolites (e.g., phosgene) by cytochrome P-450
and is modulated by hepatic GSH. Brown et al. (1974b) found that expo-
sure of rats to chloroform for 2 h at either 5,000 or 10,000 ppm produced
hepatic necrosis and destruction of microsomal enzymes. Pretreatment of
rats with phenobarbital to induce microsomal enzyme activity before expo-
sure to chloroform markedly increased the hepatotoxic response to anesthe-
sia. It also produced a 70-80°/0 decrease in hepatic GSH levels compared
with uninduced rats in which chloroform exposure resulted in neither deple-
tion of GSH nor in hepatic necrosis at 24 h after exposure (Brown et al.
1974b). Experimental depletion of hepatic GSH by pretreatment with di-
ethy! maleate also resulted in centrilobular necrosis after exposure to chio-
roform (Brown et al. 1974b).
In cytotoxicity studies at CIIT, freshly isolated hepatocytes cultured
from B6C3F, mice and F-344 rats were exposed to solutions of chloroform
for up to 3 h. Concentration-dependent cytotoxicity (lactate dehydrogenase
release) was seen in culture at concentrations higher then 1 millimolar (mM)
(Ammann et al. 1998~. Co-treatment with the cytochrome P-450 inhibitor
1-phenylimidazole prevented both cytolethality and GSH depletion, indicat-
ing that metabolism is necessary for chloroform-induced cytotoxicity. These
results correlate well with simulations of a physio-Iogically based dosimetry
model for chloroform, which indicated that the livers of mice and rats were
exposed to chloroform concentrations up to 5 mM for 3 h after hepatotoxic
doses of chloroform (Ammann et al. l 998~. The high (>1 mM) concentra-
tions of chloroform necessary to produce hepatotoxicity can be achieved
only by bolus dosing, such as gavage. Drinking water exposure results in
much lower hepatic chloroform concentrations than bolus gavage and elimi-
nates the hepatotoxic effects (Larson et al. 1994b).
Nephrotoxicity
Unpublished studies at CIIT (B. Butterworth, CIIT, personal commun.,
Sept.21,1998) using mice in which the CYP-450 IIE1 gene had been inac-
tivated showed that the metabolism of chloroform was completely elimi-
nated. Thus, chloroform metabolism in mice is entirely dependent on cyto-
OCR for page 46
46
Spacecraft Water Exposure Guidelines
Reduced Water Consumption
ACs for reduced water consumption for 1-d and 10-d exposures are
based on Larson et al.'s (1994b) results in mice given chloroform in drink-
ing water at 0, 60,200,400, 900, or 1,800 ppm. At chloroform concentra-
tions of 200 ppm and above, the average daily doses were lower for the first
4 ~ of exposure than for the entire 3 wk of exposure because ofthe mice's
initial aversion to the drinking water. The 1-d and 10-d ACs are set at the
60 ppm (mg/L) NOAEL for reduced water consumption during the initial
exposure period. No adjustment was made for potential species differences
in taste aversion.
1-d and 10-d ACs = 60 mg/L.
Spaceflight Effects
Spaceflight is believed to increase the susceptibility of crew members
to noncritical cardiac arrhythmias and could amplify the arrhythmogenic
effects of chloroform. The blood levels of chloroform that can be achieved
by ingesting drinking water are too low, however, to pose a concern for
induction of cardiac arrhythmia.
Comparison of SWEG Values with
Inhalation Limits for Chloroform
The amount of chloroform to which an individual would be exposed
through drinking water at the SWEG values is compared in Table 1-6 with
the exposures experienced through inhalation of the recommended space-
craft maximum allowable concentrations (SMACs) for chloroform vapors.
The daily amounts ingested using the SWEG values assume consumption
of 2.8 L of water per day and 100% absorption. Calculation of the daily
amounts that would be absorbed during inhalation of air containing the
SMACs for chloroform assumes inhalation of 20 m3 of chloroform vapor
per day end retention of 45°/O (NRC 2000, pp.264-306~. Forty-f~ve percent
is probably low because it was estimated from experiments with humans
inhaling much higher concentrations. At concentrations near the SMACs,
the retention could approach 100%, and the values in Table 1 -6 for milli-
grams per day at the SMAC values would need to be adjusted.
OCR for page 47
Chloroform
TABLE 1-6 Comparison of Daily Amounts of Chloroform Exposure
Allowable Under SWEGs and SMACs
47
F,xnos,~,re SWEGs
SMACs
~--r ~
Duration mg/L mg/d Effect
1 h
mg/m3 mg/d Effect
10 90 CNS depression
10 90 CNS depression
24h
1 d 60 120 Reduced water
consumption
7 d 10 90 CNS depression,
hepatotoxicity,
nephrotoxicity, car-
cinogenicity
10 d 60 120 Reduced water
consumption
30 d 5 45 Hepatotoxicity,
CNS depression
100 d 18 36 Hepatotoxicity
180 d 5 45 Hepatotoxicity
1,000 d 6.5 13 Hepatotoxicity
Abbreviations: SMACs, spacecraft maximum allowable concentrations; SWEGs,
spacecraft water exposure guidelines.
The daily amounts absorbed (mg/~) are comparable for the two routes
of exposure. At SMAC values for durations of <7 4, inhalation leads to
CNS depression, whereas, due to the first-pass effect, similar amounts in-
gested from drinking water do not reach the CNS because much of the
chloroform is metabolized by the liver before it reaches the general circula-
tion.
Comparison of SWEG Values with
Standards Set by Other Organizations
The daily amounts ingested using the ACs recommended above and
assuming consumption of 2.8 L of drinking waterper day and 100% absorp-
tion are compared, in Table 1-7, with the drinking water standards set by
other organizations.
OCR for page 48
48
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OCR for page 49
Chloroform
49
RECOMMENDATIONS FOR FUTURE RESEARCH
Research is needed to quantitate the organ-specific (liver and kidney)
levels of chloroform metabolism in humans, compare them with those in
rodents, and elucidate factors, such as glutathione levels, that could modu-
late the threshold level of chloroform required for toxicity. Once all ofthat
is determined, a PBPK model incorporating those values and addressing
both oral and inhalation exposures would be users.
REFERENCES
Agustin, J.S., and C.Y. Lim-Sylianco. 1978. Mutagenic and clastogenic effects of
chloroform. Bull. Phil. Biochem. Soc. 1:17-23.
Ahmed, A.E., V.L. Kubic, and M.W. Anders. 1977. Metabolism of haloforms to
carbon monoxide. I. In vitro studies. Drug Metab. Dispos. 5:198-204.
ACGIH. 1991. Chloroform. Pp.198-204 in Documentation ofthe Threshold Limit
Values and Biological Exposure Indices, Vol. 1, 6 Ed. American Conference
of Governmental Industrial Hygienists, Cincinnati, OH.
Ammann, P., C.L. Laethem, and G.L. Kedderis. 1998. Chloroform-induced cyto-
lethality in freshly isolated male B6C3F1 mouse and F-344 rat hepatocytes.
Toxicol. Appl. Pharmacol. 149:217-225.
Anders, M.W., J.L. Stevens, R.W. Sprague, Z. Shaath, and A.E. Ahmed. 1978.
Metabolism of haloforms to carbon monoxide. II. In vivo studies. Drug
Metabol. Dispos. 6:556-560.
ATSDR. 1997. Toxicological Profile for Chloroform. TP-92-07. U.S. Department
of Health and Human Services, Public Health Service, Agency for Toxic Sub-
stances and Disease Registry, Washington, DC.
Baeder, C., and T. Hotmann.1988. Inhalation Embryotoxicity Study of Chloroform
in Wistar Rats. Frankfurt: Pharma Research Toxicology and Pathology,
Hoechst Aktiengesellschaft.
Branchflower, R.V., D.S. Nunn, R.J. Highet, J.H. Smith, J.B. Hook, and L.R. Pohl.
1984. Nephrotoxicity of chloroform: Metabolism to phosgene by the mouse
kidney. Toxicol. Appl. Pharmacol. 72:159-1168.
Brown, D.M., P.F. Langley, D. Smith, and T.D.C. 1974a. Metabolism of chloro-
form.I. ThemetabolismofE14C]-chloroformbydifferentspecies.Xenobiotica
4:151-163.
Brown, B.R., Jr., I.G. Sipes, and A.M. Sagalyn. 1974b. Mechanisms of acute
hepatic toxicity: Chloroform, halothane, and glutathione. Anesthesiology
41 :554-561.
Bull, R.J., J.M. Brown, E.A. Meierhenry, T.A. Jorgenson, M. Robinison, and J.A.
Stober. 1986. Enhancement of the hepatotoxicity of chloroform in B6C3F1
mice by corn oil: Implications for chloroform carcinogenesis. Environ. Health
Perspect. 69:49-58.
OCR for page 50
so
Spacecraft Water Exposure Guidelines
Butterworth, B.E., M.V. Templin, A.A. Constan, C.S. Sprankle, B.A. Wong, L.J.
Pluta, J.I. Everitt, and L. Recio. 1998a. Long-term mutagenicity studies with
chloroform and dimethylnitrosamine in female lacI transgenic B6C3F1 mice.
Environ. Mol. Mutagen. 31 :248-256.
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Representative terms from entire chapter:
corn oil
