* i -
xvEPA
United States
Environmental Protection
Agency
FINAL DRAFT
ECAO-CIN-HOlOa
April, 1988
Research and
Development
UPDATED HEALTH EFFECTS ASSESSMENT
FOR CHLOROFORM
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
f
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
DRAFT: DO NOT CITE OR QUOTE
500/
ECAO-
CIH
-HOlOa
NOTICE
This document Is a preliminary draft. It has not been formally released
by the U.S. Environmental Protection Agency and should not at this stage be
construed to represent Agency policy. It Is being circulated for comments
on 11s technical accuracy and policy Implications.
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' 1 '
DISCLAIMER
This report has been funded wholly or In part by the United States
Environmental Protection Agency under Contract No. 68-03-3112 to Syracuse
Research Corporation. It has been subject to the Agency's peer and adminis-
trative review, and U has been approved for publication as an EPA document.
Mention of trade names or commercial products does not constitute endorse-
ment or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with chloro-
form. All estimates of acceptable Intakes and carcinogenic potency present-
ed 1r this document should be considered as preliminary and reflect limited
resources allocated to this project. Pertinent toxlcologlc and environ-
mental data were located through on-line literature searches of the Chemical
Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data bases. The
bask literature searched supporting this document 1s current up to May,
1987. Secondary sources of Information have also been relied upon 1n the
prepcratlon of this report and represent large-scale health assessment
efforts that entail extensive peer and Agency review. The following Office
of Health and Environmental Assessment (OHEA) sources have been extensively
utilized:
l.S. EPA. 1980a. Ambient Water Quality Criteria Document for
Chloroform. Prepared by the Office of Health and Environmental
/ssessment, Environmental Criteria and Assessment Office,
dnclnnatl, OH for the Office of Water Regulations and Standards,
Hashlngton, DC. EPA-440/4-BO-033. NTIS PB 81-117442.
U.S. EPA. 1982. Hazard Profile for Chloroform. Prepared by the
dfflce of Health and Environmental Assessment, Environmental
(,r1ter1a and Assessment Office, Cincinnati, OH for the Office of
!,o!1d Waste, Washington. DC.
U.S. EPA. 1983. Review of Toxlcologlc Data In Support of Evalua-
,1on for Carcinogenic Potential of Chloroform. Prepared by the
Office of Health and Environmental Assessment, Carcinogen Assess-
nent Group, Washington, DC for the Office of Solid Waste and
! mergency Response.
U.S. EPA. 1985. Health Assessment Document for Chloroform.
i)ff1ce of Health and Environmental Assessment, Environmental
ilrlterla Assessment Office, Research Triangle Park, NC. EPA
'>00/8-84/004F. NTIS PB 86-105004.
J.S. EPA. 1987a. Integrated Risk Information System (IRIS).
Reference dose (RfD) for oral exposure for chloroform. On-L1ne:
[Verification date 12/02/85). Office of Health and Environmental
\ssessment, Environmental Criteria and Assessment Office,
:indnnat1, OH.
J.S. EPA. 1987b. Integrated Risk Information System (IRIS). Risk
estimate for carclnogenldty for chloroform. On Line: Input
sending. (Verification Date 8/26/87). Office of Health and
Environmental Assessment, Environmental Criteria and Assessment
Dfflce, Cincinnati, OH.
Ill
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Tie Intent In these assessments 1s to suggest acceptable exposure levels
for loncarclnogens and risk cancer potency estimates for carcinogens
whene/er sufficient data were available. Values were not derived nor were
large- uncertainty factors employed when the variable data were limited In
scope, which tended to generate conservative (I.e., protective) estimates.
Never iheless, the Interim values presented reflect the relative degree of
hazarj or risk associated with exposure to the chemlcal(s) addressed.
Wienever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer 1s not the endpolnt of
conce-n). The first, RfDg (formerly AIS) or subchronlc reference dose, Is
an estimate of an exposure level that would not be expected to cause adverse
effects when exposure occurs during a limited time Interval (I.e., for an
Internal that does not constitute a significant portion of the Hfespan).
This type of exposure estimate has not been extensively used, or rigorously
defln'd, as previous risk assessment efforts have been primarily directed
towar Is exposures from toxicants In ambient air or water where lifetime
exposjre 1s assumed. Animal data used for RFD$ estimates generally
IncluJe exposures with durations of 30-90 days. Subchronlc human data are
rarely available. Reported exposures are usually from chronic occupational
exposjre situations or from reports of acute accidental exposure. These
value; are developed for both Inhalation (RfDgj) and oral (RfOgnJ
exposjres.
Tie RfD (formerly AIC) Is similar In concept and addresses chronic
exposure. It 1s an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the llfespan [see U.S. EPA (1980b) for a discussion of this concept]. The
RfO s route-specific and estimates acceptable exposure for either oral
(RfD0) or Inhalation (RfDj) with the Implicit assumption that exposure
by otier routes Is Insignificant.
Composite scores (CSs) for noncarclnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development Is explained In U.S.
EPA (1984).
Far compounds for which there Is sufficient evidence of carclnogenldty
RfD$ and RfD values are not derived. For a discussion of risk assessment
methoJology for carcinogens refer to U.S. EPA (1980b). Since cancer Is a
process that Is not characterized by a threshold, any exposure contributes
an Ircrement of risk. For carcinogens, q-|*s have been computed, 1f appro-
priate, based on oral and Inhalation data If available.
1v
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ABSTRACT
!n order to place the risk assessment evaluation In proper context,
refei to the preface of this document. The preface outlines limitations
appl cable to all documents of this series as well as the appropriate
Interpretation and use of the quantitative estimates.
Chloroform has been shown to be carcinogenic by the oral route In
rodents In several Independent Investigations. Human data are suggestive
for chlorinated drinking water, but are Inadequate for chloroform alone.
Chloroform Is classified as an EPA Group B2 carcinogen, probable human
care nogen, based on sufficient evidence from animal studies and Inadequate
evidence from human studies.
U.S. EPA (1985) has estimated a unit risk for Inhalation exposure of
2.3x (Ts (jig/m3)"1 based upon route extrapolation from a qi* of
8.1x O"2 (mg/kg/day)'1. This assessment Is based upon data for
Incidence of liver tumors In male and female mice (NCI, 1976).
U.S. EPA (1987b) has estimated an oral q-|* of 6.1xlO~» (mg/kg/day)"1
baseiJ upon kidney tumors In male rats exposed In the drinking water In a
studf by Jorgenson et al. (1985).
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ACKNOWLEDGEMENTS
Tlie Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Dr. Christopher DeRosa and Karen
Blackliurn were the Technical Project Monitors and Helen Ball was the Project
Officer. The final documents In this series were prepared for the Office of
Emergency and Remedial Response, Washington, DC.
S:1ent1sts from the following U.S. EPA offices provided review comments
for tils document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of Air Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by the following:
Jjdlth Olsen and Erma Durden
Eivlronmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by the
following:
B?tte Zwayer, Jacky Bohanon and Kim Davidson
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
1.
2.
3.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1.
;.2.
ORAL
INHALATION
10XICITY IN HUMANS AND EXPERIMENTAL ANIMALS
5.1.
-.2.
SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
CHRONIC
3.2.1. Oral
3.2.2. Inhalation
Page
1
, , , 3
. . . 3
. . . 3
5
5
... 5
7
7
... 7
. . . 8
4.
5.
^
-
.0. i Lnru UULHIUI i i nnu umtn ni.rnuixui> 1 1 »t LI i tv
3.3.1. Oral
3.3.2. Inhalation
.4. TOXICANT INTERACTIONS
CARCINOGENICITY
4
4
4
4
F
.1. HUMAN DATA
4.1.1. Oral
4.1.2. Inhalation
.2. BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
.3. OTHER RELEVANT DATA
.4. WEIGHT OF EVIDENCE
EGULATORY STANDARDS AND CRITERIA
9
10
10
12
12
12
12
12
12
16
16
19
20
V11
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TABLE OF CONTENTS
Page
6. ?ISK ASSESSMENT 22
'>.!. SUBCHRONIC REFERENCE DOSE (RfDs) 22
'>.2. REFERENCE OOSE (RfD) 22
i>.3. CARCINOGENIC POTENCY (q-,*) 22
6.3.1. Oral 22
6.3.2. Inhalation 22
7. REFERENCES 25
APPENDIX: Summary Table for Chloroform 36
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LIST OF TABLES
No. Title Page
3-1 Subchronlc ToxUHy of Chloroform 6
4-1 Oral Bloassays of Chloroform Carclnogenldty 13
4-2 Kidney Tumors 1n Male Osborne-Mendel Rats Exposed to
Chloroform 1n Drinking Water for 104 Weeks 17
1x
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LIST OF ABBREVIATIONS
ADI
ATP
bw
CAS
CS
OENA
DNA
GGTase
LOAEL
ppm
RfD
RfDj
RfD0
RfDs
SGOT
SGPT
STEL
TLV
TWA
Acceptable dally Intake
Adenoslne trlphosphate
Body weight
Chemical abstract service
Composite score
Dlethyl nltrosamlne
Deoxyrlbonuclelc acid
Gamma glutamyl transpeptldase
Soil sorptlon coefficient
Octanol/water partition coefficient
Lowest-observed-adverse-effect level
Parts per million
Reference dose
Inhalation reference dose
Oral reference dose
Subchronlc reference dose
Subchronlc Inhalation reference dose
Subchronlc oral reference dose
Serum glutamlc oxaloacetlc transamlnase
Serum glutamlc pyruvlc transamlnase
Short-term exposure limit
Threshold limit value
Time-weighted average
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Tre relevant physical and chemical properties and environmental fate of
chlorcform (CAS No. 67-66-3) are as follows:
Cremlcal class:
Mclecular weight:
Vipor pressure:
Meter solubility:
K(w:
Bloconcentratlon factor:
(1n blueglll, Lepomls macrochlrus)
Helf-Hves 1n
air:
water:
halogenated aliphatic hydrocarbon
(purgeable halocarbon)
119.38 (Callahan et al., 1979)
150.5 mm Hg at 20°C
(Callahan et al., 1979)
8200 mg/i at 20°C
(Callahan et al., 1979)
93 (Callahan et al., 1979)
0-40 (Hutzler et al., 1983)
6 (Barrows et al., 1978)
70-79 days
(Atkinson, 1985; NLM, 1987)
0.3-3 days In rivers
3-30 days 1n lakes
(Zoeteman et al., 1980)
V( Utilization Is the primary fate process for chloroform In water
because of the relatively high vapor pressure {NLM, 1987). Adsorption to
susperded solids and sediments and bloaccumulatlon In aquatic organisms will
not bt significant {NLM. 1987).
Be half-life of chloroform In soil could not be located 1n the litera-
ture ;earched; however, evaporation Is expected to be the predominant loss
mechaMsm from the soil surface. The half-life for soil evaporation should
be longer than Its evaporation half-life from water. This compound 1s
hlghlj mobile 1n most soils, especially those with high organic carbon
contert, {Hutzler et al., 1983) and In subsurface soil 1t 1s expected to
001 OH
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01/15/88
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remaU stable enough to leach Into groundwater (NLH, 1987). Upon
contanlnatton of groundwater, chloroform Is likely to persist for long
periods of time (no degradation was observed when Incubated with aquifer
mater al for 27 weeks) (Wilson et al., 1983).
In the atmosphere, reaction with photochemically generated hydroxyl
radicals will be the predominant removal mechanism (NLM, 1987). Based on a
tropoipheMc to stratospheric turnover time of 30 years and a half-life of
70-79 days, <1X of the tropospherlc chloroform 1s expected to diffuse Into
the itratosphere (Callahan et al., 1979; Atkinson. 1985; NLH, 1987).
Chloriform Is expected to be transported long distances from Its emission
sources based on the relatively slow rate of degradation In air.
00101!
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01/20/88
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Evidence from human assays (Fry et al., 1972), as well as from animal
experiments (Brown et al., 1974; Taylor et al., 1974), Indicates that
Ingested chloroform Is absorbed nearly completely from the gastrointestinal
tract, Brown et al. (1974) orally administered a 60 mg/kg dose of
14C-ciloroform to mice, rats and squirrel monkeys and recovered 93-98% of
the administered dose of radioactivity In the expired air, urine and carcass
48 hours after treatment. That gastrointestinal absorption was rapid as
well as extensive was further Indicated by the observation that peak blood
levels of radioactivity occurred at 1 hour In the mice and monkeys. In man,
peak levels of 13C 1n the blood occurred 1 hour after an oral 500 mg dose
of "^-chloroform In olive oil by gelatin capsule (Fry et al., 1972).
Wlthey et al. (1982) administered a 75 mg/kg dose of chloroform In ~4
ml of water or corn oil to mature fasted rats to Investigate the effect of
vehicle on gastrointestinal absorption. The times to Initial peak blood
concentrations were nearly equivalent at 5.6 minutes for water and 6.0
minutes for corn oil. A second peak 1n blood concentration occurred at 40
minutes for corn oil-treated rats. The postabsorptlon peak blood concen-
tration was 39.3 vg/mi when administered In water and 5.9 tig/mi when
administered In corn oil, and the area under the blood concentration curves
was li.7 times greater for water than for corn oil, which suggests that the
large volume (for a rat) of corn oil substantially slowed gastrointestinal
absorption.
2.2. INHALATION
Hthout providing documentation, U.S. EPA (1980a) stated that 49-77% of
the chloroform present In Inspired air 1s absorbed by the respiratory tract,
presimably In humans.
OOlOt
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01/15/88
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U.S. EPA (1985) reviewed pulmonary retention data from humans during the
use cf chloroform as an anesthetic (Lehmann and Hasegawa, 1910; Smith et
al., 1973). Pulmonary retention, estimated by measuring the difference
between Inhaled and exhaled concentrations of chloroform and by measuring
respl -atory rate, was observed to decrease as duration of exposure
Increased. U.S. EPA (1985) estimated retention at equilibrium at -65-67%.
It w
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3. TOXICITY IN HUHANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
Table 3-1 presents a summary of the effects of subchronlc chloroform
exposure.
3.1.1. Oral. DeSalva et al. (1975) reported that chloroform at dose
level; of 1.0 and 2.5 mg/kg/day for 1 year produced no effects on the
functioning of the human liver and kidney.
N> effects In rats were reported at dose levels of 15 and 30 mg/kg/day
(Palmar et al., 1979); however, Increased relative liver and kidney weight
was cnserved at 150 mg/kg/day, and severe toxic effects, such as necrosis of
the "Iver and dysfunction of the gonads were produced at 410 mg/kg/day
(Palmur et al., 1979).
Ii an experiment to Investigate the effect of vehicle on the hepato-
toxicity of chloroform In mice. Bull et al. (1986) administered chloroform
In corn oil or 2% Emulphor to groups of 9-10 male and 9-10 female B6C3F1
mice at 0, 60, 130 or 270 mg/kg/day for 91-94 consecutive days. In male
mice, chloroform Increased liver weights when given In corn oil but not when
given In Emulphor. Chloroform In either vehicle Increased the liver weights
of female mice, but the effect was greater with corn oil. Elevated SGOT
occur-ed In a dose-related manner 1n both sexes, but only when the vehicle
was (orn oil. Upon hlstopathologlc examination, fatty degeneration was
obser'ed 1n chloroform-treated groups with the corn oil vehicle. At 270
mg/kg/day, the hepatic architecture was disrupted severely and early cirrho-
sis wis evident. These lesions were not observed In corn oil controls or 1n
mice treated with chloroform In Emulphor. Minimal to mild focal necrosis
was tie only lesion observed In mice treated with chloroform In Emulphor.
0010H -5- 01/20/88
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The Investigators concluded that the vehicle strongly Influences the
hepatitoxUlty of chloroform 1n mice and that the difference In vehicle may
explain the markedly different results observed 1n cancer studies In mice
when nearly equivalent total doses were given In corn oil (NCI, 1976) or
drinking water (Jorgenson et al., 1985) (Chapter 4).
3.1.2. Inhalation. Torkelson et al. (1976) exposed rats, guinea pigs and
rabbits to 25, 50 or 85 ppm (122, 244 or 415 mg/m3, respectively), 7
hours/day, 5 days/week for 6 months (see Table 3-1). Exposure to 25 ppm
chloroform produced hlstopathologlcal changes In the livers and kidneys of
male but not female rats. At higher doses, lobular granular degeneration
and :ocal necrosis were Increased In the liver, and cloudy swelling of
epithelial cells was Increased In the kidney. These changes were reported
to b? reversible after 6 weeks. Hematologlcal, clinical chemistry and
urlnalysls values were "within normal limits." The results obtained from
chloroform exposure In guinea pigs and rabbits are difficult to Interpret
becaise adverse effects were seen at the low-dose (25 ppm) and high-dose (85
ppm) levels, but no effects were reported at the Intermediate-dose level
(50 fpm).
3.2. CHRONIC
3.2.1. Oral. Several chronic oral studies (NCI, 1976; Palmer et al.,
1979; Roe et al., 1979) were designed to test the cardnogenlclty of chloro-
form (Chapter 4). Depression of body weight was observed at chloroform
dose: >60 mg/kg/day In rats (NCI, 1976; Palmer et al., 1979) and mice (Roe
et al., 1979). Palmer et al. (1979) exposed Sprague-Dawley rats of both
sexei to 60 mg/kg/day of chloroform In a toothpaste base for 80 weeks
followed by 15 weeks of observation. Decreased relative liver weight and
plasna chollnesterase levels were reported In female rats (Palmer et al.,
1979 . Rats of both sexes survived better than the controls, though both
001011 -7- 01/15/88
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groups had a high Incidence of non-neoplast1c respiratory and renal
disease. There were no treatment-related effects on the Incidence of liver
or kMney tumors following treatment of 60 mg/kg/day for 80 weeks. Although
hlsto oglcally - malignant mammary tumors were reported more In treated than
In ccntrol female rats, the difference was not statistically significant
(Palmi-r et al., 1979). Higher chloroform doses (90 and 180 mg/kg/day, 5
days/ueek for 78 weeks) resulted 1n an Increased Incidence of noncancerous
respiratory diseases In rats (NCI, 1976), and a gavage dose of 477 mg/kg/day
for 71! weeks resulted In decreased survival 1n female mice (NCI, 1976).
Hnywood et al. (1979) administered chloroform In a toothpaste base In
gelat n capsules at 15 or 30 mg/kg/day, 6 days/week for 7.5 years to groups
of e1 }ht male and eight female beagle dogs. A control group of 16 dogs/sex
was maintained. Fatty cysts developed 1n the livers of some dogs In each of
the treated groups, and was considered to be treatment-related. SGPT and
other serum enzyme Indicators of liver damage were elevated In a
dose-ielated fashion.
Clironlc exposure of humans to chloroform appears to result In adverse
effec-s on the central nervous system (NIOSH, 1974), although there are no
data )n the dose relation of the effects. In addition, chloroform affects
the liver and kidneys In humans (NIOSH, 1974). The potential for chronic
human oral exposure to chloroform has Increased because of the widespread
pract ce of chlorinating drinking water (U.S. EPA, 1980a).
3.2.2 Inhalation. Epldemlologlcal studies of humans exposed to chloro-
form in the workplace at levels ranging from 22-237 ppm have Indicated that
tiredness, depression, gastrointestinal disturbances (e.g., flatulence,
nausei), headache and frequent and scalding urination are the primary
symptoms (Challen et al., 1958; Bomskl et al. 1967). Regarding long-term
effeds, Challen et al. (1958) reported that there was no evidence of
0010H
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01/20/88
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organic lesions attributable to chloroform, based on physical exams and
liver function tests. Bomskl et al. (1967) reported that chloroform
exposjre at levels as low as 2 ppm for 1-4 years may result In an Increased
Incidence of toxic hepatitis, splenomegaly and hepatomegaly, although no
statistical analysis and adequate controls were presented.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Thompson et al. (1974) performed oral range-finding and
developmental toxlclty studies where Sprague-Dawley rats and Dutch-Belted
rabbi .s were used. In the range-finding study, groups of six rats were
treated by gavage with 79, 126, 300, 316 or 516 mg/kg/day of chloroform 1n
corn )11 on days 6-15 of gestation. Maternal toxlclty was observed at >126
mg/kg/'day and fetotoxldty was observed at >316 mg/kg/day. In the defini-
tive study, groups of 25 rats were treated with 20, 50 or 126 mg/kg/day.
Materral toxlclty was observed at >50 mg/kg/day, but no adverse develop-
menta" effects were reported at any level. The range-finding study used
groups of five rabbits and doses of 25, 63, 100, 159, 251 or 398 mg/kg/day
on da/s 6-18 of gestation; maternal toxlclty was observed at all dosage
levels. In the two dams that survived at 100 mg/kg/day one had four
resorptlons and the other was not pregnant. The definitive rabbit study was
performed with groups of 15 rabbits treated with at 20, 35 and 50
mg/kg/day. Reduced maternal body weight was observed at 35 but not at 50
mg/kg/day and reduced fetal body weight was observed at 35 but not at 20 or
50 mgAg/day.
RuJdlck et al. (1983) administered chloroform at 100, 200 or 400 mg/kg/
day to groups of 15 mated Sprague-Dawley rats on days 6-15 of gestation. A
dose-related decrease 1n maternal body weight gain was observed at all
dosage levels, while fetal body weight was decreased only at 400 mg/kg/day.
0010H -9- 01/20/88
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This group also had a higher Incidence of sternebral anomalies and fetal
runts
Palmer et al (1979) performed a study In which Sprague-Oawley rats were
given dally gavage doses of 0, 15. 30, 150 and 410 mg/kg/day of chloroform
1n toothpaste (10 of each sex per dose level) for 13 weeks and observed
gonad.il atrophy In both sexes treated with 410 mg/kg/day.
Burkhalter and Balster (1979) Investigated the effects of chloroform at
31.1 ng/kg/day on behavior In developing ICR mice. Mice were treated from
21 dafs before mating until 21 days after birth. The offspring were treated
on da/s 7-21 of age. Treatment had no effect on Utter size, but offspring
body weights were reduced. There was no definite effect of treatment on the
behav or of the offspring.
3.3.2 Inhalation. Schwetz et al. (1974) exposed groups of 20 female
Sprague-Dawley rats to chloroform at 30, 100 or 300 ppm (146, 488 or 1465
mg/m3 , 7 hours/day on gestation days 6-15. Maternal toxlclty, manifested
as derreased maternal weight gain, occurred In all exposed groups. Reduced
fetal crown-rump length was observed at 30 and 300 ppm but not at 100 ppm.
Severo teratogenlc effects were observed at >100 ppm. Fetal resorptlon was
great y Increased at 300 ppm. Murray et al. (1979) exposed groups of mated
CF-1 nice to chloroform at 100 ppm, 7 hours/day on days 6-15 of gestation.
Other groups of mice were exposed to 100 ppm, 7 hours/day on days 1-7 or
8-15 of gestation. Effects reported during one or more of the three periods
of exposure Include Increased resorptlons/Htter, decreased fetal body
weigh, and crown-rump length, delayed skeletal ossification. Increased Inci-
dence of cleft palate and maternal toxldty manifested as reduced rate of
body weight gain and Increased liver weight.
001 OH
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01/15/88
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3.4. TOXICANT INTERACTIONS
Tlie toxlclty of chloroform 1s greatly Influenced by anything that alters
m1cro;omal enzyme activity or hepatic GSH levels (U.S. EPA, 1985). The
substmces that potentiate the toxic effects of chloroform are methyl
n-butfl ketone (Branchflower and Pohl, 1981), alcohol (Kutob and Plaa,
1961), carbon tetrachlorlde (Harris et al., 1982), chlordecone (I1J1ma et
al., 1983), ODT and phenobarbltal (McLean, 1970). Methyl n-butyl ketone
Increases the toxlclty of chloroform by lowering glutathlone levels and by
Increasing the levels of hepatic cytochrome P-450 (which, In turn, Increases
the netabollsm of chloroform to phosgene) and by decreasing GSH levels
(Bran:hflower and Pohl, 1981). Harris et al. (1982) reported that carbon
tetrachlorlde potentiated the toxic effects of chloroform because of
Increased phosgene formation and the Initiation of llpld peroxldatlon. The
mechanism of Interaction for alcohol, chlordecone, DDT and phenobarbltal was
not Jlscussed. von Oettlngen (1964) reported that high-fat/low-protein
diets potentiated the hepatotoxlc effects of chloroform In animals.
00101
-11-
01/20/88
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4. CARCINOSENICITY
4.1. HUMAN DATA
4.1.1. Oral. Although chloroform has not unequivocally been shown to
cause human cancer, ecological and case control studies (Alavanja et a!.,
1978; Cantor et al., 1978; Brennlman et al., 1978; Hogan et al.( 1979;
Struba, 1979; Gottlieb et al., 1981; Young et al,, 1981) have consistently
supported the association of Increased risk of bladder, colon and rectal
cancer with oral exposure to chlorinated drinking water (U.S. EPA, 1983) In
which trlhalomethanes and chloroform are the contaminants present 1n
greatest quantities. A detailed description of these studies and their
strengths and weaknesses Is available 1n U.S. EPA (1985).
4.1.2. Inhalation. Pertinent data regarding an association between
chloroform Inhalation and an Increased Incidence or risk of cancer were not
located In the available literature.
4.2. BIOASSAYS
4.2.1. Oral. Table 4-1 summarizes the available data from several early
gavace bloassays of chloroform carclnogenldty. Eschenbrenner and Miller
(1945) reported that a dose level of chloroform that caused hepatic necrosis
when given once would cause hepatic carcinoma when given repeatedly. The
NCI |1976) found a dose-related Increase 1n hepatomas 1n both sexes when
mice received chloroform In corn oil by gavage, and an Increase 1n renal
eplttellal tumors In male rats receiving chloroform In corn oil by gavage
(see Table 4-1). The Increased Incidence of hepatic and renal tumors was
statistically significant (p<0.05). Palmer et al. (1979) criticized the NCI
(1974) study because rats being treated with other volatile carcinogenic
substances were housed In the same room as the chloroform-treated rats.
0010* -12- 04/12/88
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Because chloroform has been a contaminant 1n toothpaste, rats {Palmer et
al., 1979), mice (Roe et al., 1979) and dogs (Heywood et al, 1973) were
treated with chloroform In a toothpaste base Including essential oils as
flavo' components. Range-finding studies were performed 1n all experiments.
No effects at dose levels of 15, 75 and 165 mg/kg/day for 52 weeks were
reported 1n rats. When female rats were treated with 60 mg/kg/day for 96
weeks, however, there was an Increase (p=0.056) 1n malignant mammary gland
tumor> In the chloroform-treated group, although the untreated group
devel>ped benign mammary tumors (Palmer et al., 1979). There was an
Increjsed Incidence of kidney tumors In the high-dose (60 mg/kg/day) level
In male mice (Roe et al., 1979). The females had no Increased Incidence of
cance-, but there appeared to be some confounding Influence because of the
vehicle. The authors addressed, but did not resolve, the problem of the
effect produced by different vehicles (Roe et al., 1979).
Rjcent studies Indicate that chloroform Is carcinogenic to rats and mice
when administered In drinking water. Tumasonls et al. (1985) provided
group; of 32 male and 45 female Hlstar rats with drinking water containing
chlorjform for lifetime. The Initial concentration, 2.9 g/B. (2900 ppm),
was reduced by one-half after 72 weeks to maintain a fairly constant Intake
of cliloroform because water consumption had Increased. The dosage of
chlorjform Is estimated at -200 mg/kg/day for both sexes, based on graphic
data provided by the Investigators. Controls consisted of 28 male and 22
femal? rats provided with tap water. Treated rats weighed substantially
less than their sex-matched controls throughout the experiment. Survival
appea-ed not to be affected by treatment. The most noteworthy observation
was a significantly Increased Incidence of neoplastlc nodules In the liver
of female rats, 10/40 compared with 0/18 In controls (p<0.03).
0010H -15- 04/12/88
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Jorgenson et al. (1985) provided drinking water containing chloroform at
0, 2dQ, 400, 900 or 1800 mg/i (ppm) to groups of male Osborne-Mendel rats
and female B6C3F1 mice for 104 weeks. Because water consumption 1s reduced
with high concentrations of chloroform, a matched control group was provided
water 1n amount to match the consumption of the high-dose groups. For rats,
group sizes were 330 for controls and 200 ppm, 150 at 400 ppm and 50 for
matched controls, 900 and 1800 ppm. Group sizes for mice were Identical to
rats, except that the control and 200 ppm groups contained 430 mice.
Survival of mice appeared to be unaffected by treatment. Treated rats
survived longer than controls, attributed by the Investigators to the fact
that treated animals were leaner because of decreased water and food
Intake. Several tumor types occurred 1n rats at a significantly Increased
Indcence, but only kidney tumors, which occurred 1n a dose-related manner,
were attributed to treatment with chloroform. The Incidence of kidney
tumors In the rats 1s presented In Table 4-2. No tumor type occurred In
fema'e mice at a significantly greater Incidence In treated groups than 1n
controls.
4.2.!. Inhalation. Pertinent data regarding the carclnogenlclty of
Inha ed chloroform were not located 1n the available literature.
4.3. OTHER RELEVANT DATA
(hloroform was not mutagenlc 1n Escher1ch1a coll strains K12, WP2p and
HP2uvrA"p or 1n Salmonella typh1mur1um strains TA98, TA100, TA1535, TA1537
and "A1538 (Klrkland et al., 1981) with or without S-9 metabolic activation.
Chloioform was not mutagenlc 1n cultured Chinese hamster lung flbroblasts at
the 3-azaguan1ne locus (Sturrock, 1977), nor did chloroform Increase sister
chronatld exchanges In cultured Chinese hamster ovary cells or human lympho-
cyte: (White et al., 1979; Uehleke et al., 1977). In a recent experiment 1n
0010II -16- 04/12/88
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which chloroform was used at a higher concentration, chloroform Induced
sister chromatld exchange In cultivated human lymphocytes (HoMmoto and
Koizumi, 1983). Chloroform was reported to be weakly positive or "sugges-
tive" In mutagenlcHy assays 1n Saccharomyces cerevlslae D7 1n the presence
of S-9 metabolic activation, and In the Induction of murlne sperm head
abnormalities (Agustln and Llm-Syllanco, 1978; Callen et al., 1980; Land et
al., 1981; Topham, 1980; Gocke et al., 1981).
Several authors have Investigated the mechanism for chloroform-Induced
cardnogenlclty In laboratory animals. ReHz et al. (1982) measured DNA
alkylatlon and repair and cellular regeneration In male B6C3F1 mice given
single 15, 60 or 240 mg/kg oral doses of chloroform. DNA alkylatlon,
estlnated as ymol of bound chloroform/mo 1 of DNA, was 1.5, compared with
6000-7430 vmol/mol for dlmethylnUrosamlne, a known genotoxlc carcinogen.
Uslnc a technique Involving Incorporation of 3H-thym1d1ne Into DNA
follcwlng treatment with hydroxyurea sufficient to depress normal DNA
syntresls, these Investigators determined that chloroform did not Induce DNA
repa'r In the livers of treated mice. Cellular regeneration, estimated by
3H-trym1d1ne Incorporation Into DNA 1n nonhydroxyurea-treated mice, was
Increased 14-fold In the liver and 25-fold 1n the kidneys of
chloroform-treated mice. The authors concluded that cardnogenlclty
associated with chloroform was due to cellular necrosis rather than to DNA
damace.
!n Initiation-promotion experiments with male Sprague-Dawley rats,
Pere'ra et al. (1982) determined that chloroform did not Initiate the
deve opment of G6Tase-pos1t1ve fod In the livers of rats promoted with
phenobarbltal, and the results concerning the promoting activity In rats
pretr eated with dlethylnUrosamlne (DENA), was not conclusive. Demi and
00101!
-18-
04/12/88
-------
Oesterle (1985), however, reported that chloroform promoted the development
of DENA-lnduced ATPase deficient foci and GGTase-pos1t1ve foci 1n the Hvers
of fenale Sprague-Dawley rats.
Klaunlg et al. (1986) provided chloroform 1n drinking water for 52 weeks
to mile B6C3F1 mice that were treated with DENA 1n drinking water for 4
weeks to Initiate tumor formation. Neither DENA nor chloroform alone
Increased the Incidence of tumors, but chloroform Inhibited liver and lung
tumorlgenesls In the DENA-lnltlated mice.
4.4. WEIGHT OF EVIDENCE
Cral exposure to chloroform has caused hepatic carcinomas In male and
female B6C3F1 mice (NCI, 1976), renal carcinomas and adenomas In male
Osborne-Hendel rats (NCI, 1976; Jorgenson et al., 1985) and 1n male ICI mice
(Roe et al., 1979), thyroid tumors In female Osborne-Mendel rats (NCI. 1976)
and
-------
5. REGULATORY STANDARDS AND CRITERIA
Tie ACGIH (1986a,b) recommends a TWA-TLV of 10 ppm (50 mg/m3) for
occupational exposure to chloroform and also notes that chloroform has
Induced cancer In animals by the oral route at high and Intermediate dose
levels and Is a suspected carcinogen for humans. OSHA (1985) has set a
celHig limit for chloroform of 50 ppm (240 mg/m3) 1n the workroom
atmosshere.
U.S. EPA (1987a) reports an RfD for oral exposure to chloroform of
1x10"z mg/kg/day or 1 mg/day for a 70 kg human, based on the development
of fatty cysts In the livers of dogs treated with 15 mg/kg/day, 6 days/week
for 7.5 years (Heywood et al., 1979).
Tie Carcinogen Assessment Group (U.S. EPA, 1985) analyzed the following
data: liver tumors In female mice (NCI, 1976); liver tumors In male mice
(NCI, 1976); kidney tumors In male rats (NCI, 1976; Jorgenson et al., 1985);
and kidney tumors In male mice (Roe et al., 1979). The largest estimates of
carcinogenic potency were derived from the liver tumor data 1n male and
femal; mice 1n the NCI (1976) gavage study. A q^ of S.lxlO'2
{mg/kg/day)'1 was derived as the geometric mean of the q,*s derived
separately for male and female mice. A complete discussion of this deriva-
tion 1s presented In U.S. EPA (1985). More recently, the CRAVE work group
(U.S. EPA, 1987b) recommended that the q * for oral exposure via drinking
water be based upon the drinking water study by Jorgenson et al. (1985).
The Jorgenson study was Included 1n the Health Assessment Document for
Chlooform (U.S. EPAS, 1985) but was not selected as the primary basis for
drinking water risk estimation. Given the CRAVE action (U.S. EPA, 1987b).
the \gency now uses the q,* value of 6.1xlO~3 (mg/kg/day)"1 based on
001 OH
-20-
04/12/88
-------
the Incidence of kidney tumors 1n male rats 1n the study by Oorgenson et al.
(1985). The upper bound estimate of cancer risk for exposure to 1 ^g/L of
chloroform 1n water 1s 1.7xlO~7.
Islng q-j* of 8.1xlO~a (mg/kg/day)'1, EPA (1985) calculated
upper-bound estimates of cancer risk for exposure to 1 ug/m3 In air to
be >.3xlO~5. This q,* for Inhalation exposure to chloroform was
vallcated by the CRAVE work group on August 26, 1987 (EPA, 1987).
00101 -21- 04/12/88
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfD$)
Chloroform 1s known to be carcinogenic to animals and Is suspected of
being carcinogenic to humans. Data are sufficient for derivation of a
q *; therefore. It 1s Inappropriate to derive an RfO_ for this chemical.
6.2. REFERENCE DOSE (RfD)
Chloroform 1s known to be carcinogenic to animals and 1s suspected of
being carcinogenic to humans. Data are sufficient for derivation of a
q *; therefore, 1t Is Inappropriate to derive an RfD for this chemical.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. The CRAVE work group (EPA, 1987) validated a q.,* of
6.1xlQ~3 (mg/kg/day)"1 based on the Incidence of kidney tumors In male
rats exposed In drinking water 1n the study by Jorgenson et al. (1985). The
upper bound estimate of cancer risk for exposure to 1 ^g/L of chloroform
In water 1s 1.7xlO~7.
In this reevaluatlon, H was concluded that oral exposure 1n the drink-
Ing water approximated potential human exposure more appropriately than did
gavace exposure using an oil vehicle. For this reason, the Jorgenson et al.
(1985) study was selected as the basis for potency estimation as compared to
a previous estimate which utilized data from NCI (1976) as the basis.
6.3.2. Inhalation. Data regarding the carclnogenlclty of Inhaled
chloroform 1n humans and animals were not available. Studies 1n animals
Indicate that chloroform Is carcinogenic by the oral route. NCI (1976)
founc dose-related Increased Incidences of hepatocellular carcinoma In male
and :emale mice treated by gavage at time-weighted average (TWA) doses of
>138 mg/kg/day 6 days/week for 78 weeks, and a dose-related Increased
Inclcence of kidney epithelial tumors In male rats similarly treated by
00101-
-22-
04/12/88
-------
gavage at 90 and 180 mg/kg/day. Roe et al. (1979) found an Increased
Incidence of kidney epithelial tumors 1n male mice given 60 mg/kg/day 6
days/week for 78 weeks. Dose-related Increased Incidences of renal tubular
cell adenomas and/or carcinomas were found In male rats treated with chloro-
form 1n the drinking water at levels equivalent to dosages >38 mg/kg/day for
104 veeks (Jorgenson et al., 1985).
Ihe U.S. EPA (1985a) considered these five data sets In determining the
q.* :or chloroform. The five data sets were as follows: 1) liver tumors
In fjmale mice (NCI, 1976), 2) liver tumors 1n male mice (NCI, 1976), 3)
kidney tumors In male rats (NCI, 1976), 4) kidney tumors 1n male mice (Roe
et ai., 1979), and 5) kidney tumors In male rats (Jorgenson et al., 1985).
U.S. EPA (1985a) used available pharmacoklnetic data to calculate an
effective dose for these studies, assuming that the amount metabolized to
read We metabolites Is the gavage dose minus the amount excreted
unchanged. For mice given 60 mg/kg, as 1n the Roe et al. (1979) study, the
correction was 6%. for rats at the same dosage, It was 20%. In the NCI
(197t) study In which rats and mice received doses of -200-500 mg/kg/day, a
20% :orrect1on was considered conservative and would probably overestimate
the amount metabolized from these doses. U.S. EPA (1985a) used these
correction factors to reduce the administered dose by the unmetabollzed
port1 on (6% 1n mice and 20% In rats when given as a bolus by gavage 1n corn
oil, 0% when administered In drinking water). Doses were also corrected for
differences between animal and human pharmacoklnetlcs by using a surface
area correction. Using these corrected doses, maximum likelihood estimates
of tie parameters of the multistage model were calculated for each of the
five data sets. U.S. EPA (1985a) chose the mouse liver tumor data from the
NCI 11976) study as the basis of the potency factor for Inhalation exposure
OOlOli
-23-
04/12/88
-------
to chloroform. The NCI (1976) study Is considered to be appropriate for use
In the Inhalation risk estimate because there were no Inhalation cancer
bloassays and no pharmacoklnetlc data to contralndlcate the use of gavage
data (U.S. EPA, 1987b). The geometric mean of the estimates for male and
female mice 1n the NCI (1976) study, 8.1x10~2 (mg/kg/day)'1, was
recontnended as the Inhalation q * for chloroform. U.S. EPA (1985a)
combined the estimates for both data sets because the data for males
Included observations at a lower dose, which appeared to be consistent with
the :emale data. U.S. EPA (1985a) noted that the recommended q * was
similar to the geometric mean calculated from all five estimates and was
also similar to the estimate calculated 1f data for both sexes of B6C3F1
mice 1n the NCI (1976) study were pooled. Using q * of S.lxlO"2
(ing/kg/day)"1, U.S. EPA (1985) calculated upper-bound estimates of cancer
risk for exposure to 1 »q/ma 1n air to be 2.3xlO~5. This q * for
Inhalation exposure to chloroform was validated by the CRAVE work group on
August 26, 1987 (U.S. EPA, 1987b).
001 OH
-24-
04/12/88
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7. REFERENCES
AC6IH (American Conference of Governmental Industrial Hyglenlsts). 1986a.
Threslold Limit Values for Chemical Substances and Physical Agents 1n the
Workroom Environment. Cincinnati, OH. p. 13.
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986b.
Documentation of the threshold limit values and biological exposure Indices,
5th e«l. Cincinnati, OH. p. 130-131.
Agust n, J.S. and C.Y. L1m-Syl1anco. 1978. Mutagenlc and clastogenlc
effee ;s of chloroform. Bull. Philadelphia Blochem. Soc. 1: 17-23. (Cited
In U.S. EPA, 1982)
Alavaija, H., I. Goldstein and M. Susser. 1978. A case control study of
gastrointestinal and urinary tract cancer mortality and drinking water
chlor(nation. in: Water Chlorlnatlon: Environmental Impact and Health
Effecis, Vol. 2, R.L. Jolley, H. Gorchey and D.H. Hamilton, Jr., Ed. Ann
Arbor Science Publishers, Ann Arbor, MI. p. 394-409. (Cited In U.S. EPA,
1983)
Atkinson, R. 1985. Kinetics and mechanisms of the gas-phase reactions of
hydro
-------
Bomsk , H.. A. Sobolweska and A. Strakowskl. 1967. Toxic damage of the
liver by chloroform In chemical Industry workers. Arch. Gewerbepathol.
Gewerhehy. 24: 127-134. (Ger.) (CHed 1n U.S. EPA, 1982)
Brancliflower, R.V. and L.R. Pohl. 1981. Investigation of the mechanism of
the p)tent1at1on of chloroform-induced hepatotoxlclty and nephrotoxldty by
methy n-butyl ketone. Toxkol. Appl. Pharmacol. 16(3): 407-413.
Brenn man, G.R., J. Vasllomanolakls-Lagos, J. Amsel, T. Namekata and A.H.
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001 OH
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001 OH
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001 OH
-35-
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