TECHNICAL REPORT DATA
fftffte rttd instructions on the reverse be fort compliant)
1. REPORT NO.
EPA-/600/8-88/059
3. RECIPIENT'S ACCESSION NO
PB88-176375
4. TITLE AND SUBTITLE
Health Effects Assessment for Trihalogenated Methanes
6. REPORT DATE
s. PERFORMING ORGANIZATION CODE
7 AUTHOR(S)
i. PERFORMING ORGANIZATION REPORT NO.
9. PERFORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
13. TYPE OF REPORT AND PERIOD COVERED
14. SPONSORING AGENCY CODE
EPA/600/22
15. SUPPLEMENTARY NOTES
16. ABSTRACT
This report summarizes and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses under Executive Order 32991 for decision-making under
CERCLA. All estimates of acceptable intakes and carcinogenic potency presented in
this document should be considered as preliminary and reflect limited resources
allocated to this project. The intent in these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. The interim values presented
reflect the relative degree of hazard associated with exposure or risk to the
chemical(s) addressed. Whenever possible, two categories of values have been
estimated for systemic toxicants (toxicants for which cancer is not the endpoint of
concern). The first, RfDs or subchronic 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. The RfD is an estimate of an exposure level that would not
be expected to cause adverse effects when exposure occurs for a significant portion
of the lifespan. For compounds for which there is sufficient evidence of
carcinogenicity, qi*s have been computed, if appropriate, based on oral and
inhalation data if available.
7.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b. IDENTIFIERS/OPEN ENDED TERMS C. COSATI Field/Group
8. DISTRIBUTION STATEMENT
Public
19. SECURITY CLASS (THu Report!
Unclassified
21. NO. OF PAGES
2O. SECURITY CLASS (This page!
Unclassified
22. PRICE
EPA Perm 2220-1 (fU*. 4-77) PACVIOU* COITION is OMOLKTC
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EPA/600/8-88/059
July, 1987
HEALTH EFFECTS ASSESSMENT
FOR TRIHALOGENATED METHANES
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
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DISCLAIMER
This document has been reviewed In accordance with the U.S.
Environmental Protection Agency's peer and administrative review policies
and approved for publication. Mention of trade names or commercial products
does not constitute endorsement 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 selected
trlhalogenated methanes. All estimates of acceptable Intakes and carcino-
genic potency presented In this document should be considered as preliminary
and reflect limited resources allocated to this project. Pertinent toxlco-
loglc and environmental data were located through on line literature
searches of the TOXLINE, CANCERLINE and the CHEMFATE/OATALOG data bases.
The basic literature searched supporting this document Is current up to May,
1985. Secondary sources of Information have also been relied upon In the
preparation 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:
U.S. EPA. 1980a. Ambient Hater Quality Criteria Document for
Halomethanes. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincin-
nati, OH for the Office of Water Regulations and Standards, Wash-
ington, DC. EPA 440/5-80-051. NTIS PB81-117624.
U.S. EPA. 1982. Errata for Ambient Water Quality Criteria
Document for Halomethanes. Prepared by the Office of Health and
Environmental Assessment, Environmental Criteria and Assessment
Office, Cincinnati, OH for the Office of Water Regulations and
Standards, Washington, DC.
U.S. EPA. 1983a. Reportable Quantity Document for Chlorodlbromo-
methane (Dlbromochloromethane). Prepared by the Office of Health
and Environmental Assessment, Environmental Criteria and Assessment
Office, Cincinnati, OH for the Office of Emergency and Remedial
Response, Washington, DC.
U.S. EPA. 1983b. Reportable Quantity Document for Trlbromomethane
(Bromoform). Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincin-
nati, OH for the Office of Emergency and Remedial Response, Wash-
ington, DC.
U.S. EPA. 1985. Health and Environmental Effects Profile for
Bromochloromethanes. Prepared by the Office of Health and Environ-
mental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Solid Waste and Emergency
Response, Washington, DC.
The Intent In these assessments Is to suggest acceptable exposure levels
for noncardnogens and risk cancer potency estimates for carcinogens
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited 1n
scope tending to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard or risk associated with exposure to the chemlcal(s) addressed.
111
-------
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer Is not the endpolnt of
concern). The first, RfD$ (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
Interval that does not constitute a significant portion of the Hfespan).
This type of exposure estimate has not been extensively used, or rigorously
defined, as previous risk assessment efforts have been primarily directed
towards exposures from toxicants 1n ambient air or water where lifetime
exposure 1s assumed. Animal data used for RFD$ estimates generally
Include exposures with durations of 30-90 days. Subchronlc human data are
rarely available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure. These
values are developed for both Inhalation (RfD$j) and oral (RfD$Q)
exposures.
The RfO (formerly AIC) Is similar In concept and addresses chronic
exposure. It Is an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the Hfespan [see U.S. EPA (1980a,b) for a discussion of this concept]. The
RfD Is route-specific and estimates acceptable exposure for either oral
(RfDrj) or Inhalation (RfDi) with the Implicit assumption that exposure
by other routes 1s Insignificant.
Composite scores (CSs) for noncardnogens 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).
For compounds for which there 1s sufficient evidence of carclnogenlclty
RfD$ and RfD values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980b). Since cancer 1s a
process that Is not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-|*s have been computed, 1f appro-
priate, based on oral and Inhalation data 1f available.
1v
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ABSTRACT
In order to place the risk assessment evaluation In proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate
Interpretation and use of the quantitative estimates presented.
In this document, quantitative risk assessments for three tMhalo-
methanes are reported. Only oral data were used In these assessments
because the Inhalation data were considered Inadequate. A 90-day drinking
water study In rats defined a NOAEL of 50 ppm (5.6 mg/kg/day) for bromoform
(Chu et al., 1982b). Higher doses caused an Increased Incidence and
Intensity of liver lesions. Using these data, RfD$o and RfDQ values of
0.056 and 0.0056 mg/kg/day (4.0 and 0.4 mg/day for a 70 kg human), respec-
tively, were calculated for bromoform.
All three trlhalomethanes have been tested for cardnogenlcHy by the
National Toxicology Program, but only the results of the bromodlchloro-
methane and chlorodlbromomethane studies are available. The chlorodlbromo-
methane study (NTP, 1985) provided no evidence of carclnogenUHy In F344/N
rats, equivocal evidence of cardnogenlcHy 1n male B6C3F1 mice, and some
evidence of cardnogenlcHy 1n female B6C3F1 mice. The data determined to
be most appropriate for risk assessment were those that showed a significant
dose-related Increase In combined Incidences of hepatocellular carcinomas or
adenomas In female mice. These data were used to calculate a human q-j* of
8.4xlO~a (mg/kg/dayr1 for chlorodlbromomethane.
The results of the bromodlchloromethane bloassay were available only as
a board draft report (NTP, 1986a), but the data provided "clear evidence" of
the cardnogenlcHy of this compound 1n rats and mice. Statistically
significant Increases In tumor Incidence occurred for tumors of the large
Intestine and kidneys In both sexes of F344/N rats, for kidney tumors In
male B6C3F1 mice, and liver tumors 1n female mice. NTP (1986a) noted that
the tumors of the large Intestine and kidney are uncommon 1n these strains
of rats and mice. The data for combined Incidence of hepatocellular
adenomas or carcinomas 1n female mice were selected to calculate a human
q-|* of l.SxlO'1 (mg/kg/day)'1 for bromodlchloromethane.
Because bromodlchloromethane and chlorodlbromomethane have been found to
be carcinogenic, and because bromoform has given positive results In muta-
genldty assays, the toxldty-based RfOgg and RfDQ values for bromoform
should be considered provisional pending release of the results from the NTP
(1986b) bromoform bloassay.
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ACKNOWLEDGEMENTS
The 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 OeRosa and Karen
Blackburn were the Technical Project Monitors and John Helms (Office of
Toxic Substances) was the Project Officer. The final documents In this
series were prepared for the Office of Emergency and Remedial Response,
Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of A1r 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:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by the
following:
Bette Zwayer, Jacky Bohanon and K1m Davidson
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
6.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1. ORAL
2.2. INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
3.2. CHRONIC
3.2.1. Oral
3.2.2. Inhalation
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral
3.3.2. Inhalation
3.4. TOXICANT INTERACTIONS. . . . .
CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral
4.1.2. Inhalation
4.2. BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
4.3. OTHER RELEVANT DATA
4.4. WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfDs)
6.1.1. Oral (RfDso)
6.1.2. Inhalation (RfDSi)
Page
. . . 1
4
. . . 4
4
. . . 5
. . . 5
. . . 5
. . . 9
. . . 9
. . . 9
. . . 10
11
. . . 11
. . . 12
12
14
, , 14
. . . 14
. . . 15
. . . 15
. . . 15
17
. . . 17
. . . 21
23
. , 24
... 24
... 24
... 24
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TABLE OF CONTENTS (cont.)
Page
6.2. REFERENCE DOSE (RfD) 25
6.2.1. Oral (RfD0) 25
6.2.2. Inhalation (RfDj) 26
6.3. CARCINOGENIC POTENCY (q-j*) 26
6.3.1. Oral 26
6.3.2. Inhalation 29
7. REFERENCES 30
APPENDIX A: Summary Table for Bromodlchloromethane 1n Female
B6C3F1 Mice 38
APPENDIX B: Summary Table for Bromoform 39
APPENDIX C: Summary Table for Chlorodlbromomethane In Female
B6C3F1 Mice 40
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LIST OF ABBREVIATIONS
ADI . Acceptable dally Intake
BCF Bloconcentratlon factor
BUN Blood urea nitrogen
CAS Chemical Abstract Service
CS Composite score
DMBA Dimethyl benzanthracene
MED Minimum effective dose
NOAEL No-observed-adverse-effect level
NOEL No-observed-effect level
ppm Parts per million
RfD Reference dose
RfOj Inhalation reference dose
RfOg Oral reference dose
RfD$ Subchronlc reference dose
RfD$j Subchronlc Inhalation reference dose
RfDso Subchronlc oral reference dose
RQ Reportable quantity
RV
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Selected physical and chemical properties and environmental fates of
bromodlchloromethane, chlorodlbromomethane and bromoform are presented In
Table 1-1.
Although the atmospheric half-lives of these chemicals resulting from
their reactions with HO radical are not known, they are expected to be <2
years, based on the half-lives of structurally similar halomethanes (Lyman
et al., 1982). Such long half-lives Indicate that significant transport of
these chemicals from troposphere to stratosphere will occur. Aquatic half-
lives for bromodlchloromethane, chlorodlbromomethane and bromoform are the
estimated volatilization half-lives based on published oxygen reaeratlon
values. The half-lives 1n lakes and ponds are expected to be shorter with
other removal processes such as photolysis, blodegradatlon and oxidation
contributing to the loss of these compounds (Tabak et al., 1981; Kaczmar et
al., 1984; Francois et al., 1979).
Based on the measured Henry's Law constant as well as the vapor
pressures listed, volatilization from both wet and dry soil surfaces should
be relatively rapid. .
0083h -1- 02/06/87
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
The U.S. EPA (1980a) reported that absorption of halomethanes can occur
by the gastrointestinal tract, but no specific details concerning the three
trlhalomethanes In this document were provided. Smith et al. (1985)
reported that gastrointestinal absorption of bromodlchloromethane was
"judged to be nearly complete" and fairly rapid 1n rhesus monkeys given an
oral dose of 10 mg/kg l4C-bromod1chloromethane. Peak blood levels of
radioactivity occurred at -4 hours after treatment. Cumulative excretion
from the feces accounted for only -0.06-1.65/4 of the dose of radioactivity
over a 24- to 72-hour period.
2.2. INHALATION
The U.S. EPA (1980a) reported that absorption of halomethanes by the
lungs Is "fairly efficient" and 1s of "primary Importance" relative to
gastrointestinal and dermal routes. No details concerning the trlhalo-
methanes discussed In this report were provided.
0083h -4- 02/06/87
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Chu et al. (1982b) conducted a 90-day study In which groups
of 20 male and 20 female Sprague-Dawley rats were exposed to 0, 5, 50, 500
or 2500 ppm of chlorodlbromomethane, bromodlchloromethane or bromoform In
their drinking water. After the 90-day exposure, half of the animals In
each group were sacrificed and the other half allowed to live for an addi-
tional 90-day recovery period. Bromodlchloromethane caused decreased food
consumption and weight gain at the highest dose level. Chlorodlbromomethane
and bromoform caused decreased food consumption and decreased lymphocyte
counts at 2500 ppm. The highest levels that caused no adverse effects 1n
this study were 5 ppm bromodlchloromethane, 5 ppm chlorodlbromomethane and
50 ppm bromoform. In all cases, higher doses caused mild hlstologlcal
effects, which were dose-related In Incidence and Intensity, 1n the liver
and thyroid. These effects were reversible and were not apparent 90 days
after the end of the exposure. As calculated by the U.S. EPA (1982) using
data provided by the primary author, these drinking water concentrations
correspond to male-female average doses of 0.56 mg/kg/day bromodlchloro-
methane, 0.515 mg/kg/day chlorodlbromomethane, and 5.6 mg/kg/day bromoform.
As stated by the U.S. EPA (1982), an average value was used to estimate a
more accurate animal NOAEL, since there were no major differences between
sexes In sensitivity to these compounds.
Chu et al. (1982a) conducted similar studies of shorter duration with
groups of 10 male SO rats exposed to 0, 5, 50 or 500 ppm of each trlhalo-
methane 1n drinking water for 28 days. No effects 1n terms of growth, food
Intake, hlstopathology, serum biochemical parameters, and hepatic mlcrosomal
0083h -5- 02/11/87
-------
enzyme activities were observed. A slight Increase In relative kidney
weight occurred In rats exposed to 500 ppm bromoform and 5 and 500 ppm
bromodlchloromethane.
The NTP (1985) conducted studies 1n which groups of 10 F344/N rats/sex
and 10 B6C3F1 mice/sex received 0, 15, 30, 60, 125 or 250 mg/kg chlorodl-
bromomethane by gavage 1n corn oil 5 days/week for 13 weeks. In rats, toxic
effects occurred only In the high-dose group and Included liver and kidney
lesions and mortality of 9/10 rats of each sex. No treatment-related deaths
occurred among the mice, but liver and kidney lesions were observed In
high-dose males.
The NTP (1986a) conducted 14-day and 13-week studies with F344-N rats
and B6C3F1 mice exposed to bromodlchloromethane. In the 14-day studies,
groups of five male and five female rats received oral doses of 38-600
mg/kg/day and equal numbers of mice 19-300 mg/kg/day. Decreased weight gain
occurred 1n rats of both sexes at 300 and 600 mg/kg/day. All male mice
receiving 150 and 300 mg/kg/day died. In the 13-week studies, groups of 10
rats/sex received oral doses of 19-300 mg/kg/day; groups of 10 male mice
received 6.25-100 mg/kg/day; and groups of 10 female mice received 25-400
mg/kg/day. Terminal body weights of rats at 150 and 300 mg/kg/day were
lower than vehicle controls. Hlstopathologlcal changes In the liver
occurred In rats at 300 mg/kg/day and female mice at 200 and 400 mg/kg/day.
Degeneration and necrosis of the kidneys occurred 1n male mice at 100
mg/kg/day and male rats at 300 mg/kg/day.
EG and G (1980) conducted 13-week gavage studies using Fischer 344 rats
and B6C3F1 mice (10/sex/specles) given bromoform at dosages of 12-400
mg/kg/day. Body weight gain depression >10% occurred In male mice at >50
mg/kg/day and 1n female mice at all doses. Fatty metamorphosis occurred In
0083h -6- 02/06/87
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the "Mvers of male mice at >200 mg/kg/day. Male rats had clear cell foci of
the liver at doses of 12 mg/kg/day and above. No compound-related lesions
were observed 1n females of either species.
Schuller et al. (1978) and Munson et al. (1978) studied the effects of
these three trlhalomethanes on humoral and cell-mediated Immunity. These
studies, however, were published only as abstracts and are difficult to
evaluate. In both studies, male and female ICR mice were treated with
gavage dosages of 0, 0.2-0.3, 12.5 or 125 mg/kg/day for 90 days. In the
Schuller et al. (1978) study, no compound affected liver function, kidney
function or hematologlcal parameters. Bromodlchloromethane at 125 mg/kg/day
depressed delayed hypersens1t1v1ty 1n males and females. Chlorodlbromo-
methane and bromoform had no such effect at any dosage. In the Munson et
al. (1978) study, all three compounds caused a "dose-dependent" suppression
of hepatic phagocytosis of L1ster1a monocytogenes 1n males and females.
Chlorodlbromomethane also Inhibited splenic phagocytosis In the 12.5 and 125
mg/kg/day male mice.
In a H-day gavage study (Condle et al., 1983), groups of 5-10 male CD-I
mice were exposed to bromodlchloromethane (0, 37, 74 and 148 mg/kg/day),
Chlorodlbromomethane (0, 37, 74 and 147 mg/kg/day), and bromoform (0, 72,
145 and 289 mg/kg/day). In the mice exposed to bromodlchloromethane, kidney
function was affected at 74 and 148 mg/kg/day. Clinical chemistry effects
and hlstopathologlcal effects on liver and kidneys also occurred at the
highest dose. Similar effects occurred 1n the mice exposed to Chlorodl-
bromomethane, but only at the highest dose level. In the mice exposed to
bromoform, effects on kidney function and hlstopathologlcal effects on liver
and kidneys occurred at the two highest doses. The highest NOAELs from
these experiments were 37 mg/kg/day bromodlchloromethane, 74 mg/kg/day
Chlorodlbromomethane and 72 mg/kg/day bromoform.
0083h -7- 02/06/87
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Munson et al. (1982) conducted a study 1n which groups of 7-12 CD-I mice
of each sex were exposed to one of the three tMhalomethanes by gavage for
14 days at dosages of 50, 125 or 250 mg/kg/day. Among the mice exposed to
bromodlchloromethane, high-dose mice experienced decreased body weight gain
and effects on clinical chemistry (SGOT, SGPT, BUN and glucose), hematologl-
cal parameters (flbrlnogen) and the Immune system. Middle- and high-dose
mice both had significantly Increased relative liver weights and decreased
spleen weights (females only). There were no differences between low-dose
mice (50 mg/kg/day) and controls 1n any of the parameters examined (body
weights, organ weights, clinical chemistry, hematology and humoral
Immunity). High-dose mice exposed to chlorodlbromomethane experienced
decreased body weight gain. Increased liver weights, decreased spleen
weights, decreased flbrlnogen concentrations, decreased serum glucose
levels, Increased SGOT and SGPT and effects on the Immune system. Middle-
dose mice also had Increased relative liver weights and Immune system
effects. There were no differences between low-dose mice and controls In
any of the parameters measured. Male mice exposed to bromoforro experienced
decreased body weight gain, Increased liver weight, and hematologlcal
effects at the middle and high doses. High-dose males and females also
experienced effects on clinical chemistry parameters and the Immune response
(males only). Once again, the 50 mg/kg/day dosage was a NOEL. H1stolog1cal
examinations of major organs were apparently not performed 1n this study.
Ounnlck et al. (1985) conducted a 13-week study 1n which male and female
Fischer 344/N rats and B6C3F1 mice received gavage doses of 0, 15, 30, 60,
125 and 250 mg/kg/day of chlorodlbromomethane. Unspecified hepatic and
renal toxlclxy occurred In high-dose male and female rats and male mice.
Mortality was Increased 1n high-dose male and female rats.
0083h -8- 02/06/87
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Balster et al. (1979) reported negative results 1n behavioral studies
with groups of eight mice receiving gavage doses of trlhalomethanes for 14
or 90 days. Swimming behavior was unaffected by doses of 1.2 or 11.6
mg/kg/day bromodlchloromethane, 1.0 or 10.0 mg/kg/day chlorodlbromomethane
and 0.9 or 9.2 mg/kg/day bromoform administered for 14 days. No motor
Impairment was evident at these dosages when they were administered for 90
days. Dosages of 100 mg/kg/day of each trlhalomethane administered for 30
days had no effect on a passive avoidance learning task. Balster and
Borzelleca (1982) found that operant behavior of mice was affected at 100
and 400 mg/kg/day bromodlchloromethane and bromoform and at 400 mg/kg/day
chlorodlbromomethane In a 60-day gavage study. The lowest dose tested was
10 mg/kg/day.
3.1.2. Inhalation. There 1s relatively little Information concerning the
toxlclty of these three trlhalomethanes by the Inhalation route. Dykan
(1962) reported that rats exposed to 25 ppm bromoform 4 hours/day for 2
months experienced effects on liver glycogenolysls and prothrombln synthesis.
3.2. CHRONIC
3.2.1. Oral. NTP (1985) and Ounnlck et al. (1985) reported results of an
oral chronic tox1c1ty/carc1nogen1dty study of chlorodlbromomethane using
rats and mice. In this study, groups of Fischer 344/N rats and B6C3F1 mice
(50/sex/spec1es) received doses of 0, 40 or 80 mg/kg/day (rats) or 0, 50 or
100 mg/kg/day (mice) by gavage In corn oil for 104 weeks. Fatty change and
cytoplasmlc changes occurred In the livers of treated male and female rats.
High-dose male rats also experienced decreased body weight gains. In the
mouse study, high-dose males had reduced survival relative to controls.
Treated males and high-dose females had reduced body weight gains. Treated
males had necrosis and hepatocytomegaly of the liver and nephrosls of the
0083h -9- 02/06/87
-------
kidney. Treated females also had calcification and fatty changes 1n the
liver. Results of this study pertaining to possible carc1nogen1c1ty of
chlorodlbromomethane are presented 1n Section 4.2.1.
NTP (1986a) treated groups of 50 rats/sex and 50 mice/sex with bromodl-
chloromethane 1n corn oil by gavage for 102 weeks: rats received 0, 50 or
100 mg/kg; male mice received 0, 25 or 50 mg/kg; female mice received 0, 75
or 150 mg/kg, 5 days/week. No compound-related clinical signs were observed
1n treated rats, but final body weights of high-dose males were 88% and
high-dose females were 79% of those of vehicle controls. There appeared to
be no effect on survival. The most significant nonneoplastlc lesions were
the presence of cytomegaly of the tubular epithelial cells of the kidney, a
slightly Increased Incidence of liver necrosis 1n both treated groups of
male rats and an Increased Incidence of fatty liver Infiltration In treated
rats of both sexes. No compound-related signs of toxlclty were observed In
treated mice, but high-dose females had final body weights 75% of those of
vehicle controls. No effects on body weight were observed 1n males or
low-dose females. Survival of male mice was not affected by treatment, but
both treated groups of females had survival significantly less than that of
vehicle controls, which was attributed primarily to the development of
ovarian abcesses. Both treated groups of male mice had cytomegaly of renal
tubular cells, an Increased Incidence of fatty changes of the liver and
high-dose male mice had an Increased Incidence of focal atrophy of the
testlcular tubules. An Increased Incidence of ovarian abcesses was observed
In both treated groups of female mice. Neoplastlc lesions are discussed In
Section 4.2.
3.2.2. Inhalation. Chronic Inhalation studies could not be located 1n
the available literature.
0083h -10- 02/11/87
-------
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Possible teratogenldty of the three trlhalomethanes was
Investigated by Ruddlck et al. (1983) who administered gavage doses of 0,
50, 100 or 200 mg/kg/day of each compound In corn oil to groups of 9-15
pregnant SD rats on days 6-15 of gestation. No treatment-related terato-
genlc effects occurred In any group. BromodUhloromethane and chlorodl-
bromomethane caused maternal toxldty (reduced weight gain) at the highest
dosage. Bromodlchloromethane also caused Increased relative kidney and
brain weights at the highest dosage. Bromoform did not cause any maternal
toxldty. Bromodlchloromethane and bromoform appeared to cause some
fetotoxldty as determined by the Incidence of sternebred aberrations 1n all
groups of treated rats relative to controls. There was no treatment-related
fetotoxldty 1n chlorodlbromomethane-treated rats.
Borzelleca and Carchman (1982) conducted a multi-generation study 1n
which groups of 10 male and 30 female ICR mice were exposed to chlorodl-
bromomethane In emulphor (a polyoxyethylated nonlonlc surfactant) (U.S. EPA,
1985) at bromomethane concentrations of 0, 0.1, 1.0 or 4.0 mg/mi 1n drink-
Ing water. The mice were 9 weeks old at the beginning of the treatment,
which was continuous throughout the experiment. After 35 days of exposure,
animals were mated to produce the F, generation; subsequent matlngs of
FQ mice produced the F,. and F, generations. The F,. offspring
were exposed to the same chlorodlbromomethane concentrations 1n drinking
water for 11 weeks beginning after weaning at 3 weeks of age, and then were
mated to produce the F~ generation. High-dose F. mice experienced
gross liver pathology and decreased terminal body weights. Utter size,
gestation Index, pup viability and survival of the F, generation were
significantly reduced In the high-dose mice. According to the authors, the
0083h -11- 02/11/87
-------
"nominal" chlorodlbromomethane dosage at this level was 685 mg/kg/day. At 1
mg/mi 1n the drinking water, terminal body weights of females were
reduced, and gross liver pathology was evident In 70% of the FQ mice. In
certain generations, there were significant decreases In Utter size, pup
viability, postnatal body weight and lactation Index at 1 mg/mi.. The only
effects observed at 0.1 mg/ms. were decreased postnatal body weights 1n the
Fp. generation, which remained significantly reduced at 21 days after
birth. Adult mice of the FQ and F,. generations had gross liver lesions
characterized by yellow color, presumably caused by fat accumulation. No
treatment-related teratogenlc effects were reported at any dose level.
3.3.2. Inhalation. Data concerning teratogenldty or reproductive
effects of the three trlhalomethanes by Inhalation exposure could not be
located In the available literature.
3.4. TOXICANT INTERACTIONS
Several studies concerning possible potentlatlon of trlhalomethane
toxldty by chlordecone have been published. Unlike chloroform, the toxlc-
Hy of bromoform does not appear to be potentiated by chlordecone pretreat-
ment. Agarwal and Mehendale (1983) fed male Sprague-Oawley rats diets con-
taining 0 or 10 ppm chlordecone for 14 days, followed by an Intraperltoneal
Injection of 25-300 pi/kg bromoform on the 15th day. No significant
differences 1n hepatotoxlc effects (hlstopathology or serum enzyme activi-
ties) were observed between the two groups. KUngensmUh and Mehendale
(1981) also reported that chlordecone or phenobarbltol pretreatment had no
effect on the toxldty of an Intraperltoneal dose of 10 yi/kg bromoform In
rats. On the other hand, hepatotoxUHy of bromodlchloromethane and chloro-
dlbromomethane 1s apparently greatly enhanced by chlordecone pretreatment.
Plaa and Hewitt (1982) conducted a study In which groups of male rats were
0083h -12- 02/11/87
-------
treated with a gavage dose of vehicle or 50 mg/kg chlordecone 18 hours
before receiving gavage doses of 0.1 or 0.5 ml/kg of bromoform, bromo-
dlchloromethane or chlorodlbromomethane. Hepatotoxldty of bromodlchloro-
methane and chlorodlbromomethane was greatly enhanced by chlordecone, but
hepatotoxlclty of bromoform was unaffected.
Toxldty of bromodlchloromethane and chlorodlbromomethane was also
enhanced by acetone. Hewitt et al. (1983) treated male SD rats with gavage
doses of 15 mmol/kg acetone 18 hours before receiving gavage doses of
0.25-1.00 ma/kg bromodlchloromethane or chlorodlbromomethane. The acetone
pretreatment significantly Increased the hepatotoxlclty of these compounds.
0083h -13- 02/11/87
-------
4. CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral. U.S. EPA (1980a) evaluated several epldemlolog'ical studies
concerning the possible association between trlhalomethane levels 1n drink-
Ing water and cancer Incidence among the U.S. population. U.S. EPA (1980a)
concluded that the positive correlation between drinking water quality and
cancer mortality might be due to the presence of trlhalomethanes. Cantor et
al. (1978) reported positive correlations between cancer mortality rates and
levels of bromlnated trlhalomethanes (mostly bromodlchloromethane and
chlorodlbromomethane, but also bromoform) In drinking water.
Aldrlch and Peoples (1982) examined the possible association of a high
level of malignant melanoma 1n Brevard County, Florida with levels of
trlhalomethanes 1n the drinking water. The county was divided Into three
regions having low, median and high levels of trlhalomethanes. Chloroform
and bromodlchloromethane were the major water contaminants with lesser
amounts of dlbromochloromethane and still lesser amounts of bromoform. The
survey of melanoma cases showed a relationship between observed new cases of
melanoma (between 1975 and 1977) and levels of trlhalomethanes In the water.
Although there was some association between the levels of the bromochloro-
methanes and melanoma, chloroform was related 1n a dose-related manner.
Levels of chloroform In the water were also higher than either bromochloro-
methane compound. Two other factors cannot be Ignored, age and sunlight.
The entire population of Brevard County 1s older (retirees) and Inclined to
outdoor activities. However, taking these factors Into account, the above
data suggests a relationship between Increased cancer risk and trlhalo-
methanes.
0083h -14- 04/06/87
-------
Using cancer Incidence data for the state of Iowa, Isacson et al. (1983)
attempted to correlate the source of drinking water and Its trlhalomethane
contaminants with specific types of cancer. Levels of chloroform, bromodl-
chloromethane and dlbromochloromethane ranged from 0-900, 0-220 and 0-17.0
vg/l, respectively. When cancer cases were categorized as to the levels
of each contaminant 1n their drinking water, a slight dose-related Increase
In the Incidence of bladder cancer 1n males, lung cancer 1n males, and
rectal cancer 1n both sexes was noted for bromodlchloromethane. The
Incidence of bladder cancer In males, breast cancer 1n females, and stomach
cancer In males was elevated 1n a dose-related manner when categorized by
dlbromochloromethane exposure. The significance of these Increased cancer
Incidences relative to exposure levels of the bromochloroethanes was not
discussed. In most cases, the Incidence of cancers of a specific type were
only slightly elevated In the high exposure group compared with the low
exposure group. The authors {Isacson et al., 1983) proposed that these data
do suggest an association between the level of trlhalomethanes (Including
chloroform) In drinking water and bladder cancer In males, lung cancer In
females and rectal cancer 1n both species.
4.1.2. Inhalation. Data concerning cardnogenldty of the three trlhalo-
methanes to humans by Inhalation exposure could not be located In the avail-
able literature.
4.2. BIOASSAYS
4.2.1. Oral. NTP (1985) conducted a 2-year cardnogenldty bloassay with
chlorodlbromomethane In rats and mice. Groups of 50 male and 50 female
F344/N rats received gavage doses of 0, 40 or 80 mg/kg 1n corn oil 5 days/
week for 104 weeks. Groups of 50 male and 50 female B6C3F1 mice received
gavage doses of 0, 50 or 100 mg/kg 1n corn oil 5 days/week for 105 weeks.
0083h -15- 04/06/87
-------
An overdose of chemical was given to low-dose mice of both sexes at week 58,
which resulted In the deaths of 35 males, making the size of this group
Inadequate for analysis of neoplasms. Low-dose female mice were apparently
unaffected. Chlorodlbromomethane treatment significantly Increased the
Incidence of hepatocellular adenomas (control 2/50, low-dose 4/49, high-dose
11/50) and the combined Incidences of hepatocellular adenomas or carcinomas
(control 6/50, low-dose 10/49 and high-dose 19/50) 1n high-dose female mice
as determined by the Fisher Exact test (p=0.002). There was also a signifi-
cant dose-related trend 1n combined Incidences of hepatocellular adenomas or
carcinomas In female mice as determined by the Cochran-ArmHage trend test
(p=0.002). In high-dose male mice, the Incidence of hepatocellular
carcinomas was significantly Increased (control 10/50 and high-dose 19/50),
but the combined Incidence of hepatocellular adenomas or carcinomas (control
23/50 and high-dose 27/50) was marginally significant by the life table test
but not by the Incidental tumor test. NTP (1985) concluded that, under the
conditions of these studies, there was no evidence of cardnogenlcHy 1n
male or female F344/N rats. There was "equivocal evidence of cardno-
genldty" 1n male B6C3F1 mice.
A chronic tox1c1ty/cardnogen1cHy study of bromodlchloromethane using
F344/N rats and B6C3F1 mice was conducted by NTP (1986a). This study was
available as a draft report and had not yet been completely reviewed. In
this study, groups of 50 male and 50 female rats received gavage doses of 0,
50 or 100 mg/kg/day 1n corn oil 5 days/week for 102 weeks. Groups of 50
male mice received 0, 25 or 50 mg/kg/day and groups of 50 female mice
received 0, 75 or 150 mg/kg/day according to the same schedule. The study
using male rats was restarted at 10.5 months 1"to the original study because
a temperature elevation killed most of the vehicle control male rats.
0083h -16- 04/06/87
-------
Survival of treated rats was comparable with vehicle controls, but mean body
weights of high-dose rats were decreased during the last 1.5 years of the
study. Body weights of high-dose female mice were decreased during the last
1.5 years of the study, but no other significant treatment-related effects
on survival or body weight occurred 1n mice. A variety of treatment-related
nonneoplastlc lesions were observed In treated mice and rats, with liver and
kidneys being the primary target organs. Bromodlchloromethane caused
statistically significant dose-related Increases 1n Incidences of neoplasms
of the large Intestine and kidneys 1n male and female rats, the kidneys In
male mice and the liver 1n female mice. The Incidence data and statistical
test results are presented 1n Tables 4-1 and 4-2. According to NTP (1986a),
the neoplasms of the large Intestine and kidneys are uncommon tumors 1n
these strains of rats and mice. The NTP (1986a) concluded that these
studies provided "clear evidence of carcinogenic activity" of bromodlchloro-
methane 1n F344/N rats and B6C3F1 mice.
The National Toxicology Program 1s also conducting cardnogenlcHy
bloassays with bromoform (NTP, 1986b). The chronic pathology working group
for the bromoform study 1s In progress.
4.2.2. Inhalation. Data concerning cardnogenlcHy bloassays of trlhalo-
methanes by Inhalation exposure could not be located In the available
literature.
4.3. OTHER RELEVANT DATA
Thelss et al. (1977) examined production of lung adenomas 1n strain A
mice following multiple 1ntraper1toneal Injections of various compounds.
They reported that 18-24 Injections of 4, 48 or 100 mg/kg bromoform resulted
1n a significantly higher number of lung adenomas per mouse relative to
controls In the middle-dose group, but not the low- or high-dose groups.
0083h -17- 04/06/87
-------
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-20-
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-------
No significant results were obtained with' mice receiving 18-24 Injections of
20, 40 or 100 mg/kg bromodlchloromethane.
The tMhalomethanes have been tested for mutagenldty In the reverse
mutation assay In Salmonella typhlmurlum. the dominant lethal test 1n male
ICR mice and the sister chromatld exchange assay In mouse bone marrow cells
and human lymphocytes. All three tMhalomethanes were consistently positive
In S. typhlmurlum strain TA100 without metabolic activation 1n a vapor phase
test performed In a desiccator (Simmon et al., 1977). The Intensity of the
response was dose-related. Borzelleca and Carchman (1982) obtained negative
results In a dominant lethal test 1n male mice from a multi-generation
reproduction study; the mice were treated with chlorodlbromomethane 1n
drinking water at 0.1-4.0 mg/mi. All three halomethanes Increased the
frequency of sister chromatld exchanges 1n bone marrow cells 1n an \r\_ vivo
test 1n ICR mice treated for 4 days with 25 or 50 mg/kg/day (Morlmoto and
Koizumi, 1983). There appeared to be no major differences between compounds
1n the magnitude of the positive response. In an l£ vitro test 1n human
lymphocytes, all three compounds, In concentrations of 1.6xlO~5 to
5xlO~2 M, Induced sister chromatld exchanges and bromoform gave the most
positive response (Morlmoto and Koizumi, 1983).
4.4. WEIGHT OF EVIDENCE
The available ep1dem1olog1cal data suggest a possible association
between trlhalomethane levels In drinking water and Incidences of various
types of cancer. Interpretation of these data Is compromised, however, by
the presence of chloroform, which 1s considered to be a probable human
carcinogen. Therefore, the available data for evaluating the carcinogenic
potential of the three tMhalomethanes alone In humans are considered
Inadequate because of the confounding with chloroform.
0083h -21- 04/06/87
-------
NTP (1986a) conducted cardnogenlclty bloassays with rats and mice
exposed to bromodlchloromethane. These experiments provided "clear evidence
of carcinogenic activity" 1n both species. Bromodlchloromethane caused
Increased Incidences of tumors of the large Intestine, and kidney In male and
female rats, kidney tumors 1n male mice, and liver tumors In female mice.
NTP (1985) conducted lifetime animal cardnogenlcUy bloassays In rats
and mice with chlorodlbromomethane. This study provided equivocal evidence
of carclnogenlcHy In male mice (Increased Incidence of hepatocellular
carcinomas In high-dose males) and some evidence of carc1r»ogen1dty In
female mice (Increased Incidence of hepatocellular adenomas and Increased
combined Incidence of hepatocellular adenomas or carcinomas). Additional
data concerning bromoform will be provided by the National Toxicology
Program bloassay 1n progress when 1t becomes available.
Trlhalogenated methanes can be classified as follows:
Dlchlorobromomethane: Cancer bloassay studies In rats and mice
provide sufficient carcinogenic evidence 1n two species. There-
fore, according to EPA cardnoen assessment guidelines, dlchloro-
bromomethane could be placed In Group 62.
Honochlorodlbromomethane: Cancer bloassay studies on monochloro-
dlbromomethane In rats and mice provide a positive carcinogenic
evidence In B6C3F1 mice (males and females). This carcinogenic
evidence could be considered limited, and thereby monochlorodl-
bromomethane can be placed In Group C according to EPA carcinogen
assessment guidelines. However, monochlorodlbromomethane 1is muta-
genlc and structurally similar to other known animal carcinogenic
(dlchlorobromomethane, chloroform, etc.) halomethanes. This
auxiliary evidence provides us to elevate Group C carcinogen to
Group 82 carcinogen to protect public health.
Trlbromomethane: Cancer bloassays of tMbromomethane 1n rats and
mice are 1n progress. It Is mutagenlc. Its mutagenlc action Is
considered to be stronger than other known animal carcinogens
(dlchlorobromomethane). Because of Insufficient evidence trlbromo-
methane at present can be classified 1n Group D. When the cancer
bloassay data become available Us classification will be re-
evaluated.
0083h -22- 04/06/87
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5. REGULATORY STANDARDS AND CRITERIA
U.S. EPA (1980a) derived ambient water quality criteria for halomethanes
as a group, Including the three trlhalomethanes that are the subject of this
report, using the cancer-based criterion for chloroform. Although no suit-
able animal data were available for the three trlhalomethanes at that time,
U.S. EPA (1980a) concluded that the available ep1dem1olog1cal data and
positive mutagenldty test results Indicated that all of the halomethanes
should be regulated as If they had the same carcinogenic potency as chloro-
form. Therefore, the criterion for total halomethanes associated with an
Individual lifetime cancer risk of 10~5 was the same as that for chloro-
form, 1.9 vg/l.
In an update of the U.S. EPA (1980a) document, U.S. EPA (1982) recom-
mended criteria for the three trlhalomethanes based on toxlclty rather than
carclnogenldty. The RfD can be calculated from the 90-day study by Chu et
al. (1982a). The 90-day NOAEL from this study can be divided by an uncer-
tainty factor of 1000 to derive the RfO. The RfDs for bromodlchloromethane,
chlorodlbromomethane and bromoform are 0.0005, 0.0006 and 0.006 mg/kg/day,
respectively. These values were verified by the U.S. EPA (1986b,c,d). The
corresponding recommended water quality criteria are 19, 18 and 190
vg/l, respectively, based on dally consumption of 2 l water and 6.5 g
fish and shellfish (U.S. EPA, 1982).
ACGIH (1986) recommended a TLV of 0.5 ppm (5 mg/m3) for bromoform
because of Us Irritant properties, Its potential to cause liver damage and
by analogy to related bromine compounds.
0083h -23- 04/06/87
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfOc)
w
6.1.1. Oral (RfDSQ). The 90-day study by Chu et al. (1982'b) provides
the best basis for deriving RfOso values for bromoform. This study
defined a NOAEL of 50 ppm bromoform 1n the drinking water. Higher doses
caused an Increase In Incidence and Intensity of liver lesions. Using body
weight and water consumption data provided by the original authors, U.S. EPA
(1982) determined that this NOAEL was equivalent to 5.6 mg/kg/day bromoform.
This value was then divided by an uncertainty factor of 100 to account for
Interspedes extrapolation and Intraspecles variations In sensitivity,
resulting In an RfD value of 0.056 mg/kg/day (A.O mg/day for a 70 kg
human) for bromoform. The selection of the Chu et al. (1982b) experiment as
the basis for the derivation of the RfD-Q for bromoform Ignores the
observations by Schuller et al. (1978) and Munson et al. (1978) that a
dose-dependent suppression of hepatic phaojocytlc activity occurred with this
compound at doses as low as 0.2-0.3 mg/kg/day In a 90-day gavage study using
mice. In these same experiments, however, no effects were observed on liver
and kidney function or on hematologlcal parameters. It 1s not certain that
the suppressed hepatic phagocytosis reported has any biological signifi-
cance. Since these experiments were only reported In abstract form, they
can only be evaluated In a limited manner. No RfDsos are calculated for
chlorodlbromomethane and bromodlchloromethane because of positive results In
the NTP (1985, 1986a) carclnogenlcHy bloassays (Section 6.3.).
6.1.2. Inhalation (RfOSI). The available data are Insufficient for
calculating RfD§I values for any of the three trlhalomethanes.
0083h -24- 07/16/87
-------
6.2. REFERENCE DOSE (RfD)
6.2.1. Oral (RfDQ). There are no suitable chronic data available for
bromoform. Therefore, data from the Chu et al. (1982b) study are also
recommended for calculation of RfD- values for this compound. The calcu-
lations are performed as described In Section 6.1.1., except that an addi-
tional uncertainty factor of 10 Is used to extrapolate from subchronlc data
to chronic exposure. The resulting RfD. values are 5.6 yg/kg/day (0.4
mg/day for a 70 kg human) for bromoform. This value 1s the same as the ADI
calculated by U.S. EPA (1982).
U.S. EPA (1983a,b) calculated CS values for all three trlhalomethanes,
based on effects In rats and mice observed In various studies previously
discussed 1n this document, and then selected those data that gave the
maximum CS values to calculate RQs. No more recent data have been reported
that would result In higher CS values. Therefore, only those studies that
produced the maximum CS will be discussed here. In the case of bromoform,
U.S. EPA (1983b) calculated an RQ based on an effective dose level of 12.5
mg/kg/day that caused suppression of hepatic phagocytosis In mice (Munson et
al., 1978). In choosing this value, U.S. EPA (1983b) apparently assumed
that the response at the lowest dose level, 0.3 mg/kg/day, was not signifi-
cant. Using standard methodology, Including an assumed mouse body weight of
0.03 kg, and dividing by an uncertainty factor of 10 to account for use of
subchronlc data, U.S. EPA (1983b) calculated a human MED of 6.6 mg/day and
an RV. value of 4.3. An RV of 6 was assigned; the resulting CS was
25.8.
No RfDQ or CS values are calculated for chlorodlbromomethane and
bromodlchloromethane because of positive results 1n the NTP (1985, 1986a)
bloassay. Bromoform has also been tested by NTP (1986b). The chronic
0083h -25- 07/16/87
-------
pathology working group for the bromoform study 1s In progress. Because the
closely related compounds chlorodlbromomethane and bromodlchloromethane were
found to be carcinogenic, the toxlclty-based RfOSQ and RfDQ values for
bromoform should be regarded as provisional until the cardnogenldty Issue
1s resolved by the release of the NTP (1986b) results.
6.2.2. Inhalation (RfD,). Data were Inadequate to calculate RfO,
values for any of the three trlhalomethanes.
6.3. CARCINOGENIC POTENCY (q.,*)
6.3.1. Oral. The results of the NTP (1985) bloassay provide "some
evidence of cardnogenlcUy" of chlorodlbromomethane In female B6C3F1 mice.
The combined Incidences of hepatocellular adenomas or carcinomas was
significantly Increased In high-dose female mice, and there was a signifi-
cant dose-related trend (vehicle control 6/50, low-dose 10/49 and high-dose
19/50). These data were used to calculate a q * using the GLOBAL 82
multistage model (Howe and Crump, 1982) because they represented the only
statistically significant Increase In Incidence of any malignant tumor.
Data for female mice were chosen because the database for males In the NTP
(1985) study was limited (I.e., there was only one treated group available
for analysis of neoplasms). Using the data provided 1n Tables 6-1 and 6-2,
an animal q,* of 6.7xlO~3 (mg/kg/day)"1 was computed, corresponding to
a human q * of 8.4xlO~2 (mg/kg/day)'1.
The NTP (1986a) bloassay provides "clear evidence" of the carclnogenlc-
1ty of bromodlchloromethane In rats and mice. Although this report has not
yet been through peer review, H seems reasonable to perform a carclnogen-
1cHy-based rtsk assessment for this compound using data from the available
draft report. Bromodlchloromethane caused statistically significant
Increases In tumors of several types and sites In F344/N rats and B6C3F1
mice (see Section 4.2. and Tables 4-1 and 4-2). Calculations performed with
0083h -26- 07/16/87
-------
TABLE 6-1
Cancer Data Sheet for Derivation of q-j* for Chlorodlbromomethane
Compound: Chlorodlbromomethane
Reference: NTP, 1985
Specles/straln/sex: mice, B6C3F1, female
Route/vehicle: gavage, corn oil
Length of experiment (le) = 105 weeks
Length of study (Le) = 105 weeks
Llfespan of animal (L) = 105 weeks
Body weight = 0.035 kg (estimated from growth curves)
Tumor type and site: hepatocellular adenomas or carcinomas
Experimental
Doses or Exposures
0 mg/kg, 5 days/week
50 mg/kg, 5 days/week
100 mg/kg, 5 days/week
Transformed Dose
(mg/kg/day)
0
35.71
71.43
Incidence
No. Responding/No.
6/50
10/49
19/50
Examined
Unadjusted q-)* from study = 6.7xlO~3 (mg/kg/day)"1
Human q-|* = 8.4xlO~2 (mg/kg/day)'1
0083h -27- 04/06/87
-------
TABLE 6-2
Cancer Data Sheet for Derivation of q-|* for Bromodlchloromethane
Compound: bromodlchloromethane
Reference: NTP, 1986a
Specles/straln/sex: mice, B6C3F1, female
Route/vehicle: gavage, corn oil
Length of experiment (le) = 102 weeks
Length of study (Le) = 102 weeks
Llfespan of animal (L) = 102 weeks
Body weight = (estimated from growth curves)
Tumor type and site: hepatocellular adenomas or carcinomas
Experimental
Doses or Exposures
0 mg/kg, 5 days/week
(bw = 0.038 kg)
75 mg/kg, 5 days/week
(bw = 0.035 kg)
150 mg/kg, 5 days/week
(bw = 0.030 kg)
Transformed Dose
(mg/kg/day)
0
4.25
8.08
Incidence
No. Responding/No. Examined
3/50
18/48
29/50
Human q-|*
(mg/kg/day)
0083h
-28-
04/06/87
-------
these data Indicated that the largest estimate of carcinogenic potency
(q,*) would be obtained using the data for combined Incidence of hepato-
cellular adenomas or carcinomas In female mice. Incidences of these tumors
were significantly higher than controls (3/50) for both low-dose (18/48) and
high-dose (29/50) female mice (p<0.001, Fischer exact test). The dose-
related trend was also statistically significant (p<0.001, Cochran-Armltage
trend test). Data used 1n the calculation of the q,* are presented In
Table 6-2. Because the body weights of the female mice were affected by
treatment, dosages were corrected for body weight [I.e., multiplied by
1/3
(W/70) ] before entering data Into the model. Using the GLOBAL 82
a '
multistage model (Howe and Crump, 1982), a human q * of l
(mg/kg/day)"1 was calculated.
6.3.2. Inhalation. Inhalation data for the three trlhalomethanes were
Insufficient for quantitative carc1nogen1c1ty risk assessments.
0083h -29- 04/06/87
-------
7. REFERENCES
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Borzelleca, J.F. and R.A. Carchman. 1982. Effects of selected organic
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Cantor, K.P., et al. 1978. Association of halomethanes In drinking water
with cancer mortality. J. Natl. Cancer Inst. 61: 979. (Cited In U.S. EPA,
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1982a. Toxlclty of tr1 halomethanes. I. The acute and subacute toxldty of
chloroform, bromodlchloromethane, chlorodlbromomethane and bromoform In
rats. J. Environ. Scl. Health. Part B. Pestle. Food Contam. Agrlc. Wastes.
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Chu, I., D.C. VUleneuve, V.E. Seccours, G.C. Becking and V.E. Valll.
1982b. Toxlclty of trlhalomethanes. II. Reversibility of toxlcologlcal
changes produced by chloroform, bromodlchloromethane, chlorodlbromomethane
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Condle, L.W., C.L. Smallwood and R.D. Laurie. 1983. Comparative renal and
hepatotoxldty of halomethanes. Bromodlchloromethane, bromoform, chloro-
form, dlbromochloromethane and methylene chloride. Drug Chem. Toxlcol.
6(6): 563-578.
Ounnlck, J.K., J.K. Haseman, H.S. L1lja and S. Wyand. 1985. Toxlclty and
cardnogenlclty of chlorodlbromomethane In Fischer F344/N rats and B6C3F1
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EG&G Mason Research Institute. 1980. Report on the subchronlc toxlclty of
bromoform. Report No. MRI-TRA 32-80-61. Subcontract 76-32-106002.
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Morlmoto, K. and A. Koizumi. 1983. Trlhalomethanes Induce sister chromatld
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Ruddlck, J.A., D.C. VHIeneuve, I. Chu and V.E. Valli: 1983. A terato-
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Simmon, V.F., K. Kauhanen and R.G. Tardlff. 1977. Mutagenlc activity of
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Smith, C.C., S.T. Cragg, G.F. Wolfe and U.U. Welgel. 1985. Investigation
of the metabolism of chlorinated hydrocarbons In subhuman species. EPA
600/1-85-001. PB85-152387/GAR. 134 p.
Tabak, H.H., S.A. Quave, C.I. Mashnl and E.F. Barth. 1981. B1odegradab11Hy
studies with organic priority pollutant compounds. J. Water Pollut. Control
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for cardnogen1c1ty of organic contaminants of United States drinking waters
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0083h -35- 04/06/87
-------
U.S. EPA. 1980a. Ambient Water Quality Criteria Document for Halomethanes.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Water Regu-
lations and Standards, Washington, DC. EPA 440/5-80-051. NTIS PB81-117624.
U.S. EPA. 1980b. Guidelines and Methodology Used 1n the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 79347-79357.
U.S. EPA. 1982. Errata for Ambient Water Quality Criteria Document for
Halomethanes. Prepared by the Office of Health and Environmental Assess-
ment, Environmental Criteria and Assessment Office, Cincinnati, OH for the
Office of Water Regulations and Standards, Washington, DC.
U.S. EPA. 1983a. Reportable Quantity' Document for Chlorodlbromomethane
(Dlbromochloromethane). Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1983b. Reportable Quantity Document for Trlbromomethane (Bromo-
form). Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for the Office
of Emergency and Remedial Response, Washington, DC.
0083h -36- 04/06/87
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U.S. EPA. 1984. Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic Toxlclty Data. Prepared by the Office of Health
and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH, for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1986a. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
U.S. EPA. 1986b. Integrated Risk Information System (IRIS). Reference
dose (RfO) for oral exposure for bromodlchloromethane. Online. (Verifica-
tion date 5/15/86, data Input pending). Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH.
U.S. EPA. 1986c. Integrated Risk Information System (IRIS). Reference
dose (RfO) for oral exposure for chlorodlbromomethane. Online. (Verifica-
tion date 5/15/86). Office of Health and Environmental Assessment, Environ-
mental Criteria and Assessment Office, Cincinnati, OH.
U.S. EPA. 1986d. Integrated Risk Information System (IRIS). Reference
dose (RfD) for oral exposure for bromoform. Online. (Verification date
5/15/86). Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH.
Weast, R.C. 1980. CRC Handbook for Chemistry and Physics, 61st ed. CRC
Press, Inc., Boca Raton, FL. p. 409-410.
0083h -37- 07/16/87
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APPENDIX A
Summary Table for Bromodlchloromethane 1n Female B6C3F1 Mice*
Experimental Effect q-|*
Exposure/Dose
0,75,150 mg/kg/day Increased combined Incidences l
5 days/week for 102 of hepatocellular adenoma or (mg/kg/day)
weeks; gavage In carcinoma
corn oil
'Source: NTP, 1986a
0083h -38- 04/06/87
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APPENDIX C
Summary Table for Chlorodlbromomethane 1n Female B6C3F1 Mice*
Experimental Effect q-|*
Exposure/Dose
0, 50, 100 mg/kg/day, Increased combined Incidences 8.4xlO~2
5 days/week for 105 of hepatocellular adenoma (mg/kg/day)"1
weeks; gavage In or carcinoma
corn oil
'Source: NTP, 1985
0083h -40- 04/06/87
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