United States
Environmental Protection
1=1 m m Agency
EPA/690/R-09/031F
Final
9-30-2009
Provisional Peer-Reviewed Toxicity Values for
Methylene bromide
(CASRN 74-95-3)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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COMMONLY USED ABBREVIATIONS
BMD
Benchmark Dose
IRIS
Integrated Risk Information System
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELhec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
RfC
inhalation reference concentration
RfD
oral reference dose
UF
uncertainty factor
UFa
animal to human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete to complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL to NOAEL uncertainty factor
UFS
subchronic to chronic uncertainty factor
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
METHYLENE BROMIDE (CASRN 74-95-3)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (U.S. EPA) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1)	U.S. EPA's Integrated Risk Information System (IRIS).
2)	Provisional Peer-Reviewed Toxicity Values (PPRTVs) used in U.S. EPA's Superfund
Program.
3)	Other (peer-reviewed) toxicity values, including
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in U.S. EPA's IRIS. PPRTVs are developed according to a
Standard Operating Procedure (SOP) and are derived after a review of the relevant scientific
literature using the same methods, sources of data, and Agency guidance for value derivation
generally used by the U.S. EPA IRIS Program. All provisional toxicity values receive internal
review by two U.S. EPA scientists and external peer review by three independently selected
scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multiprogram consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all U.S. EPA programs, while PPRTVs are developed
specifically for the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a 5-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV documents conclude that
a PPRTV cannot be derived based on inadequate data.
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and Resource Conservation and Recovery Act (RCRA) program offices are advised to
carefully review the information provided in this document to ensure that the PPRTVs used are
appropriate for the types of exposures and circumstances at the Superfund site or RCRA facility
in question. PPRTVs are periodically updated; therefore, users should ensure that the values
contained in the PPRTV are current at the time of use.
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It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV document and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the U.S. EPA
Office of Research and Development's National Center for Environmental Assessment,
Superfund Health Risk Technical Support Center for OSRTI. Other U.S. EPA programs or
external parties who may choose of their own initiative to use these PPRTVs are advised that
Superfund resources will not generally be used to respond to challenges of PPRTVs used in a
context outside of the Superfund Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the U.S. EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
No RfD, RfC, or carcinogenicity assessment for methylene bromide (dibromomethane)
is available on IRIS (U.S. EPA, 2008). No RfC for methylene bromide is available in the Health
and Environmental Assessment Summary Tables (HEAST; U.S. EPA, 1997), although the
HEAST does include RfDs based on the route-to-route extrapolation of inhalation toxicity data,
originally derived in a Health and Environmental Effects Profile (HEEP; U.S. EPA, 1987).
Subchronic and chronic RfDs of 1E-1 and 1E-2 mg/kg-day, respectively, were extrapolated from
an inhalation NOAEL of 25 ppm for increased carboxyhemoglobin in rats exposed to methylene
bromide vapor for 90 days (Keyes et al., 1982). The HEEP (U.S. EPA, 1987) did not produce a
cancer assessment due to insufficient data. The HEEP is the only U.S. EPA document on
methylene bromide in the Chemical Assessments and Related Activities (CARA) lists
(U.S. EPA, 1991a, 1994a). The Drinking Water Standards and Health Advisories list (U.S. EPA,
2006)	does not include methylene bromide. The Agency for Toxic Substances and Disease
Registry (ATSDR, 2008) has not produced a Toxicological Profile for methylene bromide, and
no World Health Organization Environmental Health Criteria document is available (WHO,
2008). The chronic toxicity and carcinogenicity of methylene bromide have not been assessed
by the International Agency for Research on Cancer (IARC, 2008) or the National Toxicology
Program (NTP, 2005, 2008). No occupational exposure limits are available for methylene
bromide from the American Conference of Governmental Industrial Hygienists (ACGIH 2001,
2007),	the National Institute of Occupational Safety and Health (NIOSH, 2008) or the
Occupational Safety and Health Administration (OSHA, 2008). The California Environmental
Protection Agency (Cal EPA, 2002, 2005a,b) has not derived a REL or cancer potency factor for
methylene bromide.
Literature searches were conducted from 1960s through December 2007 for studies
relevant to the derivation of provisional toxicity values for methylene bromide. Databases
searched include MEDLINE, TOXLINE (Special), BIOSIS, TSCATS 1/TSCATS 2, CCRIS,
DART/ETIC, GENETOX, HSDB, RTECS, and Current Contents. An updated literature search
was conducted using PubMed through November 2008.
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REVIEW OF PERTINENT DATA
Human Studies
No information was located regarding the toxicity of methylene bromide in humans.
Animal Studies
Oral Exposure
Groups of 10 male and 10 female young-adult Sprague-Dawley rats were exposed to
methylene bromide (dibromomethane) in drinking water at concentrations of 1.0, 10.0, 100.0, or
1000.0 mg/L for 4 weeks (Komsta et al., 1988). Methylene bromide was initially solubilized
with 0.5% by weight (w/v) Emulphor followed by dilution with tap water to appropriate
concentrations. Control groups (10 per sex) were exposed to water alone or vehicle (0.5%
Emulphor). Reported approximate chemical intakes were 0.1, 1.2, 11.9, and 124 mg/kg-day in
males and 0.1, 0.9, 8.6, and 90 mg/kg-day in females (based on group water consumption and
average body weight). Endpoints evaluated throughout the study consisted of clinical
observations (daily), body weight (weekly), and food and water consumption (weekly).
Endpoints evaluated at termination of exposure included hematology, serum chemistry, and
hepatic microsomal enzyme activity (aniline hydroxylase, aminopyrine demethylase, and
ethoxyresorufin deethylase). The hematology determinations consisted of hemoglobin, packed
cell volume, erythrocyte count, total and differential leukocyte counts, and platelet counts. The
serum chemistry determinations consisted of sodium, potassium, calcium, inorganic phosphate,
total bilirubin, total protein, cholesterol, glucose, uric acid, alkaline phosphatase, aspartate
aminotransferase, and lactate dehydrogenase. Gross necropsy and selected organ weight
measurements (brain, heart, liver, spleen, and kidneys) were performed on all animals at
termination of exposure. Comprehensive histological examinations (29 tissues, including male
and female reproductive tissues) were conducted but limited to the control and high-dose groups.
The investigators used data from the water control group as baseline values for evaluation
purposes because a comparison of data from the water and vehicle control groups showed that
there were no significant differences between the groups (Komsta et al., 1988). The only effects
attributable to methylene bromide exposure were reduced serum lactate dehydrogenase activity
in females at >8.6 mg/kg-day and histological alterations in the liver and thyroid in males at
124 mg/kg-day. Serum lactate dehydrogenase activity in the 0.1, 0.9, 8.6, and 90 mg/kg-day
females was 21.6, 17.2, 27.4, and 31.2% lower than water controls, respectively. Although
statistically significant (p < 0.05) at >8.6 mg/kg-day, the investigators did not consider the
decreases in serum lactate dehydrogenase to be biologically significant or related to any
histological changes. Given the lack of a basis for toxicological concern of a decrease in serum
lactate dehydrogenase (as opposed to an increase), the effect is discounted for determination of a
LOAEL. In males, the histological changes in the liver were characterized as minimal-to-mild
increases in perivenous cytoplasmic homogeneity and periportal cytoplasmic density; the
incidence in the 124 mg/kg-day group was 8/10 compared to 3/10 in water controls and 5/10 in
vehicle controls. The histological changes in the thyroid of the 124 mg/kg-day males were also
minimal-to-mild in severity and included increased epithelial height (8/10 compared to 1/10 in
water controls and 4/10 in vehicle controls) and reduced colloid density (2/10 compared to
0/10 in water controls and 0/10 in vehicle controls). Other histological findings included low
incidences of minimal-to-mild renal tubular cytoplasmic inclusions in males at 124 mg/kg-day
(4/10 compared to 2/10 in water controls and 1/10 in vehicle controls) and females at
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90 mg/kg-day (3/10 compared to 0/10 in water controls and 0/10 in vehicle controls). Histology
examinations were not performed in any tissues at lower doses in either sex. Although these
effects were generally mild and not accompanied by overt functional changes, they are indicative
of compound-related changes that could progress to more severe outcomes. Consequently, the
highest doses tested in females (90 mg/kg-day) and males (124 mg/kg-day) are considered to be
LOAELs. NOAELs of 8.6 mg/kg-day in females and 11.9 mg/kg-day in males are established in
this study.
Inhalation Exposure
Keyes et al. (1982); 90-Day Inhalation Study in Rats and Dogs—An unpublished Dow
Chemical Company study was conducted using groups of 115 male and 15 female
Sprague-Dawley rats and three male Beagle dogs exposed to 0, 25, 75, or 150 ppm (0, 178, 533,
or 1066 mg/m3) of methylene bromide for 6 hours/day, 5 days/week, for a total of 62 or
63 exposures (rats) or 70 exposures (dogs) in approximately 90 days (Keyes et al., 1982). After
58 exposure days, five rats/sex/level were sacrificed for cytogenetic analysis of bone marrow.
On the day after the last exposures, 10 rats/sex/level and all dogs were necropsied. The 100
remaining male rats were observed for up to 2 years following exposure. Endpoints that were
evaluated during the exposure and observation parts of the study include clinical signs, body
weight, hematology, and urinalysis indices (7 rats/sex/level, all dogs at termination of exposure,
and 7 male rats/level after 1 year of observation) and clinical chemistry indices (10 rats/sex/level,
all dogs at termination of exposure, and 10 male rats/level after 1 year of observation). The
hematology determinations included red blood cell counts, hemoglobin concentration, packed
cell volume, and total and differential white blood cell counts. The urinalysis determinations
included pH, protein, ketones, bilirubin, urobilinogen, and occult blood. The clinical chemistry
determinations included blood urea nitrogen, alanine aminotransferase, aspartate
aminotransferase, and alkaline phosphatase. Cytogenetic analyses were not performed because
of inadequate slide preparation.
Additional endpoints included plasma bromine/bromide levels at various time points and
blood carboxyhemoglobin (COHb) percentages. COHb was measured using an optical method.
For each of these endpoints three rats/sex/level were evaluated preexposure and at 1, 3, 30, 41,
51, and 61 days of exposure. The authors did not specify whether the same or different animals
were used for each measurement. All dogs were evaluated at similar time points. Complete
gross necropsies and organ weight measurements (brain, heart, liver, kidneys, and testes) were
performed on 10 rats/sex/level after 61or 62 exposures and all dogs after 70 exposures.
Complete gross necropsies were also performed on 10 male rats/level at 1 and 2 years
postexposure. Comprehensive histological examinations were performed in the 0- and
150-ppm groups after 90 days of exposure (five rats/sex/level and all dogs) and at 1 year
postexposure (five male rats/level). No histological examinations were performed during the
observation period on male rats that died spontaneously, were killed in moribund condition, or
were sacrificed after 2 years. Histological examinations in the 25- and 75-ppm exposure groups
were limited to the lungs, trachea, and bronchial lymph nodes in dogs after 90 days of exposure.
There were no exposure-related changes in most of the endpoints in either species.
Dose-related increases in serum levels of free bromide ion and total bromine occurred at
>25 ppm in the rats and dogs at all times of evaluation. There were no clinical signs of
intoxication and no histopathological changes in both species. There was a slight increase in
relative liver weight at the termination of the exposure period in female rats exposed to 75 ppm
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(8.9% higher than controls,/? < 0.05) and 150 ppm (6.1% higher than controls, not statistically
significant). Male rats that were exposed to >75 ppm showed an equivocal decrease in
body-weight gain during Study Days 121-361 in the postexposure observation period, but the
decrease is not considered biologically significant.
Exposure to methylene bromide also caused increased blood COHb levels in both species
as shown in Table 1. Increases in mean COHb percentages that were statistically significant
(p < 0.05 compared to control group) occurred at >75 ppm methylene bromide; there was only
one statistically significant increase at 25 ppm (after 61 exposures in females). However, due to
the small group sizes (n = 2 or 3 rats/sex/level at each time point), the statistical tests performed
by the researchers had little power to detect an effect. Dogs were less sensitive than the rats, as
indicated by a small increase in percent COHb saturation relative to controls detectable only at
150 ppm (mean 6.0% increase at the only sampling time where the difference from the control
mean was statistically significant). Regression analysis was performed by the researchers to
quantitatively assess the effect of increasing exposure concentration on percent COHb saturation.
The analysis used pooled percentage COHb saturation values after 30 to 61 exposures; data for
each concentration were pooled to improve the precision of analysis and because COHb
percentages did not increase appreciably after more than 30 exposures. The slopes of the
regression lines predicted that the average increase in percent COHb saturation (relative to
controls) in the animals repeatedly exposed to 25, 75, and 150 ppm would be 0.4, 1.2, and
2.4%), respectively, in dogs, 2.6, 8.3, and 16.5%> in male rats, and 2.3, 6.8, and 13.5%> in female
rats. Baseline COHb in untreated control animals was 2.8%>. Table 1 shows selected data from
Table 28 of Keyes et al. (1982) that correspond to the data used by the researchers for their
regression analysis. Statistical analysis performed by Syracuse Research Corporation for this
review of the data pooled across the selected time points showed highly statistically significant
changes in COHb from control in all treated groups (two-tailed t-test,/> < 0.01). The lowest
exposure level in this study of 25 ppm (178 mg/m3) is identified as a LOAEL for increased
COHb in rats; a NOAEL is not identified.
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Table 1. Carboxyhemoglobin Concentrations (%) in
Rats Exposed to Methylene Bromidea
Exposures
Exposure Concentration (ppm)
0
0
25
25
75
75
150
150
Male
Female
Male
Female
Male
Female
Male
Female
30
—
2.7
6.4
5
9
8
20.6
20
1.3
0.6
6.9
6
7.9
8
21.7
23.2
2.5
1.1
7.9
6
16.7
8.2
20.4
23.1
41
4.5
3.9
3
2.4
6.3
4.5
15.9
12.6
0.9
4.2
5.1
3.9
4.2
2.4
14.7
14.1
1.4
—
5.4
5.1
6
6.3
14.7
17.8
61
4.1
3.1
9.2
7.8
10.8
9.2
18
14.3
2.4
2
6.1
10.2
14.6
10.2
23.8
15.6
5.1
2.7
7.5
10.9
9.5
8.5
23.8
14.3
n
8
8
9
9
9
9
9
9
Meanb
2.8
2.5
6.4°
6.4°
9.4°
7.3°
19.3°
17.2°
SDb
1.6
1.3
1.8
2.8
4.1
2.5
3.6
4.0
aKeyes et al., 1982, Table 28.
bMeans and standard deviations (SDs) were calculated from the Keyes et al. (1982) data for this review; the
selected data set is identical to that used by Keyes et al. (1982) to generate Figure 3 of that report and the
accompanying regression formulas for methylene bromide-induced COHb formation.
Statistically significant difference from control (p < 0.01) by the two-tailed t-test performed for this review.
Toxicokinetics and Toxicodynamics
The available data indicate that COHb induction is the most sensitive effect of subchronic
inhalation exposure to methylene bromide. This effect is a consequence of the cytochrome
P-450-mediated metabolism of methylene bromide to carbon monoxide and inorganic bromide
(Fozo and Penney, 1993; Kubic and Anders, 1975, 1978; Kubic et al., 1974; Stevens et al., 1980)
and is consistent with the metabolism of methylene chloride and other dihalomethanes, which
characteristically produce carbon monoxide and increases in COHb that can lead to tissue
hypoxia (ATSDR, 2000; U.S. EPA, 2008). The formation of COHb is a reversible process, but
the elimination half-time is relatively long (2-6.5 hours, depending on initial COHb levels)
because carbon monoxide is tightly bound to hemoglobin (McKee and Bachman, 2000). The
long elimination half-time may lead to accumulation of COHb, indicating that even relatively
low concentrations of carbon monoxide could produce high blood levels of COHb.
The cytochrome P-450 pathway is the major metabolic route of methylene chloride at
low exposure levels similar to the levels of methylene bromide that caused the increased COHb
levels (Keyes et al., 1982). Studies with methylene chloride have established that the
mixed-function oxidases (MFO) pathway is a high-affinity, limited-capacity pathway that
saturates at air concentrations of about 200-500 ppm (ATSDR, 2000). Thus, at low-exposure
concentrations, most of the methylene chloride is likely to be metabolized by the MFO pathway.
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As exposure concentrations increase and the MFO pathway saturates, metabolism proceeds by a
second pathway that is glutathione (GSH)-mediated (ATSDR, 2000). The GSH-dependent
pathway produces formaldehyde and carbon dioxide but no carbon monoxide. In vitro and in
vivo comparisons of methylene chloride metabolism in rats, mice, hamsters, and humans indicate
that metabolic rates for the MFO pathway are similar among the four species and saturated at
concentrations of 500 ppm and above (Green, 1997; Reitz et al., 1989).
Physiological baseline COHb saturations in the general population are estimated to
average 0.5% (range 0.3-0.7%) among nonsmokers and 4% in smokers, with a usual range of
3~8% for one- to two-packs-per-day smokers (McKee and Bachman, 2000; U.S. EPA, 2000a).
Carbon monoxide studies indicate that adverse CNS and cardiovascular effects are likely to be
associated with blood COHb levels of approximately 5% and above in healthy humans (McKee
and Bachman, 2000). CNS effects (e.g., reductions in eye-hand coordination, attention, and
vigilance) were observed at peak COHb levels of >5% in some historical reports, although more
recent investigations indicate that significant behavioral impairments in healthy individuals are
not expected until COHb levels exceed 20% (McKee and Bachman, 2000; U.S. EPA, 2000a).
COHb concentrations of 5—20% were associated with significant decreases in VO2 max (the rate
of maximal oxygen consumption during strenuous exercise) following exposure to carbon
monoxide in healthy young adult nonsmokers (U.S. EPA, 2000a). Maximal exercise duration
and performance in healthy individuals were reduced at COHb concentrations of >2.3% and
>4.3%, respectively, but the performance decrements at these COHb levels were small and likely
to affect only competing athletes rather than people in everyday activities (McKee and Bachman,
2000; U.S. EPA, 2000a). No effects were observed during submaximal exercise in healthy
individuals at COHb levels as high as 15—20% (U.S. EPA, 2000a). Blood COHb concentrations
as low as 2.4-3.0%) have been associated with adverse effects in people with coronary artery
disease; at these COHb levels, individuals with reproducible exercise-induced angina are likely
to experience a reduced capacity to exercise because of decreased time to onset of angina
(U.S. EPA, 2000a; McKee and Bachman, 2000).
Following a review of the toxicity database for carbon monoxide, U.S. EPA (2000a)
concluded that myocardial ischemia1 during exercise in nonsmokers with coronary artery disease
(i.e., the sensitive human population) is the endpoint of most concern and established it as the
basis for the derivation of the National Ambient Air Quality Standard (NAAQS) for carbon
monoxide. In addition, U.S. EPA (2000a) advised caution in comparing results across the
studies as they used different methods for determining COHb with widely varying sensitivities.
The lowest levels of COHb (>2.4%) associated with myocardial ischemia in the sensitive
population were determined by gas chromatography and reported by Allred et al. (1989a,b;
1991). When COHb was measured by carbon monoxide oximetry (CO-OX: spectrophotometric
or optical method with a precision of ± 1% COHb), myocardial ischemia in the sensitive
population was associated with COHb >2.9% (Anderson et al., 1973; Sheps et al.,1987;
Adams et al., 1988; Kleinman et al., 1989, 1998; Allred et al., 1989a,b, 1991). Based on an
evaluation of these studies, U.S. EPA (2000a) concluded that when optical methods are used to
determine COHb, (1) a COHb range of 2.9-5.9% (rounded to 3—6%) is associated with
myocardial ischemia and (2) this range is associated with incremental increases of 1.5-4.4%)
COHb from preexposure baseline values. The current 1-hour (35 ppm) and 8-hour (9 ppm)
Measured as a decrease in the time to onset of angina pain and by decreased time to onset of significant
EKG S-T segment depression during exercise.
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NAAQS for carbon monoxide are intended to keep COHb levels below 2.1% to protect the most
cardiovascular-sensitive members of the general population. These values were determined from
models that quantify the relationship between carbon monoxide exposure and COHb
concentrations.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL p-RfD VALUES FOR METHYLENE BROMIDE
Subchronic p-RfD
The only available study is the 28-day drinking water study in male and female rats
(Komsta et al., 1988). Effects included reduced serum lactate dehydrogenase in females at
8.6 and 90 mg/kg-day (highest tested dose in females) and histological changes in the liver
(minimal-to-mild increases in perivenous cytoplasmic homogeneity and periportal cytoplasmic
density) and thyroid (minimal-to-mild increase in epithelial height) in males at 124 mg/kg-day
(highest tested dose in males) and in the kidney (minimal-to-mild increases in tubular
cytoplasmic inclusions) in females at 90 mg/kg-day. LOAELs of 90 and 124 mg/kg-day are
established for females and males, respectively, based on kidney effects in male and female rats
and liver and thyroid effects in males. The corresponding NOAELs are 8.6 mg/kg-day (females)
and 11.9 mg/kg-day (males).
The 8.6 mg/kg-day NOAEL for female rats (Komsta et al., 1988) was used to derive the
subchronic p-RfD. The NOAEL of 8.6 mg/kg-day was divided by a composite uncertainty factor
(UF) of 1000 to derive a subchronic p-RfD of 9 x 10"3 mg/kg-day, as follows:
Subchronic p-RfD = NOAEL UF
= 8.6 mg/kg-day ^ 1000
= 0.009 or 9 x 10 3 mg/kg-day
The composite UF of 1000 is composed of the following:
•	A full UF of 10 for intra-species differences is used to account for potentially
susceptible individuals in the absence of information on the variability of
response in humans.
•	A full UF of 10 is applied for inter-species extrapolation to account for potential
pharmacokinetic and pharmacodynamic differences between rats and humans.
•	A full UF of 10 is employed to account for deficiencies in the database. The
toxicological database for oral exposure to methylene bromide is limited to a
single, but adequate, 4-week study in one species. The database lacks true
subchronic, reproductive, and developmental toxicity studies.
•	Although the study duration of 28 days is much shorter than a standard
subchronic study (90 days), an adjustment for exposure duration is not considered
necessary as the 10-fold difference between the LOAEL and NOAEL provides a
sufficient margin for both exposure-duration uncertainty and the minimal
toxicological effects at the LOAEL.
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Confidence in the key study is low-to-medium. This study tested a range of doses and a
variety of endpoints, but the histopathology examinations were limited to the high-dose group of
each sex and the study duration was only 28 days. Confidence in the database is low because it
lacks reproductive and developmental toxicity data. Low confidence in the subchronic p-RfD
results.
Chronic p-RfD
No chronic oral toxicity studies of methylene bromide were located. The only adequate
repeated-dose oral study is the 28-day drinking water study in rats (Komsta et al., 1988) used to
derive the subchronic p-RfD. The short duration of this study precludes using it for derivation of
a chronic p-RfD.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION p-RfC VALUES FOR METHYLENE BROMIDE
It is inappropriate to derive provisional toxicity values for methylene bromide. However,
information is available for this chemical which, although insufficient to support derivation of a
provisional toxicity value, under current guidelines, may be of limited use to risk assessors. In
such cases, the Superfund Health Risk Technical Support Center summarizes available
information in an Appendix and develops a "screening value." Appendices receive the same
level of internal and external scientific peer review as the PPRTV documents to ensure their
appropriateness within the limitations detailed in the document. Users of screening toxicity
values in an appendix to a PPRTV assessment should understand that there is considerably more
uncertainty associated with the derivation of an appendix screening toxicity value than for a
value presented in the body of the assessment. Questions or concerns about the appropriate use
of screening values should be directed to the Superfund Health Risk Technical Support Center.
PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR METHYLENE BROMIDE
Weight-of-Evidence Descriptor
The only study providing information on the carcinogenicity of methylene bromide is the
previously summarized Keyes et al. (1982) inhalation study in rats. Male rats (100 per group)
were exposed to 0, 25, 75, or 150 ppm of methylene bromide by inhalation 6 hours/day,
5 days/week, for 90 days and observed for up to 2 years (Keyes et al., 1982). Complete gross
necropsy was performed on 10 rats from each group at 1 year, all rats dying spontaneously
during the study, and all surviving rats at 2 years. Histopathological examination was limited to
5 rats in the control and 150-ppm groups sacrificed at 1 year. Therefore, assessment of
tumorigenic potential is based mainly on evaluation of gross pathology data. No
exposure-related effect on tumor incidence was observed. This study is not an adequate
evaluation of the carcinogenic potential of methylene bromide due to the short (90-day) exposure
duration and insufficient histopathological follow-up.
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Mutagenicity studies showed that methylene bromide was mutagenic in S. typhimurium
strains TA100, TA1950, and BA13 (but not TA1535) when tested without metabolic activation
and mutagenicity in S. typhimurium TA100 and TA1535 was enhanced by the addition of S9 or
GST metabolic activation preparations or by the expression of GSTs (Buijs et al., 1984;
Kundu et al., 2004; Osterman-Golkar et al., 1983; Roldan-Arjona and Pueyo, 1993;
Simmon et al., 1977; Thier et al., 1993, 1996; Van Bladeren et al., 1980, 1981; Wheeler et al.,
2001). Methylene bromide was mutagenic in E. coli strains K39 and WU361189 (but not Sd-4)
without metabolic activation and mutagenicity in E. coli K12 and TRG8, as well as in Chinese
hamster fibroblasts, was enhanced by the expression of DNA alkyltransferases (Abril et al.,
1995, 1997, 1999; Liu et al., 2004; Osterman-Golkar et al., 1983). Aneuploidy was not induced
in A. nidulans diploid strain PI (Parry et al., 1996) and inhalation exposure did not cause
sex-linked recessive lethal mutations in D. melanogaster (Kramers et al., 1991).
Methylene chloride, a structural analog of methylene bromide, is carcinogenic in
long-term rodent inhalation and drinking water bioassays and there are metabolic similarities
between methylene chloride and methylene bromide (ATSDR, 2000; Fozo and Penney, 1993;
IARC, 1999; Kubic and Anders, 1975, 1978; Kubic et al., 1974; U.S. EPA, 1987). The
metabolism of both dihalomethanes occurs through the same pathways, producing potentially
reactive intermediates that can bind to DNA (summarized in ATSDR, 2000 and IARC, 1999).
In accordance with current EPA cancer guidelines (U.S. EPA, 2005), there is "Inadequate
Information to Assess the Carcinogenic Potential' of methylene bromide.
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Abril, N., F.L. Luque-Romero, M.-J. Prieto-Alamo et al. 1997. Bacterial and mammalian DNA
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dibromoalkanes. Mol. Carcinogen. 18:1883-1888.
Abril, N. and G.P. Margison. 1999. Mammalian cells expressing Escherichia coli
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Allred, E.N., E.R. Bleecker, B.R. Chaitman et al. 1989a. Short-term effects of carbon monoxide
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Fozo, M.S. and D.G. Penney. 1993. Dibromomethane and carbon monoxide in the rat:
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Green, T. 1997. Methylene chloride induced mouse liver and lung tumors: An overview of the
role of mechanistic studies in human safety assessment. Human Exper. Toxicol. 16:3-13.
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IARC (International Agency for Research on Cancer). 1999. IARC Monographs on the
Evaluation of the Carcinogenic Risk of Chemicals to Humans. Re-evaluation of some Organic
Chemicals, Hydrazine and Hydrogen Peroxide (Part One). Dichloromethane. 71:251-315.
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Keyes, D.G., J.W. Henck, G.C. Jersey et al. 1982. Methylene bromide: A ninety-day repeated
inhalation toxicity study in rats and dogs with a subsequent two-year holding period for rats.
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Midland, MI. U.S. EPA/OPTS Public Files. Fiche No. OTS0516108. Doc. No. 86-870001205.
Section 8D.
Kleinman, M.T., D.M. Davidson, R.B. Vandagriff, R.B. et al. 1989. Effects of short-term
exposure to carbon monoxide in subjects with coronary artery disease. Arch. Environ. Health
44:361-369. (Cited by U.S. EPA, 2000a).
Kleinman, M.T., D.A. Leaf, and E. Kelly. 1998. Urban angina in the mountains: effects of
carbon monoxide and mild hypoxemia on subjects with chronic stable angina. Arch. Environ.
Health 53:388-397. (Cited by U.S. EPA, 2000a).
Komsta, E., I. Chi, V.E. Valli et al. 1988. Results of a short-term toxicity study for three
organic chemicals found in Niagara river drinking water. Bull. Environ. Contam. Toxicol.
41:515-522.
Kramers, P.G.N., H.C.A. Mout, B. Bissumbhar et al. 1991. Inhalation exposure in Drosophila
mutagenesis assays: Experiments with aliphatic halogenated hydrocarbons, with emphasis on the
genetic activity profile of 1,2-dichloroethane. Mutat. Res. 252:17-33.
Kubic, V.L. and M.W. Anders. 1975. Metabolism of dihalomethanes to carbon monoxide. I.
In vitro studies. Drug Metab. Dispos. 3:104-112.
Kubic, V.L. and M.W. Anders. 1978. Metabolism of dihalomethanes to carbon monoxide. III.
Studies on the mechanism of the reaction. Biochem. Pharmacol. 27:2349-2355.
Kubic, V.L., M.W. Anders, R.R. Engel et al. 1974. Metabolism of dihalomethanes to carbon
monoxide. I. In vivo studies. Drug Metab. Dispos. 2:53-57.
Kundu, B., S.D. Richardson, C.A. Granville et al. 2004. Comparative mutagenicity of
halomethanes and halonitromethanes in Salmonella TA100: Structure-activity analysis and
mutation spectra. Mutat. Res. 554:335-350.
Liu, L., K.M. Williams, F.P. Guengerich et al. 2004. 06-Akylguanine-DNA alkyltransferase has
opposing effects in modulating the genotoxicity of dibromomethane and bromomethyl acetate.
Chem. Res. Toxicol. 17:742-752.
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McKee, D.J. and J.D. Bachman. 2000. Air pollution. Section 3.5, Carbon Monoxide.
In: Patty's Industrial Hygiene, 5th ed. Volume 4, Chapter 58. R.L. Harris, Ed. John Wiley and
Sons, Inc., New York. p. 2811-2814.
NIOSH (National Institute for Occupational Safety and Health). 2008. NIOSH Pocket Guide to
Chemical Hazards. Online, http://www.cdc.gov/niosh/npe/.
NTP (National Toxicology Program). 2005. 11th Report on Carcinogens. Online.
http://ntp.niehs.nih.eov/ntp/roc/tocl 1 .htm.
NTP (National Toxicology Program). 2008. Management Status Report. Online.
http://ntp.niehs.nih.eov/index.cfm?obiectid=78CC7E4C-FlF6-975E-72940974DE301C3F.
OSHA (Occupational Safety and Health Administration). 2008. OSHA Standard 1910.1000
Table Z-l. Part Z, Toxic and Hazardous Substances. Online, http://www.osha.eov/pls/
oshaweb/owadisp.show document?p table STANDARDS&p id=9992.
Osterman-Golkar, S., S. Hussain, S. Walles et al. 1983. Chemical reactivity and mutagenicity of
some dihalomethanes. Chem.-Biol. Interact. 46:121-130.
Parry, J.M., E.M. Parry, R. Bourner et al. 1996. The detection and evaluation of aneugenic
chemicals. Mutat. Res. 353:11-46.
Reitz, R.H., A.L. Mendrala and F.P. Guengerich. 1989. In vitro metabolism of methylene
chloride in human and animal tissues: Use in physiologically based pharmacokinetic models.
Toxicol. Appl. Pharmacol. 97:230-246.
Roldan-Arjona, T. and C. Pueyo. 1993. Mutagenic and lethal effects of halogenated methanes
in the Ara test of Salmonella typhimurium: Quantitative relationship with chemical reactivity.
Mutagenesis. 8:127-131.
Sheps, D.S., K.F. Adams, Jr., P. A. Bromberg et al. 1987. Lack of effect of low levels of
carboxyhemoglobin on cardiovascular function in patients with ischemic heart disease. Arch.
Environ. Health 42: 108-116. (Cited by U.S. EPA, 2000a).
Simmon, V.F., K. Kauhanen and R.G. Tardiff 1977. Mutagenic activity of chemicals identified
in drinking water. Dev. Toxicol. Environ. Sci. 2: 249-258.
Stevens, J.L., J.H. Ratnayake and M.W. Anders. 1980. Metabolism of dihalomethanes to carbon
monoxide. IV. Studies in isolated rat hepatocytes. Toxicol. Appl. Pharmacol. 55:484-489.
Thier, R., J.B. Taylor, S. E. Pemble et al. 1993. Expression of mammalian glutathione
S-transferase 5-5 in Salmonella typhimurium TA1535 leads to base-pair mutations upon
exposure to dihalomethanes. Proc. Natl. Acad. Sci. 90:8576-8580.
Thier, R., S.E. Pemble, H. Kramer et al. 1996. Human glutathione S-transferase Tl-1 enhances
mutagenicity of 1,2-dibromoethane, dibromomethane and 1,2,3,4-diepoxybutane in Salmonella
typhimurium. Carcinogenesis. 17:163-166.
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U.S. EPA (Environmental Protection Agency). 1987. Health and Environmental Effects Profile
(HEEP) for Methylene Bromide. 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 (Environmental Protection Agency). 1991a. Chemical Assessments and Related
Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. April.
U.S. EPA (Environmental Protection Agency). 1991b. Air Quality Criteria for Carbon
Monoxide. Prepared by the Office of Research and Development, Washington, DC. NTIS
PB93-167492.
U.S. EPA (Environmental Protection Agency). 1994a. Chemical Assessments and Related
Activities (CARA). Office of Health and Environmental Assessment, Washington, DC.
December.
U.S. EPA (Environmental Protection Agency). 1994b. Methods for Derivation of Inhalation
Reference Concentrations and Application of Inhalation Dosimetry. Office of Research and
Development, Washington, DC. October. EPA/600/8-90/066F.
U.S. EPA (Environmental Protection Agency). 1997. Health Effects Assessment Summary
Tables. FY-1997 Update. Prepared by the Office of Research and Development, National
Center for Environmental Assessment, Cincinnati OH for the Office of Emergency and Remedial
Response, Washington, DC. July. EPA/540/R-97/036. NTIS PB97-921199.
U.S. EPA (Environmental Protection Agency). 2000a. Air Quality Criteria for Carbon
Monoxide. Office of Research and Development, National Center for Environmental
Assessment, Research Triangle Park, NC. EPA/600/P-99/001F. Online.
http://cfpub.epa.gov/ncea/isa/recordisplav.cfm?deid=18163#Download.
U.S. EPA (Environmental Protection Agency). 2000b. Benchmark Dose Technical Guidance
Document. Risk Assessment Forum, National Center for Environmental Assessment,
Washington, DC. External Review Draft. October 2000. EPA/630/R-00/001.
U.S. EPA (Environmental Protection Agency). 2005. Guidelines for Carcinogen Risk
Assessment and Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure
to Carcinogens. Risk Assessment Forum, Washington, DC. EPA/630/P-03/001F. Online.
http://www.epa.gov/raf/publications/pdfs/CANCER GUIDELINES FINAL 3-25-05.PDF.
U.S. EPA (Environmental Protection Agency). 2006. 2006 Edition of the Drinking Water
Standards and Health Advisories. Office of Water, Washington, DC. EPA 822-R-02-038.
Washington, DC. Online.
http://www.epa.gov/waterscience/drinking/standards/dwstandards.pdf.
U.S. EPA (Environmental Protection Agency). 2008. Integrated Risk Information System
(IRIS). Online. Office of Research and Development, National Center for Environmental
Assessment, Washington, DC. http://www.epa.gov/iris/.
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Van Bladeren, P. J., D.D. Breimer, G.M.T. Rottveel-Smijs et al. 1980. Mutagenic activation of
dibromomethane and dibromoethane by mammalian microsomes and glutathione S-transferases.
Mutat. Res. 74:341-346.
Van Bladeren, P. J., D.D. Breimer, G.R. Mohn et al. 1981. Metabolism and mutagenicity of
dibromoethane and dibromomethane. Mutat. Res. 85:270.
Wheeler, J.B., N.V. Stourman, R. Thier et al. 2001. Conjugation of haloalkanes by bacterial and
mammalian glutathione transferases: Mono- and dihalomethanes. Chem. Res. Toxicol.
14:1118-1127.
WHO (World Health Organization). 2008. Online Catalogs for the Environmental Health
Criteria Series. Online, http://www.who.int/ipcs/publications/ehc/ehc alphabetical/en/
index.html.
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APPENDIX A. DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION p-RfC VALUES FOR METHYLENE BROMIDE
For reasons noted in the main PPRTV document, it is inappropriate to derive provisional
toxicity values for methylene bromide. However, information is available for this chemical
which, although insufficient to support derivation of a provisional toxicity value, under current
guidelines, may be of limited use to risk assessors. In such cases, the Superfund Health Risk
Technical Support Center summarizes available information in an Appendix and develops a
"screening value." Appendices receive the same level of internal and external scientific peer
review as the PPRTV documents to ensure their appropriateness within the limitations detailed in
the document. Users of screening toxicity values in an appendix to a PPRTV assessment should
understand that there is considerably more uncertainty associated with the derivation of an
appendix screening toxicity value than for a value presented in the body of the assessment.
Questions or concerns about the appropriate use of screening values should be directed to the
Superfund Health Risk Technical Support Center.
Screening Subchronic p-RfC
The unpublished Keyes et al. (1982) study is the only adequate evaluation of the
inhalation toxicity of methylene bromide in animals. The only effect observed was an increase
in blood COHb levels in both rats and dogs. The rats were more sensitive than the dogs and had
mean COHb percentages that were significantly higher than control values at all exposure levels;
COHb percentages were significantly increased in the methylene bromide-exposed rats at
>25 ppm, where mean values ranged from 3-7% compared to 2-4% in unexposed controls
(Keyes et al., 1982). Regression analysis by the researchers predicted that the average increase
in percent COHb saturation (above controls) at 25 ppm was 2.6 in male rats and 2.3 in female
rats. Assessment of the toxicological significance of the 2-3% absolute increase in average
COHb levels in rats exposed to 25 ppm methylene bromide is complicated by the fact that most
of the relevant data on effects associated with increased COHb levels are in humans exposed to
methylene chloride or carbon monoxide (ATSDR, 2000; McKee and Bachman, 2000; U.S. EPA,
1987, 1991b). Methylene chloride and carbon monoxide do not necessarily produce the same
effects at the same COHb saturation percentages (ATSDR, 2000; Fozo and Penney, 1993).
Examination of other study endpoints in Keyes et al. (1982) showed no overtly adverse
effects or any other changes that could be related to increased COHb levels, but endpoints known
to be particularly sensitive to carboxyhemoglobinemia were not investigated. In particular,
based on human studies with methylene chloride and carbon monoxide, as summarized above,
the most sensitive health effects likely to be associated with increased COHb from exposure to
methylene bromide are subtle CNS and cardiovascular effects.
Based on the association of COHb and adverse effects in humans, the data on COHb
levels in rats (Keyes et al., 1982) are used as the basis for a provisional RfC for methylene
bromide. The data in Table 1 are amenable to Benchmark Concentration (BMC) analysis.
Pooling the data by sex across timed measurements for 30 days or longer, as was done in the
original study for regression analysis, appears reasonable on the basis of similarity of mean
COHb values. However, the study authors were not explicit about how the animals were
selected for each of the timed measurements, such that some of the measurements may have been
from the same animals. If that were the case, treating the measurements as independent
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observations would not be valid. This is particularly an issue for females, in which the
population from which to select was small (15 for the first two measurements, 10 for the last).
The same would hold for males if the selection was made from the animals set aside for the
90-day sacrifice but would not be considered an issue if animals were randomly selected from
the total population of 115 animals. Assuming the latter, BMC analysis was conducted on the
pooled male data as shown in Table 1. BMC analysis of female COHb levels was conducted on
the pooled data and on data from the last timed measurement (61 days). All BMC analyses were
performed using all the continuous models in BMDS (Ver. 2.12; U.S. EPA, 2008).
In the absence of information on a clear COHb increase that would be considered adverse
in rats, the default BMR, recommended for continuous data, of one estimated standard deviation
(SD) from the control mean was selected (U.S. EPA, 2000b); resulting in a 1 SD (1.6%) change
from the control mean (2.8%). This BMR is at or below the range of percent increase in COHb
(from baseline) associated with cardiovascular effects in sensitive human subpopulations
discussed previously. The linear and power models with nonhomogeneous (modeled) variance
provide the best fits (identical) and lowest BMCL for the male data set. None of the BMDS
models adequately fit the female data. None of the BMCLs for the female data were lower than
the lowest male BMCL. Otherwise, the data did not suggest that the females were more sensitive
than the males. Details of the modeling are presented in Appendix B.
The BMC results for the rats are converted to human equivalent concentrations (HEC) by
standard U.S. EPA methods (U.S. EPA, 1994b). The rat BMCL in mg/m3 is duration-adjusted
for intermittent exposure. Exposure in the Keyes et al. (1982) study was 6 hours per day, 5 days
per week. The resulting exposure adjustment factor is 0.1786. Because methylene bromide
exhibits its toxic effects outside of the respiratory tract, it is treated as a Category 3 gas for
purposes of calculating the p-RfC. The HEC for extrarespiratory effects produced by a
Category 3 gas is calculated by multiplying the duration-adjusted BMCL by the ratio of
blood:gas partition coefficients (Hb/g) in animals and humans. Hb/g values were not available for
methylene bromide in rats or humans. Using the default value of 1 for the ratio of partition
coefficients (U.S. EPA, 1994b), the BMCLhec is equivalent to the BMDLadj The BMDLhec
derivation is shown in Table A-l.
Table A-l.
BMC Modeling Resultsa for Carboxyhemoglobin (%)
in Male Rats Exposed to Methylene Bromide


BMC
BMCL
BMCL
BMCLhec
BMR
(ppm)
(ppm)
(mg/m3)0
(mg/m3)d
1 SD
14.67
10.15
72.17
12.9
aLinear model, modeled variance, AIC = 111.32; means p = 0.3598; variance p = 0.1374; details are shown in
Appendix B.
bKeyes et al., 1982.
°1 ppm =7.1 mg/m3; unadjusted for exposure protocol.
dBMCLnEc = BMCL x 6/24 hr x 5/7 days/week * [(Hb/g)RAT / (Hb/g)HUMANl, where
[(Hb/g)RAT / (Hb/g)HXJMANl = 1 •
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The POD (BMCLhec) of 12.9 mg/kg-day, based on increased COHb in rats
(Keyes et al., 1982), is used to derive the subchronic p-RfC as follows:
Screening Subchronic p-RfC = POD UF
= 12.9 mg/m3 - 300
= 0.04 or 4 x 10"2 mg/m3
The UF of 300 is composed of the following factors:
•	A partial UF of 3 (10°5) is applied for interspecies extrapolation to account for
potential pharmacodynamic differences between rats and humans. Converting the
rat data to human equivalent concentrations by the dosimetric equations accounts
for pharmacokinetic differences between rats and humans; thus, a full UF of 10
for interspecies extrapolation is not used.
•	A UF of 10 is applied for protection of sensitive human subpopulations.
•	A UF of 10 is applied to account for deficiencies in the database. Developmental
and reproductive toxicity studies are missing.
Screening Chronic p-RfC
No chronic inhalation toxicity study of methylene bromide was located. The critical
effect (increased COHb; Keyes et al, 1982) and the POD (12.9 mg/m3) is appropriate for the
screening chronic p-RfC derived as follows:
Screening Chronic p-RfC = POD UF
= 12.9 mg/m3 - 3000
= 0.004 or 4 x 10 3 mg/m3
The UF of 3000 is composed of the following factors:
•	A partial UF of 3 (10°5) is applied for interspecies extrapolation to account for potential
pharmacodynamic differences between rats and humans. Converting the rat data to
human equivalent concentrations by the dosimetric equations accounts for
pharmacokinetic differences between rats and humans; thus, a full UF or 10 for
interspecies extrapolation is not used.
•	An UF of 10 is applied for protection of sensitive human subpopulations.
•	An UF of 10 is applied to account for deficiencies in the database. Developmental and
reproductive toxicity studies are missing.
•	An UF of 10 is applied for extrapolation from subchronic to chronic duration.
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APPENDIX B. DETAILS OF BENCHMARK DOSE MODELING
FOR SUBCHRONIC INHALATION p-RfC
Results of Model Fitting for Blood COHb in Male and Female Rats (Keyes et al., 1982)
BMD modeling was conducted for increased blood carboxyhemoglobin (COHb) levels in
male and female rats observed by Keyes et al. (1982) using BMDS version 1.4.1 with default
parameter restrictions. The model-fitting procedure was run initially with a BMR of 1 standard
deviation change from the control mean as recommended by U.S. EPA (2000b).
The data for male rats were successfully fit to a linear model with modeled variance, as
shown in Table B-l. The best fitting model is illustrated in Figure B-l. The female data were
not amenable to BMD modeling, even with the highest concentration dropped. For females, both
with or without the high dose, the assumption of constant variance was not met. Although the
variance model built into the BMDS fit the data adequately, none of the available models fit the
means adequately with the variance model applied.
Table B-l. Model Predictions for Increased Carboxyhemoglobin in Rats
Model
Variance
/>-Valuc
Means
/>-Valuc
AIC
BMC
(ppm)
BMCL
(ppm)
Males, All dose groups, BMR = 1 Standard Deviation
Linear (modeled variance)13
0.137
0.360
111.32
14.676
10.155
Polynomial (2nd degree)
0.137
0.157
113.28
15.678
10.183
Polynomial (3rd degree)
0.137
0.173
113.13
16.433
10.279
Power0
0.137
0.360
111.32
14.676
10.155
Hilld
0.137
0.336
111.46
14.405
11.406
Females, All dose groups, BMR = 1 Standard Deviation
Linear (modeled variance)13'6
0.745
0.0041
114.50
19.130
12.607
Females, 61-day, BMR = 1 Standard Deviation
Linear (constant variance)13'6
0.230
0.00032
30.92
58.635
35.097
aValues <0.10 fail to meet conventional goodness-of-fit criteria.
bThe Constant Variance model did not fit.
°Power restricted to > 1.
intercept specified at control level to obtain sufficient degrees of freedom.
"Poorer fit obtained with other models (polynomial, power, Hill).
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Linear Model with 0.95 Confidence Level
Dose
10:51 05/06 2008
Figure B-l. Fit of Linear Model with Nonhomogeneous (Modeled) Variance to Data on
Increased Carboxyhemoglobin in Male Rats from Keyes et al., 1982
BMDs and BMDLs indicated are associated with a change of 1 SD from the control and are in units of ppm.
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