Toxicological
Profile
for
BROMODICHLOROMETHANE
Agency for Toxic Substances and Disease Registry
U.S. Public Health Service
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TOXICOLOGICAL PROFILE FOR
BROMOOICHLOROMETHANE
Prepared by:
Clement Associates
Under Contract No. 205-88-0608
Prepared for:
Agency for Toxic Substances and Disease Registry
U.S. Public Health Service
In collaboration with:
U.S. Environmental Protection Agency (EPA)
December 1989
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il
DISCLAIMER
Mention of company name or product does not constitute endorsement
by the Agency for Toxic Substances and Disease Registry.
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iii
FOREWORD
The Superfund Amendments and Reauthorization Act of 1986 (Public
Law 99-499) extended and amended the Comprehensive Environmental Response,
Compensation, and Liability Act of 1980 (CERCLA or Superfund). This public
law (also known as SARA) directed the Agency for Toxic Substances and Disease
Registry (ATSDR) to prepare toxicological profiles for hazardous substances
which are most commonly found at facilities on the CERCLA national Priorities
List and which pose the most significant potential threat to human health, as
determined by ATSDR and the Environmental Protection Agency (EPA). The lists
of the most significant hazardous substances were published in the Federal
Register on April 17, 1987, and on October 20, 1988.
Section 110 (3) of SARA directs the Administrator of ATSDR to prepare a
toxicological profile for each substance on the list. Each profile must
include the following content:
(A) An examination, summary and interpretation of available
toxicological information and epidemiological evaluations on the
hazardous substance in order to ascertain the levels of significant
human exposure for the substance and the associated acute, subacute,
and chronic health effects,
(B) A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, or chronic
health effects, and
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may present
significant risk of adverse health effects in humans.
This toxicological profile is prepared in accordance with guidelines
developed by ATSDR and EPA. The original guidelines were published in the
Federal Register on April 17, 1987. Each profile will be revised and
republished as necessary, but no less often than every 3 years, as required
by SARA.
The ATSDR toxicological profile is intended to characterize succinctly
the toxicological and health effects information for the hazardous substance
being described. Each profile identifies and reviews the key literature that
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iv
describes a hazardous substance's toxicological properties. Other literature
is presented but described in less detail than the key studies. The profile
is not intended to be an exhaustive document; however, more comprehensive
sources of specialty information are referenced.
Each toxicological profile begins with a public health statement, which
describes in nontechnical language a substance's relevant toxicological
properties. Following the statement is material that presents levels of
significant human exposure and, where known, significant health effects. The
adequacy of information to determine a substance's health effects is described
in a health effects summary. Data needs that are of significance to
protection of public health will be identified by ATSDR, the National
Toxicology Program of the Public Health Service, and EPA. The focus of the
profiles is on health and toxicological information; therefore, we have
included this information in the front of the document.
The principal audiences for the toxicological profiles are health
professionals at the federal, state, and local levels, interested private
sector organizations and groups, and members of the public. We plan to revise
these documents as additional data become available.
This profile reflects our assessment of all relevant toxicological
testing and information that has been peer reviewed. It has been reviewed by
scientists from ATSDR, EPA, the Centers for Disease Control, and the National
Toxicology Program. It has also been reviewed by a panel of nongovernment
peer reviewers and was made available for public review. Final responsibility
for the contents and views expressed in this toxicological profile resides
with ATSDR.
Ws >h.D.
Acting Administrator
Agency for Toxic Substances and
Disease Registry
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V
CONTENTS
DISCLAIMER il
FOREWORD iii
LIST OF FIGURES ix
LIST OF TABLES xi
1. PUBLIC HEALTH STATEMENT 1
1.1 WHAT IS BROMODICHLOROMETHANE? 1
1.2 HOW MIGHT I BE EXPOSED TO BROMODICHLOROMETHANE? 1
1.3 HOW CAN BROMO DI CHLOROMETHANE ENTER AND LEAVE MY BODY? 2
1.4 HOW CAN BROMODICHLOROMETHANE AFFECT MY HEALTH? 2
1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE
BEEN EXPOSED TO BROMODICHLOROMETHANE? 2
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL
HEALTH EFFECTS? 3
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE
TO PROTECT HUMAN HEALTH? 3
1.8 WHERE CAN I GET MORE INFORMATION? 3
2. HEALTH EFFECTS 9
2.1 INTRODUCTION 9
2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 9
2.2.1 Inhalation Exposure 10
2.2.1.1 Death 10
2.2.1.2 Systemic Effects 10
2.2.1.3 Immunological Effects 10
2.2.1.4 Neurological Effects 10
2.2.1.5 Developmental Effects 10
2.2.1.6 Reproductive Effects 10
2.2.1.7 Genotoxic Effects 10
2.2.1.8 Cancer 10
2.2.2 Oral Exposure 11
2.2.2.1 Death 11
2.2.2.2 Systemic Effects 11
2.2.2.3 Immunological Effects 19
2.2.2.4 Neurological Effects 20
2.2.2.5 Developmental Effects 20
2.2.2.6 Reproductive Effects 21
2.2.2.7 Genotoxic Effects 21
2.2.2.8 Cancer 21
2.2.3 Dermal Exposure 21
2.2.3.1 Death 22
2.2.3.2 Systemic Effects ..... 22
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Vi
2.2.3.3 Immunological Effects 22
2.2.3.4 Neurological Effects . 22
2.2.3.5 Developmental Effects 22
2.2.3.6 Reproductive Effects ... 22
2.2.3.7 Genotoxic Effects 22
2.2.3.8 Cancer 22
2.3 RELEVANCE TO PUBLIC HEALTH 22
2.4 LEVELS IN HUMAN TISSUES AND FLUIDS ASSOCIATED WITH
HEALTH EFFECTS 23
2.5 LEVELS IN THE ENVIRONMENT ASSOCIATED WITH LEVELS
IN HUMAN TISSUES AND/OR HEALTH EFFECTS 25
2.6 TOXICOKINETICS 25
2.6.1 Absorption 25
2.6.1.1 Inhalation Exposure , 25
2.6.1.2 Oral Exposure 25
2.6.1.3 Dermal Exposure 26
2.6.2 Distribution 26
2.6.2.1 Inhalation Exposure 26
2.6.2.2 Oral Exposure 26
2.6.2.3 Dermal Exposure . 26
2.6.3 Metabolism 26
2.6.4 Excretion 27
2.6.4.1 Inhalation Exposure 27
2.6.4.2 Oral Exposure 27
2.6.4.3 Dermal Exposure . 27
2.7 INTERACTIONS WITH OTHER CHEMICALS 27
2.8 POPULATIONS THAT ABE UNUSUALLY SUSCEPTIBLE 28
2 .9 ADEQUACY OF THE DATABASE 28
2.9.1 Existing Information on Health Effects of BDCM 29
2.9.2 Data Needs 29
2.9.3 On-going Studies 33
3. CHEMICAL AND PHYSICAL INFORMATION 35
3.1 CHEMICAL IDENTITY 35
3.2 PHYSICAL AND CHEMICAL PROPERTIES 35
4. PRODUCTION, IMPORT, USE, AND DISPOSAL 39
4.1 PRODUCTION 39
4.2 IMPORT 39
4.3 USE 39
4.4 DISPOSAL 39
4.5 ADEQUACY OF THE DATABASE 40
4.5.1 Data Needs 40
5. POTENTIAL FOR HUMAN EXPOSURE 41
5.1 OVERVIEW 41
5.2 RELEASES TO THE ENVIRONMENT 41
5.2.1 Air 41
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vit
5.2.2 Water 41
5.2.3 Soil 42
5.3 ENVIRONMENTAL FATE 42
5.3.1 Transport and Partitioning 42
5.3.2 Transformation and Degradation 43
5.3.2.1 Air 43
5.3.2.2 Water 43
5.3.2.3 Soil 44
5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 44
5.4.1 Air 44
5.4.2 Water 44
5.4.3 Soil 45
5.4.4 Other Media 46
5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 46
5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 46
5.7 ADEQUACY OF THE DATABASE 47
5.7.1 Data Needs 47
5.7.2 On-going Studies 49
6. ANALYTICAL METHODS 51
6.1 BIOLOGICAL MATERIALS 51
6.2 ENVIRONMENTAL SAMPLES 53
6.3 ADEQUACY OF THE DATABASE 53
6.3.1 Data Needs 53
6.3.2 On-going Studies 55
7. REGULATIONS AND ADVISORIES 57
8. REFERENCES 59
9. GLOSSARY 71
APPENDIX 77
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ix
LIST OF FIGURES
2-1 Levels of Significant Exposure to BDCM--Oral 16
2-2 Existing Information on Health Effects of BDCM 30
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xi
LIST OF TABLES
1-1 Human Health Effects from Breathing BDCM 4
1-2 Animal Health Effects from Breathing BDCM 5
1-3 Human Health Effects from Eating or Drinking BDCM 6
1-4 Animal Health Effects from Eating or Drinking BDCM 7
2-1 Levels of Significant Exposure to BDCM - Oral 12
2-2 Genotoxicity of BDCM 24
3-1 Chemical Identity of BDCM 36
3-2 Physical and Chemical Properties of BDCM 37
6-1 Analytical Methods for BDCM in Biological Samples ......... 52
6-2 Analytical Methods for BDCM in Environmental Media 54
7-1 Regulations and Guidelines Applicable to BDCM 58
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1. PUBLIC HEALTH STATEMENT
1.1 WHAT IS BROMODICHLOROMETHANE?
Bromodichloromethane (BDCM) is a colorless, heavy, nonburnable
liquid. BDCM does not usually exist as a liquid in the environment.
Rather, it usually is found evaporated In air or dissolved in water.
Most BDCM in the environment is formed as a by-product when
chlorine is added to drinking water to kill disease-causing organisms.
Small amounts of BDCM are also made in chemical plants for use in
laboratories or in making other chemicals. A very small amount (less
than 1% of the amount coming from human activities) is formed by algae
in the ocean.
BDCM evaporates quite easily, so most BDCM that escapes into the
environment from chemical facilities, waste sites, or drinking water
enters the atmosphere as a gas. BDCM is slowly broken down (about 90%
in a year) by chemical reactions in the air. Any BDCM that remains in
water or soil may also be broken down slowly by bacteria.
Further information on the properties and uses of BDCM, and how It
behaves in the environment, may be found in Chapters 3, 4, and 5.
1.2 HOW MIGHT I BE EXPOSED TO BROMODICHLOROMETHANE?
For most people, the most likely means of exposure to BDCM is by
drinking chlorinated water. Usually the levels in drinking water are
between 1 and 10 ppb (parts per billion). BDCM is also found in some
foods and beverages such as ice cream or soft-drinks that are made using
chlorinated water, but this is probably not a major source of exposure.
BDCM has been found In chlorinated swimming pools, where exposure might
occur by breathing the vapors or through the skin. Exposure to BDCM
might also occur by breathing BDCM in the air in or near a laboratory or
factory that made or used BDCM. However, BDCM is not widely used in
this country, so this is not likely for most people. Average levels of
BDCM in air are usually quite low (less than 0.2 ppb). Another place
where human exposure might occur is near a waste site where BDCM has
been allowed to leak into water or soil. In this situation, people
could be exposed by drinking the water or by getting the soil on their
skin. BDCM has been found in water and soil at some waste sites (about
1% to 10% of those tested), usually at levels of 1 to 50 ppb. Further
Information on how people might be exposed to BDCM is given in
Chapter 5.
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1. PUBLIC HEALTH STATEMENT
1.3 HOW CAN BROMODICHLOROMETHANE ENTER AND LEAVE MY BODY?
Studies in animals show that almost all BDCM swallowed in water or
food will enter the body by moving from the stomach or intestines into
the blood. It is likely that BDCM would also move from the lungs into
the blood if it were breathed in and would cross the skin if skin
contact occurred, but this has not been studied. Bromodichloromethane
leaves the body mostly by being breathed out through the lungs. Smaller
amounts leave in the urine and feces. BDCM removal is fairly rapid and
complete (about 95% in 8 hours), so it does not usually build up in the
body. Further information on how BDCM enters and leaves the body is
given in Chapter 2.
1.4 HOW CAN BROMODICHLOROMETHANE AFFECT MY HEALTH?
The effects of BDCM depend on how much is taken into the body. In
animals, the main effect of eating or drinking large amounts of BDCM is
injury to the liver and kidneys. These effects can occur within a short
time after exposure. High levels can also cause effects on the brain,
leading to incoordination and sleepiness. There is some evidence that
BDCM can be toxic to developing fetuses, but this has not been well-
studied. Studies in animals show that intake of BDCM for several years
in food or water can lead to cancer of the liver, kidney and intestines.
Although effects of BDCM have not been reported in humans, effects would
probably occur if enough BDCM were taken into the body.
Further information on how BDCM can affect the health of humans and
animals is presented in Chapter 2.
1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE BEEN EXPOSED TO
BROMODICHLOROMETHANE?
Methods are available to measure low levels of BDCM in human blood,
breath, urine and fat, but not enough information is available to use
such tests to predict if any health effects might result. Because
special equipment is needed, these tests are not usually done in
doctors' offices. Because BDCM leaves the body fairly quickly, these
methods are best suited to detecting recent exposures. Further
information on how BDCM can be measured in exposed humans is presented
in Chapter 6.
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1. PUBLIC HEALTH STATEMENT
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?
Tables 1-1 through 1-4 show the relationship between exposure to
BDCM and known health effects. Minimal Risk Levels (MRLs) are also
included in Table 1-3. These MRLs were derived from animal data for
both short-term and longer-term exposure, as described in Chapter 2 and
in Table 2-1. These MRLs provide a basis for comparison with levels
that people might encounter either in food or drinking water. If a
person is exposed to BDCM at an amount below the MRL, it is not expected
that harmful noncancer health effects will occur. Because these levels
are based only on information currently available, some uncertainty is
always associated with them. Also, because the method for deriving MRLs
does not use any information about cancer, a MRL does not imply anything
about the presence, absence or level of risk of cancer. Further
information on the levels of BDCM that have been observed to cause
health effects in animals is presented in Chapter 2.
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT
HUMAN HEALTH?
The U.S. Environmental Protection Agency (EPA) has set a Maximum
Contaminant Level in drinking water of 0.10 ppm (parts per million) for
the combination of BDCM and a group of similar compounds
(trihalomethanes). Most water samples in the U.S. have BDCM levels
lower than this. The Food and Drug Administration (FDA) has set the
same limit for bottled water, but no tolerance limits have been set for
BDCM in food. Because it has such limited use in industry, there is no
Occupational Safety and Health Administration standard for BDCM.
Further information on regulations concerning BDCM is presented in
Chapter 7.
1.8 WHERE CAN I GET MORE INFORMATION?
If you have further questions or concerns, please contact your
State Health or Environmental Department or:
Agency for Toxic Substances and Disease Registry
Division of Toxicology
1600 Clifton Road, E-29
Atlanta, Georgia 30333
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1. PUBLIC HEALTH STATEMENT
TABLE 1-1. Human Health Effects from Breathing BDCM*
Short-term Exposure
(less than or equal to 14 days)
Levels in
Length of
Air (ddih)
Exposure Descriotion of Effects
The health effects resulting from
short-term human exposure to air
containing specific levels of
BDCM are not known.
Long-term Exposure
(greater than 14 days)
Levels in
Length of
Air (mm)
Exposure Descriotion of Effects
The health effects resulting from
long-term human exposure to air
containing specific levels of
BDCM are not known.
* See Section 1.2 for a discussion of exposures encountered in daily
life.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-2. Animal Health Effects from Breathing BDCM
Short-term Exposure
(less than or equal to 14 days)
Levels in
Length of
Air (ppm">
Exposure Descriotion of Effects
The health effects resulting from
short-term animal exposure to
air containing specific levels
of BDCM are not known.
Long-term Exposure
(greater than 14 days)
Levels in
Length of
Air fppm)
Exposure Descriotion of Effects
The health effects resulting from
long-term animal exposure to
air containing specific levels
of BDCM are not known.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-3. Hunan Health Effects from Eating or Drinking BDCM*
(less
Short-term Exposure
than or equal to 14 days)
Levels in
Food fppm")
Length of
ExDosure
DescriDtion of Effects
1.3
Levels in
Water (ppm)
Estimated Minimal Risk Level
(based on studies in animals;
see Section 1.6 for discussion)
The health effects resulting from
short-term human exposure to
water containing specific
levels of BDCM are not known.
Long-term Exposure
(greater than 14 days)
Levels in
Food ( ddid)
Length of
ExDosure
Descrintion of Effects
0.6
Estimated Minimal Risk Level
(based on studies in animals;
see Section 1.6 for discussion)
Levels in
Water (dditA
The health effects resulting from
long-term human exposure to
water containing specific
levels of BDCM are not known.
* See Section 1.2 for a discussion of exposures encountered In daily
life.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-4. AnLmal Health Effects from Eating or Drinking BDCH
Short-term Exposure
(less than or equal to 14 days)
Levels in
Food (ppra)
Length of
Exposure
Description of Effects
280
14 days
Liver injury in mice.
570
14 days
Kidney injury in mice.
1,000
10 days
Impaired fetal development in rats.
1,200
14 days
Death in mice.
Levels in
Water (m>m}
The health effects resulting from
short-term animal exposure to
water containing specific
levels of BDCM are not known.
Long-term Exposure
(greater than 14 days)
Levels in
Food fppm)
Length of
Exposure
DescriDtion of Effects*
190
2 years
Kidney injury in mice.
380
2 years
Liver injury in mice.
Levels in
Water (oom)
The health effects resulting from
long-term animal exposure to
water containing specific
levels of BDCM are not known.
* These effects are listed at the lowest level at which they were first
observed. They may also be seen at higher levels.
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2. HEALTH EFFECTS
2.1 INTRODUCTION
This chapter contains descriptions and evaluations of studies and
interpretation of data on the health effects associated with exposure to
BDCM. Its purpose is to present levels of significant exposure for BDCM
based on toxicological studies, epidemiological investigations, and
environmental exposure data. This information is presented to provide
public health officials, physicians, toxicologists, and other interested
individuals and groups with (1) an overall perspective of the toxicology
of BDCM and (2) a depiction of significant exposure levels associated
with various adverse health effects.
2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE
To help public health professionals address the needs of persons
living or working near hazardous waste sites, the data in this section
are organized first by route of exposure--inhalation, oral, and dermal--
and then by health effect--death, systemic, immunological, neurological,
developmental, reproductive, genotoxic, and carcinogenic effects. These
data are discussed in terms of three exposure periods--acute,
intermediate, and chronic.
Levels of significant exposure for each exposure route and duration
(for which data exist) are presented in tables and illustrated in
figures. The points in the figures showing no-observed-adverse-effect
levels (NOAELs) or lowest-observed-adverse-effect levels (LOAELs)
reflect the actual doses (levels of exposure) used in the studies.
LOAELs have been classified into "less serious" or "serious" effects.
These distinctions are intended to help the users of the document
identify the levels of exposure at which adverse health effects start to
appear, determine whether or not the intensity of the effects varies
with dose and/or duration, and place into perspective the possible
significance of these effects to human health.
The significance of the exposure levels shown on the tables and
graphs may differ depending on the user's perspective. For example,
physicians concerned with the interpretation of clinical findings in
exposed persons or with the identification of persons with the potential
to develop such disease may be interested in levels of exposure
associated with "serious" effects. Public health officials and project
managers concerned with response actions at Superfund sites may want
information on levels of exposure associated with more subtle effects in
humans or animals (LOAEL) or exposure levels below which no adverse
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2. HEALTH EFFECTS
effects (NOAEL) have been observed. Estimates of levels posing minimal
risk to humans (minimal risk levels, MRLs) are of interest to health
professionals and citizens alike.
For certain chemicals, levels of exposure associated with
carcinogenic effects may be indicated in the figures. These levels
reflect the actual doses associated with the tumor incidences reported
in the studies cited. Because cancer effects could occur at lower
exposure levels, the figures also show estimated excess risks, ranging
from a risk of one in 10,000 to one in 10,000,000 (10"* to 10"7), as
developed by EPA.
Estimates of exposure levels posing minimal risk to humans (MRLs)
have been made, where data were believed reliable, for the most
sensitive noncancer end point for each exposure duration. MRLs include
adjustments to reflect human variability and, where appropriate, the
uncertainty of extrapolating from laboratory animal data to humans.
Although methods have been established to derive these levels (Barnes
et al. 1987; EPA 1980d), uncertainties are associated with the
techniques.
2.2.1 Inhalation Exposure
No studies were located regarding the following health effects in
humans or experimental animals following inhalation exposure to BDCM:
2.2.1.1
Death
2.2.1.2
Systemic Effects
2.2.1.3
Immunological Effects
2.2.1.4
Neurological Effects
2.2.1.5
Developmental Effects
2.2.1.6
Reproductive Effects
2.2.1.7
Genotoxic Effects
2.2.1.8
Cancer
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2. HEALTH EFFECTS
2.2.2 Oral Exposure
No studies were located regarding health effects in humans
associated with ingestion of BDCM. Figure 2-1 and Table 2-1 summarize
the health effects observed in experimental animals following oral
exposure to BDCM. These effects are discussed below.
2.2.2.1 Death
Most estimates of acute oral LDS0 values for BDCM in rodents range
between 400 and 1000 mg/kg (Aida et al. 1987; Chu et al. 1980; Bowman
et al. 1978). Typical pathological changes observed in acutely poisoned
animals include fatty infiltration of liver and hemorrhagic lesions in
kidney, adrenals, lung and brain (Bowman et al. 1978). In a 14-day
repeated-dose study in mice, all animals dosed with 150 mg/kg/day died
(NTP 1987). This dose has been converted to an equivalent concentration
of 1,200 ppm in food for presentation in Table 1-4. Males appear to be
slightly more susceptible to the lethal effects of BDCM than females,
both in rats (Aida et al. 1987; Chu et al. 1980, 1982a; NTP 1987), and
in mice (Bowman et al. 1978; NTP 1987).
The highest NOAEL values and all reliable LOAEL values for death in
each species and duration category are recorded in Table 2-1 and plotted
in Figure 2-1.
2.2.2.2 Systemic Effects
No studies were located regarding effects on the respiratory,
cardiovascular, gastrointestinal, musculoskeletal, or dermal systems in
humans or animals following oral exposure to BDCM.
Hematological Effects. Hemoglobin and hematocrit were
significantly reduced in male rats following a single dose of 390 mg/kg
of BDCM (Chu et al. 1982a). The basis of this effect was not
investigated. Exposure in drinking water for 90 days to a dose of
213 mg/kg/day caused no effect on lymphocyte levels in either males or
females (Chu et al. 1982b). A slight reduction in lymphocyte count was
noted in females 90 days after exposure ceased, which the authors felt
might be related to endogenous release of steroids. Rats fed BDCM in
their diets at intake levels of 130 mg/kg/day for 24 months exhibited no
hematological changes compared to controls (Tobe et al. 1982).
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12
2. HEALTH EFFECTS
TABLE 2-1. Levels of Significant Exposure to BDCM - Oral
Graph
Expoaura
Duration/ Syat.
bjr Spaclaa Fraquancy If fact
(Route)
MOAEL Lata Serloua
l/kc/day /day
LOAIL (Itfact>
Serloua
I/kg/day
Rafaranca
ACUTE EXPOSURE
Daach
1
rat
1 doaa
Ranal
390
Chu at al. 1982a
10
rat
(C>
1 doaa
Beaato
390 decreaaed
haoatocrlt
Chu at al. 1982a
11
rat
(0)
1 doaa
Bapatle
)9«
495 SPT
990 OPT
Bawltt at al.
1983
12
¦ouaa
<«
14 d
Ranal
75
150 raddanad
aadullaa
¦TP 1987
13
aouia
(S)
14 d
Ranal
250 BUR
Munaon at al.
1982
14
aouaa
14 d
Bapatle
125 fibrinogen
Hum on at al.
1982
15
¦euaa
(0)
14 d
Bapatle
37Bleroaooplc
letloni
Condla at al.
1983
16
aouaa
(0)
14 d
Ranal
74 PAH
lnhlb.
148 aleroicople
laalona
Condla at al.
1983
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2. HEALTH EFFECTS
TABLE 2-1. - continued
Graph
Exposure
DuratIon/
Sjrst.
LOAEL (Effect)
Key
Species
(Rout*)
^Fyequsney
Effsct
BQAEL
mg/kg/day
Leas Serious Serious
mg/kg/day mg/kg/day
Reference
17
mouse
«!)
14 d
Bepat ie
123 liver vt.
Inc.
Munson et al.
1982
IS
¦oute
1 dose
273 coordination
Balster and
Borselleca 1962
22
mouse
CO)
1 dose
600 lethargy
HTP 1987
23
mouse
(C)
14 d
11.6
Balster and
Borselleca 1982
Developmental
2*
rat
(C)
10 d
d. 6-10
of gest.
50 fatotox.
Ruddiek et al.
1983
INTERMEDIATE EXPOSURE
Death
23
rat
00
28 d
120
Chu at al. 1982a
26
mouse
28 d
Renal
120
Chu at al. 1982a
28
rat
cwj
SO d
Bepatlo
7 lesions
Chu et al. 1982b
29
rat
00
28 d
Hepatic
120
Chu et al. 19(2a
30
rat
(0)
13
3d/vk
Bepatie
130
300 lesions
KTP 1987
31
rat
90 d
Bemato
213
Chu at al. 1982b
33
rat
(G)
13 wk
5d/vk
Renal
190
300 lesions
m 1987
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14
2. HEALTH EFFECTS
TABLE 2-1.
- continued
Graph
Expoaure
DuratIon/
Syat.
LOAEL (Effact)
Key
Special
(Rout*)
^F^requency
Effect
MGAEL
mt/kt/dajr
Lata Serloui Sarloua
ag/kg/day ag/kg/diy
Reference
34
mouae
(C)
13 wk
5d/wk
Hepatic
100
200
lea ion*
HTP 1987
35
nun
(C)
13 wk
5d/wk
Hepatic
100
HTP 1987
36
moult
24 ao
Ranal
220
Toba at al. 1982
44
rat
CI)
24 ao
Hamato
220
Toba at al. 1982
45
rat
(6)
104 Vk
Sd/wk
Ranal
50 cytooegaly
KT? 1987
46
rat
CP)
24 mo
Hapat Le
41
220 CPI
Toba at al. 1982
47
aouaa
(C)
104 wk
5d/wk
Ranal
25eytomegaly
MTP 1987
4B
I
m
•
(C)
104 wk
54/wk
Ranal
150
HTP 1987
49
mouaa
(0)
104 wk
Sd/wk
Hepatic
50 fatty degn.
MTP 1987
-------
15
2. HEALTH EFFECTS
TABLE 2-1. - continued
Craph
Exposure
Duration/ Syst
Frequency Ef f ec
(Rout*)
NOAEL Less Serious Serious
og/kg/day Bt/kg/day sig/kg/dey
LOAEL (Effect)
Reference
Cancer
rat (U) 180 trie
7d/vk
ISO CEL (liver Tuoasonls at al.
tumors) 1985
51
rat (G) 104 vk
5d/vk
50 CEL
(intestinal
earclnooa)
HTP 1987
52
mouse (S) 104 *k
Sd/vk
50 CEL (renal KTP 1987
careLnooa)
53
mouaa (C) 104 vk
3d/vk
75 CEL (llvar HTP 1987
tumora)
* G " Cavagei U - DrinkIn* Water, F - Peed.
'"'used to darlv* acuta oral MRL: doae divided by an uncertainty factor of 1,000 (10 for uaa
of a LOAEL, 10 for extrapolation from animals to humans, and 10 for human variability).
'c^Uied to dorlva chronic oral MRL: doaa adjusted for intermittent expoiure and dividad
by uncertainty factor of 1,000 (10 for uaa of a LOAEL, 10 for extrapolation from animala
to humana, and 10 for human variability), resulting in an MRL of 0.018 og/kg/day. Thi* MRL has
been converted to an equivalent concentration in food (O.i ppm) for preaentation in Table 1-3.
LOAEL ™ lowest-obaerved-adveraa-affact leveli HOAEL " no-observed-adverae-effect leveli aig/kg/day ¦
siilligram/kilograa/dayi (C) ¦ gavagei LD50 * lethal doaa, 50X mortality! d - dayi vt. - weight) hemato ¦
hematologicali CPT - glutamate-pyruvate tranaaainaaei BUH ¦ blood urea nltrogem PAH - para-aolno hippurlc
aeldi inhib. - inhibition) inc. " increasedi fetotox - fetotoxicltyi geat - gestation! (W) ¦ drinking
vateri vk - veeki degen - degeneration* (F) - food) mo - monthi CEL - cancer effect level.
-------
(mg/kg/d)
10,000
ACUTE
(£14 Days)
~ / S /
/
&
/
1,000
100
sp I
cr
10
O?
o* o—
Am
•••
o»«
1.0
0.1
0.01
0.001
Key
r m
Mrand nih lor bWhIi
m mouM
• LOAEL lor awtm (fee* (arm**)
oNr tan uncar
CJ LQAEL tor tan MriM aUtcfe (anbnab)
O NOAEI (arm*)
rnnttoMdt^DNcorwponAtotnMMln N aocon
1*nytng
FIGURE 2-1. Levels of Significant Exposure to BDCM - Oral
-------
INTERMEDIATE
(15-364 Days)
CHRONIC
(>365 Days)
(mgftgMay)
10.000 r
1.000
100
s / s //
* £ £
s M
# lOMEl k»Mriou> (animri«|
' WIVWH 11^ wv
¦l MM
9 LCMEL k> lm MrfcM >4tocli (arfcnah)
» oNrtHncflnoit
O MCMEl InMi)
0.001
L
^ CEl-Camr Effect (ml
Tin nwnbar naif to Mch poM conapoMb to anfrtoi In tw aeoo
Mw.
v/
A51"
*
I
X
FJ
~*1
W
O
H
Vi
FIGURE 2-1. (con't)
-------
18
2. HEALTH EFFECTS
Hepatic Effects. A number of studies in animals indicate that the
liver is susceptible to injury by BDCM. Typical signs include increased
liver weight, pale discoloration, increased levels of hepatic tissue
enzymes in serum, decreased levels of secreted hepatic proteins
(fibrinogen) in blood, and focal areas of inflammation or degeneration.
In acute (single dose) studies, these effects have been noted at doses
of around 1,250 mg/kg or higher (NTP 1987). It should be noted that
this dose level causes death within two weeks (NTP 1987).
In subchronic studies (10 to 14 days) in mice and rats, mild
effects on liver have been noted at doses as low as 37 mg/kg/day (Condie
et al. 1983) and 50 mg/kg/day (Ruddick et al. 1983). Effects included
slightly increased liver weights (Ruddick et al. 1983) and microscopic
changes that were rated as "minimal" (Condie et al. 1983). The effects
become more pronounced at doses of 125 to 300 mg/kg/day (Condie et al.
1983; Munson et al. 1982). The dose of 37 mg/kg/day has been converted
to an equivalent concentration of 280 ppm in food for presentation in
Table 1-4.
Although hepatic effects at doses of 40 to 50 mg/kg/day are
minimal, it appears that this is the approximate threshold for the
appearance of more marked effects at higher doses, so the dose of
37 mg/kg/day (Condie et al. 1983) has been used to derive the acute MRL
for BDCM. Based on this value, an acute oral MRL of 0.037 mg/kg/day was
calculated, as described in the footnote in Table 2-1. This MRL has
been converted to an equivalent concentration in food (1.3 ppm) for
presentation in Table 1-3.
Most longer-term studies report signs of liver injury in rats or
mice at doses of 50 to 200 mg/kg/day (Dunnick et al. 1987; NTP 1987;
Tobe et al. 1982). These doses are not significantly different from
those observed to cause hepatic injury in acute and short-term studies,
suggesting that there is a relatively low tendency toward cumulative
injury to liver.
An exception is the study of Chu et al. (1982b), where
statistically significant effects on liver were noted in rats exposed to
doses as low as 7 mg/kg/day for 90 days. However, these effects were
minimal (the authors assigned a severity score of 2 on a scale of I to
10) and showed essentially no dose-response tendency. Because this
observation is of uncertain significance and is inconsistent with NOAEL
-------
19
2. HEALTH EFFECTS
estimates from other intermediate and chronic studies, it has not been
selected for calculation of a longer-term MRL. The chronic dose level
of 50 mg/kg/day (NTP 1987) has been converted to an equivalent
concentration of 380 ppm in food for presentation in Table 1-4.
The highest NOAEL values and all reliable LOAEL values for hepatic
injury in each species and duration category are recorded in Table 2-1
and plotted in Figure 2-1.
Renal Effects. Studies in animals reveal that the kidney is also
susceptible to injury by BDCM, typically at dose levels similar to those
that effect the liver. For example, in 14-day studies, Munson et al.
(1982) observed increases in blood urea nitrogen (BUN) in mice dosed
with 250 mg/kg/day, and Condie et al. (1983) reported decreased uptake
of p-aminohippurate (PAH) into kidney slices from mice dosed with 74 to
148 mg/kg/day. Similarly, Ruddick et al. (1983) observed increased
renal weight in rats dosed with 200 mg/kg/day for 10 days. The dose of
74 mg/kg/day has been converted to an equivalent concentration of
570 ppm in food for presentation in Table 1-4.
In longer-term studies, areas of focal necrosis were observed in
the proximal tubular epithelium in male mice exposed for 13 weeks to
doses of 100 mg/kg/day, and cytomegaly was noted following chronic
exposure to 25 mg/kg/day (Dunnick et al. 1987; NTP 1987). Female mice
were somewhat less susceptible than males. In rats, cytomegaly and
nephrosis were observed in both males and females at chronic exposure
levels of 50 to 100 mg/kg/day (NTP 1987). The dose of 25 mg/kg/day has
been converted to an equivalent concentration of 190 ppm in food for
presentation in Table 1-4. This dose has also been selected as the most
appropriate value for calculation of the chronic MRL for BDCM. Based on
this value, a chronic oral MRL of 0.018 mg/kg/day was calculated, as
described in the footnote in Table 2-1. This MRL has been converted to
an equivalent concentration in food (0.6 ppm) for presentation in
Table 1-3.
The highest NOAEL values and all reliable LOAEL values for renal
injury in each species and duration category are recorded in Table 2-1
and plotted in Figure 2-1.
2.2.2.3 Immunological Effects
The effects of BDCM on the immune system have not been thoroughly
studied. Munson et al. (1982) administered BDCM to mice for 14 days,
and observed a decrease in female mice in the number of antibody forming
-------
20
2. HEALTH EFFECTS
cells in spleen and a decrease In the hemagglutination titer at doses of
125 to 250 mg/kg/day. The authors felt that the humoral immune system
may have potential to serve as an early indicator of halomethane
toxicity.
2.2.2.4 Neurological Effects
No studies were located regarding histological or
electrophysiological effects of BDCH on the nervous system. Rats and
mice administered oral doses of 150 to 600 mg/kg often display acute
signs of CNS depression, including lethargy, labored breathing, sedation
and flaccid muscle tone (NTP 1987; Aida et al. 1987; Balster and
Borzelleca 1982; Chu et al. 1980). These effects tend to reverse after
a period of several hours.
To determine whether BDCM exposure resulted in any longer-lasting
changes in behavior, Balster and Borzelleca (1982) performed a series of
tests in mice 24 hours or more after the last of a series of doses of
BDCM. Exposure to doses of 1.2 to 11.6 mg/kg/day for 14 to 90 days had
no effect on tests of coordination, strength, endurance or exploratory
activity, and 90 days exposure to 100 mg/kg/day did not effect passive-
avoidance learning. Exposure to 100 or 400 mg/kg/day for 90-days did
result in an acute effect on operant behavior (decreased pressing of a
lever that presented food), but this change tended to diminish over the
exposure period, suggesting there was no progressive effect and that
partial tolerance developed.
The highest NOAEL values and all reliable LOAEL values for
neurological effects in each species and duration category are recorded
in Table 2-1 and plotted in Figure 2-1.
2.2.2.5 Developmental Effects
Ruddick et al. (1983) reported an increased incidence of sternebral
anomalies in fetuses from rats that had been exposed to BDCM at doaes of
50 to 200 mg/kg/day on days 6 to 15 of gestation (the critical period
for organogenesis). No other dose-related visceral or skeletal
anomalies were observed. The authors interpreted the sternebral
anomalies to be evidence of a fetotoxic (rather than a teratogenic)
effect. These doses also resulted in significant maternal toxicity, as
evidenced by a 40% reduction in body weight gain. The dose of 50
mg/kg/day has been converted to an equivalent concentration of 1,000 ppm
in food for presentation in Table 1-4.
-------
21
2. HEALTH EFFECTS
2.2.2.6 Reproductive Effects
No studies were located regarding reproductive effects in humans or
animals following oral exposure to BDCM.
2.2.2.7 Genotoxic Effects
An increased frequency of sister chromatic exchange (SCE) in mice
exposed to BDCM was reported by Morimoto and Koizumi (1983).
Statistically significant increases in SCEs in bone marrow cells were
observed in animals dosed with 50 or 100 mg/kg/day for 4 days. Mice
given the highest dose tested, 200 mg/kg/day for 4 days, died and could
not be evaluated for SCEs in bone marrow cells.
2.2.2.8 Cancer
No studies were located regarding carcinogenic effects in humans
following chronic oral exposure to BDCM per se. There are several
epidemiological studies that indicate there may be an association
between ingestion of chlorinated drinking water (which typically
contains BDCM) and increased risk of cancer in humans (Gottlieb et al.
1981; Kanarek and Young 1982; Marienfeld et al. 1986), but such studies
cannot provide information on whether any effects observed are due to
BDCM or to one or more of the hundreds of other byproducts that are also
present in chlorinated water.
However, chronic oral studies in animals provide convincing
evidence that BDCM is carcinogenic. In rats, increased frequency of
liver tumors was observed in females exposed to 150 mg/kg/day for
180 weeks (Tumasonis et al. 1985), and kidney tumors were observed in
both males and females exposed to 100 mg/kg/day (NTP 1987; Dunnick
et al. 1987). Incidences of renal tumors were 13/50 and 15/50 in males
and females, respectively. Tumors of the large intestine were also
observed in rats, at incidences of 13/50 and 45/50 in males exposed to
50 and 100 mg/kg/day, and at an incidence of 12/47 in females dosed at
100 mg/kg/day. In mice, renal tumors were observed in males dosed with
50 mg/kg/day, and hepatic tumors were observed in females dosed with 75
or 150 mg/kg/day. Increased intestinal tumors were not observed in mice
(Dunnick et al. 1987; NTP 1987).
2.2.3 Dermal Exposure
No studies were located regarding the following toxic effects in
humans or animals following dermal exposure to BDCM:
-------
22
2. HEALTH EFFECTS
2.2.3.1
Death
2.2.3.2
Systemic Effects
2.2.3.3
Immunological Effect:
2.2.3.4
Neurological Effects
2.2.3.5
Developmental Effects
2.2.3.6
Reproductive Effects
2.2.3.7
Genotoxic Effects
2.2.3.8
Cancer
2.3 RELEVANCE TO PUBLIC HEALTH
Oral exposure studies in animals identify the central nervous
system, the liver, the kidney and the intestine as the principal target
tissues of BDCM. Effects on the central nervous system (lethargy,
sedation) are observed mostly following large doses, and are likely the
result of a direct narcotic or anaesthetic effect similar to other
related chemicals (e.g., chloroform, carbon tetrachloride).
Effects on the liver and kidney include increased organ weight,
focal areas of inflammation or degeneration, and decreased function.
These effects tend to appear in both tissues at roughly similar doses,
usually between 25 and 100 mg/kg/day. This indicates that both tissues
are approximately equally susceptible to BDCM. The doses which lead to
renal and hepatic injury following intermediate or chronic exposure are
generally similar to those causing acute effects (e.g., see Figure 2-1),
suggesting that there is a relatively low tendency toward cumulative
injury for these noncarcinogenic endpoints. This is probably because
both the liver and the kidney are able to repair damaged cells or
replace dead cells within a short period after exposure.
BDCM exposure has also been observed to result in developmental
toxicity (Ruddick et al. 1983). However, data are available only for
doses that cause significant maternal toxicity, so it is not possible to
judge whether developmental effects are likely to occur in animals or
humans exposed at lower dose levels.
-------
23
2. HEALTH EFFECTS
The greatest reason for concern with BDCM exposure is evidence from
animal studies that BDCM is carcinogenic. Compared with other
trihalomethanes (THMs), BDCM causes the widest spectrum of neoplasms in
rats and mice, and is the only THM observed to cause intestinal tumors
(Dunnick et al. 1987). In addition, BDCM has been found to be mutagenic
in some (but not all) in vitro gene mutation and sister chromatid
exchange assays (summarized in Table 2-2). BDCM has also been reported
to cause increased sister chromatid exchange in bone marrow cells of
mice exposed in vivo (Morimoto and Koizumi 1983). These positive
carcinogenicity and genotoxicity studies indicate that exposure to BDCM
in chlorinated water or near waste sites might contribute to increased
risk of cancer in humans.
Several studies indicate that there are differences in
susceptibility to BDCM between species and between sexes. With regard
to lethality, for example, male mice are more susceptible than female
mice, and both male and female mice are more susceptible than rats.
Male mice are also more susceptible to the renal effects of BDCM than
females, while in rats, males respond to BDCM with renal cytomegaly and
females develop nephrosis. Intestinal tumors are observed in both male
and female rats, but not in mice. The basis of these differences is not
known, but may possibly be attributed to differences in disposition and
metabolism of BDCM between sexes and species. That significant
differences exist have been demonstrated by Mink et al. (1986) and Smith
et al. (1985), as discussed below in Section 2.6.
Because of the differences in dose susceptibility and tissue
specificity observed between sexes and species in animal studies, it Ik
difficult to extrapolate the observations in animals to humans. Until
an improved understanding of the mechanistic or toxicokinetic basis of
these variables is achieved, it is prudent to assume that the same
effects observed In animals will be observed in humans Ingesting
comparable dose levels.
2.4 LEVELS IN HUMAN TISSUES AND FLUIDS ASSOCIATED WITH HEALTH EFFECTS
BDCM was not detected in samples of human fat studied in the
National Human Adipose Tissue Survey (NHATS) (EPA 1986c), and was not
detected in the blood of 250 patients studied by Antoine et al. (1986).
-------
24
2. HEALTH EFFECTS
TABLE 2-2. Genotoxicity of BDCM
End
Point
Speciea/
Teat Sytttm
Result
Reference
Cane Mutation
Salmonella
(4 strains)
Negative, vlth and
without activation
KTP 1987
G«na Mutation
Saccharooyces
XVI85-14C
reveralon
Negative, vlth
activation!
weakly positive,
without activation
Neatmann and
Lee 1985
Gene Mutation
Saccharomycea
D7 gene
converj ion
Negative, vlth
activation]
weakly positive,
without activation
Neatmann and
Lee 1985
Gene Mutation
Mouse
lymphoma
Positive, with
actlvatloni
negative, without
activation
NTP 1987
Chromosomal
aberration*
Chinese Hamster
ovary (CHO) cella
Negative, vlth
and without
activation
NTP 1987
Slater Chromatid
Exchange
CBO cella
Negative, vlth
and without
activation
NTP 1987
Slatar Chromatid
Exchange
Human
lymphocytes
Delayed cell
turnoveri
moderate activity
Mo r I mot o
and Kolguml
1983
Slatar Chromatid
Exchange
Human lymphoid
cells
Elevation In
frequency of SCE's
Sobtl
1984
Slatar Chromatid
Exchange
Rat liver
cells
Increased SOX
above control
Sobtl 1984
-------
25
2. HEALTH EFFECTS
A BDCM concentration of 14 ng/ml was found in a blood sample from one
resident living near a waste site in New York (Barkley et al. 1980), but
the significance of this isolated observation is difficult to judge. No
other studies were located regarding levels of BDCM in human tissues and
fluids.
2.5 LEVELS IN THE ENVIRONMENT ASSOCIATED WITH LEVELS IN HUMAN TISSUES
AND/OR HEALTH EFFECTS
No studies were located regarding the relationship between
environmental levels of BDCM and levels of BDCM in human tissues or
fluids or the occurrence of any adverse health effects. Epidemiological
studies which indicate there may be an association between consumption
of chlorinated water (which contains BDCM) and increased risk of cancer
are consistent with, but do not establish, the hypothesis that BDCM
increases cancer risk in humans, since chlorinated water contains
hundreds of other chemicals as well.
2.6 TOXICOKINETICS
No studies were located regarding BDCM toxicokinetics in humans,
but there are limited data from studies in animals. These data are
summarized below.
2.6.1 Absorption
2.6.1.1 Inhalation Exposure
No studies were located regarding absorption following inhalation
exposure to BDCM. By analogy with other similar chemicals, it seems
likely that BDCM would be well absorbed across the lung in both humans
and animals.
2.6.1.2 Oral Exposure
Female monkeys, dosed with radioactive BDCM by gavage, excreted 2%
of the administered radioactivity in feces, indicating that
gastrointestinal absorption was essentially complete (Smith et al.
1985). In mice, absorption was also rapid and extensive (Mink et al.
1986). Within eight hours of administration, 90% of the administered
radioactivity was excreted in urine or expired air, indicating that
-------
26
2. HEALTH EFFECTS
absorption was at least 90% complete. In rats, BDCM was not absorbed as
readily as in mice and monkeys with only about 60% of the orally
administered dose appearing in the expired air and urine (Mink et al.
1986) .
2.6.1.3 Dermal Exposure
No studies were located regarding absorption following dermal
exposure to BDCM. By analogy with other similar chemicals, it seems
likely that BDCM will be absorbed across the skin.
2.6.2 Distribution
2.6.2.1 Inhalation Exposure
No studies were located regarding distribution in humans or animals
following inhalation exposure to BDCM.
2.6.2.2 Oral Exposure
When BDCM was administered to rats by gavage, the compound was slow
to leave the stomach (Smith et al. 1985). Three hours after
administration, 21.5% of the dose was still in the stomach. Fat,
muscle, and liver each contained from 1.8 to 2.8% of the dose, with
lower levels in other tissues.
2.6.2.3 Dermal Exposure
No studies were located regarding distribution in humans or animals
following dermal exposure to BDCM.
2.6.3 Metabolism
Pathways of BDCM metabolism have not been characterized. Studies
in mice indicate that carbon dioxide is a major endproduct in that
species, accounting for 81% of the administered dose (Mink et al. 1986).
In rats| only 14% of the administered dose was expired as carbon
dioxide, and 42% as the parent compound (Mink et al. 1986). As
discussed previously, toxicology studies in rats and mice showed that
BDCM was more toxic to mice than to rats, and it is possible that these
toxicokinetic differences in metabolism may contribute to these
differences.
-------
27
2. HEALTH EFFECTS
2.6.4 Excretion
2.6.4.1 Inhalation Exposure
No studies were located regarding excretion in humans or animals
following inhalation exposure to BDCM.
2.6.4.2 Oral Exposure
The major route of excretion of BDCM in rats, mice, and monkeys is
expiration through the lung, either as parent BDCM, or as volatile
metabolites such as C02 (Mink et al. 1986; Smith et al. 1977; Smith
et al. 1985). Excretion via the urine accounts for only a minor
fraction of the administered dose (1.4% in rats, 2.2% in mice, and 2% to
6% in monkeys) (Mink et al. 1986; Smith et al. 1985).
Fecal excretion in monkeys accounted for less than 2% of the
administered dose 72 hours after dosing (Smith et al. 1985). In rats,
Smith et al. (1985) found no detectable amounts of radiolabelled BDCM or
metabolites in the feces, but the feces were evaluated only up to
6 hours after administration of BDCM. The shortness of the time
interval does not give an accurate assessment of the feces as a route of
excretion for BDCM, since 37% of the administered dose in the rats was
accounted for in the gastrointestinal tract. No data were available on
fecal excretion in mice.
The half-life of BDCM in rats and mice was estimated to be 1.5 and
2 hours, respectively (Mink et al. 1986), and the half-life in monkeys
was 4 to 6 hours (Smith et al. 1977). This indicates that BDCM is
effectively excreted and that tissue accumulation of BDCM is unlikely.
2.6.4.3 Dermal Exposure
No studies were located regarding excretion in humans or animals
following dermal exposure to BDCM.
2.7 INTERACTIONS WITH OTHER CHEMICALS
Hewitt et al. (1983) reported that pretreatment of rats with an
oral dose of acetone dramatically increased the hepatic and renal
toxicity of an oral dose of BDCM given 18 hours later. This is very
similar to the well-documented potentiation of CC14 by a variety of
alcohols, ketones and other chemicals, suggesting that BDCM and CClt may
-------
28
2. HEALTH EFFECTS
exert their toxicity through common mechanisms. Because of the
widespread use of alcohols and ketones in industry and in consumer
products, this sort of potentiation could be quite important.
A study in rats by Wester et al. (1985) evaluated the effects of
ingestion of a mixture of 11 halogenated hydrocarbon contaminants of
drinking water, including BDCM. No effects were observed after
25 months of exposure, but the doses employed were so low (0.003 to
0.28 mg/kg/day for BDCM) that this observation does not constitute
strong evidence that BDCM does not interact with other chemicals.
2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE
No studies were located regarding human populations that are
unusually susceptible to BDCM. Because BDCM is known to cause liver
injury in animals, humans with preexisting liver diseases (e.g.,
hepatitis, cirrhosis) may be particularly susceptible to the hepatotoxic
effects of BDCM. Likewise, humans with preexisting kidney diseases may
be susceptible to BDCM. By analogy with CC14, persons who are heavy
drinkers and/or take certain drugs that affect the liver may also be
particularly susceptible to the effects of BDCM.
2.9 ADEQUACY OF THE DATABASE
Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of
the Public Health Service) to assess whether adequate information on the
health effects of BDCM is available. Where adequate information is not
available, ATSDR, in cooperation with the National Toxicology Program
(NTP), is required to assure the initiation of a program of research
designed to determine these health effects (and techniques for
developing methods to determine such health effects). The following
discussion highlights the availability, or absence, of exposure and
toxicity information applicable to human health assessment. A statement
of the relevance of identified data needs is also included. In a
separate effort, ATSDR, in collaboration with NTP and EPA, will
prioritize data needs across chemicals that have been profiled.
-------
29
2. HEALTH EFFECTS
2.9.1 Existing Information on Health Effects of BDCM
As summarized in Figure 2-2, there are no data on the health
effects of BDCM in humans. In animals, there are a number of studies of
health effects following oral exposure, and information exists for most
endpoints except reproduction. However, no animal toxicity data exist
for inhalation or dermal exposure to BDCM.
2.9.2 Data Needs
Single Dose Exposure. There are a number of single dose studies in
animals by the oral route, and the range of intake doses leading to
lethal and most sublethal effects is reasonably well defined. However,
the mechanism of toxicity has not been studied. Such studies would be
useful in revealing why there are significant differences in
susceptibility between males and females, and whether this is pertinent
to the evaluation of human health risk from BDCM. Studies by the oral
route are likely to be most relevant, but studies of acute inhalation
and dermal toxicity would also be useful, since humans may be exposed by
these pathways while bathing or swimming.
Repeated Dose Exposure. Existing studies of health effects in
animals administered repeated oral doses of BDCM indicate that there is
a relatively low tendency toward cumulative toxicity and that chronic
noncarcinogenic effects resemble short-term effects. However, the
threshold dose for noncarcinogenic effects is not known with certainty.
For example, the study by Chu et al. (1982b) identified minimal effects
on the liver at doses of 7 mg/kg/day or higher, while other studies (NTP
1987; Tobe et al. 1982) did not detect effects at doses 6- to 20-times
higher. Thus, additional studies to define long-term no-effect levels
with greater certainty would help improve risk assessments for BDCM.
Chronic Exposure and Carcinogenicity. Several studies have
indicated that chronic oral exposure to BDCM increases cancer risk in
animals. Tumors were observed in both liver and kidney tissues (known
to be target tissues from subchronic studies of this chemical), and
tumors were also observed in the large intestines in rats. This is an
unusual tumorigenic response in rats, and the basis for the
susceptibility of the large intestine is not known. Further studies
would be valuable to reveal the basis for this tissue selectivity, and
to obtain improved dose-response data to allow reliable quantitative
cancer risk assessment.
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30
2. HEALTH EFFECTS
SYSTEMIC
/
/
Inhalation
Oral
Dermal
HUMAN
Inhalation
Oral
Dermal
ANIMAL
Existing Studies
SYSTEMIC
FIGURE 2-2. Existing Information on Health Effects of BDCM
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31
2. HEALTH EFFECTS
Genotoxicity. An in vivo mutagenicity study in mice indicated that
BDCM has potential to cause genetic damage, and is vitro studies also
suggest that BDCM has genotoxic potential. Additional in vitro and in
vivo studies to evaluate the genotoxicity of BDCM and to identify the
mechanism of genotoxic damage in intact mammalian cells would be
valuable.
Reproductive Toxicity. No studies were located regarding effects
of BDCM on reproduction. Multigeneration studies in animals to evaluate
effects of BDCM on reproduction would be valuable.
Developmental Toxicity. One study in rats (Ruddick et al. 1983)
indicates that BDCM is fetotoxic at doses that cause maternal toxicity,
but effects at lower doses were not evaluated. Additional developmental
studies at lower doses and in several other species would be helpful in
evaluating more fully the potential of BDCM to cause effects on the
developing organism.
Immunotoxicity. Limited data from subchronic oral studies in mice
indicate that BDCM adversely affects the immune system. However, the
data do not define the threshold for the effect with certainty, nor do
the data reveal whether the function of the immune system is
significantly impaired. Further studies on the immunotoxicity of BDCM
in animals would be valuable in establishing the no-effect level and the
relevance to human health.
Neurotoxicity. High doses of BDCM affect the CNS like other
halocarbons, causing depressed function and anesthesia. Limited data
indicate that repeated exposures may lead to transient effects on
behavior, but this has not been investigated in detail. Further
neurobehavioral studies using more sensitive operant measures would help
define the exposure levels that lead to these effects, and whether any
permanent neurological changes occur.
Epidemiological and Human Dosimetry Studies. No epidemiological
studies were located regarding human health effects from exposure to
BDCM per se. Epidemiological studies of cancer frequency in populations
consuming chlorinated drinking water have been performed, but since BDCM
levels tend to vary in concert with the levels of other trihalomethanes
and numerous other byproducts of disinfection, it is unlikely that
studies of this sort will be able to provide information on the risks
contributed specifically by BDCM.
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32
2. HEALTH EFFECTS
Biomarkers of Disease. Since no cases of human disease due to BDCM
exposure have been reported, it is not possible to Identify biomarkers
of disease in humans. Assuming that hepatic and renal injury similar to
that observed in animals might occur in exposed humans, early signs of
these effects could be detected by standard clinical methods such as
serum enzyme levels, PAH clearance, and so on. These tests would not be
specific for BDCM, however, and would only detect effects after injury
to the tissues has occurred. Efforts to identify a sensitive and
specific biomarker of BDCM-induced disease would be helpful.
Disease Registries. No disease registry exists for BDCM-induced
diseases in humans. Since the effects observed in animals (hepatic and
renal injury, cancer of liver, kidney and intestines) are common
diseases in humans, it is likely that a registry of individuals with
these diseases would contain only a small number of cases that might be
attributable solely to BDCM exposure.
Bioavailability from Environmental Media. No studies were located
on the relative bioavailability of BDCM in different environmental
media. Based on the physical properties of BDCM, it is not expected
that bioavailability would vary widely between water, soil, food, and
other media. Studies to investigate this would, nevertheless, be
helpful.
Food Chain Bioaccumulation. BDCM is biosynthesized by a variety of
marine macroalgae, but whether BDCM from this source or other sources
enters the food chain has not been studied. While the relatively rapid
metabolism and excretion of BDCM in laboratory animals suggest that
marked bioaccumulations is not likely, information on BDCM uptake and
retention by fish, plants, and other food sources would be helpful.
Absorption, Distribution, Metabolism, and Excretion. Currently
there are no toxicokinetic studies on BDCM following inhalation
exposure. Consequently, it would be helpful to determine the fraction
of BDCM that is absorbed via inhalation and to investigate whether any
significant differences in metabolism or retention exist between
inhalation and oral exposures. Similarly, there are no toxicokinetic
data regarding dermal exposure to BDCM. Although direct dermal contact
with concentrated BDCM is unlikely, dermal contact with water containing
BDCM is very common. Consequently, information on dermal absorption
rates from aqueous solutions would be helpful.
Most toxicokinetic studies were conducted prior to the findings of
cancer in the large intestine of male and female rats following chronic
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33
2. HEALTH EFFECTS
ingestion of BDCM. Since tumors in the gastrointestinal tract are
uncommon in rats, additional toxicokinetic studies focusing on BDCM
metabolism and distribution in this tissue would be valuable in
understanding the metabolic pathways for BDCM and how the metabolism may
be related to the mechanism of toxicity and carcinogenicity of BDCM.
Detailed studies of the enzymic pathways of BDCM metabolism and of
the intermediates formed would also be valuable. Metabolic activation
to yield highly toxic intermediates is known to be a critical step in
the toxicity of some similar compounds (e.g., CClt). Investigations to
determine whether similar pathways are involved in BDCM toxicity might
help resolve many of the special aspects of the toxicity of this
compound.
Comparative Toxicokinetics. Since BDCM toxicity appears to differ
significantly between sexes and species, additional toxicokinetic
studies in several species would be valuable. Such studies would aid in
understanding the differences in toxicity between species, and could
help identify the most appropriate animal species for use as a model for
humans.
2.9.3 On-going Studies
Dr. James Mathews (Research Triangle Institute) is currently
performing studies of the dose-dependency of absorption, metabolism and
clearance of BDCM following oral exposure of rodents. This research is
sponsored by the National Toxicology Program.
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35
3. CHEMICAL AND PHYSICAL INFORMATION
3.1 CHEMICAL IDENTITY
Table 3-1 lists common synonyms, trade names and other pertinent
identification information for BDCM.
3.2 PHYSICAL AND CHEMICAL PROPERTIES
Table 3-2 lists important physical and chemical properties of BDCM.
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36
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-1. Chemical Identity of BDCM
Value
Raferencea
Chemical Ram
Synonyma
Trad* Ham* (a)
Chemical Formula
Chemical Structure
Brooodlchloroaethana
Identification Hunbera:
CAS Registry
KIOSH RTECS
EPA Baiardout Uaate
OHM-TADS
DOT/OH/NA/IMCO
Shipping
HSDB
NCI
Dlchlorobrooooethanei
Monobromodlchloroetethanei
Methane, bromodtchloro-
CHBrCl,
Br
I
a-
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37
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-2. Physical and Chemical Properties of BDCM
Property
Valua
Rafarancaa
Molacular valght
Color
Physical Stat*
Malting point, °C
Boiling point, °C
Danalty, 20/4
Odor
Odor thraahold
Watar
Air
Solubility
Watar, m*/L
Organic Solvanta
Partition coafflclant*
Lot octanol/watar
Log koc
Vapor Praaaura, an Hg (20°C)
Hanry'a Law Constant,
ata id /doI
Autolgnltlon
teaparstur*, °C
Fla«h point
Flaonablllty lisle*
Convaralon Factor*
ppoi (v/v) to mg/o
In air (20 °C)
mg/m3 to ppm (v/v)
In air (20 °C)
163.83
colorlaaa
liquid
-57.1
90
1.980
HD<">
ND
*,500
aolubla
2.1
1.8
SO
2.41E-0J
KD
HD
ND
1 ppm — (.70 at la?
1 mg/m3 " 0.15 ppo
Uaait 1985
Varachuaran
1977
Varachuaran
1977
Vcait 1985
Waaat 1985
Waaat 1985
Kabay at al.
1982
Waaat 1985
Mabay at al.
1982
Mabay at al.
1982
Mabay at al.
1982
Mabay at al.
1982
Varachuaran
1977
Mo dttt locatad.
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39
4. PRODUCTION, IMPORT, USE, AND DISPOSAL
4.1 PRODUCTION
BDCM is produced commercially by the reaction of dichloromethane
with aluminum bromide. Small quantities of BDCM are currently produced
in the United States, but quantitative production volumes are not
available.
4.2 IMPORT
No data on imports or exports of BDCM were located. Little, if
any, of either is expected.
4.3 USE
In the past, BDCM has been used as a solvent for fats, waxes, and
resins, as a flame retardant, as a heavy liquid for mineral and salt
separations, and as a fire extinguisher fluid ingredient (Sax 1984). At
present, the principal use of BDCM is as a chemical intermediate for
organic synthesis and as a laboratory reagent (Sittig 1985; Verschueren
1983) . BDCM is not listed as a current ingredient in fire
extinguishers, solvents or other commercial products (Gosselein et al.
1984).
4.4 DISPOSAL
Bromodichloromethane is categorized as a hazardous waste
constituent (40 CFR 261 App. VIII) and, therefore, must be disposed of
in accordance with RCRA regulations. Acceptable disposal methods
include incineration using liquid injection, rotary kiln or fluidized
bed techniques. At the present time, land disposal of BDCM is also
permitted, although trihalomethanes are being evaluated for land
disposal prohibition.
BDCM has been detected in the raw and treated wastewater of
numerous industries (EPA 1983), but no quantitative data on amounts of
BDCM disposed of to the environment were located. BDCM has been
detected at 7% of chemical waste sites investigated under Superfund
(CLPSD 1988).
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40
4. PRODUCTION, IMPORT, USE AND DISPOSAL
4.5 ADEQUACY OY THE DATABASE
Section 104(i){5) of CERCLA, directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of
the Public Health Service) to assess whether adequate information on the
health effects of BDCM is available. Where adequate information is not
available, ATSDR, in cooperation with the National Toxicology Program
(NTP), is required to assure the initiation of a program of research
designed to determine these health effects (and techniques for
developing methods to determine such health effects). The following
discussion highlights the availability, or absence, of exposure and
toxicity information applicable to human health assessment. A statement
of the relevance of identified data needs is also included. In a
separate effort, ATSDR, in collaboration with NTP and EPA, will
prioritize data needs across chemicals that have been profiled.
4.5.1 Data Needs
Production, Use, Release and Disposal. The minimal commercial use
of BDCM is reflected in the absence of available production data. Data
on current uses and disposal practices would be valuable in determining
whether industrial activities pose an important source of human exposure
to BDCM.
According to the Emergency Planning and Community Right to Know Act
of 1986 (EPCRTKA), (§313), (Pub. L. 99-499, Title III, §313), industries
are required to submit release information to the EPA. The Toxic
Release Inventory (TRI), which contains release information for 1987,
became available in May of 1989. This database will be updated yearly
and should provide a more reliable estimate of industrial production and
emission.
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41
5. POTENTIAL FOR HUMAN EXPOSURE
5.1 OVERVIEW
The major source of BDCM in the environment is formation as a by-
product during chlorination of water, and many people are exposed to low
levels of BDCM in their drinking water. Industrial use of BDCM is
sufficiently limited that exposures to industrial emissions outside the
workplace are not expected to be of general concern. BDCM has been
detected in water and soil at some chemical waste sites, and human
exposure may potentially occur in such cases.
BDCM is a volatile chemical, so most of the BDCH that is formed in
water or released by industry tends to evaporate into air. BDCM does
not adsorb strongly to soils or sediments, nor does it tend to
bioaccumulate in fish or other animals.
In the atmosphere, BDCM is thought to undergo slow destruction
through oxidative pathways, with a half-life of about two to three
months. BDCM remaining in soil or water may undergo microbial
degradation. However, these fate processes have not been studied in
detail.
5.2 RELEASES TO THE ENVIRONMENT
5.2.1 Air
No studies were located regarding industrial release of BDCM into
air. Because of the low volume of BDCM currently in use, it is expected
that releases from industrial activities are probably small.
5.2.2 Water
The principal source of BDCM in the environment is from
chlorination of water. EPA (1980a) estimated that over 800 kkg (1 kkg -
1 metric ton) are produced annually in this way. It is presumed that
essentially all of this is ultimately released into the environment,
mainly through volatilization. This may occur either indoors (e.g.,
while showering, washing, cooking, etc.) or outdoors after discharge of
the water to the surface.
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42
5. POTENTIAL FOR HUMAN EXPOSURE
Class et al. (1986) observed trace levels (<1 parts per trillion
(ppt)) of BDCM and other brominated methanes in seawater and in the air
above the ocean at several locations in the Atlantic. The presence of
BDCM can be attributed to biosynthesis and release of BDCM by macroalga*
(Class et al, 1986; Gschwend et al. 1985). BDCM from this source
accounts for less than 1% of the anthropogenic burden of broraomethanes
in the atmosphere (Class et al. 1986).
BDCM has been detected in wastewater from a number of industrial
discharges and municipal wastewater treatment facilities, usually at
concentrations between 1 and 100 fig/L (Staples et al. 1985; Perry et al
1979; Dunovant et al. 1986). These levels of BDCM are similar to those
found in many chlorinated drinking water supplies (see Section 5.4.2,
below), and probably most discharges of this sort do not represent a
major source of BDCM release to the environment.
5.2.3 Soil
No studies were located regarding release of BDCM to soil.
5.3 ENVIRONMENTAL TATE
5.3.1 Transport and Partitioning
Because of the relatively high vapor pressure of BDCM (50 mm Hg at
20°C), the principal transport process in the environment is
volatilization (Class et al. 1986; Gschwend et al. 1985). Over 99% of
all BDCM in the environment is estimated to exist in air (EPA 1980a).
Volatilization from surface waters depends on factors such as
turbulence and temperature. The volatilization half-life from rivers
and streams has been estimated to range from 33 minutes to 12 days, wit
a typical half-life of 35 hours (Kaczmar et al. 1984). Volatilization
rates from surface soils have not been studied in detail, but Wilson
et al. (1981) found that about 50% of BDCM applied to a soil column in
the laboratory escaped by volatilization.
BDCM may be removed from air by washout in rainfall (Class et al.
1986) , but the average rate of this transport process has tiot been
estimated. It is expected that BDCff removed from air in this way would
be largely returned to air through volatilization.
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43
5. POTENTIAL FOR HUMAN EXPOSURE
BDCM is moderately soluble in water (4,500 mg/L), and significant
transport of BDCM can occur in water, especially in groundwater where
volatilization is restricted. This transport pathway may be important
at waste sites or other locations where BDCM spills lead to groundwater
contamination,
In soil, the relatively low log octanol-water partition coefficient
(Kow) indicates that adsorption is not likely to be a dominant factor,
and that BDCM spilled into soil will be relatively mobile and may
migrate into groundwater (EPA 1985a; Piet et al. 1981). In support of
this, Wilson et al. (1981) found that BDCM was not significantly
retarded during percolation through a column of sandy soil.
The moderate solubility and low log Kow indicate that
bioaccumulation of BDCM by fish or other aquatic species is likely to be
minor, but no estimate of a bioaccumulation factor in aquatic species
was located.
5.3.2 Transformation and Degradation
5.3.2.1 Air
Pathways responsible for BDCM destruction in the atmosphere are not
well studied, but probably involve oxidative reaction with hydroxyl
radicals or singlet oxygen (EPA 1980a; Mabey et al. 1982). Direct
photochemical decomposition is not likely to be significant (EPA 1980a).
The typical atmospheric lifetime of BDCM has been estimated to be two to
three months (EPA 1980a). This relatively persistent tropospheric half-
life of BDCM suggests that a small percentage of the BDCM present in air
will eventually diffuse into the stratosphere where it will be destroyed
by photolysis. In addition, long-range global transport is possible.
5.3.2.2 Water
Hydrolysis of BDCM in aqueous media is very slow, with an estimated
rate constant at neutral pH of 5.76 x 10"B hr"1 (Mabey et al. 1982).
This corresponds to a half*life of more than 1,000 years.
Biodegradation in aqueous media may be significant in some cases.
For example, Tabak et al. (1981) reported 35% transformation after seven
days incubation in a medium inoculated with sewage. Repeated culturing
lead to increased losses, indicating gradual adaptation of the
degradative microbes.
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44
5. POTENTIAL FOR HUMAN EXPOSURE
Under aquatic conditions where volatilization cannot occur,
biodegradation may be the predominant mechanism for degradation of BDCM.
Bouwer et al. (1981) and Bouwer and McCarty (1983a) studied the
degradation of BDCM under aerobic and anaerobic conditions in both
static and continuous flow systems inoculated with mixed methanogenic
bacterial cultures from sewage. Degradation was found to be very
limited under aerobic conditions, but essentially complete within 2 days
under anaerobic conditions. Slow degradation (50% to 70% in 16 weeks)
occurred in sterile media, indicating that a chemical mechanism
(hypothesized to be reductive dehalogenation) was operative in addition
to the rapid microbial degradation. Microbial degradation was also
observed under anaerobic conditions in media inoculated with
denitrifying bacteria (Bouwer and McCarty 1983b).
5.3.2.3 Soil
Biodegradation of BDCM in soil has not been studied, but studies in
aqueous media indicate that biodegradation might occur under anaerobic
conditions (Bouwer et al. 1981; Bouwer and McCarty 1983a, 1983b; Tabak
et al. 1981). This suggests that, in regions of soil where
volatilization is restricted, biodegradation could be a major removal
process,
5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
5.4.1 Air
Ambient air monitoring data compiled by Brodzinsky and Singh (1983)
identified BDCM at four of six sites investigated. Concentrations
ranged from 0.76 to 180 ppt, with a mean value of 1.1 ppt. BDCM levels
from four sites monitored in California were reported to range from 20
to 100 ppt (Shikiya et al. 1984). BDCM was not detected in a survey of
bromine-containing gasses in the atmosphere at the South Pole (Rasmussen
and Khalil 1984), although trace levels (1 ppt) were detected in air at
several locations in the Atlantic Ocean (Class et al. 1986). This was
judged by the authors to be due to releases from macroalgae.
5.4.2 Vater
BDCM occurs in water primarily as a by-product of chlorination.
Surveys of BDCM levels in chlorinated public drinking water systems
across the United States have revealed that BDCM is present in most
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45
5. POTENTIAL FOR HUMAN EXPOSURE
systems at concentrations averaging around 1 to 20 Jig/L, but ranging up
to 125 jUg/L in some cases (Coleman et al. 1975; EPA 1979; Furlong and
D'itri 1986; Symons et al. 1975).
The concentration of BDCM in chlorinated water depends on reaction
conditions during the chlorination process. Important parameters
include temperature, pH, bromide ion concentration in the source water,
fulvic and humic substance concentration in the water, and the
chlorination treatment practices (EPA 1985b). The amount of BDCM tends
to increase as a function of increasing organic content and bromide ion
in the source water (Bellax et al. 1974; Arguello et al. 1979). Studies
by Brett and Calverly (1979) and Arguello et al. (1979) indicate that
BDCM levels increased by 30 to 100% in water system distribution pipes,
presumably because formation continues as long as a chlorine residual
and organic precursors remain.
BDCM is also formed in chlorinated swimming pools. Beech et al.
(1980) measured THM levels in several swimming pools in Miami, and found
total THM concentrations averaged from 120 to 660 /ig/L. In freshwater
pools, most of the total THM was chloroform, with BDCM levels ranging
from 13 to 34 jtig/L. In saltwater pools, bromoform was the principal THM
present, and BDCM concentrations were roughly the same as in freshwater
pools.
Monitoring studies of groundwater and surface water at chemical
waste sites indicate that BDCM is a relatively infrequent contaminant.
BDCM was detected at only 4 of 818 sites on the National Priority List
(NPL), and at 7% of a number of other sites being investigated under
Superfund (CLPSD 1988). The average concentration of BDCM in
groundwater at these sites was 30 Hg/L. Quantitative data for surface
water were not available.
5.4.3 Soil
No studies were located on BDCM levels in ambient soil. Because of
Its volatility, it is likely that BDCM would be present only at low
levels in most soils. BDCM was detected in 2% of soil samples taken
near chemical waste sites being investigated under Superfund (CLPSD
1988), but quantitative estimates of soil concentration are not
available.
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46
5. POTENTIAL FOR HUMAN EXPOSURE
5.A.4 Other Media
BDCM is not a common contaminant of food, occurring only in trace
quantities in some samples. A market basket study of 39 food items
detected BDCM in one dairy composite at 1.2 ppb and in butter at 7 ppb
(Entz et al. 1982). A study of BDCM in food processing water and
processed foods revealed no detectable levels except in ice cream at one
processing plant (0.6 to 2.3 ppt) (Uhler and Diachenko 1987). Soft
drinks have been found to contain BDCM (Abdel-Rahman 1982; Entz et al.
1982), but usually at concentrations (0.1 to 6 /Ug/L) below those found
in municipal water supplies. Cooking foods in water containing BDCM is
unlikely to lead to contamination, since BDCM would rapidly volatilize
(Kool et al. 1981).
BDCM is biosynthesized by marine macroalgas, and has been measured
in these organisms at 7-22 ng/g dry weight (Gschwend et al. 1985).
Whether BDCM enters and accumulates in the food chain from this source
appears to be unlikely, but has not been studied.
5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE
The estimated exposure of the general human population to BDCM from
drinking water, assuming a median BDCM concentration of 0.014 mg/L and a
water intake for an adult of 2.18 L/day, would be 0.03 mg/day (EPA
1980a). Low levels of exposure might also occur by inhalation of BDCM
volatilized from chlorinated water (e.g., while showering, cooking, or
swimming), or by dermal contact with such water. Based on a chemical
structure analogy to chloroform, an estimated dermal exposure to BDCM in
a child swimming two hours/day in a saline pool would typically be
0.003 mg/day, with a maximum of 0.04 mg/day (Beech 1980). Higher
exposure levels might occur through ingestion of water contaminated with
BDCM near a waste site, but available data suggest that this is not a
common occurrence.
No studies were located on human exposure levels in the workplace.
5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES
The environmental medium most likely to be contaminated with BDCM
is chlorinated water, so any person with above-average contact with such
water could have above-average exposures. This includes individuals who
drink very large quantities of water, such as diabetics, workers in hot
climates, and so on. It may also include persons with swimming pools or
saunas, where exposure could occur by inhalation (especially if the pool
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47
5. POTENTIAL FOR HUMAN EXPOSURE
or sauna is indoors) or by dermal contact. Since BDCM levels depend on
the organic content of the source water before chlorination, persons
whose water source is high in organics are likely to have finished water
with higher-than-average BDCM levels.
People working in chemical plants or laboratories where BDCM is
made or used would also have potentially high exposures to the chemical,
most likely by inhalation exposure. Persons living near waste sites may
have potentially high exposure to BDCM, but this can only be evaluated
on a case-by-case basis.
5.7 ADEQUACY OF THE DATABASE
Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of
the Public Health Service) to assess whether adequate information on the
health effects of BDCM is available. Where adequate information is not
available, ATSDR, in cooperation with the National Toxicology Program
(NTP), is required to assure the initiation of a program of research
designed to determine these health effects (and techniques for
developing methods to determine such health effects). The following
discussion highlights the availability, or absence, of exposure and
toxicity information applicable to human health assessment. A statement
of the relevance of identified data needs is also included. In a
separate effort, ATSDR, in collaboration with NTP and EPA, will
prioritize data needs across chemicals that have been profiled.
5.7.1 Data Needs
Physical and Chemical Properties. The physical and chemical
properties of BDCM have been determined (see Table 3-2), and further
studies on these parameters do not appear to be essential.
Environmental Fate. There are very few quantitative data on the
environmental fate and transport of BDCM, and most evaluations are
based, entirely or in part, on extrapolations from studies of other
similar compounds such as chloroform. Consequently, studies to obtain
reliable quantitative rate values for the key fate processes of BDCM
would be valuable. Of particular importance would be studies on the
volatilization of BDCM from chlorinated drinking water, and on the
atmospheric reactions of BDCM. Studies of chemical and biological
transformation and degradation rates in soil and water under conditions
comparable to those around waste sites would also be helpful.
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5. POTENTIAL FOR HUMAN EXPOSURE
Exposure Levels in Environmental Media. Data are available on BDCM
levels in drinking water and on how these levels depend on water organic
content and treatment conditions. Nevertheless, continued monitoring
will be valuable in revealing whether changes in drinking water
treatment and disinfection procedures are effective in reducing levels
of BDCM and other contaminants.
Studies of BDCM levels in air (especially indoor air) in the
vicinity of open bodies of chlorinated water would also be helpful.
This would include water treatment plants, swimming pools, and perhaps
even home bathtubs or showers. In view of the ready volatilization of
BDCM from water, airborne levels in such locations might be significant.
Further monitoring of groundwater, soil and ambient air in the
vicinity of chemical waste sites Is also needed to determine whether
emissions of BDCM from such sites adds significantly to total BDCM
exposure.
Exposure Levels in Humans. Current data on BDCM levels in air are
not adequate to estimate inhalation exposure in ambient air or the
workplace. Collection of such information would be helpful in
evaluating the relative contribution of this exposure pathway to the
total intake of BDCM. Similar data would be useful for airborne levels
of BDCM around swimming pools (especially indoor pools). Data on the
presence of BDCM in drinking water appears to be adequate for estimating
exposure from consumption of water immediately after taking it from the
tap. However, it would be helpful to know how rapidly the BDCM would
volatilize from a glass of water or from a bathtub full of water, and
what concentration would then be in the breathing zone of occupants of
the house.
Exposure Registries. No registry exists for humans known to have
been exposed to BDCM. Although exposure to BDCM through drinking water
is common, a registry of humans exposed in this way Is not likely to
help identify BDCM-related diseases in humans, since exposure to BDCM in
water are usually low and typically involve exposure to other
trihalomethanes and many other byproducts of disinfection as well, a
registry of individuals exposed to BDCM during manufacture or use of
this chemical might be helpful in identifying possible health effects in
humans, although the size of the exposed population is believed to be
small.
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5. POTENTIAL FOR HUMAN EXPOSURE
5.7.2 On-going Studies
No information was located on any on-going studies on the potential
for human exposure to BDCM.
As part of the Third National Health and Nutrition Evaluation
Survey (NHANES III), the Environmental Health Laboratory Sciences
Division of the Center for Environmental Health and Injury Control,
Centers for Disease Control, will be analyzing human blood samples for
BDCM and other volatile organic compounds. These data will give an
indication of the frequency of occurrence and background levels of these
compounds in the general population.
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6. ANALYTICAL METHODS
6.1 BIOLOGICAL MATERIALS
As a volatile organohalide, BDCM may be measured with good
sensitivity and specificity using gas-chromatographic methods employing
halide-specific or election-capture detection. Methods available for
separation of BDCM from biological samples prior to analysis include
headspace analysis, purge-and-trap collection, solvent extraction, and
direct collection on resins.
Headspace analysis offers speed, simplicity, and good
reproducibility for a particular type of sample. However, partitioning
of the analyte between the headspace and the sample matrix is dependent
upon the nature of the matrix and must be determined separately for
different kinds of matrices (Walters 1986).
Purge-and-trap collection is well suited to biological samples that
are soluble in water (Peoples et al. 1979), and is readily adapted from
techniques that have been developed for the analysis of BDCM and other
VOCs in water and wastewater. This method consists of bubbling inert
gas through a small volume of the sample and collecting the vapor in a
trap packed with sorbent. The analytes are then removed from the trap
by heating it and backflushing the analytes onto a gas chromatographic
column (Pankow et al. 1988). The two materials most widely used for
adsorption and thermal desorption of volatile organic compounds
collected by the purge-and-trap technique are Carbotrap, consisting of
graphitized carbon black, and Tenax.a porous polymer of 2,6-diphenyl-p-
phenylene oxide (Fabbri et al. 1987).
Solvent extraction of volatile components from biological fluids is
usually performed using dimethyl ether (Zlatkis and Kim 1976).
Homogenization of tissue with the extractant and lysing of cells
improves extraction efficiency. When, as is often the case, multiple
analytes are being determined using solvent extraction, selective
extraction and loss of low-boiling compounds can cause errors.
Supercritical fluid extraction using pure carbon dioxide or carbon
dioxide with additives offers some exciting potential for the extraction
of organic analytes such as BDCM from biological samples (Hawthorne
1988).
Analytical methods for the determination of BDCM in biological
samples are given in Table 6-1.
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52
6. ANALYTICAL METHODS
TABLE 6-1. Analytical Methods for BDCM In Biological Samples
Sample type
Adipose tissue
Bll« acids
Breath, blood,
and urine
Blood serum
Blofluida^*'
Grain^'
Extraction/cleanup
Purge from liquified
fat at 115*C, trap on
aillea (*1, thermal
deaorption
HR
HR
Purge from water-serum
mixture containing
antifoam reagent at
115SC, trap on Tenax/
alllea gal, thermal
detorption
Dilute with water,
aealed vial, collection
of headipace vapors
Extract vlth acetone/
water (i/1), dry.
Inject acetone aolutlon
Detection
GC/HSD
GC/ECD
GC/MS
GC/BSD
CC/ECD
CC/ECD
Limit of
detection
<0.8 JigII
HR
HR
<0.8 Mg/L
HR
HR
Referencea
People! et al. 1979
Brechbuehler et al. 1977
Berkley et al. 1980
Peoples et al. 1979
Sulthelmer at al. 19B2
AOAC 1984
Abbreviations t CC ¦¦ gas chromatography! BSD » haIids selective deteetori ECD " electron capture detectori
NR m not reported) MS ¦ mass spectrometry.
'4'This method for volatilea by headspace chromatography can be adapted to braaodichloroaMthane
although the procedure does not liat It apaciflcally aa an analyte.
^^Hethod for carbon tetrachloride, but applicable to bromodlchloromethane because of their alailar
propartiaa.
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53
6. ANALYTICAL METHODS
6.2 ENVIRONMENTAL SAMPLES
BDCM may be isolated from environmental samples using the same
methods and principles used for biological samples, followed by gas
chromatographic analysis. The most convenient procedure for most liquid
and solid samples is the purge-and-trap method. A similar procedure is
used for air, involving passing the air through an adsorbent canister,
followed by thermal desorption.
Analytical methods for the determination of BDCM in environmental
samples are given in Table 6-2.
6.3 ADEQUACY OF THE DATABASE
Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of
the Public Health Service) to assess whether adequate information on the
health effects of BDCM is available. Where adequate information is not
available, ATSDR, in cooperation with the National Toxicology Program
(NTP), is required to assure the initiation of a program of research
designed to determine these health effects (and techniques for
developing methods to determine such health effects). The following
discussion highlights the availability, or absence, of exposure and
toxicity information applicable to human health assessment. A statement
of the relevance of identified data needs is also included. In a
separate effort, ATSDR, in collaboration with NTP and EPA, will
prioritize data needs across chemicals that have been profiled.
6.3.1 Data Needs
Methods for Determining Parent Compounds and Metabolites in
Biological Materials. Methods are available for the determination of
BDCM in biological samples, but there is a need for development of
validated standard methods of analysis with well-defined limits of
detection, such as those that exist for water and wastewater (EPA 1982a,
EPA 1982b) and for solid wastes (EPA 1986a, EPA 1986b).
Animal studies show that BDCM is excreted via the lungs as parent
compound or carbon dioxide. Small amounts of carbon monoxide have also
been measured in animals after administration of BDCM (Anders et al.
1978). Other metabolites of BDCM have not been identified. Since
carbon dioxide and carbon monoxide are not specific to BDCM, measurement
of these metabolites is not likely to provide a good index of BDCM
exposure.
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54
6. ANALYTICAL METHODS
TABLE 6-2. Analytical Methods for BDCM In Environmental Media
Sample type
Extractlon/clesnup
Detection
Limit of
detection
Reference*
Alr<»>
Coconut (hall charcoal sorption
carbon dlaulflda d«sorption
GC/FID
10 «(g per
sample
MIOSB 1984
Air
Sorption
CC/CLMD
S*10"1J
g/sec
Yamada et al.
1982
Air and vatar
MR
CC/MS
MR
Barkley at al
Drinking vatar
Purgs and trap
CC/MWED
<1 <»g/L
Qulmby et al.
Vatar
Purge and trap
CC/MS
10 Mg11
EPA 1960c
Watar
Purge and trap
CC/BSD
o.i2 ml
EPA 1982a
Hatar
Purga and trap
CC/MS
2.2 ltt/L
EPA 1982b
Watar
Purga and trap
CC/BSD
0.5 Jtg/L
APHA 1985s
Watar
Purga and trap
CC/MS
<0.27
-------
55
6. ANALYTICAL METHODS
Methods for Biomarkers of Exposure. No biomarkers of exposure to
BDCM are currently known. By analogy with CCl*, it is possible that
BDCM may be metabolized to reactive intermediates that form covalent
adducts with cellular macromolecules. If so, immunoassays and 32 P-post
labeling assays might be capable of identifying and quantifying these
adducts, although levels would likely be very low. Efforts to identify
such adducts and to develop appropriate measurement techniques would be
valuable for determining exposure.
Methods for Determining Parent Compounds and Degradation Products
in Environmental Media. BDCM can be analyzed in water, air, and waste
samples with good selectivity and sensitivity. However, since BDCM may
be carcinogenic in humans, very low levels in water, air or other media
may be of concern, so improvements in sensitivity would be valuable.
6.3.2 On-going Studies
The development of supercritical fluid (SCF) extraction holds great
promise for analysis of nonpolar organic analytes such as BDCM. Current
research in this area has been summarized by Hawthorne (1988).
Research is ongoing to develop a "Master Analytical Scheme" for
organic compounds in water (Michael et al. 1988), which includes BDCM as
an analyte. The overall goal is to detect and quantify organic
compounds at 0.1 /ig/L (1 ppb)in drinking water, 1 Jig/L in surface
waters, and 10 Mg/L in effluent waters. A comprehensive review of the
literature leading up to these efforts has been published (Pellizzari
et al. 1985).
The introduction of capillary column chromatography has markedly
improved both sensitivity and resolution of gas chromatographic
analysis, but because of the very small quantities of sample required,
has made sample delivery more difficult. One of the more promising
approaches to sample introduction using capillary columns with purge-
and-trap collection is the use of cryofocusing. Basically, this
procedure consists of collecting purged analyte on a short section of
the capillary column cooled to a low temperature (e.g., -lOO'C),
followed by heating and backflushing of the sample onto the analytical
column. Several compounds closely related to BDCM have been determined
in water by this method (Washall and Wampler 1988), including methylene
chloride, chloroform, chlorobromomethane and bromoform.
-------
56
6. ANALYTICAL METHODS
Methods are also being developed for In situ measurement of
organohalide levels in water. This has been demonstrated for
chloroform-contaminated well water using remote fiber fluorimetry (RFF)
and fiber optic chemical sensors (FOCS) (Milanovich 1986). With this
approach, fluorescence of basic pyridine in the presence of organohalide
(the Fujiwara reaction) is measured from a chemical sensor immersed in
the water at the end of an optical fiber. If conditions can be found
under which BDCM undergoes a Fujiwara reaction, its determination might
be amendable to this approach.
The Environmental Health Laboratory Sciences Division of the Center
for Environmental Health and Injury Control, Centers for Disease
Control, is developing methods for the analysis of BDCM and other
volatile organic compounds in blood. These methods use purge and trap
methodology and magnetic mass spectrometry which gives detection limits
in the low parts per trillion range.
-------
57
7. REGULATIONS AND ADVISORIES
Because of its potential to cause adverse effects In exposed
people, a number of regulations and advisory values have been
established for BDCM by various national and state agencies. These
values are summarized in Table 7-1. No international values were
located.
-------
58
REGULATIONS AND ADVISORIES
TABLE 7-1. Regulations and Guidelines Applicable to BDCM
Agency
Deecriptlon
Value
ktiaitncfi
Reeulatlon*
a. Water
EPA ODW
SPA OSH
EPA OMRS
FDA
b. Mcm-ipaelfLe Madia
EPA OKRR
Culdallne*
SPA OWRS
EPA
Stata
Environmental
Agencle*
btlooil
Maximum Contaminant Laval (KCL>
for 7otal Trihalonethane*
Monitoring Raquired for All
Sy* tenia
Groundwater Monitoring Llat
(Append 1b IX)
General PermitJ Under the
Rational Pollutant Dlacharga
Elimination Syitea (KPDES)
General Pretreatment Ragulatlone
for Islftlng and daw Source•
of Pollution (haloaethanaa)
Permlialble Laval In Bottlad Water
(Total. Trihalooethane*)
Reportable Quantity
Ambient Hater Quality Criteria
to Protect Human Health* '
Instating Hatar and Organlesj
"-6
l0-«
10 7
Ingeating Organian* Only
"I*
"It
io 7
Reference Dote (RfD)
Stata Regulation*
Drinking Uatar Standard! and
Guidelines
Illlnola
Vermont
0.10 ag/L
HA"'
HA
KA
MA
o.io ata/L
sooc lb
and Culdalloae
40 CTR 1*1.12
40 CTR 1*1.40
KPA 1987a
40 CTR 264
EPA 198Tb
40 era 122
Appendix D
Tablt II
40 CTR 403
21 ere ioj.ss
40 ere S02.4
EPA 1985a
EPA 1980b
1.9 Ms/L
0.19 Mt/L
0.019 JCg/L
137 M«/L
15.7 Ms/L
1.37 Mg/L
2E-2 mg/kt/d EPA 198B
PSTRAC 1988
1.0 MSII
100 MS/L
^*'Hot applleable.
Became of It* carcinogenic potential, the EPA-reeoonanded concentration for BDCM in anbient water la
aero. However, becauae attainment of thl* levjjl may not be poielble, level* which oorreapond to upper bound
Incremental lifetime cancer rlak* of 10"5, 10~* and 10~7 are estimated. Since no quantitative data are
available on the cancer rlak from BDCM, the value* are a(turned to be equal to thoae for ehloroforn.
-------
59
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9. GLOSSARY
Acute Exposure - - Exposure to a chemical for a duration of 14 days or
less, as specified in the Toxicological Profiles.
Adsorption Coefficient (K,,,.) -- The ratio of the amount of a chemical
adsorbed per unit weight of organic carbon in the soil or sediment to
the concentration of the chemical in solution at equilibrium.
Adsorption Ratio (Kd) -- The amount of a chemical adsorbed by a sediment
or soil (i.e., the solid phase) divided by the amount of chemical in the
solution phase, which is in equilibrium with the solid phase, at a fixed
solid/solution ratio. It is generally expressed in micrograms of
chemical sorbed per gram of soil or sediment.
Bioconcentration Factor (BCF) -- The quotient of the concentration of a
chemical in aquatic organisms at a specific time or during a discrete
time period of exposure divided by the concentration in the surrounding
water at the same time or during the same time period.
Cancer Effect Level (CEL) -- The lowest dose of chemical in a study or
group of studies which produces significant Increases in incidence of
cancer (or tumors) between the exposed population and its appropriate
control.
Carcinogen -- A chemical capable of inducing cancer.
Celling value (CL) -- A concentration of a substance that should not be
exceeded, even instantaneously.
Chronic Exposure -- Exposure to a chemical for 365 days or more, as
specified in the Toxicological Profiles.
Developmental Toxicity -- The occurrence of adverse effects on the
developing organism that may result from exposure to a chemical prior to
conception (either parent), during prenatal development, or postnatally
to the time of sexual maturation. Adverse developmental effects may be
detected at any point in the life span of the organism.
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9. GLOSSARY
Embryotoxlcity and Fetotoxicity -- Any toxic effect on the conceptus as
a result of prenatal exposure to a chemical; the distinguishing feature
between the two terms is the stage of development during which the
insult occurred. The terms, as used here, include malformations and
variations, altered growth, and in utero death.
EPA Health Advisory -- An estimate of acceptable drinking water levels
for a chemical substance based on health effects information. A health
advisory is not a legally enforceable federal standard, but serves as
technical guidance to assist federal, state, and local officials.
Immediately Dangerous to Life or Health (IDLH) -- The maximum
environmental concentration of a contaminant from which one could escape
within 30 min without any escape-impairing symptoms or irreversible
health effects.
Intermediate Exposure -- Exposure to a chemical for a duration of 15-364
days, as specified in the Toxicological Profiles.
Immunologic Toxicity - - The occurrence of adverse effects on the immune
system that may result from exposure to environmental agents such as
chemicals.
In vitro -- Isolated from the living organism and artificially
maintained, as in a test tube.
In vivo -- Occurring within the living organism.
Lethal Concentration(LO) (LCy,) -- The lowest concentration of a
chemical in air which has been reported to have caused death in humans
or animals.
Lethal Concentration(50) (LC50) — A calculated concentration of a
chemical in air to which exposure for a specific length of time is
expected to cause death in 50% of a defined experimental animal
population.
Lethal Dose(LO) (LD^) -- The lowest dose of a chemical introduced by a
route other than inhalation that is expected to have caused death in
humans or animals.
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9. GLOSSARY
Lethal Dose(50) (LDJ0) -- The dose of a chemical which has been
calculated to cause death in 50% of a defined experimental animal
population.
Lowest-Observed-Adverse-Effect Level (LOAEL) -- The lowest dose of
chemical in a study or group of studies which produces statistically or
biologically significant increases in frequency or severity of adverse
effects between the exposed population and its appropriate control.
LT50 (lethal time) -- A calculated period of time within which a
specific concentration of a chemical is expected to cause death in 50%
of a defined experimental animal population.
Malformations -- Permanent structural changes that may adversely affect
survival, development, or function.
Minimal Risk Level - - An estimate of daily human exposure to a chemical
that is likely to be without an appreciable risk of deleterious effects
(noncancerous) over a specified duration of exposure.
Mutagen -- A substance that causes mutations. A mutation is a change in
the genetic material in a body cell. Mutations can lead to birth
defects, miscarriages, or cancer.
Neurotoxicity -- The occurrence of adverse effects on the nervous system
following exposure to a chemical.
No-Observed-Adverse-Effect Level (NOAEL) -- That dose of chemical at
which there are no statistically or biologically significant increases
in frequency or severity of adverse effects seen between the exposed
population and its appropriate control. Effects may be produced at this
dose, but they are not considered to be adverse.
Octanol-Water Partition Coefficient (K^,) -- The equilibrium ratio of
the concentrations of a chemical in n-octanol and water, in dilute
solution.
Permissible Exposure Limit (PEL) --An allowable exposure level in
workplace air averaged over an 8-h shift.
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9. GLOSSARY
qx* -- The upper-bound estimate of the low-dose slope of the dose-
response curve as determined by the multistage procedure. The qx* can
be used to calculate an estimate of carcinogenic potency, the
incremental excess cancer risk per unit of exposure (usually Mg/L for
water, mg/kg/day for food, and /ig/m3 for air).
Reference Dose (RfD) -- An estimate (with uncertainty spanning perhaps
an order of magnitude) of the daily exposure of the human population to
a potential hazard that is likely to be without risk of deleterious
effects during a lifetime. The RfD is operationally derived from the
NOAEL (from animal and human studies) by a consistent application of
uncertainty factors that reflect various types of data used to estimate
RfDs and an additional modifying factor, which is based on a
professional judgment of the entire database on the chemical. The RfDs
are not applicable to nonthreshold effects such as cancer.
Reportable Quantity (RQ) -- The quantity of a hazardous substance that
is considered reportable under CERCLA. Reportable quantities are: (1) 1
lb or greater or (2) for selected substances, an amount established by
regulation either under CERCLA or under Sect. 311 of the Clean Water
Act. Quantities are measured over a 24-h period.
Reproductive Toxicity - - The occurrence of adverse effects on the
reproductive system that may result from exposure to a chemical. The
toxicity may be directed to the reproductive organs and/or the related
endocrine system. The manifestation of such toxicity may be noted as
alterations in sexual behavior, fertility, pregnancy outcomes, or
modifications in other functions that are dependent on the integrity of
this system.
Short-Term Exposure Limit (STEL) -- The maximum concentration to which
workers can be exposed for up to 15 min continually. No more than four
excursions are allowed per day, and there must be at least 60 min
between exposure periods. The daily TLV-TWA may not be exceeded.
Target Organ Toxicity -- This term covers a broad range of adverse
effects on target organs or physiological systems (e.g., renal,
cardiovascular) extending from those arising through a single limited
exposure to those assumed over a lifetime of exposure to a chemical,
TD50 (toxic dose) -- A calculated dose of a chemical, introduced by a
route other than inhalation, which is expected to cause a specific toxic
effect in 50% of a defined experimental animal population.
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9. GLOSSARY
Teratogen -- A chemical that causes structural defects that affect the
development of an organism.
Threshold Limit Value (TLV) -- A concentration of a substance to which
most workers can be exposed without adverse effect. The TLV may be
expressed as a TWA, as a STEL, or as a CL.
Time-weighted Average (TWA) --An allowable exposure concentration
averaged over a normal 8-h workday or 40-h workweek.
Uncertainty Factor (UF) - - A factor used in operationally deriving the
RfD from experimental data. UFs are intended to account for (1) the
variation in sensitivity among the members of the human population, (2)
the uncertainty in extrapolating animal data to the case of humans, (3)
the uncertainty in extrapolating from data obtained in a study that is
of less than lifetime exposure, and (4) the uncertainty in using LOAEL
data rather than NOAGL data. Usually each of these factors is set equal
to 10.
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APPENDIX: PEER REVIEW
A peer review panel was assembled for BDCM. The panel consisted of
the following members: Dr. Sheldon Murphy, Professor of Environmental
Health, University of Washington; Dr. Joseph Gould, Research Scientist,
Georgia Institute of Technology; Dr. Nancy Reiches, Director of
Research, Riverside Methodist Hospital, Columbus, Ohio; and
Dr. Sanford Bigelow, President, MultiSciences, Inc. These experts
collectively have knowledge of BDCM's physical and chemical properties,
toxicokinetics, key health end points, mechanisms of action, human and
animal exposure, and quantification of risk to humans. All reviewers
were selected in conformity with the conditions for peer review
specified in the Superfund Amendments and Reauthorization Act of 1986,
Section 110.
A joint panel of scientists from ATSDR and EPA has reviewed the
peer reviewers' comments and determined which comments will be included
in the profile. A listing of the peer reviewers' comments not
incorporated in the profile, with a brief explanation of the rationale
for their exclusion, exists as part of the administrative record for
this compound. A list of databases reviewed and a list of unpublished
documents cited are also included in the administrative record.
The citation of the peer review panel should not be understood to
imply their approval of the profile's final content. The responsibility
for the content of this profile lies with the Agency for Toxic
Substances and Disease Registry.
* U.S. GOVERNMENT PRINTING OFFICE:! 9 9 0 -7 S 2 - 3 3 2/
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