BERYLLIUM
Agency for Toxic Substances and Disease Registry
U.S. Public Health Service
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3
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ATSDR/TP-88/07
TOXICOLOGICAL PROFILE FOR
BERYLLIUM
Date Published — December 1988
Prepared by-
Syracuse Research Corporation
under Contract No. 68-C8-0004
for
Agency for Toxic Substances and Disease Registry (ATSDR)
U.S. Public Health Service
in collaboration with
U.S. Environmental Protection Agency (EPA)
Technical editing/document preparation by
Oak Ridge National Laboratory
under
DOE Interagency Agreement No. 1857-B026-A1
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DISCLAIMER
Mention of company name or product does not constitute endorsement by
the Agency for Toxic Substances and Disease Registry
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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 list of the 100
most significant hazardous substances was published in the Federal
Register on April 17, 1987.
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 epidemiologic evaluations on a
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, and chronic
health effects.
(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 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 three 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 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.
iii
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Foreword
Each toxicologlcal 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.
Research gaps in toxicologic and health effects information are
described in the profile. Research gaps 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 in response to public comments and as
additional data become available; therefore, we encourage comment that
will make the toxicological profile series of the greatest use.
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.
James 0. Mason, H.D., Dr. P.H.
Assistant Surgeon General
Administrator, ATSDR
iv
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CONTENTS
FOREWORD
LIST OF FIGURES ix
LIST OF TABLES xi
1. PUBLIC HEALTH STATEMENT 1
1.1 WHAT IS BERYLLIUM? 1
1.2 HOW MIGHT I BE EXPOSED TO BERYLLIUM? 1
1.3 HOW DOES BERYLLIUM GET INTO MY BODY? 2
1.4 HOW CAN BERYLLIUM AFFECT MY HEALTH? 2
1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE BEEN
EXPOSED TO BERYLLIUM? 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
2. HEALTH EFFECTS SUMMARY 7
2.1 INTRODUCTION 1
2.2 LEVELS OF SIGNIFICANT EXPOSURE 8
2.2.1 Key Studies and Graphical Presentations 8
2.2.1.1 Inhalation exposure 13
2.2.1.2 Oral exposure 16
2.2.1.3 Dermal exposure 17
2.2.2 Biological Monitoring as a Measure of
Exposure and Effects 17
2.2.3 Environmental Levels as Indicators of
Exposure and Effects 19
2.2.3.1 Levels found in the environment 19
2.2.3.2 Human exposure potential 20
2.3 ADEQUACY OF DATABASE 20
2.3.1 Introduction 20
2.3.2 Health Effect End Points 21
2.3.2.1 Introduction and graphic summary 21
2.3.2.2 Description of highlights
of graphs 21
2.3.2.3 Summary of relevant ongoing
research 24
2.3.3 Other Information Needed for Human
Health Assessment 24
2.3.3.1 Pharmacokinetics and mechanisms
of action 24
2.3.3.2 Monitoring of human biological
samples 24
2.3.3.3 Environmental considerations 25
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Concents
CHEMICAL AND PHYSICAL INFORMATION . . 27
3 .1 CHEMICAL IDENTITY .' ,?
3.2 PHYSICAL AND CHEMICAL PROPERTIES 27
TOXICOLOGICAL DATA 33
4.1 OVERVIEW 33
4. 2 TOXICOKINETICS '.'.'.'.'.'.'.'.'.'.'.'.'.".'. 34
4.2.1 Absorption 34
4.2.1.1 Inhalation 34
4.2.1.2 Oral '.'.'.'.'.'.'.'.'.'.'.'.'.'.' 34
4.2.1.3 Dermal \ 35
4.2.2 Distribution '.'.'.'.'.'.'" 35
4.2.2.1 Inhalation 35
4.2.2.2 Oral '.'.'.'.'.'.'.'.'.'.'.'.". '. 36
4.2.2.3 Dermal 36
4.2.3 Metabolism '.'.'.'.'.'.'.'.'.'.'.'.'." 36
4.2.4 Excretion '// ' 36
4.2.4.1 Inhalation 36
4.2.4.2 Oral '.'.'.'.'.'.'.'.'.'.'.'.'.'. 37
4.2.4.3 Dermal 37
4.3 TOXICITY '.'.'.'.'.'.'.'.'.'.'.'.'.'. 37
4.3.1 Lethality and Decreased Longevity 37
4.3.1.1 Inhalation 37
4.3.1.2 Oral '.'.'.'.'.'.'.'.'.'.'.'.'.' " 38
4.3.1.3 Dermal '.'.'.'.'.'.'..'.'.'. 38
4.3.2 Systemic/Target Organ Toxicity '.'.'.'.".'.'. 38
4.3.2.1 Pulmonary effects 33
4.3.3 Developmental Toxicity '.'.'.'.'.'.' 44
4.3.4 Reproductive Toxicity \\\ \ 44
4.3.5 Genotoxicity !!!!!! ' .'. 44
4.3.6 Carcinogenicity 44
4.3.6.1 Inhalation 44
4.3.6.2 Oral '.'.'.'.'.'. 47
4.3.6.3 Dermal '.'.'.'.'.'.'.'..'.'. 48
4.3.6.4 General discussion 43
4.4 INTERACTIONS WITH OTHER CHEMICALS .'!!.'.'.." ' 48
MANUFACTURE, IMPORT. USE, AND DISPOSAL 51
5.1 OVERVIEW 51
5.2 PRODUCTION 51
5.3 IMPORT 52
5.4 USE 52
5.5 DISPOSAL '.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'. .' 53
ENVIRONMENTAL FATE 55
6.1 OVERVIEW '.'.'.'.'.'.'.'.'. 55
6. 2 RELEASES TO THE ENVIRONMENT . 55
6 . 3 ENVIRONMENTAL FATE '.'.'.'.'.'.'.'.".'.'.'.'.'.' 57
vi
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Concents
7 POTENTIAL FOR HUMAN EXPOSURE 59
7.1 OVERVIEW 59
7.2 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 59
7.2.1 Air 59
7.2.2 Water 59
7.2.3 Soil 61
7.2.4 Other 61
7.2.4.1 Foodstuffs 61
7.2.4.2 Miscellaneous 61
7.3 OCCUPATIONAL EXPOSURES 62
7.4 POPULATIONS AT HIGH RISK 62
8. ANALYTICAL METHODS 63
8.1 ENVIRONMENTAL MEDIA 63
8.2 BIOMEDICAL SAMPLES 63
9. REGULATORY AND ADVISORY STATUS 69
9 1 INTERNATIONAL 69
9.2 NATIONAL 69
9.2.1 Regulations 69
9.2.2 Advisories 69
9.2.2.1 Air 69
9.2.2.2 Water 69
9.2.3 Data Analysis 70
9.2.3.1 Reference dose 70
9.2.3.2 Carcinogenic potency 70
9.3 STATE 71
10. REFERENCES 73
11. GLOSSARY 87
APPENDIX: PEER REVIEW 91
vii
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LIST OF FIGURES
1.1 Health effects from breathing beryllium and compounds 4
1.2 Health effects from ingesting beryllium and compounds 5
2.1 Effects of beryllium and compounds--inhalation exposure 9
2.2 Effects of beryllium and compounds--oral exposure 10
2.3 Levels of significant exposure for beryllium and compounds--
inhalation 11
2.4 Levels of significant exposure for beryllium and compounds--
oral , 12
2.5 Relationship between urine level of beryllium and
air concentration 18
2.6 Availability of information on health effects of beryllium
and compounds (human data) 22
2.7 Availability of information on health effects of beryllium
and compounds (animal data) 23
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LIST OF TABLES
3.1 Chemical identity of beryllium and compounds 28
3.2 Physical and chemical properties of beryllium and compounds ,. 30
4.1 Acute oral LDcns for beryllium compounds 39
4.2 Genotoxicity of beryllium compounds in vitro 45
6.1 Natural and anthropogenic emissions of beryllium 56
7.1 Potential human consumption of beryllium from normal
sources in a typical residential environment 60
8.1 Analytical methods for environmental samples 64
8.2 Analytical methods for biomedical samples 66
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1. PUBLIC HEALTH STATEMENT
1.1 WHAT IS BERYLLIUM?
Pure beryllium is a hard grayish metal. Beryllium occurs naturally
as a chemical component of certain kinds of rocks. Two kinds of mineral
rocks, bertrandite and beryl, are mined commercially for the recovery of
beryllium. Very pure gem-quality beryl is better known as either
aquamarine (blue or blue-green) or emerald (green). Beryllium is also
present in a variety of compounds.
Host of the beryllium ore that is mined is converted into metal
alloys. Most of these alloys are used in the electronics field or in
structural applications. Pure beryllium metal has applications in
nuclear weapons and reactors, aircraft-satellite-space vehicle
structures and instruments, X-ray transmission windows, and mirrors.
Beryllium oxide is also manufactured from beryllium ores and is used to
make specialty ceramics for electrical and high-technology applications
1.2 HOW MIGHT I BE EXPOSED TO BERYLLIUM?
Everyone is exposed to low levels of beryllium in the air that chey
breathe, in many foods and waters that are consumed, or through its
natural occurrence in many soils. Most of the beryllium that can be
inhaled is released into the air by the burning of coal or fuel oil.
Beryllium occurs as an impurity in coal and fuel oil and is emitted into
the air with the fly ash and dusts that escape through chimney stacks
Beryllium occurs naturally in various tobaccos and is inhaled during
smoking. People who smoke cigarettes may breathe considerably more
beryllium than people who do not smoke. Beryllium is present in many
fruits and vegetables.
Beryllium metal and metal alloys may be found in consumer products
such as electronic devices (e.g., televisions, calculators, and personal
computers) and special nonsparking tools.
The greatest exposures to beryllium, mostly in the form of
beryllium oxide, occur in the workplace. Occupational exposure to
beryllium occurs at places where it is mined, processed, and converted
into metal, alloys, and chemicals. People who live near these industries
can also be exposed to small amounts. Workers engaged in machining
metals containing beryllium, in reclaiming beryllium from scrap alloys,
or in using beryllium products will also be exposed occupationally.
Beryllium can be transferred to individuals from workers' clothing. Most
of what is known about how beryllium affects health is based on studies
of workers.
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2 Section 1
1.3 HOV DOES BERYLLIUM GET INTO MY BODY?
Animal studies have shown that only small amounts of beryllium are
absorbed after ingestion of beryllium or its compounds or after
beryllium comes in contact with the skin, although physical contact with
the skin is in itself sufficient to cause irritation. These studies have
also shown that the most efficient way in which beryllium enters the
body of an animal is inhaling particles of beryllium suspended in the
air.
1.4 HOV CAN BERYLLIUM AFFECT MY HEALTH?
Beryllium is a toxic substance that can be harmful, depending on
the amount and duration of exposure to it. Not all of the effects that
beryllium and its compounds have on human health are well understood,
and not all forms of beryllium are equally toxic. The primary organ that
beryllium affects is the lung. Short-term human and animal exposure to
high levels of soluble beryllium compounds can lead to the development
of inflammation or reddening and swelling of the lungs, a condition
known as Acute Beryllium Disease (similar to pneumonia). Removal from
exposure results in a reversal of symptoms. Long-term exposure to
beryllium or beryllium oxide at much lower levels has been reported to
cause Chronic Beryllium Disease in sensitive individuals, characterized
by shortness of breath, scarring of the lungs, and berylliosis
(noncancerous growths in the lungs of humans). Both Acute and Chronic
Beryllium Disease can be fatal, depending on the severity of the
exposure. In addition, a skin allergy has been shown to develop when
soluble beryllium compounds come in contact with the skin of sensitized
individuals. Noncancerous growths that can ulcerate can form on the skin
if beryllium enters cuts. Experiments with laboratory animals indicated
that breathing beryllium and some of its compounds, both soluble and
insoluble, causes lung cancer; therefore, inhalation of beryllium and
its compounds is presumed by the U.S. Environmental Protection Agency
(EPA) to have some cancer-causing potential in humans. No studies in
animals or humans provided convincing evidence that the ingestion of
beryllium or its compounds causes cancer.
1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE BEEN EXPOSED TO
BERYLLIUM?
Beryllium levels can be measured in the urine and blood, but levels
in the urine may be highly variable. Elevated levels in urine and blood
indicate exposure but not necessarily disease. Another procedure
involving the sampling of tissues (i.e., biopsy) may be performed so
that beryllium levels can be measured in those tissues. There is a
medical test, which involves the examination of cells that have been
washed out of the lungs, to diagnose the condition of noncancerous
growths in the lungs; however, this test cannot distinguish growths thac
were caused by beryllium (Chronic Beryllium Disease) from growths caused
by other factors. A test in which lymphocytes (blood cells involved in
immunity) are transformed in the presence of beryllium can definitively
diagnose Chronic Beryllium Disease.
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Public Health Statement 3
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?
The graphs on the following pages show the relationship between
exposure to beryllium and its compounds and known health effects. In the
first set of graphs (Fig. 1.1). labeled "Health effects from breathing
beryllium and compounds," exposure is measured in milligrams of
beryllium per cubic meter of air. In the second set of graphs (Fig.
1.2), the same relationship is represented for the known "Health effects
from ingesting beryllium and compounds." Exposures are measured in
milligrams of beryllium per kilogram of body weight per day. In all
graphs, effects in animals are shown on the left side, effects in humans
on the right. There was insufficient information to graph exposure
levels of beryllium that cause toxic effects from skin contact.
Short-term refers to exposures lasting 14 days or less, and long-
term refers to exposures lasting for IS days or more. The levels marked
on the graphs as anticipated to be associated with minimal risk for
effects other than cancer are based on available information from animal
studies, but some uncertainty still exists.
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT
HUMAN HEALTH?
Because of the potential for beryllium to cause cancer, the
National Institute for Occupational Safety and Health (NIOSH) has
recommended a standard for occupational exposure of 0.5 microgram
beryllium per cubic meter of workroom air to protect workers during an
8-hour shift. The Occupational Safety and Health Administration (OSHA)
has set a limit of 2 micrograms of beryllium per cubic meter of workroom
air for an 8-hour work shift. The EPA restricts the amount of beryllium
emitted into the environment by industries that process beryllium ores,
metal, oxide, alloys, or waste to 10 grams in a 24-hour period, or to an
amount that would result in atmospheric levels of 0.01 microgram
beryllium per cubic meter of air, averaged over a 30-day period.
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Section 1
SHORT-TERM EXPOSURE
(LESS THAN OR EQUAL TO 14 DAYS)
EFFECTS
IN
ANIMALS
CONG IN
AIR
(mg/m3)
100
DEATH AND
LUNG EFFECTS-
10
1 0
01
001
0001
00001
0 00001
EFFECTS
IN
HUMANS
QUANTITATIVE
DATA WERE
NOT AVAILABLE
EFFECTS
IN
ANIMALS
DEATH-
LONG-TERM EXPOSURE
(GREATER THAN 14 DAYS)
LUNG
EFFECTS—<
CONC IN
AIR
(mg/m3)
100
10
000001
EFFECTS
IN
HUMANS
s~
1
0
0
OC
OOI
0
1
)1
01
101
LUNG EFFECTS
0 000001 0 000001
Fig. 1.1. Health effects from breathing beryllium and compounds.
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Public Health Statement
SHORT-TERM EXPOSURE
(LESS THAN OR EQUAL TO 14 DAYS)
LONG-TERM EXPOSURE
(GREATER THAN 14 DAYS)
EFFECTS EFFECTS
IN DOSE IN
ANIMALS (mg/kg/day) HUMANS
/"
DEATH <
1
1
0
0.
0.(
)0 DATA REGARDING
HEALTH EFFECTS
FROM INGESTION
WERE NOT
AVAILABLE
0
0
1
)1
01
EFFECTS EFFECTS
IN DOSE IN
ANIMALS (mg/kg/day) HUMANS
1
1
DECREASED
GROWTH
1
0
0
0(
30 DATA REGARDING
HEALTH EFFECTS
FROM INGESTION
WERE NOT
AVAILABLE
9
0
1
>1 MINIMAL RISK FOR
gggg*»^«« fYTHFB THftM
CANCER
101
0 0
Fig. 1.2. Health effects from ingesting beryllium and compounds.
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2. HEALTH EFFECTS SUMMARY
2.1 INTRODUCTION
This section summarizes and graphs data on the health effects
concerning exposure to beryllium and its compounds. The purpose of this
section is to present levels of significant exposure for beryllium based
on key toxicological studies, epidemiological investigations, and
environmental exposure data. The information presented in this section
is critically evaluated and discussed in Sect. 4, Toxicological Data,
and Sect. 7, Potential for Human Exposure.
This Health Effects Summary section comprises two major parts.
Levels of Significant Exposure (Sect. 2.2) presents brief narratives and
graphics for key studies in a manner that provides public health
officials, physicians, and other interested individuals and groups with
(1) an overall perspective of the toxicology of beryllium and (2) a
summarized depiction of significant exposure levels associated with
various adverse health effects. This section also includes information
on the levels of beryllium that have been monitored in human fluids and
tissues and information about levels of beryllium found in environmental
media and their association with human exposures.
The significance of the exposure levels shown on the graphs may
differ depending on the user's perspective. For example, physicians
concerned with the interpretation of overt 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 frank effects (Frank Effect Level, FEL). 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 (Lowest-Observed-Adverse-Effect Level,
LOAEL) or exposure levels below which no adverse effects (No-Observed-
Adverse-Effect Level, NOAEL) have been observed. Estimates of levels
posing minimal risk to humans (Minimal Risk Levels) are of interest to
health professionals and citizens alike.
Adequacy of Database (Sect. 2.3) highlights the availability of key
studies on exposure to beryllium in the scientific literature and
displays these data in three-dimensional graphs consistent with the
format in Sect. 2.2. The purpose of this section is to suggest where
there might be insufficient information to establish levels of
significant human exposure. These areas will be considered by the Agency
for Toxic Substances and Disease Registry (ATSDR), EPA. and the National
Toxicology Program (NTP) of the U.S. Public Health Service in order to
develop a research agenda for beryllium.
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8 Section 2
2.2 LEVELS OF SIGNIFICANT EXPOSURE
To help public health professionals address the needs of persons
living or working near hazardous waste sites, the toxicology data
summarized in this section are organized first by route of exposure--
Inhalation, ingestion, and dermal--and then by toxicological end points
that are categorized into six general areas--lethality, systemic/target
organ toxicity. developmental toxicity, reproductive toxicity, genetic
toxicity, and carcinogenicity. The data are discussed in terms of three
exposure periods--acute, intermediate, and chronic.
Two kinds of graphs are used to depict the data. The -first type is
a "thermometer" graph. It provides a graphical summary of the human and
animal Coxicological end points (and levels of exposure) for each
exposure route for which data are available. The ordering of effects
does not reflect the exposure duration or species of animal tested. The
second kind of graph shows Levels of Significant Exposure (LSE) for each
route and exposure duration. The points on the graph showing NOAELs and
LOAELs reflect the actual doses (levels of exposure) used in the key
studies. No adjustments for exposure duration or intermittent exposure
protocol were made.
Adjustments reflecting the uncertainty of extrapolating animal data
to man, intraspecies variations, and differences between experimental vs
actual human exposure conditions were considered when estimates of
levels posing minimal risk to human health were made for noncancer end
points. These minimal risk levels were derived for the most sensitive
noncancer end point for each exposure duration by applying uncertainty
factors. These levels are shown on the graphs as a broken line starting
from the actual dose (level of exposure) and ending with a concave-
curved line at its terminus. Although methods have been established to
derive these minimal risk levels (Barnes et al. 1987), shortcomings
exist in the techniques that reduce the confidence in the projected
estimates. Also shown on the graphs under the cancer end point are low-
level risks (10'a to 10'7) reported by EPA. In addition, the actual dose
(level of exposure) associated with the tumor incidence is plotted.
2.2.1 Key Studies and Graphical Presentations
Oose-response-duration data for the toxicity and carcinogenicity of
beryllium compounds are displayed in two types of graphs. These data are
derived from the key studies described in the following sections The
"thermometer" graphs in Fig. 2.1 and 2.2 plot NOAELs and LOAELs for
various effects and durations of inhalation and oral exposure.
respectively. The graphs of levels of significant exposure in'Figs. 2 3
and 2.4 plot end-point-specific NOAELs and LOAELs and minimal levels of
risk for acute (s!4 days), intermediate (15 to 364 days), and chronic
(>365 days) durations for inhalation and oral exposure, respectively.
Although skin contact with soluble beryllium salts can result in contacc
dermatitis (EPA 1980), exposure levels were not available for graphical
depiction.
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Health Effects Summary
ANIMALS
(mgm*)
100 f-
HUMANS
10 -
01
001^
• RAT AND MOOSE. LUNG EFFECTS 1 h (BERYLLIUM SULFATE)
r» RAT GUINEA PIG AND HAMSTER. DEATH 14 DAYS. INTERMnTTENT (BERYLLIUM SULFATE)
• MULTIPLE SPECIES'LUNG EFFECTS. 14 DAYS INTERMITTENT (BERYLLIUM SULFATE)
U 000 DECREASED WEIGHT GAIN. LUNG EFFECTS 40 DAYS INTERMITTENT (BERYLLIUM OXIDE)
O MONKEY LUNG EFFECTS, a MONTHS INTERMITTENT (BERYLLIUM DUST)
• RAT. CAT. RABBIT. GUINEA PIG DEATH. 95 DAYS INTERMITTENT (BERYLLIUM SULFATE)
fQ MONKEY LUNG EFFECTS. 23 MONTHS. INTERMITTENT(BERTRANDITE DUST)
{• MONKEY. DECEASED LONGEVITY 13 OR 18 DAYS INTERMITTENT (BERYLLIUM PHOSPHATE)
JO MULTIPLE SPECIES.'DEATH. 100 DAYS INTERMITTENT (BERYLLIUM SULFATE)
I • MULTIPLE SPECIES " LUNG EFFECTS 100 DAYS INTERMITTENT (BERYLLIUM SULFATE)
• RAT LUNG EFFECTS. 72 WEEKS INTERMITTENT (BERYLLIUM SULFATE)
BERYLUOSIS AND
CHEMICAL PNEUMONITIS
MAY RESULT FROM
EXPOSURES OF
iTOIOOOWRi'Bi
• LOAEL
O NOAEL
'HAT DOG. CAT. RABBIT. GUINEA PC. HAMSTER. MONKEY MOUSE
Fig. 2.1. Effects of beryllium and compounds—inhalation exposure.
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10 Section 2
ANIMALS
(mg/kg/dBy)
1000r-
HUMANS
100
_• RAT. LO,,, ACUTE
X)
• MOUSE. LO^ ACUTE
O RAT DECREASED GROWTH. LIFETIME
DATA REGARDING
HEALTH EFFECTS
FROM INGESTION
WERE NOT
AVAILABLE
• LOAEL
O NOAEL
Fig. 2.2. Effects of beryllium and compounds—oral exposure.
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Health Effects Summary 11
(mg/m3)
100 r
10
01
001
0001
00001
0 00001
0 000001
00000001 I-
ACUTE
(S14 DAYS)
INTERMEDIATE
(15-364 DAYS)
CHRONIC
(2365 DAYS)
TARGET TARGET TARGET
LETHALITY ORGAN LETHALITY ORGAN CANCER ORGAN CANCER
• r. m(LUNG)
• r, g, s • r. d. c. h. g. s. k. m (LUNG)
r. c. h. g
Or. d. c. h. •r. d. c. h 0r
g. s. k g. s. k
(LUNG)
O k (LUNG)
K(LUNG) «r
10-4-,
10-*-
10
,-6 .
10
,-7 J
ESTIMATED
UPPER-BOUND
HUMAN
CANCER
RISK LEVELS
r RAT
m MOUSE
d DOG
k MONKEY
g GUINEA PIG
c CAT
S HAMSTER
h RABBIT
f LOAEL AND NOAEL
O IN THE SAME SPECIES
• LOAEL
O NOAEL
Fig. 2.3. Levels of significant exposure for beryllium and compounds—inhalation.
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12 Section 2
(mg/kg/day)
1000
100
10
1
0.1
0.01
0001
0.0001
0.00001
0 000001
0.0000001
00000001
ACUTE INTERMEDIATE CHRONIC
(S14 DAYS) (15-364 DAYS) (2365 DAYS)
LETHALITY TARGET ORGAN
QUANTITATIVE
DATA WERE NOT
AVAILABLE
• r
• m
—
0 r (DECREASED
BODY WEIGHT)
-
-
• LOAEL
| MINIMAL RISK LEVEL FOR
ONOAEL ^EFFECTS OTHER THAN CANCER
m MOUSE
Fig. 2.4. terete of significant exposure for beryllium and
-------
Health Effects Summary 13
2.2.1.1 Inhalation exposure
Lethality and decreased longevity. Decreased longevity following
inhalation exposure to beryllium compounds in humans is related to the
pulmonary effects (Hardy and Tabershaw 1946), but dose-response data are
inadequate. Inhalation LC5Q values for beryllium compounds were not
available. Stokinger et al. (1950) found that exposure to an aerosol of
beryllium sulfate at 4.3 mg/ra3 beryllium for 6 h/day, 5 days/week for 14
days was lethal to 10/10 rats, 2/10 hamsters, and 3/10 guinea pigs
Although this study did not report the use of controls (and exposure
concentrations fluctuated widely), it does provide the only available
dose response data on lethality following acute inhalation exposure
Thus, the level of 4.3 mg/m3 is plotted in Figs. 2.1 and 2.3 for acute
inhalation exposure.
Concentrations of beryllium that caused death in monkeys following
intermediate exposure to beryllium fluoride and beryllium phosphate were
185 and 202 ^g/m3 beryllium, respectively (Schepers 1964). Reeves (1986)
reported that fluoride potentiates the toxicity of inhaled beryllium;
therefore, the exposure level of 202 Mg/m3 beryllium from beryllium
phosphate was selected for plotting in Figs. 2.1 and 2.3 for
intermediate exposure. Deaths occurred in rats, cats, rabbits, and
guinea pigs exposed to beryllium sulfate at 0.43 rag/m3 beryllium (FEL),
6 h/day, 5 days/week for 95 days, but no deaths occurred in rats, dogs,
cats, rabbits, guinea pigs, monkeys, or hamsters similarly exposed to
beryllium sulfate at 0.04 mg/m3 beryllium (NOAEL) for 100 days
(Stokinger et al. 1950). Although these studies had limitations, they
provide the only data on the lethality of intermediate inhalation
exposure to beryllium compounds. The FEL and NOAEL for lethality for
intermediate inhalation exposure are plotted in Figs. 2.1 and 2.3. Ic
should be noted, however, that the NOAEL for lethality also produced
adverse effects on the lungs.
Systemic/target organ toxicity. The lung is the main target organ
for toxicity following exposure to beryllium and beryllium compounds by
inhalation. In humans, this toxicity is manifested in the form of an
acute pneumonitis or a more chronic form of lung disease (berylliosis)
in which granulomas develop in the lung (EPA 1987a). EPA (1987a)
reviewed a number of studies in which workers exposed to beryllium
developed berylliosis. Uorkplace concentrations of beryllium in these
studies were <1000 pg/m3. EPA (1987a) stated that new cases of chronic
beryllium disease are being reported in instances where the OSHA
standard of 2 pg/m3 has been exceeded; however, in industries where
exposures are <2 /*g/m3, very few new cases have been reported. Although
Cullen et al. (1987) reported four cases of berylliosis in precious
metal refinery workers exposed to <2 /*g/m3 beryllium between 1972 and
1985, there were limitations in exposure measurements (see Sect. 4.3 2 1
on pulmonary effects in humans due to inhalation exposure). Furthermore,
Eisenbud and Lisson (1983) documented the 30-year effectiveness of the
OSHA standard of 2 /*g/m3 in controlling acute and chronic beryllium
disease. Because the actual lowest exposure level resulting in
beryllium disease cannot be determined from these data, no points can be
graphed on Figs. 2.1 or 2.3. However, the range possibly associated with
berylliosis is indicated on Fig. 2 1.
-------
14 Section 2
In animals, the toxic response in the lung following exposure to
beryllium and its compounds is much the same as in humans (i e
pneumonitis and granuloma formation). ' ''
In a study by Sendelbach et al. (1986), rats and mice exposed to
beryllium sulfate at 13 mg/m3 beryllium for 1 h developed cellular
proliferative changes in the lung (see Figs. 2.1 and 2.3). In a study by
Stokinger et al. (1950), rats, dogs, cats, rabbits, monkeys, guinea
pigs, hamsters, and mice exposed to beryllium sulfate at 4.3 me/m3
beryllium for 6 h/day, 5 days/week for 14 days developed pneumonitis
This exposure is an acute inhalation LOAEL for target organ toxicity
(see Figs. 2.1 and 2.3). No acute study defined a NOAEL.
For intermediate exposure durations, dogs exposed to beryllium
oxide 6 h/day. 5 days/week at 30 or 82 mg/m3 beryllium for 15 days or at
3.6 mg/m-5 beryllium for 40 days had marked weight loss (Hall et al
1950). Exposure at 30 or 82 mg/m3 for 15 days resulted in moderate'lune
damage, while exposure to 3.6 mg/m3 for 40 days resulted in more severe
lung damage (Fig. 2.1). In the study by Stokinger et al. (1950) rats
dogs, cats, rabbits, guinea pigs, hamsters, monkeys, and mice developed
pneumonitis following exposure to beryllium sulfate 6 h/day, 5 days/week
3tJ A n?8/ beryllium for 51 days, 0.43 mg/m3 beryllium for 95 days
and 0 04 mg/m3 beryllium for 100 days. Although there were no controls
in this study, effects typical of beryllium exposure were found in many
species. As all exposures produced adverse effects, a NOAEL for
intermediate inhalation exposure was not defined, but the lowest
exposure level (0.04 mg/m3) resulting in adverse effects is indicated in
Figs. 2.1 and 2.3.
Rats exposed to beryllium sulfate at 34 /jg/m3 beryllium 7 h/day 5
days/week for 72 weeks developed proliferative and inflammatory changes
in the lungs (Reeves et al. 1967). Thus. 34 ^g/m3 is a chronic
inhalation LOAEL in rats. The LOAEL for chronic inhalation target organ
toxicity in rats is plotted in Figs. 2.1 and 2.3.
In monkeys, chronic inhalation NOAELs were provided in a study by
Wagner et al. (1969). Monkeys exposed to either beryl dust at 620 Lg/m3
beryllium or bertrandite dust at 210 Mg/m3 beryllium. 6 h/day 5
days/week for 23 months had macrophage clusters in the lung but no other
e™C£fngeS (S6e Fig' 2'1)- The 620-"g/»3 exposure level is indicated
as a NOAEL in monkeys in Fig. 2.3. These NOAELs are higher than the
levels producing adverse effects in chronic studies in rats and in the
intermediate duration studies in many species, probably because not all
forms of beryllium are equally toxic.
Because adverse effects occurred in animals even at the lowest
exposures in acute and intermediate duration experiments, and because
berylliosis may occur in humans at exposure levels lower than the
chronic animal LOAEL, minimal risk levels cannot be derived for
inhalation exposure to beryllium and its compounds.
Developmental toxicity. No studies were available regarding the
developmental effects of beryllium following inhalation exposure in
humans and animals.
-------
Health Effects Summary 15
Incratracheal administration of beryllium chloride or beryllium
oxide to pregnant rats at SO mgAg on day 3, 5, 8, or 20 of gestation
resulted in increased fetal mortality, decreased fetal weight, and
increased percentages of pups with internal abnormalities (Selivanova
and Savinova 1986).
Reproductive tozicity. The only data regarding reproductive
effects of beryllium or its compounds were reported by Clary et al.
(1975), who found no consistent effect on reproductive performance in
rats treated intratracheally with beryllium oxide at 0.2 mg beryllium
per rat and allowed to mate repeatedly over a 15-month period.
Genotozicity. Beryllium sulfate and beryllium chloride tested for
mutagenicity in bacteria provide both positive and negative responses
depending on the strain and the assay. Beryllium sulfate was generally
negative in Ames assays, but caused chromosome aberrations and sister
chromatid exchange (SCE) in mammalian cells in vitro (see Sect. 4.3.5 on
genotoxicity). Data were not available on the in vivo induction of
chromosomal aberrations in humans and animals.
Carcinogenicity. Several epidemiology studies reviewed by EPA
(1987a) suggested a connection between exposure to beryllium and its
compounds and lung cancer in humans, but the data are inadequate for
several reasons. A study by Wagoner et al. (1980) reported a significant
increased risk of lung cancer for workers in a beryllium processing
facility in Pennsylvania, but when the data were corrected for cigarette
smoking, the significant association could no longer be demonstrated
(EPA 1987a). Although the reanalysis of the Wagoner et al. (1980) study
indicated no significant increased risk of cancer, beryllium is
considered to be a probable human carcinogen because its compounds are
carcinogenic in animals by inhalation. EPA (1987a) used data from the
Wagoner et al. (1980) study, instead of animal data, as the basis for an
upper-bound estimate of cancer risk because, given the uncertainty
inherent in the use of animal data, it is more desirable to use the
available human data. As discussed by EPA (1987a), information supplied
by NIOSH (1972) and Eisenbud and Lisson (1983) regarding typical
workroom- levels for beryllium in production plants, for the period of
time covered by the Wagoner et al. (1980) study, indicates that the
narrowest range for median exposure that could be obtained on the basis
of available information was 100 to 1000 j*g/m3. Using this range of
exposure levels, the upper-bound estimate of cancer risk was calculated
to be 2 x 10"^ (/ig/m3)'!. This estimate was compared with potency
factors calculated from animal data: the potency factors derived from
animal studies of beryllium salts overestimate the human risk, but
potency factors derived from animal studies of beryllium oxide are quite
similar to the risk estimates derived from human data. Because of
weaknesses in the animal studies using beryllium oxide, however, the
derived potency values are not adequate as a basis for a recommended
potency, but they can be used to provide support for the upper-bound
risk estimate derived from human data. Because of uncertainties in the
human data, however, a low degree of confidence was placed in the
upper-bound risk estimate of 2 x 10"3 (pg/m^)'!. The exposures
associated with individual lifetime upper-bound risks of 10~4. 10"5,
10'6, and 10'7 are 5 x 10'5. 5 x 10'6. 5 x 10'7. and 5 x 10'8 mg/m3,
respectively. These exposure levels and the associated risk levels are
-------
16 Section 2
indicated in Fig. 2.3. Because of uncertainties in the human data these
estimates are controversial.
Reeves and Deitch (1969) found pulmonary carcinomas in 19/22 rats
after 3 months of exposure to beryllium sulfate at 36 /*g/m3 beryllium.
35 h/week. Higher incidences were seen after 6. 9, 12, and 18 months.
This level is plotted under the cancer end point for both intermediate
and chronic exposure.
2.2.1.2 Oral exposure
Lethality and decreased longevity. No human data were available
regarding lethality or decreased longevity following oral exposure to
beryllium compounds. Reeves (1986) reported acute oral LDSQs of 18 to 20
mgAg beryllium for beryllium fluoride in mice and 120 mgAg beryllium
for beryllium sulfate in rats. These values are indicated in Figs. 2.2
and 2.4 for acute oral exposure.
Systemic/target organ toxicity. Pertinent data regarding toxic
effects on the lung following oral exposure to beryllium compounds in
humans were not found in the available literature. Rats exposed orally
to 20 mg beryllium nitrate (1.35 mg beryllium or 3.9 mgAg) in the diet
every third day for 2.5 months developed harder and more opaque lungs
and a number of pathological disturbances in the bronchioles and alveoli
(Goel et al. 1980). Because the lung effects may have been due to
aspiration of the beryllium nitrate into the lungs during feeding,
however, the dose of 3.9 mgAg cannot be regarded as an intermediate
oral LOAEL for target organ effects in rats.
In studies by Schroeder and Kitchener (1975a,b), the only
treatment-related effect in rats and mice exposed to beryllium sulfate
in the drinking water at 5-ppm beryllium for life was decreased body
weight gain. Although lungs were not examined histologically, the 5 ppm
level is a. chronic oral NOAEL for systemic toxicity. EPA (1986) used the
NOAEL of 5 ppm in rats (equivalent to a dosage of 0.54 mgAg/day) to
derive a chronic oral reference dose (RfD) of 0.005 mgAg/day (see Sect
9.2.3 on data analysis) for beryllium. The NOAEL and the RfD (minimal
risk level for chronic systemic toxicity) are indicated in Fig. 2.4.
Developmental toxicity. No studies were available regarding the
developmental toxicity of beryllium following oral exposure in either
animals or humans.
Reproductive toxicity. No studies were available regarding the
reproductive effects of beryllium following oral exposure in either
animals or humans.
Genotoxicity. See the subsection on genotoxicity in Sect. 2.2.1 1
on inhalation exposure.
Carcinogenicity. Although beryllium compounds have not been
reported to cause cancer following oral exposure, the data are too
limited and inadequate to clarify whether or not a carcinogenic risk
exists. In a study by Morgareidge et al. (1975). analysis of data by the
Carcinogen Assessment Group (EPA 1980) indicated a statistically
significant increased incidence of reticulum cell sarcoma in the lungs
of rats exposed to 5 and 50 ppm. but not 500 ppm, beryllium sulfate in
-------
Health Effects Summary 17
the diet. EPA (1980) considered this study to be only suggestive of a
carcinogenic effect. In a study by Schroeder and Kitchener (1975a),
there was no carcinogenic response, compared with controls, in rats
treated with drinking water containing beryllium sulfate at 5 ppm
beryllium
2.2.1.3 Dermal Exposure
Pertinent data regarding the effects of beryllium or beryllium
compounds following dermal exposure of animals were not located in the
available literature. In humans, skin contact with soluble beryllium
compounds can cause contact dermatitis in sensitized individuals (Van
Ordstrand et al. 1945). Williams et al. (1987) reported that beryllium
can enter cuts in the skin of workers handling beryllium (metal, alloys.
and ceramics) and cause ulcerative granulomas on the skin. As beryllium
exposure levels resulting in contact dermatitis and ulcerative skin
granulomas were not available, these effects cannot be depicted
graphically.
2.2.2 Biological Monitoring as a Measure of Exposure and Effects
There are several tests for measuring beryllium in biological
fluids and tissues. These include measurement of beryllium levels in the
urine and blood, and a lymphocyte transformation test that measures
hypersensitivity to beryllium in previously exposed individuals.
Background urinary levels of beryllium have been determined by
several investigators using flameless atomic absorption spectroscopy to
be -0.9 ng beryllium per gram of urine (Stiefel et al. 1980, Grewel and
Kearns 1977). In a study by Stiefel et al. (1980), the urinary levels of
beryllium were analyzed in eight laboratory workers and compared with
the levels of beryllium in the laboratory atmosphere for a period of 30
days following an accidental leakage of beryllium chloride. The average
urinary and atmospheric levels of beryllium were plotted against time in
days. Replotting of urinary levels vs atmospheric levels results in the
relationship presented in Fig. 2.5. The urinary levels are directly
proportional to the atmospheric levels up to a concentration of 8 ng/m
It should be emphasized that the data of Stiefel et al. (1980) are the
only experimental data presented that relate airborne beryllium levels
with urinary levels in humans. Furthermore, Reeves (1986) stated that
the urinary excretion of beryllium is irregular and not useful for
diagnostic purposes.
In addition to the above-mentioned tests for determining exposure
to beryllium, a more invasive procedure for measuring beryllium levels
in the tissues of exposed individuals is the biopsy. This procedure has
been used by Kanarek et al. (1973) to determine beryllium levels in the
lung tissue of two employees of a beryllium extraction and processing
plant. At the plant, beryllium concentrations were known to exceed che
recommended standards of 2 Mg/m3 for an 8-h day and 25 Mg/n3 as the
acceptable maximum peak for 30 min. Peak concentrations in the Kanarek
et al. (1973) study exceeded 1 mg/m3 The normal level of beryllium in
lung tissue was reported by Kanarek et al. (1973) to be 0.02 /ig/g dry
weight. The beryllium levels in the lungs of the two subjects were 0.18
-------
O)
ill L IJ ill
456
AIR (ng/m3)
00
ft
o
Fig. 2.5. Relationship between urine level of beryllium and air concentration.
-------
Health Effects Summary 19
and 0.65 pg/g dry weight. Ic should be noted, however, that the subject
with the higher beryllium level did not have lung lesions, while the
subject with the lower beryllium level had granulomas. Thus, while
levels of beryllium in the lungs may indicate exposure, they are not
useful for diagnosing the presence or absence of chronic beryllium
disease.
There are several methods for measuring the effects due to
beryllium exposure. One test for measuring the effects of beryllium on
the lung is the X-ray. Hardy and Tabershaw (1946) described three stages
of chronic beryllium poisoning based on X-ray patterns of the lung. The
three stages were characterized by a fine diffuse granularity in the
lungs, followed by a diffuse reticular pattern, followed by the
appearance of distinct nodules. The lung X-ray does not appear to be
useful, however, in distinguishing between chronic beryllium disease and
sarcoidosis (EPA 1987a). Another useful method for testing the effects
of beryllium exposure on the lung is lung function tests. Andrews et al
(1969) performed lung function tests (forced expired volume in 1 second,
or FEVl, and forced vital capacity, or FVC) on 41 patients designated as
having chronic beryllium disease. Sixteen patients showed evidence of
airway obstruction, and only 2/41 patients were considered normal. These
tests, however, cannot tell whether the lung problems are due to
beryllium exposure. Broncho-alveolar lavage, which samples secretions
of the lower respiratory tract by fiberoptic bronchoscopy, is useful for
detecting granulomatous lung diseases; however, it cannot distinguish
chronic beryllium disease from sarcoidosis (James and Williams 1985). An
antigen-specific lymphocyte transformation test is useful for measuring
hypersensitivity in individuals previously exposed to beryllium and has
been used in the diagnosis of individuals with chronic beryllium disease
(Williams and Williams 1982,1983). The test was positive in all 16
individuals with chronic beryllium disease, negative in 10 subjects who
were suspected of having chronic beryllium disease, and positive in only
2 of 117 healthy beryllium workers. The positive test in the 2 healthy
workers indicated both exposure and sensitization (Williams and Williams
1983). According to James and Williams (1985), the in vitro beryllium
lymphocyte transformation test is always positive in beryllium patients
and negative in patients with sarcoidosis; thus, this test
authoritatively distinguishes chronic beryllium disease from
sarcoidosis. Williams and Kelland (1986) reported that laser ion mass
analysis of histological sections of lung or skin granulomas can
distinguish chronic beryllium disease from other granulomatous diseases
such as sarcoidosis. This technique was used to detect beryllium at
parts-per-million levels in the granulomas (but not in the surrounding
tissue)-of persons with definite chronic beryllium disease. While this
technique was only qualitatively useful at the time of the report,
attempts to quantitate the method are in progress.
2.2.3 Environmental Levels as Indicators of Exposure and Effects
2.2.3.1 Levels found in the environment
Data regarding the association between significant human exposure
or effects and levels of beryllium found in soil and water were not
encountered in the available literature.
-------
20 Section 2
2.2.3.2 Human exposure potential
It has been predicted that beryllium compounds resulting from human
releases will adsorb quite strongly to sediment, clay, and organic
matter in soil and water, because of the relative water insolubility of
the beryllium compounds involved. The distribution of these compounds
therefore, should generally be greater in the upper layers of soil that
have been contaminated than in the underlying layers and greater in the
sediments of bodies of water than in the water column. In general.
compounds become less bioavailable to animals and plants via uptake
mechanisms as adsorption increases. Conversely, factors that help
mobilize chemicals from soil through solubilization or other mechanisms
will increase their bioavailability. At waste sites, factors that result
in mobilization of beryllium may permit leaching into groundwater and
thereby increase the human exposure potential through consumption of
drinking water or foods originating from the groundwater.
Beryllium ore is mined in open pits in the United States in Utah
The bioavailability of beryllium in the air (from dusts) and in the soil
at these sites can be expected to be significantly higher than in other
areas of the country, increasing the human exposure potential.
The release of beryllium to the environment from human sources is
associated with the combustion of coal and the release of fly ash and
particulates. The exposure potential of beryllium via inhalation can be
expected to be elevated in the vicinity of coal-burning sources.
2.3 ADEQUACY OF DATABASE
2.3.1 Introduction
Section 110 (3) of SARA directs the Administrator of ATSDR to
prepare a toxicological profile for each of the 100 most significant
hazardous substances found at facilities on the CERCLA National
Priorities List. Each profile must include the following content:
"(A) An examination, summary, and interpretation of available
toxicological information and epidemiologic evaluations on a
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, and
chronic health effects.
(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 section identifies gaps in current knowledge relevant to
developing levels of significant exposure for beryllium. Such gaps are
identified for certain health effect end points (lethality,
systemic/target organ toxicity. developmental toxicity, reproductive
toxicity. and cancer) reviewed in Sect. 2.2 of this profile in
-------
Health Effects Summary 21
developing levels of significant exposure for beryllium, and for other
areas such as human biological monitoring and mechanisms of toxicity
The present section briefly summarizes the availability of existing
human and animal data, identifies data gaps, and summarizes research in
progress that may fill such gaps
Specific research programs for obtaining data needed to develop
levels of significant exposure for beryllium will be developed by ATSDR,
NTP, and EPA in the future
2.3.2 Health Effect End Points
2.3.2.1 Introduction and graphic summary
The availability of data for health effects in humans and animals
is depicted on bar graphs in Figs. 2.6 and 2.7, respectively.
Bars of full height indicate that there are data to meet at least
one of the following criteria:
1. For noncancer health end points, one or more studies are available
that meet current scientific standards and are sufficient to define
a range of toxicity from no-effect levels (NOAELs) to levels that
cause effects (LOAELs or FELs).
2. For human carcinogenicity, a substance is classified as either a
"known human carcinogen" or a "probable human carcinogen" by both
EPA and the International Agency for Research on Cancer (IARC)
(qualitative), and the data are sufficient to derive a cancer
potency factor (quantitative).
3 For animal carcinogenicity. a substance causes a statistically
significant number of tumors in at least one species and the data
are sufficient to derive a cancer potency factor.
4. There are studies which show that the chemical does not cause chis
health effect via this exposure route.
Bars of half height indicate that "some" information for the end
point exists but does not meet any of these criteria.
The absence of a column indicates that no information exists for
that end point and route.
2.3.2.2 Description of highlights of graphs
There are practically no dose-response data for the health effects
of beryllium and compounds in humans Some data exist for the inhalation
route of exposure regarding decreased longevity and pulmonary effects.
but dose-response relationships are not defined. EPA and IARC have
classified beryllium as a probable human carcinogen based on sufficienc
animal data and inadequate (EPA 1987a) or limited (IARC 1987) human
data, and EPA (1987a) has derived an upper-bound risk estimate for
cancer from inhalation exposure, thus fulfilling the criteria for data
adequacy (see item 2 under Sect 2321, Introduction and graphical
-------
HUMAN DATA
to
r>
n
§
SUFFICIENT
INFORMATION*
J
SOME
INFORMATION
NO
INFORMATION
ORAL
INHALATION
DERMAL
LETHALITY ACUTE INTERMEDIATE CHRONIC DEVELOPMENTAL REPRODUCTIVE CARCINOOENICITY
^ --- / TOXICITY TOXICITY
SYSTEMIC TOXICITV
'Sufficient information exists to meet at least one of the criteria for cancer or noncancer end points.
Fig. 2.6. Availability of information on health effects of beryllium and compounds (human data).
-------
ANIMAL DATA
SUFFICIENT
INFORMATION*
SOME
INFORMATION
NO
INFORMATION
INHALATION
n
n
DERMAL
LETHALITY ACUTE INTERMEDIATE CHROMC DEVELOPMENTAL REPRODUCTIVE CARCINOOENKITV
Z / TOXICITV TOXICITV
SVSTEMIC TOXICITV
'Sufficient information exists to meet at least one of the criteria for cancer or noncancer end points.
Fig. 2.7. Availability of information on health effects of beryllium and compounds (animal data).
-------
24 Section 2
summary). The bar for carclnogenicity in humans by inhalation, however,
indicates only some data, because the data in humans are considered
inadequate by EPA (1987a) Acute skin contact with soluble beryllium
salts may cause contact dermatitis, but exposure levels causing skin
lesions were not available.
No data exist regarding the effects of dermal exposure on animals
Inhalation exposure levels that result in death in animals are available
for acute and intermediate exposure, and inhalation exposure levels that
do not result in death of animals are available for intermediate
exposure. LCSQs for inhalation exposure are not available; therefore,
the bar for lethality indicates only some data. Data exist indicating
that acute, intermediate, and chronic inhalation exposure of animals
results in pulmonary effects, but NOAELs or LOAELs are not defined.
There are adequate data showing that beryllium compounds are
carcinogenic in animals by the inhalation route. For oral exposure, only
a few LDso values were available; therefore, the bar indicates some
data. Data for systemic toxicity due to oral exposure are limited. As
discussed above, data that beryllium compounds are carcinogenic by the
oral route are also limited. Data regarding reproductive and
developmental effects of beryllium compounds by the dermal, oral, or
inhalation routes were not available; however, experiments in which the
intratracheal route was used indicate that beryllium oxide did not
impair reproductive function of rats, but that beryllium oxide and
beryllium chloride may be fetotoxic and teratogenic in rats.
2.3.2.3 Summary of relevant ongoing research
NIOSH is evaluating the mortality experience of approximately 9000
workers employed from January 1, 1940, to December 31, 1969, at seven
U.S. beryllium processing facilities. The vital status of workers
through December 31. 1983. will be followed. The risk of lung cancer
will be evaluated with respect to U.S. death rates through 1983, and
adjustment will be made for smoking. A case-control study is planned to
evaluate the effects of estimated beryllium dose on lung cancer risk
(NIOSH 1988).
2.3.3 Other Information Needed for Human Health Assessment
2.3.3.1 Pharmacokinetics and mechanisms of action
The pharmacokinetics and mechanisms of action of beryllium lung
toxicity in animals are fairly well understood.
2.3.3.2 Monitoring of human biological samples
Methods exist for measuring beryllium in hair, fingernails, urine,
feces, blood, and lung tissue. One study indicated that urine levels
could be correlated with atmospheric levels, but the study was the only
one providing such data. The reliability, therefore, has not been
substantiated.
-------
Health Effects Summary 25
2.3.3.3 Environmental considerations
Methods of sufficient sensitivity and specificity to measure
beryllium in soil, food, and water exist, but studies relating levels of
beryllium in these media to human exposure or health effects were not
found.
The environmental fate and transport of beryllium have been
predicted from its physical and chemical properties and by analogy to
other metals. Therefore, its predicted fate in the environment is only
an estimation and is not documented by specific experimental studies.
No studies are known to be available pertaining to interactions
between beryllium and other environmental pollutants.
There are no known ongoing experimental studies pertaining to the
environmental fate of beryllium.
-------
3. CHEMICAL AND PHYSICAL INFORMATION
3 1 CHEMICAL IDENTITY
Data pertaining co che chemical identity of beryllium and beryllium
compounds are listed in Table 3.1.
3.2 PHYSICAL AND CHEMICAL PROPERTIES
The physical and chemical properties of beryllium and beryllium
compounds are listed in Table 3.2. Beryllium chloride, fluoride.
nitrate, phosphate, and sulfate (tetrahydrate) are all soluble in water.
while the remaining compounds in Table 3.2 are either insoluble or
sparingly soluble.
-------
Table 3.1. Chemical ideality of beryllium and compounds
Chemical name
Synonyms
Tradenamcs
Chemical formula
Wuwesscr line notation
Chemical structure
Identification Nos
CAS Registry No
NIOSH RTECS No
EPA Hazardous Waste No
OHM-TADS No
DOT/UN/NA/IMCO Shipping No
STCC No
Hazard Substance Data Bank No
National Cancel Institute No
Beryllium
Berylhum-9,
Glucinium,
Glucinum.
beryllium
metallic
Unknown
Be
Be
Be
Beryllium
chloride
Beryllium
dichluride
Unknown
BeCI,
BcG2
BeCI,
Beryllium
fluoride
Beryllium
difluondc
Unknown
BeF,
BcF2
Bet,
Beryllium oxide
Beryllia.
Beryllium monoxide
Thermalox
BeO
BeO
BeO
Beryllium hydroxide
Beryllium hydrate.
Beryllium
dihydroxide
Unknown
Be(OU),
Be Q2
Be(OH),
Reference*
IAR( 1980
IISUB 1987
IAKC 1980
HSDB 1987
IISUB 1987
HSDB 1987
IAKC 1980
7440-41-7
OS 1750000
POI5
7216604
UN 1567
7787-47-5
DS2625000
Unknown
7217359
NA 1566
7787-49-7
DS2800000
Unknown
7800049
NA 1566
1104-56-9
DS4025000
Unknown
Unknown
Unknown
13327-32-7
DS3 150000
Unknown
Unknown
Unknown
Unknown 49 233 05 Unknown Unknown
512 Unknown Unknown Unknown
Unknown Unknown Unknown Unknown
Unknown
Unknown
Unknown
HSDB 1987
Chemlme 1987
HSDB 1987
Chcmlinc 1987
HSDB 1987
NIOSH 1987
HSDB 1987
l/l
(ft
O
n
h-
0
-------
Table 3.1 (coMtautd)
Chemical name
Synonyms
Tradcnames
Chemical formula
Wiswcsscr line notation
Chemical structure
Identification Nos
CAS Registry No
NIOSH RTECS No
LPA Hazardous Waste No
OHM-TADS No
DOT/UN/NA/IMCO Shipping No
STCC No
Hazard Substance Data Bank No
National Cancer Institute No
Beryllium phosphate
Phosphoric acid.
Beryllium salt.
Beryllium orthophosphaie
Unknown
Be,(P04), 3H,0
Be,(PO.), 3H,0
330*9-00-0
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
Beryllium nitrate
Nitric acid.
Beryllium salt
Unknown
Bet NO,),
Be N-O3*2
Be( NO,),
13397-99-4
(anhydrous)
7787-566
(lelrahydrale)
DS3673000
(anhydrous)
Unknown
7217227
(anhydrous)
UN 2464
49 187 59
Unknown
Unknown
Beryllium sulfale
Sulfuric acid.
Beryllium salt
Unknown
BeSO.
BcS-04
BeSO.
I3MO-49-I
(anhydrous)
1421 5-00-0 (2H,O)
7787-S6-6 (4H,O)
DS48000000
(anhydrous)
Unknown
7217228
(anhydrous)
Unknown
Unknown
Unknown
Unknown
Beryllium carbonate
Bauc beryllium
Carbonate. bu|carbonalo
(2-)|dibydro*y tn-
bcryllium
Unknown
(BeCO,), Be(OH),
(BeCO,), Be(OH),
66104-24-3
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
References
IARC 1980
IARC 1980
HSOB 1987
IARC 1980
IISDB 1987
HSUB 1987
IISDB 1987
IISDB 1987
q>
a
r>
(b
tu
a.
ti
n
0)
3
O
0
n
-------
Table 3.2. Physical and cbraical propcnm of btryllhM and conpouada
Molecular weight
Color
Physical slate
Odor
Melting point (°C)
Boiling point I'll
Beryllium
metal
9012
Steel gray
Solid, hexagonal
structure
None
1287-1292
2970
Beryllium
fluoride
4701
White, colorless
Glassy, hygroscopic
mass
None
555
117$
Beryllium
hydroxide
4303
White
Amorphous, crystalline
or granular solid
None
Decomposes (loses water)
when healed
Not applicable
Beryllium
oxide Reference*
"01 Weasi 198$
Wh"« Wea.1 1985. Dean
198$, Hawley 1981
Light, amorphous powder Wmdholi 1983.
Walsh and Reei
1978
None
2508-2547 Dean 1985. Wmd-
hol* 1983. Walsh
and Rees 1978.
Ballancc el al
1978
"87 Walsh and Rees
1978. Ballance
el al 1978
i_>
n>
n
n
i
U)
Unknown
icinperalurc
Unknown
Unknown
Unknown
Solubility
Waier
Organic solvents
Density
Log octanol-waicr
partition coefficient
Vapor pressure
Henry's law constant
Rcfracuvc index
1 Ijih puinl
1 Ijiniiuhilii) liiiiii>
Insoluble
Soluble in dilute
acid and alkali
1 846 g/cm1
Unknown
1 mmHg(l520°C)
Unknown
Unknown
Unknown
Unknown
Very soluble
Slightly soluble
in alcohol
1986 g/cm' (25°C)
Unknown
Unknown
Unknown
-------
Table 3.2 (continued)
Molcculai weight
Color
Physical stale
Odor
Melting point (°C)
Boiling point (°C)
Auloignilion temperature
Solubility
Water
Organic solvents
Density
Log ocianol-walcr
parlilion coefficient
Vapor pressure
Henry's law constant
Refractive index
Flash point
Fldmmabiliiy limns
Beryllium
carbonate
(basic)
112 OS
While
Powder
None
Unknown
Unknown
Unknown
Insoluble (cold)
decomposes (hot)
Soluble in acid, alkali
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
Beryllium
chloride
7992
Colorless
Needles, crystals
None
40S
520
Unknown
Very soluble
Very soluble in
alcohol, ether.
pyridme, slightly
soluble in benzene and
chloroform
1 899 g/cm1 (25-C)
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
Beryllium
nitrate
(lelrahydrale)
20508
White
Crystals
None
60S
142 (decomposes)
Unknown
166 parts/ 100 pans H,O (20°C)
Unknown
1 SS7 g/cm1
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
References
Weasl I98S. Dean I98S
Weasi I98S. Dean I98S
Weasi I98S, Dean I98S
Weasl I98S, Dean I98S
Weasl I98S. Dean I98S
Weast I98S, Dean I98S
Weast I98S. Dean I98S
A
B
n
0)
5
n
HI
-------
TaUe 3.2 (continued)
Molecular weight
Color
Physical state
Odor
Melting point (°C)
Boiling point (°C)
Auloigmiion temperature
Solubility
Water
Organic solvents
Density
Log octanol-waler
parlilion cocmcteni
Vapor pressure
Henry's law constant
Refractive index
Flash point
Flammabihly limits
Beryllium
phosphate
(3H,0)
27103
While
Solid
None
100 (loses H,O)
Unknown
Unknown
Soluble
Soluble in acid, alkali
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
Beryllium
sulfalc
(anhydrous)
10507
Colorless
Tetragonal crystals
None
550-600
(decomposes)
Unknown
Unknown
Insoluble
Unknown
2443g/cm'
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
Beryllium
<4H>°> References
17713 Weasl 1985
Colorless Octn 1985
Tetragonal crystals Weasl 1985. Dean 1985
None
100 (loses 2H10) Weasl 1985
400 (loses 4H,0) Weast 1985
Unknown
3 91 parts/100 parts H,O (20«C) Weasl 1985. Dean 1985
slightly soluble in H,SO4,
insoluble in alkali
1 7l3g/cm'(l05°C) Weasl 1985
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
O
These compounds do not exist in the atmosphere in the vapor phase, therefore, an air conversion factor is not applicable
-------
4. TOXICOLOGICAL DATA
4.1 OVERVIEW
There are several different compounds of beryllium, and, judging
from animal studies, all appear to be poorly absorbed through both the
gastrointestinal tract and the skin. The most important route by which
beryllium compounds are taken into the animal body is inhalation, and
absorption even by this route does not appear to be extensive Very
little data are available on the absorption of beryllium compounds by
humans, but dose, size, and solubility may determine rates of absorption
and clearance. Once beryllium is absorbed, it appears to be circulated
in the blood as an orthophosphate colloid and is then distributed
primarily to the bone (skeleton), liver, and kidneys in both humans and
animals. Beryllium and its compounds are not biotransformed, but soluble
beryllium compounds are partially converted to more insoluble forms in
the lungs.
In animals, the excretion of beryllium after oral administration of
beryllium compounds is primarily in the feces, with only very small
amounts appearing in the urine. This appears to be due to the poor
absorption of beryllium compounds through the gastrointestinal tract
After inhalation exposure, a large part of the absorbed beryllium is
excreted in the urine. Clearance of beryllium and its compounds from the
lung after inhalation exposure is slow in comparison with other metals
Following inhalation of soluble beryllium compounds in both humans
and animals, lethality and decreased longevity appear to be due to the
development of chemical pneumonitis. Very few data are available
regarding the toxicity of beryllium compounds following oral or dermal
exposure.
The lung appears to be the main target organ for toxicity following
exposure to beryllium. Exposure to low-fired beryllium oxide or to
soluble beryllium compounds (due to acidity) may lead to the development
of acute chemical pneumonitis, while chronic exposure to insoluble forms
may lead to chronic beryllium disease (berylliosis) in which granulomas
develop in the lung. There appears to be an immunologic component to
chronic beryllium disease, as evidenced by the fact that lymphocytes
from people with the disease undergo transformation in the presence of
beryllium. Dermal exposure to soluble beryllium salts also appears to
cause a dermatitis reaction in humans.
In the only studies regarding developmental effects of beryllium,
injection of beryllium salts into pregnant mice resulted in behavioral
abnormalities in the offspring, and intratracheal administration of
beryllium oxide and chloride to pregnant rats resulted in increased
fetal mortality, decreased fetal weight, and increased internal
abnormalities.
-------
Secczon 4
Pertinent data regarding the reproductive toxicity of beryllium
after inhalation, oral, or dermal exposure in humans or animals were nc
located in the available literature Intratracheal administration of
beryllium oxide did not affect the reproductive performance of rats
Only beryllium sulfate and beryllium chloride have been tested for
genotoxicity. Metabolic activation is not an issue for beryllium
mutagenicity. but a positive or negative response apparently depends on
the type of bacterial strain and the type of assay system that is used
Beryllium sulfate appears to be clastogenic in mammalian cells in
culture.
A variety of beryllium compounds have been demonstrated to be
carcinogenic in animals following inhalation exposure Beryllium
compounds have not been demonstrated to be carcinogenic by the oral
route. Several epidemiological investigations studying the connection
between beryllium exposure and lung cancer in humans were negative or
inadequate.
4.2 TOXICOKINETICS
4.2.1 Absorption
4.2.1.1 Inhalation
Human. Pertinent data regarding the absorption of beryllium or its
compounds in humans after exposure by inhalation were not found in the "
available literature.
Animal. The primary route by which beryllium compounds are
absorbed in animals is through the lung. Following inhalation of an
aerosol of beryllium nitrate, the concentration of beryllium in the
blood of exposed rats and guinea pigs reached steady-state levels afcer
8 to 12 h of exposure (Stiefel et al. 1980). The rate of accumulation of
beryllium in the lungs of rats exposed to an aerosol of beryllium
sulfate (34.25 jig/ra3 beryllium) decreased during continuing exposure.
and the beryllium concentration then reached a plateau (-13.5 ng in
whole lungs) after 36 weeks of exposure (Reeves and Vorwald 1967) In
contrast, the beryllium concentration in the tracheobronchial lymph
nodes did not reach a plateau, but reached a maximum between 36 and 52
weeks of exposure and then declined.
4.2.1.2 Oral
Human. Pertinent data on the absorption of beryllium following
exposure by the oral route were not found in the available literature
Animal. Absorption of beryllium and compounds following exposure
by the oral route is poor. Several investigators have found that after
ingestion of beryllium compounds, a majority of the beryllium passes
through the gastrointestinal tract unabsorbed and appears in the feces
(Reeves 1965, Shima et al. 1983. Furchner et al. 1973. Hyslop et al
1943. Watanabe et al. 1985). These investigators typically found that
<1% of the amount of ingested beryllium was absorbed through the gut
The absorption of beryllium through the gut also depends on the
beryllium compound administered Uatanabe et al. (1985) found measurable
-------
ToxicoLogical Data 35
amounts of beryllium in the liver, large and small intestines, kidneys.
lungs, stomach, and spleen following dietary administration of beryllium
sulfate to hamsters. In contrast, beryllium was found mainly in the
large and small intestines of hamsters following dietary administration
of beryllium oxide or beryllium metal. The results indicate that the
soluble beryllium sulfate was better absorbed from the gastrointestinal
tract than were the insoluble beryllium oxide and beryllium metal.
Bugryshev et al. (1984) found that beryllium oxide was absorbed more
readily in rats than was the hydroxide, and beryllium fluoride was
absorbed more readily than were the chloride, sulfate, nitrate, and
hydroxide.
4.2.1.3 Dermal
Human. Suskind (1983) stated that beryllium compounds are able co
penetrate the human skin and cause irritant and/or allergic reactions in
man, but he did not provide supporting data. As reviewed by EPA (1980),
acute dermal exposure to soluble beryllium compounds can cause contact
dermatitis, but exposure level producing skin lesions were not
available.
Animal. Dermal absorption of beryllium and compounds is poor Only
small amounts of beryllium were absorbed through the tail skin of rats
(Petzow and Zorn 1974). EPA (1987a) concluded that significant
absorption of beryllium or its compounds through intact skin is unlikely
because of its chemical properties.
4.2.2 Distribution
4.2.2.1 Inhalation
Human. There are few data on the distribution of beryllium in
humans following inhalation exposure. Analysis of tissues from people
occupationally exposed to beryllium indicates that other than in the
lungs, the highest levels of beryllium are found in the bone, followed
by lower levels in the liver and kidneys (Tepper et al. 1961, Meehan and
Smyth 1967).
Animals. Immediately following exposure to a radioactive beryllium
sulfate. aerosol, 67% of the retained amount of beryllium was found in
the lungs of exposed rats and guinea pigs and 15% was found in the
skeleton (Zorn ec al. 1977). After 17 days, -80% of the total body
burden of radioactive beryllium was found in the skeleton and -18% was
in the lungs. In a reproductive study (see Sect. 4.3.4 on reproductive
toxicity), Clary et al. (1975) treated male and female Sprague-Dawley
rats with 7BeO intratracheally at a dose of 0.2 mg beryllium per rat
Controls were given saline intratracheally. Interval sacrifices were
performed five times over a 15-month period. In the beryllium oxide-
treated rats, beryllium was found in the lungs, femur, liver, kidneys.
and heart after the first sacrifice (during the last third of the firsc
pregnancy) and in the lungs and femur after the second sacrifice (after
the first litter was weaned), but only the lungs contained beryllium ac
later sacrifices.
-------
36 Section 4
4.2.2.2 Oral
Human. Pertinent data regarding the distribution of beryllium
following oral exposure In humans were not found In the available
literature.
Animal. Watanabe et al. (1985) administered dally diets containing
5 mg beryllium as beryllium sulfate. beryllium oxide, or beryllium mecal
to hamsters for 3 to 12 months. The hamsters were sacrificed at various
times, and tissues (brain, heart, lungs, stomach, liver, spleen,
kidneys, small Intestines, large intestines, and testis) were analyzed
for beryllium. Administration of beryllium sulfate, a soluble compound.
resulted in appreciable distribution of beryllium to the liver, large
intestine, small Intestine, kidneys, lungs, stomach, and spleen.
Beryllium was found, however, mainly in the large and small intestines
following administration of beryllium metal or beryllium oxide, which
are insoluble compounds.
Beryllium storage in the bone was found to be proportional to
intake In rats fed different levels of beryllium sulfate in the diet
(Morgareidge et al. 1977), and the general trend of beryllium being
distributed to the skeleton and liver appears to be independent of the
type of beryllium compound administered (Reeves 1965. Bugryshev et al
1984, LeFevre and Joel 1986).
4.2.2.3 Dermal
Pertinent data regarding the distribution of beryllium following
dermal exposure In humans or animals were not found in the available
literature.
4.2.3 Metabolism
Beryllium and its compounds are not biotransformed, but soluble
beryllium salts are partially converted to more insoluble forms in the
lung (EPA 1987a).
4.2.4 Excretion
4.2.4.1 'inhalation
Human. Pertinent data regarding the excretion of beryllium in
occupatlonally or experimentally exposed humans were not found in the
available literature. Several reports have indicated, however, that the
level of beryllium in the urine of persons not exposed to an
occupational source of beryllium is -0.9 /ig/L beryllium (Stiefel et al
1980, Grewel and Kearns 1977). The urinary beryllium level increased co
2 Mg/L beryllium in cigarette smokers (Stiefel et al. 1980).
Animal. Following inhalation of an aerosol of beryllium nitrate.
Stiefel et al. (1980) found peak beryllium levels of 300 ng/g in the
urine of exposed rats and guinea pigs, and the maximum urinary
elimination of beryllium was reached 10 h after the end of exposure
The clearance of beryllium oxide from the lung following inhalation
exposure appears to be fairly slow Rhoads and Sanders (1985) exposed
rats to oxides of various metals, including beryllium, by inhalation for
-------
Toxicologies! Data 37
exposures Lasting from 30 to 180 min. The half-time for removal of 50%
of the initial lung burden of beryllium (400 days) was the longest
measured for all of the metals. The level of beryllium in the lungs of
rats exposed to beryllium oxide (447 ^g/m3) for 1 h remained the same
(-200 ng) for 3 weeks after exposure had ended (Hart et al. 1984) The
beryllium levels in the lavage fluid did, however, decrease from 280 co
16 ng during the 3-week period
4.2.4.2 Oral
Human. Pertinent data regarding the excretion of beryllium
following oral exposure in humans were not located in the available
literature.
Animal. After oral administration of beryllium compounds to
animals, most of the beryllium passes through the gastrointestinal trace
unabsorbed and is excreted in the feces. Reeves (1965) found that
between 60 and 90% of the beryllium taken in by rats through the
drinking water was excreted in the feces and <1% of the dose was
excreted in the urine. Morgareidge et al. (1977) reported that rats fed
beryllium sulfate in the diet (5, 50, or 500 mg/kg) over a 2-year period
have urinary beryllium levels proportional to dietary intake. Reeves
(1986), however, stated that skeletal accumulation was proportional to
dose but excretion in the urine was 30 to 77 mg/mL beryllium for all
exposure levels.
4.2.4.3 Dermal
Pertinent data regarding the excretion of beryllium after dermal
exposure in humans or animals were not found in the available
literature.
4.3 TOXICITY
4.3.1 Lethality and Decreased Longevity
4.3.1.1 Inhalation
Human. Hardy and Tabershaw (1946) reported on 17 workers (mostly
females under the age of 30) who were exposed to beryllium compounds
present in fluorescent powders used in a fluorescent lamp manufacturing
plant. The workers developed a delayed granulomatosis, and in many cases
the prognosis was poor. Five of 17 died, and disability persisted in
most of the other cases. Although the levels of beryllium to which these
workers were exposed were not reported, they were probably very high
Animal. The lethality and decreased longevity caused by inhalation
of soluble beryllium compounds in experimental animals appear to be due
mainly to the development of a chemical pneumonitis which may be a
result of the acidity of the aerosol. Inhalation LCSQs for beryllium ard
beryllium compounds were not found in the available literature.
Stokinger et al. (1950) exposed a variety of species to an aerosol of
beryllium sulfate for 6 h/day. 5 days/week as follows: 4.3 mg/ra3
beryllium for 14 days, 2.0 mg/m3 beryllium for 51 days, 0.43 mg/ra3
beryllium for 95 days, and 0 04 rng/ra^ beryllium for 100 days. The
exposure of 4.3 mg/m3 for 14 days was lethal to 10/10 rats and 3/10
-------
38 Section 4
guinea pigs. The exposure of 2.0 mg/m3 for 51 days was lethal to 13/13
rats, 4/5 dogs, 4/5 cats, 1/10 rabbits, 7/12 guinea pigs, 1/1 monkey,
5/10 hamsters, and 4/38 mice. The exposure of 0.43 mg/m3 for 95 davs •-«-,
lethal to 23/47 rats, 1/5 cats, 2/24 rabbits, and 2/34 guinea pigs' No'
deaths occurred in any species exposed to 0.04 mg/m3 for 100 days
Groups of four female monkeys were exposed to aerosols of either
beryllium fluoride (185 Mg/m3 beryllium), beryllium sulfate (202 Mg/m3
beryllium), or beryllium phosphate (202, 1141, or 8427 Mg/m3 beryllium;
6 h/day for 7 to 30 days Death due to pneumonitis was observed in all
exposure groups, and all of the animals exposed to beryllium phosphace
at 8427 /ig/m3 beryllium died of pneumonitis within 20 days following
termination of exposure (Schepers 1964). Although these .studies did noc
report the use of controls (and exposure concentrations fluctuated
widely), they did provide the only available data on the lethalicy and
decreased longevity resulting from acute and intermediate inhalation
exposure to beryllium.
4.3.1.2 Oral
Human. Pertinent data regarding lethality and decreased longevic-
following oral intake of beryllium in humans were not found in the
available literature.
Animal. The acute oral LDsos for several beryllium compounds
(i.e., beryllium fluoride, beryllium chloride, beryllium sulfate. and
beryllium phosphate) are presented in Table 4.1. As noted in the table,
it is not clear whether the LDSQs reported by Luckey and Venugopal
(1977) are expressed as rag of beryllium per kg or mg of beryllium
compound per kg; therefore, greater confidence is given to the values
reported by Reeves (1986).
4.3.1.3 Dermal
Pertinent data regarding lethality and decreased longevity
following dermal exposure to beryllium in humans or animals were noc
found in the available literature.
4.3.2 Systemic/Target Organ Toxicity
4.3.2.1 Pulmonary effects
Inhalation, human. Following an accidental leakage of beryllium
dust, 25 laboratory workers were exposed to an undetermined
concentration of beryllium over a period of 10 to 20 h (Zorn et al
1986). The exposure resulted in elevated serum beryllium levels 5 times
greater than background levels. No exposure-related effects were found
as determined by thorax X-ray, spirometry, measurements of gamma-
globulin, serum glutamic oxaloacetic transaminase (SCOT), serum
glutamic-pyruvic transaminase (SGPT). or neopterin (a pteridine
synthesized by activated macrophages after stimulation by gamraa-
interferon derived from sensitized T-lymphocytes). As reviewed by EP*
(1987a), inhalation of soluble beryllium compounds by occupationally
exposed workers has been linked to the development of an acute chemica.
pneumonitis, while exposures to less soluble forms may lead to chronic
beryllium disease (berylliosis) in which granulomatous lesions develop
-------
Toxicologies! Daca 39
Table 4.1. Acute oral LD^s for beryllium compounds
Compound
Beryllium fluoride
Beryllium chloride
Beryllium sulfate
Beryllium phosphate
Species
Mouse
Mouse
Rat
Ral
Mouse
Ral
Rat
Rat
LD.0
(mg/kg Be)"
100
18-20
100
86
200
80
80
120
82
References
Luckey and Venugopal 1977
Reeves 1986
Luckey and Venugopal 1977
Luckey and Venugopal 1977
Reeves 1986
Luckey and Venugopal 1977
Luckey and Venugopal 1977
Reeves 1986
Luckey and Venugopal 1977
"It is not clear if the concentrations reported by Luckey and Venugopal
(1977) are expressed as mg/kg of beryllium or mg/kg of a beryllium
compound.
-------
Seccion 6
in the lung. Dose-response relationships are difficult to establish in
the cases of beryllium disease resulting from occupational exposure
because workroom beryllium levels generally have been determined to'b>
<2 to 1000 ^g/m3 beryllium. EPA (1987a) stated that new cases of
chronic beryllium disease are being reported in instances where the OSHA
standard of 2 jig/m-> has been exceeded; however, in industries where
exposures are <2 ^g/m3, very few new cases have been reported. Cullen ec
al (1987). however, reported cases of five workers at a precious metal
refinery who developed lung granulomas between 1972 and 1985 Although
these workers were originally diagnosed as having sarcoidosis,
measurements of in vitro proliferative responses of lymphocytes obtained
by bronchoalveolar lavage indicated that 4/5 workers were hypersensiti-e
to beryllium. Results of industrial hygiene monitoring of the plant
showed that the four beryllium-sensitive individuals worked in the
furnace area where beryllium fume concentrations were consistently
<2 /jg/m-5. Time-weighted-average personal air samples throughout the
refinery ranged from 0.22 to 42.3 pg/m3. with 10% of the measured
samples in excess of 2 Mg/m3 Cullen et al. (1987) discussed limitations
of the study, which included underestimation of exposure levels by the
standard filter method of collection, which was performed in two
discrete 1-week periods, 3 months apart; measurement of levels only in
1983, although exposures occurred between 1964 and 1977; limited
sampling, which may have missed high concentrations; and the possibility
that the workers in question were also exposed to high levels that were
measured outside the furnace area. Furthermore, Eisenbud and Lisson
(1983) documented the 30-year effectiveness of the OSHA standard of
2 /ig/mj in controlling acute and chronic beryllium disease. Thus, it is
not possible to determine an occupational exposure level associated wi
beryllium disease. Cases of beryllium disease are recorded in the U S
Beryllium Case Registry; currently, there are -900 cases of beryllium
disease, both acute and chronic, in the United States (CDC 1983)
Inhalation, animal. Sendelbach et al. (1986) exposed 40 mice and
36 rats to a beryllium sulfate aerosol (13 ng/L beryllium) for 1 h by
nose-only exposure. Groups of four rats and four mice were, then killed
on various days following exposure, with the final group of animals
sacrificed on day 21 following exposure. Rats demonstrated a
proliferative response involving type-II alveolar epithelial cells.
interstitial cells and capillary endothelial cells, whereas the
proliferative response in mice was seen mainly in the alveolar
macrophage population and in interstitial and endothelial cells
Exposure to low-fired beryllium oxide aerosol produced
polymorphonuclear leucocyte infiltration in rats (Hart et al. 1984)
Acute exposure to high-fired beryllium oxide may also lead to chronic
toxic effects such as the appearance of granulomatous lesions in rats
(Sanders et al. 1975). Also, exposure to beryllium-containing dusts
leads to chronic beryllium disease in dogs (Robinson et al. 1968).
Stokinger et al. (1950) exposed a variety of species including
monkeys, rats, dogs, cats, rabbits, guinea pigs, hamsters, and mice co
an aerosol of beryllium sulfate for 6 h/day. 5 days/week at 4.3 mg/m3
beryllium for 14 days. 2 0 mg/m3 beryllium for 51 days, 0.43 mg/m3
beryllium for 95 days, and 0 04 rag/m3 beryllium for 100 days. There vas
high mortality at all exposure levels and durations except 0.04 mg/m3
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ToxicoLogical Daca 6L
for 100 days, and there was histological evidence of pulmonary
pneumonitis in most of the species at all exposure levels and duracions
Hall et al. (1950) produced an acute pneumonitis in dogs exposed by
inhalation to a special grade of beryllium oxide that was calcined ac a
low temperature (400°C). Two dogs were exposed to the beryllium oxide
(82 mg/m3 or 30 mg/m3 beryllium) 6 h/day. 5 days/week for a total of 90
h (15 days), and four dogs were exposed to 10 mg/m3 beryllium oxide (3 6
mg/m3 beryllium) on the same exposure schedule for 236 h (-40 days)
Histological examination revealed that dogs exposed for 90 h had
moderate lung damage, whereas dogs exposed for 236 h had marked lung
damage. There was marked weight loss in both dogs exposed for 90 h and
in three of the four dogs exposed for 236 h.
Vorwald et al. (1966) exposed rats by inhalation to beryllium
sulfate at beryllium concentrations of 2.8, 21, 42, or 194 pg/ra3. There
were 100 to 180 rats in each group, and exposure was for 7 h/day from L
to 560 days. An exposure level of 2.8 A»g/n beryllium produced no
pulmonary changes. Exposure to 21 A»g/m3 beryllium produced significant
inflammatory changes, and the 42-Mg/m3 beryllium exposure level produced
diffuse chronic pneumonitis. Exposure to 194 /ig/ra3 beryllium was acuteIv
toxic. EPA (1987a) reported that this experiment was poorly controlled
and no confidence could be placed in the 2.8-Mg/m3 exposure level.
Reeves et al. (1967) exposed 150 rats to beryllium sulfate 7 h/day,
5 days/week for 72 weeks. The atmospheric concentration of beryllium
sulfate was 34 ± 24 Mg/m3 beryllium. Following exposure, the weights of
the lungs of exposed animals were -4 times those observed in control
animals, and histological examination revealed inflammatory and
proliferative changes and clusters of macrophages in the alveolar
spaces.
Chronic exposure to beryllium ores (beryl and bertrandite) has been
shown to produce granulomas and atypical proliferation in the lungs of
exposed rats and hamsters (Wagner et al. 1969). Squirrel monkeys exposed
to the same beryllium ores, beryl (620 Mg/m3 beryllium) and bertrandice
(210 Mg/m3 beryllium). 6 h/day, 5 days/week for 23 months had no marked
changes in their lungs other than the appearance of macrophage clusters
(Wagner et al. 1969). Chronic inhalation of beryllium sulfate or
beryllium oxide has also been demonstrated to produce inflammatory
changes and chronic pneumonitis with granuloma formation in the lungs of
exposed rats (Vorwald et al. 1966, Wagner et al. 1969).
Oral, human. Pertinent data regarding pulmonary effects in humans
exposed to beryllium by the oral route were not found in the available
literature.
Oral, animal. Eight male albino rats were exposed to 20 mg
beryllium nitrate (1.35 mg beryllium) in the diet every third day for
2.5 months (Goel et al. 1980). The lungs of beryllium-treated rats were
harder and more opaque than those of untreated rats, and a number of
pathological disturbances were noted in the bronchioles, alveoli, and
arterioles of the treated rats. In addition, the activities of alkaline
phosphatase, acid phosphatase, and 5*-ribonucleotide phosphohydrolase
were increased in the lungs during beryllium treatment. Since the
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42 Section 4
beryllium nicrace was mixed with food pellets, the lung effects may hav-
resulted from aspiration of the compound into the lungs during feedin,
Schroeder and Mitchener (1975a) administered beryllium sulfate co
groups of 52 rats/sex in the drinking water at concentrations of
beryllium of 0 and 5 ppra for life. No effects were observed on survival
urinalysis. cholesterol, or uric acid, and histological examination of
the heart, kidney, liver, and spleen revealed no treatment-related
lesions. Decreased body weight gain was noted in male rats from 2 to 6
months of age. Schroeder and Mitchener (1975b) also treated groups of 54
mice/sex with beryllium sulfate in drinking water at beryllium
concentrations of 0 and 5 ppm for life. The only effects were decreased
body weight gain of treated females and increased body weight gain of
male mice. Females had an increased incidence of leukemia, but this was
not considered to be treatment-related. These studies did not examine
the lungs for pathological effects, but indicate that 5 ppm in the
drinking water of rats and mice is a NOAEL with decreased body weight
gain as the effect of concern.
Dermal. Pertinent data regarding pulmonary effects in humans or
animals exposed to beryllium by the dermal route were not found in the
available literature.
General discussion. The lung appears to be the main target organ
for beryllium toxicity in humans and animals. Acute exposure to
beryllium sulfate or low-fired beryllium oxide (see below) leads to
proliferative changes in the lung, accompanied by cellular infiltrations
consisting mainly of macrophages and polymorphonuclear leucocytes
(Sendelbach et al. 1986. Hart et al. 1984). Acute chemical pneumonitis
has been found to develop in both humans and animals (EPA 1987a,
Stokinger et al. 1950) following acute inhalation exposure to soluble
beryllium salts, and acute exposure to beryllium-containing dusts or
high-fired beryllium oxide may lead to a more chronic toxic response in
the lung (Sanders et al. 1975, Robinson et al. 1968). The acidity of
soluble beryllium salt aerosols contributes to their toxicity. The
chronic form of beryllium disease in both humans and animals, caused
primarily by insoluble forms, is characterized by a chronic pneumonicLS
and the development of granulomatous lesions in the lung (EPA 1987a
Vorwald et al. 1966, Vorwald and Reeves 1959). The cellular mechanism by
which beryllium oxide induces the formation of granulomas in rats
appears to be Induction of hyperplasia and hypertrophy of histiocytes
(reticulo-endothelial system) (Policard 1950). Another cellular
mechanism by which beryllium is thought to induce toxicity is
interaction with the lysosome of the cell (Uitschi and Aldridge 1968)
It has been postulated that beryllium destroys the integrity of the
lysosomal membrane, with the subsequent release of lysosomal enzymes
which are injurious to the cell (Reeves and Preuss 1985).
In a study to determine the effect of the adrenal stimulation
resulting from repeated pregnancies and lactation on the onset of
beryllium disease (Sect. 4.3.4 on reproductive toxicity), Clary et al
(1975) treated male and female Sprague-Dawley rats intratracheally with
'BeO fired at 960 or 500'C at a dose of 0.2 mg beryllium per rat or with
saline. Half of the females were allowed to breed repeatedly with the
males. Beryllium oxide-treated rats developed hyperplasia of the
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Toxicologies! Data 63
bronchial mucosa and granulomas, but there was no effect of pregnancy or
lactation on the incidence, severity, or time of onset of the lung
lesions. Furthermore, there was no difference in serum alkaline
phosphatase, isocitric dehydrogenase, lactic dehydrogenase, or SGPT
activities or in the concentrations of triglyceride or cholesterol
between the beryllium oxide-treated rats and controls. Clary et al.
(1975) concluded that adrenal stress is not an inducer of latent chronic
beryllium disease.
Early studies of the chronic toxicity of beryllium indicated chac
rats fed large amounts of beryllium carbonate in the diet (1000 to 5000
rag per kg of food) developed rickets (Guyatt et al. 1933, Jacobson
1933). This effect has been regarded as being caused by the binding of
phosphate to beryllium in the gut, with the subsequent depletion of
phosphorus in the body (EPA 1987a).
The toxicity of beryllium oxide appears to depend on its method of
preparation. Beryllium oxide prepared at higher temperatures is
relatively inert compared with beryllium oxide calcined at lower
temperatures (Stokinger 1981). Monkeys and dogs exposed by inhalation co
beryllium oxide calcined at 14008C had no pathological changes (Conradi
et al. 1971), whereas rats exposed by inhalation to beryllium oxide
prepared at 560°C manifested a number of cellular changes in the lung
(Hart et al. 1984). These differences in the toxicity between high-fired
and low-fired beryllium oxide have also been noted in a number of
studies in which the oxide was administered by intratrachael injection
(Spencer et al. 1965, 1968; Litvinov and Kazenasev 1982).
There appears to be an immune component of chronic beryllium
disease, in that lymphocytes from people with the disease undergo
transformation in the presence of beryllium (EPA 1987a); a lymphocyte
transformation test has been used in the diagnosis of this disease
(Williams and Williams 1982, Bargon et al. 1986). Reeves and Preuss
(1985) state that berylliosis represents an immune reaction to beryllium
compounds, which is expressed as granulomatous hypersensitivity. This
hypersensitivity represents an accumulation and proliferation of
reticuloendothelial cells. Interaction of beryllium with the membrane of
the lymphocyte (human and guinea pig) was demonstrated by Skilleter and
Price (1984), and the mitogenic effects of beryllium salts on mouse
spleen cells in vitro were proposed to be due to direct interaction of
Be2+ with the lymphocyte membrane (Price and Skilleter 198S, 1986). The
hypersensitivity reaction to beryllium that is seen in guinea pigs and
humans was attributed by Reeves (1986) to the formation of a beryllium-
protein complex that is antigenic in vivo and provokes a cell-mediated
immune response. Dermal exposure to soluble beryllium compounds can also
cause contact dermatitis (Van Ordstrand et al. 1945). The available
human and animal exposure data on the effects of beryllium on the immune
system and the contact dermatitis produced by soluble beryllium salts
are not extensive enough, however, to warrant the treatment of these
effects as the most sensitive toxic end points for beryllium. Williams
et al. (1987) reported that beryllium can enter cuts in the skin of
workers handling beryllium (metal, alloys, and ceramics) and cause
ulcerative granulomas on the skin. Exposure levels were not reported
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44 Section 4
4.3.3 Developmental Toxicity
Pertinent data regarding the developmental toxicity of beryllium
after inhalation, oral, or dermal exposure in animals or humans were not.
located in the available literature. Selivanova and Savinova (1986)
treated pregnant rats intratracheally with beryllium chloride or
beryllium oxide at 0 or 50 mg/kg on day 3, 5. 8. or 20 of gestation
Statistically significant (p < 0.05) differences compared with controls
included increased fetal mortality in rats treated with beryllium
chloride on day 5 and with beryllium oxide on days 3 and 5, decreased
average fetal weight in rats treated with either compound on day 3, and
increased percentage of pups with internal abnormalities in rats treated
with beryllium chloride on days 3 and 5 and with beryllium oxide on days
3. 5, and 8. There were no differences in the number of live births/dam
or in fetal length. Two studies that were done by injecting beryllium
salts into pregnant female mice indicated that beryllium can penetrate
the placenta and reach the fetus and can cause behavioral abnormalities
in the offspring of beryllium-treated dams (Tsujii and Hoshishima 1979
Bencko et al. 1979).
4.3.4 Reproductive Toxicity
Pertinent data regarding the reproductive toxicity of beryllium
after inhalation, oral, or dermal exposure in humans or animals were noc
located in the available literature.
Clary et al. (1975) treated male and female Sprague-Dawley rats
intratracheally with 7BeO fired at 960 or 500°C at a dose of 0.2 mg
beryllium per rat or with saline. The rats were allowed to mate
repeatedly over a 15-month period. There were no consistent effects on
reproductive performance as determined by the average number of
pregnancies per female, live pups per litter, dead pups per litter, and
live pups per female, or lactation index or average weight of live pups
per female.
4.3.5 Genotoxicity
Studies of the genotoxicity of beryllium compounds are summarized
in Table 4.2. The mutagenicity of various beryllium compounds is not
clear. Metabolic activation is not an issue for beryllium mutagenicity,
but a positive or negative response apparently depends on the type of
bacterial strain and the type of assay system that is used. Beryllium
sulfate was generally negative in Ames assays. Beryllium sulfate appears
to be mutagenic in mammalian cells (Hsie et al. 1979a,b; Miyaki et al
1979) and induces chromosome aberrations and sister chromatid exchanges
in mammalian cells (Larramendy et al. 1981).
4.3.6 Carcinogenicity
4.3.6.1 Inhalation
Human. A number of epidemiological studies have investigated the
possibility of a relationship between exposure to beryllium by
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ToxLcoLogicaL Data
Table 4.2. Cenotoxicily of beryllium compounds in vitro"
End point
Species (lest system)
Result'
References
Gene mutation
Chromosome
abberations
Salmonella lyphimunum
(Ames assay)
Bacillus subtilis
Saccharomyces cerevisiae
Eschenchia coli
Chinese hamster ovary cells
Chinese hamster V79 cells
Chinese hamster ovary cells
Human lymphocytes
Yeast
Sister chromatid Syrian hamster embryo cells
exchange
Human lymphocytes
— Simmon I979a. Rosenkranz and Poirier
1979. Arlauskas et al I98S. Simmon
et al 1979
+ Kanematsu et al 1980
- Simmon et al 1979
Mixed Zakour and Glickman 1984. Arlauskas
et al 1985. Ishizawa 1979.
Rosenkranz and Poirier 1979.
Rosenkranz and Leifer 1980
+ Hsieetal I979a.b
+• Miyaki et al 1979
+ Larramendy et al 1981
-t- Larramendy el al 1981
- Simmon 1979b
+ Larra'mendy et al 1981
+ Larramendy et al 1981
'Beryllium sulfate was tested in most assays except for Zakour and Glickman (1984) and Miyaki
et al (1979). who tested beryllium chloride, and Ishizawa (1979). who did not report the compound
tested
'Metabolic activation does not appear to be an issue for beryllium compounds.
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Section
inhalation and lung cancer (Wagoner et al. 1980; Bayliss ec al 1971
Bayliss and Lainhart 1972; Bayliss and Wagoner 1977; Bayliss 1980
Infante et al. 1980; Mancuso and El-Attar 1969; Mancuso 1970 1979
1980). All of these studies are based on data either from employees of
two beryllium-processing industries (Brush Wellman Inc. of Ohio and NGK
Metal Corporation of Pennsylvania) or from reported cases of acute and
chronic beryllium disease found in the U.S. Beryllium Case Registry
Some studies (Bayliss et al. 1971, Bayliss and Lainhart 1972) found no
increased incidence of lung cancer in people exposed to beryllium, some
studies (Bayliss and Wagoner 1977; Wagoner et al. 1980; Bayliss 1980
Infante et al. 1980; Mancuso 1970, 1979. 1980) found evidence of
increased lung cancer in people exposed to beryllium, and one study
(Mancuso and El-Attar 1969) was inconclusive. The studies that reported
a positive association between beryllium exposure and lung cancer,
however, were severely criticized for one or more of the following
reasons: inadequate adjustment for the contribution to lung cancer
incidences of smoking, improper calculation of expected deaths from lung
cancer, inclusion of employees of the beryllium industry who were noc
actually exposed to beryllium (i.e., salesmen and clerks), and use of
improper control groups (EPA 1987a). Nevertheless, EPA (1987a) used the
data of Wagoner et al. (1980), along with data from industrial hygiene
reviews by NIOSH (1972) and Eisenbud and Lisson (1983) regarding
exposure levels, to calculate a carcinogenic potency estimate for
beryllium. Because of the uncertainties, however, a low degree of
confidence was placed in this upper limit value.
Wagoner et al. (1980) studied a cohort of 3055 white male workers
at a beryllium-processing facility who had been employed some time
between January 1. 1942. and December 31. 1967. The investigators
reported that there were significantly high risks of lung cancer in
individuals followed until December 31, 1975, in those members of the
cohort followed for >24 years since initial employment, in those --hose
initial employment occurred prior to 1950 and who were followed for ac
least 15 years from the date of employment, and in those whose initial
employment occurred after 1950. This study was criticized for a number
of reasons, and when EPA (1987a) corrected the data to eliminate an 11%
underestimate of expected deaths and to account for the smoking
contribution, none of the comparisons of observed vs expected were
statistically significant. Although this study did not show carcinogen.c
effects, beryllium compounds are carcinogenic in animals by the
inhalation route. Potency values derived from animal studies of
beryllium sales were calculated by EPA (1987a) but were not recommended
because the potency factors overestimate the human risk. Beryllium oxide
exposures in animals do approximate human exposures, and potency factors
derived from studies using beryllium oxide provide a reasonable estimate
of risk, but the studies have too many weaknesses.
Animal. A variety of beryllium compounds have been demonstrated :o
cause pulmonary tumors following inhalation in animals. Reeves and
Deitch (1969) exposed rats to beryllium sulfate (36 fig/m3 beryllium) J:
h/week for either 3, 6, 9. 12, or 18 months. After 3 months of exposure
19/22 rats developed pulmonary carcinomas, and after longer periods of
exposure, the tumor incidence was -100% (33/33 rats at 6 months, 15/15
at 9 months, 21/21 at 12 months, and 13/15 at 18 months). Other studios
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ToxicoLogicaL Daca 67
in which rats have been exposed Co beryllium compounds for periods
ranging from 6 Co 18 months have, in general, indicated a positive
correlation between number of tumor-bearing animals and duration of
exposure Co Che beryllium compounds (Schepers et al. 1957, Schepers
1961, Reeves eC al. 1967).
Several chronic studies of beryllium compound carcinogenicity have
also been conducted. Vorwald et al. (1955) exposed female albino rats to
beryllium sulfate aerosol (33 /ig/m^ beryllium), 33 to 38 h/week. Four of
eight rats maintained on this exposure schedule for 1 year developed
pulmonary adeno- and epidermoid carcinomas, and four of five animals
exposed for 420 days developed tumors. Rats chronically exposed to lover
concentrations of beryllium sulfate (2.8 Mg/m^ beryllium) also developed
tumors (Vorwald et al., 1966) but no confidence was placed in this
exposure level (EPA 1987a). Rats chronically exposed to the beryllium
ore, beryl (but not bertrandite), developed lung tumors (Wagner et al
1969). Monkeys also developed pulmonary carcinomas after chronic
exposure to beryllium sulfate (Vorwald 1968).
Beryllium oxide has also been shown to be carcinogenic to animals
by the inhalation and intratracheal routes. Reeves (1978) presented data
in which 22/36 rats exposed for 3 to 12 months to 9 mg/m-* beryllium
oxide (firing temperature not stated) developed lung tumors.
Intratracheally administered beryllium oxide fired to 1600, 1100, and
500"C resulted in pulmonary adenocarcinomas in 3/28, 3/19, and 23/45
rats, respectively (Spencer et al. 1965, 1968, 1972). Lung tumors
developed in 7/29 rats exposed intratracheally to beryllium oxide
(calcined at 900°C) at 15 weekly doses of 1 mg each (Ishinishi et al
1980).
4.3.6.2 Oral
Human. Pertinent data regarding the carcinogenicity of beryllium
following oral exposure in humans were not found in the available
literature.
Animal. Beryllium was not demonstrated to induce a carcinogenic
response following administration by the oral route, probably because
beryllium compounds are poorly absorbed from Che gascrointestinal tract
(EPA 1987a). EPA (1980), however, determined that the ingesCion of
beryllium could possibly cause a carcinogenic risk, based on several
lines of evidence. A study in racs (Morgareidge et al. 1975), in which
beryllium sulfate was administered in the diet at 5, 50, and 500 ppm for
2 years resulted in statistically significant increases in lung
reticulum cell sarcomas at the two lowest doses but not at the highest
dose. Several studies in rabbits have shown that intravenous
administration of beryllium produces osteogenic sarcomas. On the other
hand, in one long-term study in rats (Schroeder and Kitchener 1975a). ir.
which beryllium sulfate was given in drinking water at 5 ppm beryllium.
no carcinogenic response occurred, and several epidemiology studies of
workers exposed to beryllium have failed to show a convincing
association between cancer mortality and beryllium inhalation exposure
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48 Section 4
4.3.6.3 Dei
Human. Pertinent data regarding the carclnogenicity of beryllium
following dermal exposure in humans were not found in the available
literature.
Animals. EPA (1987a) reported that no carcinogenic response has
been observed in any species following dermal exposure to beryllium
compounds.
4.3.6.4 General discussion
There is strong evidence that beryllium is carcinogenic in animals
following inhalation. Both short-term and long-term animal experiments
with a variety of beryllium compounds have indicated that inhaled
beryllium is able to induce a variety of different types of lung tumors
(Schepers 1961, 1964; Reeves and Deitch 1969; Schepers et al. 1957;
Reeves et al. 1967; Wagner et al. 1969; Vorwald et al. 1955. 1966;
Vorwald 1968). The data are much less clear in humans. It is currently
unknown whether inhaled beryllium produces an excess incidence of lung
cancer in humans.
In addition to the positive carcinogenic response produced in
animals exposed by inhalation to beryllium compounds, EPA (1987a)
reviewed numerous early studies in which intravenous injection of
beryllium compounds into laboratory animals produced osteosarcomas.
Furthermore, positive mutagenicity and clastogenicity results with
beryllium sulfate support the carcinogenic potential.
There is insufficient evidence for the carcinogenicity of beryllium
following oral exposure in animals and humans. One study (Morgareidge ec
al. 1975) indicated that beryllium may be carcinogenic in rats following
administration of beryllium sufate in the diet over a 2-year period. No
carcinogenic response occurred in any species of animal exposed dermallv
to beryllium compounds (EPA 1987a).
Beryllium exposure has been postulated to be the cause of several
cases of malignant mesothelioma in humans where there has been no known
exposure to asbestos (Peterson et al. 1984).
4.4 INTERACTIONS WITH OTHER CHEMICALS
Vorwald et al. (1966) summarized several studies that attempted to
find an antidote to the acute toxicity of beryllium. Aurintricarboxylic
acid (ATA) together with salicylates was considered to be beneficial.
and ATA formed a chelate with beryllium in spleen and kidneys. Chelae ing
agents may not be effective against chronic beryllium toxicity (Reeves
1977). Josht et al. (1984) found that ferritin chelated with beryllium
to protect against the inhibition of phosphoglucomutase. Sendelbach and
Witschi (1987) found that pretreatment and concurrent treatment of racs
with intraperitoneal injections of ferric ammonium citrate resulted in
lower cumulative mortality during 14 days of nose-only inhalation
exposure to beryllium sulfate at 2.59 mg/m3 beryllium for 2 h/day. The
protective effect of iron on beryllium toxicity may be related to the
ability of iron to increase the production of ferritin, making more
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ToxicoLog Leal Daca ^9
ferritin available Co bind with beryllium (Sendelbach and Wicschi 1987.
Lindenschmidt et al. 1986). Beryllium oxide was a greater potentiator of
20-methyIchoIanthrene- induced carcinogenicity than was carbon black
(Uzawa 1963).
-------
5. MANUFACTURE. IMPORT. USE. AND DISPOSAL
5 1 OVERVIEW
The primary source of commercial beryllium in the United States is
the open-pit mining of bertrandite ore deposits near Spor Mountain,
Utah. The ore is processed into beryllium hydroxide, which is further
processed into beryllium metal, alloys, and oxide. Beryllium alloys ard
metal, which comprise -90% of beryllium's commercial uses, have a wide
variety of applications in electrical components, tools, structural
components for aircraft, missiles, and satellites, and other metal-
fabricating uses. Disposal of beryllium dust wastes must meet federal
regulations.
5.2 PRODUCTION
Commercial production of beryllium and its compounds begins with
the processing of beryllium-containing ores. The only two ores that
have been used commercially in the United States are bertrandite
(4BeO-2Si02'H20) and beryl (3BeO-Al203'6Si02) (Ballance et al 1978,
Weast 1985). Bertrandite ore is mined by open-pit methods from deposits
near Spor Mountain, Utah, and taken to the Brush Wellman mill near
Delta, Utah, where it is processed. The processing method involves
leaching the ore with sulfuric acid to form a beryllium sulfate leach
solution, from which the sulfate is extracted with an organic solvent
Reaction with aqueous ammonium carbonate and subsequent heating yields
basic beryllium carbonate and finally beryllium hydroxide, which is
processed into metal, alloys, and beryllium oxide. Beryllium hydroxide
is also the end result of beryl ore processing which has been done via a
sulfate extraction process.
Beryllium metal is commercially produced from the hydroxide by the
reduction of beryllium fluoride with magnesium (Ballance et al. 1978)
The hydroxide is initially reacted with ammonium bifluoride to form
beryllium fluoride, which is then reduced with magnesium metal to yield
beryllium metal and magnesium fluoride. A purer beryllium metal can be
obtained by electrolysis of beryllium scrap, pebbles, or salts.
Copper-beryllium alloy is the most important beryllium alloy. Copper-
beryllium master alloy is manufactured commercially by an arc-furnace
method in which beryllium oxide is reduced by carbon in the presence of
molten copper at 1800-2000°C. The resulting master alloy typically
contains 4.0-4.25 we % beryllium. Copper-beryllium alloys can be
produced by melting the two metals together, but it is not economical on
a commercial scale because of the high cost of beryllium metal. The
master alloy produced by the arc-furnace method is then melted togecher
with virgin copper or copper scrap and/or other metals to produce the
desired alloy, which is customarily cast into billets (Ballance et al
1978).
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52 Section 5
Beryllium oxide, the most important end-product beryllium chemical
is manufactured from the technical-grade hydroxide by dissolving the
hydroxide in sulfuric acid to form the sulfate (BeS04-4H20) which is
calcined carefully at selected temperatures to yield the oxide (Walsh
and Rees 1978)
The United States is the leading world producer of beryllium ores
and the leading producer and consumer of beryllium metal, alloys and
oxide (Kramer 1986) In 1985, U.S. mine shipments of beryllium-
containing ore amounted to 230 short tons of beryllium metal equivalent
Including imports of beryllium ore, stockpiling, and inventory uses, the
apparent U.S. consumption of beryllium in 1985 was 316 tons of metal
equivalent.
Brush Wellman Inc. remained the only major U.S. producer of
beryllium ores in 1985 (Kramer 1986). This company rained bertrandite ore
from its Spor Mountain open pit in Utah and processed this ore and
imported beryl ore into beryllium hydroxide at its Delta, Utah, mill
According to its annual report, Brush Wellman processed 95,000 tons of
bertrandite ore and recovered 377,000 pounds of beryllium contained in
concentrates.
The major U.S. manufacturers of beryllium alloys are Brush Wellman.
Inc., in Elmore, Ohio, and NGK Metals Corporation (formerly Cabot
Wrought Products and Kawecki-Berylco) in Reading, Pennsylvania (Kramer
1986; EPA 1987a).
5.3 IMPORT
In 1985, the United States imported 1646 tons (total weight) of
beryl ore, of which 1262 tons was imported from Brazil (Kramer 1986)
Other countries exporting beryl ore to the United States included
Argentina, China. Madagascar, Rwanda, South Africa, Switzerland, and
Zimbabwe.
5.4 USE
The percentage use of technical-grade beryllium hydroxide resulting
from ore processing has been estimated as follows (EPA 1987a):
Production of pure metal 10%
Production of beryllium oxide 15%
Production of beryllium alloys 75%
Pure beryllium metal is used in aircraft disc brakes. X-ray
transmission windows, space-vehicle optics and instruments,
aircraft/satellite structures, missile parts, nuclear-reactor neutron
reflectors, nuclear weapons, fuel containers, precision instruments.
rocket propellants, navigational systems, heat shields, and mirrors (EPA
1987a).
Beryllium oxide is used in high-technology ceramics, electronic
heat sinks, electrical insulators, microwave-oven components,
gyroscopes, military-vehicle armor, rocket nozzles, crucibles,
thermocouple tubing, and laser structural components (EPA 1987a).
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Manufacture, Import, Use, and Disposal 53
Beryllium alloys have a wide variety of uses, including electrical
connectors and relays, springs, precision instruments, aircraft engine
parts, nonsparking tools, submarine cable housings and pivots, wheels,
and pinions (EPA 1987a).
5.5 DISPOSAL
Beryllium dust has been designated as a hazardous waste by EPA. EPA
requires that persons who dispose of hazardous wastes comply with
regulations of the Federal Resource Conservation and Recovery Act (known
as RCRA). In addition, EPA has issued final regulations under the Clean
Water Act for specified non-ferrous metals manufacturing operations that
limit the discharge of pollutants by existing and new operations into
navigable waters and into publicly owned treatment works (Kramer 1986)
A major portion of beryllium waste results from pollution control
methods such as containment of solid particulates or aqueous suspensions
resulting from air-scrubbing processes. The most desirable method of
handling beryllium wastes is recycling them to the producers, but burial
in plastic-lined metal drums has also been recommended (Fishbein 1981)
-------
55
6. ENVIRONMENTAL FATE
6.1 OVERVIEW
Although beryllium is a naturally occurring substance, the major
source of its emission to the environment is the combustion of coal and
fuel oil, which releases particulates and fly ash containing beryllium
into the atmosphere. Beryllium released to the atmosphere from coal
combustion is likely to be in the form of beryllium oxide. Atmospheric
beryllium particulates will eventually settle to the earth's surface by
dry deposition or may be removed from the atmosphere by wet deposition
(i.e., rainfall). Upon reaching soil and sediment, beryllium will
probably be retained in an insoluble form and be generally immobile.
6.2 RELEASES TO THE ENVIRONMENT
Table 6.1 lists anthropogenic and natural emissions of beryllium
from various sources. Emissions of beryllium from coal and fuel oil
combustion account for 99% of the U.S. beryllium emissions (EPA 1987a).
The average concentration of beryllium in coal is between 1.8 and 2.2
Aig/g. Based on data from various sources, it has been estimated that 70
to 90% of the beryllium in the coal fly ash is captured by emission
control devices and that 10 to 30% is emitted to the ambient atmosphere
The concentration of beryllium in coal ash is -5 to 23 /*g/g (Holcombe ez
al. 1985, Pougnet et al. 1985). The disposal of coal ash remaining in
incineration units is most likely accomplished by land filling. Fuel oil
can contain -0.08 ppm beryllium (Fishbein 1981); it has been assumed
that -40% of the beryllium contained in fuel oil is lost to the
atmosphere from burning (EPA 1987a).
Atmospheric emissions of beryllium dusts and particulates are also
associated with ore processing, metal fabrication, and beryllium oxide
production and use (EPA 1987a, Fishbein 1981). The amounts of beryllium
released to the atmosphere are only a fraction of the amounts emitted
from coal and oil combustion.
Anthropogenic emission sources of beryllium to the water
environment include industrial wastewater effluents. A compilation of
data regarding raw and treated wastewater levels of beryllium from a
variety of industrial sources can be found in EPA (EPA 1981).
Natural emission sources include windblown dusts and volcanic
particles. The amounts of beryllium released to the atmosphere from
these sources are very small compared with anthropogenic sources (see
Table 6.1).
-------
56
Section 6
Table 6.1. Natural and anthropogenic emissions of beryllium
Total U S Emission
production" factor Emission
Emission source (I06t/year) (g/t) (t/year)
Natural
Windblown dust
Volcanic particles
Total
Anthropogenic
Coal combustion
Fuel oil
Beryllium ore processing
Total
82
041
640
148
0.008*
0.6
06
028
0.048
375*
5
02
5 2
180
7 1
03
1874
"Units are m metric tons.
*The production of beryllium ore is expressed in equivalent
tons of beryl; the emission factor of 37 S is hypothetical.
Source: EPA 1987a
-------
Environmental Face 57
6.3 ENVIRONMENTAL FATE
Because most atmospheric beryllium results from coal combustion, L-
is likely that the chemical form would be beryllium oxide (EPA 1987a)
Conversion to ionized salts may be possible but has not been reported
Beryllium oxide is relatively insoluble and would not be mobilized in
soil or surface water at normal pH ranges of 5 to 8.
Soluble beryllium salts are hydrolyzed to form insoluble beryllium
hydroxide (Cotton and Wilkinson 1972), which would have a low solubility
in the pH range of most natural waters (Callahan et al. 1979)
Complexing with hydroxide ions may increase solubility somewhat, but ic
is likely that in most natural environments beryllium is present in
particulate form rather than the dissolved form (Hem n.d.). This is
substantiated by empirical data which indicate that, even in polluted
rivers, dissolved beryllium levels are very low (Callahan et al. 1979)
In most types of soil, beryllium is expected to be tightly adsorbed
because it displaces divalent cations which share common sorption sices
(Fishbein 1981). Due to its geochemical similarity to aluminum,
beryllium may be expected to adsorb onto clay surfaces at low pH and be
complexed into some insoluble compounds at high pH (Callahan et al
1979).
Removal of beryllium from the atmosphere results from wet and dry
deposition (EPA 1987a). The rate of dry deposition of aerosol particles
is a function of particle size, windspeed, and surface roughness. A
study of stack emissions from coal combustion found that most beryllium
is found on particles smaller than 1 urn (Gladney and Owens 1976);
particles of this size remain aloft for -10 days. By analogy to other
elements, a typical dry deposition rate for beryllium particles over a
vegetative surface would be 0.25 cm/sec (EPA 1987a).
The amount of beryllium particles removed from the atmosphere by
wet deposition has not been determined experimentally. Rainwater in
Australia has been found to have an average beryllium concentration of
0.05 to 0.08 j*g/L (Meehan and Smyth 1967), which indicates that wet
deposition occurs.
No evidence was found that any environmental process results in the
volatilization of beryllium into the atmosphere from water or soil.
No data were found regarding the aquatic or soil biotransformation
of beryllium or its compounds.
A measured bioconcentration factor of 19 was reported for
beryllium, using bluegill fish (EPA 1980). Chapman et al. (1968)
reported a bioconcentration factor (BCF) of 100 for freshwater and
marine- plants, invertebrates, and fish. According to Kenaga (1980),
chemicals with BCFs < 1000 will not bioaccumulate significantly.
According to Fishbein (1981), there is no evidence that beryllium is
significantly biomagnified within food chains.
-------
59
7. POTENTIAL FOR HUMAN EXPOSURE
7.1 OVERVIEW
Beryllium is a naturally occurring element which cannot be degraded
by environmental fate processes. Although environmental fate processes
may transform one beryllium compound into another beryllium-compound,
the beryllium will still be available for human exposure.
The general population is exposed to beryllium through inhalation
of air, consumption of food, and contact with water. The potential for
human consumption of beryllium from sources in a typical residential
environment has been estimated in Table 7.1. From Table 7.1, the typical
American consumes -400 ng/day of beryllium, most of which comes from
food and water. This overall determination is extremely sensitive to che
average concentrations in food and water. Variations in these numbers
can be expected, depending on the types of food and beverages consumed
and the atmospheric contribution to the beryllium concentrations of food
and beverages.
7.2 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
7.2.1 Air
Beryllium in the ambient air is measured at many of the stations .1
the SLAMS (State and Local Air Monitoring Stations) and NAMS (National
Air Monitoring Stations) network. The data are available from the SAROAD
(Storage and Retrieval of Aerometric Data) database of the EPA (1987a)
The beryllium detection limit for these analyses is 0.03 ng/m3, and che
annual averages at most of the monitoring stations are listed at this
concentration. Between 1977 and 1981. annual averages exceeded 0.1 ng/m^
in 50 U.S. cities, with the highest average being 0.40 ng/m3 in Dallas.
Texas, in 1979. Based on earlier monitoring data from the National Air
Surveillance Network, the atmospheric background level of beryllium was
estimated to be <0.1 ng/m3 (Drury et al. 1978), which is consistent with
the more recent data.
7.2.2 Water
The concentration of beryllium in a variety of environmental
surface waters was found to range from 10 to 1000 ng/L (Bowen 1979)
Although concentrations as high as 1000 ng/L have been found in the
environmental waters, beryllium concentrations in surface water,
groundwater, and rainwater are generally well below 1000 ng/L (Callahan
et al. 1979). Beryllium concentrations ranging from 0.5 to 56 ng/L have
been detected in the open waters of the Earth's oceans (Meehan and Smy:;i
1967, Merrill et al. 1960. Bowen 1979. Measures and Edmond 1986).
-------
60
Section 7
Table 7.1. Potential human consumption of beryllium from normal
sources in a typical residential environment
Sources
Air
Food
Water
Total
Environmental
concentration
0.08 ng/m3
0.1 ng/g
0.19ng/ga
Total daily
human intake
20m3
1200 g
1500 g
Consumption
(ng/day)
1 6
120
285
406.6
Percentage of
total daily
consumption
04
295
70.1
"Mean concentration of positive drinking water samples as reported in
Sect. 72.2.
Source- EPA I987a
-------
Pocenciai for Human Exposure 61
An analysis of 1577 drinking water samples for trace metals has
been conducted (Kopp and Kroner 1967). Beryllium was detected in 5 4% of
the samples, with concentrations ranging from 10 to 1220 ng/L (mean
concentration 190 ng/L).
7.2.3 Soil
The average concentration of beryllium in the Earth's crust is -2 8
to 5 0 jig/g (Mason 1966, Reeves 1986). Various geochemical surveys have
found typical beryllium concentrations in soil to range from 0 6 co 6 0
jig/g (Shacklette et al. 1971, Vinogradov 1960, Hawkes and Webb 1962.
Mitchell 1964).
7.2.4 Other
7.2.4.1 Foodstuffs
Meehan and Smyth (1967) analyzed a number of foodstuffs from New
South Wales in Australia and found the following average beryllium
concentrations in ng/g fresh weight: beans (0 065), cabbage (0 234). hen
eggs (0.06 to 0.175), milk (0.17), mushrooms (1.6), edible nuts (0 21 co
0.52), tomatoes (0.21). crabs (15.4 to 26.2), fish fillets (0 16 to
1.48), oyster flesh (0.6 to 2.0), and scallops (0.34).
Petzow and Zorn (1974) reported the following beryllium
concentrations in /Jg/g dry weight in food samples from West Germany
polished rice (80), toasted bread (120) and green head lettuce (330)
When the West German and Australian figures are converted to a common
basis, the levels in the West German food are nearly 2 orders of
magnitude higher than those in the Australian food (Reeves 1986) The
discrepancy may be explained by a higher atmospheric fallout rate ac ch
-------
62 Section 7
7.3 OCCUPATIONAL EXPOSURES
In 1970. NIOSH Indicated that 30,000 workers are potentially
exposed to the dust or fumes of beryllium, of which 2500 were employed
JSniS pr°*UCti0nU(IARC L980>' A National Occupational Hazard Survey
(NOHS) conducted between 1972 and 1974 estimated that 19 867 U S
workers may be exposed (NIOSH 1984). which was somewhat lower than the
earlier estimate. The preliminary results of a National Occupational
Exposure Survey (NOES) conducted in the 1980s has estimated that 10 373
workers may be exposed (NIOSH 1985).
The current occupational standard for worker exposure to beryllium
is 2 Mg/mJ over an 8-h work shift (OSHA 1985).
7.4 POPULATIONS AT HIGH RISK
Several populations are at high risk for exposure to beryllium the
most obvious being individuals who are occupationally exposed in
beryllium manufacturing, fabricating, or reclaiming industries. However
no cases of health effects have been attributed to beryllium ore mining'
operations (EPA 1987a; Eisenbud and Lisson 1983; Hamilton and Hardy
1974). In addition to people at high risk because of occupational
exposure, people living near beryllium-emitting industries may be at a
small increased risk because of beryllium-contaminated dust within the
household rather than in ambient air levels. The NESHAP standard
restricts the amount of beryllium emitted into the environment by
industries that process beryllium ores, metal, oxide, alloys, or waste
to 10 g in a 24-h period (EPA 1982). No new cases of "neighborhood-
beryllium disease have been reported since the 1940s (EPA 1987a)
Sterner and Eisenbud (1951) have suggested that a small percentage of
the population is sensitive to extremely low concentrations of berylliu-
in the air. J
Smokers may inhale an unusually high concentration of beryllium
Based on an analysis of West German cigarettes and smoke (Petzow and
Zorn 1974). an average of 35 ng of beryllium is inhaled per cigarette
A person smoking a pack of cigarettes per day would inhale -700 ng of
beryllium, which is nearly twice the daily consumption from other
sources (EPA 1987a). This estimate depends on the amount of beryllium
contained in the native tobacco leaf and may vary depending on the
source of the tobacco.
According to EPA (1980). a small percentage of the population is
sensitive to very low concentrations of beryllium, but there is no
evidence that sensitivity develops at concentrations of beryllium
present in food or water or that sensitivity is aggravated by ingestion
of beryllium. No other special groups at risk were identified.
-------
63
8. ANALYTICAL METHODS
8.1 ENVIRONMENTAL MEDIA
Methods used for the analysis of beryllium in environmental media
are presented in Table 8.1. EPA Test Methods 210.1 and 210.2, which are
the methods required by the EPA Contract Laboratory Program for analysis
of beryllium in water, are included in Table 8.1. Environmental samples
analyzed by atomic absorption spectroscopy and gas chromatography
require pretreatment to remove interfering substances and increase
sensitivity (EPA 1987a). At high concentrations (500 mg/kg), aluminum
and silicon interfere with beryllium analysis by atomic absorption
spectroscopy. Separation of these elements is achieved by chelation and
extraction with an organic solvent.
8.2 BIOMEDICAL SAMPLES
Methods used for the analysis of beryllium in biomedical media are
presented in Table 8.2. Reviews of beryllium analysis methods in
biological media have been published (Tsalev and Zaprianov 1984, Delves
1981).
-------
Table 8.1. Analytical methods for emiranmNlal umplt*
Sample matrix
Sample preparation
Air
Air
Air
Air
Air
Ash collection filter strips.
reflux with mixture of nitric
and hydrochloric acids containing
SS 5 Mg/mL indium and yttrium.
concentrate extraction liquid,
add nitric acid, centrifuge, add
40% lithium chloride solution
containing 20% nitric acid and
200 j
-------
Title 8.1 (continued)
Sample matrix
Water (standard
reference
material 1643)
Scawater
Sample preparation
Acidify with nitric acid
Add specific volumes of EDTA,
Analytical method
FAES(2349nm)
FA AS (2 34 9 nm)
GC/EC
Detection limn
006«>g/L
2pM
Accuracy/precision
Not reported
S% RSD at 23 pM
sodium acetate, benzene and Hfla
to collected seawaicr. rinse
organic phase with NaOH, UV oxidize
Sediment Collect and dry sediment, extract
with HCI solution
Food Dry samples in electric furnace.
grind and powder, dissolve in HNO,.
dry. then treat with HCI-HCIO. and
heal, filler
Hood Hrecic-dry or blender-grind food
composites, solubilizc with nitric,
perchloric, sulfuric. or
hydrochloric acid
AAS — Atomic absorption speclromelry.
AES — atomic emission speclromclry.
FAAS — flamelcss atomic absorption speclromelry.
HAES — flameless atomic emission speclromelry.
GC/EC - gas chromalography-electron capture,
Hfla - l.l.l-irinuoro-2.4-peniancdione.
RSO - relative standard deviation
AES (argon plasma)
0 02 /ig/g
Inductive coupled plasma Not reported
AES
Inductive coupled plasma- 0001 jig/mL
optical emission spec-
lromelry
Not reported
Not reported
Not reported
References
Epstein el al
1978
Mcasuics and
Edmond 1986
l.um and Gammon
1985
Awadallah el al
1986
Wolmck el al
1984
rt
h-
n
o
Q.
-------
Table 8.2. Aoalylical methods for biomedical samples
Sample malm
Sample preparation
Analytical method
Detection limn Accuracy/precision
Biological tissue Wet-ash samples with mixture of
nitric, sulfuric and perchloric
acid. dry. dissolve in dilute
sulfuric acid
Hair-fingernails Clean (acetone, distilled water,
detergent, nitric acid), dry with
nitric acid, then again with nitric
acid perchloric acid (II), add
nitric acid containing lanthanum
Urine Add nitric acid containing lanthanum
or add nitric acid and excess
ammonium hydroxide: centrifuge.
decani solution, heal 10 80°C
|-ccal sample Add nitric acid, apply heal, add
hydrogen peroxide and nitric acid,
bring mixture to a boil, add ferrous
chloride, controlling the foaming by
adding water, nitric acid or oclanol.
evaporate, heat, dissolve residue in
nitric acid containing lanthanum
Urine (human and Add EDTA to aqueous sample, adjust to
rat) pH 6. add trifluoroaceiylaceione in
benzene, extract
Dog blood, rat Add sodium hydroxide, dissolve by
liver homogenale heating, dilute and wash with mini:
acid, neutralize with sodium
hydroxide to a phcnolphlhalcm end
point, adding solutions of sodium
EDTA and acetate buffer, add m-
fluoroaiclyl-acelone ben/ene
solution. wa»h bcn/cnc aliquul*
ammonium hydrouJc wlution
AAS (graphite furnace) 2 5 pg/aliquol 10% KSD
FAAS
FAAS
FAAS
-------
Table 8.2 (continued)
Sample matrix
Sample preparation
Analytical method Delect ion limn Accuracy/precision Reference:.
Human blood plasma
I ting tissue, hilar
Ijinph nude
Buvine liver/
orchard leaves
(Standard Reference
Materials Ii7l and
1577)
Urine (human)
Extract (chloroform and 2.4-dioxo-4-
(4-hydroxy-6-methyl-2-pyronc-3-yl)
butyric acid ethyl ester|, dilute
chloroform layer with clhanol
Ash homogenized samples, mix with
graphite and an indium internal
standard, compact mixture into
electrodes
Wet-ash dried tissue in mixture of
nitric perchloric acids (II), add
water, EOTA solution and phenol red.
adjust pH to 7-8. add aceiylacelone
solution, extract (chloroform), per-
form a scries of acidtficalions and
evaporations, add water, cyclohcxanc-
diammc-lelraacclic acid solution
and phenol red, adjust pH to 7-8,
add buffer solution and 2-hydroxy-3-
naphlhoic acid reagent
Urine sample is diluted with a matrix
modifier (aqueous MgNO,, Triton
X-IOO. HNO,)
Fluorescence speclromelry 0 5 «ig
Not reported
Spark source mass
Not reported Not reported
Huorescence speclromelry Nut reported Not reported
Drevenkar el al
1976
Brown and Taylor
1975
Wicks and Burke
1977
blectrolhermal atomic
absorption (slabilucd
temperature platform
furnace)
0 05 dg/L 107% al 19 pg/L and Paschal and
16% al 0 5 /ig/L Bailey 1986
AAS = atomic absorption speclromelry,
ALS = atomic emission spcuromciry,
hAAS — flamcless atomic absorption speclromelry.
I AI:S = flamclcss atomic emission speuromciry,
d( /I-C - gas ihromalugraphy electron capture,
Rbl) - relative standard deviation
£
Di
n
Bl
PI
a-
o
Q.
in
-------
69
9. REGULATORY AND ADVISORY STATUS
9.1 INTERNATIONAL
The World Health Organization has not set a guideline for drinking
water quality for beryllium (IRPTC 1987)
9.2 NATIONAL
9.2.1 Regulations
AGENCY REGULATION
OSHA PEL--8-h TWA--2 /ig/™3
Acceptable ceiling limit--5 /Jg/m^
Acceptable maximum peak above ceiling- -25 jig/ra3 for 30 min
(OSHA 1985)
EPA National Emissions Standard for Hazardous Air Pollutants
10 g in a 24-h period (EPA 1982). The standard was
promulgated under Section 112 of the Clear Air Act in 1973
and amended in 1978.
The reportable quantity for beryllium and compounds is 1 Ib (EPA
1985).
9.2.2 Advisories
9.2.2.1 Air
AGENCY ADVISORY
NIOSH Occupational exposure limit--0.5 /*g/m3 (NIOSH 1972)
ACGIH TWA-TLV--0.002 mg/m3 Group A2 (ACGIH 1987)
9.2.2.2 Water
AGENCY ADVISORY
EPA AWQC--0.68 to 68 ng/L for consumption of 2 L of ambient
water and fish; 11.7 to 1170 ng/L for consumption of aquaeu
organisms only for risk levels of 10'7 to 10*5 (EPA 1980)
-------
70 Seccion 9
9.2.3 Data Analysis
9.2.3.1 Reference dose
EPA (1987b) has verified an oral RfD of 0 005 mg/kg/day, based OP
che lifetime study by Schroeder and Mitchener (1975a) in which racs -.ere
exposed co beryllium sulface in the drinking water at a concentration of
beryllium of 5 mg/L. The only effect was a decreased body weight gain
during the first few months of the study. The 5 mg/L concentration -as.
therefore, a NOAEL. Based on drinking water consumption data and bodv
weight data, the 5 mg/L level was transformed into a dose of 0 54
mg/kg/day by multiplying by 0.035 L/day and dividing by 0 325 kg The
RfD was derived according to the methods described in Barnes et al
(1987) as follows:
RfD - (0.54 mg/kg/day)/(100) - 0.005 mg/kg/day
Where- 0.54 mg/kg/day - NOAEL
100 - uncertainty factor for inter- and intraspecies
extrapolation appropriate with a chronic animal NOAEL
9.2.3.2 Carcinogenic potency
EPA (1986a) has derived a quantitative unit cancer risk estimate of
2 x 10'-5 (fig/m3)'1 based on the epidemiological study by Wagoner et aL
(1980). Wagoner et al. (1980) reported a significant increased risk of
lung cancer for workers in a beryllium processing facility in
Pennsylvania, but when the data were corrected for cigarette smoking
the significant association could no longer be demonstrated (EPA 192 7r>:
Although the reanalysis of the Wagoner et al. (1980) study indicated ro
significant increased risk of cancer, beryllium is considered to be a
probable human carcinogen because beryllium compounds are carcinogenic
in animals by inhalation. EPA (1987a) used data from the Wagoner et al
(1980) study, instead of animal data, as the basis for an upper-bound
estimate of cancer risk because, given the uncertainty inherent in che
use of animal data, it is more desirable to use the available human
data. As discussed by EPA (1987a), information supplied by NIOSH (1972)
and Eisenbud and Lisson (1983) regarding typical workroom levels for
beryllium in production plants, for the period of time covered by the
Wagoner et al. (1980) study, indicates that the narrowest range for
median exposure that could be obtained on the basis of available
information was 100 to 1000 Mg/m3. Using this range of exposure levels.
the upper-bound estimate of cancer risk was calculated to be 2 x 10"3
(Mg/m ) . This estimate was compared with potency factors calculated
from animal data: the potency factors derived from animal studies of
beryllium salts overestimated the human risk, but potency factors
derived from animal studies of beryllium oxide are quite similar to the
risk estimates derived from human data. Because of weaknesses in che
animal studies using beryllium oxide, however, the derived potency
values are not adequate as a basis for a recommended potency, but the-.-
can be used to provide support for the upper-bound risk estimate derr eel
from human data. The upper-bound risk estimate of 2 x 10*3 (/ig/m3)'1 -..is
verified on May 4, 1988, by the EPA's overall Carcinogen Risk Assessment
Verification Endeavor (CRAVE) workgroup.
-------
Regulacory and Advisory Scacus ~ >.
EPA (1980) calculated a q.* for oral exposure based on che study b
Schroeder and Mitchener (1975aJ. The rats in this study were exposed ro
beryllium sulfate in drinking water at 5 ppm beryllium and did not have
statistically significant increased incidences of tumors. Because
beryllium is carcinogenic in animals by the inhalation route and because
a study by Morgareidge et al. (1975) found a statistically significant
increased incidence of reticulum cell sarcoma in the lungs of rats
exposed to 5 and 50 ppm, but not 500 ppm, beryllium sulfate in the diet
EPA (1980) decided that the potential for carcinogenicity by the oral
route could not be ignored and derived a q,* for the oral route Because
the incidences in the Morgareidge et al. (1975) study were not dose-
related, EPA (1980) did not calculate the q* from this study, but
rather from the study by Schroeder and MitcRener (1975a). The q * for
oral exposure is 4.86 (mg/kg/day)"^ and is regarded as an upper-limit
estimate, since it was derived from the upper limit of a study showing
no carcinogenic response The issue of the potential carcinogenicity of
beryllium by the oral route and the oral q1 was also discussed by the
CRAVE workgroup on May 4, 1988. Because of limitations of the study by
Schroeder and Mitchener (1975a), the CRAVE workgroup did not verify che
oral q.* calculated from this study, but will reconsider the issues
after the analysis by the EPA Office of Drinking Water, which is
considering the possibility of reevaluating the study by Morgareidge ec
al. (1975) for the purposes of deriving an oral q,*.
Based on the positive carcinogenicity data in animals exposed by
inhalation, beryllium compounds, specifically the oxide and some salts,
are classified in group B2 as probable human carcinogens (EPA 1987a)
according to the criteria described by EPA (1986). The IARC
classification is 2A (IARC 1987).
9.3 STATE
No state regulations were available.
-------
73
10. REFERENCES
ACGIH (American Conference of Governmental Industrial Hygieniscs) 1987.
Threshold Limit Values and Biological Exposure Indices for 1986-1987
Cincinnati, OH: ACGIH. p. 10.
Andrews JL. Kazemi H. Hardy HL. 1969. Patterns of lung dysfunction in
chronic beryllium disease. Am Rev Respir Dis 100:791-800.
Arlauskas A, Baker RS. Bonin AM. Tandon RK, Crisp PT, Ellis J 1985.
Mutagenicity of metal ions in bacteria. Environ Res 36(2) : 379-388.
Awadallah RM, Sherif MK. Amrallah AH, Grass F. 1986. Determination of
trace elements of some Egyptian crops by instrumental neutron
activation, inductively coupled plasma-atomic emission spectrometric and
flameless atomic absorption spectrophotometric analysis. J Radioanal
Nucl Chem 98(2):235-246.
Ballance J, Stonehouse AJ, Sweeney R, Walsh K. 1978. Beryllium and
beryllium alloys. In: Grayson M, Eckroth D, eds. Kirk-Othmer
Encyclopedia of Chemical Technology, 3rd ed.. Vol. 3. New York: John
Wiley & Sons, Inc., pp. 803-823.
Bargon J. Kronenberger H. Bergmann L. et al. 1986. Lymphocyte
transformation test in a group of foundry workers exposed to beryllium
and non-exposed controls. Ur J Respir Dis (Denmark) 69(suppl 146) 211-
215.
Barnes D. Bellin J, DeRosa C, et al. 1987. Reference Dose (RfD):
description and use in health risk assessments. Appendix A of the
Integrated Risk Information System (IRIS). Washington, DC: OHEA, ORD.
EPA 600/8-86-0321.
Bayliss DL. 1980. Letter to William H. Foege, MD, Director, Centers for
Disease Control, Atlanta. GA (cited in EPA 1987a).
Bayliss DL, Lainhart WS. 1972. Mortality patterns in beryllium
production workers. Presented at the American Industrial Hygiene
Association Conference, OSHA exhibit No. 66, docket no. H-005 (cited in
EPA 1987a).
*Key studies.
-------
74 Section 10
Bayliss DL. Wagoner JK. 1977. Bronchogenic cancer and cardiorespiracor-
disease mortality among white males employed in a beryllium productic
facility. OSHA Beryllium Hearing, 1977, exhibit 13 F (cited in EPA
19S7a).
Bayliss DL, Lainhart WS, Crally LJ, Ligo R, Ayer H, Hunter F. 197L
Mortality patterns in a group of former beryllium workers In.
Transactions of the 33rd Annual Meeting of the American Conference of
Governmental Industrial Hygienists, Toronto. Canada, pp. 94-107 (cited
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87
11. GLOSSARY
Acute Exposure--Exposure to a chemical for a duration of 14 days or
less, as specified in the Toxicological Profiles.
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.
Carcinogen--A chemical capable of inducing cancer.
Ceiling 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.
Embryotoxicity 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.
Frank Effect Level (FEL)--That level of exposure which produces a
statistically or biologically significant increase in frequency or
severity of unmistakable adverse effects, such as irreversible
functional impairment or mortality, in an exposed population when
compared with its appropriate control.
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.
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88 Section II
Intermediate Exposure--Exposure to a chemical for a duration of 15-36<
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.
Key Study--An animal or human toxicological study that best illustrates
the nature of the adverse effects produced and the doses associated with
those effects.
Lethal Concentratlon(LO) (LCL0)--The lowest concentration of a chemical
in air which has been reported to have caused death in humans or
animals.
Lethal Concentratlon<50) (LCso)--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) (LDLO)--The lowest dose of a chemical introduced by a
route other than inhalation that is expected to have caused death in
humans or animals.
Lethal Dose(50) (LD50)--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
Lowest-Observed-Effect Level (LOEL)--The lowest dose of chemical in a
study or group of studies which produces statistically or biologically
significant increases in frequency or severity of effects between the
exposed population and its appropriate control.
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
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Glossary 89
Neurotoxlcity- -The occurrence of adverse effects on the nervous system
following exposure Co 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.
No-Observed-Effect Level (NOEL) --That dose of chemical at which there
are no statistically or biologically significant increases in frequency
or severity of effects seen between the exposed population and its
appropriate control.
Permissible Exposure Limit (PEL) --An allowable exposure level in
workplace air averaged over an 8-h shift.
q *--The upper-bound estimate of the low-dose slope of the dose -response
curve as determined by the multistage procedure. The q.* can be used to
calculate an estimate of carcinogenic potency, the incremental excess
cancer risk per unit of exposure (usually j*g/L for water, mg/kg/day for
food, and /ig/m^ 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 Ib
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.
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90 Section 11
Target Organ Toxiclty--This term covers a broad range of adverse effee-
on target organs or physiological systems (e.g., renal, cardiovascula
extending from those arising through a single limited exposure to thos.
assumed over a lifetime of exposure to a chemical.
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 NOAEL data. Usually each of these factors is set
equal to 10.
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9L
APPENDIX: PEER REVIEW
A peer review panel was assembled for beryllium and compounds The
panel consisted of the following members: Dr. Herbert Cornish, (retired)
Professor of Toxicology, University of Michigan; Dr. Daniel Byrd,
Director of Scientific Affairs, Halogenated Solvents Indust-ry Alliance,
and Dr. Andrew Reeves, Professor of Occupational and Environmental
Health, Wayne State University. These experts collectively have
knowledge of beryllium'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 co
imply their approval of the profile's final content. The responsibility
of the content of this profile lies with the Agency for Toxic Substances
and Disease Registry.
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