FINAL
Unned States ECAQ-C IN-D0Q3
Environmental Protecnon January, 1990
Aseftcv Revised September, 1991
&EPA Research and
Development
DRINKING WATER CRITERIA DOCUMENT
FOR BERYLLIUM
Prepared for
HEALTH AND ECOLOGICAL CRITERIA DIVISION
OFFICE OF SCIENCE AND TECHNOLOGY
OFFICE OF WATER
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
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DISCLAIMER
This document has been reviewed In accordance with the U.S. Environ-
mental Protection Agency's peer and administrative review policies and
approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
j
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available from the original submission.
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FOREWORD
Section 1412 (b)(3)(A) of the Safe Drinking Hater Act, as amended In
1986, requires the Administrator of the Environmental Protection Agency to
publish maximum contaminant level goals (HCLGs) and promulgate National
Primary Drinking Water Regulations for each contaminant, which, In the
Judgment of the Administrator, may have an adverse effect on public health
and which 1s known or anticipated to occur 1n public water systems. The
HCLG Is nonenforceable and Is set at a level at which no known or antici-
pated adverse health effects tn humans occur and which allows for an
adequate margin of safety. Factors considered In setting the HCLG Include
health effects data and sources of exposure other than drinking water.
This document provides the health effects basis to be considered In
establishing the HCLG. To achieve this objective, data on pharmacokinetics,
human exposure, acute and chronic toxicity to animals and humans, epidemi-
ology and mechanisms of toxicity are evaluated. Specific emphasis is placed
on literature data providing dose-response Information. Thus, while the
literature search and evaluation performed In support of this document has
been comprehensive, only the reports considered most pertinent 1n the deri-
vation of the HCLG are cited In the document. The comprehensive literature
data base In support of this document Includes Information published up to
1986; however, more recent data have been added during the review process,
and final revisions updating this document were made.
When adequate health effects data exist, Health Advisory values for less
than lifetime exposures (1-day, 10-day and longer-term, *10* of an Indi-
vidual's lifetime) are included 1n this document. These values are not used
In setting the HCLG, but serve as Informal guidance to municipalities and
other organizations when emergency spills or contamination situations occur.
Tudor Davles, Director
Office of Science and
Technology
James Elder, Director
Office of Ground Water
and Drinking Water
111
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DOCUMENT DEVELOPMENT
Linda R. Papa, M.S., Document Manager
Environmental Criteria and Assessment
U.S. Environmental Protection Agency
Helen H. Ball, M.S.. Project Officer
Environmental Criteria and Assessment
U.S. Environmental Protection Agency
Scientific Reviewers
Robert E. McGaughy, Ph. D.
Carcinogen Assessment Group
U.S. Environmental Protection Agency
Washington, DC
Vlasta Molak, Ph.D.
Environmental Criteria and Assessment
Office
U.S. Environmental Protection Agency
Cincinnati, Ohio
Les Newland, Ph. D.
Department of Environmental Science
Texas Chrlstaln University
Fort Worth, Texas
William E. Pepelko, Ph.D.
Carcinogen Assessment. Group
U.S. Environmental Protection Agency
Washington, DC
Office, Cincinnati
Office, Cincinnati
Andrew L. Reeves, Ph. D.
Department of Occupational and
Environmental Health
Wayne State University
Detroit, Michigan
Flo H. Ryer
Exposure Assessment Group
U.S. Environmental Protection Agency
Washington, OC
Lawrence R. Valcovlc, Ph.D.
Reproductive Effects Assessment
Group
U.S. Environmental Protection Agency
Washington, DC
Technical Editor
Judith Olsen, B.A.
Environmental Criteria and Assessment Office, Cincinnati
U.S. Environmental Protection Agency
Support Staff
Bette Zwayer
Environmental Criteria and Assessment Office, Cincinnati
U.S. Environmental Protection Agency
1 v
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TABLE OF CONTENTS
Pa^e
I. SUMMARY 1-1
II. PHYSICAL AND CHEMICAL PROPERTIES II-l
CHARACTERISTICS OF BERYLLIUM (Be) II-l
CHARACTERISTICS OF BERYLLIUM COMPOUNDS II-2
METHODS OF DETERMINATION II-5
SUMMARY 11-6
III. TOXICOKINETICS. . . ' Ill-1
ABSORPTION III-l
DISTRIBUTION 111-2
METABOLISM 111 -6
EXCRETION . 111 -6
SUMMARY 111-7
IV. HUMAN EXPOSURE IV-1
[To be provided by the Office of Drinking Water]
V. HEALTH EFFECTS IN ANIMALS V-l
GENERAL TOXICITY V-l
Acute Toxicity V-l
Subchronlc and Chronic Toxicity 1 V-4
TARGET ORGAN TOXICITY V-0
CARCINOGENICITY V-9
DEVELOPMENTAL TOXICITY V-l9
REPRODUCTIVE TOXICITY V-21
MUTAGENICITY V-22
Gene Mutations In Bacteria V-22
Gene Mutations 1n Yeast and Cultured Mammalian Cells . . V-27
Chromosomal Aberrations. . . V-28
Sister Chromatid Exchanges V-28
Cytogenetic Effects V-28
Other Tests of Genotoxlc Potential V-29
Other Effects 1n Cell Cultures . V-31
SUMMARY V-31
v
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TABLE OF CONTENTS (cont.)
Page
VI. HEALTH EFFECTS IN HUMANS VI-1
INTRODUCTION VI-1
GENERAL TOXICITY VI-1
Acute VI-1
Chronic VI-4
OTHER EFFECTS VI-7
Carcinogenicity VI-7
Mutagenicity and Teratogenicity v 1-33
SUMMARY VI —33
VII. MECHANISMS OF TOXICITY VII-1
EFFECTS ON ENZYMES VII-1
EFFECT ON NUCLEIC ACIDS VII-4
EFFECT ON PROTEINS VII-5
IMMUNOLOGIC EFFECTS VI1-5
SYNERGISM AND ANTAGONISM VI1-9
SUMMARY VII-11
VIII. QUANTIFICATION OF TOXICOLOGIC EFFECTS ... VIII-1
INTRODUCTION .^ VIII-1
NONCARCINOGENIC EFFECTS VIII-6
QUANTIFICATION OF NONCARCINOGENIC EFFECTS VI11-7
Derivation of 1-day HA VIII-8
Derivation of 10-day HA VIII-8
Derivation of a Longer-term HA VIII-9
Assessment of Lifetime Exposure and Derivation of DUEL . V111-10
CARCINOGENIC EFFECTS VIII-12
QUANTIFICATION OF CARCINOGENIC EFFECTS VIII-15
EXISTING GUIDELINES, REGULATIONS AND STANDARDS VIII-19
SPECIAL GROUPS AT RISK VII1-20
SUMMARY VII1-21
IX. REFERENCES. IX-1
v1
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LIST OF TABLES
No. Title Page
II-l Physical and Chemical Properties of Beryllium Compounds . . 11-3
V-l Induction of Osteosarcomas In Experimental Animals by
Beryllium V-11
V-2 Induction of Pulmonary Cancer 1n Experimental Animals by
Beryllium Compounds . V-l5
V-3 Mutagenicity Testing of Beryllium: Gene Mutations 1n
Bacteria. V-23
V-4 Mutagenicity Testing of Beryllium: Gene Mutations 1n
Yeast and Mammalian Cells ]_n vitro. V-24
V-5 Mutagenicity Testing of Beryllium: Mammalian In vitro
Cytogenetics Tests V-25
VI-1 Comparison of Study Cohorts and Subcohorts of Two
Beryllium Companies VI-29
VI-2 Problems with Beryllium Cohort Studies VI-30
V11-1 Effect of Beryllium on Various Enzymes VII-3
VIII-1 HAs and DWEL for Noncarc1nogen1c Effects VI11-13
v 11
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LIST OF ABBREVIATIONS
ATPase Adenos1ne triphosphatase
CNS Central nervous system
DNA DeoxyrIbonuclelc acid
OWEL Drinking water equivalent level
GI Gastrointestinal
HA Health advisory
Hb Hemoglobin
1.v. - Intravenous
LOAEL Lowest-observed-adverse-effeet level
LOEL Lowest-observed-effeet level
HTD Maximum tolerated dose
NOAEL No-observed-adverse-effect level
NOEL No-observed-effect level
RBC Red blood cell
RfD Reference dose
RNA Ribonucleic add
v111
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I. SUMMARY
Beryllium (Be) Is a hard grayish-white metal of the alkaline earth
family. It occurs In nature.as a mineral component of pegmatite rocks. In
addition to the gemstones emerald (chromium-containing beryl) and
aquarmarlne (Iron contalnlng-beryl), beryl and bertrandlte are the only two
beryllium minerals of economic significance. Because of Its low atomic
number (9Be), beryllium Is very permeable to x-rays and Is used as a
window for x-ray tubes. Although pure beryllium metal has a unique
combination of properties that makes It particularly useful 1n the
manufacture of high performance products In metallurgical, aerospace and
nuclear technologies, most of the beryllium ore mined Is converted into
metal alloys. Beryllium alloys are used 1n the electronics, plastics and
tooling Industries. Beryllium oxide Is used to make high-technology
ceramics as well as laser structural components.
Methods used to detect beryllium Include flame and flameless absorption
spectroscopy, spectrophotometry, gas chromatography/electron capture and
laser 1on mass analysis (LIMA). Generally, beryllium behaves as a cation
with a 2* valence at a pH of >5; It forms poorly soluble compounds at a pH
of 5-8 and forms beryllate-llke complexes at a pH of >8, It Is likely to
occur In natural waters only In trace amounts since beryllium compounds are
relatively Insoluble at the pH of natural waters. Detectable concentrations
of beryllium are found in acidified waters, and In view of the Increased
acidification of some natural waters, there is a potential for an Increased
solubility of beryllium salts.
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Beryllium may enter the body by Ingestion, Inhalation and skin absorp-
tion. Inhalation and Ingestion are the main routes of beryllium Intake for
man. When Ingested, beryllium Is only minimally absorbed (<1%) by the GI
tract because at neutral pH of the Intestines, the major site of GI
absorption, precipitation of beryllium compounds occurs. Absorption through
unbroken skin, even following prolonged or repeated contact, adds
Insignificant amounts of beryllium to the body, although a contact
dermatitis may occur.
The major route of exposure by which beryllium enters the body Is
Inhalation. Most of the beryllium that can be Inhaled Is emitted Into the
air by the burning of coal or fuel oil in which beryllium occurs as an
Impurity. Beryllium also occurs naturally In various tobaccos and may be
Inhaled during smoking. The greatest potential for beryllium exposure
occurs in the work place and 1n the vicinity of the Industries that process
beryllium ore or compounds. Atmospheric beryllium eventually reaches soils
and sediments where It 1s retained 1n the relatively Insoluble form of
beryllium oxide.
Beryllium compounds may be mobilized from the lungs, but the rate of
mobilization (clearance and deposition) depends on the solubility, of the
compound, particle size and dose. Blood steady state Is reached within 8-12
hours of exposure. A large portion of the beryllium transported by the
blood is deposited 1n the skeleton. Intratracheal doses have been measured
1n the liver, spleen, kidney and muscle. Beryllium has also been shown to
accumulate 1n the lung following interaction with macromolecules In lung
cells. Increased beryllium levels have been detected 1n human lungs as long
as 20 years after the last exposure.
04160 1-2 08/14/91
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The major route of excretion following oral exposure 1s through the
feces. Urine represents the major route of excretion If beryllium Is
administered Intratracheally or parenterally.
Systemic toxicity associated with oral administration of beryllium to
animals Is limited to the development of beryllium rickets and a slight
growth depression in male rats.
Inhalation exposure results In both acute and chronic lung disease, as
well as anemia. Short-term exposure to high concentrations of beryllium
salts can cause inflammation of the lungs (similar to pneumonia) and
long-term exposure to beryllium at low air concentrations can cause
berylliosis (manifested by the appearance of granulomas In the lung).
Intratracheal administration of beryllium sulfate has also produced
pulmonary lesions. Injection of even small amounts of beryllium oxide,
silicate and phosphate are extremely toxic to animals, with reports of lung
and liver effects, CNS changes and osteosclerotic changes.
Experimental beryllium carcinogenesis has been Induced by Intravenous or
Intramedullary Injection of rabbits and ' by Inhalation or Intratracheal
exposure of rats and monkeys. Carcinogenic responses have been Induced by a
variety of forms of beryllium including beryllium sulfate, phosphate, oxide,
and beryl ore. The carcinogenic evidence in mice (Intravenously Injected or
exposed by Inhalation), guinea pigs and hamsters (exposed by Inhalation) 1s
equivocal.
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Osteosarcomas are the predominant types of tumors Induced In rabbits.
These tumors are highly Invasive, metastasize readily, and are Judged to be
histologically similar to human osteosarcomas. In rats, pulmonary adenomas
and/or carcinomas have been found, although pathologic end points have not
been well documented In many cases. While Inhalation, Intratracheal
Instillation, and intravenous or Intramedullary Injection have produced
positive results, evidence of animal carcinogenesis resulting from drinking
water or dietary exposure Is not definitive. In the only published oral
study with rats, however, the dose levels were well below the MTD. Studies
using mice and dogs were of Inadequate duration.
Although, individually, many of the animal /studies have methodologlc and
reporting limitations compared with current standards for bloassays,
collectively, the studies provide evidence for carcinogenicity. Tumorgenlc
responses have been noted 1n multiple species at multiple sites and, In some
cases, afford evidence of a dose-response. On this basis, the U.S. EPA has
classified the weight of evidence for carcinogenicity In experimental
animals as sufficient. Since positive responses were seen for a variety of
beryllium compounds, all forms of beryllium are considered to be
carcinogenic. While evidence for oral exposure is Inconclusive, the nature
of the nonoral positive data suggests that beryllium may also pose a risk by
the Ingestion route.
Occupational epidemiologic studies provide equivocal conclusions on the
carcinogenicity of beryllium and beryllium compounds. Early 1970s
epidemiologic studies of beryllium exposed workers do not report positive
evidence for Increased cancer Incidence. However, recent 1980s studies do
report a significantly Increased risk of lung cancer In exposed workers.
04160 1-4 09/24/91
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The absence of beryllium exposure levels and a demonstrated concern about
possible confounding factors within the workplace make the reported positive
correlations between beryllium exposure and Increased risk of cancer
difficult to substantiate. This relegates the reported statistically
significant Increases 1n lung cancer to, at best, a somewhat elevated risk
that 1s not statistically significant. Because of these limitations, the
available epidemiologic evidence Is considered to be "Inadequate" to support
or refute the existence of a carcinogenic hazard for humans exposed to
beryl 1lum.
Using the U.S. EPA welght-of-evldence criteria for evaluating both human
and animal evidence, beryllium is classified In Group B2, Indicating that,
on the strength of animal studies, beryllium should be considered a probable
human carcinogen. In this particular case, the animal evidence demon-
strates that all beryllium species should be regarded as probably being
carcinogenic for humans.
Beryllium sulfate and chloride have been shown to be nonmutagenlc In all
bacterial and yeast gene mutation assays. Mutagenicity studies of beryllium
sulfate Indicate that beryllium has the potential to cause gene mutations,
chromosomal aberrations and sister chromatid exchange In cultured human
lymphocytes and Syrian hamster embryo cells. Beryllium was found to block
the cell cycle and Inhibit cell division. It has also been reported to
affect DNA polymerase and thus, Increase the frequency of mutations.
However, the lack of data 1n whole animals preclude any definitive statement
on the potential heritable effects of beryllium.
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Teratogenicity studies have^ found positive results In snails, sala-
manders and chick embryos. Limited Information is available regarding
teratogenic and reproductive effects In animals. Results of a recent
Russian study In pregnant rats indicated that beryllium chloride compounds
produced some teratogenic effects described only as "Internal abnormal-
ities. " The available Information Is not sufficient to determine whether
beryllium compounds have the potential to produce adverse reproductive or
teratogenic effects In humans.
Numerous studies have Identified possible mechanisms resppnslble for the
effects observed following beryllium exposure. Beryllium has been noted to
Inhibit several enzyme systems, such as alkaline phosphatase, and has also
been shown to affect nucleic acid protein production and metabolism In the
cell. The Involvement of an Immunologic factor following beryllium exposure
is now generally accepted as a cell-mediated hypersensitivity reaction.
Responses observed varied with the individual; humans and guinea pigs can be
sensitized, whereas present data Indicate that no such mechanism exists for
the rat. Sensitization In yuinea pigs has buen shown to be controlled and
transmitted as a dominant, nonsex-1Inked trait. Presently, the lymphoblast
transformation test Is regarded as the most useful test to detect
hypersensitivity to beryllium.
The following health advisories were derived from ingestion studies In
which beryllium was added to the drinking water or diet of rats. For
noncarclnogenlc effects a 10-day HA (10 kg child) of 30 mg/i was
calculated based on an animal feeding study. The 10-day HA (10 kg child) of
30 mg/i was adopted for the 1-day HA as a conservative estimate since no
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suitable data were located 1n the available literature on which to base this
criterion directly. Longer-term HAs of 4 mg/l (10 kg child) and 20 mg/2.
(70 kg adult) were derived from a subchronlc dietary study In rats. A
drinking water equivalent level (DWEL) of 0.2 mg/l was derived based on a
NOAEL of 0.5 mg/kg/day 1n rats from a drinking water study.
Although evidence exists that beryllium is a carcinogen by the Inhala-
tion route, no definitive evidence exists that correlates the Ingestion of
beryllium with tumor appearance since It has not been tested orally at the
MTD. However, since beryllium 1s carcinogenic by Inhalation and parenteral
routes, and also Induces chromosomal abnormalities, It Is possible that
beryllium In water could pose a carcinogenic risk to man. The quantitative
estimate by Ingestion Is regarded as an upper,limit estimate since It was
derived from the upper limit of a study that showed no significant
carcinogenic effects: q-j* = 4.3 (mg/kg/day)'1. The concentration
corresponding to lifetime risk of 10~* is 8 ug/i, or for a risk of
10"s Is 80 jig/l. These numbers should be used with caution because of
the severe limitations In their derivation.
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II. PHYSICAL AND CHEMICAL PROPERTIES
Characteristics of Beryllium (Be)
Beryllium (Be) Is a lightweight, grayish-white metal of the alkaline
earth family with an atomic weight of 9.01. A fairly rare element, It ranks
44th In abundance and was originally called gluclnum (Gl) because beryllium
salts have a sweet taste. In nature, beryllium exists in mineralized forms
such as beryl and bertrandlte. The most Important forms commercially are
the metal Itself, beryllium-copper alloys and beryllium oxide. Beryllium 1s
often used In high-performance products In metallurgical, aerospace and
nuclear technologies because of its unique combination of properties, such
as an unusually high melting point, high modulus of elasticity, extreme
hardness, low coefficient of thermal expansion and a high stiffness-to-
weight ratio (Weast, 1977). Also, because beryllium has a low atomic
weight, It is highly permeable to X-rays, and thin sheets are commonly used
as windows for X-ray tubes.
Beryllium has a Chemical Abstracts (CAS) Registry number of 7440-41-7
and a Registry of Toxic Effects of Chemical Substances (RTECS) number of
DS 1750000. It has the following physical and chemical properties:
Molecular weight:
Boiling point:
Melting point:
Brlnell hardness:
Vapor pressure:
Specific gravity:
Conversion factor
(ppm (a 1r) to
mg/m3):
9.012
2500°C
1287°C
60-125
10 mm Hg at 1860°C
1.85 at 20°C (solid
1 ppm = 0.375 mg/m3
gas at 2500°C
Wlndholz, 1976
U.S. EPA, 1980a
U.S. EPA, 1980a
U.S. EPA, 1980b
Toxicology Data Bank, 1985
Weiss, 19B0
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The Ionic radius of beryllium Is only 0.3U, with a large Ionic
charge-to-rad1us ratio of 6.45. Because of this, the most stable beryllium
compounds are formed with smaller anions such as fluoride and oxide (Krejd
and Scheel, 1966). This high charge-to-radius ratio of bivalent beryllium
also accounts for the amphoteric nature of the ion (Basolo, 1956; Cartledge,
1928) and the strong tendency of beryllium to hydrolyze. Generally, 1t
behaves Nas a cation with a 2* valence at pH values <5, forms Insoluble
hydroxides or hydrated complexes at pH values of 5-8, and forms beryllate-
llke complexes at pH values >8 (Drury et al.f 1978).
Many common beryllium compounds (for example, the chloride and nitrate)
are readily soluble In water. Others, such as the sulfate complex, the
carbonate and hydroxide compounds, are almost Insoluble In cold water (McKee
and Wolf, 1963). Beryllium 1s not likely to be found In natural waters
except 1n trace amounts because In the normal pH range of such water the
oxides and hydroxides are relatively Insoluble (oxide solubility reported at
20-70 yg/l 1n pure water at 28°C) (NAS, 1977). Hem (1970) estimates
that the average concentration of beryllium In fresh surface waters Is
<1 vg/*.
Characteristics of Beryllium Compounds
An Important beryllium compound 1s beryllium oxide (BeO), a chemical
Intermediate In the extraction of beryllium from beryl and bertrandlte. It
Is soluble 1n acids and alkalis, but mostly Insoluble In water (Table II-l).
It Is an extremely stable compound, with a negligible vapor pressure <2000°C
(Erway and Selfert, 1951).
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TABLE 11-1
Physical and Cheated 1 Properties of Beryllium Compounds*
Beryllium
Oxide
Beryllium
Sulfate
Beryllium
Hydroxide
Beryllium
Carbonate
Beryllium
Fluoride
Beryllium
ChlorIde
Beryllium
Nitrate
Molecular formula
BeO
BeS0«
Be(0H)?
BeCOj » Be(0H)?
Bef 2
BeClp
Be(N03>2 • 3H;0
Molecular weight
25.01
105.07
43.03
112.05
47.01
79.93
187.07
CAS registry number
1304-56-9
13510-49-1
13327-32-7
13106-47-3
7787-49-7
7787-47-5
13597-99-4
Specific gravity (20*)
3.01
2.44
1.92
NR
1.986 (25*)
1.899 (25*)
1.557
Boiling point, *C
3900
NR
NR
NR
NR
482.3
142
Melting point, *C
2530 » 30
decomposes
550-600
NR
NR
555
399.2
60
Vapor pressure, m Hg
NR
NR
NR
NR
NR
1291-C
NR
Mater solubility, mg/ft
0.2, 30*C
Insoluble In
cold water;
converted to
tetrahydrate
In hot water.
i
Slightly
soluble
Insoluble In
cold water.
Decomposes In
hot water.
Extremely
soluble
Very soluble
Very soluble
'Sources: Mlndholi, 1976; Heist, 1977
NR . Not reported
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Beryllium sulfate 1s a pure Intermediate In the production of beryllium
oxide. It 1s most often found as the tetrahydrate form (BeS0^»4Hp0),
which 1s Insoluble In ethanol but soluble 1n water. Like other soluble
beryllium salts, the sulfate 1s hydrolyzed 1n aqueous solution. If the
excess hydrogen 1ons are removed from this system, such as happens 1n the
living cell, the soluble salts convert to Insoluble products, which have
long residence times in the body (Krejcl and Scheel, 1966).
Beryllium hydroxide [Be(OH)^3 Is an Important Intermediate In all of
the current methods of extracting the metal from Its ores, and It Is also
formed and retained 1n some tissues of the body. The hydroxide occurs In
several forms, the amorphous form being more soluble than the a or [3
form. The a product solubility Is reported to be <10"7 mole/1
(Gilbert and Garrett, 1956).
The most Important beryllium hallde 1s the fluoride (BeF^), which Is
extremely soluble In water. Aqueous solutions of BeF^ are only slightly
hydrolyzed (-1%). The other Important hallde 1s beryllium chloride
(BeCl^); anhydrous form of the chloride Is very soluble In water and
ethanol and Is hydrolyzed to 4.6% In a 0.1 N solution (Drury et al., 1978).
Beryllium nitrate [BefNO^'SH^O] was formerly used In gas and
acetylene lamps (Stecher, 1968); however, Its use was discontinued In 1973
because It represented a potential health hazard (Griggs, 1973; Lerza,
1974). Data on the above described beryllium compounds are listed In
Table II-l.
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Methods of Determination
Several methods are used to determine beryllium content In air, water,
biologic tissues and urine. Two of these methods are flame and flameless
absorption spectroscopy. In the flame technique, the photodetector 1s
usually calibrated to read the concentration directly (Environmental Instru-
mentation Group, 1973) and has a detection limit of 2-10 ng/ma, (Hurlbut,
1974). The flameless technique 1s more sensitive, with a detection limit of
0.1 ng/ma, for urine (Hurlbut, 1974). A third method for determining
beryllium 1s spectrophotometry, which has a detection limit of -5 ng/mi,
but this method 1s sometimes a long and tedious process. Atomic absorption
spectrometry Is a useful and convenient procedure, but Is not as sensitive
as other techniques. Determinations that require even greater sensitivity
and specificity are possible through the use of gas chromatography.
Measures and Edmond (1986) describe a method for the determination of
beryllium content In seawater at oceanic concentration levels (2-30 pM).
The technique uses gas chromatography/electron capture detection of the
1,1 ,l-tr1fluoro-2,4-pentaned1one derivative and has a detection limit of -2
pM and a relative precision of +5X at 23 pH. The method has been utilized
1n the laboratory on stored acidified seawater samples as well as at sea on
three oceanographlc cruises. In addition, the technique has been applied to
hydrothermal fluids and other natural waters such as river and rain water.
Beryllium is measured In urine with use of the Stabilized Temperature
Platform Furnace (STPF) technology recently developed for electrothermal
atomic absorption (Paschal and Bailey, 1986). Urine is diluted with a
matrix modifier containing magnesium nitrate, nitric acid and Triton X-100
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and 1s quantified with simple aqueous standards. The characteristic amount,
which Is the amount In plcograms needed for 0.0044 Absorbance seconds
(A*s), was calculated to be 1.7 pg. A detection limit of 0.05 pg/a
was calculated (three standard deviation). Linearity Is observed from 0-16
yg/l beryllium 1n the undiluted specimen. The precision and accuracy of
the method have been evaluated with lyophlllzed urine reference material
prepared by the National Bureau of Standards, as well as with J_n vitro
spiked, frozen urine material. This procedure Is rapid, simple, and highly
accurate. Within- and among-day precision values of 4.1 and 10% were
observed for an U» vitro spiked urine with a mean value of 4.8 yg/l
beryl Hum.
Williams and Kelland (1986) Investigated the value of laser ion mass
analysis (LIMA) for the detection of beryllium disease In routine histo-
logic sections. LIMA uses a pulsed mlcrofocused laser beam to Ionize a
small volume (ym3) of material. The 1ons released are detected by a
time of flight mass spectrometer, producing a complete mass spectrum of all
elements In the periodic table with a sensitivity range from 1-10 ppm.
Conventional 5 ym histologic sections mounted on plastic film or on glass
slides are used. The sections are viewed through a standard optical
microscope, and the micron diameter laser beam Is directed as required.
Spectra can thus be obtained from Individual or groups of cells, such as
granulomas, and values compared with those of adjacent normal tissue.
Summary
Beryllium (Be) Is a lightweight, grayish-white metal of the alkaline
earth family with an atomic weight of 9.01. In nature, beryllium exists In
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mineralized forms such as beryl and bertrandUe. The most commercially
Important forms are the metal Itself, beryllium-copper alloys- and beryllium
oxide. Beryllium Is often used In high-performance products of the
metallurgical, aerospace and nuclear technologies because of Its unique
combination of properties, such as an unusually high melting point, high
modulus of elasticity, extreme hardness, low coefficient of thermal
expansion and a high stiffness-to-we1ght ratio. Also, because beryllium has
a low atomic weight. It Is highly permeable to X-rays, and thin sheets are
commonly used as windows for X-ray tubes.
Many common beryllium compounds (for example, the chloride and nitrate)
are readily soluble In water. Others, such as the sulfate complex, the
carbonate and hydroxide compounds are almost Insoluble In cold water.
Beryllium Is not likely to be found In natural waters except 1n trace
amounts, because in the normal pH range of such water the oxides and
hydroxides are relatively Insoluble. The average concentration of beryllium
In fresh surface waters Is <1 yg/l.
Several methods are used to detect beryllium content 1n air, water,
biologic tissues and urine. Two of these methods are flame and flameless
absorption spectroscopy. In the flame technique, the photodetector 1s
usually calibrated to read the concentration directly and has a detection
limit of 10 to 2 ng/ml. The flameless technique Is more sensitive, with a
detection limit of 0.1 ng/mi for urine. A third method for determining
beryllium Is spectrophotometry, which has a detection limit of ~5 ng/ml.
Gas chromatography/electron capture techniques have been used for the
determination of beryllium 1n seawater at a concentration of 2-30 ppm.
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Laser 1on mass analysis (LIMA) has been used for the detection of beryllium
disease 1n routine histologic sections.
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III. TOXICOKINETICS
The absorption, distribution, retention, metabolism and excretion of
beryllium was most recently reviewed by U.S. EPA (1907).
Absorption
The three major routes by which beryllium may. enter the body are by
Ingestion, Inhalation and dermal absorption. Several Investigators have
found that following oral administration of beryllium compounds, a majority
of the beryllium passes through the GI tract unabsorbed; <1% Is absorbed
through the gut (Reeves, 1965; Hyslop et al., 1943; Shlma et al., 1983;
Furchner et al., 1973; Uatanabe et al., 1985). Studies on guinea pigs fed.
10 or 30 mg/day beryllium sulfate (-0.08 or 0.24 mg/kg/day) showed that the
amount of beryllium absorbed was 0.006% of that Ingested (Hyslop et al.f
1943).
Reeves (1965) gave two groups of rats (4/group) either 6.6 or 66.6 ^g
Be. In their drinking water. One rat/group was killed at 6, 12, 18 and 24
weeks after exposure. The results of these studies Indicated, that 60-90% of
the Ingested beryllium was eliminated. . Reeves (1965) concluded that the low
solubility of beryllium In Intestinal fluid was due mainly to Its
precipitation as a phosphate.
Watanabe et al. (1985) investigated the absorption of different
beryllium compounds following oral administration In hamsters. Measurable
amounts of beryllium were found In the liver, kidneys, lungs and Intestines
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following dietary administration of beryllium sulfate (5 mg Be/day);
however, beryllium was found only In the Intestine when given as the oxide
or metal.
The primary route by which beryllium 1s absorbed Into the body Is
through the lungs (Inhalation). Animal studies have shown that following
the inhalation of beryl 1lum nltrate (aerosol), beryl 1lum concentrations In
the blood reached a steady state within 8-12 hours of exposure In rats and
hamsters (Stlefel et a 1., 1980). Reeves and Vorwald (1967) studied the rate
of accumulation of beryllium sulfate In the lungs of rats exposed to 34
yg/m3 beryllium. After 36 weeks of exposure, beryllium concentration 1n
the whole lung reached steady state; however, tracheobronchial lymph node
concentration peaked at about week 36 for females and week 52 for males and
then declined. Rats exposed to 447 yg/m3 beryllium oxide for 1 hour
absorbed -200 ng beryllium In 2.5 hours (Hart et al., 1984). Oermal
absorption of beryllium or beryllium compounds 1s very poor even following
prolonged or repeated contact, although contact dermatitis can occur (Berry
et al., 1974).. Petzow and Zorn (1974) showed that small quantities of
beryllium can be absorbed through the tails of rats.
Distribution
Once beryllium enters through the lungs, its compounds may be trans-
ported to other tissues. The rate of mobilization, however, may depend on
the solubility of the specific compound. A study by Van Cleave and Kaylor
(1955) reported that soluble, nonionizing beryllium-citrate was completely
mobilized from the lung after 4 days following Intratracheal injection,
while BeSO, was either retained In the lung for longer periods or mobl-
4
11 zed after 16 days. Insoluble compounds, such as beryllium ores, tend to
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remain In the lung for Indefinite periods of time (Wagner et al., 1969).
Increased beryllium levels have been detected 1n human lungs as long as >20
years after the last exposure occurred (SpMnce et al., 1976).
Beryllium Is transported from the lungs by the blood and lymph. In
vitro studies with artificial serum Indicated that orthophosphate and
hydroxide are the forms of beryllium compounds transported by the body
fluids (Reeves and Vorwald, 1961). According to Reeves (1977), the avail-
able evidence Indicates that colloidal phosphate, probably adsorbed on
plasma <*-globul1n, represents the major form of circulating beryllium,
with minor portions carried as hydroxide or citrate.
Transport of beryllium 1n the body Is a function of the physlcochemlcal
state of the metal (Stoklnger, 1972). However, regardless of the beryllium
form or the route of administration, a large portion of the beryllium
transported In the blood goes to the skeleton. Studies have Indicated that
both 1on1c and cltrated beryllium are bone seekers when Injected Intra-
venously or Intramuscularly Into rats (Crowley et al., 1949; Klemperer et
al., 1952). Deposits of beryllium In the osteoid tissue adjacent to the
epiphyseal plate have been noted on radiographs (Van Cleave and Kaylor,
1955). Other studies have Indicated that BeO administered Intratracheally
Is deposited 1n greatest concentrations in the bone and in lesser
concentrations 1n the spleen, liver, kidney and muscle (Spencer et al..
1972). Van Cleave and Kaylor (1955) reported that In rats during the first
several weeks after Injection, doses of 50 ^g Be/kg accumulated In the
bone while doses of 500 yg Be/kg were deposited In the liver. Klemperer
et al. (1952) noted that the soluble beryllium settles rapidly In the
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skeleton, while the colloidal beryllium Is taken up by the reticuloendo-
thelial organs first, mainly the liver. Beryllium deposited In the liver Is
gradually mobilized and then either transferred to bone or excreted.
The organs that retain beryllium In significant amounts are the
skeleton, liver and kidney. Crowley et al. (1949) reported that 1n rats,
40% of 20 yC1 of 7Be as BeC 1 ^ w*s absorbed from an Intramuscular
Injection site after 24 hours, with 29% of that amount absorbed and main-
tained In the bone up to the 64th day. Levels 1n the liver and kidney were
comparable with those In the bone at first, but decreased by a factor of 10
by the 64th day. Clkrt -and Bencko (1975) reported that after Intravenous
administration of beryllium as BeCl^ or BeSO^, rat liver and kidneys
contained 23.6% and 1.6%, respectively, of a dose of 25 yg/kg bw and 32.3%
and 1.3%, respectively, of a dose of 0.250 yg/kg bw. A study by Furchner
et al. ( 1973) reported that, 1n rats and mice, bone and muscle tissue
retained >1% of an l.p. dose of BeCT2 ^ days after administration.
Beryllium was retained to a greater degree following l.v. administration
than following l.p. administration; almost no beryllium was retained
following Ingestion. Furchner et al. (1973) reported retention half-Hves
of 1210, 890, 1770 and 1270 days for mice, rats, monkeys and dogs,
respectively, after l.v. administration of BeC1^-
Reeves (1965) also studied the tissue distribution of beryllium.
Beryllium sulfate (6.6 or 66.6 yg Be/day) was added to the drinking water
of male Sprague-Oawley rats for 24 weeks. The levels of beryllium were
highest 1n the GI tract and the skeleton, with somewhat lower levels In the
blood and liver. Watanabe et al. (1985) gave powdered foods containing 5 mg
beryllium as BeSO^, BeO or Be-metal to hamsters every day for 3-12
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months. Body weight and beryllium distribution 1n various organs was
studied. The results of the study demonstrated that when BeSO. was
4
administered, beryllium was mainly retained In the liver, large Intestine,
small Intestine, kidneys, lungs, stomach, and spleen. Be-metal and BeO were
absorbed poorly and beryllium was mainly found 1n the Intestine.
Rhoads and Sanders (1985) reanalyzed the data of an earlier study
(Sanders and Cannon, 1975) In which young adult Wlstar rats {35/sex) were
administered beryllium oxide by nose Inhalation only for 30-100 minutes.
Serial necropsies were performed on 5 rats/sex at 1, 7, 14, 21, 35, 49 and
63 days after exposure. Feces, urine, lungs, thoracic lymph nodes, liver,
kidneys and skeleton were analyzed for beryllium content. Beryllium was
cleared slowly from the lung. After 63 days, only 12-21% of the beryllium
had cleared the lungs (Sanders and Cannon, 1975). The time to clear 50% of
the initial lung burden (138-156 yg total deposition) was 405 days. The
data for beryllium demonstrated a two-phase lung clearance curve; during the
rapid Initial phase, 30% of Initial lung burden was cleared with a half-time
of 2.5 days and during the second phase, 70% of the Initial lung burden was
cleared with a half-time of 833 days. Beryllium had a whole-body clearance
time very similar to that of the lung. However, whole-body clearance was
best fit by a one-stage model. Beryllium did not concentrate In any tissue
outside of pulmonary tissue and was not detected 1n the'liver or skeleton at
any time. Nearly all the material cleared from the lungs was recovered 1n
the feces.
Metabolism
A few data are available on the metabolism of beryllium In the body.
Early work on metabolism centered on the capacity of beryllium to produce
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rickets In animals, which was thought to be partially due to an Inactlvatlon
of alkaline phosphatase. More recent work Is generally discussed In terms
of the toxic effect mechanisms of beryllium. Therefore, these studies will
be presented In Chapter VII, "Mechanism of Toxicity."
Excretion
The route of administration Influences the route of excretion, at least
In rats. Fecal excretion 1s the major route of excretion If administration
Is oral or inhalation. Approximately 60-90% of an oral dose of 6.6 and 66.6
yg/day was recovered In the feces of rats (Reeves, 1965). Rhoads and
Sanders (1985) showed that nearly all the beryllium cleared from the lungs
was excreted 1n the feces. Urinary excretion Is the major route following
parenteral administration of beryllium (Furchner et al., 1973). Small dases
of Intravenously administered beryllium In rats were excreted primarily
through the urine; however, Increasing the dose lowered the urinary excre-
tion rate (Scott et al., 1950). Rats given an Intravenous dose of beryllium
at 9.3xlQ"11 g/kg bw excreted 38.8% of the dose within 24 hours; however,
only 24.2% of a 1.5x10"4 g/kg bw dose of BeSO^ was excreted. Cltrated
beryllium sulfate, when administered Intratracheally, was mobilized from the
lungs after 4 days and 79% was excreted, primarily In the urine. Non-
cltrated BeSO^ stayed In the lungs for a longer period (<16 days), but the
fate of both forms of BeSO^ were ultimately the same (Van Cleave and
Kaylor, 1955).
Over a 10-month period, Zorn et al. (1986) studied the changes 1n
analytical and clinical parameters of 25 people accidentally exposed to
beryllium dust for 10-20 hours. Although no exposed person showed any
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symptoms of an acute beryllium Intoxication, Increased beryllium concentra-
tions <5-fold could be detected In serum samples -10 hours after exposure.
The beryllium clearance showed a biologic half-time In the range of 2-8
weeks.
Summary
The three routes by which beryllium may enter the body are by Ingestion,
skin absorption and Inhalation. From an exposure standpoint, the oral route
Is less significant since beryllium Is only minimally absorbed from the GI
tract. This poor rate of absorption of beryllium can be explained by its
chemical properties. Because It Is amphoteric, In aqueous solutions it can
form positive or negative 1ons In acidic or basic media, but at pH 5-0, It
forms only the hydroxide and poorly soluble particulates. Consequently, In
the neutral environment of human tissues, beryllium salts are readily
precipitated. Absorption of beryllium through unbroken skin adds only
insignificant quantities to the body, . even after prolonged or repeated
contact. However, a contact dermatitis can occur.
The major route by which beryllium enters the body Is by the lungs,
where absorption and distribution to other tissues may occur. Following an
Initial clearance of 2.5 days, the time required to remove 50% of the
deposited beryllium from the lungs Is 405 days.
Once the beryllium enters through the lungs, Us compounds may be trans-
ported from the lungs by the blood and lymph to other tissues. Insoluble
compounds, however, such as beryllium ores, tend to remain in the lung for
Indefinite periods of time. Increased beryllium levels have been detected
In human lungs as long as >20 years after the last exposure occurred.
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The route of administration Influences the route of excretion, at least
In rats. Fecal excretion Is the major route of excretion If administration
Is oral, since lUtle beryllium Is absorbed In the GI tract. Urinary excre-
tion Is the major route following parenteral administration of beryllium.
Small doses of Intravenously administered beryllium In rats were excreted
primarily through the urine or deposited In the kidneys. Following
Inhalation exposure, urinary and fecal excretion appear to be the major
routes of elimination.
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IV. EXPOSURE
(Text to be provided by the Office of Drinking Water)
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V. HEALTH EFFECTS IN ANIMALS
General Toxicity
Acute Toxicity.
Oral -- Beryllium compounds are less acutely toxic 1n animals when
oral exposures are compared with other modes of administration. Lower acute
oral toxicity has been attributed to the low rate of beryllium absorption
from the GI tract. U.S. EPA (1977) reported the oral LD^g of beryllium to
be 9.7 mg Be/kg (as BeCl^y. Oral LD^s 1n rats for beryllium fluoride,
beryllium chloride and beryllium sulfate were reported as 20, 200 and 120 mg
Be/kg, respectively (Reeves, 1986). Rats fed diets of <2% beryllium
carbonate survived for several weeks (Guyat.t et al., 1933).
Parenteral Exposure -- Intravenous Injections of small doses of
beryllium are highly toxic to animals. Wltschl and Aldrldge (1967) reported
an LDgg for soluble beryllium salts of 0.44 mg Be/kg for 200 g male rats,
while Vacher and Stoner (1968) found an LD^ of 0.51 mg Be/kg for female
rats Injected with BeSO^. Cheng (1956) showed that a single Intravenous
dose of 1.1 mg Be/kg^ bw as BeSO^ could produce Hver necrosis 1n rats.
The Intraperitoneal LD^ In mice was 18 mg/kg bw when administered as a
sulfate (Baslnger et al.» 1982). Injection of beryllium Into the spinal
subarachnoid space or cerebello-medullary cistern resulted In changes In the
CNS of rabbits (Zelman et al., 1967), and one study of rabbits noted
osteosclerotic changes by this route (Gardner and Hesllngton, 1946).
Inhalation Exposure — Inhalation represents the most common route of
exposure to beryllium and Its compounds. The most common effect of acute
Inhalation exposure 1s chemical pneumonitis. Susceptibility to the toxic
effects of Inhaled beryllium . varies between species. Stoklnger et al.
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(1950) exposed several species to BeSO^ for 6 hours/day, 5 days/week for
51 days at 2 mg Be/m3 and for 14 days at 4.3 mg Be/m3. Mortality rates
for exposure to 2 mg Be/m3 varied greatly: 13/15 rats, 4/5 dogs, 4/5
cats, 1/10 rabbits, 7/12 guinea pigs, 1/1 monkeys, 5/10 hamsters and 3/48
mice. Exposure to 4.3 mg Be/m3 was lethal to 10/10 rats and 3/10 guinea
pigs. Drury et al. (1978) noted that a variety of species exposed to
BeSO^ at 2 mg Be/m3 displayed two separate types of responses; 1) an
acute phase 1n which the most susceptible species die and 2) a delayed phase
1n which there Is little effect Initially, but Increasingly severe changes
occur at <7-10 weeks of exposure. Pulmonary lesions were similar to those
found In humans with acute beryllium disease.
Schepers (1964) exposed female monkeys to various beryllium compounds
(fluoride, sulfate, phosphate) and found BeF^ to be the most toxic while
BeHPO^ was least toxic. Monkeys (4/group) exposed to aerosols of either
beryllium sulfate (202 yg Be/m3), beryllium fluoride (185 yg Be/m3)
or beryllium phosphate (1141 or 8380 yg Be/m3) died of pneumonitis. The
highest concentrations of BeHPO^ studied (8380 yg Be/m3) killed all
the monkeys within 20 days and concentrations of 1141 yg Be/m3 killed
all the monkeys In 92 days. Reported effects Included severe pulmonary
reactions as well as changes 1n the liver, pancreas, spleen, adrenals,
kidneys and thyroid. Many of these effects cannot be attributed to the high
phosphate or fluoride concentrations of these compounds (Schepers, 1964).
The acute, cellular kinetic and histopathologic response of rat and
mouse lung to BeSO^ was Investigated by Sendelbach (1986) and Sendelbach
et al. (1986). Animals were exposed to 13 yg/l (13 mg/m3) BeSO^
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In a nose-only chamber for 1 hour and killed over a period of 21 days;
H^SO^ aerosol was used as a positive control. Cellular kinetics were
measured as the labeling Index (LI), defined as the percentage of cells
labeled with trltlated thymidine and differentiated as to type. A peak LI
response was seen in rats 8 days after exposure was terminated, while for
mice a maximum response occurred on day 5. In rats, a proliferative
response Involving type II alveolar epithelial cells. Interstitial and
capillary endothelial cells was observed. Hyperplasia and vacuolization of
the type II alveolar cell cytoplasm and a thickened Interstltlum with
Infiltrates of Interstitial macrophages and segmental leukocytes was noted
upon histopathologic examination. Alveolar macrophages with ragged
membranes were also observed. Three weeks after exposure, the Interstitial
response was largely resolved. In mice, the proliferative response was
mainly found in the alveolar macrophage population and the Interstitial and
endothelial cells. Histopathologic changes were similar to those found In
rats, although less severe.
"Intratracheal Instillation Is another route by which beryllium Is admin-
istered. When used In a study 1n rabbits, Spencer et al. (1968) showed that
at dose levels of 2 mg/kg bw, low-fired BeO (calcined at 500°C) caused
pulmonary damage while h1gh-f1 red BeO (calcined at 1600°C) produced a
reaction roughly equivalent to that expected of an Inert dust. These
findings may again be related to solubility; calcining at 500°C produces a
relatively soluble product with a large surface area, whereas beryllium
calcined at 1600°C produces an Insoluble compound.
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Subchronlc and Chronic Toxicity.
Oral Exposure -- There Is only limited evidence of toxic effects
following oral beryllium exposure. One of the earliest effects observed was
the development of rickets in young rats fed diets containing soluble
beryllium salts (Branlon et al., 1931; Guyatt et al., 1933; Kay and Skill,
1934). Guyatt et al. (1933) reported that 21- to 24-day-old rats fed diets
containing 0.125-3.0% beryllium carbonate developed rickets after 3 weeks.
The effects were dose dependent with the lowest dose {1.25 g BeCO^/kg diet
or 163 mg Be/kg diet) resulting In a mild case of rickets while at higher
doses there appeared to be an almost complete lack of calcification of the
long bones (femur and tibia). Buslnco (1940) conducted a series of experi-
ments 1n which young rats (30-40 g) were fed beryllium carbonate produced by
different manufacturers. In one study, rats received dally doses of 0.06 g
BeCO^/anlmal on days 0-14, 0.16 g BeCO^/anlmal on days 15-34 and 0.24 g
BeCO^/anlmal on days 35-83. A time-weighted average (TWA) dose of 0.19 g
BeCO^/rat (0.025 g Be) was estimated from the data provided by the author.
No effects on body weight or general appearance were observed in animals fed
0.06 g BeCOg. After 40 days of exposure, a 25% weight loss was observed
1n treated rats compared with controls. A reduction in weight gain of >50%
was seen In treated animals at the end of the study (day 83). In addition,
histologic and radiographic examination of the long bones (femur, tibia and
fibula) and vertebrae revealed typical rackltlc lesions.
Goel et al. (1980) gave 20 mg beryllium nitrate (1.35 mg Be) to eight
male albino rats in their diet every third day for 2.5 months. Histopatho-
logic examination of the lungs of treated animals revealed a number of
pathogenic changes In the bronchioles, alveoli and arterioles Including a
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general hardening of the lungs. Since the compound was administered as a
powder mixed with food pellets, lung effects may have resulted from
aspiration of beryllium.
Schroeder and Mltchener (1975a) administered 5 mg/i beryllium (as
BeS04) In the drinking water of Long-Evans rats (52/group/sex) for life.
Based on data provided In the study, this level corresponds to 0.530 mg
Be/kg/day. At the time of natural death, the rats were weighed and
dlssec ted; gross and microscopic pathologic changes were evaluated.
Specific organs examined Included the heart, lung, liver, kidney and spleen,
as well as any tumors. Blood and urine samples were also taken and clinical
chemistry and urine analysis were performed. No treatment-related effects
were observed In any parameter tested. There was a slight depression In
growth of male rats from 2-6 months of age. A similar study was also
conducted in Swiss (CD) mice, 54/sex, at doses of 0.98 mg Be/kg/day
(Schroeder and Mltchener, 1975b). A slight decrease in body weight at 2 and
8 months of age- was seen 1n females and a slight Increase in male body
weight was noted. No other treatment-related effects were found.
Morgareldge et al. (1977) fed beryllium sulfate at 0, 5, 50 or 500 ppm diet
to rats for 2 years. The only effect reported was a slight decrease In body
weight In the high-dose group.
The b 1 otox1 c 1 ty of beryllium by the oral route was studied In hamsters
(Watanabe et al., 1985). Powdered foods containing 5 mg Be as 8eS0^, BeO
or Be-metal were fed to hamsters dally for 3-12 months. Body and organ
weights and beryllium retention and distribution were monitored. The only
toxic effects reported were a slight reduction In body weight In the BeS04
group when compared with controls, BeO or Be-metal fed groups.
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Inhalation Exposure — There are a number of chronic Inhalation
studies of beryllium In animals that report effects similar to humans.
Several Investigators have studied the effects of beryllium exposure In
monkeys (Vorwald et al.( 1966; Schepers, 1964), dogs (Robinson et a 1.,
1968b; Conradl et al., 1971), guinea pigs (Reeves et al., 1971, 1972) and
hamsters (Wagner et al., 1969). The most common effect seen In all species
was chronic beryllium disease and pneumonitis.
Robinson et al. (1966a) reported that beagles exposed to rocket fuel
exhaust containing beryllium fluoride, chloride and oxide at an average
concentration of 115 mg .Be/m3 developed lung tissue lesions representing
early stages of chronic beryllium disease. Sanders and Cannon (1975)
exposed rats and hamsters to BeO (calcined at 1000°C) at concentrations of
1-100 yg Be/l (1-100 mg/m3) of a1rt and reported rapid damage to
alveolar macrophages that developed Into a mild granulomatous reaction
within 8 months of the exposure.
In a review of their earlier work, Vorwald et al. (1966) reported that
In rats exposed to beryllium sulfate aerosol at concentrations of 2.0-194
wg/m3, 7 hours/day for 1-560 days, there was a dose-related Increase In
lung toxicity. While exposures of 2.8 yg/m3 did not result In any
significant changes, exposure to 21 yg/ma caused significant Inflamma-
tory changes. At 42 yg/m3 chronic pneumonitis was produced and exposure
to 194 yg/m* resulted 1n acute beryllium disease.
Reeves et al. (1967) exposed Sprague-Oawley (CD strain) rats (150/sex/
group) to 0 or 34 yg Be/m3 (as BeSO^) for 7 hours/day, 5 days/week for
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72 weeks. Three rats/sex were killed every 3 months and histopathology of
the lung tissue was performed. The most common findings were Increased lung
weight, Inflammation and proliferation of lung tissue and Increased
macrophage Infiltration of alveolar spaces.
Monkeys exposed Intermittently to average dally concentrations of 35
yg/m3 beryllium sulfate for several months developed typical chronic
beryllium disease with pneumonitis and granulomatosis (Vorwald et al.,
1966). Monkeys exposed to beryllium salts (sulfate, fluoride or phosphate)
at levels of 200 yg Be/m3 (6 hours/day up to 30 days) developed signs of
toxicity typical of human chronic beryllium disease within 1-2 weeks
following exposure to the sulfate or fluoride compounds and 30 days for the
phosphate (Schepers, 1964). Exposure to 3.3 or 4.4 mg Be/m3 for 30
minutes at 3-month Intervals resulted in no pathologic changes In monkeys or
dogs (Conradl et al., 1971).
One systemic effect shown In animals exposed by Inhalation to beryllium
Is a mild, macrocytlc-11ke anemia. Dogs, rats and rabbits exposed to
beryllium fluoride at 2.2*0.25 mg/m3 for 6 hours/day, 5 days/week for 23
weeks all developed anemia, but the exact parameters were somewhat different
for each, species. In the dog, a decrease In hemoglobin level, red blood
cell count and mean corpuscular volume that conformed to a normochromic
macrocytic anemia was observed. Rabbits had less of a tendency toward
lowered hemoglobin levels and tended to return to normal values. The rat
maintained normal hemoglobin levels but the other two parameters resembled
those seen In macrocytic anemia (Stok 1nger and Stroud, 1951).
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Dermal Exposure — Although Inhalation of beryllium has been consid-
ered the classic route of exposure producing beryllium lung disease, MoMtz
et al. (1982) suggested that Intradermal exposure should also be considered.
Guinea pigs were Injected with BeF^ Intradermally 2 times/week for 6 weeks
at 10 yg/treatment. Since earlier studies 1n animals had shown dermal
exposure to produce mononuclear cell alveolitis consisting of sensitized
lymphocytes and activated alveolar macrophagest mononuclear eel Is were
analyzed from the lung, spleen and blood. While there was no beryllium
detected from the blood or spleen of the exposed animals, significantly
large amounts of beryllium were detected In the mononuclear cells of the
lung. This finding suggested that Intradermal exposure may result 1n
selective accumulation of beryllium In the lung.
Target Organ Toxicity
While several organs may be affected by beryllium exposure, the signifi-
cant target organ 1s the lung. Insoluble forms of. beryllium remain 1n the
lungs for Indefinite periods of time (Wagner et al., 1969), and Increased
levels have been detected In humans >20 years after the last exposure
(Sprlnce et al., 1976). Beryllium may also accumulate In the lung following
Intradermal exposure (Morltz et al., 1982). The noncarclnogenlc effects of
beryllium In the lung (acute and chronic disease) have been discussed 1n
previous sections and the carcinogenic effects (lung cancer) are described
1n following sections.
A large portion of the beryllium entering the body by any route Is
deposited In the skeleton, which Is a second major target organ. Ionic and
cltrated beryllium are bone seekers (Crowley et al., 1949; Klemperer et al.,
04200
08/14/91
-------
1952), and Intratracheally administered BeO was also reported to be
deposited 1n greatest concentrations In the bone (Spencer et al.f 1972).
The latter study also showed that lesser concentrations were deposited In
the liver, spleen, kidney and muscle. The effects on the bone Include
beryllium rickets (Branlon et al.p 1931; Guyatt et al., 1933; Kay and Skill,
1934) and osteosarcoma (Dutra et al., 1951; Gardner and Hesllngton, 1946).
Liver necrosis was reported to occur following a single Intravenous dose
of BeSO^ In rats (Cheng, 1956) on Injection of beryllium Into the
subarachnoid space or cerebello-medullary cistern has caused CNS changes In
rabbits (Zelman et al., 1967). Beryllium also exerts an effect on the blood
system, as demonstrated by the development of a macrocytlc-Uke anemia 1n
dogs, rats and rabbits exposed to Inhaled BeF^ (Stoklnger and Stroud,
1951).
Carcinogenicity
Beryllium compounds can Induce malignant tumors In laboratory animals
either by Injection or Inhalation (Vorwald et al., 1966). The two types of
cancers observed to date are lung cancer and osteosarcoma. Gardner and
Hesllngton (1946) reported Induction of osteosarcoma following Injections of
zinc beryllium oxide into rabbits. Since then, numerous other studies of
beryllium compounds have produced similar results. Most of the studies
utilized Intravenous exposure and demonstrated that many different beryllium
compounds. Including beryllium metal, are tumorlgenlc by this route. Tapp
(1969) surgically Implanted 10 mg of zinc beryllium silicate, beryllium
silicate, or beryllium oxide Into rabbits and reported the development of
osteogenic sarcomas within a period of 10-25 months for all three. The
Initial finding was a granulomatous reaction, which was more severe with the
04200 V-9 09/24/91
-------
silicate than the oxide. Subsequent tumors were shown to have metastasized
to the lung. The only study reporting the development of osteosarcoma
following Inhalation exposure was that of Dutra et a.l. (1951) 1n which 1/6
rabbits exposed to 6 mg Be/m3 as BeO for 25 hours/week for 11 months
developed malignancies. A summary of the studies resulting In osteosarcoma
Is presented In Table V-l. Studies of oral exposures conducted 1n the
1930s, described earlier, produced a type of osteosclerosis but not
osteosarcoma. However, these experiments were conducted In a shorter time
frame than that expected to allow for the development of tumors.
A study using two dogs fed 1.3 g beryllium carbonate for 104 days or
0.5-1.5 g beryllium carbonate for 109 days revealed no tumors upon examina-
tion of the teeth and parathyroid glands (Casarotto, 1952). Likewise, no
tumors were found In mice given 1% beryllium sulfate In drinking water over
a period of 1 year (Barnes et al-., 1950). Schroeder and Mltchener (1975a,b)
reported a slight but nonsignificant Increase in leukemlas 1n female mice
and a slightly higher but nonsignificant Incidence of grossly observed
tumors In male rats fed beryllium sulfate at a concentration of 5 ppm In
drinking water over a lifetime.
)
In an unpublished 2-year study, Horgareldge et al. (1975) administered
dietary levels of 0, 5, 50 and 500 ppm Be as beryllium sulfate to Wlstar
albino rats (50/sex/group). Reticulum cell sarcoma In the lung was seen In
all dose groups and In controls, and the same lesions were seen 1n lymph
nodes, bone marrow and abdominal organs. The Incidence of lung reticulum
cell sarcoma was higher In males than females and was statistically signifi-
cant In males at the lowest two doses but not the highest dose. This study
04200
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1ABLF VI
Induction of Osteosarcomas In Experimental Animals by Beryllium8
Compound
Dose
Exposure Route
Exposure
DuratIon
Species
Percent
Exhibiting
Tumors'*
lime of
Heasurement
(months)
Reference
Beryllium
oxide
6 mg/m*
NR
90-660 mg as
Be. 13-116
mg/kg bw as Be
100-200 mg
total
1250 mg total
large animals:
1 g total
small animals:
<1 g
100 mg total
4S0 mg total
300 mg total
300 mg total
10 mg
220-400 mg
InhalatIon
multiple t.v.
17-21 l.v.
1-45 l.v.
l.v.
l.v.
Injection Into
femur
Injection Into
femur
one Injection
Into femur
Injection, femur
periosteum
Implanted under
right tibia
periosteum
Injected Into
femur
S hours/day,
5 days/week,
11 months
25 weekly
Inject Ions
10 weekly
Inject Ions
45 weekly
Inject Ions
twice weekly
for 1-43 weeks
rabbit
rabbit
rabbi I
rabbit
rabbit
rabbit
rabbit
rabbit
rabbit
rabbit
rabbit
male and
female
rabbit
16
25
89
0
72
6
60
88
70
78
33
89
11
NR
9»
NR
NR
15
19
11
12
14.5
10-25
Outra et al.,
1951
Nash, 1950
Dutra and
Largent, 1950
Kawada. 1963
fodor, 1971
Komltowskl. 1969
Kawada. 1963
Kawada. 1963
Kawada, 1963
Kawada. 1963
Tapp, 1969
85 days-average Yamaguchl and
latency from Katsura, 1963
last Injection
-------
TABLE V-l (cont.)
Coapound
Dose
Exposure Route
Exposure
DuratIon
Species
Percent
Exhibiting
Tuaors'*
Tlae of
Neasureaent
(aonths)
Reference
Berylllua
oxide
(cont.)
420-600 ag
Injected Into
feaur
twice weekly
for 1-43 weeks
rabbit
100
85 days-average
latency froa
last Injection
Vaaaguchl and
Katiura. 1963
620-800 ag
Injected Into
feaur
twice weekly
for 1-43 weeks
rabbit
SO
86 days-average
latency froa
last Injection
Vaaaguchl and
Katsura, 1963
820-860 ag
Injected Into
feaur
twice weekly
for 1-43 weeks
rabbit
75
86 days-average
latency froa
last Injection
Vaaaguchl and
Katsura. 1963
Zinc
beryllium
oxldec
1 g total
l.v.
20 Injections
over 6 weeks
rabbit
100
7»
Gardner and
Hesllngton, 1946
1 g
aultlple l.v.
Injections
rabbit
26
30*
Barnes et al..
1950; Slssons,
1950
I 9
l.v.
22 seal-weekly
Injections
rabbit
80
12»
Cloudaan et al.,
1949
Zlnc
berylllua
silicate
0.264 ag
aultlple l.v.
Inject Ions
alee
Soae positive,
percent not
reported
NR
Cloudaan et al.,
1949
1 g total
l.v.
10 weekly
Injections
rabbit
60
11-24
Hoagland et al.,
1950
1 g total
l.v.
20 twice-weekly
Injections
rabbit
SO
9-11
Janes et al.,
1954
NR
l.v.
10 weekly
Inject Ions
rabbit
71
9-14
Kelly el al..
1961
1 g total
Injection
20 weekly
Injections
rabbit
30
NR
Hlgglns et al..
1964
10 ag
laplanted under
right tibia
perlosleun
rabbit
16
10-25
Tapp, 1969
-------
TABLE V-l (cont.)
Compound
Dose
Exposure Route
E xposure
DuratIon
Species
Percent
Exhibit Ing
Tumors'*
Tlae of
Measurement
(months)
Reference
Zinc
beryllium
silicate (cont
33 ag as Be
-)
Injection Intra-
osseous
rabbit
70
4
Mazabraud. 1975
Beryl 1lum
silicate
10 ag
Inplanted under
right tibia
perlosleua
rabbit
16
10-25
Tapp. 1969
Metallic
beryl 1 luii
40 ag
l.v.
-
rabbit
40
NR
Barnes et al..
1950
Berylllua
phosphate
16 ag total
l.v.
10 weekly
Injections
rabbit
Soae positive,
percent unknown
11-24
Hoagland et al.,
1950
Berylllua
phosphor*'
90 ag
l.v.
rabbit
1/1
12-14
Outra and
Largent. 1950
BO ag
I.v.
rabbit
1/1
12-14
Outra and
Largent, 1950
64 ag
l.v.
rabbit
0/1
12-14
Outra and
Largent. 1950
aSource: U.S. EPA, 1980a
''Percent exhibiting tuaors or cancer
C1 g of zinc berylllu« silicate contains 33.6 ag of Be expressed as the oxide
''Be oxide, Zn oxide and silica In a aolar ratio of 1:1:1
NR = Not reported
-------
Is considered to be suggestive of a carcinogenic response to Ingested beryl-
lium, but the . lack of a response at the highest dose level severely limits
Interpretation as a positive, study.
Numerous studies have demonstrated the development of pulmonary cancer
In animals exposed to beryllium. The majority of these studies used an
inhalation or Intratracheal route of exposure; a summary of these data are
presented In Table V-2. A more detailed discussion of these studies can be
found In U.S. EPA (1987). Development of lung cancer generally required
7-18 months In rats and 5-6 years 1n monkeys (Vorwald et al., 1966).
Pulmonary tumors were produced 1n 18/19 rats that survived exposure to 15 mg
beryl ore/m3 over 17 months (Wagner et al., 1969). Reeves et al. ( 1967)
exposed 150 rats to 34 wg Be/m3 In an aerosol for 35 hours/week for a
72-week period. The Initial response appeared 4 weeks after the first
exposure and consisted of hyperplasia of the pulmonary epithelium, which
progressed to metaplasia and lung cancer. The first tumors were discovered
after 9 months of exposure, and the Incidence rate was 100% at 13 months.
The tumor type was alveolar adenocarcinoma.
Studies by Groth et al. (1976) found that the size, number and charac-
teristics of lesions produced by single intratracheal Injections of beryl,
BeO, BefOH)^, beryl 1lum metal, Be-aluminum alloy and chromlum-passlvated
beryllium were determined by the age of the rat and the dose of the
compound. Metaplastic foci were found" In greater numbers 1n the older rats
at the higher doses;^no fod were found In the low-dose group. Groth et al.
(1972) showed- that the lowest dose producing Interstitial fibrosis, mast
cell and lymphocytic Infiltrates and protelnaceous material In the alveoli
04200
V -14
08/14/91
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1AHU V ?
Induction of Pulmonary Cancer In I xperlmental Animals by Beryllium Compounds*
Compound
Dose
Exposure Route
Exposure
Duration
Specles
Percent
fihlbltIng
lumors
1 line of
Measurement
(months)
Reference
Beryl Hum
sulfate
0.11 mg
as Be
Intratracheal
NA
rat
Some positive,
percent not
reported
9 or longer
Vorwald and
Reeves. 1959
6 »9/ma
as Be
InhalatIon
6 hours/day,
5 days/week
until sacrifice
rat
Some positive,
percent not >
reported
9 or longer
Vorwald and
Reeves. 1959
SS pg/m*
as Be
Inhalat ton
6 hours/day.
S days/week
until sacrifice
rat
Some positive,
percent not
reported
9 or longer
Vorwald and
Reeves, 1959
35 hQ/ib1
as Be
InhalatIon
6 months
rat
Some positive
percent not
reporled
18
Schepers.
1961
?.8 pg/m*
as He
Inhalation
7 hours/day.
5 days/week.
16 months
rat
62
16
Vorwald
et al., 1966
?1 iig/m1
as Be
Inhalation
7 hours/day,
5 days/week.
18 months
rat
almost 100
18
Vorwald
et al.. 1966
4? pg/m'
as Be
InhalatIon
7 hours/day,
5 days/week.
18 months
rat
almost 100
18
Vorwald
et al., 1966
34 Mg/a»
as Be
InhalatIon
7 hours/day,
5 days/week,
until sacrifice
rat, male
and female
100
13
Reeves
et al.. 1967
35 iig/m1
as Be
InhalatIon
7 hours/day,
5 days/week,
IB iitonlhs
monkey,
rhesus
?0. 2 of 10
exposed 3241
3871 hours
5-6 years
Vorwald
et al.. 1966
?.3? mg/m*
0.?0 mg/ma
as Be
Inhalation
6 hours/day.
7 days
monkey.
Macacos
mullata
0, only 1 of 4
survived 160
days
Schepers,
1964
-------
1AHII V-2 (conl.)
Compound
Beryl 1 tun
ox Ide
Dose
4.5 ay
ds Be
25 mg
cak Ined
a I SOO*C
tiposure Route
intratracheal
Intratracheal
fxposure
DuratIon
NA
NA
$pect«s
ral
rat. sale
and female
Percent
Inhibiting
lumors
Some positive,
percent unknown
100
line of
Heasurciwnl
(months)
9 or longer
15-20
Reference
Vorwald and
Reeves, 1959
Spencer
et al.. 19bB
25 mg/kg
calcIned
at 1100*C
Intratracheal
rat. male
and female
25
15 17
Spencer
et al., I960
25 iag
calcIned
at 1600°C
Intratracheal
rat. male
and female
30
16 24
Spent er
el al.. 1966
50 mg/kg
calcIned
a I 500*C
Intratracheal
NA
rat. female
11
Spencer
el al.. 1972
50 mg/kg
calcIned
at 500*C
Intratracheal
NA
ral. female
40
Spencer
et al.. 1972
50 mg/kg
calcined
at 500*C
Intratracheal
NA
rat. female
100
23
Spencer
et al., 1972
Beryllium
fluorIde
Beryllium
fluoride and
chlorIde
250-500 mg
40 Mg/ma
950 Mg/m*
180 |ig/m'
as Be
0.2 or 0.4
fug/m*
Intratracheal
Inhalation
Inhalation
InhalatIon
NA
6 months
6 hours/day.
7-16 days
1 hour/day.
5 days/week.
4 months
monkey.
rhesus
rat
monkey.
Hacacus
mullata
rat
15
JO-12 In 200
0. all died
within 2B days
of exposure
Some posItIve,
percent unknown
54*
15
<1
22
Vorwald
el al.. 1966
Scheper s.
1961
Schepers.
1964
I llvlnov
el al.. 1975
-------
TABIE V ? (cont.)
Compound
Dose
Exposure Route
Exposure
Our atIon
Specles
Beryl 1lum
phosphate
3.S ag/a*
2.3? ag/a*
0.?0 ag/a*
as Be
Inhalation
InhalalIon
b Months
b hours/day,
30 days
rat
Monkey,
Hacacus
nullata
13.1 ag/a*
1.1) ag/a*
as Be
InhalatIon
b hours/day,
10 days
aonkey,
Hacacus
aullala
Zinc
beryl I turn
s 11 W ale
24 ag/n*
InhalatIon
b aonths
rat
Beryl ore
IS ag/m*
?10 nq/m*
as Be
InhalalIon
b hours/day.
S days/week
until sacrifice
rat
IS ag/a*
210 Mg/m»
as Be
InhalalIon
b hours/day,
5 days/week
until sacrifice
hanster
IS ag/m*
210 iig/m'
as Be
InhalalIon
b hours/day,
S days/week
until sacrifice
squirrel
aonkey.
Salalrl
sclurea
Berlrandlte
ore
IS ag/a*
b?0 „g/«*
as Be
InhalatIon
b hours/day,
S days/week
until sacrifice
squirrel
aonkey,
SalalrI
sclurea
Berlrandlte
ore
IS ag/a*
b?0 iig/a1
as Be
InhalatIon
b hours/day,
S days/week
until sacrifice
rat
IS ag/n*
b?0 wg/a1
as Be
InhalalIon
b hours/day,
S days/week
until sacrifice
hamster
Percent
E xhlbltIng
Tumors
1lae of
Measurement Reference
(months)
Some positive,
percent unknown
1?
Schepers,
1961
up to 9 post
exposure
Schepers,
1964
1 of 4 (25X)
exposed survived
B2 days post
exposure and
developed cancer
up to B? days
Schepers,
1964
Some positive,
percent unknown
Schepers.
1961
9S
17
Uagner
el al.. 1969
17
Uagner
el al., 19b9
23
Uagner
el al.. 19b9
23
Uagner
et al., 19b9
17
Uagner
et al.. 19b9
0
17
Uagner
el al., 1969
-------
TABU V 2 (cunt.)
Compound
Dose
Exposure Route
E xposure
Duration
Species
Percent
ExhlblI Imj
lunors
1 Ime of
Measurement
(months)
Reference
Beryl 1lun
hydro*Ide
0.4 Be
Intratracheal
NA
rat. 3
months old
0
b
Groth
et al.. 197b
0.4 m9 Be
Intratracheal
NA
rat, 12
Months old
0
6
Groth
et al.. 197b
4 |ig Be
Intratracheal
NA
rat, 6
ninths old
0
6
Groth
el al.. 1972
4 m
-------
was 4 yg. Metaplasia was produced at the 4 m9 dose and was considered
by the authors to represent a probable precancer condition (Groth and
HacKay, 1971).
Developmental Toxicity
Limited Information Is available concerning the teratogenic potential of
beryllium and Us salts. Raven and Spronk (1953) reported that beryllium
exposure resulted In morphogenlc abnormalities In the embryo of the snail
(Lvmnea staqnalis). Limb regeneration of the salamander (Amblvstoma
punctatum) was Inhibited when Immersed In a 0.05 molar solution of beryllium
nitrate (Thornton, 1950).
Pertinent data regarding the developmental toxicity of beryllium after
Inhalation, oral . or dermal exposure 1n animals were not located In the
aval lab!e 11terature. Sellvanova and Savlnova (1986) treated pregnant rats
Intnatracheally with beryllium chloride or beryllium oxide at 0 or 50 mg/kg
on day 3, 5, 8f 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.
Hoshlshlma et al. (1978) presented a brief abstract and later a more
extensive report (TsuJ11 and Hoshlshlma, 1979) on the effects of trace
04200
V-19
08/14/91
-------
quantities of beryllium Injected Into pregnant CFW strain mice. Six females
per group were exposed to BeSO^ (140 ng/mouse/day). The mice received
Intraperitoneal Injections (0.1 ma) 11 times during pregnancy. The
Injections were given once for 3 consecutive days and then every other day
for eight treatments. The offspring (24/group) were tested for changes 1n
reflexes and behavioral characteristics from days 1-16 of birth. Beryllium
(140 ng/day) produced the following differences 1n the pups exposed 1n utero
as compared with the control group: delayed response In head turning In the
geotaxls test, acceleration 1n the straight walking test, delayed bar
holding (for a moment) response, and acceleration of bar holding (for 60
seconds).
In a study by Bencko et al. (1979) the soluble salt of beryllium,
BeC^, was evaluated for Its ability to penetrate the placenta and reach
the fetus. Radiolabeled 'BeCl^ (0.1 mg/kg) was Injected Into the caudal
vein of 7-9 ICR SPF mice and was administered In three different time
periods: 1) before copulation (group A), 2) the 7th day of gestation
(group B), and 3) the 14th day of gestation (group C). The animals were
sacrificed on the 18th to 19th day of pregnancy and the radioactivity
associated with the fetal and maternal compartment were evaluated.
In fetuses exposed on the 14th day of gestation, higher levels of radio-
activity were associated with the fetal compartment as compared with other
exposure periods, (group A, 0.0002 \iq 7Be/g fetus, group B, 0.0002 yg
7Be/g fetus, and group C, 0.0013 yg 7Be/g fetus). The amount of
radioactivity 1n selected organs of the mothers was generally not influenced
by beryllium exposure, except the spleen and liver. The amount of 7Be
04200
V-20
08/14/91
-------
penetrating the spleen was decreased, while 1n the liver It was Increased
when 7BeCl was given on the Hth day of pregnancy.
Puzanova et al. (1978) conducted a two-phase study on the effects of
beryllium on the development of chick embryos. In the first phase, BeCl^
(0.00003-300 yg dissolved In 3 yl tw1ce-d1stnled water) was Injected
subgermlnally Into chick embryos (10 embryos per dose) on the second day of
embryogenesls. After a 24-hour Incubation, the eggs were opened and stained
with 0.1% neutral red, and the distance between the origin of the vitelline
arteries and the caudal tip of the body measured. In the second phase, the
doses of BeCl^ that were toxic but not lethal (0.03-0.3 yg) were
administered subgermlnally to 2-day embryos, and 1ntra-amn1ot1cally to
3- and 4-day -embryos. The surviving embryos were examined after the sixth
day of Incubation.
A dose of 300 yg BeC1^ caused complete embryolethallty while 0.3
yg was not lethal to any embryos. Doses of <0.003 yg had no observable
effect on the development of the embryos.. When the eggs were treated on day
2, the most common malformation was caudal regression, open abdominal cavity
and ectopia cordis. When administered on the fourth day, malformations
described as strait jacket syndrome, exencephalla and mandibular
malformation were described. It Is not known, however, 1f these types of
teratogenic effects In chick embryos are reflective of effects that might
occur 1n humans. Additional studies would have to be conducted using
mammals to determine whether beryllium has teratogenic potential.
04200
08/14/91
-------
Reproductive Toxicity
Pertinent data regarding the reproductive toxicity of beryllium after
Inhalation, oral or dermal exposure In animals were not located In the
available literature.
Clary et al. (1975) treated male and female Sprague-Dawley rats Intra-
tracheal^ with 7BeO (0.2 mg Be/rat) calcined at 960°C or 500°C 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/Utter, dead
pups/litter, live pups/female, lactation Index or average fetal weight.
Mutagenicity
Beryllium has been tested for Its ability to cause genetic damage 1n
both prokaryotlc and eukaryotlc systems. The prokaryotlc systems Include
gene mutations and DNA damage 1n bacteria. The eukaryotlc systems Include
DNA damage and gene mutations In yeast and cultured mammalian cells and
studies for chromosomal aberrations and sister chromatid exchanges In
mammalian cells In vitro. The available literature Indicates that beryllium
does not Induce mutations in bacteria and yeast but does cause gene
mutations, chromosomal aberrations, and sister chromatid exchange 1n
mammalian somatic cells In culture (Tables V-3, V-4 and V-5).
Gene Mutations 1n Bacteria.
Simmon (1979a) found beryllium sulfate to be negative In mutagenic
response In Salmonella typhlmurlum strains TA1535, TA1536, TA1537, TA98 and
TA100. Liquid Incubation assay with and without S-9 metabolic activation as
04200
V-22
09/24/91
-------
TABU V-3
o
o Mutagenicity Testing of Beryllium: Gene Nutations In Bacteria*
Test System Strain Concentration of S-9 Activation Results Comments Reference
Test Compounds System
Salmonella
typhlmurlum
TA1535
TA1536
TA1537
TA100
TA98
2S0 tig/plate
BeS04
Reported
negative
In all
strains
Highest
concentratIon
tested
Simmon, 1979a
I
ro
CO
s.
typhlmur turn
E. coll
Tpol assay)
o
®»
TA1530 mice treated with
TA1535 BeS04, 25 mg/kg
TA1538 bw l.m. or 1200
mg/kg bw gavage
S. TA1535
typhlmurlum TA1538
Escherichia HP2
coll
Pol Af
Pol A"
25 pg/plate
250 yg/plate
BeS04
0.1-10 iimol/plate
(10.5-105 vq Be/
plate)
250 pg/plate
BeS04
Host-mediated
assay
Reported
negatIve
In all
strains by
both routes
of exposure
Reported
negatIve
Reported
negative
Reported
negatIve
Mice served
as host for
4 hours
Simmon
et al.. 1979
Rosenkranz
and Polrler,
1979
Ishlzawa,
1979
Rosenkranz
and Polrler,
1979
O
-j *Source:
N
CD
CD
U.S. EPA. 1907
-------
rj
o
o
TABLE V 4
Mutagenicity Testing of Beryllium: Gene Mutations In Yeast and Mammalian Cells Ui vitro*
Test System
Strain Concentration of
Test Compounds
S-9 Activation
System
Results
Comments
Reference
Chinese
hamster
Chinese
^ hamster
Saccharomyces
cerevlslae .
V79 cells;
resistance
to 8-
azaguanlne
CHO cells;
res(stance
to 8-
azaguanlne
°3
2 mN (10 wg/mi)
3 mM (IS |ig/mi)
berylllum chlorlde
Not stated
mice treated with
BeSOf, 25 mg/kg
bw l.m., or 1200
mg/kg bw gavage
None
Host-mediated
assay
Reported 99% pure,
positive no dose
response
Reported
positive,
weakly
mutagenic
Reported
negative
No details
Mice served
as host for
4 hours
Mlyakl
et al.. 1979
Hsle et al
1979a,b
Simmon
et al.. 1979
•Source: U.S. EPA, 1987
CJ
CD
CD
-------
TABLE V-5
Mutagenicity Testing of Beryllium: Mammalian 1n vitro Cytogenetics Tests*
S-9
Test System Species Concentration Activation Results
BeSO^HjO System
Chromosomal
aberrations
Human
lymphocytes
2.82 x 10's M
(5 jig/mi)
Reported
positive
Chromosomal
aberrations
Syrian
hamster
embryo
eel Is
2.82 x 10'5 M
(5 vg/m*)
Reported
positive
Sister
chromatid
exchanges
Human
lymphocytes
5.6 x 10"* M
(1 vg/ml)
1.41 x 10"5 M
(2.5 vg/ml)
2.82 x 10"' M
(5 vg/mi)
Reported
positive
Sister
chromatid
exchanges
Syrian
hamster
embryo
cells
5.6 x 10'* M
(1 vg/mi)
1.41 x 10"' M
(2.5 vg/mi)
2.82 x 10~5 M
(5 vg/ml)
- . Reported
positive
~Source: Larramendy et al.f 1981
04200
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described by Ames was employed. The highest concentration of beryllium
sulfate tested was 250 yg/plate (1.41 ymole).
No significant differences In the mutation frequencies between the
experimental and the control plates were noted In S. typhlmurlum strains
TA1535 and TA1538 with and without S-9 activation system (Rosenkranz and
Polrler, 1979). The concentrations of the BeStL used were 25 and 250
4
vg/plate.
Beryllium sulfate (BeSO^) was assayed in the Ames S. typhlmuHum
mutagenesis assay using the usual five tester strains with and without
metabolic activation (Tong et al.# 1985). BeSO^ was not mutagenic in this
assay.
The mutagenic activity of beryllium sulfate was tested In the Intraperi-
toneal host-mediated assay, with the tester strains of S. typhlmuHum
TA1530, TA1535 and TA1538 (Simmon et al., 1979). Mice were Injected
Intramuscularly with 25 mg BeSO^/kg bw or were administered 1200 mg
BeSO^/kg bw orally. Four hours after the treatment, microorganisms were
recovered from the peritoneal cavity and plated for mutant colonies.
Mutation frequencies significantly different from control frequencies were
not observed.
A negative mutagenic response in the Escherichia coll WP2 system was
obtained with beryllium sulfate at concentrations ranging from 0.1-10
umole/plate (Ishlzawa, 1979).
04200
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These results should not be taken as proof that beryllium Is
nonmutagenlc because as discussed by McCann et al. (1976), bacterial and
yeast systems are generally Insensitive for the detection of metal mutagens,
and because of the large amounts of magnesium salts, citrate and phosphate
1n the minimal medium, which prevents the entry of metal mutagens Into
bacterial cells.
Gene Mutations 1n Yeast and Cultured Harmallan Cells. Beryllium has
been tested for mutagenic activity 1n yeast assay systems. Simmon (1979b)
tested BeSO^ (0.5%) In the tester strain of Saccharomyces cerevlslae
with and without S-9 activation. BeSO^ did not Increase mitotic
recombination. The mutagenic activity of BeSO^ was also tested Vn the
Intraperitoneal host-mediated assay with strain of S. cerevlslae
(Simmon et al., 1979). Mice were Injected Intramuscularly with 25 mg
BeSO^/kg bw or were administered 1 200 mg BeSO^/kg bw orally. Four hours
after the treatment, microorganisms were recovered from the peritoneal
cavity and plated for mutant colonies. Mutation frequencies significantly
different from control frequencies were not observed.
The Induction of 8-azaguanlne-reslstant mutants by beryllium chloride
was demonstrated In the Chinese hamster V79 cells {M1yak 1 et al., 1979).
Beryllium chloride at concentrations of 0, 2 and 3. mM Induced mutations
(35.01+1.4 and 36,5+1.7 mutant colonies per 10® survivors) at -6 times the
control. The cell survival rates were 56.9% at 2 mM concentration and 39.4%
at 3 mM. Analysis of mutant colonies revealed that they were deficient 1n
the enzyme hypoxanthlne guanine phosphoMbosyl transferase (HGPRT)
Indicating that the mutation had occurred at the HGPRT locus.
04200
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Tong et al. (1985) tested BeSO^ In the adult rat liver epithelial cell
hypoxanthlne guanine phosphorIbosyl transferase (ARL/HGPRT) mutagenesis
assay. BeSO^ did not Induce a significant Increase In mutant Incidence.
Hsle et al. (1979a,b) also reported that beryllium sulfate Induced
8-azaguan1ne-res1stant mutants In the Chinese hamster ovary (CHO) cells.
However, the authors did not provide details about the concentrations of the
test compound and the number of mutants Induced per 10® survivors.
These studies Indicate that beryllium has the ability to cause gene
mutations In cultured mammalian cells.
Cytogenetic Effects. Beryllium causes chromosomal abnormalities and
mitotic changes In cell cultures (Vegnl-Tallurl and Gu1gg1an1t 1967). It
also Induces molecular aggregation and flocculatlon, suggesting an
Irreversible nucleic add effect (Needham, 1974). Beryllium sulfate
(2.82xl0~5 M; 5 yg BeSO^/ml) was tested for Its clastogenlc
potential In cultured human lymphocytes and Syrian hamster embryo cells
(Larramendy et al., 1981). A minimum of 200 metaphases were scored for
chromosomal aberrations. In the treated human lymphocytes, there were
19/200 cells (9.5%) with chromosomal aberrations or 0.10*0.02 aberrations
per metaphase. In the control cells, only three cells (1.5%) had
chromosomal aberrations. This 6-fold Increase 1n the aberration frequency
was primarily due to an Increase in DNA breaks.
A concentration of 2.82x10~5 H beryllium sulfate Induced aberrations
In 38/200 Syrian hamster embryo cells (19%) 24 hours after the treatment.
04200
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Aberrations per metaphase were 0.21+0.03 and 0.01+0.01 aberrations per cell
In treated and control cells, respectively. In these studies, chromosomal
gaps were also considered as aberrations; however, this does not
significantly enhance the aberration frequency. These results Indicate that
beryllium sulfate has clastogenlc potential In cultured mammalian cells
(Larramendy et al., 1981).
Larramendy et al. (1981) also studied the potential of beryllium to
Induce sister chromatid exchanges. Both cultured human lymphocytes and
Syrian hamster embryo cells were employed In these studies. Exposure of
lymphocytes to 5-6x10~® M (1.0 vg/mt), 1.41*10"® H (2.5 pg/ml)
and 2.82xl0~s M (5 yg/mfc) of beryllium sulfate resulted In
dose-dependent Increases in sister chromatid exchanges of 17.75+1.10,
18.15+1.79 and 20.70+1.01, respectively. At least 30 metaphases were scored
for each concentration of the test compound. The background sister
chromatid exchange level was 11.30+0.60.
In the Syrian hamster embryo cells the same concentrations of beryllium
sulfate induced sister chromatid exchanges of 16.75+1.52, 18.40+1.49 and
20.50+0.98, respectively. The background sister chromatid level was
11.55+0.84. Although the authors state that a dose-response relationship
was shown, 1t should be noted that Increases were <2-fold.
Other Tests of Senotoxlc Potential. Kanematsu et al. (1980) found
beryllium sulfate (0.01 M) to be weakly positive In the Rec assay.
Inhibitions of growth were measured In both Bacillus subtIlls strains H17
free*) and H75 (rec"). The difference In growth between wild-type and
04200
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sensitive strain was 4 mm, which was considered to Indicate a weak positive
.response. Similar results were also obtained by Kada et al. (1980).
However, Rosenkranz and Polrler (1979) and Rosenkranz and Lelfer (1980)
reported beryllium sulfate (250 yg) did not result In differential killing
In the E. coll Pol A assay.
Willi am et al. (1982) reported that beryllium sulfate at concentrations
<10 mg/ml did not Induce unscheduled DNA Synthesis In primary rat
hepatocytes.
Kublnsky et al. (1981) reported that beryllium Induces DNA-prote1n
complexes (adducts) when E. coll cells and Ehrllch ascitis cells were
treated with radioactive DNA In the presence of 30 mM of beryllium.
Skilleter et al. (1983), using cytofluorometrlc analysis In cultured
synchronized rat liver-derived epithelial cells, demonstrated that beryllium
blocked the cell cycle at the G^-S phase and caused Inhibition of cell
division. The remaining parts of the cell cycle, namely the final portion
of S, Gp and H, showed no significant variation In DNA content.
Beryllium sulfate did not Induce mitotic recombination In the yeast
Saccharomyces cerevlslae D3 (Simmon, 1979b). A single concentration
(0.5%) of beryllium Induced 10 mutant colonies/103 survivors; 1n the
control the frequency was 6 colonles/105 survivors, a 3-fold Increase.
The negative response of beryllium may be due to the fact that It 1s not
able to penetrate Into the cell as In other microbial tests.
04200
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Other Effects In Cell Cultures. Newman and Campbell (1986) cultured
B6D2Fmouse spleen cells, bone marrow cells, thymus cells, nylon non-
adherent spleen T-cell, and nude mouse spleen cells 1n the presence of
varying concentrations of BeSO^. Hltogenesls was measured as the Increase
In 1 odourac11deoxyriboside (l"IUdR) Incorporation Into lymphocyte DNA.
BeSO^ was weakly mltogenlc For mouse B6D2F.J spleen cells. However a
more marked response occurred with bone marrow cells and nude mouse spleen
cells suggesting an effect on B-cells. Thymocytes and B-cell depleted nylon
nonadherent T-cells showed no response to beryllium.
The toxicity of beryllium was evaluated using a mammalian cell culture
system (Hochlda and Gomyoda, 1986). Since the ID^ (a 5Q% Inhibitory dose
to growth of cells after 72 hours of Incubation) values for HEL-R66, KB,
Vero and MOCK cells to beryllium were 0.8x10"*, lxlO"3, 0.9xl0-a and
1.2x10"3 mM, respectively, there was no remarkable difference 1n the
sensitivity for these cells to beryllium.
Summary
Beryllium Is toxic by several routes of exposure. Oral exposure
represents the least toxic route, presumably because of poor absorption.
Beryllium rickets and slight growth depression have been reported In male
rats following chronic oral exposures. The available cancer bloassay data
base for oral exposure Is limited to two studies, both of which have major
deficiencies. From these studies, no substantial evidence exists that the
Ingestion of beryllium In any form causes tumors. For these reasons, the
oral carcinogenic potential of beryllium can be neither demonstrated nor
refuted. However, evidence of Inhalation, Injection and l.v. exposures with
04200
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notable carcinogenic responses raises suspicion that beryllium may be a
carcinogenic risk by oral exposure. The tumorlgenlc potential of beryllium
by Ingestion exposure may be modulated by minimal Intestinal absorption
(<1%). Inhalation exposure results 1n both acute and chronic lung disease,
anemia and cancers of the lung and bone. Pulmonary lesions observed In
various species resembled those of humans with acute beryllium disease, and
the toxic effect varied both with the species exposed and the beryllium
compound used. One study has reported changes In the liver, pancreas,
kidneys, thyroid, adrenals and spleen. A mild, macrocytlc-Uke anemia has
also been produced by Inhalation exposure 1n rats, rabbits and dogs, with
specific reactions varying between species. One study provided suggestive
evidence of the Induction of osteosarcomas by Inhalation, and numerous
studies confirm the development of pulmonary cancer 1n animals exposed to
Inhaled beryllium. Pulmonary lesions are also produced by Intratracheal
administration.
Administration by Injection of even small amounts of beryllium 1s
extremely toxic to animals, with toxic effects produced 1n the liver and
lung. One study has also reported CNS changes, while others have noted
osteosarcoma.
Dermal absorption was recently reported as a route deserving more
attention because of a possible selective accumulation of beryllium In the
lung when administered Intradermal^.
Very few studies have Investigated the teratogenic or reproductive
effects produced by beryllium exposure. An evaluation of reflexes and
04200
V-32
08/14/91
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behavioral responses of offspring exposed to beryllium sulfate during
pregnancy showed delayed responses In the glotaxls test and bar holding
response. Soluble beryllium salts have been shown to penetrate the placenta
and accumulate In the fetal compartment. However, results of a recent
Russian study In pregnant rats Indicate that beryllium compounds may have
the potential to produce adverse teratogenic effects. A study designed to
Investigate the reproductive toxicity In rats showed no consistent effect on
reproductive performance. The current reproductive and teratogenic data are
not sufficient to determine whether beryllium or Its compounds have the
potential to produce adverse effects.
Beryllium has been tested for Us ability to cause genetic damage In
both prokaryotlc and eukaryotlc systems. The prokaryotlc systems include
gene mutations and DNA damage 1n bacteria. The eukaryotlc systems Include
DNA damage and gene mutations in yeast and cultured mammalian cells and
studies for chromosomal aberrations and sister chromatid exchanges In
mammalian cells In vitro. The available literature Indicates that beryllium
has the potential to cause gene mutations, chromosomal aberrations, and
sister chromatid exchange In mammalian somatic cells. In addition beryllium
salts are mltogenlc for mouse B-cells jn^ vitro and not for T-cells.
04200
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VI. HEALTH EFFECTS IN HUMANS
Introduction
Exposure to beryllium causes a variety of toxic effects 1n both animals
and humans. In humans, dose-response relationships are much less certain
than In animals. For example, one study reported that a concentration of 30
mg/m3 BeO 1n the air produced no acute effects from short-term exposure,
while another study showed a high Incidence of both acute disease and
fatalities associated with an exposure of 4 mg/m3 (NAS/NRC, 1958). This
apparent discrepancy, however, may be explained by differences In the method
of beryllium production, duration of exposure, solubility, particle size,
susceptibility or the resulting product chemistry. When beryllium Is
calcined at 500°C (the low-fired beryllium), the product 1s a relatively
soluble substance with Increased surface area; however, calcining at 1600'C
(high-fired beryllium) results In a highly Insoluble form (Spencer et al.,
1968).
In humans, acute disease has been reported following Inhalation exposure
of soluble beryllium salts at concentrations of <100 yg/m3 for an
unspecified time period (Hall et al., 1959). Ambient air concentrations of
<25 vg/m3 appear not to cause acute beryllium disease In humans (NAS/
NRC, 1958). The acute disease seems related to the Intensity of exposure,
with symptoms disappearing following termination of exposure (Hardy, 1955).
General Toxicity
Acute. Acute beryllium disease was defined by Tepper et al. (1961) as
beryllium-Induced disease patterns that persist for <1 year. These disease
processes Include an acute Inflammatory reaction at the site of deposition
04210
VI-1
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following Inhalation of beryllium compounds either as a mist, vapor or dust
(Vorwald, 1966). The amount of exposure, the degree of toxicity, concentra-
tion of the compound and host susceptibility may all play a role In -the
severity of symptoms (Van Ordstrand et al-., 1945). Respiratory disorders
ranging from upper respiratory tract Irritation and Inflammation to damage
of the lung parenchyma occur following Inhalation of beryllium (Tepper,
1972a).
The respiratory response to Inhalation of beryllium compounds Includes
Inflammation of the nasal mucosa, pharynx and tracheobronchial tree and
acute pneumonitis (Tepper et al., 1961). The Involvement of the upper
respiratory tract Is a direct result of contact secondary to Inhalation of
beryllium partlrles. The resultant rhinitis and pharyngitis are frequently
associated with nosebleeds, and ulceration may occur In the mucous membranes
because of blood and fluid accumulation. Diagnosis may be difficult because
of similarity between beryllium-related symptoms and those associated with
the common cold.^ Depending on the extent of exposure, beryllium-Induced
acute tracheobronchitis may be rapid or Insidious 1n Its onset. Symptoms
Include a nonproductive spasmodic cough, chest tightness and burning, as
well as moderate dyspnea with exertion. Inflammation of the tracheobron-
chial tree will usually resolve within 1-4 weeks {DeNard1 et al., 1953).
Acute pneumonitis 1s associated with the Inhalation of almost all beryl-
lium compounds, Including the metal, oxide, sulfate, hydroxide, chloride and
fluoride (Durocher, 1969). The observed effects have followed pulmonary
deposition of beryllium In the form of a mist of the soluble salt or as a
fume of the Insoluble compounds. The reaction with the relatively soluble,
04210
09/24/91
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low-fired beryllium oxide has been a widely dispersed focal pneumonitis of a
granulomatous nature as noted by Tepper (1972b). These Investigators found
that BeO particles were surrounded by a dense central core of proliferating
histiocytes and often Invaded by epithelioid cells and one or two layers of
fibroblasts. Some lymphocytes, plasma cells, and an occasional multinucle-
ated giant cell were noted. The area of Involvement eventually became less
cellular, more collagenous and then hyallnlzed. Recovery times from this
acute pneumonitis varied from 1-6 weeks In mild cases and <6 months In more
severe forms. Tepper et al. (1961) noted 18 deaths Involving the develop-
ment of pulmonary edema and subsequent progression to acute beryllium
pneumonitis.
Symptoms resulting from dermal exposure to beryllium have been reported
by numerous authors (U.S. EPA, 1980a). The characteristic symptoms of acute
toxicity are dermatitis, skin ulceration or conjunctivitis (Vorwald, 1966;
Hlgglns, 1968). The solubility of the beryllium compound 1s a factor In
dermatitis, since the lesions have only been reported following contact with
soluble beryllium salts (HcCord, 1951). An allergic dermatitis Is occa-
sionally observed and 1s expressed as itching with reddened, elevated or
fluid-accumulated lesions In exposed areas of the face, neck and sometimes
the arms and hands. The chest and back may also be Involved 1f In contact
with contaminated hands or clothing (Tepper et al., 1961).
A beryllium ulcer occasionally occurs following deposition of crystal-
line beryllium compounds 1n skin abrasions or cuts {U.S. EPA, 1980a). The
dermatoses begins as a localized, indurated, raised, reddened lesion that
progresses to an ulcer (Vorwald, 1966). The lesion persists until removal
04210
VI -3
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of the crystal and curettage of the ulcer base (Tepper et al., 1961). Heal-
Ing usually occurs within 2 weeks. The Incidence rate of skin ulceration In
a beryllium refining plant has been reported at 5.7% (Nlshlmura, 1966).
Eye Involvement may also occur and has been manifested as a conjuncti-
vitis secondary to splash burns or contact dermatitis. The symptoms can
range from Inflammatory congestion and hyperemia to cellular Infiltration.
This ocular damage cannot be differentiated from that caused by other chemi-
cal Irritants (Vorwald, 1966). The Incidence of conjunctivitis has been
reported at 20.3%t usually among workers exposed to high concentrations of
BeO (Nlshlmura, 1966).
Chronic. Chronic beryllium disease 1s the result of Inhalation of
beryllium compounds over a considerable period of time. According to Tepper
et al. (1961), the chronic disease differs from the acute form by^a latent
period of up to 20 years or more, a long duration, a progressive severity
despite the termination of exposure and systemic manifestation of the
disease. The acute disease may progress to the chronic form with an asymp-
tomatic period between the resolution of the acute form and the emergence of
the chronic disease (Hardy and Chamber 1 In, 1972). The dose of beryllium
that will result In chronic disease 1s not known. In 1949 before air stan-
dards were set to control beryllium exposure, both acute and chronic forms
of toxicity were common; however, consistent monitoring was not performed
before 1949, so 1t Is difficult to relate the disease to specific conditions
of exposure. It 1s known that the concentrations were high; a 1946 survey
by Laskln et al. (1946) reported concentrations of beryllium dust of 0.1-0.5
mg/m3 during beryllium furnace coke removal operations, and Zlellnskl
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(1961), studying a beryllium alloy plant, reported concentrations of
11.3-43.3 mg/m3. No cases related to ambient air dispersion or contact
with dust brought home on work clothes have been reported since the 1949 air
standard was established and exposure control procedures were put Into
effect.
One recent study also Identified another possible high-risk group for
the respiratory effects of beryllium. Rom et al. (1984) reported an epide-
miologic study of 178 dental laboratory technicians that Included a chest
radiograph and pulmonary function test. They concluded that dental labora-
tory technicians are at risk for beryllium-related lung disorders and simple
pneumoconiosis from grinding nonpreclous metal alloys. This study 1s of
very limited value In assessing risks since the Individuals studied were
exposed simultaneously to a variety of potentially toxic metals, such as
nickel and chromium, 1n the manufacture of dental fillings and prostheses.
The symptoms associated with chronic disease Include granulomatous
Inflammation of the lungs with accompanying cough, chest pain and general
weakness (Hardy and Stoeckle, 1959). R1ght-s1ded cardlomegaly secondary to
congestive heart failure, as well as liver and spleen enlargement, cyanosis,
digital clubbing and kidney stones are other potential effects. The symp-
toms of weight loss, fatigue and anorexia usually Imply a poor prognosis
with a high case fatality rate and some degree of permanent disability In
survivors (Greenburg, 1972).
Lymphocyte transformation (IT) was studied as an endpolnt related to
beryllium exposure. Lymphocytes have been shown to undergo blast transfor-
mation J_n vitro when exposed to beryllium salts (Epstein et al., 1982). Rom
04210 VI-5 09/24/91
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et al. (1983) conducted a 3-year study Investigating the relationship
between beryllium exposure and pulmonary changes( Including biastogenlc
transformation of lymphocytes obtained by bronchoalveolar lavage. The
subjects exposed to beryllium were male employees of a surface mine and
process mill 1n Utah. Mean exposures were estimated to be 7.18, 0.25, 0.40
and 0.99 yg Be/m3 (an 8-hour TWA) for the years 1979, 1980, 1981 and
1982, respectively. Positive LTs were reported for 15.9% (13/82 exposed
workers) In 1979 and 8.2* (5/61 exposed workers) In 1982. Eleven of the
positive LTs In 1979 were retested In 1982 and eight of these were found to
be negative. This reduction correlates with the significant reduction 1n
exposure during these years. A positive LT was not associated with reduced
pulmonary function. Also, chest radiographs of the exposed workers revealed
no changes associated with beryllium disease. The authors conclude that
lymphocyte transformation 1s related to beryllium exposure and that It 1s
reversible upon reduction of exposure levels.
Lung Inflammation, which characterizes chronic beryllium disease, Is a
diffuse Interstitial lesion that lacks the edematous and exudative changes
of acute disease. Scattered densities seen on X-rays are mostly large
Irregularly shaped monocytes caused by extension of thickened alveolar walls
(Vorwald, 1966). Granulomatous lesions are also noted within other organ
systems, such as the skin, lymph nodes, kidney, liver and skeletal muscles
(Dudley, 1959).
Rossman et al. (1986) have demonstrated in vitro proliferation of lung
cells in response to the presence of beryllium salts. The proliferation
test may be used to Identify workers with chronic hypersensitivity to
beryllium.
04210 VI-6 09/24/91
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Cullen et al. (1987) undertook a clInlcal-epldemlologlc Investigation of
employees 1n a precious metal refinery. Five workers developed granulo-
matous lung disease between 1972 and 1985. The original diagnosis was
sarcoidosis, but four of the workers were subsequently proven to have a
hypersensitivity to beryllium when tested for j_n vitro proliferative
responses of lymphocytes obtained by bronchoalveolar lavage. A review of
medical records of coworkers and extensive Industrial hygiene surveillance
of the plant demonstrated that four cases resulted from exposure 1n the
furnace area where air concentrations of beryllium fume were consistently
below the permissible exposure limit of 2 yg/m3. A single case was
attributed to exposure 1n parts of the refinery where levels of cold
beryllium dust often exceeded the standard by as much as 20-fold. These
data demonstrate that chronic beryllium disease still occurs and confirm the
Importance of specific Immunologic testing In patients suspected of having
sarcoidosis but with potential exposure to beryllium. The data raise
concern about the adequacy of modern Industrial controls, especially In the
setting of exposure to highly resplrable beryllium fume.
Other Effects
Carcinogenicity. The carcinogenic potential of beryllium and Its
compounds In man, unlike that shown 1n animals, has not been clearly
demonstrated or refuted. Epidemiologic cohort studies have focused on
beryllium exposure in occupational settings. Since the effects of beryllium
exposure were not recognized until about 1950, the data base was not
established until 1951, and therefore, little monitoring data are available
before that time. Consequently, attempts to relate beryllium exposure to
the development of respiratory cancer did not begin until much later (U.S.
EPA, 1980a).
04210 VI-7 09/24/91
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Nlemoller (1963) reported two cases of delayed lung carcinoma thought to
be caused by occupational exposure to beryllium, along with one case from a
smoker. The two Industrial cases were both detected 16 years after the
exposure, and the Investigator's conclusions were based on knowledge of past
exposure, tumor location and presence of beryllium In the tissue.
Gold (1967) described a woman who had a history of traumatic vaginal
lesions after repeated douching with water containing 0.035 pg/fi. of
soluble beryllium, and who had developed a peritoneal mesothelioma of the
recto-vaginal septum. Tissue analysis showed beryllium to be present at a
level of 0.04 yg/g and also revealed asbestos, to which the patient was
also exposed environmentally. The author concluded that the etlologlc
factor was beryllium, although as In Nlemoller (1963), some conjecture Is
apparent (U.S. EPA, 1980a).
Hardy et al. (1967) studied a group of 535 members of the Beryllium Case
Registry, and found 14 cases of cancer, Including three with lung cancer and
three with bone sarcoma. However, the same author reported In 1976 that the
bone sarcomas were not listed correctly and confirmed only one case.
The first In a series of government-sponsored studies of cancer 1n
workers exposed to beryllium was accomplished by Bay11ss et al. (1971).
This cohort mortality study consisted originally of some 10,365 former and
current employees of the beryllium-processing Industry (two companies in
Ohio and Pennsylvania). Selection criteria ultimately reduced the cohort to
6818 males. Only a slightly elevated risk of lung cancer was evident
overall (36 observed deaths vs. 34.06 expected). No significant risk of
04210
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lung cancer was found to exist 1n relation to length of employment,
beginning date of employment, or kind of employment (office vs. production),
nor were significant risks of other forms of cancer evident from these data.
This study had several deficiencies, Including the fact that over 2000
Individuals had to be eliminated from the original cohort because data
regarding birth date, race and sex could not be obtained. The authors
' Indicated that this reduction In the size of the study necessitated the
elimination of some 251 deaths, and represented a loss of >20% of the cohort
and 25% of the known deaths, a factor that has the potential for Introduc-
ing considerable bias Into the1 results. A second major problem with the
study Is that'it did not analyze the data according to length of time since
Initial employment In the Industry. The lack of such an analysis meant that
questions dealing with latency could not be addressed In the study. A third
deficiency .Is that the populations of several different plants were* combined
Into one cohort for the study. As a result, the study failed to consider
the many potential differences of exposure levels In different plants.
Individuals were studied In groups according to their beginning dates and
durations of employment, despite the fact that their exposure histories may
have been totally dissimilar. For these reasons, this study {Bay 11ss et
al., 1971) was deemed not adequate for the evaluation of cancer mortality In
beryllium-exposed workers.
In an attempt to remedy the deficiencies of their earlier study. Bay11ss
and Lalnhart (1972) narrowed the scope of the study to only one beryllium-
processing company, which had seemingly complete employment records for two
locations In Pennsylvania. This change effectively reduced the size of the
cohort to 3795 white males, while retaining the same starting date and
04210 VI-9 09/24/91
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cut-off date as was used in the earlier study. Bay11ss and Lalnhart (1972)
found that 601 members of the cohort had died, as compared with 599.9
expected deaths based on period- and age-specific U.S. white male death
rates. Again, no significant excess of unusual mortality from any cause was
evident. For lung cancer overall, 25 deaths were observed vs. 23.69
expected. Even when latency was considered, no significant excess risk of
lung cancer was apparent after a lapse of 15 years from Initial exposure, at
which time 14 deaths were observed vs. 13.28 expected. In addition, no
significant risks were apparent In relation to Intensity and duration of
exposure or beginning date of employment. The Bay11ss and Lalnhart (1972)
study was criticized by Bay11ss and Wagoner ( 1977 ) 1n a third version of the
study. Among the criticisms were the following: 1) the study Included
clerical and administrative workers who presumably had not been exposed to
beryllium; 2) the data were obtained from Industrial representatives, which
precluded an Independent assessment of plant employment files to ensure that
all potentially exposed workers were Included; and 3) the study did not
assess latency >20 years after Initial employment, although 1t did examine
mortality after a 15-year lapse.
The Bay11ss and Wagoner (1977) cohort mortality study consisted of
workers employed at only one of the original company's plants. The cohort
studied was composed of 3070 white males, who were followed until January 1,
1976. Vital status was unknown for only 80 members of the cohort (3%), and
these Individuals were considered to be alive until the end of the study's
cut-off period. Altogether, 884 deaths were observed, as compared with
829.41 expected deaths based on period- and age-specific U.S.- white male
death rates. A significant excess of lung cancer was noted, with 46 cases
04210
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observed vs. 33.33 expected (p<0.05). A significant excess of heart disease
was also noted (399 observed vs. 335.15 expected, p<0.05), as was a
significant excess of nonmallgnant respiratory disease (32 observed vs.
19.02 expected, p<0.01). Irrespective of duration of employment, a
significant excess was noted 1n bronchogenic cancer following a lapse of >25
years since Initial employment.
In the Bayllss and Wagoner (1977) study, the authors discussed for the
first time the Impact of cigarette smoking as a possible confounding agent
contributing to the excess risk of lung cancer. A study by the U.S. Public
Health Service (PHS) In I960 revealed some difference In the cigarette
smoking patterns of the surveyed employees, as compared with smoking
patterns 1n the United States as a whole. An Increase 1n the percentage of
heavier smokers was Indicated 1n the 1968 survey, as compared with national
data (21.4 vs. 15.3%). Cigarette smoking however, was dismissed by the
authors as the cause of the Increased risk of bronchogenic cancer and other
diseases In the cohort under study; this may have been unwarranted for
several reasons. First, the smoking patterns of the 379 employees surveyed
In 1968 were probably not the same as those of the entire cohort of 3795,
which Included employees from as early as 1942. Second, the first national
reports of smoking as a cause of lung cancer were produced 1n 1964 and were
accompanied by a great deal of media attention. By 1968, Intense media
coverage dealing with the health consequences of smoking probably produced a
diminution of cigarette smoking among various subgroups,of the population 1n
the 4-year Interim period between surveys. Furthermore, while the 1968
survey done at the plant did speak of current cigarette smoking patterns,
the Issue of prior cigarette smoking was not addressed, nor was the Issue of
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pipe smoking and cigar smoking. Additional criticisms of the Bayllss and
Wagoner (1977) study, as well as subsequent Iterations of the same study,
Including the final version (Wagoner et al.t 1980), are discussed In the
following review.
Wagoner et al. (1980) slightly reduced the cohort of Bay 11ss and Wagoner
(1977) to a study of 3055 white males employed at some time between January
1 , 1942 and December 31 , 1967 , In the same beryllium-processing facility.
The results showed - a significantly high Incidence of lung cancer (47
observed vs. 34.29 expected, p<0.05) for those Individuals followed until
December 31, 1975. This excess extended to members of the cohort followed
for more than 24 years since Initial employment (20 observed vs. 10.79
expected, p<0.01). When the analysis was confined to those whose Initial
employment occurred before 1950, but who were followed for 15 years or more
from date of Initial employment, a significantly high risk of lung cancer
was apparent (34 observed vs. 22.46 expected, p<0.05). Deaths from lung
cancer for those whose Initial employment occurred after 1950 was 4 observed
vs. 2.4 .expected. The authors concluded that this excessive risk of lung
cancer "could not be related to an effect of age, chance, self-selection,
study group selection, exposure to other agents In the study facility, or
place of residence."
This study has received severe criticism from several sources; an
Internal Center for Disease Control (CDC) Review Committee was appointed to
Investigate defects In the study, plus several professional epidemiologists
(HacHahon, 1977, 1978; Roth, 1983), Including one of the study's co-authors
(Bayllss, 1980). An extensive review of these reports Including a detailed
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discussion of the association between lung cancer and cigarette smoking can
be found in U.S. EPA (1987) and therefore will only be summarized In this
document.
The cohort studied in Wagoner et al. (1980) was composed of workers at
the facility who had been employed before December 31, 1967. The cohort
excluded employees who were not directly engaged In the extraction, process-
ing or fabrication of beryllium, or 1n on-site administrative, maintenance
or support activities. The numbers of expected deaths used 1n the study
were based on U.S. white male death rates that had been generated by an
analytic life table program designed by the National Institute for Occupa-
tional Safety and Health (NIOSH). Unfortunately, at the time of this study
and subsequent studies on beryllium, cause of death Information was not
available on a year-to-year basis after 1967. In order to estimate expected
deaths during the period from 1968 through 1975, death rates were assumed by
the authors to be unchanged from those generated by the NIOSH life table
program for the period from 1965 through 1967. The result was that for
causes of death with declining death rates, expected deaths were overesti-
mated, with a resultant underestimate of risk. Similarly, for those causes
with Increasing death rates during the Interval studied, expected deaths
were underestimated, with a resultant upward risk bias, as was the case with
respect to all of the lung cancer risk calculations made by the authors.
After this problem had been corrected by the Inclusion of actual lung cancer
mortality data for the period 1n question, expected lung cancer deaths were
recomputed before the publication of the Wagoner et al. (1980) study by
Bay11ss (1980). The result was an Increase from 34.29 to 38.2 expected lung
cancer deaths, or an excess of 1IX. This correction In Itself was enough to
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eliminate the statistical significance calculated by Wagoner et al. (1980)
1n their overall lung cancer tabulation. With respect to latency, the risk
of lung cancer was reduced to one of only borderline significance In the
cohort subgroup that was observed for 25 years or more after Initial employ-
ment. These corrections have been confirmed as correct by Richard Monson
(HacHahon, 1977, 1978).
An extensive discussion of the Influence of cigarette smoking on the
Increase In cancer reported by Wagoner et al. (1980) 1s presented In U.S.
EPA (1987). Contrary to the findings by Wagoner et al. (1980) that smoking
Influence was negleglble, U.S. EPA (1987) estimated a 4.1% Increase in
expected lung cancer cases.
The authors (Wagoner et al.t 1980) have stated that the expected deaths
were overestimated by 19% because of the use of death rates for white males
In the United States as a whole, rather than those for Berks County.
Pennsylvania, where the plant was located. This statement was based on a
comparison In Mason and McKay (1973) of the 1950-1969 age-adjusted lung
cancer death rate for white males In Berks County, Pennsylvania, United
States. Bayllss (1980) has criticized this statement by the fact that the
periods of observation were different, I.e., that the Mason data covered the
period from 1950 through 1969, while that of Wagoner et al. (1980) covered
the period from 1942 through 1975. Roth (1983) criticized the use of Berks
County rates as not being reflective of greatly elevated lung cancer death
rates for the City of Reading, which they maintained were 12% higher than
the national rates. U.S. EPA (1987) concluded that death rates calculated
for Berks County should be weighted toward the higher City of Reading rates,
which Increases the number of estimated expected deaths.
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Wagoner et al. (1980) have also noted an unusual histopathologic distri-
bution of cell types In the cases of 27 of the 47 lung cancer deaths for
which pathologic specimens could be obtained. Adenocarcinomas were noted In
8/25 Individuals histologically confirmed to have died from bronchogenic
carcinoma (Smith and Suzuki, 1980). Smith and Suzuki (1980) concluded,
however, that "the prevalence of histopathologic cell types of bronchogenic
carcinomas among beryllium-exposed workers could not be presently defined."
Wagoner et al. (1980), however, citing data from earlier studies (Haenszel
et al., 1962; Axtell et al., 1976) to the effect that the frequency of
adenocarcinomas in U.S. white males was 15 or 16%, concluded that a signifi-
cant "shift" of histologic cell types was apparent In lung cancer deaths In
beryllium workers. Smith (1978) discussed more recent data by Vincent et
al. (1977) that Indicated a shift In the prevalences of histopathologic cell
types of lung cancer 1n the general population over time has led to an
Increase 1n the prevalence of adenocarcinoma to 24%, and therefore the
prevalence of adenocarcinomas In the lung cancer deaths of beryllium workers
Is not significantly different from that expected.
To summarize, 1t appears that the authors of the Wagoner et al. (1980)
study tended to exaggerate the risk of lung cancer 1n a population of
workers potentially exposed to beryllium, and underemphaslzed or did not
discuss sufficiently the shortcomings of the study. The net effect was to
turn a "suggested association" of lung cancer with beryllium exposure Into a
questionable "significant association." However, despite the study's
problems, there still remains a possibility that the elevated risk of lung
cancer reported therein was due In part to beryllium exposure, and although
the Human Health Assessment Group (HHAG) of the U.S. EPA considers the study
04210 VI-15 09/24/91
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Inadequate to assess the risk of lung cancer from exposure to beryllium,
further refinement and follow-up of this cohort was recommended to determine
If the reported Increase would become statistically significant.
In a companion paper by Infante et al. (1980), lung cancer mortality was
studied In white males for whom data had been entered into the Beryllium
Case Registry (BCR) with diagnoses of beryllium disease. A person was
adjudged to have beryllium disease If three or more (two were mandatory) of
the following five criteria were met (Hasan and Kazeml, 1974):
Mandatory -- 1. Establishment of significant beryllium exposure
based on sound epidemiologic history.
2. Objective evidence of lower respiratory tract
disease and a clinical course consistent with
beryllium disease.
Mandatory -- 3. Chest X-ray films with radiologic evidence of
Interstitial flbronodular disease.
4. Evidence of restrictive or obstructive defect with
diminished carbon monoxide diffusing capacity by
physiologic studies of lung function.
5. a. Pathologic changes consistent with beryllium
disease on examination of lung tissue.
b. Presence of beryllium In lung tissue or
thoracic lymph nodes.
Close to 900 Individuals had been entered Into the BCR as of August 1983,
based on evidence of nonmallgnant respiratory disease objectively determined
by appropriate and established medical procedures.
Infante et al- (1980) eliminated from their cohort all nonwhlte and
female subjects because of their lack of "statistical sensitivity," and also
eliminated all subjects who were deceased at the time of the BCR entry.
04210 VI-16 09/24/91
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Altogether, Infante et al. (1980) Included 1n their study cohort only
421 members of the BCR, <50% of the total. Of these, vital status could not
be determined on 64 (15%), while 139 (33%) were found to have died by
December 31, 1975. In this latter group, the causes of death could not be
ascertained for 15 Individuals.
Since the same NIQSH life table program that was used to calculate lung
cancer deaths In the Wagoner et al. (1980) study was the method used to
derive expected lung cancer deaths In the Infante et al. (1980) study, 1t
was subject to the same problems mentioned previously, I.e., a -11% error In
the calculated expected lung cancer deaths.
As expected, Infante et al. (1980) found a significantly high excess
risk of "nonneoplastic" respiratory disease (52 observed deaths vs. 3.17
expected). In terms of total cancer, 19 deaths were observed vs. 12.41
expected. With respect to lung cancer, 6 deaths occurred >15 years after
the onset of beryllium exposure vs. 2.81 expected (p<0.05). If the expected
deaths are adjusted upwards by 11% to compensate for the underestimate
produced by the NIOSH life table program, the authors' p value 1s reduced to
one of borderline significance (6 observed vs. 3.12 expected deaths; p<0.05).
Infante et al. (1980) divided their cohort on the basis of "acute" vs.
"chronic" beryllium disease. However, the authors definition of acute vs.
chronic differed from that commonly accepted for describing acute and
chronic beryllium dlease. Subjects were considered acute If the BCR records
Indicated a diagnosis of chemical bronchitis or pneumonitis or other acute
respiratory Illness at time of entry Into the registry. Subjects were
04210
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called chronic If BCR records Indicated a diagnosis of pulmonary fibrosis or
some recognized chronic lung condition at time of entry into the registry.
The authors found no excess: of lung cancer 1n their chronic respiratory
disease group of 198 persons (1 observed death vs. 1.38 expected). However,
In their acute respiratory disease group, they found 6 observed lung cancer
deaths vs. 1.91 expected (p<0.05), and 1n the Interval of >15 years since
Initial onset of beryllium exposure, 5 observed lung cancer deaths were
found vs. 1.56 expected (p<0.05). These findings must be regarded as
questionable with respect to their Implications because of the previously
discussed weaknesses.
The possibility cannot be discounted that cigarette smoking may have
also contributed to an excess risk In the Infante et al. (1980) study,
despite the authors1 claim that 1t Is unlikely to have played a role.
Although the criteria for Inclusion In the BCR have been evolving and
undergoing revision to Improve their sensitivity and specificity since the
Registry's Inception In 1952, It Is possible that In the early years of the
Registry, the criteria could have allowed the Inclusion of Individuals with
respiratory disease either brought on or exacerbated by cigarette smoking.
Of the 7 lung cancer cases discussed by Infante et al. (1980), 6 were
admitted to the hospitals for treatment before 1955, and one was admitted In
1964. The ability to detect subtle radiographic changes consistent with a
diagnosis of beryllium disease was relatively undeveloped In the early
1950s. Given current practices In the Interpretation of X-rays and
pulmonary function data, such a misdiagnosis would be unlikely today.
Any one of the factors referred to above could have been of sufficient
magnitude to produce a significant excess lung cancer risk In the group
04210 VI-18 09/24/91
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under study. The findings of Infante et al. (1980) are thus seen to be, at
best, only suggestive of an Increased risk of lung cancer from exposure to
beryllium.
The first In a series of four epidemiologic studies of mortality In
workers exposed to beryllium was conducted by Hancuso and El-Attar (1969) on
the same study population as was used In the Bay11ss and Wagoner ( 1977) and
Wagoner et al. (1980) studies. The cohort 1n the Hancuso and El-Attar
(1969) study, however, was derived from quarterly earnings reports provided
by the Social Security Administration. With respect to beryllium, Hancuso
and El-Attar (1969) obtained reports for both companies studied by Bayllss
and Wagoner (1977) and Wagoner et al. (1980), but limited their study to the
period of employment from 1937-1948. Altogether, they Identified 3685 white
males from two beryllium plants. Only 729 white males were found to have
died through the year 1966. Included 1n this group were 31 lung cancers.
The authors contrasted Internally generated age-, plant- and period-specific
death rates by cause with Internally generated age-specific death rates by
cause from an unidentified "Industrial control." Unfortunately, because of
the small numbers Involved, the authors did not Include any employees of age
55 or over. The 729 deaths were distributed Into 160 narrow subcategories,
based on four broad age groups, two companies, four periods of time, and
five broad death categories. Internal death rates were computed In each
subcategory. Because the numbers from which these Internal rates were
derived are so small (1n some Instances nonexistent) from one subcategory to
another, the comparisons with 20 rates generated from the Industrial control
are shaky at best and appear to vary considerably. No trends are evident;
no significance tests were done; thus, the data are open to Interpretation.
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The authors themselves conclude, based on their analysis, that their data
are "severely limitedn with respect to answering the question of carcino-
genic risk.
In the second study of the same cohort, Hancuso (1970) added duration of
employment as a variable and divided his cohort Into a 1937-1944 component
and a 1945-1948 component, by dates of Initial employment. A higher rate of
lung cancer was noted by the author among workers whose first employment
occurred during the period 1937-1944 in age category 25-64, and who were
employed for 5 or fewer quarters (99.9 per 100,000) compared with those
employed 6 quarters or Tonger (33.2 per 100,000) based on 16 and 4 lung
cancers, respectively. In one company, a higher rate of lung cancer was
found among workers with histories of chemical respiratory Illness versus
those who did not have this condition. During the period 1940-1940, 142
white males with respiratory Illness were Identified In this plant. Of a
total of 35 deaths occurring In this group, 6 were due to lung cancer.
Based on these six lung cancers, an age-adjusted lung cancer death rate of
284.3 per 100,000 was calculated, compared with an age-adjusted rate of 77.7
per 100,000 (based upon nine lung cancer deaths) In the total cohort of this
company's workers employed from 1937-1948. These calculations were confined
to Individuals who were In the age group 25-64 In the year 1940. No signif-
icance tests were done, and the observations were based upon small numbers,
as was pointed out by the author.
Although Hancuso (1970) found elevated risks. 1n these groups, the
results are subject to considerable variability. Kancuso criticized his own
study for several alleged deficiencies. The deficiencies, according to
Hancuso, consisted of the following:
04210 VI-20 09/24/91
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"The marked Influence of labor turnover on duration of employment,
perhaps Induced by the presence of respiratory disease; the Inabil-
ity to define the specific populations by department, process, or
by type or form of beryllium exposure; the presence of competing
causes of death; and the shortness of the period of observation.11
Other potential problems with these data, which were not mentioned by the
author, are a lack of consideration of the effects of smoking and the
effects of exposure to potential carcinogens In other Jobs the workers may
j
have had before and after their exposure to beryllium, since the suggested
Increase appeared only In "short-term employees." This Is discussed further
In a later description of the study (Mancuso, 1979). The author's conclu-
sion that prior chemical respiratory Illness Influenced the subsequent
development of lung cancer among beryllium workers may be somewhat over-
stated, In view of the many limitations of the study.
In the third update of this study, Mancuso (1979) divided his cohort
Into two subgroups, each consisting of former and current employees of the
two beryllium-manufacturing companies. Employees were Included In the study
If -they had worked at any time during the period from 1942-1948. The Ohio
cohort consisted of 1222 white males, of which 334 were deceased. The Penn-
sylvania cohort consisted of 2044 white males, of which 787 were deceased.
A life table analysis was performed by NIOSH, utilizing U.S. white male age-
and period-specific rates (5-year age groupings) to generate expected lung
cancer deaths, through 1974 for the Ohio cohort, and through 1975 for the
Pennsylvania cohort. An excess risk of lung cancer appeared 1n the Ohio
employees after a lapse of 15 years from the onset of employment (22
observed vs. 9.9 expected; p<0.01). The same was true for the Pennsylvania
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employees (36 observed vs. 22.0 expected; p<0.01) following a similar latent
period. The author noted that this risk occurred 1n workers who had been
employed for <1 year In the Industry.
Several questions must be considered before any conclusions can be
accepted as valid. These data, although derived from social security quar-
terly earnings reports and not from personnel records, are not Independent
of the data set utilized In the Wagoner et al. (1980) study. Both sets of
data were analyzed through the use of the NIOSH life table program. The
expected deaths generated 1n both studies are subject to the same Influences
introduced by the use of the same life table program, and by the use of the
same comparison rates (U.S. white male lung cancer rates). In addition, the
extensive cooperation between Hancuso (at the University of Pittsburgh) and
Wagoner (at NIOSH) in the search for causes of death 1n the respective
cohorts for study, contributed to the Inclusion of lung cancer deaths known
to one but not the other In both studies. As discussed previously, because
of the use of the NIOSH life tables In the Hancuso study, the calculation of
expected lung cancer deaths was on the low side (-11%). Hence, these
results should not be considered Independent of the results of the Wagoner
study.
Another problem with this cohort 1s the use of social security quarterly
earnings reports to constitute a cohort of potentially exposed employees.
These files, for the most part, are limited with respect to the data avail-
able. It was not possible to determine from the reports what Jobs these
Individuals performed for the companies, where their Job stations were
located, whether their Jobs were on or off the premises, whether they had
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actually been exposed to beryllium, or even precisely when during the
3-month period they actually started work. And, of course, these records
give no Information on workers who were^not covered by the Act. Further-
more, In the period before 1942, the social security system was In the
process of being established, and tremendous logistic problems In setting up
the system were encountered during this time. Thus, questions remain
concerning this cohort.
Another difficulty with the Mancuso (1979) study, as with his earlier
studies, 1s a lack of discussion of other exposures these workers may have
received. The author observed that the main effect (lung cancer) occurred
1n short-term employees >15 years after Initial employment. These workers
had an opportunity to be exposed to other potential carcinogens at ]obs they
may have held before or Immediately following their short employment 1n the
beryllium Industry. This 1s a distinct possibility because the beryllium-
manufacturing companies are located In or near heavily Industrialized areas
of Ohio (Cleveland, Toledo) and Pennsylvania (Reading). Roth (1983) reported
the presence of several Industries In the Lorain, Ohio area in the period
from 1942-1948 that conceivably could have provided an opportunity for
short-term employees to receive exposure to potential carcinogens.
Another serious omission of the Mancuso (1979) study Is the lack of a
discussion of the effect of cigarette smoking on the target organ of
Interest, the lung. With respect to the question of smoking, 1t would
appear likely that since there was considerable overlapping of this study
with the Wagoner et al. (1980) study, it 1s probable that most of the lung
cancer victims 1n the Pennsylvania cohort of the Mancuso (1979) study were
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smokers. Hence, It 1s possible that cigarette smoking contributed to the
Increased risk of lung cancer 1n the Pennsylvania cohort. No Information
was provided 1n the Ohio portion of the Mancuso (1979) study regarding the
smoking influence, an exposure of considerable Import In lung cancer. The
findings of significant excesses of lung cancer In both plants must be seen
as limited because of the Inadequate consideration of the confounding
effects of these two likely exposures, the problem with the NIOSH life table
programs, and the Inadequate nature of social security quarterly earnings
reports In defining an occupationally-exposed cohort for study.
In the fourth update to his study of workers potentially exposed to
beryllium In two beryl!1 urn-manufacturing facilities, Mancuso (1980) found
statistically significant elevated risks of lung cancer In 3685 white males
employed In the period from 1937-1948 and followed until the end of 1976,
when contrasted with viscose rayon workers. The beryllium cohort, as
mentioned earlier, was derived from quarterly earnings reports filed with
the Social Security Administration by the two companies. The only new
addition to this latest update was the Introduction of a new comparison
population, that of viscose rayon workers. The origin and description of
this group of workers 1s inadequately discussed, although the Wagoner et al.
(1980) study states that the viscose rayon workers cohort utilized In the
Mancuso (1980) study was located somewhere In the vicinity of the Mancuso
cohort.
Lung cancer mortality experience In the beryllium cohort was contrasted
with that expected based on rates specific to age and duration of employment
generated from the mortality experience of the viscose rayon workers cohort.
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Rates were generated In two ways, the first based on the total group of
employees 1n the viscose rayon Industry, and the second based on employees
with permanent assignments to only one department. Presumably, those who
exhibited mobility In their employment by moving from one department to
another were excluded from the lung cancer death rate calculations In the
second method. No rationale Is presented by the author to explain why
mortality In beryllium workers should be contrasted with expected deaths
derived In these two separate ways. However, the net results was to produce
two separate sets of expected lung cancer rates that differed considerably
from each other. Mancuso (1980) observed 80 lung cancer deaths In his
beryllium cohort of employees from the two companies combined, as compared
with 57.06 expected deaths based on the former set of derived rates and
50.63 expected deaths based on the latter subset of employees working their
entire time In only one department. The author did not compare his beryl-
lium workers on the basis of time since onset of employment, but ,did con-
trast them by duration of employment. He found a statistically significant
excess risk of lung cancer In employees who had been employed for <1 year,
and also In employees who had been employed for >4 years by the beryllium
companies.
In this study there 1s no consideration of the effects of latency
according to duration of employment. The major output of the NIOSH life
table program, which was utilized by Mancuso, Is a set of tabulations by
time since onset of employment. Lung cancers diagnosed within 10 years of
Initial exposure probably were not a consequence of that exposure. Further-
more, the designation "duration of employment" 1s not necessarily uninter-
rupted continuous employment. In reality, what Is meant Is "total employ-
ment" (I.e., periods of time when the employee was not exposed or not
04210 VI-25 09/24/91
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actually working). These periods of time are not counted by the NIOSH life
table program 1n the category duration of employment. Therefore, It Is
possible that Included In the observed deaths are the deaths of Individuals
who had worked only a few days for the companies, and who died from lung
cancer 20 years later, as well as Individuals who worked for the companies
for many years continuously but who died within 5 years of Initial
employment.
Additionally, the viscose rayon cohort appears to have been a somewhat
younger population by age at hiring than was the beryllium cohort (47.2% 1n
the viscose rayon cohort were hired at under age 25, as compared with 38.4%
hired at under age 25 In the beryllium cohort). Whether or not the author
adjusted for age differences Is questionable. In U.S. EPA (1983) 1t was
reported that NIOSH had reanalyzed the data and found serious problems with
Hancuso's analysis and efforts to resolve this Issue have been unsuccess-
ful. Since the viscose rayon cohort was younger than the beryllium cohort,
the net Impact 'of an adjustment would be to decrease the gap between
observed lung cancer deaths based upon the beryllium cohort and expected
deaths based upon the viscose rayon cohort.
Another problem concerns the acquisition of cause-of-death data. Some
4.3% of the reported deceased members of the viscose rayon cohort remained
without a cause of death, versus only 1.5% of the beryllium cohort. This
could potentially lead to a greater underestimate of lung cancer 1n the
viscose rayon cohort compared with the beryllium cohort 1f the causes of
death In these two groups were fairly evenly distributed.
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As In the earlier studies by the same author, the lack of discussion of
the confounding effects of smoking and the disregard of potential exposures
received while not working for the beryllium companies are a weakness In
this study: This Is a particular problem since a large majority of this
cohort worked for <1 year. Nothing Is revealed In the study of the origin
or make-up of the viscose rayon cohort. What Is known about Us location
comes from the Wagoner et al. (1980) study 1n which the authors stated that
Mancuso's viscose rayon cohort was located In the vicinity of the beryllium
companies.
Furthermore, since both cohorts were run utilizing the NIOSH life table
program, both cohorts suffer from the previously discussed 11% underestima-
tion of expected lung cancer deaths.
In conclusion, despite the author's certainty regarding the existence of
a causal relationship between beryllium exposure and lung cancer, the evi-
dence presented In this study Is not convincing because of the many limita-
tions of the study, as described previously. Hence, 1t would appear that
the study Is at best only suggestive of an Increased risk of lung cancer
from exposure to beryllium.
Although several studies show a statistically significant excess risk of
lung cancer In Individuals exposed to beryllium, all of the studies cited
have deficiencies that limit any definitive conclusion that a true associa-
tion exists. Support for a finding of an excess risk of lung cancer In
beryllium-exposed persons consists of evidence from cohort mortality studies
of two companies (Table VI-1) and one cohort mortality study of cases
04210
V3-27
09/24/91
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o
Jk
IV)
TABU VI-I
Comparison of Study Cohorts and Subcohorts of Two Beryllium Companies8
Company Where
Employed'*
Source
Period of
Employment
ComparIson
Population
Termination
Date of
follow-up
Chief Lung Cancer Results'*
Reference
KBI, BRUSH
6B1B males
KBI only
3795 white
males
KBIReadlng
facility only
3070 white
males
KBI-Readtng
fact llty only
30S5 white
males
I
££ KBI. BRUSH
368S white
ma les
KBI, BRUSH
36BS white
males
KBI 2044
BRUSH-122?
white males
KBI
0 36BS white
^ males
s
INJ
personnel
records
same as
above
same as
above
same as
above
social
security
quarterly
earnings
repor ts
social
secur1ty
quarterly
earnings
repor ts
same as
above
same as
above
1942-1967
1942-1967
1942-1967
1942-1967
1937-1948
1937 1944
and
194S-I94B
1942-1948
1937-1948
U.S. males
U.S. white
males
U.S. white
males
U.S. white
males
Industrial
control
(unidentified)
Internal
control
U.S. white
males
vl scose
rayon
workers
1967
1967
1975
1975
1966
1966
BRUSH
1974
KBI
1976
Total: 36 (0). 34.1 (E)
Total: 25 (0). 23 (E)
Latency 15 years*: 14 (0). 13.3 (E)
Total: 46 (0). 33 (E) (p<0.05)
Latency 15 years*:
37 (0). 24 (E) (p<0.OS)
Total: 47 (0). 34.3 (E) (p<0.05>
Latency 15 years*:
34 (0). 24.86 (E) (p<0.05)
equivocal
Duration of employment (rate):
>1.25 years. 33.2/10*
<1.25 years. 99.9/10*
Prior respiratory disease only:
with 284.3/10*
without 77.7/10*
Latency 15 years* only:
Ohio - 22 (0). 9.9 (E) (p<0.01)
Pennsylvania - 36 (0). 22 (E) (p<0.01)
Nobility (deaths): Among departments.
80 (0). 57.1 (E) (p<0.0l)
Remained In same department:
80 (0). 50.6 (E) (p<0.0l)
Bayllss et al..
1971
Bayllss and
Lalnhart. 1972
Bayllss and
Wagoner. 197 7
Wagoner et al.,
1980
Nancuso and
El-Attar, 1969
Nancuso. 147'.:
Nancuso. 1979
Nancuso. 1980
'Source: U.S. fPA, 198?
KBI = Kaweckt-Berylco Industries (Pennsylvania); BRUSH - Brush Beryllium Company (Ohio)
(0)
= observed; (E)
= expected
-------
admitted to the BCR. None of these studies can be said to be Independent
since all are studies of basically the same groups of workers. Extensive
cooperation existed between the authors of all of these studies. Further-
more, the authors could not adequately address the confounding effects of
smoking or of exposures received during prior and subsequent employment In
other nonberylHum Industries In the area known to produce potential
carcinogens (especially 1n beryllium workers with short-term employment).
Problems In the design and conduct of the studies further weaken the
strength of the findings. There appeared to be a tendency on the part of
the authors to overemphasize the positive nature of their results and
minimize the contribution of qualifying factors. A list of these problems
Is presented in Table VI-2. If the errors detailed In the preceding
paragraphs were corrected and proper consideration given to addressing the
problems, described, the finding of a significant excess risk would probably
no longer be apparent, although the possibility nevertheless remains that a
portion of the reported excess lung cancer risk may 1n fact be due to
beryllium exposure. Thus, the Human Health Assessment Group of the U.S. EPA
feels that the findings of these studies and the more recent tabulations
should be considered Inadequate evidence to demonstrate or refute carcino-
genicity In humans.
The International Agency for Research on Cancer (IARC) has concluded
that beryllium and Its compounds should be classified as "limited" with
respect to the human epidemiologic evidence of carcinogenicity. IARC's
classification can be explained by the fact that IARC uses only data
contained 1n published literature. In the case of beryllium more recent
tabulations of the published data were available to the U.S. EPA Human
04210
VI-29
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TABLE VI-2
Problems with Beryllium Cohort Studies*
A. Loss of 2000 Individuals because of Insufficient
data.
B. No latency considerations,
C. Combined study populations of several plants from
two companies.
Bay11ss et al.,
1971
B.
C.
A.
B.
C.
D.
E.
B.
C.
D.
Includes clerical and administrative personnel
with no exposure.
No Independent assessment of plant employment files
Latency after 20 years not assessed.
Cigarette smoking a possible confounder.
Underestimate of lung cancer deaths 1n comparison
population by 11%.
Inclusion of one lung cancer victim who did not
fit definition for Inclusion.
Loss of 295 Individuals from study cohort.
Exposure to potential carcinogens before and fol-
lowing beryllium employment.
Unidentified comparison population.
Internal rates based upon small numbers.
Tremendous variability and Impossible to test
significance.
No smoking consideration as possible confounder.
Internal rates based upon small numbers.
Inappropriate comparison (age group 15-24 left
out of comparison).
No consideration of smoking as possible confounder.
No consideration of latency.
Exposure to potential carcinogens before and fol-
lowing beryllium employment.
Underestimate of expected lung cancer deaths
In comparison population by 11%.
No consideration of smoking as possible confounder.
Incomplete delineation of cohort from use of Social
Security Quarterly Earnings reports.
Exposure to potential carcinogens before and fol-
lowing beryllium employment.
Bayllss and
Lalnhart, 1972
Bayllss and
Wagoner, 1977;
Wagoner et al.,
1980
Mancuso and
El-Attar, 1969
Mancuso, 1970
Mancuso, 1979
04210
VI-30
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TABLE VI-2 (cont.)
A. No consideration of latent effects. Hancuso, 1980
B. Probable lack of age adjustment.
C. No consideration of effects of smoking.
D. No description of origin or makeup of comparison
cohort except for age.
E. Underestimate of lung cancer deaths by 11% In both
beryllium cohort and comparison population.
•Source: U.S. EPA, 1987
04210
VI-31
06/15/90
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Health Assessment Group. These data have not been published, however,
based on the reports of lung tumors In animals by Inhalation exposure and
previously mentioned recalculation of the epidemiologic data, beryllium 1s
classified by the U.S. EPA as B2 (a probable human carcinogen) (U.S. EPA,
1987).
The relationship between trace metals concentration In drinking water
and cancer deaths 1n 15 regions of the United States was studied by Berg and
Burbank (197?). Ten of these regions include entire states, which were
relatively well sampled. For each of these 10 basins a summary statistic,
the product of the frequency of detection and the average detected concen-
tration of the metal, was calculated. This summary statistic was used to
determine the rank order of the region. This rank was then compared with
the rank of the region for mortality from each of 34 types of cancer. The
18-year incidence rates were calculated separately for four groups: white
men, white women, nonwhlte men and nonwhlte women. Spearman rank correla-
tions between metal concentrations and cancer death rate were calculated for
each of four population groups. The results were translated Into probabil-
ities and the probabilities combined to produce a summary probability of the
likelihood of this degree of positive association being observed. A
significant positive correlation was observed for beryllium, with cancers of
the breast, bone and uterus appearing to have a probability of positive
association ranging from 0.006-0.040. The association within subgroups was
weak. Mortality rates for regions with beryllium In the water are really
excessive only for non-white males. The mean positive level of beryllium
was 0.3 yg/l found for the states of Delaware, Maryland, West Virginia
and Kentucky. However, since the results are based on Imperfect analytical
04210
VI-32
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results and sampling, and are contradicted 1n part by other studies of
correlation and metal distribution, the positive associations for beryllium
In drinking water and cancer are not proof of cause and effect relationships.
Mutagenicity and Teratogenicity. No evidence on the mutagenicity or
teratogenicity of beryllium 1n humans was found (Drury et al.f 1978).
Sunmary
Beryllium causes_ a number of toxic effects In humans. However, exact
parameters for toxic concentrations and exposure times have not been deter-
mined. The acute effects are usually the result of Inhalation or direct
contact with beryllium salts. Symptoms of a dermatitis, conjunctivitis and
a range of respiratory Involvement can occur. Respiratory sequelae include
rhinitis, pharyngitis, tracheobronchitis and acute pneumonitis. Pneumonitis
has accounted for 18 deaths after development of pulmonary edema.
The chronic disease Is usually the result of occupatlonally related
Inhalation of beryllium. The acute disease may progress to the chronic form
with an asymptomatic period 1n between. The reaction to beryllium Is a
granulomatous Inflamatlon of the lung, which 1s a diffuse Interstitial
process. Other potential effects Include right heart enlargement, cyanosis,
digital clubbing and kidney stones. Granulomatous lesions have been noted
within the skin, lymph nodes, kidney, liver and skeletal muscles, as well as
the lungs.
The carcinogenic potential of beryllium 1n humans remains controversial.
Epidemiologic studies demonstrating increased Incidences of lung cancer in
beryllium workers have been criticized. However, enough evidence has been
04210 VI-33 09/24/91
-------
produced to suggest that beryllium may be carcinogenic In humans when
Inhaled. Based on several reports of lung tumors 1n animals by Inhalation
exposure and the above-mentioned epidemiologic data, beryllium 1s classi-
fied by the U.S. EPA as B2 (a probable human carcinogen). More studies are
needed to confirm these results and to exclude other alternative explana-
tions for the epidemiologic findings.
04210
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VII. MECHANISM OF TOXICITY
Because the toxic effects of beryllium and Us compounds are well known,
numerous Investigators have attempted to Identify the specific mechanisms by
which these effects are exerted.
Effects on Enzymes
Studies with beryllium Indicated that 1t 1s capable of Inhibiting
several enzyme systems. Mlcromolar concentrations of beryllium Inhibit
alkaline phosphatase (Klemperer et al., 1949; Grler et al., 1949), phospho-
glucomutase (Hashimoto et a 1 -, 1967) and sodium-activated ATPase (Toda,
1968) systems. Alkaline phosphatase Inhibition was thought 1n turn to
Inhibit the endochondral calcification of cartilage and produce the rlcket-
llke effects observed in animals (Vorwald et al.f 1966). Enzyme Inhibition
has been reported at concentrations as low as 10~* M by Vorwald and Reeves
(1959). Some enzymes Inhibited by beryllium, such as the nucleotidases,
hyaluronldases, and alkaline phosphatases, are also altered 1n hosts having
cancer Induced by nonberylHum agents.
Although beryllium Inhibits alkaline phosphatase, studies of rats
exposed to beryllium sulfate by Inhalation showed that serum alkaline phos-
phatase activity was not affected (Reeves, 1974). However, hlstochemlcally
' *1
measured alkaline phosphatase activity was decreased 1n all parenchymatous
organs of rabbits given 25 mg beryllium orally or a IX beryllium solution
Intravenously (Komltowskl, 1972). A study by Arkhlpova and Demokldova
(1967) showed that rats given BeSO^ orally had a decreased alkaline
phosphatase activity In the kidney and an Increased activity In the blood
04220
VII-1
06/07/88
-------
serum, while both parameters were Inhibited In mice when given as BeCl^ or
BeSO^. Bamberger et al. (1968) showed that below a TO"7 M concentra-
tion, no Inhibition occurred when added to media containing the enzyme,
while maximum Inhibition occurred at 10~5 H,
The effects of beryllium on several enzymes are shown 1n Table VII-1.
Alkaline phosphatase was the only one of the phosphatases to be Inhibited at
beryllium concentrations of <1 and phosphoglucomutase was the only
phosphotransferase showing Inhibition (Thomas and Aldrldge, 1966). Beryl-
lium also appears to block the tricarboxylic acid cycle by Inhibiting the
activity of the ketoglutarlc, malic and succinic acid dehydrogenases
(Mukhlna, 1967). Other enzymes Inhibited by beryllium are deoxythymldlne
kinase (Halnlgl and Bresnlck, 1969), DNA polymerase, thymidine kinase and
thymldylate kinase (WUschl, 1970; Wltschl and Harchandi 1971). The
Induction of enzymes such as tryptophan pyrrolase, amlnopyrlne demethylase
and acetanlllde hydroxylase by beryllium has been documented In rat liver
(Wltschl and Marchand, 1971), and sodium and potassium-activated ATPase are
A A
Inhibited In the presence of Mg * or Hn * (Toda, 1968; Toda et al.,
1971). Williams and Skilleter (1983) also noted that beryllium Inhibited
the enzymes Involved in the phosphorylation of nuclear proteins.
Beryllium also has the ability to Increase the activity of some enzymes
such as ATPase and succlnoxldase. For example, intravenous Injection of
12.5-1000 yg Be/kg bw produced an Increased activity of plasma B-glucu-
ronldase In mice (Vacher et al., 1975). Beryllium also Irreversibly
Inhibits the (Na+K) dependent ATPase (Robinson et al., 1986) and this
1nact1vat1on requires divalent cations, Is augmented by K*, but Is
diminished by Na* and by ATP. Similarly, prior Incubation of the enzyme
04220 VI1-2 08/14/91
-------
TABLE VII-1
Effect of Beryllium on Various Enzymes3^
Enzyme
Activated
by
pH of
Assay
Effect of BeSO* at the
Concentration Indicated
Alkaline phosphatase (kidney)
-f
9.4
50% Inhibition, 1 VM
Acid phosphatase
-
5.0
No inhibition, 0.6 mM
Phosphoproteln phosphatase
-
6.0
No inhibition, 0.1 mM
Adenosine triphosphatase
(liver nuclei)
+
6.B
No Inhibition, 0.5 mM;
97% Inhibition, 5 mM
Adenosine triphosphatase
(liver mitochondria)
6.8
No Inhibition, 0.2 mM;
40% Inhibition, 2 mM
Adenosine triphosphatase
(brain microsomes)
-f
7.4
20% Inhibition, 0.64 mM
Glucose 6-phosphatase
-
6.5
No Inhibition, 0.8 mM
Polysaccharide phosphorylasec
-
6.0
No Inhibition, 0.64 mM
91% Inhibition, 6.4 mM
Phosphoglucomutase
+
7.5
50% Inhibition, 5 VH
Hexoklnase
¦f
7.4
45% Inhibition, 1.5 mM;
no inhibition, 0.15 mM
Phosphoglyceromutase
-
7.0
No Inhibition, 2.0 mM;c
15% Inhibition, 1.0
Rlbonuclease
-
7.5
No "Inhibition, 1.0 mM
A-esterase (rabbit serum)
-
7.6
No Inhibition, 1.0 mM
Chollnesterase (horse serum)
-
7.6
No Inhibition, 1.0 mM
Chymotrypsln
-
7.0
10% Inhibition, 1.0 mM
aSource: Drury et a 1.. 1978
^Beryllium sulfate was used, and prelncubated with enzyme for 10 minutes
1n the absence of substrate. At pH >7, precipitates were obtained with
concentrations of BeS04 of >1 mM. Inhibition at these concentrations may
be nonspecific.)
c134 mH 3-phosphoglycerlc acid as substrate.
^20 mM 2-phosphoglycerlc acid as substrate.
04220
VII-3
04/13/88
-------
with vanadate blocks InactWatlon by beryllium added subsequently. Inactl-
vatlon by beryllium, however, does not require a hallde, and, unlike Inactl-
vatlon by fluoride, Increases at basic pHs. These observations suggest that
beryllium, as beryllium hydroxide complexes, acts as a phosphate analog,
similar to AlF^ and vanadate.
Effect on Nucleic Acids
Numerous studies examining the mechanism of beryllium toxicity demon-
strated Its effect on nucleic acids 1n the cell. Vorwald and Reeves (1959)
found that beryllium oxide altered the cell RNA distribution when Injected
Intratracheally at 10.8 mg of total beryllium. A concentration of 1 mM
BeSO^ Inhibited cell division In metaphase (Chevremont and Flrket, 1951),
and the presence of beryllium was found to block the cell cycle at the
G^-S phase (Skllleter et al., 1983). The effects were only shown In DNA;
the synthesis of RNA did not change (Wltschl, I960).
Kharlamova and Potapova (1968) showed that beryllium accumulates 1n the
nuclei, and other authors showed It to Interfere with the metabolism of DNA
In the liver (Marcotte and Wltschl, 1972; Wltschl, 1968, 1970). Skllleter
(1984) noted that this localization of beryllium In the nucleus could
account for the direct effects on the fidelity of DNA synthesis, but
reported that the Inhibition of the G^-S phase would account for the major
mutagenic effects since phosphorylation of nonhistone proteins occurs during
this phase. The Be^+ 1on also Increased the mlslncorporatlon of nucleo-
tides during polymerization by DNA polymerase (Luke et al.# 1975). Results
of Slrover and Loeb (1976) showed that Be^+ altered the accuracy of DNA
synthesis. The ability of beryllium to Influence this accuracy 1_n vitro
also suggests the possibility of the same effect In vivo (U.S. EPAt 1980a).
04220 VI1-4 06/07/88
-------
Effect on Proteins
Beryllium also reacts with proteins (Reiner, 1971). Rats given an
Intratracheal Injection of 33 mg beryllium 1n three equal doses had altered
cellular distribution of proteins (Vorwald and Reeves, 1959). The injected
rats showed almost double the amount of protein In microsomes of lung tissue
cells as untreated rats; however, no protein change was seen In the mito-
chondria or nuclei. Protein metabolism was studied In rats under conditions
.of experimental berylliosis (Pavlova et al., 1970). The authors found an
Increase In both reactive sulfhydryl groups and In the rate at which
lys1ne-l-14C was Incorporated Into soluble hepatic proteins. Kurysheva
(1969) considered this Indicative of an Increase In the rate of protein bio-
synthesis. Vacher et al. (1974) reported that an Immunologically specific
a-macro-feto protein appeared 1n the serum of rats Injected with beryl-
lium. Wltschl and Aldrldge (1967) also found that rats Injected with 0.75
mg Be/kg bw showed a decreased ability to Incorporate amino acids Into liver
protein 24 hours after administration.
Immunologic Effects
The Involvement of an Immunologic factor 1n the development of chronic
beryllium disease was suggested by Sterner and Elsenbud (1951). Hyper-
sensitivity reactions were produced In guinea pigs by Intradermal Injections
(Alekseeva, 1965) or by application of BeF^ to the skin (Belman, 1969).
BeCl 2 also Induced skin hypersensitivity In rats (Vasll'eva, 1969).
Curtis (1951) developed a 'patch test that Involved application of nonlrrl-
tatlng concentrations of soluble beryllium. Curtis showed that this test
had a sensitizing effect and could elicit a.positive reaction 1n subsequent
testing.
04220
VI1-5
08/16/88
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Most patients who previously had acute beryllium reactions or a history
of dermatitis showed an increased IgG fraction of Immunoglobulin (Resnlck et
al.# T970). The phenomenon Indicated that beryllium was antigenic, and the
hypersensitivity Is now generally agreed to be essentially a cell-mediated
response (Alekseeva, 1965; C1rla et al., 1968)~ The basic Immune reaction
Is an accumulation and proliferation of reticuloendothelial cells In
response to contact with a poorly soluble particle (Reeves, 1983).
According to a review by Reeves and Preuss (1985), berylliosis Is essen-
tially an Immune reaction expressed as granulomatous hypersensitivity In
which reticuloendothelial cells accumulate and proliferate. Most or all
cases appear to Involve small-crystallite beryllium oxide. The proximate
antigen Is probably an adsorptlve protein complex. The cellular response Is
Initiated by phagocytosis of beryllium by macrophages. This results In
swelling and rupture of lysosomes. Ultimately vacuolization and eventual
necrosis of the cells occur. This process Is accompanied by the development
of delayed cutaneous hypersensitivity. The ability to respond Immunologi-
cally to beryllium was genetically controlled In guinea pigs as a dominant
nonsex-llnked trait. It was also found that the Immune response could be
suppressed with lymphocyte antiserum, with large doses of beryllium lactate,
or by inhalation exposure to beryllium sulfate.
The Interdependence between the antigenic challenge and Immune response
Is complex. The measurable parameters show the state of beryllium hyper-
sensitivity rather than the state of berylliosis. In guinea pigs, mainte-
nance of cutaneous hypersensitivity through booster shots decreased the
vulnerability of the lungs to concurrent beryllium Inhalation. Beryllium
\
04220
VII-6
08/16/88
-------
neoplasia was observed 1n those experimental animals not Irnnunologlcally
responding to beryllium. Therefore, Immunocompetence may be a factor In
determining whether or not the response to beryllium will be neoplastic
(Reeves and Preuss, 1985).
The transfer of lymphoid cells to guinea pigs could result In a passive
transfer of hypersensitivity, while serum transfer did not produce the same
results. Chlapplno et al. (1968, 1969) showed that Injection of rabbit
antllymphocyte serum could Inhibit the skin reaction of guinea p 1 gs to
beryllium. Intravenous Injection of beryllium lactate could suppress the
response as well (Turk and, Polak, 1969) and Inhalation exposure also reduced
skin reactivity (Reeves et al., 1975). Additionally, studies have demon-
strated Individual variations 1n responsei Sensitization 1s controlled and
transmitted as a dominant, nonsex-1Inked trait (Polak et al. 1968). The
hypersensitivity was measured by lymphocyte blast transformation (Hanlfln et
al.# 1970; Rom et al.t 1983), macrophage migration Inhibition (Henderson et
al., 1972) and by skin response. These methods were used both on guinea
pigs (Marx and Burrell, 1973; Palazzolo and Reeves, 1975) and on humans
(Jones-Williams et al., 1972; Deodhar et al., 1973).
Shlma et al. (1986) conducted a study to clarify the relationship
between the humoral immune response and the concentration of beryllium In
the blood and In the spleen of mice. Mice were IntraperItloneally Injected
with 0.075, 0.15, 0.3 or 0.6 mg BeCl^/kg bw every day for 2 weeks.
Changes In the antibody production of the spleen In response to SRBC
\
04220
VII-7
06/07/88
-------
and the beryllium concentration In the blood and spleen of mice were studied
for a 10-day period after Injections were stopped. The following conclu-
sions from the study were obtained;
1. The Igfl or IgG-PFC 1n the spleen of mice Injected with BeCl2
Increased when the beryllium concentration In the blood was
kept between 5 and 35 ng/mi, and decreased when the level was
>35 ng/mi.
2. A relationship between the change of the IgH or IgG-PFC to SRBC
and the beryllium concentration In the spleen was not
recognized.
It was suggested that the adjuvant activity of beryllium on the humoral
Immune response was related to the concentration of beryllium in the blood
(Shlma et al.r 1986).
The relationship between the lung reactions seen 1n beryllium disease
and the skin hypersensitivity 1s not understood. It has been suggested that
the responses of the skin and lung may have an Inverse relationship to each
other (Reeves et al.t 1971, 1972). For example, Reeves and Krlvanek (197*)
found that the pulmonary response could be modified by maintaining a hyper-
sensitivity through Intracutaneous Injection. This Inverse relationship may
be similar to that shown by tuberculin sensitivity and resistance to tuber-
culosis (Orury et al., 1978).
The bioavailability of the beryllium compound used and the route of
administration also seems to determine the degree of reaction. The Immuno-
genic forms and routes were those that formed complexes with skin constitu-
ents, and even a very low Intraperitoneal dose (4.78 v9/*9) or a
Intravenous dose (400 yg/kg) were "tolerogenic11 If the form used was
04220
-¦>
VII-8
04/11/88
-------
freely diffusible. Unavailable forms ^citrate and aurlntrlcarboxylate) did
not produce sensitivity, while an enhanced reaction resulted from the use of
berylHum-serum-albumlnate (Krlvanek and Reeves, 1972). Vasll'eva ( 1 969,
1972) discovered antigenic beryllium nucleoproteln complexes, but Jones and
Amos (1974, 1975) also presented evidence that beryllium can .act without
complexlng and can Inhibit the response of allerglzed lymphocytes to an
antigen.
Synergism and Antagonism
Several studies have attempted to find an agent that might be effec-
tively used to Inhibit the acute toxicity of.beryllium. These studies were
summarized by Vorwald et al. (1966). AurIntrlcarboxyl1c acid (ATA) formed a
chelate that accumulated In the spleen and kidneys but not In the bones, and
the use of ATA In conjunction with salicylates was also considered benefi-
cial. ATA had a ml Yd toxicity., level with Intravenous LD^s of 440 mg/kg
for mice and 450 mg/kg for rats. However, Reeves (1977) reported chelating
agents to be Ineffective in clinical trials Involving chronic beryllium
toxicity. Joshl et al. (1984) reported that ferritin had a protective
effect on the Inhibition of phosphoglucomutase (PGM) through chelation.
They also observed that the binding of beryllium to ferritin and PGM 1s
reversible. Undenschmldt et al. (1986) also studied the binding of beryl-
lium to ferritin. Male F344 rats were Injected dally with 1 mg Be/kg bw as
BeSO^ for 7 days and sacrificed 16 hours following the last Injection.
Induction of metallothloneln synthesis and ferritin binding was measured in
the livers of treated rats. Beryllium, unlike other divalent Ions'tested,
did not Induce the synthesis of metallothloneln. However, ferritin binding
of beryllium was measured 1n substantial quantities and was considered to be
04220
VII -9
04/13/88
-------
a protective mechanism by the authors. In rats pretreated for 3 days with 4
mg/kg bw ferric ammonium citrate (1.p.)# liver ferritin was elevated -5
times and the lethality of Intravenously Injected beryllium was signifi-
cantly reduced 1n the pretreated animals. This protective effect of Iron
was suggested to be due* at least 1n part, to an Increased production of
ferritin, which binds beryllium and transports It out of the liver.
Sendelbach and Wltschl (19B7) also showed that Iron provides protection
against beryllium toxicity. Rats were exposed for 2 hours 1n a nose-only
Inhalation chamber for 14 days to an aerosol of BeSO^ containing 2.59 yg
Be/l. One group of rats was concurrently treated with Iron salt. Mortal-
ity was significantly reduced (p<0.05) compared with animals that had not
received Iron treatment. The authors concluded that iron plays a protective
role 1n beryllium toxicity by Increasing levels of liver ferritin. Subse-
quent binding of beryllium to ferritin may render the beryllium Inaccessible
to exert cell damage.
The feeding of powdered leaves of Gymnema sylvestre (a vine that grows
1n central India) in the diet of rats for 10 days before and 15 days after
Intravenous Injections of beryllium nitrate (0.316 mg/kg bw) significantly
protected the animals from the full fall of blood glucose seen In rats
receiving beryllium nitrate alone (Prakash et al.# 1986). However, feeding
of the leaves for 25 days to normal rats did not alter blood glucose
significantly. The leaves may contain a substance that could be useful as a
prophylactic against beryllium toxicity.
04220
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A few synergistic effects have also been noted. Uzawa (1963) reported
that beryllium oxide potentiated the carcinogenic effect of 20-methyl
cholanthrene (20-MC) to a greater degree than did carbon black. Stoklnger
et al. (1950) also reported a synergistic effect of the fluoride Ion since
BeF^ nearly produced a doubling of the toxic effect of BeSO^ when
Inhaled at any given concentration.
Summary
Beryllium 1s capable of Inhibiting several enzyme systems, Including
alkaline phosphatase, sodium activated ATPase and phosphoglucomutase. It
also can Increase the activity of some enzymes, such as B-glucoronldase.
Subcellular distribution studies show that beryllium enters the cell nucleus
where It Interferes with cell division by Interacting with DNA# thymidine
kinase and DNA polymerase. Beryllium Is also antigenic and causes hyper-
sensitivity, which 1s cell-mediated. Syngerglstlc effects were noted with
20-methyl cholanthrene on carcinogenicity. Ferritin has a protective effect
on beryllium toxicity due to Its ability to bind beryllium and transport It
out of the liver or make It Inaccessible to cause cell damage.
04220
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VIII. QUANTIFICATION OF TOXICOLOGIC EFFECTS
Introduction
The quantification of toxicologic effects of a chemical consists of
separate assessments of noncarclnogenlc and carcinogenic health effects.
Chemicals that do not produce carcinogenic effects are believed to have a
threshold dose below which no adverse, noncarclnogenlc health effects occur,
while carcinogens are assumed to act without a threshold.
In the quantification of noncarclnogenlc effects, a Reference Dose
(RfD), [formerly termed the Acceptable Dally Intake (ADI)] Is calculated.
The RfD 1s an estimate (with uncertainty spanning perhaps an order magni-
tude) of a dally exposure to the human population (Including sensitive
subgroups) that Is likely to be without an appreciable risk of deleterious
health effects during a lifetime. The RfD Is derived from a no-observed-
adverse-effect level (NOAEL), or lowest-observed-adverse-effect level
(LOAEL), Identified from a subchronlc or chronic study, and divided by an
uncertainty factor(s) times a modifying factor. The RfD 1s calculated as
follows:
Selection of the uncertainty factor to be employed 1n the calculation, of
the RfD 1s based upon professional judgment, while considering the entire
data base of toxicologic effects for the chemical. In order to ensure that
uncertainty factors are selected and applied In a consistent manner,
RfD »
(NOAEL or LOAEU
mg/kg bw/day
[Uncertainty Factor(s) x Modifying Factor]
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the U.S. EPA (1991) employs a modification to the guidelines proposed by the
National Academy of Sciences (NAS, 1977, 1980) as follows:
Standard Uncertainty Factors (UFs)
Use a 10-fold factor when extrapolating from valid experimental
results from studies using prolonged exposure to average healthy
humans. This factor is Intended to account for the variation
In sensitivity among the members of the human population. [10H]
Use an additional 10-fold factor when extrapolating from valid
results of long-term studies on experimental animals when
results of studies of human exposure are not available or are
Inadequate. This factor Is Intended to account for the uncer-
tainty In extrapolating animal data to the case of humans.
[10A]
Use an additional 10-fold factor when extrapolating from less
than chronic results on experimental animals when there Is no
useful long-term human data. This factor Is Intended to
account for the uncertainty In extrapolating from less than
chronic NOAELs to chronic NOAELs. [10S]
Use an additional 10-fold factor when deriving an RfD from a
LOAEL instead of a NOAEL. This factor is Intended to account
for the uncertainty In extrapolating from LOAELs to NOAELs.
[101]
Modifylng Factor (MF)
• Use professional judgment to determine another uncertainty
factor (MF) that 1s greater than zero and less than or equal to
10. The magnitude of the HF depends upon the professional
assessment of scientific uncertainties of the study and data
base not explicitly treated above, e.g., the completeness of
the overall data base and the number of species, tested. The
default value for the HF Is 1.
The uncertainty factor used for a specific risk assessment Is based
principally upon scientific judgment rather than scientific fact and
accounts for possible Intra- and Interspecies differences. Additional
considerations not incorporated in the NAS/ODW guidelines for selection of
an uncertainty factor Include the use of a less than lifetime study for
deriving an RfD, the significance of the adverse health effects and the
counterbalancing of beneficial effects.
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From the RfD, a Drinking Water Equivalent Level (DWEL) can be calcu-
lated. The DWEL represents a medium specific (I.e., drinking water)
lifetime exposure at which adverse, noncarclnogenlc health effects are not
anticipated to occur. The DWEL assumes 100% exposure from drinking water.
e
The DWEL provides the noncarclnogenlc health effects basis for establishing
a drinking water standard. For Ingestion data, the DWEL 1s derived as
follows:
DWEL = (Rf[M * = mg/1
Drinking Water Volume 1n 1,/day
where:
Body weight = assumed to be 70 kg for an adult
Drinking water volume = assumed to be 2 fc/day for an adult
In addition to the RfD and the DWEL, Health Advisories (HAs) for expo-
sures of shorter duration (1-day, 10-day and longer-term) are determined.
The HA values are used as Informalj guidance to municipalities and other
organizations when emergency spills or contamination situations occur. The
HAs are calculated using an equation similar to the RfD and DWEL; however,
the NOAELs or LOAELs are Identified from acute or subchronlc studies. The
HAs are derived as follows:
HA - * . mg/l
(UF) x ( l/day)
Using the above equation, the following drinking water HAs are developed
for noncarclnogenlc effects:
1. 1-day HA for a 10 kg child Ingesting 1 t water per day.
2. 10-day HA for a 10 kg child Ingesting 1 1 water per day.
3. Longer-term HA for a 10 kg child Ingesting 1 I water per day.
4. Longer-term HA for a 70 kg adult Ingesting 2 t water per day.
04230
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09/16/87
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The 1-day HA calculated for a 10 kg child assumes a single acute
exposure to the chemical and Is generally derived from a study of <7 days
duration. The 10-day HA assumes a limited exposure period of 1-2 weeks and
is generally derived from a study of <30 day$ duration. The longer-term HA
Is derived for both the 10 kg child and a 70 kg adult and assumes an
exposure period of -7 years {or 10% of an Individual's lifetime). The
longer-term HA Is generally derived from a study of subchronlc duration
(exposure for 10% of animal's lifetime).
The U.S. EPA categorizes the carcinogenic potential of a chemical, based
on the overall welght-of-evldence, according to the following scheme:
Group A: Human Carcinogen. Sufficient evidence exists from
epidemiology studies to support a causal association between
exposure to the chemical and human cancer.
Group B: Probable Human Carcinogen. Sufficient evidence of
carcinogenicity 1n animals with limited (Group Bl) or Inade-
quate (Group B?) evidence In humans.
Group C: Possible Human Carcinogen. Limited evidence of
carcinogenicity In animals 1n the absence of human data.
Group D: Not Classified as to Human Carcinogenicity. Inade-
quate human and animal evidence of carcinogenicity or for which
no data are available.
Group E: Evidence of Noncarcinogenlclty for Humans. No
evidence of carcinogenicity In at least two adequate animal
tests In different species or In both adequate epidemiologic
and animal studies.
If toxicologic evidence leads to the classification of the contaminant
as a known, probable or possible human cardnogent mathematical models are
used to calculate the estimated excess cancer risk associated with the
Ingestion of the contaminant In drinking water. The data used In these
04230
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estimates usually come from lifetime exposure studies using animals. In
order to predict the risk for humans from animal data, animal doses must be
converted to equivalent human doses. This conversion Includes correction
for noncontlnuous exposure, less than lifetime studies and for differences
1n size. The factor that compensates for the size difference Is the cube
root of the ratio of the animal and human body weights. It Is assumed that
the average adult human body weight Is 70 kg and that the average water
consumption of an adult human Is 2 a of water per day.
For contaminants with a carcinogenic potential, chemical levels are
correlated with a carcinogenic risk estimate by employing a cancer potency
(unit risk) value together with the assumption for lifetime exposure from
ingestion of water. The cancer unit risk Is usually derived from a linear-
ized multistage model with a 95% upper confidence limit providing a low dose
estimate; that 1s, the true risk to humans, while not Identifiable, Is not
likely to exceed the upper limit estimate and. In fact, may be lower.
Excess cancer risk estimates may also be calculated using other models such
as the one-hit, Welbull, 1og1t and problt. There Is little basis In the
current understanding of the biologic mechanisms Involved 1n cancer to
suggest that any one of these models Is able to predict risk more accurately
than any other. Because each model Is based upon differing assumptions, the
estimates derived for each model can differ by several orders of magnitude.
The scientific data base used to calculate and support the setting of
cancer risk rate levels has an Inherent uncertainty that Is due to the
systematic and random errors In scientific measurement. In most cases, only
studies using experimental animals have been performed. Thus, there 1s
04230
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uncertainty when the data are extrapolated to humans. When developing
cancer risk rate levels, several other areas of uncertainty exist, such as
the incomplete knowledge concerning the health effects of contaminants In
drinking water, the Impact of the experimental animal's age, sex and
species, the nature of the target organ system(s) examined and the actual
rate of exposure of the Internal targets In experimental animals or humans.
.Dose-response data usually are available only for high levels of exposure
and not for the lower levels of exposure closer to where a standard may be
set. When there Is exposure to more than one contaminant, additional
uncertainty results from a lack of Information about possible synergistic or
antagonistic effects.
Noncarcinoqenic Effects
The effects of beryllium have been demonstrated by several routes of
administration. Studies of intravenous Injections of beryl Hum have shown
It to be highly toxic, with an LD^q of 0.44 mg Be/kg reported for 200 g
male rats (Wltschl and Aldrldge, 1967). A single intravenous dose of 1.1 mg
Be/kg bw as BeSO^ has been found to cause liver necrosis In rats (Cheng,
*1356). The LDj.q Intraperitoneal Injection for mice Is 18 mg/kg when
administered as a sulfate (Bas'lnger et al., 1982). Inhalation of beryllium
continues to be the major route of toxicity, with acute toxicity reported In
rats at a concentration of 194 vg/m3 as an aerosol, and pathologic
changes reported within a 3-month period at a concentration of 42 yg/m3
(Vorwald et al., 1966). A mild, macrocytlc-llke anemia has also been
produced in dogs, rats and rabbits from Inhalation, but this effect has not
been shown in man (Stoklnger and Stroud, 1951).
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There 1s only limited evidence of toxic effects following oral exposure
to beryllium. Beryllium rickets, one of the earliest effects observed, has
been demonstrated In young animals exposed to soluble beryllium salts
(Branlon et al., 1931; Guyatt et al., 1933; Kay and Skill, 1934). Guyatt et
al. (1933) reported that 21- to 24-day-old rats fed diets containing
0.125-3.0% beryllium carbonate developed rickets after 3 weeks. No adverse
effects on body weight or general appearance were observed In young rats fed
diets containing 0.06 g BeCO^/day for 14 days (Buslnco, 1940). Increasing
the dose to 0.16 g BeCO^/rat/day resulted 1n decreased body weight after
10 days of-exposure. A further Increase In the dose to 0.24 g BeCO^/rat
resulted In a >50% reduction 1n body weight, decreased calcification and
development of the long bones, characteristics typical of rickets. The low
oral toxicity of beryllium Is attributable to Us minimal absorption from
the GI tract (Schroeder and Mltchener, 1975b).
Dietary administration of 5 mg Be as BeSO^, BeO or Be-metal dally for
3-12 months resulted In a slight reduction In body weight of hamsters fed
the BeSO^ compound (Watanabe et al., 1985). Horgareldge et al. (1975), 1n
an unpublished study, reported a slight decrease In body weight 1n rats fed
diets containing 500 ppm beryllium sulfate for 2 years. Schroeder and
Mltchener (1975a) reported a slight decrease 1n growth of male rats given 5
ppm (5 mg/l) beryllium sulfate In their drinking water over a lifetime.
No effects were seen In females given the same dose.
Quantification of Noncardnoqenlc Effects
The calculation of a drinking water criterion for beryllium may be made
based on the available toxicity data.
04230
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Derivation of 1-Day HA. Studies with the exposure duration data
appropriate for the derivation of a 1-day HA could not be located 1n the
available literature. It 1s recommended therefore that the 10-day HA of 30
mg/i be used as an estimate of exposure for a 1-day HA.
Derivation of 10-Dav HA. Beryllium carbonate fed to young rats
(30-40 g) at a dally dose of 0.06 g BeCO^ (0.26 g Be/kg bw) for 14 days
resulted 1n no adverse effects on body weight or general appearance
(Buslnco, 1940). No other endpolnts of toxicity were measured for this time
period or dose; however, animals fed higher doses showed a dose-related
Increase 1n body weight reduction and a decrease In calcification and
development of long bones. A N0AEL of 260 mg Be/kg bw/day can be derived
based on the absence of adverse body weight and gross toxicologic effects In
this study.
The 10-day HA for the 10 kg child 1s calculated as follows:
26 mg/l
(rounded to 30 mg/1 or
30,000 Pg/l)
where: 260 mg/kg/day = N0AEL based on the absence of adverse effects
on body weight and general appearance in rats
fed beryllium carbonate for 2 weeks (Buslnco,
1940)
10 kg = assumed weight of a child
1 t/day = assumed water consumption by a child
100 = uncertainty factor chosen 1n accordance with
NAS/0DW and Agency guidelines 1n using a NOAE.L
from an animal study
260 mq/kq/dav x 10 kq
10-day HA = a 1 a
1 l/day x 100
04230
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Derivation of a Longer-term HA. A longer-term HA can also be derived
from the subchronlc oral studies by Buslnco (1940) 1n which young rats
(30-40 g) were fed increasing doses of BeCO^ for 83 days. Rats received
dally doses of 0.06 g BeCO^ (7.8 mg Be) on days 0-14, 0.16 g BeCO^ (20.8
mg Be) on days 15-34 and 0.24 g BeCO^ (31.2 mg Be) on days 35-83.
Estimated average body weight of treated animals was 55.5 g. A TWA dose of
0.191 g BeC03/rat/day (3.4 g BeCO^/icg bw) can be estimated from the
Information provided by the authors. The dose of 3.4 g BeCO^/kg bw (443
mg Be) resulted In a >50% reduction 1n body weight gain and decreased
development and calcification of the long bones (rickets-like characteris-
tics). Therefore, the dose of 443 mg Be/kg bw 1s considered a L0AEL,
However, this L0AEL should be viewed with caution because of the degree of
body weight loss.
The only other oral study that may be appropriate for the derivation of
a longer-term HA Is the study by Watanabe et al. (1985) In which hamsters
given dally doses of 5 mg Be for >12 months showed only a slight reduction
1n body weight gain. It appears that the only endpolnts of toxicity
measured were body weight and organ weight; however, at this time only a
brief abstract of this study Is available. Until more details of this study
become available, the L0AEL of 443 mg Be/kg bw for the Buslnco (1940) study
1s recommended for the derivation of the longer-term HA.
The longer-term HA for the 10 kg child 1s calculated as follows:
"longer-term HA =
443 mq/kq/day x 10 kg
1 l/day
= 4.43 mg/SL
(rounded to 4.0
4000 vg/l)
04230
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where: 443 mg/kg/day =
NOAEL based on suppressed body weight and
development of rickets 1n rats fed BeCC>3 for
83 days (Buslnco, 1940)
10 kg
= assumed weight of a child
1 i/day
1000
= uncertainty factor chosen in accordance with
NAS/0DW and Agency guidelines In using a L0AEL
from an animal study
= assumed water consumption by a child
The longer-term HA for the 70 kg adult Is calculated as follows:
longer-term HA =
443 mq/kq/dav x 70 kg
2 l/day x 1000
= 15.5 mg/i
(rounded to 20 mg/i or
20,000 wg/l)
where: 443 mg/kg/day = NOAEL based on suppressed body weight and
development of rickets In rats fed BeC03 for
83 days (Buslnco, 1940)
Assessment of Lifetime Exposure and Derivation of DUEL. The only oral
study of the effects of beryllium In drinking water that may be considered
for the derivation of a OWEL Is that by Schroeder and Mltchener (1975a). In
this study male and female rats were administered 5 ppm Be 1n their drinking
water for a lifetime. The only significant effect was a slight reduction in
body weight In males from 2-6 months of age. A NOAEL of 0.538 mg Be/kg bw
can be calculated by multiplying the dose of 5 ppm (5 mg/l) by the average
water consumption (0.035 l/day) of rats In this study and dividing by the
average rat body weight (0.325 kg) given 1n this study. An RfD of 0.005
mg/kg/day has been derived for this NOAEL by the application of an
70 kg = assumed weight of an adult
2 fc/day = assumed water consumption by an adult
1000
= uncertainty factor chosen In accordance with
NAS/0DW and Agency guidelines In using a L0AEL
from an animal study
04230
VIII-10
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uncertainty factor of 100, according to U.S. EPA (1991) guidelines. It
should be noted, however, that several weaknesses have been cited 1n this
study such as the presence of other trace elements and minerals Including
chromium In the drinking water, the use of nonrandomized animals, and the
administration of only one dose.
The unpublished study of Morgareldge et al. ( 1975 ) Is the only other
study that can be considered for the derivation of an RfD for beryllium. In
this study rats were exposed to 0, 5, 50 or 500 ppm Be In the diet for 2
years. The only toxic effect observed was a slight decrease 1n body weight
1n the highest dose group. A N0AEL of 25 mg/kg bw can be calculated
assuming an average food consumption of 0.05 mg/kg bw 1n a rat. Since this
study Is unpublished and presumably not peer-reviewed. It cannot at this
time be used 1n the derivation of a OWEL for beryllium. The current
verified RfD (verification date 12/02/85) (U.S. EPA, 1991) for beryllium Is
recommended for use In deriving the DWEL until this Issue has been resolved.
Step 1: Determination of the Reference Dose (RfD)
RfD _ (0.53B^mq/kq/daY) = 0>005 mg/kg/day
where: 0.538 mg/kg/day = adjusted N0AEL based on .the absence of
effects In rats fed BeS04 1n drinking water
over a lifetime (Schroeder and MHchener,
1975a)
100 = uncertainty factor chosen In accordance with
NAS/0DW and Agency guidelines In using a
N0AEL from an animal study
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Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL . <0-005 l,,/kq/aaY| » 70 k, _ _
2 1/day
where: 0.005 mg/kg/day = RfD
70 kg = assumed weight of an adult
2 l/day = assumed water consumption by an adult
The HAs are summarized In Table VIII-1.
Carcinogenic Effects
Beryllium Is carcinogenic In laboratory animals When administered by
Inhalation, Intratracheal Instillation or Intravenous Injection (see Tables
V-l and V-2). An 1_n vitro assay by Slrover and Loeb (1976) designed to
detect potential metal mutagens and carcinogens also showed that BeCl^
Increased the error frequency of the incorporation of nucleotide bases into
DNA.
Epidemiologic studies of the relationship between beryl 1lum occupa-
tional exposure and the development of human cancer, while presenting
evidence that a relationship may exist, have not been sufficient to exclude
other possible explanations. The human evidence Is therefore considered to
be Inadequate for determining a relationship between beryllium exposure and
cancer 1n humans.
04230
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TABLE VI11-1
HAs and DWEL for Noncardnogenlc Effects
-
Drinking Water
Concentration
(mg/i)
Reference
1-Day HA (10 kg child)
30*
Buslnco, 1940
10-Day HA (10 kg child)
30
Buslnco, 1940
Longer-term HA (10 kg child)
4
Buslnco, 1940
Longer-term HA (70 kg adult)
20
Buslnco, 1940
DWEL
0.2
Schroeder and
Mltchener, 1975a
*Adopted from 10-day HA
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Very limited work has been performed with long-term oral exposures.
Schroeder and Mltchener (1975a) administered 5 ppm beryllium in the drinking
water over the lifetime of rats. Although no statistically significant
differences were found In the Incidence of tumors between the control and
experimental groups, the authors did report a slight excess of grossly ob-
served tumors In exposed male rats. These authors also conducted a similar
study with mice (Schroeder and Mltchener, 1975b). In this study the authors
reported an excess of lymphoma leukemlas In the exposed females, but again
the excess was not statistically significant. --In an unpublished study,
Morgareldge et al. (1975) exposed rats to beryllium at concentrations of 5,
50 or 500 ppm In the diet for 2,years. These data were also analyzed by the
U.S. EPA's Human Health Assessment Group. This analysis revealed that a
significantly higher number of lung reticulum cell sarcomas occurred 1n two
of the three dose groups In males. The relationship between the dose and
response was Inverse; the most significant response occurred at a dose of 5
ppm and no significant response occurred at 500 ppm. The Fischer Exact
p values for the lowest and Intermediate dose groups were 0.0065 and 0.036,
respectively. Because of this uncertain dose-response finding, limitations
in design and execution of study, and because these results have never been
published, the Morgareldge et al. (1975) study should not be considered a
key or pivotal study for the derivation of a criterion. It can, however, be
used to support a concern that such a calculation be pursued using other
data.
Using the U.S. EPA welght-of-evldence criteria for evaluating both human
and animal evidence, beryllium Is classified In Group B2 Indicating that on
the strength of positive animal data and inadequate human data beryllium 1s
04230
VIII-14
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regarded as a probable human carcinogen. In the case of beryllium, the
animal evidence Indicates that all beryllium species should be regarded as
probable carcinogens.
Because of the positive carcinogenic findings In animals exposed to
beryllium by Inhalation and Injection, and the suggestive evidence by
drinking water supported by positive mutagenicity results, 1t 1s concluded
that beryllium In drinking water presents a carcinogenic risk to humans. It
Is therefore considered appropriate to derive a cancer potency factor for
oral exposure to beryllium.
Quantification of Carcinogenic Effects
A potency estimate can be derived using data from the Schroeder and
Mltchener (1975a) study, 1n which rats were exposed continuously to
beryllium in the drinking water at 5 ppm for a lifetime, resulting In a
nonsignificant Increase In tumors at all sites 1n exposed males. The
parameters used to calculate the criterion are as follows:
/
Dose
(mg/kg/day)
Incidence
(No. responding/No. Tested)
0.0
0.538
4/26
9/33
le = 1126 days
Le = 1126 days
L = 1126
W = 0.325 kg
WC = 0.035 t/day
where
le = duration of exposure
Le = duration of experiment
L = lifespan of test animal
W = average weight of the
experimental animal
WC = average water consumption
04230
VIII-15
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The carcinogenic potency factor, q^*f for humans obtained from these
parameters 1s 4.3 (nig/kg/day)"1 using Global '86 (linearized multistage
model). An oral quantitative estimate for beryllium of 4.86 (mg/kg/day)"1
was originally verified by the U.S. EPA CRAVE Workgroup In February 1989.
The Shroeder and Kitchener (1975a) study was used as the basis for both the
oral RfD and the slope factor for beryllium. Although Identical NOAELs and
animal body weights were used by both workgroups, different transformed
animal doses were derived (0.538 vs. 0.455 mg/kg/day, respectively). This
discrepancy appears to be due to the use of different water consumption
rates (0.035 i/day vs 0.029 i/day). The Crave Workgroup has reevalu-
ated these data and has recalculated the oral slope factor for beryllium
based on the parameters previously described. The resulting slope factor of
4.3 (mg/kg/day)"A was verified by the workgroup (December 1989) and Input
onto IRIS Is pending. The same data set was also used to derive a potency
factor In the 1980 Ambient Water Quality Criteria document (U.S. EPA,
1980a). The greater q^* (8.8) was also due to the use of different
estimates of watef Intake and slightly different mean body weights.
A potency estimate for oral exposure can also be derived by extrapola-
tion from the recommended value of 2 (mg/m3)"1 for Inhalation exposure
(U.S. EPA, 1967). For a 70 kg man breathing 20 m3/dayf making no adjust-
ment for differences In absorption efficiency, the potency would equal 2
(mg/m3)*1 x 70 kg/20 m3/day, or 7 (mg/kg/day)"1. Exposure of
160-180 g Fischer rats to beryllium oxide at a concentration of 447
ug/m3 for 1 hour resulted In the Incorporation of 0.2 yg of beryllium
Into the lung tissue (Hart et al., 1984). Assuming respiration equals
04230
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0.0057 m3/hour, the percent uptake equals 0.2/(0.0057 m® x 447
vg/m3), or 7.79%. Absorption from the GI tract has been reported to
equal 0.6% (Furchner et al.t 1973). Oral uptake can then be estimated to be
0.6/7.79 x 100, or 7.7% as efficient as the Inhalation route. Adjusting for
this difference the extrapolation based oral potency estimate would equal 7
(mg/kg/day)"1 x 0.077, or 0.54 (mg/kg/day)"1.
A carcinogenic potency factor can also be derived from Intravenous
Infusion studies, In which osteosarcomas were Induced. Barnes et a.l. (1950)
Injected rabbits, via the ear vein, twice weekly for 5 weeks with an aqueous
suspension of zinc beryllium silicate containing a total of 7.2 mg beryl-
lium, This amount averaged over the 120-week period of the experiment Is
equal to a dally dose of 0.0086 mg/day. Body weights were estimated to
equal 4 kg and lifespan 6 years. No adjustment was made for a less-than-
Hfetlme observation period since It was shown In other studies that the
osteosarcomas almost always developed within 2 years of exposure. Four of
nine animals surviving 32 weeks or longer developed bone tumors. Based upon
these data, a human carcinogenic potency of 1843 (mg/kg/dayJ"1 for
intravenous Infusion can be derived. After adjustment for an absorption
efficiency of 0.6% an oral potency of 11 (mg/kg/day)"1 1s obtained.
A considerable degree of uncertainty 1s associated with both of the
estimates requiring route extrapolation. Because of the quality of the
Inhalation studies available, the Inhalation q^* has a low degree of
confidence. Extrapolation to the oral route decreases confidence further
since It requires the use of two absorption estimates and since the critical
target organs are likely to be different with possibly differing degrees of
sensitivity. Extrapolation from the Intravenous Infusion route also results
04230 VIII-17 08/14/91
-------
In considerable uncertainty since the dose was given over a short period of
time, the maximum tolerated dose may have been exceeded, the beryllium was
In a different form than commonly found 1n drinking water, small numbers of
animals were used and controls were lacking.
The carcinogenic potency estimate of 4.3 (mg/kg/day)"1, based upon the
Schroeder and Hltchener (1975a) drinking water study, 1s therefore
recommended, despite the lack of a significant tumorlgenlc response. Since
no significant response was detected, this estimate Is an upper-bound value,
that Is, the risk Is not expected to be greater, but may be less than the
derived value. Despite uncertainties In the potency estimates derived from
extrapolation of the Intravenous and. Inhalation studies, the relatively good
agreement with the upper bound carcinogenicity potency estimate Increases
the likelihood that It Is not overly conservative. Limited evidence for
carcinogenicity In the Morgareldge et al. (1975) study( at the same dose
level used by Schroeder and MHchener (1975a), provides further support for
this conclusion.
When the upper bound potency estimate of 4.3 (mg/kg/day)"1 Is applied
to the logarithm for deriving drinking water criteria, the resulting
criteria are:
Exposure Assumptions Risk Levels and Corresponding Criteria (nq/D
(per day)
0
1CT7
1(T«
10"5
2 St of drinking water
0
0.8
8
80
04230
VIII-18
08/14/91
-------
The linearized multistage model Is discussed In the Human Health
Methodology Appendices to the October 1980 Federal Register notice, which
announced the availability of the 1980 Ambient Water Quality Criteria
Documents (U.S. EPA, 1900c). The model 1s linear at low doses, so the
lifetime risk Is proportional to the water concentration. Therefore, other
risk levels and corresponding water concentrations may be obtained by
multiplying or dividing the given criteria by factors of 10, 100, 1000 and
so forth. Levels were obtained by assuming a lifetime exposure to drinking
water containing the corresponding concentrations of beryllium. The
criteria levels pertain to the Incremental risks associated with this route
only since data regarding other sources of beryllium exposure and their
contribution to the total body burden are not adequate for quantitative use.
Existing Guidelines. Regulations and Standards
The World Health Organization has not set a guideline for drinking water
quality for beryllium (IRPTC, 1987). National regulation by 0SHA (1985)
established a PEL - 8-hour TWA of 2 yg/m3, an acceptable .celling limit
of 5 yg/m3, and an acceptable maximum peak above celling of 25 yg/m3
for 30 minutes. The reportable quantity for beryllium and compounds Is 1
pound (U.S. EPA, 1985). Advisories Issued by various agencies for air are
as follows: NI0SH (1972) set an occupational exposure limit of 0.5
yg/m3; ACGIH (1987) advised a TWA-TLV of 0.002 mg/m3 Group A2. The
U.S. EPA (1980a) established an ambient water quality criterion of 68 ng/fi.
for the consumption of 2 l of ambient water and fish and 1170 ng/i for
the consumption of aquatic organisms only for a risk level of 10~5.
04230
VI11-19
09/24/91
-------
The U.S. EPA (1991) has an oral RfD (verified December 1985 ) of 0.005
mg/kg/day based on the lifetime study by Schroeder and Kitchener (1975a) In
which rats were exposed to beryllium sulfate In the drinking water at a
concentration of 5 mg/i beryllium.
The U.S. EPA (1987) has derived a carcinogenic potency factor of
2.4xl0~3 (yg/m3) based on the epidemiologic study by Wagoner et al.
(1980) and the industrial hygiene reviews by NIOSH (1972) and Elsenbud and
Llsson (1983) have been combined to estimate a plausible upper bound for
Incremental cancer risk associated with exposure to air. The upper bound
Incremental lifetime risk associated with 1 yg/m3 of beryllium Is
2.0xl0~3., These values are thought to be most representative for
beryllium oxide, compounds. Potency factors derived from animal studies
using beryllium salts other than oxides provide higher potency estimates,
while potency factors derived from animal studies using beryllium oxide
agree quite well with the risk estimate derived from the human data.
Special Groups at Risk
It has been suggested that a small portion of the population Is sensi-
tive to very low concentrations of beryllium In the air, most likely as a
result of the development of an Immune reaction (Sterner and Elsenbud,
1951). However, this sensitivity has not been demonstrated to occur as a
result of beryllium In food or water, and there Is no evidence that the air
sensitivity Is aggravated by oral exposure. In terms of exposure, persons
engaged In handling beryllium in occupational environments are at risk.
With regard to the population at large, there may be a risk for persons
living near beryllium-emitting Industries.
04230
VII1-20
09/24/91
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04240
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REPORT DOCUMENTATION PAGE
Form Aporcved
QMB No. 0704-0 J38
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acute and chronic toxicity to animals and humans,.epidemiology and mechanisms
of toxicity are evaluated. Specific emphasis is placed on literature data
providing dose-response information. Thus, while the literature search and
evaluation performed in support of this document has been comprehensive, only
the reports considered most pertinent in the derivation of the MCLG are cited
in the document. The comprehensive literature data base in support of this
document includes information published up to 1986; however, more recent data
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