xvEPA
United States
Environmental Protection
Agency
Office of Wnt'-r
Regulations and Standards
Criteria and Standards Division
Washington DC 20460
EPA 440 5-80-024
October 1980
Ambient
Water Quality
Criteria for
Beryllium
-------
AMBIENT WATER QUALITY CRITERIA FOR
BERYLLIUM
Prepared By
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Water Regulations and Standards
Criteria and Standards Division
Washington, D.C.
Office of Research and Development
Environmental Criteria and Assessment Office
Cincinnati, Ohio
Carcinogen Assessment Group
Washington, O.C.
Environmental Research Laboratories
Corvalis, Oregon
Duluth, Minnesota
Gulf Breeze, Florida
Narragansett, Rhode Island
-------
DISCLAIMER
This report has been reviewed by the Environmental Criteria and
Assessment Office, U.S. Environmental Protection Agency, and approved
for publication. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
AVAILABILITY NOTICE
This document is available to the public through the National
Technical Information Service, (NTIS), Springfield, Virginia 22161.
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FOREWORD
Section 304 (a)(l) of the Clean Water Act of 1977 (P.L. 95-217),
requires the Administrator of the Environmental Protection Agency to
publish criteria for water quality accurately reflecting the latest
scientific knowledge on the kind and extent of all identifiable effects
on health and welfare which may be expected from the presence of
pollutants in any body of water, including ground water. Proposed water
quality criteria for the 65 toxic pollutants listed under section 307
(a)(l) of the Clean Water Act were developed and a notice of their
availability was published for public comment on March 15, 1979 (44 FR
15926), July 25, 1979 (44 FR 43660), and October 1, 1979 (44 FR 56628).
This document is a revision of those proposed criteria based upon a
consideration of comments received from other Federal Agencies, State
agencies, special interest groups, and individual scientists. The
criteria contained in this document replace any previously published EPA
criteria for the 65 pollutants. This criterion document is also
published in satisifaction of paragraph 11 of the Settlement Agreement
in Natural Resources Defense Council, et. al. vs. Train. 8 ERC 2120
(D.D.C. 1976), modified, 12 ERC 1833 (D.D.C. 1979).
The term "water quality criteria" is used in two sections of the
Clean Water Act, section 304 (a)(l) and section 303 (c)(2). The term has
a different program impact in each section. In section 304, the term
represents a non-regulatory, scientific assessment of ecological ef-
fects. The criteria presented in this publication are such scientific
assessments. Such water quality criteria associated with specific
stream uses when adopted as State water quality standards under section
303 become enforceable maximum acceptable levels of a pollutant in
ambient waters. The water quality criteria adopted in the State water
quality standards could have the same numerical limits as the criteria
developed under section 304. However, in many situations States may want
to adjust water quality criteria developed under section 304 to reflect
local environmental conditions and human exposure patterns before
incorporation into water quality standards. It is not until their
adoption as part of the State water quality standards that the criteria
become regulatory.
Guidelines to assist the States in the modification of criteria
presented in this document, in the development of water quality
standards, and in other water-related programs of this Agency, are being
developed by EPA.
STEVEN SCHATZOW
Deputy Assistant Administrator
Office of Water Regulations and Standards
111
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ACKNOWLEDGEMENTS
Aquatic Life Toxicology:
Charles E. Stephan, ERL-Duluth
U.S. Environmental Protection Agency
John H. Gentile, ERL- Narragansett
U.S. Environmental Protection Agency
Mammalian Toxicology and Human Health Effects:
William Pepelko, NERL (author)
U.S. Environmental Protection Agency
Michael L. Oourson, (doc. mgr.) ECAO-Cin
U.S. Environmental Protection Agency
Jerry F. Stara (doc. mgr.) ECAO-Cin
U.S. Environmental Protection Agency
Patrick Durkin
Syracuse Research Corporation
Hans Falk
National Institute of Environmental
Health Sciences
Si Duk Lee, ECAO-Cin
U.S. Environmental Protection Agency
Genevieve M. Matanoski
Johns Hopkins University
Samuel Milham, Jr.
Washington State Department of Social
and Health Services
Andrew L. Reeves
Wayne State University
Herbert E. Stokinger
National Institute for Occupational
Safety and Health
Technical Support Services Staff: D.J. Reisman, M.A. Garlough, B.L. Zwayer,
P.A. Daunt, K.S. Edwards, T.A. Scandura, A.T. Pressley, C.A. Cooper,
M.M. Denessen.
Clerical Staff: C.A. Haynes, S.J. Faehr, L.A. Wade, D. Jones, B.J. Bordicks,
B.J. Quesnell, R. Swantack, B. Gardiner, C. Russom.
*CAG Participating Members: Elizabeth L. Anderson, Larry Anderson, Dolph Arnicar,
Steven Bayard, David L. Bayliss, Chao W. Chen John R. Fowle III, Bernard Haberman
Charalingayya Hiremath, Chang S. Lao, Robert McGaughy, Jeffrey Rosenblatt,
Dharm B. Singh, and Todd W. Thorslund.
Roy E. Albert*
Carcinogen Assessment Group
U.S. Environmental Protection Agency
John J. Carroll
U.S. Environmental Protection Agency
Dr. David P. Discher
San Jose Medical Clinic
Philip Enterline
University of Pittsburgh
Jerome Kleinerman
National Institute of Environmental
Health Sciences
Steven D. Lutkenhoff, ECAO-Cin
U.S. Environmental Protection Agency
Robert E. McGaughy, CAG
U.S. Environmental Protection Agency
Hugh Pettigrew
National Cancer Institute
Carl M. Shy
University of North Carolina
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TABLE OF CONTENTS
Criteria Summary
Introduction A-l
Aquatic Life Toxicology B-l
Introduction B-l
Effects B-l
Acute Toxicity B-l
Chronic Toxicity B-3
Plant Effects B-3
Residues B-3
Miscellaneous B-4
Summary B-4
Criteria B-5
References B-14
Mammalian Toxicology and Human Health Effects C-l
Exposure C-l
Ingestion from Water C-l
Ingesiton from Food C-l
Inhalation C-2
Dermal C-3
Pharmacokinetics C-3
Absorption C-3
Distribution C-3
Metabolism C-5
Excretion C-6
Effects C-8
Acute, Subacute, and Chronic Toxicity C-8
Synergism and/or Antagonism C-15
Teratogenicity C-16
Carcinogenicity C-l7
Criterion Formulation C-31
Existing Guidelines and Standards C-31
Current Levels of Exposure C-32
Special Groups at Risk C-33
Basis and Derivation of Criteria C-33
References C-39
Appendix C-58
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CRITERIA DOCUMENT
BERYLLIUM
CRITERIA
Aquatic Life
The available data for beryllium indicate that acute and chronic tox-
icity to freshwater aquatic life occur at concentrations as low as 130 and
5.3 ug/1, respectively, and would occur at lower concentrations among spe-
cies that are more sensitive than those tested. Hardness has a substantial
effect on acute toxicity.
The limited saltwater data base available for beryllium does not permit
any statement concerning acute or chronic toxicity.
Human Health
For the maximum protection of human health from the potential carcino-
genic effects due to exposure of beryllium through ingestion of contaminated
water and contaminated aquatic organisms, the ambient water concentration
should be zero based on the non-threshold assumption for this chemical.
However, zero level may not be attainable at the present time. Therefore,
the levels which may result in incremental increase of cancer risk over the
lifetime are estimated at 10"5, 10~°, and 10~/. The corresponding
recommended criteria are 37 ng/1, 3.7 ng/1, and 0.37 ng/1, respectively. If
the above estimates are made for consumption of aquatic organisms only, ex-
cluding consumption of water, the levels are 641 ng/1, 64.1 ng/1, and 6.41
ng/1, respectively.
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INTRODUCTION
Beryllium, atomic weight 9.01, is a dark gray metal of the alkaline
earth family. It is less dense than aluminum and is used in the production
of light alloys, copper, and brass (Lange, 1956). Its physical properties
include a melting point of 1,287*C and a boiling point of 2,500"C (Windholz,
1976). World production was reported as approximately 250 tons annually,
but much more reaches the environment as emissions from coal burning opera-
tions (Tepper, 1972). Most common beryllium compounds are readily soluble
in water. The hydroxide is soluble only to the extent of 2 mg/1 (Lange,
1956). Beryllium forms chemical compounds in which its valence is +2. At
acidic pH it behaves as a cation but forms anionic complexes at pH greater
than 8 (Krejci and Scheel, 1966). The major source of beryllium in the en-
vironment is the combustion of fossil fuels (Tepper, 1972). Beryllium en-
ters the waterways through weathering of rocks and soils, through atmospher-
ic fallout and through discharges from industrial and municipal operations.
Analyses of surface, ground, and rain waters have shown that, in gen-
eral, beryllium concentrations are well below 1 ug/1. Meehan and Smythe
(1967) reported that the maximum beryllium concentration in 20 rain water
samples and 56 river water samples (from 5 different Australian rivers) was
0.18 ug/1. In a study of beryllium in ground water, drinking water, and
surface water, Reichert (1973) found that even in the heavily polluted Rhine
and Main Rivers (Germany), the concentration was below 0.02 yg/1. Hem
(1970) estimates that the average concentration of beryllium in fresh sur-
face waters is less than 1 ug/1.
Beryllium is concentrated in silicate minerals relative to sulfides. In
common crystalline rocks, the element is enriched in the feldspar minerals
relative to ferromagnesium minerals and apparently replaces the silicon ion;
A-1
-------
85-98 percent of the total crustal beryllium may be bound in the feldspar
structures (Beus, 1966). Beryllium is thought to become concentrated in the
later stages of magmatic differentiation. The greatest known concentrations
of beryllium are found in certain pegmatite bodies, where crystals of beryl
account for a few percent of the total pegmatite volume, and may be found in
several of the strata of zoned-dykes. The element is sometimes concentrated
in hydrothermal veins, and some granitic rocks contain sufficient amounts to
permit the crystallization of small amounts of beryl. During the weathering
of crystalline rocks and during sedimentation processes, beryllium appears
to follow the course of alumium, and it becomes enriched in some bauxite de-
posits, clays, and deep-sea sediments.
Beryllium has a complicated coordination chemistry and can form com-
plexes, oxycarboxylates, and chelates with a variety of materials (Bertin
and Thomas, 1971). In aaueous solution, beryllium does not exist as actual
+2
Be ions, but as hydrated complexes (Cotton and Wilkinson, 1972). Com-
plexing of beryllium may result in soluble beryllium concentrations in ex-
cess of those predicted on the basis of conventional thermodynamic consider-
ations.
A-2
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REFERENCES
Bertin, F. and G. Thomas. 1971. Sur la chimi de coordination du beryl-
lium. Bull. Soc. Chim. 10: 3467. (Fre.)
Beus, A.A. 1966. Distribution of beryllium in granites. Geochemistry
(USSR). 5: 432.
Cotton, F.A. and G. Wilkinson. 1972. Advanced inorganic chemistry. Inter-
science Publishers, New York.
Hem, J.D. 1970. Study and interpretation of the chemical characteristics
of natural water. U.S. Geol. Survey Water Supply Pap. 1473. Washington,
D.C.
Krejci, I.E. and L.D. Scheel. 1966. Ln: H.E. Stokinger (ed.), Beryllium:
Its Industrial Hygiene Aspects. Academic Press, New York.
Lange, N.A., (ed.) 1956. Lange's Handbook of Chemistry. 9th ed. Handbook
Publishers, Inc., Sandusky, Ohio.
Meehan, W.R. and L.E. Smythe. 1967. Occurrence of beryllium as a trace
element in environment materials. Environ. Sci. Techno!. 1: 839.
Reichert, J.K. 1973. Beryllium, ein toxiches element in der mensch-lichen
umgebung unter besonder berucksichtigung seines vorkommens in gewassern.
Vom Wasser. 41: 209.
A-3
-------
Tapper, L.B. 1972. Beryllium. In_: D.H.K. Lee (ed.), Metallic Contami-
nants and Human Health. Academic Press, New York.
Winholz, M. (ed.) 1976. The Merck Index. 9th ed. Merck and Co., Inc.,
Rahway, New Jersey.
A-4
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Aquatic Life Toxicology*
INTRODUCTION
The available data base for the effects of beryllium on fresh-
water organisms is limited to seven species of fishes, two species
of salamanders, one invertebrate species, and one green alga.
Chronic test data are not available for any species of fish. A
chronic test has been conducted with the invertebrate Daphnia
magna. The data on a green alga indicate that it is a resistant
species. Beryllium does not appear to bioconcentrate in fish to a
great extent and has a short half-life in fish tissue.
Hardness and associated alkalinity have been shown to influ-
ence the toxicity of metals to freshwater organisms. The data
indicate that the acute toxicity of beryllium to freshwater fishes
is related to hardness, with beryllium being more toxic in soft
water.
All test results are expressed in terms of the metal.
EFFECTS
Acute Toxicity
Acute toxicity data for one freshwater invertebrate species,
Daphnia magna, are available (Table 1). The 48-hour values are
2,500 and 7,900 /jg/1. Since these tests were conducted at only
slightly different hardnesses, no relationship of toxicity and
hardness could be determined. Compared to toxicity data for fish
*The reader is referred to the Guidelines for Deriving Water
Quality Criteria for the Protection of Aquatic Life and Its Uses in
order to better understand the following discussion and recommenda-
tion. The following tables contain the appropriate data that were
found in the literature, and at the bottom of each table are the
calculations for deriving various measures of toxicity as described
in the Guidelines.
B-l
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species, at approximately the same hardness, Daphnia magna appears
to be comparably sensitive to these fish.
Tarzwell and Henderson (1960) exposed fathead minnows and
bluegills to beryllium in static toxicity tests using both soft and
hard dilution waters (Table 1). They found that beryllium was more
toxic in soft water than in hard water. The 96-hour LC5Q values for
the fathead minnow ranged from 150 ug/1 in soft water to 20,000
jug/1 in hard water. For the bluegill the 96-hour LC5Q values were
1,300 ug/1 in soft water and 12,000 ug/1 in hard water. The 96-
hour LCeQ values for the fathead minnow and bluegill tested in soft
water represent an order of magnitude difference in the sensitivity
of these two species.
Slonim and Slonim (1973) also reported on the effect of water
hardness on the toxicity of beryllium to fish (Table 1). They ex-
posed guppies in static tests to four dilution waters with differ-
ent hardnesses and developed an exponential equation to describe
the relationship of toxicity to hardness. Toxicity increased with
decreasing hardness.
Cardwell, et al. (1976) reported 96-hour LCe0 values for
beryllium for three species of fish using flow-through procedures
and measured concentrations (Table 1). In a dilution water with a
hardness of about 140 mg/1 as CaCO-, the 96-hour LC5Q values ranged
from 3,250 ug/1 for juvenile fathead minnows to 4,800 ug/1 for
juvenile goldfish. Three tests with flagfish fry gave 96-hour LC5Q
values that ranged from 3,530 to 4,440 ug/1.
The fathead minnow was the only species tested using both
static and flow-through conditions. However, the dilution waters
B-2
-------
were not similar; thus it is not possible to evaluate the effect of
test method on these results.
Chronic Toxicity
No chronic tests have been conducted with freshwater fishes.
However, the chronic effects of beryllium on Daphnia magna have
been studied (Tables 2 and 5). In the only typical chronic test
available, effects on reproduction were observed at 7.3 ug/1 and no
effects were observed at 3.8 ug/1. The 48-hour EC5Q determined
with the same species and same water is 2,500 ug/1 (Kimball, manu-
script) which indicates a large difference between acute and chron-
ic toxicity.
A multi-generation test by Lebedeva (1960) with Daphnia magna
resulted in shortened lifespan and reduced reproduction (in the
second generation) at an unmeasured beryllium concentration of 50
ug/1 (Table 5). The result is not used in the derivation of the
chronic value for that species since, according to the Guidelines,
chronic test results mus.t be based on measured concentrations.
Plant Effects
There was one study describing the effects of beryllium on
freshwater plants (Karlander and Krauss, 1972). Growth of the
green alga, Chlorella vannieli, was inhibited at a concentration of
100,000 ug/1 (Table 3).
Residues
A study of bioconcentration of beryllium by the bluegill ex-
posed for 28 days resulted in a bioconcentration factor of 19
(Table 4) with a half-life of one day in the whole body (U.S. EPA,
1978). No maximum permissible tissue concentration is available;
B-3
-------
therefore, a Residue Limited Toxicant Concentration cannot be cal-
culated.
Miscellaneous
Cardwell, et al. (1976) extended the exposure time past 96
hours for the acute tests with fathead minnows and goldfish
(Table 5). For both species there was continued mortality after
96 hours of exposure in the flow-through test. For the fathead
minnow, the LC<-0 value of 3,250 yg/1 at 96 hours decreased to
2,200 ug/1 at 336 hours. For the goldfish the LC50 value of
4,800 ug/1 at 96 hours decreased to 3,300 ug/1 at 240 hours. The
96-hour LC5Q values for the brook trout and channel catfish were
greater than 5,090 jag/1.
Slonim and Ray (1975) conducted acute tests using two species
of salamanders. The two species were similar in sensitivity to the
lethal effects of beryllium, and beryllium was more toxic in soft
water. Sensitivity of the salamanders was similar to that for the
guppy in hard water, but salamanders were less sensitive in soft
water than was the guppy.
Jackim, et al. (1970) observed reduced alkaline phosphatase
activity in the saltwater mummichog at concentrations of beryllium
as low as 9 ug/1. Gross embryonic deleterious effects were ob-
served in the sea urchin at a concentration of 9,010 jjg/1 (Evola-
Maltese, 1957). No other data on the effects of beryllium on salt-
water species are available.
Summary
Acute toxicity data are available for beryllium and the fat-
head minnow, guppy, and bluegill at different levels of hardness
B-4
-------
(about 20 and 400 mg/1) that indicate that over this range of hard-
ness acute toxicity decreases about two orders of magnitude with
increasing hardness. No relationship is available for hardness and
invertebrate species. Of the various fish species tested at simi-
lar levels of hardness, there does not appear to be much difference
in sensitivity. There is only one chronic test with a freshwater
organism and nothing can be said concerning the relationship of
hardness and chronic toxicity. The 48-hour EC5Q and chronic values
for Daphnia magna in the same test water were 2,500 and 5.3 jug/1
which indicates a very large difference between acute and chronic
toxicity. The bioconcentration factor for the bluegill was 19 and
the half-life in tissues was short.
The only data available for beryllium and saltwater species
result from physiological studies with the mummichog and embryonic
development of the sea urchin.
CRITERIA
The available data for beryllium indicate that acute and
chronic toxicity to freshwater aquatic life occur at concentrations
as low as 130 and 5.3 ug/1, respectively, and would occur at lower
concentrations among species that are more sensitive than those
tested. Hardness has a substantial effect on acute toxicity.
The limited saltwater data base available for beryllium does
not permit any statement concerning acute or chronic toxicity.
B-5
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Tab)* 1. Acute values for beryllium
Spiles
Method"
Chemical
Hardness
(•9/1 «*
CaCO,)
LC50/BC50
-------
Table 1. (Continued)
Species
Guppy,
Poecllia
Guppy,
Poecl 1
Guppy,
Poecll
Guppy,
Poec 1 1
Guppy,
Poecll
Guppy,
Poecll
la
la
la
la
la
Guppy,
Poecllia
Guppy,
Poec 1 1
Guppy,
Poecll
Guppy,
Poecl 1
Guppy,
Poec II
Guppy,
Poecl 1
Guppy,
Poecl 1
la
la
la
la
la
la
Method*
retlculata
ret 1 cu 1 ata
retlculata
retlculata
ret 1 cu 1 ata
ret 1 cu 1 ata
ret leu lata
retlculata
retlculata
retlculata
retlculata
retlculata
ret 1 cu 1 ata
Bluegl 1 1,
Lepomls macrochirus
s.
s,
s,
s.
s.
s,
s,
s.
s,
s,
s,
s.
s,
s.
u
u
u
u
u
u
u
u
u
u
u
u
u
u
Chemical
Beryl Hum
su 1 fate
Beryl Mum
su 1 fate
Bery 1 1 1 urn
sulfate
Beryl Hum
sulfate
Beryl 1 lum
su 1 fate
Beryl Hum
su 1 fate
Beryl Hum
su 1 fate
Bery 1 1 1 urn
su 1 fate
Beryl 1 lum
su 1 fate
Beryl Hum
sul fate
Beryl Hum
su 1 fate
Beryl Hum
su 1 fate
Bery II lum
su 1 fate
Beryllium
su 1 fate
Hardness
(ing/I as
CaCO,)
450
450
450
450
22
450
23
23
23
400
275
150
22
400
LC50/EC50
(lig/D"
32,000
28,000
32,000
24,000
160
19,000
450
130
200
20,000
13,700
6,100
160
12,000
Reference
Slonlm,
S lonlm,
Slonlm,
Slonlm,
Slonlm,
Slonlm,
Slonlm,
Slonlm,
Slonlm,
Slonlm
S 1 on 1 m
Slonlm
S 1 on 1 m
Tarzwel
1960
1973
1973
1973
1973
1973
1973
1973
1973
1973
& Slonlm, 1973
& Slonlm, 1973
& Slonlm, 1973
& Slonlm, 1973
1 & Henderson,
B-7
-------
Table I. (Continued)
Specie*
Blueglll,
Lepomls macrochlrus
Method* Chemical
S. U Beryl Hum
su 1 fate
Hardness
(•9/1 as LC50/EC50
CaCOj) (|ia/l)*'
20 1,300
Reference
Tarzwel 1 & Henderson,
I960
* S - static, FT = flow-through, U = unmeasured, M » measured
••Results are expressed as beryllium, not In terms of the compound.
No Final Acute Equation Is calculable since the minimum data base requirements are not met.
B-8
-------
Table 2. Chronic values for terylliiM (Mated, Manuscript)
Hardness Chronic
-------
TabU 3. Plant values for beryl Mum (Kar lander & Krauts, 1972)
Hardness
(•9/1 as Result
Species Chemical CaCOQ Effect (ug/D*
FRESHWATER SPECIES
Green alga. Beryllium - Growth Inhibited 100,000
Chloral la vannlel I chloride at suboptlmum
conditions
* Result Is expressed as beryl Hum, not In terms of the compound.
B-10
-------
Table 4. Residues for beryl HIM (U.S. EPA, 1978)
Species
Blueglll,
Lepo&Js nsacrochlrus
Tissue Che* leal
FRESHWATER SPECIES
whole body Beryllium
chloride
Hardness
(«g/i as
CaCO,)
180
b i oconcentra 1 1 on
factor
19
Duration
(days)
28
B-ll
-------
Table 5. Other data for beryl HIM
species
Chenicai
Hardness
(•g/l as
CaCGO
Duration
Effect
Result
*
Reference
FRESHWATER SPECIES
Ciadoceran,
Daphnla magna
Ciadoceran,
Daphnla magna
Ciadoceran,
Daphnla magna
Brook trout,
Salvellnus fontlnalls
Goldfish,
Carassius auratus
Goldfish,
Carassius auratus
Fathead minnow.
Pimephales proms I as
Channel catfish.
Ictalurus punctatus
Salamander,
Ambystoma macu 1 atum
Salamander,
Ambystoma macu 1 atum
Salamander,
Amby stoma macu 1 atum
Salamander,
Amby stoma macu 1 a turn
Salamander,
Ambystoma macu 1 atum
Salamander,
Ambvstoma macu 1 atum
Bery! Hum
chloride
Bery 1 1 1 urn
nitrate
Beryllium
chloride
Beryl 1 lum
su 1 fate
Beryl Hum
su i fate
Beryl i ium
nitrate
Beryllium
su I fate
Bery 1 1 1 urn
su 1 fate
Beryl Hum
su 1 fate
Beryl Hum
su 1 fate
Bery i 1 lum
su 1 fate
Beryl 1 lum
su 1 fate
Beryl I lum
su 1 fate
Beryl 1 lum
su I fate
^
300
175
140
147
50
140
140
22
22
22
400
400
400
119 days
24 hrs
21 days
96 hrs
240 hrs
3 days
336 hrs
96 hrs
96 hrs
96 hrs
96 hrs
96 hrs
96 hrs
96 hrs
Reproduction
and longevity
LC50
Survival
LC50
LC50
No hatching
of eggs
LC50
LC50
LC50
LC50
LC50
LC50
LC50
LC50
50
18,000
<620
>5,090
3,300
>200
2,200
>5,090
3,150
8,020
8,320
31,500
18,200
18,200
Lebadava, I960
Brlngman & Kuhn, 1977
U.S. EPA, 1978
Cardwel 1, et
Cardwel 1 , et
Hi idebrand &
1978
Cardwel 1, et
Card-s! !, et
Slonlm & Ray,
Slonlm & Ray,
Slonlm & Ray,
Slonlm & Ray,
Sionim & Ray,
Slonlm & Ray,
al. 1976
al. 1976
Cushman,
al. 1976
a!, 1976
1975
1975
1975
1975
1975
1975
B-12
-------
Table 5. (Continued)
Species
Salamander,
Ambystoma opacum
Salamander,
Arobystoma opacum
Chemical
Beryllium
soI fate
Beryllium
sulfate
Hardness
(mg/l
22
400
Duration
96 hrs
96 hrs
Effect
LC50
LC50
Result
(|ig/i)« Reference
3,150 Slonlm & Ray, 1975
31,500 SloniM & Ray, 1975
Sea urchin,
Paracentrotus llvldus
Munmichog,
F unduIus heteroc11tus
Mumnlchog,
Fundulus heteroc11tus
Mummlchog,
Fundulus heteroc11tus
SALTWATER SPECIES
1 hr
96 hrs
96 hrs
96 hrs
Abnormal 9,010
embryonic devel-
opment Including
delay, dwarf Ism,
no ciliary devel-
opment. Incomplete
gastrulatlon
Alkaline phospha- 9
tase activity
Inhibition: 36*
Alkaline phospha- 90
tase activity
Inhibition: 62%
Alkaline phospha- 900
tase activity
Inhibition: 70*
Evo la-Maltese, 1957
Jacklm, at al. 1970
Jacklm, et al. 1970
Jacklm. et al. 1970
* Results are expressed as beryllium, not as the compound.
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REFERENCES
Bringmann, V.G. and R. Kuhn. 1977. Befunde der schadwirkung
wassergefahrdenger stoffe gegen Daphnia magna. Z. f. Wasserund
Abwasser-Forschung. 10: 161.
Cardwell, R.D., et al. 1976. Acute toxicity of selected toxicants
to six species of fish. EPA 600/3-76-008. U.S. EPA, Duluth,
Minnesota.
Evola-Maltese, C. 1957. Effects of beryllium on the development
and alkaline phosphatase activity of Paracentrotus embryos. Acta
Embryol. Morphol. Exp. 1: 143.
Hildebrand, S.G. and R.M. Cushman. 1978. Toxicity of gallium and
beryllium to developing carp eggs (Cyprinus carpio) utilizing cop-
per as a reference. Toxicol. Lett. 2: 91.
Jackin, E., et al. 1970. Effects of metal poisoning for five liver
enzymes in the killifish (Fundulus heteroclitus). Jour. Fish.
Res. Board Can. 27: 383.
Karlander, E.P. and R.W. Krauss. 1972. Absorption and toxicity of
beryllium and lithium in Chlorella vannielii Shihira and Krauss.
Chesapeake Sci. 13: 245.
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Kimball, G. Acute and chronic effects of lesser known metals and
one organic o.n fathead minnows (Pimephales promelas) and Daphnia
magna. (Manuscript)
Lebedeva, G.D. 1960. The effect of beryllium chloride on aquatic
organisms. Zool. Zhur. 39: 1779.
Slonim, A.R. 1973. Acute toxicity of beryllium sulfate to the
common guppy. Jour. Water Pollut. Contr. Fed. 45: 2110.
Slonim, A.R. and E.E. Ray. 1975. Acute toxicity of beryllium sul-
fate to salamander larvae (Ambystoma spp.). 13: 307.
Slonim, C.B. and A.R. Slonim. 1973. Effect of water hardness on
the tolerance of the guppy to beryllium sulfate. Bull. Environ.
Contamin. Toxicol. 10: 295.
Tarzwell, C.M. and C. Henderson. 1960. Toxicity of less common
metals to fishes. Ind. Wastes. 5: 12.
U.S. EPA. 1978. In-depth studies on health and environmental
impacts of selected water pollutants. Contract No. 68-01-4646.
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Mammalian Toxicology and Human Health Effects
EXPOSURE
Ingestion from Water
Kopp and Kroner (1967) reported the results of trace metal
analyses of 1,577 drinking water samples obtained throughout the
United States. Beryllium was detected in 5.4 percent of the sam-
ples. Concentrations ranged from 0.01 to 1.22 ug/1, with a mean
value of 0.19 ug/1.
Ingestion from Food
Petzow and Zorn (1974) found beryllium concentrations (dry
weight) of 0.08 mg/kg in polished rice, 0.12 mg/kg in toasted
bread, 0.17 mg/kg in potatoes, 0.24 mg/kg in tomatoes, and 0.33
mg/kg in head lettuce.
Meehan and Smythe (1967) determined beryllium levels in a var-
iety of foodstuffs. Beryllium levels (ppm in ash) for different
foodstuffs were: beans, 0.01; cabbage, 0.03; hen eggs, 0.01 (yolk);
milk, 0.02; mushrooms 0.12; nuts, 0.01-0.47; tomatoes, 0.02; and
baker's yeast, 0.02.
A bioconcentration factor (BCF) relates the concentration of a
chemical in aquatic animals to the concentration in the water in
which they live. An appropriate BCF can be used with data concern-
ing food intake to calculate the amount of beryllium which might be
ingested from the consumption of fish and shellfish. An analysis
(U.S. EPA, 1980) of data from a food survey was used to estimate
that the per capita consumption of freshwater and estuarine fish
and shellfish is 6.5 g/day (Stephan, 1980).
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A measured BCF of 19 was obtained for beryllium using blue-
gills (U.S. EPA, 1978). For lack of other information, a value of
19 can be used as the weighted average bioconcentration factor for
beryllium and the edible portion of all freshwater and estuarine
aquatic organisms consumed by Americans.
Inhalation
The detection of beryllium in air is infrequent and usually in
trace amounts. According to Tabor and Warren (1958) and the Na-
tional Air Sampling Network (1968), beryllium was present in 12
percent of 440 samples analyzed from 16 cities. Concentrations
ranged from 0.001 to 0.002 ug/m in urban areas and considerably
lower (0.00013 ug/m ) in more rural areas. The U.S. EPA (1971)
found that samples collected at 100 stations during 1964 to 1965
had a 24-hour average beryllium concentration of less than 0.0005
ug/m . The maximum beryllium value was 0.008 jug/m . At a beryl-
lium extraction plant in Ohio, beryllium concentrations were gener-
ally around 2 ug/m over a 7-year period (Breslin and Harris,
1959).
The burning of coal for space heating and electric power gen-
eration appears to constitute the greatest threat to the environ-
ment from beryllium. Tepper (1972a) calculated that if 500 million
tons of Illinois and Appalachian coal with a beryllium content of
2.5 ppm were burned annually, the potential release of beryllium
from coal in this country would approximate 1,260 tons or five
times the world production. This could result in considerable con-
tamination of soil, water, and plants as well as air.
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Dermal
Exposure to soluble beryllium compounds can cause contact der-
matitis. It is not readily absorbed, however, since ionic beryl-
lium becomes bound to epidermal constituents, mainly alkaline phos-
phatase and nucleic acids (Belman, 1969). In general, the inci-
dence of beryllium dermatitis is primarily confined to occupational
exposure.
PHARMACOKINETICS
Absorption
Studies by Hyslop, et al. (1943) showed the amount of beryl-
lium retained by animals was small (0.006 percent) compared with
that ingested. A reason for the limited absorption was due to pre-
cipitation of soluble salts in the alimentary tract while the in-
soluble compounds were not appreciably dissolved in serum or gas-
tric juice. Low absorption was also described by Reeves (1965) who
reported that 60 to 90 percent of the beryllium ingested by rats
was recovered in the feces.
Distribution
Although the lungs are the primary point of entry for beryl-
lium, they are not the principal site of deposition for soluble
beryllium compounds. Citrated beryllium was almost completely mo-
bilized from the lungs within 4 days following exposure (Van Cleave
and Kaylor, 1955). Insoluble beryllium compounds such as beryllium
ores, however, tend to remain in the lung indefinitely (Wagner, et
al. 1969). Only 12 to 21 percent of high temperature-fired BeO
aerosols were cleared from the lungs of rats in 63 days (Sanders,
et al. 1974). Increased levels of beryllium have been reported in
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the lymph nodes and lungs of humans more than 20 years after ter-
mination of occupational exposure (Sprince, et al. 1976).
Van Cleave and Kaylor (1955) studied the distribution of
beryllium in rats. Following intravenous administration, beryllium
was carried to all tissues and could be detected in most organs.
During the first several weeks after injection, smaller doses (50
jjg Be/kg) tended to accumulate in the skeleton and larger doses
(500 ug Be/kg) in the liver. After about 100 days beryllium was
gradually mobilized from the liver of rats and transferred to the
skeleton.
Studies with intravenously or intramuscularly injected Be, a
strong gamma emitter, indicated that both ionic and citrate-com-
plexed beryllium were definitely bone seekers (Crowley, et al.
1949; Klemperer, et al. 1952). Bone radiographs of the distal end
of the femur revealed deposits of beryllium in osteoid tissue adja-
cent to the epiphyseal plate (Raylor and Van Cleave, 1953). Stud-
ies with BeO, injected intratracheally in rats, indicated that the
greatest concentrations were deposited in the bone with the next
most common sites being spleen, liver, kidney, and muscle (Spencer,
et al. 1972).
Beryllium was shown to have a special affinity for nuclei and
nucleoli in lung and liver cells (Witschi and Aldridge, 1968;
Robinson, et al. 1968). According to Reeves (1977) the concensus
of studies indicated that the bulk of circulating beryllium is in
the form of a colloidal phosphate, probably adsorbed on plasma
-------
Metabolism
Early work concerning the metabolism of beryllium centered on
its effects in producing rickets in animals. Several enzyme sys-
tems such as alkaline phosphatase (Klemperer, et al. 1949; Grier,
et al. 1949), phosphoglucomutase (Hashimoto, et al. 1967), and so-
dium and potassium activated ATPase (Toda, 1968) have been shown to
be inhibited by micromolar beryllium concentrations. The ricket-
producing effects of beryllium were thought to be due partly to the
alkaline phosphatase inactivating action of beryllium, causing, in
particular, an inhibition of endochondreal calcification of cartil-
age (Vorwald, et al. 1966).
Earlier studies suggesting that immunologic mechanisms are im-
plicated in the toxicology of beryllium in chronic beryllium dis-
ease (Sterner and Eisenbud, 1951) are supported by more recent evi-
dence. For example, Alekseeva (1965) produced hypersensitivity in
guinea pigs by intradermal beryllium injections. Belman (1969)
developed hypersensitivity in guinea pigs by the application of
beryllium fluoride to the skin. Vasil eva (1969) induced skin
hypersensitivity to beryllium chloride in rats.
In humans, Curtis (1951) showed that application of a cutane-
ous patch test containing nonirritating concentrations of soluble
beryllium could elicit a positive reaction on subsequent testing of
the same material. Resnick, et al. (1970) measured immunoglobulin
fractions and showed increased IgG in most patients who previously
had acute beryllium reactions or a history of dermatitis.
Kharlamova and Potapova (1968) have shown that beryllium can
be concentrated in the nuclei, while others (Marcotte and Witschi,
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1972; Witschi, 1968, 1970) reported that beryllium interferes with
DNA metabolism in the liver.
Beryllium has also been reported to induce chromosomal and
mitotic abnormalities in cell cultures (Vegni-Talluri and
Guiggiani, 1967). Exposure of calf thymus DNA to a 0.056N concen-
tration of beryllium caused molecular aggregation and flocculation,
pointing to an irreversible and deleterious effect of beryllium on
nucleic acid (Needham, 1974). More recently, it has been shown
that the beryllium ion (Be"*" ) increases the misincorporation of
nucleotides during polymerization by DNA polymerase (Luke, et al.
1975; Loeb and Sirover, 1977). A possible mechanism was considered
to be associated with an inhibition of 3',5'-exonuclease activity.
This exonuclease which is an integral part of the polymerase is
thought to perform an editing function to remove noncomplementary
(incorrect) nucleotides during polymerization (Brutlag and
Kornberg, 1972). Sirover and Loeb (1976) however, using polymerase
+ 2
from avian myeloblastosis virus, showed that Be altered the ac-
curacy of DNA synthesis. This polymerase lacks 3" - 5' proof read-
ing exonuclease activity and thus may not excise a mismatched
nucleotide. These results show that beryllium can influence the ac
curacy of DNA replication in vitro and suggest that it may have the
same effect ir\ vivo.
Excretion
Small doses of intravenously administered Be in rats tended
to be either excreted mostly in the urine or deposited in the kid-
ney or bone (Scott, et al. 1950). Van Cleave and Kaylor (1955)
reported that citrated beryllium sulfate given intratracheally was
C-6
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almost completely mobilized from the lungs after 4 days. Seventy-
nine percent was eliminated, primarily in the urine, with the re-
mainder deposited in the bones. At tracer levels, the non-citrated
beryllium sulfate remained in the lungs somewhat longer but was al-
so mobilized at a rapid rate after 16 days. Ultimately, the
amounts deposited in the skeleton and excreted did not differ in
comparison with the citrated form. Zorn, et al. (1977) reported
that the concentration of beryllium from aerosol inhalation was
high in the alveoli and nasopharyngeal region, but low in the ter-
minal bronchioles. Evidently ciliary action clears the small air-
ways quite rapidly. In general, a fraction of a dose of beryllium
taken in either through the lung or digestive tract is excreted
fairly quickly, with most of the remainder ultimately stored in the
long bones. Once deposited it is removed very slowly. The half-
life for Be was reported to equal 1,210, 890, 1,770, and 1,270
days in mice, rats, monkeys, and dogs, respectively (Furchner, et
al. 1973).
Underwood (1951) showed tubular excretion mechanism. Attempts
to rid the body of deposited beryllium with chelating agents have
been successful in animal experiments (Schubert and White, 1950;
Schubert and Rosenthal, 1959) but not in clinical experience
(Dequinalt and Haguenoer, 1973). In studies conducted with cows an
insignificant amount of injected radioactive beryllium was re-
covered in the milk (Mullen, et al. 1972).
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EFFECTS
Acute, Subacute/ and Chronic Toxicity
Intravenous beryllium is highly toxic to animals in small
doses. The LD5Q for 200 g male rats injected intravenously with
soluble beryllium salts was reported to be 0.44 mg Be/kg (Witschi
and Aldridge, 1967), and 0.51 mg Be/kg for female rats injected
with BeSO. (Vacher and Stoner, 1968). Death was attributed to bio-
chemical disturbances caused by progressive destruction of liver
tissue (Aldridge, et al. 1949). The toxicity of beryllium was
greatly decreased when ingested. The oral LD5Q of BeCl- in rats
was reported to be 9.7 mg/kg as Be (U.S. EPA, 1977). Rats survived
for several weeks when fed diets containing up to 2 percent beryl-
lium carbonate (Guyatt, et al. 1933) and at least 50 days when fed
0.24 gm/day beryllium carbonate (0.03 gm/day Be) (Businco, 1940).
There have been no reported cases of oral toxicity in humans.
Inhaled BeO aerosol at a concentration of 194 ^ag/rn Be was
acutely toxic to rats while 42 ug/m produced pathologic changes
within 3 months (Vorwald, et al. 1966). Concentrations acutely
toxic in humans are less well defined. For example, concentrations
of 30 mg/m beryllium oxide in the air produced no acute cases in
one short-term exposure of humans, while in another 4 mg/m pro-
duced both a high incidence of acute disease and fatalities (Na-
tional Academy of Science (NAS, 1958). The differences were proba-
bly due to the temperature at which beryllium oxide was produced.
If calcined at 500°C a relatively soluble product with large sur-
face area is formed while calcining at 1,600°C results in an in-
soluble form. Beryllium oxide calcined at 500°C caused pulmonary
C-8
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damage in rabbits at dose levels of 2 mg/kg body weight when given
intratracheally while beryllium oxide calcined at 1,600°C produced
no reaction greater than expected for an inert dust (Spencer, et
al. 1968).
Acute disease has occured in humans following inhalation of
highly soluble beryllium salts at concentrations lower than 100
ug/m (Rail, et al. 1959). Unfortunately, the time periods for the
above exposures were not specified. A report by the National
Academy of Sciences (NAS, 1958) indicated that acute beryllium
disease did not occur in humans at ambient air concentrations of 25
yg/m or less. In the same report no lung damage was reported in
experimental animals exposed to 40 jug/m . Hardy (1955) reported
that acute beryllium poisoning is related to the intensity of
exposure with removal leading to a disappearance of symptoms.
Tepper, et al. (1961) arbitrarily defined acute beryllium dis-
ease to include those beryllium induced disease patterns with less
than 1 year natural duration. Diseases fitting this definition
will be included in this category. The symptoms of acute toxicity
have been described in detail by Tepper, et al. (1961), De Nardi,
et al. (1953) and Hardy and Stoeckle (1959).
Acute skin effects include contact dermatitis characterized by
reddened, elevated, or fluid-accumulated lesions on exposed sur-
faces (Van Ordstrand, et al. 1945). This disease has not been seen
in workers handling insoluble forms of beryllium such as beryllium
hydroxide, pure beryllium, and vacuum cast beryllium (Comm. Occ.
Dis. Chest, 1965), but may occur following contact with soluble
beryllium salts (McCord, 1951).
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Beryllium ulcers result from implantation of soluble or insol-
uble beryllium materials in cutaneous areas previously injured as a
result of abrasions, cuts, etc. Removal of the foreign material is
necessary for healing to take place.
Ocular effects include inflammation of the conjunctiva from
splash burns or in association with contact dermatitis (Van
Ordstrand, et al. 1945). Corneal burns may occur resembling those
produced by acids and alkalis.
Respiratory effects include rhinitis, pharyngitis, tracheo-
bronchitis, and acute pneumonitis. The following response to a
relatively soluble compound, beryllium oxide calcined at 500°C, was
described by Tepper (1972b) as a widely dispersed focal pneumonitis
of granulomatous nature. The lesions had a dense central core of
proliferating histiocytes clustered around aggregations of beryl-
lium oxide particles often invested by epitheliod cells and one or
two layers of fibroblasts. A few lymphocytes, plasma cells, or oc-
casional multinucleated giant cells participated in the reaction.
With time the lesions became less cellular, more collagenous, and
finally hyalinized. The degree of effects can vary widely, with
recovery times ranging from 1 to 6 weeks for mild cases and up to 6
months after acute pneumonia. Tepper, et al. (1961) reported 18
cases of acute beryllium pneumonitis fatalities following develop-
ment of pulmonary edema.
Beryllium rhinitis and pharyngitis involve inflammation of the
nasal mucosa and pharynx, frequently accompanied by mild nose-
bleeds. Fluid and blood accumulate in the mucous membranes and
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ulcerations occur. This condition is difficult to diagnose since it
closely resembles that seen with the common cold.
Acute tracheobronchitis also results in nonspecific symptoms.
The effects are characterized by nonproductive spasmodic cough,
substernal discomfort, burning, tightness of the chest, and mod-
erate difficulty with breathing upon exertion. Recovery is usually
complete within 1 to 4 weeks (De Nardi, et al. 1953).
Most of the acute respiratory symptoms and pathologic changes
cannot be differentiated from the inflammatory reaction to other
types of irritants. Positive identification may require a know-
ledge of past exposure and possible tissue analysis. The onset of
acute respiratory symptoms can occur within a few hours after brief
exposure to a high concentration of beryllium. More commonly, how-
ever, the illness is insidious in nature, developing over 1 to 3
weeks (Tepper, et al. 1961).
Acute pneumonitis has been produced by inhalation of virtually
all beryllium compounds. These include beryllium metal, oxide,
sulfate, fluoride, hydroxide, and chloride (Durocher, 1969). The
acute changes result from the inhalation and deposition of beryl-
lium compounds either as mists of the soluble salts or as fumes and
dust of the relatively insoluble compounds, primarily the oxides.
Chronic beryllium disease differs from the acute form in sev-
eral ways: (1) its occurrence is often separated from the time of
exposure by periods ranging up to several years; (2) it has a pro-
longed duration with little evidence of a lasting cure; (3) it is
commonly progressive in spite of cessation of exposure; and (4) it
is a systemic disease (Tepper, et al. 1961). A study of chronic
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beryllium cases by Hardy and Stoeckle (1959) showed the latent per-
iod between last exposure and the onset of symptoms to vary, with
41 percent of the symptoms being manifested in the first month and
29 percent in 1 to 5 years. The most common clinical symptoms in-
clude granulomatous inflammation of the lungs, with accompanying
cough, chest pain, and general weakness (Hardy and Stoeckle, 1959).
Systemic effects include right heart enlargement with accompanying
cardiac failure, enlargement of the liver and spleen, cyanosis,
digital clubbing, and the appearance of kidney stones (Hall, et al.
1959). A systemic effect reported in dogs, rabbits, and rats, but
not in man, is the development of a macrocytic anemia (Stokinger,
et al. 1951).
One of the earliest observed effects of beryllium toxicity was
the development of a rachitic bone change after addition of soluble
beryllium salts to the diet of poultry and livestock (Branion, et
al. 1931; Guyatt, et al. 1933; Kay and Guyatt, 1933; Kay and Skill,
1934). Osteosclerotic changes were also noted in rabbits when
beryllium was given intravenously (Gardner and Heslington, 1946).
Beryllium rickets is a disease that has not been reported in
man. While there is no reason to believe it cannot be induced in
humans, the concentrations in the food or water required to produce
rickets in animals (0.125 percent beryllium carbonate for a mild
case) make this an unlikely occurrence (Guyatt, et al. 1933).
The predominant pulmonary pathology consists of an intersti-
tial diffuse inflammatory process which is distinctively chronic in
nature and without the edemetous and exudative changes seen in
acute disease. The scattered focal lesions are composed mainly of
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large monocytes and are irregular in shape due to extensions into
contiguous alveolar walls which are variously thickened with in-
flammatory cells (Vorwald, 1966). Granulomatous lesions are also
seen in skin, liver, kidney, lymph nodes, and skeletal muscles
(Dudley, 1959).
Chronic beryllium disease can be produced in experimental an-
imals with low concentrations of soluble beryllium compounds. Rats
exposed for up to 6 months to an aerosol of 35 jug/m BeSO. developed
typical chronic pneumonitis along with granulomatous lesions and
some neoplasms (Schepers, et al. 1957). Exposure of monkeys to 35
jjg/m BeSO. or to intratracheal instillations of a 5 percent sus-
pension of beryllium oxide resulted in chronic pneumonitis in all
animals (Vorwald, et al. 1966). Exposure of rats for 560 days to
aerosols containing 2.8 ug/m beryllium did not result in signifi-
cant effects while 21 jug/m produced changes only in long surviving
rats (Vorwald, et al. 1966).
Concentrations of beryllium resulting in chronic disease in
humans are more difficult to determine. Chronic and acute beryl-
lium poisoning were common prior to setting of air standards in
1949, but lack of consistent monitoring prior to this time makes it
difficult to relate exposure levels to disease. Ambient air con-
centrations were evidently quite high. For example, a 1946 survey
of a beryllium plant by Laskin, et al. (1946) indicated beryllium
dust concentrations of 110 to 533 ug/m" during beryllium furnace
coke removal operation, zielinski (1961) reported levels of 11,330
to 43,300 wg/m in a beryllium alloy plant.
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Since the early 1950's, evidence has been presented indicating
that the 2 ug/m standard was generally being met. For example, at
one beryllium extraction plant, ambient air concentrations measured
over a 7 year period were at or below 2 ug/m (Breslin and Harris,
1959). Williams (1961) presented results of surveys of beryllium
exposures in 15 plants of various types which indicated that expo-
sures were effectively controlled below the current standard in the
preponderance of cases. Nevertheless, 76 new cases of beryllium
disease have been added to the Beryllium Case Registry (BRC) from
1966 to 1974 of which at least 36 involved exposure since 1949
(Hasan and Kazemi, 1974).
A more recent study indicated that beryllium pollution was not
being effectively controlled at all production facilities.
Kanarek, et al. (1973) reported that ambient air concentrations at
a beryllium extraction and processing plant ranged up to 50 times
that of the accepted peak concentration of 25 jjg/m . Some of the
concentrations are listed here:
Range of beryllium..
Location Operation concentration ug/m
A. Billet Plant All 0.35-213
Fluoride area 0.67-213
Reduction 0.43-22.5
Hydroxide 2.0-33.2
Bead handling 1.8-88
B. Fabrication Plant All 0.31-1,310
vacuum drying 1.74-1,310
Vacuum furnace 3.67-15.31
Die loading 7.0-24.4
Power handling 7.85-219
Material transfer 3.90-1,290
Machine shop 0.31-6.4
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Two hundred fourteen of the 245 full-time employees at this plant
were studied in 1971. Thirty-one had chest radiographic abnormal-
ities compatible with interstitial disease and 20 had hypoxemia at
rest. A followup was conducted during 1974 (Sprince, et al.
1978). New engineering and safety controls had resulted in a de-
crease in peak concentrations of beryllium to less than 25 jug/m in
all work areas. In the vacuum drying area the peak concentration
had decreased from 1,310 jug/m to lass than 2 ug/m . Improvement
was noted in 13 of 20 workers previously identified as hypoxemic.
Eighteen of 31 with radiographic abnormalities in 1971 were avail-
able for followup. Of these 9 had reverted to normal.
Not all cases of chronic beryllium disease occurred during
industrial exposure. Sterner and Eisenbud (1951) reported 13 cases
in a population living within 3/4 of a mile from one beryllium
plant. Air concentrations of beryllium were reported to range from
0,01 to 0,1 ug/m , By 1960 the Beryllium Case Registry contained
47 well-documented cases of so-called neighborhood disease (Tepper,-
et al. 1961), Lieben and Williams (1969) reported that all the
nonoccupational cases studied by them could be attributed to con-
tact with beryllium through routes other than outdoor air pollu-
tion. This included handling of polluted garments or other contact
with contaminated objects or people. It is thus uncertain whether
concentrations of 0.01 to 0.1 ug/m beryllium in the air can cause
beryllium disease.
Synergism and/or Antagonism
Studies conducted in attempting to discover a therapeutic
agent that would neutralize the acute biologic effect of toxic
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beryllium compounds were summarized by vorwald, et al. (1966). The
only compound discovered up to this time having a reasonable degree
of effectiveness in laboratory animals was aurintricarboxylic acid
(ATA). This compound formed a chelate that tended to accumulate in
the kidneys and spleen but not in the bones. The use of salicylates
in conjunction with ATA was also considered beneficial. ATA was
mildly toxic with an intravenous LD5Q of 440 mg/kg for mice and 450
mg/kg for rats. The use of chelating agents for the alleviation of
chronic poisoning, however, was not effective in clinical trials
(Reeves, 1977).
Beryllium oxide was reported to potentiate the carcinogenicity
of 20-methyl cholanthrene (20-MC) to a much higher degree than did
carbon black (Uzawa, 1963). The fluoride ion has a synergistic
effect on the acute toxicity of beryllium. Inhaled BeF2 produced
about twice the toxic effect in laboratory animals as BeSO. at any
given concentration (Stokinger, et al. 1950).
Teratogenicity
Information relating to possible teratogenic effects of beryl-
lium is limited. Beryllium is reported to inhibit the embryonic
development of the snail, Lymnea stagnails, resulting in peculiar
morphogenic abnormalities (Raven and Spronk, 1953). Thornton
(1950) observed inhibition of regeneration of the limbs of the
salamander, Amblystoma punctatum, when immersed in 0.05 molar
beryllium nitrate solution. A pregnant rat fed 75 mg beryllium
carbonate daily delivered three offspring of normal weight and
appearance. Treatment, however, was not begun until the 18th day of
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pregnancy, well past the critical period for teratogenic effects
(Businco, 1940).
Care inogen ic ity
Lung cancer and bone cancer, or osteosarcoma, are the two
types of malignancies commonly induced in experimental animals by
beryllium. Osteosarcoma was first reported by Gardner and
Heslington (1946). Their results have since been confirmed numer-
our times. These studies are listed in Table 1. As can be seen in
the table, the great majority of the studies were carried out using
rabbits injected intravenously. Dutra, et al. (1951) reported the
only case of osteosarcoma from inhalation of a beryllium compound.
Most compounds tested appeared to be effective in producing osteo-
sarcoma when injected intravenously, even metallic beryllium.
Studies designed to induce lung cancer are listed in Table 2.
As can be seen, inhalation or intratracheal instillation of the
beryllium compounds were the primary routes of administration. The
lung was not the primary site of cancer induced by intravenous
injection but this was due to metastases from the bone. In gener-
al, the more soluble compounds are more effective in producing both
lung cancer and berylliosis. For example, beryllium oxide produced
at a temperature of 500°C was much more effective than that pro-
duced at 1,600°C, with the primary difference being solubility
(Spencer, et al. 1968).
As reviewed previously, large concentrations of beryllium car-
bonate were fed to animals in the 1930s to produce a type of osteo-
sclerosis. Although osteosarcoma was not reported, the experiments
were generally terminated before the development of cancer would be
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TABLE 1
Induction of Osteosaccomas in Experimental Animals by Beryllium
Compound
Decylli urn
ox ide
Dose
6 mg/m3
Not
reported
90-660 mg
as Be, 13-
116 rag/kg
body wt.
as Be
100-200 mg
total
Injections
1,250 mg
total
Large
animals:
1 gm. total
small
animals:
<1 gm.
100 mg
total
450 mg
total
300 mg
total
Exposure route Exposure duration Species responding*
Inhalation 5 hrs/day, 5 days/ Rabbit 16
wk. ,11 mos.
Multiple Rabbit 25
intravenous
17-21 Rabbit 89
intravenous
injections
1-45 Rabbit 0
intravenous
Intravenous 25 wkly Injections Rabbit 72
injection
Intravenous Rabbit 6
Injection 10 wkly injections Rabbit 60
into femur
Injection 45 wkly injections Rabbit 88
into femur
1 injection Rabbit 70
into femur
Time of
measurement Reference
(mos. )
11 Outra, et al. 1951
Not reported Mash, 1950
9*- Dutra d Largent,
1950
Not reported Kawada, 1963
Not reported Fodor, 1971
15 Komitowski, 1969
19 Kawada, 1963
11 Kawada, 1963
12 Kawada, 1963
C-18
-------
TABLE 1 (continued)
Compound
Be r y 1 1 i ura
ox ide
Z inc
beryllium
oxide
Dose
300 rag
total
10 mg
220-400
mg
420-600
mg
620-800
mg
820-860
mg
I gm
total
1 gn
1 g»
Exposure route
Injection, femur
per iosteum
Implanted under
right tibia
per iosteum
Injected
into femur
Injected
into femur
Injected
into femur
Injected
into femur
Intravenous
Multiple
intravenous
injections
Intravenous
Exposure duration
Twice wkly for
1-43 weeks
Twice wkly for
1-43 weeks
Twice wkly for
1-43 weeks
Twice wkly for
1-43 weeks
20 injections
over 6 wks
22 semi -wkly
injections
c . Percent
species responding»
Rabbit 78
Rabbit 33
male and
female
Rabbit 89
Rabbit 100
Rabbit SO
Rabbit 75
Rabbit 100
Rabbit 25
Rabbit 80
Time of
measurement
(mos. )
14.5
10-25
85 days-average
latency from last
injection
85 days-average
latency from last
injection
85 days-average
latency from last
injection
85 days-average
latency from last
injection
7*
30 +
12 +
Reference
Kawada, 1963
Tapp, 1969
Yamaguchi t
Katsura. 1963
Yamaguchi t
Katsura, 1963
Yamaguchi &
Katsura, 1963
Yamaguchi fc
Katsura, 1963
Gardner fc
liealington, 1946
Darnes, et al.
1950
Sissons, 1950
Cloudman, et al.
1949
C-19
-------
TADI.E 1 (continued)
Compound
Zinc
be r y 1 1 i urn
silicate
Uei y 11 i urn
si 1 ica te
Mctall ic
bor yll i um
Dose
0.264 rag
1 gm
total
1 gra
total
Not
reported
1 gra
total
10 mg
33 mg
as De
10 mg
40 mg
Exposure route Exposure duration
Multiple
intravenous
injections
Intravenous 10 wkly injections
Intravenous 20 twice-wkly
injections
Intravenous 10 wkly
injections
Injection 20 wkly
injections
Implanted under
right tibia
per iosteum
Injection
intra-osseous
Implanted under
right tibia
per iosteum
Intravenous
Species
Mice
Rabbit
Rabbit
Rabbit
Rabbit
Rabbit
Rabbit
Rabbit
Rabbit
Percent
responding*
Some positive
percent not
repor ted
Some positive
percent not
reported
SO
71
30
16
70
16
40
Time of
measurement
(roos. )
, Not reported
11-24
9-11
9-14
Not reported
10-25
4
10-25
Hot reported
Reference
Cloudman, ct al.
1949
lloagland, et al.
1950
James, et al. 1954
Kelly, et al. 1961
Iliggins, et al.
1964
Tapp, 1969
Mazabraud, 1975
Tapp, 1969
Darnes, ct al.
1950
C-20
-------
TABLE 1 (continued)
Compound
Deryll iura
phosphate
Beryllium.
phosphor
Dose
16 mg
total
90 mq
80 mg
64 mg
Exposure route Exposure duration Species *f°j? „» measurement
respond >ng* (mos.)
Injection 10 wkly injections Rabbit Some positive, 11-24
percent unknown
Intravenous Rabbit 1/1 12-14
Intravenous Rabbit 1/1 12-14
Intravenous Rabbit 0/1 12-14
Reference
lloagland, ct al.
1950
Dutra I Largent,
1950
Dutra fc Largent,
1950
Dutra fc Largent,
1950
•Percent exhibiting tumors or cancer
al gm of zinc beryllium silicate contains 33.6 mg of Be expressed as the oxide
De oxide, Zn oxide and silica in a molar ratio of 1:1:1
C-21
-------
TABLE 2
Induction of pulmonary cancer tn experimental animals by beryllium
Compound Dose
Deryll i urn . 11 mg
sulfate as Be
55 ug/m3
as De
6 ug/m3
as De
620 pg/m3
35 ug/ra
as De
2. 32 mg/ra3
0.20 mg/mj
as Be
42 ug/ra3
as Be
21 ug/m3
as Be
2.8 ug/m3
as Be
35 ug/m3
as Be
34 ug/m3
as Be
Exposure route
Intratracheal
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalat ion
Inhalation
Inhalation
I nha lat ion
Exposure duration
6 hrs/day, 5 days/
wk until sacrifice
6 hrs/day, 5 days/
wk until sacrifice
6 mos
6 hr/day, 7 days
7 hrs/day, 5 days/
wk, IB mos.
7 hrs/day, 5 days/
wk, 18 mos.
7 hrs/day, 5 days/
wk, 18 mos.
7 hrs/day, 5 days/
wk, 18 mos.
7 hrs/day, 5 days/
wk, until sacrifice
Time of
PŁ |" Cfi n t
Species •«=»». «=•_•!. measurement
v responding (mos.)
Rat
Rat
Rat
Rat
Monkey
Macacus
mullata
Rat
Rat
Rat
Rhesus
monkey
Rat, male
6 female
Some positive, 9 or longer
percent not
reported
Some positive, 9 or longer
percent not
reported
Some positive, 9 or longer
percent not
repor ted
Some positive 18
percent not
reported
0, only 1 of 4 6
survived 180
days
Almost 100 18
Almost 100 18
62 18
20, 2 of 10 5-6 yrs
exposed 3,241
& 3,871 hrs
100 13
Reference
Vorwald t Reeves,
1959
Vorwald l Reeves,
1959
Vorwald & Reeves,
1959
Schepers, 1961
Schepers, 1964
Vorwald, et al.
1966
Vorwald, et al.
1966
Vorwald, et al.
1966
Vorwald, et al.
1966
Reeves, et al.
1967
C-22
-------
TABLE 2 (continued)
Compound
Beryllium
ox ide
Be r y 1 1 i um
f luor ide
Dose
4.5 mg
as De
250-
500 mg
25 mg
calcined
at 500°C
25 mg/kg
calcined
at 1,100°C
25 mg
calcined
at 1600°C
50 mg/kg
calcined
at 500°C
50 mg/kg
calci ned
at 500 C
50 mg/kg
calcined
at 500°C
48 wg/m3
950 ug/m3
100 jjg/ro3
as lie
Exposure route Exposure duration
Intratracheal
Intratracheal
and/or broncho-
mural
Intratracheal
Intratracheal
Intratracheal
Intratracheal
Intratracheal
Intratracheal
Inhalation 6 mos.
Inhalation 6 hrs/day,
7-16 days
Time of
Species Percent measurement
K responding (mos )
Rat
Rhesus
monkey
Rat, males
and females
Rat, males
and females
Rat, males
and females
Rat, female
Rat, female
Rat, female
Rat
Monkey
Macacus
mullata
Some positive, 9 or longer
percent unknown
15 54 +
100 15-20
25 15-17
30 18-24
0 11
40 17
100 23
Some positive, 15
percent unknown
0, all died less than 1
within 28 days
of exposure
Reference
Vorwald s. Reeves,
1959
Vorwald, et al.
1966
Spencer, et al.
1968
Spencer, et al.
1968
Spencer, et al.
1968
Spencer, et al.
1972
Spencer , et al.
1972
Spencer, et al.
1972
Sctiepers, 1961
Schepers, 1964
C-23
-------
TABLE 2 (continued)
Compound
fiery Ilium
flouride &
chlor ide
DC i y 1 1 i urn
phosphate
Zinc
beryll iura
sil icate
Beryl oce
Dose Exposure route Exposure duration
0.2 or 0.4 Inhalation
mg/m
3.5 mg/m Inhalation
2.32 mg/m:? Inhalation
0.20 rag/m
as Be
13.1 mg/m. Inhalation
1.11 rag/m
as Be
24 mg/m Inhalation
15 mg/ra Inhalation
210 ug/aT
as Be
1 hr/day, 5 days/
wk, 4 mos.
6 mos.
6 hrs/day,
30 days
6 hrs/day, 10 days
6 mos.
6 hrs/day, 5 days/
wk until sacrifice
Time of
SPeciea responding ""SosT'
Rat
Rat
Monkey
Macacus
raullata
Monkey
Macacus
mullata
Rat
Squirrel
monkey
Salmi ri
sciurea
Some positive, 22
percent unknown
Some positive, 12
percent unknown
0 up to 9 post-
exposure
25 of 4 exposed up to 82 days
1 survived 82
days post expo-
sure and devel-
oped cancer
Some positive, 9
percent unknown
0 23
Reference
Li tvinov
1975
Schepers
Schepers
Schepers
Schepers
Wagner ,
1969
, et al
, 1961
, 1964
, 1964
, 1961
et al.
15 mg/m . Inhalation
210 ug/m
as Be
15 mg/ra . Inhalation
210 ug/mj
as Be
6 hrs/day/ Rat
wk until sacrifice
6 hrs/day, 5 days Hamster
wk until sacrifice
95
17
17
Wagner, et al.
1969
Wagner, ct al.
1969
C-24
-------
TABLE 2 (continued)
Compound
Bectrandite
ore
Deryllium
hydrox ide
Dose Exposure route Exposure duration
15 mg/» Inhalation 6 hrs/day, 5 days/
620 ug/m wk until sacrifice
as De
15 mg/m - Inhalation 6 hrs/day, 5 days/
620 ug/m wk until sacrifice
as De
15 mg/m , Inhalation 6 hrs/day, 5 days/
620 pg/m wk until sacrifice
as Be
40 pg De Intratracheal
40 pg De Intratracheal
4 pg Be Intratracheal
4 pg Be Intratracheal
0.4 pg De Intratracheal
0.4 pg De Intratracheal
Time of
K G spond i OQ
( ino s , j
Squirrel 0 23
monkey
Sarair i
sciurea
Rat 0 17
Hamster 0 17
Rat 10 6
12 mos.
old
Rat 0 6
3 BIOS.
old
Rat 0 6
12 mos.
old
Rat 0 6
6 mos.
old
Rat 0 6
12 mos.
old
Ra't 0 6
3 mos.
old
Reference
Wagner, et al.
1969
Wagner, et al.
1969
Wagner, et al.
1969
Groth t MacKay,
1971
Groth & Mackay,
1971
Groth, et al.
1972
Groth, et al.
1972
Groth, et al.
1976
Groth, et al.
1976
C-25
-------
expected. Casarotto (1952) failed to detect tumors in the para-
thyroid glands or teeth (the only organs studied) of two dogs; one
fed 1.3 gm beryllium carbonate per day for 104 days and the other
0.5 to 1.5 gm per day for 109 days. In longer term studies, Barnes
(1948) also failed to detect tumors in mice administered 1 percent
beryllium sulfate in the drinking water for 1 year.
More recently, beryllium sulfate at a concentration of 5 ppm
as Be in the water, over a life time, caused no change in growth
rates, longevity, or incidence of tumors in mice or rats (Schroeder
and Mitchener, 1975a,b), except for a small excess of leukemias,
termed as lymphoma leukemias by the authors, in female mice and in
grossly observed tumors of all sites in male rats. Concurrent work
by Morgareidge, et al. (1975) however, in which rats were fed
beryllium at concentrations of 5, 50 or 500 ppm in the diet for two
years showed a significant increase in lung reticulum cell sarcomas
in two of three dose groups when compared to controls for males,
according to a reanalysis of the data by the EPA Carcinogen
Assessment Group. This tumor type was also higher in females in
the lowest two dose groups, but not significantly so.
Although significant results were found upon reanalysis of the
data from this latter study, these results do not follow a typical
dose response pattern: the lowest dose (5 ppm) produced the most
significant response; the highest dose (500 ppm) produced no sig-
nificant response. Morgareidge, et al. (1975) concluded from their
results that evidence did not exist for any neoplastic or pre-neo-
plastic lesions that correlated with beryllium ingestion.
C-26
-------
The majority of industrial exposures to high levels of beryl-
lium took place in the 1940's. Due to a lack of appreciation of the
harmful effects, insufficient monitoring information, and a lack of
a centralized data base prior to 1951; studies attempting to link
beryllium to cancer in humans were not carried out until many years
later. Stoeckle, et al. (1969) reported no incidence of cancer in
60 selected cases of beryllium disease first diagnosed between 1S44
and 1966. Bayliss (1972) studied medical records of 3,921 males
employed in two beryllium plants from January 1942 through December
1967. Mortality from respiratory tract cancer revealed no signif-
icant departure from expectation in this population. Hardy, et al.
(1967) reported 14 cases of cancer among a group of 535 individuals
listed in the Beryllium Case Registry in 1966, These included 3
cases of lung cancer. 3 of bone sarcoma, and one each of cancer of
the cervix, skin, CNS, cecum, breast, eye, colon, and nasopharynx.
According to Hardy (1976), the bone sarcomas were incorrectly list-
ed and were found only in one case. A significant increase in the
incidence of bone or lung cancer could not be detected.
Mancuso (1970) reported 9 deaths due to lung cancer in a co-
hort of 594 beryllium workers above age 25 at one company, 6 of whom
were among 142 individuals indentified as having had prior beryl-
lium-related bronchitis and pneumonitis during 1937-1948. The age-
adjusted lung cancer mortality rate was calculated to be equal to
284.3 per 100,000 population for the subcohort with prior respira-
tory illness, compared with 77.7 per 100,000 for the main cohort.
Workers who were employed 1 to 5 calendar quarters had a higher lung
cancer rate than those employed for 6 quarters or more. It was
C-27
-------
concluded that prior respiratory illness of beryllium workers was
associated with high lung cancer mortality rate, but the reverse
length-of-exposure/rate-of-incidence correlation could not be
explained. Hasan and Kazemi (1974) reported 4 cases of lung cancer
among 76 cases added to_ the registry since 1966, making the total
incidence of lung cancer in the U.S. Beryllium Case Registry, as of
1974, 7 in 611, or 1.14 percent.
Niemoller (1963) described three cases of lung carcinoma that
he felt were related to beryllium exposure. Two were exposed to
beryllium industrially and the third was a smoker. Niemoller based
his conclusion on the location of tumors, a history of exposure
(either industrial or through smoking), and the presence of beryl-
lium in the tissue. Gold (1967) described a peritoneal mesothel-
ioma of the recto-vaginal septum in a 34-year-old woman. The pa-
tient had a history of traumatic vaginal lesions repeatedly exposed
by douching with hard water containing soluble beryllium at a level
of 0.035 M9/1? the patient also had environmental exposure to as-
bestos. Analysis of tumor tissue showed presence of beryllium at a
level of 0.04 jug/9? asbestos was not demonstrated. This author
also believed that the tumor was beryllium-related but the iden-
tification of the etiologic factor in all these cases was somewhat
conjectural.
Berg and Burbank (1972) observed significant positive correla-
tion between beryllium concentration in drinking water and cancer
deaths in 15 regions of the country, ranked according to levels of
trace metals. The highest mean positive level was 0.3 pq Be/1 for
Delaware, Maryland, West Virginia, and Kentucky. Cancers of
C-28
-------
breast, bone, and uterus appeared to have a probability of positive
association ranging from 0.006 to 0.040, but the association was
weak in subgroups.
Three very recently completed and thus far unpublished studies
have also claimed that beryllium exposure increased the risk of
cancer mortality. These are an updating of the former Bayliss
study (Wagoner, et al. 1978a), an updating of the former Mancuso
study (Mancuso, 1978), and a study by NIOSH based on the case re-
ports in the U.S. Beryllium Case Registry (Infante, et al. 1978).
These papers, or their preliminary drafts, were entered in the
record of the hearing on the proposed standard for exposure to
beryllium (OSHA, 1977) and were the subject of considerable contro-
versy (Shapley, 1977; Wagoner, et al. 1978b). The matter was re-
viewed by a panel of uninvolved experts convened for this purpose
by the Secretary of H.E.W., and resulted in the following
statement:
The epidemiologic evidence is suggestive that beryllium
is a carcinogen in man. The evidence is not at this time
judged to be more than suggestive because alternative ex-
planations for the positive findings have not been def-
initely excluded... Specially designed case control
studies are needed to evaluate other risk factors in the
beryllium-associated lung cancer cases. Confirmatory
retrospective cohort studies should also be conducted.
Nevertheless, it would be imprudent from a public health
perspective to delay our judgment about beryllium expo-
sure of current workers until these studies are com-
pleted. In our opinion, beryllium should be considered
as a suspect carcinogen for exposed workers. (Discher,
1978).
In contrast, MacMahon (1978) and MacMahon and Roth (1978)
reviewed the U.S. Case Registry (BRC) case studies and reported
that they found deficiencies. MacMahon (1978) concluded that the
BRC data "cannot be regarded...as evidence that beryllium is
C-29
-------
carcinogenic in humans," and suggested that the excess lung cancers
noted in the BRC case reports may have resulted from chance, selec-
tion bias, heavy smoking among members of the examined cohort, or a
combination of these factors.
C-30
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CRITERION FORMULATION
Existing Guidelines and Standards
The present standard for occupational exposure prescribes an
8-hour time weighted average of 2.0 pg/m with a ceiling concentra-
tion of 5.0 pg/m . In addition, the present standard allows a peak
concentration above the ceiling concentration of 25 pg/m for a
maximum duration of 30 minutes (40 CFR 202.48823).
The threshold limit value (TLV) for beryllium was set at
2 ug/m by the American Conference of Governmental Industrial
Hygienists (ACGIH, 1977).
National Emission Standards for Hazardous Air Pollutants set
their criterion as: not more than 10 g in 24 hours or emissions
which result in maximum outplant concentrations of 0.01 ug/m , 30-
day average (U.S. EPA, 1977).
The U.S. Environmental Protection Agency (U.S. EPA) proposed a
water quality standard of 11 ug/1 for the protection of aquatic
life in soft fresh water; 1,100 ,ug/l for the protection of aquatic
life in hard fresh water; 100 ug/1 for continuous irrigation on all
soils except 500 mg/1 for irrigation on neutral to alkaline lime-
textured soils (U.S. EPA, 1977).
The National Academy of Science/National Academy of Engineer-
ing (NAS/NAE, 1973) Water Quality Criteria recommendation for mar-
ine aquatic life is: hazard level - 1.5 ug/1; minimal risk of
deleterious effects - 0.1 mg/1; application factor - 0.01 (applied
to 96-hr LC5Q). Their recommendation for irrigation water is: 0.10
mg/1 for continuous use on all soils.
C-31
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Current Levels of Exposure
Concentrations of beryllium in the water supplies tend to be
quite low. For example, analysis of 1,577 samples from U.S. sur-
face waters and lakes showed beryllium present in 5.4 percent of
the samples with concentrations ranging from 0.01 to 1.22 ug/1 with
a mean of 0.19 ug/1 (Kopp and Kroner, 1967). The concentration of
beryllium in seawater was reported equal to 6 X 10
(Goldberg, 1965).
Measurements of beryllium in air samples collected from 100
stations of the National Air Sampling Network (U.S. EPA, 1971) in-
dicated that the average 24-hour concentration was less than 0.0005
ug/m . The maximum value recorded at these stations during 1964 -
1965 was 0.0008 ug/m . Thus, the maximum reported value was only
0.04 percent of the threshold limit value set by the American Con-
ference of Governmental Industrial Hygienists (ACGIH, 1977).
Sussman, et al. (1959) reported an average concentration of 0.0281
ug/m within one-half mile of a large beryllium plant near Reading,
PA. Concentrations closer to the plant reached 0.0827 ,ug/m .
Three brands of West German cigarettes were reported to contain
beryllium levels of 0.47, 0.68, and 0.74 ug per cigarette with 4.5,
1.6, and 10.0 percent of the beryllium content, respectively, in-
haled in the smoke (Petzow and Zorn, 1974). These investigators
estimated that the total beryllium intake for humans was about 100
ug/day with only a minor fraction by inhalation. Analysis of lung
tissue at autopsy, from persons with no known industrial exposure
to beryllium, showed maximum concentrations of 1.98 pg/100 gm tis-
sue (Cholak, 1959).
C-32
-------
Special Groups at Risk
Studies of Sterner and Eisenbud (1951) have suggested that a
small percentage of the population is sensitive to extremely low
concentrations of beryllium in the air, probably through the devel-
opment of an immune reaction. There is no evidence to date for the
development of sensitivity to concentrations of beryllium present
in food or water or that sensitivity to low levels of beryllium in
the air is aggravated by ingestion of beryllium. No other special
groups can be identified as special risks.
Basis and Derivation of Criteria
Experiments have shown that cancer can be induced by beryllium
in laboratory animals. As seen in Tables 1 and 2, cancer has been
induced by beryllium via inhalation, intratracheal instillation, or
intravenous injection. In addition, beryllium chloride has been
shown to increase the error frequency of nucleotide base incorpora-
tion into DNA in an rn vitro assay designed to detect potential
metal mutagens/carcinogens (Sirover and Loeb, 1976). Although
epidemiological studies have failed to establish an incontrovert-
ible link between beryllium exposure and human cancer, the evidence
is very suggestive.
The only experiments conducted to date in which beryllium was
ingested over a long period of time were those of Schroeder and
Mitchener (1975a,b) and Morgareidge, et al. (1975). In the first
study, 5 ppm beryllium was added to the water of rats for a lifetime
exposure. No statistically significant differences in tumor fre-
quencies between control and experimental rats were found, although
there was a slight excess of grossly observed tumors in males of
C-33
-------
the treated group (Schroeder and Mitchner, 1975a). Mice, similarly
exposed as rats, showed a statistically insignificant excess of
lymphoma leukemias in females of the treated group (Schroeder and
Mitchener, 1975b). In the latter study, Morgareidge, et al. (1975)
exposed rats to levels of beryllium in the diet at concentrations
of 5, 50, and 500 ppm. The authors concluded that evidence did not
exist for any dose- or treatment-related pathological effects, or
any neoplastic or preneoplastic lesions that correlated with beryl-
lium ingestion. However, a reanalysis of this data by the EPA
Carcinogen Assessment Group found that the incidence of lung re-
ticulum cell sarcomas was significantly higher in the lowest and
intermediate dose groups in males. The Fischer Exact p values were
0.0065 and 0.036, respectively. Lung reticulum cell sarcoma inci-
dence was also higher in females in the lowest two dose groups, but
not significantly so.
The significant results in males in this latter study do not
follow a typical dose-response pattern: the lowest dose (5 ppm)
produced the most significant response; the highest dose (500 ppm)
produced no significant response. This lack of trend with dose
makes these findings uncertain. Furthermore, these results have
never been published. Because of these two shortcomings the
Morgareidge, et al. study cannot be used to derive a cancer, or
toxicity, based criterion, although it supports such derivations.
The high frequency of osteosarcomas induced in rabbits by in-
travenous Be and of reticulum cell sarcomas in rats fed beryllium,
the positive results of mutagenicity studies, and the suggestive
human epidemiology indicate that Be-laden water poses a carcinogenic
C-34
-------
risk to man. Based on the above findings and the assumption that
beryllium is likely to be carcinogenic after oral ingestion because
it is carcinogenic via other routes of exposure, the Schroeder and
Mitchener experiment (1975a), which showed a slight insignificant
effect after oral exposure, is sufficient to calculate a criterion.
Note, however: (1) that it is not the study of Schroeder and
Mitchener, but the previously mentioned studies that suggest that
Be-laden water poses a carcinogenic risk to man, and, (2) that to
extrapolate from the Be studies where the route of administration
was by injection or inhalation would yield a lower, and, perhaps,
less valid criterion.
Under the Consent Decree in NRDC v. Train, criteria are to
state "recommended maximum permissible concentrations (including
where appropriate, zero) consistent with the protection of aquatic
organisms, human health, and recreational activities." Beryllium
is suspected of being a human carcinogen. Because there is no
recognized safe concentration for a human carcinogen, the recom-
mended concentration of beryllium in water for maximum protection
of human health is zero.
Because attaining a zero concentration level may be infeasible
in some cases and in order to assist the Agency and states in the
possible future development of water quality regulations, the con-
centrations of beryllium corresponding to several incremental life-
time cancer risk levels have been estimated. A cancer risk level
provides an estimate of the additional incidence of cancer that may
be expected in an exposed population. A risk of 10~ for example,
indicates a probability of one additional case of cancer for every
C-35
-------
100,000 people exposed, a risk of 10 indicates one additional
case of cancer for every 1,000,000 people exposed, and so forth.
In the Federal Register notice of availability of draft am-
bient water quality criteria, EPA stated that it is considering
setting criteria at an interim target risk level of 10 ,10 , or
10 as shown in the following table.
Exposure Assumptions
(per day)
2 liters of drinking
Risk Levels and Corresponding Criteria(l)
0
ng/1
0
lO'7
ng/1
0.37
io-6
ng/1
3.7
ID'5
ng/1
37
water and consumption
of 6.5 grams fish
and shellfish. (2)
Consumption of fish 0 6.41 64.1 641
and shellfish only.
(1) Calculated by applying a linearized multistage model, as dis-
cussed in the Human Health Methodology Appendices to the
October 1980 Federal Register notice which announced the
availability of this document, to the animal bioassay data
presented in Appendix I. Since the extrapolation model is
linear at low doses, the additional lifetime risk is directly
proportional to the water concentration. Therefore, water
concentrations corresponding to other risk levels can be der-
ived by multiplying or dividing one of the risk levels and
corresponding water concentrations shown in the table by fac-
tors such as 10, 100, 1,000, and so forth.
(2) Six percent of the beryllium exposure results from the con-
sumption of aquatic organisms which exhibit an average
C-36
-------
bioconcentration potential of 19-fold. The remaining 94 per-
cent of beryllium exposure results from drinking water.
Concentration levels were derived assuming a lifetime exposure to
various amounts of beryllium, (1) occurring from the consumption of
both drinking water and aquatic life grown in waters containing the
corresponding beryllium concentrations and, (2) occurring solely
from consumption of aquatic life grown in the waters containing the
corresponding beryllium concentrations. Because data indicating
other sources of beryllium exposure and their contributions to
total body burden are inadequate for quantitative use, the figures
reflect the incremental risks associated with the indicated routes
only.
The assumption that beryllium is carcinogenic after oral ad-
ministration can be questioned, however, in light of the fact that
the results of oral studies designed to test this assumption are
either negative or uncertain. An alternate method to calculate a
protective level would be to use toxicity data as suggested in
public comments. A review of the Effects section of this document
indicates that the Schroeder and Mitchner (1975a) study is the most
suitable for this derivation. The ADI for rats in this study can be
estimated by:
5 mg/1 x 0.035 1/d -f 0.325 kg/rat = 0.538 mg/d/kg/rat,
where 5 mg/1 (5 ppm) is the drinking water level showing no sig-
nificant effect, 0.035 1 is the approximate daily water intake for
rats, and 0.325 is the approximate average weight of rats of both
sexes in this study.
C-37
-------
Dividing this ADI for rats by a safety factor of 1,000, as per
NAS Guidelines (NAS, 1977) (because there is no long term or acute
oral human data for Be exposure and the results in experimental
animals are scanty), and then multiplying by 70 kg (the average
weight of a man) yields the "safe" ADI for man:
(0.538 mg/d/kg/rat -^ 1,000) x 70 kg/man = 0.0377 mg/d/man.
The ambient water concentration that results in this ADI for
man can be calculated by the following equation:
r _ ADI mg/d/man
" 2 1/d/man + (0.0065 kg/d man x BCF I/kg)'
where 2 liters represents the average daily water intake, 0.0065 kg
is the average daily fish consumption, and BCF is the bioconcentra-
tion factor for beryllium, which is 19. Thus,
_ _ _ 0.0377 mg/d/man _
~ 2 1/d/man + (0.0065 kg/d/man x 19 I/kg)
= 0.0178 mg/1, or 17.8 pg/1.
The Agency recommends the cancer-based criterion (37 ng/1)
because this criterion is more protctive of human health. The
rationale for this decision is discussed in previous pages
(pp. C-34, C-35) and in the Appendix. This criterion will be re-
evaluated in the future as additional data on the oral carcinogen-
icity and/or toxicity of beryllium are discovered.
038
-------
REFERENCES
Aldridge, W.N., et al. 1949. Experimental beryllium poisoning.
Jour. Exp. Pathol. 30: 375.
Alekseeva, O.G. 1965. Ability of beryllium compounds to cause
allergy of the delayed type. G.T.P. Zbol. 9: 20.
American Conference of Governmental Industrial Hygienists. 1977.
Threshold limit values for chemical substances in workroom air
adopted by ACGIH for 1977. Cincinnati, Ohio.
Barnes, J.M. 1948. The staining of the duodenal mucosa of rats
following the injection of solutions of tanning acid. Jour. Exp.
Pathol. 29: 495.
Barnes, J.M., et al. 1950. Beryllium bone sarcomata in rabbits.
Br. Jour. Cancer. 4: 212.
Bayliss, D. 1972. In; NIOSH Criteria for a Recommended Standard.
Occupational Exposure to Beryllium. U.S. Dep. Health Edu.
Welfare, Washington, D.C.
Belman, S. 1969. Beryllium binding of epidermal constituents.
Jour. Occup. Med. 11: 175.
C-39
-------
Berg, J.W. and F. Burbank. 1972. Correlations between carcino-
genic trace metals in water supply and cancer mortality. Ann. N.Y.
Acad. Sci. 199: 249.
Branion, H.D., et al. 1931. Beryllium rickets. Jour. Biol. Chem.
92: 11.
Breslin, A.J. and W.B. Harris. 1959. Health protection in beryl-
lium facilities. Summary of ten years of experience. AMA Arch.
Ind. Health. 19: 596.
Brutlag, D. and A. Kornberg. 1972. Enzymatic synthesis of deoxy-
ribonucleic acid. Jour. Biol. Chem. 247: 241.
Businco, L. 1940. The rickets-producing effect of beryllium car-
bonate. Rass. Med. Ind. 11: 417.
Casarotto, G. 1952. Action of BeC03 on teeth. Clin. Odontiat.
7: 113.
Cholak, J. 1959. Analysis of traces of beryllium. Arch. Ind.
Health. 19: 205.
Cloudman, A.M., et al. 1949. Bone changes following intravenous
injections of beryllium. Am. Jour. Pathol. 25: 810.
C-40
-------
Committee on Occupational Diseases of the Chest, American College
of Chest Physicians. 1965. Report of the section on nature and
prevalence of beryllium disease. Dis. Chest. 48: 550.
Crowley, J.F., et al. 1949. Metabolism of carrier-free radio-
beryllium in the rat. Jour. Biol. Chem. 177: 975.
Curtis, G.H. 1951. Cutaneous hypersensitivity to beryllium.
Arch. Dermatol. Syph. 64: 470.
Deguinalt, J. and J. Haguenoer. 1973. Action de quelques de toxi-
cants dans 1'intoxication experimentale par le beryllium. Arch.
Mai. Prof. Med. Trav. Sci. Soc. 34: 493.
DeNardi, J.M., et al. 1953. Berylliosis; summary and survey of
all clinical types observed in a 12-year period. Arch. Ind. Hyg.
Occup. Med. 8: 1.
Discher, D.P. 1978. Letter to W.H. Foege, Director, Center for
Disease Control, U.S. Dep. Health Edu. Welfare. BNA Occup. Safety
Health Rep. 8: 853.
Dudley, H.R. 1959. The pathologic changes of chronic beryllium
disease. AMA Arch. Ind. Hyg. 119: 184.
C-41
-------
Durocher, N.L. 1969. Air pollution aspects of beryllium and its
compounds. Contract No. PH-22-68-25. U.S. Dep. Health Edu. Wel-
fare.
Dutra, F.R. and F.J. Largent. 1950. Osteosarcoma induced by
beryllium oxide. Am. Jour. Pathol. 26: 197.
Dutra, F.R., et al. 1951. Osteogenic sarcoma after inhalation of
beryllium oxide. Arch. Pathol. 51: 473.
Fodor, J. 1971. Histogenesis of bone tumors induced by beryllium.
Magyar Onkol. 15: 180.
Furchner, J.E., et al. 1973. Comparative metabolism of radio-
nucleotides in mammals. VIII: Retention of beryllium in the
mouse, rat, monkey, and dog. Health Physics. 24: 293.
Gardner, L.U. and H.F. Heslington. 1946. Osteosarcoma from intra-
venous beryllium compounds in rabbits. Fed. Proc. 5: 221.
Gold, C. 1967. A primary mesothelioma involving the rectovaginal
septum and associated with beryllium. Jour. Pathol. Bacteriol.
93: 435.
Goldberg, E.D. 1965. Minor Elements in Seawater. In; J.P. Riley
and G.S. Skinow (eds.) , Chemical Oceanography. Academic Press,
New York.
C-42
-------
Grier, R.S., et al. 1949. Observations on the effects of beryl-
lium on alkaline phosphatase. Jour. Biol. Chem. 180: 289.
Groth, D.H. and C.R. MacKay. 1971. Chronic pulmonary pathology in
rats after intratracheal injection. Toxicol. Appl. Pharmacol.
19: 392.
Groth, D.H., et al. 1972. Comparative pulmonary effects of Be and
As compounds in rats. Lab. Invest. 26: 447.
Groth, D.H., et al. 1976. Interactions of Mercury, Cadmium,
Selenium, Tellurium, Arsenic, and Beryllium. In; G.F. Nordberg
(ed.), Effects and Dose-response Relationships of Toxic Metals.
Elsevier Publishing Co., Amsterdam, p. 527.
Guyatt, B.L., et al. 1933. Beryllium rickets. Jour. Nutr.
6: 313.
Hall, T.C., et al. 1959. Case data from the beryllium registry.
AMA Arch. Ind. Health. 19: 100.
Hardy, H.L. 1955. Epidemiology, clinical characteristics, and
treatment of beryllium poisoning: Progr. rep. Am. Med. Assoc.
Arch. Ind. Health. 11: 273.
C-43
-------
Hardy, H.L. 1976. Correction on the number of presumed beryllium-
induced osteosarcomas in human beings. New England Jour. Med.
295: 624.
Hardy, H.L. and J.D. Stoeckle. 1959. Beryllium disease. Jour.
Chron. Dis. 9: 152.
Hardy, H.L., et al. 1967. United States beryllium case registry
(1952-1966). Review of its methods and utility. Jour. Occup.
Med. 9: 271.
Hasan, P.M. and H. Kazemi. 1974. Chronic beryllium disease. A
continuing epidemiological hazard. Chest. 65: 289.
Hashimoto, J., et al. 1967. Phosphoglucomutase. IV. Inactiva-
tion by beryllium ions. Jour. Biol. Chem. 242: 1671.
Higgins, G.M., et al. 1964. A transplantable beryllium-induced
chondrosarcoma of rabbits. Jour. Bone Joint Surg. 46A: 789.
Hoagland, M.B., et al. 1950. Beryllium and growth. I. beryllium-
induced osteogenic sarcoma. Cancer Res. 10: 629.
Hyslop, F., et al. 1943. The toxicology of beryllium. U.S. Pub.
Health Serv. Natl. Inst. Health Bull. 181.
C-44
-------
Infante, P.F., et al. 1978. In preparation (referenced in Science
201: 303).
Janes, J.M., et al. 1954. Beryllium induced osteogenic sarcoma in
rabbits. Jour. Bone Joint Surg. 36B: 543.
Kanarek, D.J., et al. 1973. Respiratory illness in a population
exposed to beryllium. Am. Rev. Resp. Dis. 108: 1295.
Kawada, M. 1963. Experimental studies on beryllium osteoma,
especially on the method of producing the tumor. Jinkejikai. Med.
Jour. 10: 205.
Kay, H.D. and B.L. Guyatt. 1933. Experimental rickets as a phos-
phorus deficiency disease. Nature. 131: 468.
Kay, H.D. and D.I. Skill. 1934. Beryllium rickets (11). The pre-
vention and cure of beryllium rickets. Biochem. Jour. 28: 1222.
Kaylor, C.T. and C.D. Van Cleave. 1953. Radiographic visualiza-
tion of the deposition of radioberyllium in the rat. Anat. Record.
117: 467.
Kelly, P.J., et al. 1961. The effect of beryllium on bone. Jour.
Bone Joint Surg. 43A: 829.
C-45
-------
Kharlamova, S.F. and I.N. Potapova. 1968. Distribution of beryl-
lium in the liver and its cellular fractions. Farmakol. Toksikol.
31: 357.
Klemperer, F.W., et al. 1949. The inhibition of alkaline phospha-
tase by beryllium. Jour. Biol. Chem. 180: 281.
Klemperer, F.W., et al. 1952. The fate of beryllium compounds in
the rat. Arch. Biochem. Biophys. 41: 148.
Komitowski, D. 1969. Morphogenesis of beryllium-induced bone
tumors. Patol. Pol. 1: 479. (suppl.)
Kopp, J.F. and R.C. Kroner. 1967. A five year study of trace
metals in waters of the United States. Fed. Water Pollut. Control
Admin., U.S. Dep. Inter., Cincinnati, Ohio.
Laskin, S.R. , et al. 1946. An Analysis of Dust and Fume Hazards in
a Beryllium Plant. In; A.J. Vorwald (ed.), Pneumoconiosis:
Beryllium and Bauxite Fumes.
Lieben, J. and R.R. Williams. 1969. Respiratory disease associ-
ated with beryllium refining and alloy fabrication: 1968 follow-
up. Jour. Occup. Med. 11: 480.
Litvinov, N.N., et al. 1975. Toxic properties of soluble Be com-
pounds. Gig. Tr. Prof. Zabol. 7: 34.
C-46
-------
Loeb, L.A. and M.A. Sirover. 1977. Infidelity of DNA synthesis
in vitro; Screening for potential metal mutagens. Science.
194: 1434.
Luke, M.Z., et al. 1975. Beryllium-induced misincorporation by a
DNA polymerase. Biochem. Biophys. Res. Comm. 62: 497.
MacMahon, B. 1978. OSHA Beryllium Hearings, 1977. Evaluations of
epidemiological materials.
MacMahon, B. and N. Roth. 1977. An evaluation of Wagoner, et al.
Draft dated May 23, 1978.
Mancuso, T.F. 1970. Relation of duration of employment and prior
illness to respiratory cancer among beryllium workers. Environ.
Res. 3: 251.
Mancuso, T.F. 1978. Occupational lung cancer among beryllium
workers. Soc. Occup. Environ. Health. Washington, D.C. (In
press)
Marcotte, J. and H.P. Witschi. 1972. Synthesis of RNA and nuclear
proteins in early regenerating rat livers exposed to beryllium.
Res. Commun. Chem. Pat'hol. Pharmacol. 3: 97.
C-47
-------
Mazabraud, A. 1975. Experimental production of bone sarcomas in
the rabbit by a single local injection of Be. Bull. Cancer.
62: 49.
McCord, C.P. 1951. Beryllium as a sensitizing agent. Ind. Med.
Surg. 20: 336.
Meehan, W.R. and L.E. Smythe. 1967. Occurrence of beryllium as a
trace element in environmental materials. Environ. Sci. Technol.
1: 839.
Morgareidge, K. et al. 1975. Chronic feeding studies with beryl-
lium sulfate in rats. Food and Drug Research Laboratories, Inc.
Final Report to the Aluminum Company of America, Pittsburgh,
Pennsylvania. 15219.
Mullen, A.L., et al. 1972. Radioberyllium metabolism by the dairy
cow. Health Physics. 22: 17.
Nash, P. 1950. Experimental production of malignant tumors by
beryllium. Lancet. 1: 519.
National Academy of Sciences. 1977. Drinking Water and Health,
Washington D.C.
National Academy of Sciences/National Academy of Engineering.
1973. Water quality criteria 1972. A report. Natl. Acad. Sci.,
Washington, D.C.
C-48
-------
National Academy of Sciences/National Resource Council. 1958.
Report of the panel of toxicity of beryllium. Rep. MA3-135-M.
National Air Sampling Network, Air Quality Data. 1968. Pub.
Health Serv. U.S. Dep. Health Edu. and Welfare. Durham, North
Carolina.
Needham, A.E. 1974. The effect of beryllium on the ultraviolet
absorbance spectrum of nucleic acids. Int. Jour. Biochem. 5: 291.
Niemoller, H.K. 1963. Delayed carcinoma induced by beryllium
aerosol in man. Int. Arch. Gewerbepthol. Gewerbehyg. 20: 18.
Petzow, G. and H. Zorn. 1974. Toxicology of beryllium-containing
materials. Chemlker Vig. 98: 236.
Raven, C.P. and N.S. Spronk. 1953. Action of beryllium on the
development of Limnaea stagnalis. Chem. Abst. 47: 6561.
Reeves, A.L. 1965. Absorption of beryllium from the gastrointes-
tinal tract. AMA Arch. Environ. Health. 11: 209.
Reeves, A.L. 1977. Beryllium: in toxicology of metals. Vol. II.
EPA-600/1-77-022.
C-49
-------
Reeves, A.L., et al. 1967. Beryllium carcinogenesis. I. Inhala-
tion exposure of rats to beryllium sulfate aerosol. Cancer Res.
27: 439.
Resnick, H., et al. 1970. Immunoglobin concentrations in berylli-
osis. Am. Rev. Resp. Dis. 101: 504.
Robinson, F.R., et al. 1968. Ultrastructure of the lungs of dogs
exposed to beryllium containing dusts. Arch. Environ. Health.
17: 193.
Schepers, G.W.H. 1961. Neoplasia experimentally induced by beryl-
lium compounds. Prog. Exp. Tumor Res. 2: 203.
Schepers, G.W.H. 1964. Biological action of beryllium reaction of
the monkey to inhaled aerosols. Ind. Med. Surg. 33: 1.
Schepers, G.W.H., et al. 1957. The biological action of inhaled
beryllium sulfate. A preliminary chronic toxicity study in rats.
AMA Arch. Ind. Health. 15: 32.
Schroeder, H.A. and M. Mitchener. 1975a. Life-term studies in
rats: Effects of aluminum, barium, beryllium, and tungsten. Jour.
Nutr. 105: 420.
C-50
-------
Schroeder, H.A. and M. Mitchener. 1975b. Life-term effects of
mercury, methylmercury, and nine other trace metals on mice. Jour.
Nutr. 105: 452.
Schubert, J. and M.W. Rosenthal. 1959. Chemical approaches to the
treatment of beryllium poisoning. AMA Arch. Ind. Health. 19: 169.
Schubert, J. and M.R. White. 1950. Effect of citrate salts and
other chemical factors on the distribution and excretion of beryl-
lium. Jour. Clin. Med. 35: 854.
Scott, J.K., et al. 1950. The effect of added carrier on the
distribution and excretion of soluble Be. Jour. Biol. Chem.
172: 291.
Shapely, D. 1977. Occupational cancer: Government challenged in
beryllium proceeding. Science. 198: 898.
Sirover, M.W. and L.A. Loeb. 1976. Metal-induced infidelity
during DNA synthesis, Proc. Natl. Acad. Sci. 73: 2331.
Sissons, H.A. 1950. Bone sarcomas produced experimentally in the
rabbit using compounds of beryllium. Acta Unio. Int. Contra.
Cancrum. 7: 171.
C-51
-------
Spencer, H.C., et al. 1968. Toxicological studies on beryllium
oxides and beryllium-containing exhaust products. AMRL-TR-68-148.
Aeromedical Res. Lab., Wright-Patterson AFB. Dayton, Ohio.
Spencer, H.C., et al. 1972. Toxicological evaluation of beryllium
motor exhaust products. AMRL-TR-72-118. Aeromedical Res. Lab.,
Wright-Patterson AFB. Dayton, Ohio.
Sprince, N.L., et al. 1976. Current (1975) problems of differ-
entiating between beryllium disease and sarcoidosis. Anal. N.Y.
Acad. Sci. 278: 654.
Sprince, N.L., et al. 1978. Reversible respiratory disease in
beryllium workers. Am. Rev. Resp. Dis. 117: 1011.
Stephan, C.E. 1980. Memorandum to J. Stara. U.S. EPA. July 3.
Sterner, J.H. and M. Eisenbud. 1951. Epidemiology and beryllium
intoxication. Arch. Ind. Hyg. Occup. Med. 4: 123.
Stoeckle, J.D., et al. 1969. Chronic beryllium disease: long-
term followup of 60 cases and selective review of the literature.
Am. Jour. Med. 46: 545.
C-52
-------
Stokinger, H.E., et al. 1950. Acute inhalation toxicology of
beryllium I. Four definitive studies of beryllium sulfate at expo-
sure concentrations of 100, 50, 10, and 1 mg per cubic meter. AMA
Arch. Ind. Hyg. Occup. Med. 1: 379.
Stokinger, H.E., et al. 1951. Anemia in acute experimental beryl-
lium poisoning. Jour. Lab. Clin. Med. 38: 173.
Sussman, V.H., et al. 1959. An air pollution study of a community
surrounding a beryllium plant. Am. Ind. Hyg. Assoc. Jour.
20: 504.
Tabor, E.G. and w.v. warren. 1958. Distribution of certain metals
in the atmosphere of some American cities. Arch. Ind. Health.
17: 145.
Tapp, E. 1969. Osteogenic sarcoma in rabbits following subperi-
osteal implantation of beryllium. Arch. Pathol. 88: 89.
Tepper, L.B. 1972a. Beryllium. CRC Grit. Rev. Toxicol. 1: 235.
Tepper, L.B. 1972b. Beryllium. In; D.H.K. Lee (ed.), Metallic
Contaminants and Human Health. Academic Press, New York. p. 127.
Tepper, L.B./ et al. 1961, Toxicity of Beryllium Compounds,
Elsevier Publishing Co., New York,
C-53
-------
Thornton, C.S. 1950. Beryllium inhibition of regenerations.
Jour, Exp. Zool. 114: 305.
Toda, G. 1968. Effects of cations on the inhibition of sodium and
potassium-activated adenosinetriphosphatase by beryllium. Jour.
Biochem. 64: 457.
Underwood, A. L. 1951. Studies on the renal excretion of beryl-
lium. USAEC Rep. UR-71. Univ. of Rochester.
U.S. EPA. 1971. Background information - proposed national emis-
sion standards for hazardous air pollutants, asbestos, beryllium,
mercury. Research Triangle Park, North Carolina.
U.S. EPA. 1977. Multimedia environmental goals for environmental
assessment. Vol. II. MEG charts and background information. EPA-
60017-77-136b. Washington, D.C.
U.S. EPA. 1978. In-depth studies on health and environmental
impacts of selected water pollutants. Washington, D.C.
U.S. EPA. 1980. Seafood consumption data analysis. Stanford
Research Institute International. Menlo Park, California. Final
Report, Task 11. Contract No. 68-01-3887.
C-54
-------
Uzawa, T. 1963. Histopathological studies on pulmonary reaction
by beryllium oxide in rats. Experimental tumorous action of BeO
combined with carcinogenic hydrocarbons. Bull. Tokyo Med. Dent.
Univ. 9: 440.
Vacher, J. and H.B. Stoner. 1968. The transport of beryllium in
rat blood. Biochem. Pharmacol. 17: 93.
Van Cleave, C.D. and C.T. Kaylor. 1955. Distribution, retention,
and elimination of Be in the rat after intratracheal injection.
AMA Arch. Ind. Health. 11: 375.
Van Ordstand, U.S., et al. 1945. Beryllium poisoning. Jour. Am.
Med. Assoc. 129: 1084.
Vasil'eva, E.V. 1969. Immunologic assessment of a model of exper-
mental berylliosis. Bull. Exp. Biol. Med. 3: 74.
Vegni Talluri, M. and V. Guiggiani. 1967. Action of beryllium
ions on primary cultures of swine cells. Caryologia. 20: 355.
Vorwald, A.J. 1966. Medical Aspects of Beryllium Disease. In;
H.E. Stokinger (ed.), Beryllium: Its Industrial Hygiene Aspects.
Academic Press, New York.
Vorwald, A.J. and A.L. Reeves. 1959. Pathologic changes induced
by beryllium compounds. AMA Arch. Ind. Health. 19: 190.
C-55
-------
Vorwald, A.J., et al. 1966. Experimental Beryllium Toxicology.
Int H.E. Stokinger (ed.), Beryllium: Its Industrial Hygiene As-
pects. Academic Press, New York.
Wagner, W.D., et al. 1969. Comparative inhalation toxicity of
beryllium ores bertrandite and beryl with production of pulmonary
tumors by beryl. Toxicol. Appl. Pharmacol. 15: 10.
Wagoner, J.K., et al. 1978a. Beryllium: carcinogenicity studies.
Science. 201: 298.
Wagoner, J.K., et al. 1978b. Bronchogenic cancer and cardio-
respiratory disease mortality among beryllium production workers.
(Unpublished)
Williams, D.R. 1961. The effectiveness of current practices in
the control of exposure to beryllium. Workshop on Beryllium,
Kettering Lab., Univ. of Cincinnati, Cincinnati, Ohio.
Witschi, H.P. 1968. Inhibition of deoxyribonucleic acid synthesis
in regenerating rat liver by beryllium. Lab. Invest. 19: 67.
Witschi, H.P. 1970. Effects of beryllium on deoxyribonucleic
acid-synthesizing enzymes in regenerating rat liver. Biochem.
Jour. 120: 623.
C-56
-------
Witschi, H.P. and W.N. Aldridge. 1967. Biochemical changes in rat
liver after acute beryllium poisoning. Biochem. Pharmacol.
16: 263.
Witschi, H.P. and W.N. Aldridge. 1968. Uptake distribution and
binding of beryllium to organelles of the rat liver cell. Biochem.
Jour. 106: 811.
Yamaguchi, S. and H. Katsura. 1963. Study of experimental osteo-
sarcoma induced by beryllium. Trans. Soc. Pathol. Jap. 52: 229.
Zielinski, J.F. 1961. A summary of the results of seven years of
experience in investigating the dispersion of beryllium in the air
of a modern alloy foundry. Workshop on Beryllium, Kettering Lab.,
Univ. of Cincinnati, Cincinnati, Ohio.
Zorn, H., et al. 1977. The significance of beryllium. Zentralbl.
Arbeits. Med. 27: 83.
C-57
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APPENDIX I
Summary and Conclusion Regarding
Carcinogenicity of Beryllium
Epidemiological studies have failed to establish an incontro-
vertible link between beryllium exposure and human cancer. However
reticulum cell sarcomas were produced in one experimental study by
ingestion of beryllium (Morgareidge, et al. 1975). Furthermore,
beryllium has induced osteosarcomas in rabbits following intra-
venous administration (Cloudman, 1949). It has also been reported
to be mutagenic at the HGPRT locus in CHO cells (personal communi-
cation with Alexander R. Malcolm, National Marine Water Quality
Lab., U.S. EPA). In addition, BECl- at a concentration of 10mm
increased by a factor of 15 the error frequency of nucleotide base
incorporation into DNA in an rn vitro DNA polymerase assay designed
to detect potential metal mutagen/carcinogens (Sirover and Loeb,
1976).
The high frequency of osteosarcomas in rabbits induced by
intravenous Be and of reticulum cell sarcomas in rats fed beryl-
lium, the positive results from mutagenesis assays, and the sugges-
tive human epidemiology indicate that Be-laden water poses a car-
cinogenic risk to man.
Although the Morgareidge, et al. (1975) dietary study indicates
a significant excess of cancer after beryllium ingestion and, at
first appearance, would seem to be the best study from which to
C-58
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derive a criterion, it cannot be used for such a purpose for rea-
sons previously stated (p. C-34). Therefore, the Schroeder and
Mitchner dietary study was used to estimate the criterion associat-
ed with a lifetime human cancer
bient water criterion is 37 ng/1.
ed with a lifetime human cancer risk of 10~ . The resulting am-
C-59
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Derivation of Water Quality Criterion for Beryllium
The experiment of Schroeder and Mitchner (1975a) showed a
small, statistically insignificant, excess in grossly observed
tumors of all sites in male rats continuously exposed to Be at 5 ppm
in their drinking water. These results can be used to estimate the
maximum risk that beryllium could pose, or equivalently, the lowest
concentration which leads to a 10 human lifetime cancer risk.
The parameters of the extrapolation are:
Dose Incidence
(mg/kg/day) (no. responding/no, tested)
0.0 4/26
0.25 9/33
le = 1126 days W = 0.385 kg
Le = 1126 days R = 19 I/kg
L = 1126 days
With these parameters the carcinogenic potency factor for
humans, Si*/ is 8.84 (mg/kg/day)~ . The result is that the water
concentration should not exceed 37 ng/1 in order to keep the life-
time risk below 10~ .
See the discussion in the "Basis and Derivation of Criteria" sec-
tion for the justification in the use of this study.
» U S GOVERNMENT PRINTING OFFICE 19HO 7?C-016/«368
C-60
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