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seen in multiple species, at multiple sites, and often at very low doses, these
studies collectively provide sufficient animal evidence for carcinogenicity.
In the present report, data from animal inhalation and intratracheal studies
(using rats, guinea pigs, or rhesus monkeys exposed to a variety of beryllium
compounds) have been used to calculate the upper bounds for the potency of
beryllium. The maximum likelihood slope estimates, calculated on the basis of
animal data, vary from 2.1 x 10~4 to 4.3/(|jg/m3), a range of four orders of
magnitude.
The magnitude of the potency appears to depend primarily on the beryllium
compound used in the experiment, although some variability in sensitivity among
species was also seen with guinea pigs responding to a lesser degree than rats
or monkeys. Among the beryllium compounds examined in the animal studies,
beryllium oxide is the least carcinogenically potent, while beryllium sulfate
(BeSO^) is the most potent. Solubility appears to be one factor affecting
potency. In the intratracheal instillation studies of Spencer et al. (1968,
1972), beryllium oxide calcined at 1100°C and 1600°C was much less potent than
the more soluble form of beryllium oxide which was calcined at 500°C. If one
adopts the most conservative approach, the maximum potency estimate,
4.3/(fjg/m ), would be used to represent the carcinogenic potential of beryllium
sulfate. This potency is estimated on the basis of animal data (Vorwald et al.,
1966) obtained in an experiment in which the level of exposure to beryllium
sulfate was very similar to occupational exposure conditions. Thus, the high
potency estimate is not due to the use of a particular low-dose extrapolation
model. Since most beryllium compounds present in ambient air or the workplace
environment are not in the form of beryllium salts, but are, more likely to be
the less potent beryllium oxide, use of the sulfate potency estimate would
clearly overestimate the human risk. The geometric mean of 2.1 x lO'Vdjg/m3),
obtained from eight animal studies utilizing beryllium oxide or beryllium ore
is considered to more accurately represent human risk to beryllium compounds
present in ambient air.
Data from the epidemiological study by Wagoner et al. (1980) and the
industrial hygiene reviews by NIOSH (1972) and Eisenbud and Lisson (1983) have
been used to develop a cancer risk estimate associated with exposure to air
contaminated with beryllium. Two upper-bound relative risk estimates, 1.98 and
2.09 from the human data, have been used in the calculations. In recognition
of the greater uncertainty associated with the exposure estimation, four
7-86
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different "effective" levels of exposure that reflect various uncertainties,
along with two relative risk estimates, have been used in the present calcula-
tions. As a result, eight potency estimates have been calculated, ranging from
1.6 x 10~4/(ug/m3) to 7.2 x 10~3/(ug/m3), with the geometric mean of the eight
-3 3
estimates being 2.4 x 10 /(ug/m )
Rounding off this number because of the
level of uncertainty, the incremental life time cancer risk (based upon epide-
miologic data) associated with 1 ug/m3 of beryllium in the air is thus calcu-
lated to be 2 x 10~3. This estimate could be considered an upper-bound estimate
of the cancer risk because low-dose linearity is assumed in the extrapolation
and the 95 percent upper-confidence limits of the relative risks are used in
the calculations. With these quantitative approaches, the CAG has calculated
two risk estimates, one from epidemic!ogic data and one from animal data, for
exposures to mainly oxides of beryllium. These rounded estimates,
2 x I0"3/(ng/m3) each, are in complete agreement. The risk estimates for the
salts of beryllium (i.e., sulfate) are much higher and are derived from animal
data only.
7.4 SUMMARY
7.4.1 Qualitative Summary
Experimental beryllium carcinogenesis has been induced by intravenous or
intramedullary injection of rabbits, and by inhalation exposure or intratracheal
instillation of rats and monkeys.
Osteosarcomas were induced in rabbits by intravenous injection of zinc
beryllium silicate (9 studies), beryllium oxide (2 studies), metallic beryllium
(1 study) and by intramedullary injection of zinc beryllium silicate and
beryllium oxide (1 study each). Lung tumors were induced in rats by intratra-
cheal instillation of beryllium oxide (4 studies), beryllium hydroxide (2 stu-
dies), metallic beryllium (2 studies), beryl ore (1 study) and in monkeys by
beryllium oxide (1 study). Lung tumors were also induced in rats by inhalation
of beryllium sulfate (5 studies), beryllium phosphate, beryllium fluoride, and
beryl ore (1 study each), and in monkeys by beryllium sulfate (1 study). No
significant neoplastic responses were observed via the intracutaneous or per-
cutaneous routes, while the responses via the dietary routes were either nega-
tive or equivocal. This was considered to be due to low absorption efficiency
resulting from precipitation of beryllium compounds in the small intestine.
7-87
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The beryl 11 urn-induced osteosarcomas in rabbits were shown to be highly
invasive and to readily metastasize. They were judged to be histologically
indistinguishable from non-beryllium-induced human osteosarcomas, although the
sites may be different.
As noted above, positive carcinogenic responses in animals were obtained
in multiple species and through various routes of exposure. In studies using
either inhalation or the intravenous injection route, positive results were
obtained in multiple experiments. For several of the beryllium compounds
tested, such as beryllium sulfate, significant responses were obtained at low
dose levels. Based on the above findings, the overall evidence for carcino-
genicity of beryllium in animals is convincing despite the limitations of many
of the studies. According to EPA's criteria for evaluating the weight of
evidence for carcinogenicity (U.S. EPA, 1986), the evidence for carcinogenicity
of beryllium in animals is considered to be "sufficient".
Although several studies (Wagoner et. al., 1980; Mancuso, 1979; Manusco,
1980) claim a statistically significant excess risk of lung cancer in individ-
uals exposed to beryllium, all of the studies cited have deficiencies that
limit definitive conclusions regarding a true carcinogenic association.
Support for finding an excess risk of lung cancer in beryllium-exposed persons
consists of evidence from cohort mortality studies of two beryllium production
facilities. None of these studies are independent, as they are all based on
the same groups of workers. Extensive collaboration existed between the
authors of these studies. The expected lung cancer deaths used in all of these
studies were based on a NIOSH computer-based life-table program known to pro-
duce an 11-percent underestimation of expected lung cancer deaths. Further-
more, the studies did not adequately address the confounding effects of smoking
or of exposures received during prior or subsequent employment in other non-
beryllium industries in the area. Many of these industries were known to
produce other potential carcinogens. Problems in the design and conduct of the
studies further weaken the strength of the findings. After correcting the
life-table error and adjusting for some of the problems described above, the
finding of a significant excess risk is no longer apparent. While the possibi-
lity remains that the portion of the reported excess lung cancer risk remaining
in these studies may, in fact, be due to beryllium exposure, the epidemiologic
evidence is, nevertheless, considered to be "inadequate" according to EPA's
criteria for evaluating the weight of evidence provided by epidemiologic data.
7-88
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Limited testing has shown beryllium sulfate and beryllium chloride to be
nonmutagenic in bacterial and yeast gene mutation assays. In contrast, gene
mutation studies in cultured mammalian cells, Chinese hamster V79 cells, and
Chinese hamster ovary (CHO) cells have yielded positive mutagenic responses for
beryllium. Beryllium increased the infidelity of DNA and RNA polymerase in
prokaryotes. Chromosomal aberration and sister chromatid exchange studies in
cultured human lymphocytes and Syrian hamster embryo cells have also resulted
in positive mutagenic responses for beryllium. In DNA damage and repair
assays, beryllium is negative in the pol, rat hepatocyte, and mitotic recombina-
tion assays but is weakly positive in the rec assay. Based on the information
available, beryllium appears to have the potential to cause mutations.
Using the EPA criteria for evaluating the overall weight of evidence for
carcinogenicity in humans, beryllium is most appropriately classified as group
82, a probable human carcinogen. This category is reserved for those chemicals
having sufficient evidence for carcinogenicity in animals but inadequate
evidence in humans.
7.4.2 Quantitative Summary
Both animal and human data are used to estimate the carcinogenic potency
of beryllium. Among the animal studies, only data from inhalation exposures
or intratracheal instillation are used because the intravenous or intramedullary
exposure routes are not considered to be directly relatable to human exposures,
and all dietary ingestion studies yielded negative results. Many of the animal
inhalation studies for beryllium are not well documented, were conducted at
single-dose levels, and, in some cases, did not utilize control groups.
Collectively, however, the studies provide a reasonable basis for estimating
potency (at least for beryllium sulfate and beryllium oxide), as exemplified by
the consistency of response in rats. Data from nine studies (7 studies of
rats, 1 study of guinea pigs, and 1 study of monkeys) using beryllium sulfate,
phosphate, and fluoride have been used to calculate the upper bounds for the
carcinogenic potency of beryllium salts. Data from eight studies with rats
have been used to calculate the upper bounds for the carcinogenic potency of
beryllium oxide. The upper-bound potency estimates from the data based on
3 ~2 3
exposure to beryllium sulfate equal 3.6/(ng/m ) in monkeys, 6.5 x 10 /(|jg/m )
in guinea pigs and range from 4.3/(|jg/m3) to 3.7 x lO'Vdjg/m ) in rats. Esti-
mates derived from responses in rats exposed to beryllium fluoride and beryllium
7-89
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phosphate equal 1.4 x lO'V^g/m3) and 3.0 x I0"2/(ug/m3), respectively.
Potency estimates derived from responses of rats exposed to beryllium oxides
ranged from 7.4 x 10"2/(|jg/m3) to 2.1 x 10"4/(|jg/in3).
The magnitude of the potency estimates from animal data depends to a large
extent on the beryllium compound used in the experiment, although some varia-
bility in sensitivity among species is also seen, with guinea pigs responding
to a lesser degree than rats or monkeys. Among the beryllium compounds
examined in the animal studies, beryllium sulfate (BeS04) is the most potent,
with beryllium fluoride and beryllium phosphate somewhat less so and beryllium
oxide the least potent. There is some indication that the carcinogenic potency
of beryllium oxide varies with the firing temperature. The low-temperature
fired, more soluble oxides appear somewhat more potent than those fired at
higher temperatures. If one adopts an approach which selects data from the
most sensitive experimental animal species and the most potent compound as
being representative of risk to humans, the maximum potency estimate,
4.3/(ug/m ), would be used to represent the carcinogenic potential of beryllium.
This potency is estimated on the basis of data from rats exposed by inhalation
(Vorwald et al., 1966). Since beryllium is most commonly present in the
ambient air as the oxide, a potency estimate based upon the beryllium oxide
studies is considered to be most representative of human risk. Due to the
individual weaknesses of each of the eight beryllium oxide studies, a potency
estimate of 2.1 x 10" /(pg/m3) was derived by calculating the geometric mean of
the individual potency estimates from each of the studies.
Information from the epidemiologic studies by Wagoner et al. (1980) and
the industrial hygiene reviews by NIOSH (1972) and Eisenbud and Lisson (1983)
have been used to estimate the cancer risks associated with exposure to work-
place air contaminated with beryllium. Even though the epidemiologic evidence
does not demonstrate a statistically significant causal association between
beryllium and cancer, that does not mean that no risk exists. The size of the
study population, the background risk, and a variety of other factors limit the
ability of a study to detect small risks. Each study has a level of sensi-
tivity, and the study population may be too small to show a statistically
significant association if the true risk is below this level. An upper-bound
risk estimate can be calculated from a non-positive, or even negative, study to
describe the study's level of sensitivity. Risk levels below that upper bound
are completely compatible with the study data. The upper bound may be thought
7-90
-------
of as indicating the largest plausible risk that is consistent with the avail-
able data. Thus, the epidemiologic studies can be used to estimate a plausible
upper bound for the increased cancer risk from human exposure to beryllium.
In the Wagoner et al. (1980) study, 20 lung cancer deaths were observed
in a cohort of workers followed for at least 25 years compared with 13.91 to
14 67 expected (p <0.lO). Using the revised estimates of relative risk from
this study, two upper-bound relative risk estimates, 1.98 and 2.09, have been
used by the CAG to calculate the carcinogenic potency of beryllium. In recog-
nition of the greater uncertainty associated with the exposure estimation, four
different "effective" levels of exposure that reflect various uncertainties,
along with the two relative risk estimates, have been used in the present
calculations. As a result, eight unit risk estimates have been calculated,
ranging from 1.6 x
. to 7.2 x Nf3/(pgV) , with the geometric mean
of the eight estimates being 2.4 x lO^/Cug/m3). After rounding to one signifi-
cant figure, the incremental lifetime cancer risk associated with 1 ug/m of
beryllium oxide in the air is thus estimated to be 2 x l
-------
metal are most commonly present. When animals are exposed to beryllium oxide
or oxide-containing beryllium ore, the potency estimates agree with those
derived from human exposures.
A major uncertainty of the risk estimate based on human data comes from
the derivation of exposure levels in the workplace and the temporal effect of
the patterns of exposure. To account for these uncertainties, the "effective"
exposure level of beryllium is derived in several ways, and the geometric mean
of different potency estimates thus calculated is used to represent the
carcinogenic potency of beryllium.
Another uncertainty concerns the use of potency values derived from ex-
posures in the workplace environment to estimate potency from exposure in
ambient air. The types of sources which emit beryllium to the ambient air are
limited. There is little evidence^that ore production is a significant source
of beryllium emissions. Metallurgical processing is likewise considered an
insignificant source. As much as 95 percent of atmospheric beryllium emissions
are estimated to come from coal-fired electric power plants, with most of the
remainder resulting from fuel oil combustion (see Chapter 3). During coal com-
bustion beryllium is likely emitted as a relatively insoluble oxide, generally
as a trace contaminant of fly ash particles which are even more insoluble. On
this basis, the potency of beryllium from this source would be expected to be
quite low. Beryllium emissions from fuel oil combustion are similarly likely
to occur primarily in the oxide form. Experimental evidence also indicates
that beryllium in fly ash has a low degree of potency, since even very high
concentrations of fly ash containing other known carcinogens have failed to
induce cancer in laboratory animals. On this basis, it is unlikely that values
derived from exposure in the workplace will significantly underestimate the
potency of beryllium in ambifent air, unless soluble beryllium compounds such as
fluoride, phosphate, or sulfate are known to be present.
Because of the weaknesses of the animal studies upon which some of the
carcinogenic potency estimates were derived, these estimates are judged to be
less reliable than those derived from human occupational exposures. They do,
however, provide support for the occupationally-derived estimates. Despite'
some uncertainties concerning exposure levels in the workplace and possible
differences in the forms of beryllium found in ambient air compared with the
workplace environment, the CAG-revised relative risks from the Wagoner et al.
(1980) epidemiologic study were considered to be the best choice for estimating
7-92
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the upper-bound incremental cancer risk for inhalation exposure to mixtures of
beryllium compounds (mostly beryllium oxide) likely to be present in ambient
air. 33
The upper-bound incremental unit risk of 2 x 10 /(ug/m ) results in a
potency index of 2 x 10+2, which places beryllium oxide in the third quartile
of the 59 suspect carcinogens evaluated by the CAG.
7.5 CONCLUSIONS
Using EPA's Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1986) to
classify the weight of evidence for carcinogenicity in experimental animals,
there is sufficient evidence to conclude that beryllium and beryllium compounds
are carcinogenic in animals. This evidence is based upon the induction of
osteosarcomas and chondrosarcomas by intravenous and intramedullary injection
in rabbits and upon the induction of lung tumors in rats and monkeys by inhala-
tion and intratracheal instillation. Although results were equivocal or
negative for ingestion, it is believed that if an agent is carcinogenic by one
route it is potentially carcinogenic by any route. The lack of a definitive
response via the ingestion route is considered most likely due to low absorp-
tion efficiency. Due to limitations in methodology, the epidemiological
evidence is considered to be "inadequate", even though significant increases in
lung cancer were seen in some epidemiology studies of occupationally exposed
persons.
A potency of 2.4 x 10~3/(ug/m3) was derived from the occupational studies
involving human exposure to beryllium compounds (thought to be mostly beryllium
oxide) commonly present in the workplace.
The carcinogenic potency of inhaled beryllium derived from animal studies
varies with-the form of beryllium. Potency values for beryllium sulfate ranged
from 4.3 to 3.7 x lo'V^g/m3) with the most reliable estimate being 8.1 x 10 ,
while those derived from studies using beryllium fluoride or phosphate equalled
1.4 x 10"1 and 3.0 x 10"2/(|jg/m3), respectively. The geometric mean of potency
values derived from eight studies utilizing beryllium oxide was 2.1 x 10 /
(Mg/m3). Since beryllium oxide is considered to be the major form of human
exposure, this latter value provides support for the occupational^ derived
potency of similar magnitude, even though individual weaknesses in each of the
animal studies argue against the recommendation of an animal-only based car-
cinogenic potency.
7-93
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Recognizing, that the carcinogenic potency of inhaled beryllium varies
according to the form of beryllium present, an upper-bound incremental lifetime
cancer risk for continuous inhalation exposure at 1 ug Be/m3, rounded to one
-• ^
significant figure, is estimated to be 2 x 10 for general ambient conditions.
This presumes that beryllium is present in ambient air primarily in the oxide
form. The upper bound means that the actual unit risk is not likely to be
higher, but could be lower than 2 x Iff3. In addition, there is an added un-
certainty regarding this value in the sense that it may over- or underestimate
an upper bound due to assumptions made about dosimetry in the animal and human
risk modelling. This value places beryllium oxide in the the third quartile of
59 suspect carcinogens evaluated by the CAG. It should be cautioned, however,
that if compounds such as beryllium fluoride, phosphate, and sulfate are known
to be present in other than a small percentage of total beryllium in the ambient
air, this potency estimate (2 x 10"3) will likely underestimate the potential
carcinogenic risk. Conversely, since beryllium has not been shown definitively
to induce neoplasms via oral ingestion in any studies to date, this potency
estimate is likely to overestimate risk by this route.
The question of beryllium potency by ingestion is highly uncertain and
debatable due to the equivocal or negative results from ingestion studies.
From a weight-of-evidence point of view, however, the potential for human
carcinogenicity by this route cannot be dismissed. The Ambient Water Quality
Criteria Document for Beryllium (U.S. EPA, 1980) provided an upper-limit
potency estimate based upon the negative oral study of Schroeder and Mitchener
(1975a). This 1980 estimate was even higher than the inhalation potency
estimate presented in this assessment, thus, casting much doubt on its
reasonableness. The lack of clear-cut tumor induction, coupled with the
demonstrated very low beryllium absorption in the intestinal tract, suggests
that the oral potency could not be higher than the inhalation estimate and is
just as likely to be insignificant (i.e., close to zero).
7-94
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8. REFERENCES
Aldridge, W. N. ; Barnes, J. M. ; Denz, F. A. (1949) Experimental beryllium
poisoning. Br. J. Exp. Pathol. 30: 375-389
Alekseeva 0 G. (1965) Ability of beryllium compounds to produce delayed
allergy. Gig. Tr. Prof. Zabol. (11): 20-25.
Anderson, D. (1973) Emission factors for trace substances Research Triangle
Park NC- U. S. Environmental Protection Agency, Office of Air Quality
Nanning and Standards; EPA report no. EPA-450/2-73-001. Available from:
NTIS, Springfield, VA; PB-230894/AS.
Andrews, J. L. ; Kazemi , H. ; Hardy, H. L. (1969) n
chronic beryllium disease. Am. Rev. Respir. Dis. 100:
Anonymous. (1980) Beryllium mineral s--bertrandite now established. Industrial
Minerals (June): 55-63.
Araki, M.; Okada, S. ; Fujita, M. (1954) Experimental studies on
beryllium- induced malignant tumors in rabbits, Gann 45: 449-451.
Armitaae P • Doll R. (1961) Stochastic models for carcinogenesis. In: Pro-
ceedings of the fourth Berkeley symposium on mathematical statistics and
probability, v. 4. Berkeley, CA: University of California Press; pp.
19-38.
ta G • Wei J" • lorio, G. (1979) Theory of dispersion, transformation
and' deposition of atmospheric pollution using modified Green's functions.
Atmos. Environ. 13: 239-246.
Axel son, 0. (1978) Aspects on confounding in occupational health epidemiology.
Scand. J. Work Environ. Health 4: 98-102.
Av+oii I M • Asire A J • Myers, M. H. (1976) Cancer patient survival.
"Washington, DC: US Department of Health, Education, and Welfare;
publication no. (NIH) 77-992. Available from: GPO, Washington, DC. .
Balmes J R • Cullen, M. R. ; Robins, J. M. (1984) Epidemic chronic beryllium
63 disease among scrap metal refiners. In: Gee, J. B I . ; Morgan > U K C ^
Brooks, S. M. , eds. Occupational lung disease. New York, NY. Raven Press,
p. 225.
Barna B P • Chiang, T. ; Pillarisetti, S. G. ; Deodhar, S. D. (1981) Immuno-
logic studies of experimental beryllium lung disease in the guinea pig.
Clin. Immunol. Immunopathol . 20: 402-411.
8-1
-------
Arch. Allergy Appl. Inimunol. 73: 42-48.
»<•
Bayliss, D. L. (1980) [Letter to'William H. Foege, M. D. Director Centers for
Disease Control, Atlanta, GA]. Alexandria, VA; November 12
workp' ,V'+(19I2) Mortal1ty P^terns in beryllium produc-
workers. Presented at: American Industrial Hyqiene Association
Conference; OSHA exhibit no. 66, docket no. H-005. ygiene rtssociatlon
Bayliss, D. L. ; Wagoner, J. K. (1977) Bronchogenic cancer and cardio-resoiratorv
disease mortality among white males employed in a beryl!?™ product™
SSih y'TnCH,n<;lnnat-V °?; 5at1onal Inst1tute for Occupational'safety and
exhibit 1I3ndFUstry-wlde Studles Br^h; OSHA beryllium hearing, 1977;
y. L. J.; Ugo, R.; Ayer, H.; Hunter, F.
ln a 9rouP.of former beryllium workers. In:
Gnnmn i ^ • u a.nnual meetln9 of the American Conference of
Governmental Industrial Hygienists; Toronto, Canada; pp. 94-107.
of epidermal constituents. JOM J. Occup.
1 MV BeneS-' B'; C1krt' M" (1979) Penetration of beryllium
in the mouse- j-
Bencko V.; Vasilieva, E. V.; Symon, K. (1980) Immunological aspects of expo-
Res 22: e™39S-S449S burn1n9 CQ^ ^ high beryllium content. Environ.
Beus A. A. (1962) Beryllium in foreign countries. In: Beryllium: evaluation of
deposits during prospecting and exploratory work. San Francisco, CA- W H
series) ' PP' 3"42' (Gl'lluly> J" ' Woodford, A. 0., eds. A geology
Beus, A. A. (1966) Geochemistry of beryllium and genetic types of beryllium
S°?l7S' /•ra"iiFianCliSC°'uCA: W' H- Freeman and C°'; PP- 13'23' 312-339,
342-347 (Gilluly, J. ; Woodford, A. 0., eds. A series of books in
geology).
Bowen, H. J. M. (1979) Environmental chemistry of the elements. 'New York NY-
Academic Press. '
8-2
-------
Brown R 0 (1979) Beryllium pollution (a bibliography with abstracts).
Springfield! VA: National Technical Information Service; report no.
PB80-801202.
lun9
Health 29: 211-213.
131-140.
Cholak, J. (1959) The analysis of traces of beryllium. AMA Arch. Ind. Health
19: 205-210.
53-60.
810-811.
study. Arch. Environ. Health 23: 348-358
Cox, C. B. (1972) Regression model and life tables. J. R. Stat. Soc. B 34:
187-220.
163-176.
H A • Deal K L (1977) Confidence intervals and test of
ypoce^n'ng dSi' respond re, at, ons Inferred fro. an,ma,
carcinogenicity data. Biometrics 33: 437-451.
Curtis, G. H. (1951) Cutaneous ^ersensltlvlty due to ^-ngllu.: a study of
thirteen cases. AMA Arch. Dermatol. Syphilol. 64. 4/0 «*.
Curtis, G. H. (1959) The diagnosis of beryllium disease^ with special reference
to the patch test. AMA Arch. Ind. Health 19: 150-153.
8-3
-------
> K>; .Mas1te"»a". M- (1980) Asymptotic theory for analyzing
to low-dose
^
™
no.
Davidson, C. I.; Miller, J. M. ; Pleskow, M. A.
The influence of surface
™"
D1Pa°l!!A*;?'iA;; Ca|t0' B.' C" (1979) Quantitative studies of in vitro morpho-
^1R.tr389f?T5g-°^f. Syn'an ^^^ C6llS ^ -orga-nl-c-i^rsTus.
^
-dels of
^ HT-'-J- :»"*«. H'-p- Lafrenz, U. ; Reckzeh, G. ;
r« , - ? ^ .Investl flations on the effects of chronic
lift 5^1781-1832 tl0n ^ Syn"an 9°lden hamsters' JNCI J- Natl- Cancer
L
Introduction to anesthe-
£ R-;.Lew1s> E- B- Towm, L. E.; Hammons, A. S.
Cincinnat nH-°H J' L (195D Osteogenic sarcoma after
of beryllium oxide. Arch. Pathol. 51: 473-479.
Eisenbud, M. (1955) Health hazards from beryllium. In: White, D. W. • Burke J
Metals' metal beryl11um' C1eveland, Ohio: American Society for
Eisenbud M (1982) Origins of the standards for control of beryllium disease
(1947-1949). Environ. Res. 27: 79-88.
8-4
-------
Elsenbud, M.; Lisson, 0. (1983) Epidemiological. aspects of beryl Hum-induced
nonmalignant lung disease: a 30-year update. JOM J. Occup. Med. 25:
196-202.
Eisenbud, M.; Berghout, C. F.; Steadman, L. T, (1948) Environmental studies in
plants and laboratories using beryllium: the acute disease. J. Ind. Hyg.
Toxicol. 30: 281-285.
Eisenbud, M.; Wanta, R. C.; Dus tan, C.; Steadman L T; Harris W B.; Wolf,
B. S. (1949) Non-occupational berylliosis. J. Ind. Hyg. loxicoi. cJi.
282-294.
Federation of American Societies for Experimental Biology. (1974) 2nd ed. Vol.
III. Altman, P. L.; Dittmen, D. S., eds. Bethesda, MD. Library of Congress
no. 72-87738.
Ferin J • Leach, L. J. (1977) The effects of selected air pollutants on
clearance of titanic oxide particles from the lungs of rats. In: Walton
W. H., ed. Inhaled particles and vapors IV (in two parts): proceedings of
an international symposium, part 1; September 1975; Edinburgh.United
Kingdom. Oxford, United Kingdom: Pergamon Press Ltd.; pp. 333-341.
Firket, H. (1953) Mise en evidence histochimique du beryllium Jans les cellules
cultivees in vitro. C. R. Seances Soc. Biol. Ses Fil. 147: 167-168.
Fishbein, L. (1981) Sources, transport and alterations of metal compounds: an
overview. I, Arsenic, beryllium, cadmium, chromium, and nickel. EHP
Environ. Health Perspect. 40: 43-64.
Fisher, G. L.; Silberman, D.; Raabe, 0. 6. (1980) Chemical characterization of
coal fly ash and quantification of lung deposition -in rodent inhalation
studies. Environ. Res. 22: 298-306.
Flinn J E • Reimers, R. S. (1974) Development of predictions of future
pollution problems. Research Triangle Park, NC: US. Environmental
pollution prou E^ ^ ^ EPA-600/5-74-005. (Socioeconomic envi-
series). Available from: NTIS, Springfield, VA;
Protection. Agency,
ronmental studies
PB-233117.
Acta Morphol.
Fodor I (1977) Histogenesis of beryllium-induced bone tumors.
Acad. Sci. Hung. 25: 99-105.
Freiman D G •' Hardy, H. L. (1970) Beryllium disease: the relation of pulmo-
nary pathology to clinical course and prognosis based on a study of 130
cases from the U. S. Beryllium Case Registry. Hum. Pathol. 1: 25-44.
Furchner J E • Richmond, C. R.; London, J. E. (1973) Comparative metabolism
ofradionuclides in mammals. VIII. Retention of beryllium in the mouse,
rat, monkey and dog. Health Phys. 24: 293-300.
Gardner, L. U.; Heslington, H. F. (1946) Osteo-sarcoma from .
lium compounds in rabbits. Fed. Proc. Fed. Am. Soc. Exp. Biol. 5. 221.
8-5
-------
Gilbert, R. A.; Garrett, A. B, (1956) The equilibria of the metastable crystal-
line form of beryllium hydroxide: Be(OH)2 in hydrochloric acid, perchloric
acid and sodium hydroxide solutions at 25°. J. Am. Chem Soc 78-
5501-5505.
Gladney, E. S.; Owens, J. W. (1976) Beryllium emissions from a coal-fired power
plant. J. Environ. Sci. Health A 11: 297-311.
Goldschmidt, V. M.; Peters, C. (1932) Zur Geochemic der Beryllium. Nachr. Akad
Wiss. Goettingen, Math.-Phys. Kl. 2360-2376.
Grewal, D. S.; Kearns, F. X. (1977) A simple and rapid determination of small
amounts of beryllium in urine by flame!ess atomic absorption. At. Absorpt
News!. 16: 131-132.
Groth, D. H. (1980) Carcinogenicity of beryllium: review of the literature
Environ. Res. 21: 56-62.
Groth, D. H.; Mackay, G. R. (1971) Chronic pulmonary pathology in rats after
the intratracheal injection of-0.4, 4, and 40 pg of beryllium as beryllium
hydroxide. Toxicol. Appl. Pharmacol. 19: 392.
Groth, D. H.; Kommineni, C.; Mackay, G. R. (1980) Carcinogenicity of beryllium
hydroxide and alloys. Environ. Res. 21: 63-84.
Guyatt, B. L.; Kay, H. D.; Branion, H. D. (1933) Beryllium "rickets." J. Nutr.
6: 313-324.
Haenszel, W.; Loveland, D. B.; Sirken, M. G. (1962) Lung cancer mortality as
related to residence and smoking histories. I. White males. JNCI J. Natl.
Cancer Inst. 28: 947-1001.
Hall, R. H.; Scott, J. K.; Laskin, S.; Stroud, C. A.; Stokinger, H. E. (1950)
Toxicity of inhaled beryllium. Arch. Ind. Hyg. Occup. Mecl. 2: 25-33.
Hall, T. C.; Wood, C. H.; Stoeckle, J. D.; Tepper, L. B. (1959) Case data from
the Beryllium Registry. AMA Arch. Ind. Health 19: 100-103.
Hammond, E. C. (1966) Smoking in relation to the death rates of one million men
and women. In: Haenszel, W., ed. Epidemiological approaches to the study
of cancer and other chronic diseases. Bethesda, MD: U. S. Department of
Health, Education, and Welfare, National Cancer Institute; pp. 127-204.
(National Cancer Institute monograph no. 19).
Hard, G. C.; Skilleter, D. N.; Reiner, E. (1977) Correlation of pathology with
distribution of Be following administration of beryllium sulfate and
beryllium sulfosalicylate complexes to the rat. Exp. Mol. Pathol 27-
197-212.
Hardy, H. L. (1980) Beryllium disease: a clinical perspective. Environ. Res.
21: 1-9.
8-6
-------
Hardy, H. L. ; Tabershaw, I. R. .(1946) Deljyed dheillcalpneujonltls °^ring in
workers exposed to beryllium compounds. J. Ind. Hyg. Toxicol. 28. iy/ *LL.
Hart, B. A.; Pittman, D. G. (1980) The uptake of beryllium by the alveolar
macrophage. J. Reticuloendothel. Soc. 27: 49-58.
R A • Harmsen A G : Low, R. B. ; Emerson, R. (1984) Biochemical,
'cyBtologicaHl and' historical' alterations in rat lung following acute
beryllium aerosol exposure. Toxicol. Appl. Pharmacol. 75: 454-465.
Hasan F M • Kazemi , H. (1974) Chronic beryllium disease: a continuing epidem-
iologic hazard. Chest 65: 289-293.
Hawkes, H. E. ; Webb, J. S. (1962) Geochemistry in mineral exploitation. New
York, NY: Harper.
Henrv W M. (1979) Methods for analyzing inorganic compounds in particles
emitted from stationary sources: interim report. Research Triangle Park
NC US Environmental Protection Agency, Environmental Sciences Research
Laboratory; EPA repoVt no. EPA-600/7-79-206. Available from: NTIS, Spring-
field, VA; PB80-141781.
B L (1964) A transplantable
AbbUs.' J.. Bone Jt. s"urg. «.. Vol.
46A: 789-796.
Hoagland, M. B. ; Grier, R. • S. ; Hood, M. B. (1950) Beryllium and growth: I.
beryllium- induced osteogenic sarcomata. Cancer Res. 10: 629-635.
Hnnhora J • Rais J (1980) Two cases of sudden death due to granulomatous
"°fl Socardltl? among beryllium exposed workers. Toxicol. Lett. (Spec. Iss.)
1: 203.
Hooper, W. F. (1981) Acute beryllium lung disease. N. C. Med. J. 42: 551-553.
The effects of the administration of
Press; pp. 569-570.
(1986) GLOB A L86: A computer program
*. . data to low do s^ Prepared tj r th,
U. S. Environmental Protection Agency under "J^0"^"* ^ 251U 2745
Research Triangle Institute. EPA contract no. EPA-68-01-6826.
Hsie, A. W.; Johnson, N. P.; Couch, D.
P.; Hoeschele, J. D.; Rahn, R. 0.;
mammalian cell mutagenesis and a
ootential of metallic compounds. .•. . ' 'cc. ca
health and disease. New York, NY: Raven Press; pp. 55-69.
.
8-7
-------
Sun V 2 rll7p J' P';,San Sebastl'an> J- R-; Couch, D. B. ; Brimer P A •
Hsi'e M H Vl97U9^°ennJV-C;V-FOrbeS' N'. L' ' Ma^anoff, R. Riddle J c! |
of the cvLnv?r?tw Quantl*atlve. mammalian cell genetic toxicology: study
^^^
in the CHO/HGPRT system. Environ. Sci Res 15° 291-315
Hyslop F.; Palmes, E. D. ; Alford, W. C. ; Monaco, A. R. ; Fair-hall L T (19431
(UN MlSS n°of. yll1U1"- Washi"9to". "C: 'Allied' !nstTtutes of
^
International Commission on Radiological Protection. (1977) Recommendation of
Press"" *' ^^ Jm' 17> ^ ' °*f^> United
19-26
>; Miz.unoe' .M'.' Inamasu, T. ; Hisanaga, A. (1980) [Experimental
nC1eni-C\ty.0f bkeryllium oxide and arsenic trioxide to the
mtratracheal instillation]. Fukuoka Igaku Zasshi 71:
Ishizawa^M. (1979) Mutagenicity testing of carcinogens using E. coli WP2
strains carry! ng plasmid PKM 101. Hen'ign to Dokusei 8: 29-36.
'
r»«V» °neif4 •' 19f;i The different^tion of sarcoidosis and beryl-
disease. AMA Arch. Ind. Health 19: 160-163.
hPwiH,,m (1933i) -B°^ ^u1"0"? 1n rats Produced by the substitution of
beryllium for calcium in the diet. .Arch. Pathol. 15: 18-26.
f S'K.?-; "erDr1clc» J' F' (1954) Beryl! ium- induced osteo-
rabbits. J. Bone Jt. Surg. Br. Vol. 36B: 543-552.
1- MV Herr1ck> J- F- (1956) The influence of splenec-
°Steogen1c sarcoma ^. rabbits. J. Bone Jt. Surg.
nir«m
gemc sarcoma
Vol L
8-8
-------
Kada, T.; Hirano, K. ; Shirasu, Y. (1980) Screening of environmental chemical
mutagens by the Rec-assay system with Bacillus subtil is. In: de Serres, F.
J • Hollaender, A., eds. Chemical mutagens: principles and methods for
their detection: v. 6. New York, NY: Plenum Press; pp. 149-173.
Kanarek, D. J. ; Wainer, R. A. ; Chamberlin, R. I."; Weber A L ; Kazemi , H
(1973) Respiratory illness in a population exposed to beryllium. Am. Kev.
Respir. Dis. 108: 1295-1302. ,
Kanematsu, N. ; Hara, M. ; Kada, T. (1980) Rec assay and mutagenicity studies on
metal compounds. Mutat. Res. 77: 109-116.
Kay H. D. ; Skill, D. L. (1934) Prevention and cure of beryllium rickets.
Biochem. J. 28: 1222-1229.
Kelley, W. N. ; Goldfinger, S. E. ; Hardy, H. L. (1969) Hyperuricemia in chronic
beryllium disease. Ann. Intern. Med. 70: 977-983.
Kelly, P. J.; Janes, J. M. ; Peterson, L. F. A. (1961) The effect of beryllium
on bone: a morphological study of the progressive changes observed in
rabbit bone. J. Bone Jt. Surg. Am. Vol. 43A: 829-844.
Klemperer, F. W. ; Martin, A. P.; Liddy, R . E (1952) The fate of beryllium
compounds in the rat. Arch. Biochem. Biophys. 41: 148-152.
Knapp, C. E. (1971) Beryllium - hazardous air pollutant. Environ. Sci. Techno!.
5: 584-585.
Komitowski, D. (1968) Experimental beryllium- induced bone tumors as a model of
osteogenic sarcoma. Chir. Narzadow Ruchu Ortop. Pol. 33: 237.
Kramer D A (1984) Beryllium. In: Minerals yearbook, 1984: v. I, metals and
minerals. Washington, DC: U. S. Department of the Interior, U. S.* Bureau
of Mines.
Kubinski, H.; Gutzke, G. E. ; Kubinski, ZO. ^981)
assay for suspected carcinogens and mutagens. Mutat. Res. 89.
Kuschner, M. (1981) The carcinogenicity of beryllium. EHP Environ. Health
Perspect. 40: 101-105.
sov A F • Matveev, 0. G. ; Suntsov, G. D. (1974) Differences in the
utribution' of radioactive beryllium chloride with and without carrier in
rats during intratracheal administration. Gig. Sanit. (10): 113-114.
Kwapulinski, J. ; Pastuszka, J. (1983) Application of the mass b^lan.ce e^j°n
in the estimation of beryllium and radium concentrations in the lower
atmosphere. Sci. Total Environ. 26: 203-207.
Larramendv M L - Popescu, N. C. ; DiPaolo, J. A. (1981) Induction by inorganic
""TeJal'salts of s'ister' chromatid exchanges and chromosome 'Rations- in
human and Syrian hamster cell strains. Environ. Mutagen. 3. 597 606.
o F ir • Duffield F V (1979) Sources of environmentally important
' metais 'n the atmosphere. In: Risbi, T. H. , ed. Ultratrace meta! analyse
8-9
-------
in biological sciences and environment: symposium-
Washington, DC: American Chemical Society- pp
chemistry series no. 172). '
LeSSer;a!; J; Jpres1d1ng Judge) (1977) Informal public hearing on the proposed
^^^W^^^^SfeiS.u-l °—-'-
in, J.; Dattoli, J. A.; Vought, V. M. (1966) The significance of hprvliinm
concentrations in urine. Arch. Environ. Health 12: 331-334 beryllium
Lippmann M (1977) Regional deposition of particles in the human respiratory
tract. In. Lee, D. H. K., ed. Handbook of physiology: section 9 reactions
^environmental agents. Bethesda, MD: American Physiologic™ Society! pp'
Litvinov, N. N.; Bugryshev, P. F.; Kazenashev, V. F. (1975) 0 toksicheskikh
sroistvakh nekotorykh rastrovimykh soedinenii berillya po dannym
eksperimentaTnomorfologicheskikh issledovanii) [Toxic properties of some
compounds (based on experimental morphological investi-
Tr. Prof. Zabol. (7): 34-37.
'
Lee' J' S'' Abraham' J- L. (1983)
laboratory technician. Am. Rev.
Respir
Luke, M. Z. ; Hamilton, L. ; Hollocher, T. C. (1975) Beryllium- induced
Br?ocLnmbyR-a hDNA"PP°lyme,raSe: a P°"1b1^ ^tyor in beryllium
Biochem. Biophys. Res. Commun. 62: 497-501.
MacMahonB (1978) Evaluation of epidemiological materials. Cleveland, OH:
Brush Well man; OSHA beryllium hearings, 1977; 5. January 10.
MacMahon, B. (1979) OSHA beryllium hearings, comment on recent post-hearing
Pro?IrtSJ°nS A FebrUS7 !' Ava11able for inspection at: U. S. Environmental
Protection Agency, Central Docket Section, Washington, DC; docket no.
Mancuso T. F. (1970) Relation of duration of employment and prior respiratory
illness to respiratory cancer among beryllium workers. Environ. Res. 3-
-------
Mantel, N.; Schneiderman, M. A. (1975) Estimating "safe" levels, a hazardous
undertaking. Cancer Res, 35: 1379-1386.
Mason, B. (1966) Principles of geochemistry. 3rd ed. New York, NY: John Wiley &
Sons, Inc.
Mason, T. J.; McKay, F. W. (1973) U.S. cancer mortality by county: 1950-1969.
Washington, DC: U. S. Department of Health, Education, and Welfare; DHEW
publication no. (NIH) 74-615.
Mazabrau, A. (1975) Experimental osteosarcoma induced by single local injection
of beryllium in rabbit. Bull. Cancer 62: 49-58f
McCann, J.; Choi, E.; Yamasaki, E.; Ames, B. N. (1975) Detection of carcinogens
as mutagens in the Salmonel1 a/microsome test: assay of 300 chemicals.
Proc. Natl. Acad. Sci. U. S. A. 72: 5135-5139.
McMahon, T. A.; Brain, J. D.; Lemott, S. (1977) Species differences in aerosol
deposition. In: Walton, W. H., ed. Inhaled particles IV (in two parts):
proceedings of an international symposium; part 1; September 1975; Edin-
burgh, United Kingdom. Oxford, United Kingdom: Pergamon Press Ltd.; pp.
23-33.
Meehan, W. R. ; Smythe, L. E. (1967) Occurrence of beryllium as a trace element
in environmental materials. Environ. Sci Technol. 1: 839-844.
Merrill, J. R.; Lyden, E. F. X.; Honda, M.; Arnold, J. .R. (1960) Sedimentary
geochemistry of the beryllium isotopes. Geochim. Cosmochim. Acta 18:
108-129.
Mitchell, R. L. (1964) In: Bear, F. E., ed. Chemistry of the soil. 2nd ed.
London, United Kingdom: Chapman and Hall.
Miyaki, M.; Akamatsu, N.; Ono, T.; Koyama, H. (1979) Mutagenicity of metal
cations in cultured cells from Chinese hamster. Mutat. Res. 68: 259-263.
Morgareidge, K.; Cox, G. E.; Bailey, D. E.; Gallo, M. A. (1977) Chronic oral
toxicity of beryllium in the rat. Toxicol. Appl. Pharmacol. 41: 204-205.
Mullan, R. J. (1983) [Personal communication with David L. Bayliss Chief,
Project Officer]. Cincinnati, OH: Centers for Disease Control, National
Institute for Occupational Safety and Health, beryllium case registry;
October 14.
Mullen, A. L. ; Stanley, R. E. ; Lloyd, S. R.; Moghissi, A. A. (1972)
Radioberyllium metabolism by the dairy cow. Health Phys. 22: 17-22.
Nash, P. (1950) Experimental production of malignant tumors by beryllium.
Lancet 1: 519.
National Center for Health Statistics. (1967) Cigarette smoking and health
characteristics, United States, July 1964-June 1965. Washington, DC: PHS
publication no. 1000, series 10, no. 34.
8-11
-------
National Institute for Occupational Safety and Health. (1972) Criteria for a
recommended standard. . .occupational exposure to beryllium. Washington DC-
e?noSent Of Healtn> Education, and Welfare; NIOSH report no. :
.~ 10268.
Newland, L W. (1982) Arsenic, beryllium, selenium and vanadium. In: Hutzinger,
u. , ed. The handbook of environmental chemistry: v. 3, part B, anthropo-
genic compounds. New York,. NY: Springer-Verlag; pp. 27-67.
Nishimura, M. (1966) Clinical and experimental studies on acute beryllium
disease. Nagoya J. Med. Sci. 28: 17-44.
Niyogi, S. K. ; Feldman, R. P.; Hoffman, D. J. (1981) Selective effects of metal
ions on RNA synthesis rates. Toxicology 22: 9-21.
Novoselova, A. V.; Batsanova, L. R. (1969) Analytical chemistry of beryllium
Ann Arbor, MI: Ann Arbor-Humphrey Science.
Occupational Safety and Health Administration. (1978) Supplemental summation on
epidemiology of Brush Wellman Inc. with respect to proposed occupational
safety and health standard for exposure to beryllium. OSHA Technical Data
Center, docket no. H005.
Owens, J. W.; Gladney, E. S. (1975) Determination of beryllium in environmental
materials by flameless atomic absorption spectroscopy. At. Absorpt. News!.
14: 76~77.
Parker, V.^ H. ; Stevens, C. (1979) Binding of beryllium to nuclear acidic
proteins. Chem. Biol. Interact. 26: 167-177.
Pasupathy, K. ; Pradhan, D. S. (1981) Extreme chemical mutagen sensitivity of
respiratory adaptation in yeast. Mutat. Res. 80: 65-74.
Pennington, J. A. T. (1983) Revision of the total diet study food list and
diets. J. Am. Diet. Assoc. 82: 166-173.
Pepelko, W. E. (1987) The feasibility of dose adjustment based on differences
in long-term clearance rates of inhaled parti cul ate matter in humans and
laboratory animals. Regul. Toxicol.: in press.
Perry, S. T. ; Kulkarni, S. B. ; Lee, K.-L. ; Kenney, F. T. (1982) Selective
effect of the metal! ocarcinogen beryllium on hormonal regulation of gene
expression in cultured cells. Cancer Res. 42: 473-476.
Petzow, G. ; Zorn, H. (1974) Zur Toxikologie beryl! iumhal tiger Stoffe [Toxicol-
ogy of beryllium-containing substances]. Chem. Ztg. 98: 236-241.
Phillips, M. A. (1973) Investigations into levels of both airborne beryllium
and beryllium in coal at the Hayden power plant near Hayden, Colorado.
Environ. Lett. 5: 183-188.
Policard, A. (1950) Histological studies of the effects of beryllium oxide
(glucine) on animal tissues. Br. J. Ind. Med. 7: 117-121.
8-12
-------
Preuss, 0.; Oster, H. (1980) Zur Gesundheitsgefaehrdung durch Beryllium aus
heutiger Sicht [The current view of beryllium as a health hazard].
Arbeitsmed. Soziaimed. Praeventivmed. 15: 270-275.
Puzanova, L.; Doskocil, M.; Doubkova, A. (1978) Disturbances of the development
of chick embryos after the administration of beryllium chloride at early
stages of embryogenesis. Folia Morphol. (Prague) 26: 228-231.
Raabe, 0. G.; Yeh, H.-C.; Newton, G. J.; Phalen, R. F.; Velasquez, D. J. (1977)
Deposition of inhaled monodisperse aerosols in small rodents. In: Walton,
W. H., ed. Inhaled particles IV (in two parts): proceedings of an interna-
tional symposium, part 1; September 1975; Edinburgh, United Kingdom;
Oxford, United Kingdom: Pergamon Press Ltd.; pp. 3-21.
Rees, P. J. (1979) Unusual course of beryllium lung disease. Br. J. Dis. Chest
73: 192-194.
Reeves, A. L. (1965) The absorption of beryllium from the gastrointestinal
tract. Arch. Environ. Health 11: 209-214.
Reeves, A. L. (1977) Beryllium in the environment. Clin. Toxicol. 10: 37-48.
Reeves, A. L. (1978) Beryllium carcinogenesis. In: Schrauzer, G. N., ed.
Inorganic and nutritional aspects of cancer. New York, NY: Plenum Publish-
ing Corp.; pp. 13-27.
Reeves, A. L. (1979) Beryllium. In: Friberg, L.; Nordberg, G. F.; Vouk, V. B.,
eds. Handbook on the toxicology of metals. Amsterdam, The Netherlands:
Elsevier-North Holland; pp. 329-343.
Reeves, A. L. ; Deitch, D. (1969) Influence of age. on the carcinogenic response
to beryllium inhalation. In: Harishima, S., ed. Proceedings of the 16th
international congress on occupational health. Tokyo, Japan: Japan Indus-
trial Safety Association; pp. 651-652.
Reeves, A. L.; Krivanek, N. D. (1974) The influence of cutaneous hypersensitiv-
ity to beryllium on the development of experimental pulmonary berylliosis.
Trans. N. Y. Acad. Sci. 36: 78-93.
Reeves, A. L.; Vorwald, A. J. (1961) The humoral transport of beryllium. JOM J.
Occup. Med. 3: 567-574.
Reeves, A. L.; Vorwald, A. J. (1967) Beryllium carcinogenesis: II. pulmonary
deposition and clearance of inhaled beryllium sulfate in the rat. Cancer
Res, 27: 446-451.
Reeves, A. L.; Deitch, D.; Vorwald, A. J. (1967) Beryllium carcinogenesis: I.
inhalation exposure of rats to beryllium sulfate aerosol. Cancer Res. 27:
439-445.
Reeves, A. L. ; Swanborg, R. H.; Busby, E. K. ; Krivanek, N. D (1971) The role
of immunologic reactions in pulmonary berylliosis. In: Walton, W. H., ea.
Inhaled particles III: proceedings of an international symposium, y. II;
8-13
-------
September 1970; London, United Kingdom. Surrey, United Kingdom: Unwin
Brothers Limited; pp. 599-608.
Reeves, A. L.; Krivanek, N. D.; Busby, E. .K.; Swanborg, R. H. (1972) Immunity
to pulmonary berylliosis in guinea pigs. Int. Arch. Occup. Environ. Health
29: 209-220.
Rhoads, K.; Sanders, C. L. (1985) Lung clearance, translocation, and acute
toxicity of arsenic, beryllium, cadmium, cobalt, lead, selenium, vanadium,
and ytterbium oxides following deposition in rat lung. Environ. Res. 36:
359-378.
Robinson, F. R.; Schaffner, F.; Trachtenberg, E. (1968) Ultrastructure of the
lungs of dogs exposed to beryllium-containing dusts. Arch. Environ. Health
17:. 193-203.
Rom, W. N.; Lockey, J. E.; Bang, K. M.; Dewitt, C. ; Johns, R. E., Jr. (1983)
Reversible beryllium sensitization in a prospective study of beryllium
workers. Arch. Environ. Health 38: 302-307.
Rosenkranz, H. S.; Leifer, Z. (1980) Detecting the DNA-modifying activity of
chemicals using DNA polymerase-deficient Escherichia coli. In: de Serres,
F. J.; Hollaender, A., eds. Chemical mutagens: principles and methods for
their detection, v. 6. New York, NY: Plenum Press; pp. 109-147.
Rosenkranz, H. S.; Poirier, L. A. (1979) Evaluation of the mutagenicity and
DNA-modifying activity of carcinogens and noncarcinogens in microbial
systems. JNCI J. Natl. Cancer Inst. 62: 873-892.
Ross, W. D.; Sievers, R. E. (1972) Environmental air analysis for ultratrace
concentrations of beryllium by gas chromatography. Environ. Sci. Technol.
6: 155-158.
Roth, H. D. (1983) [Letter to David Bayliss,. Carcinogen Assessment Group].
Rockville, MA: Roth Associates, Inc., Statistical Consultants; August 22.
Sanders, C. L.; Cannon, W. C.; Powers, G. J.; Adee, R. R.; Meier, D. M. (1975)
Toxicology of high-fired beryllium oxide inhaled by rodents: 1. metabolism
and early effects. Arch. Environ. Health 30: 546-551.
Sanders, C. L.; Cannon, W. C.; Powers, G. J. (1978) Lung carcinogenesis induced
by inhaled high-fired oxides of beryllium and plutonium. Health Phys. 35:
193-199.
Schepers, G. W. H. (1961) Neoplasia experimentally induced by beryllium com-
pounds. Prog. Exp. Tumor Res. 2: 203-244.
Schepers, G. W. H. (1964) Biological action of beryllium: reaction of the
monkey to inhaled aerosols. Ind. Med. Surg. 33: 1-16.
Schepers, G. W. H. (1971) Lung tumors of primates and rodents: part II. Ind.
Med. 40: 23-31.
8-14
-------
Schepers, G, W. H. ; Durkan, T. M. ; Delahant, A. B. ; Creedon, F. T. (1957) The
biological action of inhaled beryllium sulfate: a preliminary chronic
toxicity study on rats. AMA Arch. Ind. Health 15: 32-58.
Schlesinger, R. B. (1985) Comparative deposition of inhaled aerosols in experi-
mental animals and humans: a review. J. Toxicol. Environ. Health 15:
197-214.
Schroeder, H. A.; Mitchener, M. (1975a) Life-term studies in rats: effects of
aluminum, barium, beryllium, and tungsten. J. Nutr. 105: 421-427.
Schroeder, H. A.; Mitchener, M. (1975b) Life-term effects of mercury methyl
mercury, and nine other trace metals on mice. J. Nutr. 105: 4b^-4b«.
Scott, J. K.; Neuman, W. F. ; Allen, R. (1950) The effect of added carrier on
the distribution and excretion of soluble Be7. J. Biol. Chem. 182:
291-298.
Shacklette, H. T. ; Hamilton, J. C. ; Boerngen, J. G.; Bowles J. M. (1971)
Elemental composition of surficial materials in the conterminous United
States. Washington, DC: U. S. Department of the Interior, Geological
Survey; Geological Survey professional paper no. 574-D.
Shapley D (1977) Occupational cancer: government challenged in beryllium
proceeding. Science (Washington, DC) 198: 898-901.
Simmon V F. (1979a) In vitro mutageni city assays of chemical carcinogens and
related compounds with Salmonella typhimurium. JNCI J. Natl. Cancer Inst.
62: 893-899.
Simmon, V. F. (1979b) In vitro assays for recombinogenic activity of chemical
carcinogens and related compounds with Saccharomyces cerevisiae D3. JNCI
J. Natl. Cancer Inst. 62: 901-909.
Simmon, V. F. ; Rosenkranz, H. S. ; Zeiger, E ; Poirier, LA. (1979) Mutageni c
activity of chemical carcinogens and related compounds in the intrapen to
neal host-mediated assay. JNCI Ji Natl. Cancer Inst. 62: 911-918.
Si rover M A : Loeb, L. A. (1976) Metal -induced infidelity during DNA synthe-
sis. Proc. Natl. Acad. Sci. U. S. A. 73: 2331-2335.
Skilleter, D. N. ; Price, R. J. (1979) The role of lysosomes in the 'hepatic
accumulation and release of beryllium Biochem. Pharmacol. 28: 3595-3599.
Ski lister D N • Price, R. J. (1984) Lymphocyte beryllium binding: relation-
ship to' development of delayed beryllium hypersensitivity. Int. Arch.
Allergy Appl. Immunol. 73: 181-183.
Smith, B. (1978) [Memorandum to Director, DSHEFS, from Chief, IWSB . Concerning
review of paper "Beryllium: an etiologic agent in the induction of lung
cancer," by Wagoner et al.]. U. S. Department of Health, Education and
Welfare, Public Health Service, National Institute for Occupational Safety
and Health; June 13.
8-15
-------
Smith, R. J. (1981) Beryllium report disputed by listed author: a standina
controversy over a NIOSH study is revived by one of the scientists in-
volved. Science (Washington, DC) 211: 556-557.
Sm1th' * B- ; Suzuk1» Y' <1980) Histopathologic classification of bronchogenic
°21: V-i4°.Pt °f ^^ OCCUPat1onally exP°sed *> beryllium'
(195i:) Beryllium granuloma of the skin. Br. Med. J. 1:
Srteddon, I. B. (1955) Berylliosis: a case report. Br. Med. J. 1: 1448-1450.
Beryllium and i^stinal absorption. Rev. Esp.
Southwest Energy Federal Task Force. (1972) Southwest Energy Study. Appendix J
Xll frnSm°UrNCTeTS< ^H^ °? U' S' °^^^ of the • Interior? Avail -
able from: NTIS, Springfield, VA; PB-232095-set.
Handb°°k °f b1ol°9ical data. Philadelphia, PA: W. B.
Spencer, H.C.; Jones, J. C. ; Sadek, J. S. ; Dodson, K. B. ; Morgan, A H (1965)
lexicological studies on beryllium oxides. Toxicol. 'Appl9 Pharmacol 7
-
Spencer, H. C. ; Hook R H. ; Blumenshine, J. A.; McCollister, S. B. ; Sadek, S
hli ri0"655' Jl P-.^1968) Toxicological studies on beryllium oxides and
FpHpIliT90"^"1"9 ^xhaust products. Springfield, VA: Clearinghouse for
Federal Scientific and Technical Information; report no. AMRL-TR-68-148.
Spencer, _H.CV- McCollister, S. B. ; Kociba, R. J. ; Humiston, C. G. (1972)
Toxicological studies on beryllium exhaust product. In: Proceedings of the
!•• ul"1^ conference on environmental toxicology; October; Fairborn, OH
Wright-Patterson Air Force Base, OH: Aerospace Medical Research Laborato-
«ilffVA? AD^7737SPOrt "°' AMRL"TR"72'130- Available from: NTIS, Spring-
Sprince, N. L; Kazemi, H. ; Hardy, H. L. (1976) Current (1975) problem of
differentiating between beryllium disease and sarcoidosis. Ann N Y
Acad. Sci. 278: 654-664. ...
Sprince N L. ; Kanarek, D. J. ; Weber, A. L. ; Chamber! i n, . R. I.; Kazemi, H.
(1978) Reversible respiratory disease in beryllium workers. Am. Rev.
Respir. Dis. 117: 1011-1017.
Sprince N. L. ; Kanarek, D. J. ; Weber, A. L. ; ChambeHin, R. I.; Kazemi, H.
(1979) Reversible interstitial disease in beryllium workers. Am. Rev
Respir. Dis. 119: 237.
Stiefel, ™.; Schulze, K. ; Zorn, H. ; Toelg, G. (1980) Toxicokinetic and
toxicodynamic studies of beryllium. Arch. Toxicol. 45: 81-92.
8-16
-------
Stoeckle, J. D.; Hardy, H. L.; Weber, A. L. (1969) Chronic beryllium disease:
long-term follow-up of sixty cases and selective review of the literature.
Am. J. Med. 46: 545-561.
Stokinger, H. E., ed. (1966) Beryllium: its industrial hygiene aspects. New
York, NY: Academic Press. (Clayton, G. D., ed. Monograph series on indus-
trial hygiene).
Stokinger, H. E.; Sprague, G. F., III; Hall, R. H.; Ashenburg, N, J.; Scott J.
K ; Steadman, L. T. (1950) Acute inhalation toxicity of beryllium. Arch.
Ind. Hyg. Occup. Med. 1: 379-397.
Sumino, K.; Hayakawa, K.; Shibata, T.; Kitamura, S. (1975) Heavy metals in
normal Japanese tissues: amounts of 15 heavy metals in 30 subjects. Arch.
Environ. Health 30: 487-494.
Japp, E. (1969) Beryllium induced sarcomas Of the rabbit tibia. Br. J. Cancer
20: 778-783.
Tepper, L. B.; Hardy, H. L.; Chamberlin, R. J. (1961) Toxicity of beryllium
compounds. New York, NY: Elsevier; pp. 146-168.
Tsuiii, H.; Hoshishima, K. (1979) The effect of the administration of trace
amounts of metals to pregnant mice upon the behavior and learning of their
offspring. Shinshu Daigaku Nogakubu Kiyo 16: 13-27.
U S. Bureau of Mines. (1950) Beryllium. In: Minerals yearbook, 1950: v. I,
metals and minerals. Washington, DC: U. S. Department of the Interior; pp.
1310-1319.
U. S. Centers for Disease Control. (1983) Beryllium disease among workers In a
spacecraft-manufacturing plant - California. Morb. Mortal. Wkly. Rep. 32:
419-425.
U.
U.
U.
S. Environmental Protection Agency. (1973, April 6). National emission
standards for hazardous air pollutants: asbestos, beryllium, and mercury.
Federal Register 38(227): 8820-8850.
S. Environmental Protection Agency. (1980) Ambient water quality criteria
document for beryllium. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office Cincinnati, OH
for the Office of Water Regulations and Standards, Washington, DC.
ERA-440/5-80-024. NTIS PB81-117350.
S. Environmental Protection Agency. (1983) Health assessment document for
beryllium [preliminary workshop draft]. Research Triangle Park, NC: Office
of Health and Environmental Assessment, Environmental Criteria and
Assessment Office. Available for inspection at US. Environmental
Protection Agency, Research Triangle Park, NC; docket no. ECAO-HA-83-4.
S. Environmental Protection Agency. (1984) Health assessment documentfor
beryllium [review draft]. Research Triangle Park, NC: Office of Health and
Environmental Assessment, Environmental Criteria and Assessment Office,
8-17
-------
EPA-600/8-84-°2M- Bailable from: NTIS, Springfield, VA;
u-
the current work force at the Kawecki-Berylco Plant, Reading, PA.
^ (1968a) The removal of Injected beryllium from the
Pattol 49-32?e " °f ^ reticulo-endothelial system. Br J Exp.
°f
'"
blood.
t^ ?raedt> R'j Benzonl, J. (1974) Role of the reticuloendothelial
system in the production of a-macrofetoprotein in the rat following
Toxicol. Appl
Cti?oaneofC RP?' ;• Ka-yJ°r5 ?' I' (1?55) Distribution, retention, and elimina-
375-392 rat after intratracheal injection. Ind! Health 11:
°fodrStbearnvdnl!;mSh (1984) -S1"! °- the 'W04^ blast transformation test
for beryllium hypersensitivity in beryllium workers: a twelve-year experi-
ence. In: Gee, J. B. L. ; Morgan, W. K. C. ; Brooks, S. M eds Occuoation-
al lung disease. New York, NY: Raven Press; pp. 220-221. Occupation
Van Ordstrand, H. S. ; Hughes, R. ; Carmody, M. G. C1943) Chemical pneumonia in
Q?riorS10-18aCt1n9 beryll1um «1de.' Report of three c?ses? ClSXlSd CllU.
Van Ordstrand, H S.; Hughes, R. ; DeNardi, J, M. ; Carmody, M. G (1945) Bervl-
lium poisoning. JAMA J. Am. Med. Assoc. 129: 1084-1090.
Vincent, R. G. ; Pickren, J. W. ; Lane, W. W. ; Bross, I.; Takita H • Houten L •
Gutierrez, A._C.; Rzepka, T. (1977) The changing ^i s%hoVoi of luna *
cancer: a review of 1682 cases. Cancer (Philadelphia) 39: 1647-1655.
Vinogradov, A P. (1960) Average contents of chemical elements in the principal
641-664 19neous rocks of the earth's crust. Geochemistry (USSR) 5:
pp.
o
" 425.
In: Vorwald' A' J" ed' Pneumoconiosis:
compensation. New York, NY: Paul B. Hoeber, Inc.-
'
Vorwald, A. J. (1953) Adenocarcinoma in the lung of albino rats exposed to
compounds of beryllium. In: Cancer of the lung: an evaluation of the
£2 YnUL PMTeMdlT uof *heASCle"t1f1c session' annua1 meeting; November;
New York, NY. New York, NY: American Cancer Society, Inc.; pp 103-109
8-18
-------
Vorwald, A. J. (1962) Progress report (unpublished). Am. Cancer Society; grant
no. F-253-6.
Vorwald, A. J. (1968) Biologic manifestations of toxic inhalants in monkeys.
In: Vagtborg, H., ed. Use of nonhuman primates in drug evaluation. Austin,
TX: University of Texas Press; pp. 222- 228.
Vorwald, A. J.; Reeves, A. L. (1959) Pathologic changes induced by beryllium
compounds: experimental studies. AMA Arch. Ind. Health 19: 190-199.
Vorwald, A. J.; Pratt, P. G. ; Urban, E. J. (1955) The production of pulmonary
cancer in albino rats exposed by inhalants to an aerosol of beryllium
1 sulfate. Acta Unio Int. Cancrum 11: 735.
Vorwald, A. J.; Reeves, A. L.; Urban, E. C. J. (1966) Experimental beryllium
toxicology. In: Stokinger, H. E., ed. Beryllium: its industrial hygiene
aspects. New York, NY: Academic Press; pp. 201-234.
Wagner, W. D.; Groth, D. H.; Holtz, J. L.; Madden, G. E.; Stokinger, H. E.
(1969) Comparative chronic inhalation toxicity of beryllium ores,
bertrandite and beryl, with production of pulmonary tumors by beryl.
Toxicol. Appl. Pharmacol. 15: 10-29.
Wagoner, J. K.; Infante, P. F.; Mancuso, T. (1978) Beryllium—carcinogenicity
studies. Science (Washington, DC) 201: 298-303.
Wagoner, J. K.; Infante, P. F.;. Bayliss, D. L. (1980) Beryllium: an etiologic
agent in the induction of lung cancer, nonneoplastic respiratory disease,
. _i i_ _ t_ _i • _____ _*__.„.._ .?«Ji.A-l-u^—.11*( jix^wrt^-rti-J \.iji v\\ss\v\f Cr^\i^ V*f\r\ f) f^C ^ I *
and heart
15-34.
disease among industrially exposed workers. Environ. Res. 21:
Weber, H.; Engelhardt, W. E. (1933) Anwendung bei der Untersuchungen von
Stauben aus der Berylliumgewinnung [Application of the research on dusts
from beryllium production]. Zentralbl. Gewerbehyg. Unfallverhuet. 10: 41-.
Wehner, A. P. (1981) Investigation of effects of prolonged inhalation of
nickel-enriched fly ash in Syrian golden hamsters. Project summary.
Cincinnati, OH: U. S. Environmental Protection Agency, Health Effects
Research Laboratory; EPA report no. EPA-600/S.1-81-009.
Whitman, R. A. (1970) Beryllium. In: Minerals yearbook, 1970: v. I, metals and
minerals. Washington, DC: U. S. Department of the Interior, U. S. Bureau
of Mines.
Williams. W. R.; Williams, W. J. (1982a) Development of beryllium lymphocyte
transformation tests in chronic beryllium disease.. Int. Arch. Allergy
Appl. Immunol. 67: 175-180.
Williams, W. R.; Williams, W. J. (1982b) Comparison of lymphocyte transforma-
tion and macrophage migration inhibition tests in the detection of beryl-
lium hypersensitivity. J. Clin. Pathol. 35: 684-687.
Williams, W. J.; Williams, W. R. (1983) Value of beryllium lymphocyte transfor-
mation tests in chronic Beryllium disease and in potentially exposed
workers. Thorax 38: 41-44.
8-19
-------
Williams, G. M.; Laspia, M. F.; Dunkel, V. C. (1982) Reliability of hepatocyte
primary culture/DNA repair test in testing of coded carcinogens and
noncarcinogens. Mutat. Res. 97: 359-370.
Witschi, H.^ P.; Aldridge, W. N. (1968) Uptake, distribution and binding of
beryllium to organelles of the rat liver cell. Biochem. J. 106: 811-820.
Wood, J. M.; Wang, H.-K. (1983) Microbial resistance to heavy metals Environ
Sci. Techno!. 17: 582A-590A.
Yamaguchi, S. (1963) Studies on osteogenic sarcoma induced experimentally bv
beryllium. Nagasaki Iggakai Zasshi 38: 127-139.
Zakour, R. A.; Tkeshelashvili, L. K.; Shearman, C. W.; Koplitz, R. M • Loeb L
A. (1981) Metal-induced infidelity of DNA synthesis. J. Cancer Res. Cl'in
Oncol. 99: 187-196.
Zorn, H.; Diem, H. (1974) Die Bedeutung des Berylliums und seiner Verbindungen
fuer den Arbeitsmediziner--!. Mitteilung [The significance of beryllium
and its compounds for occupational medicine professionals]. Zentralbl
Arbeitsmed. Arbeitsschutz 24: 3-8
Zorn, H.; Stiefel, Th.; Diem, H. (1977) Die Bedeutung des Berylliums und seiner
Verbindungen fuer den Arbeitsmediziner - 2. Mitteilung [The significance
of beryllium and its compounds for occupational medicine professionals].
Zentralbl. Arbeitsmed. Arbeitsschutz Prophyl. 27: 83-88.
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APPENDIX
ANALYSIS OF INCIDENCE DATA WITH TIME-DEPENDENT DOSE PATTERN
Table A-l presents time-to-death data with or without lung tumors. These
data are reconstructed from Figure 1 in Reeves and Deitch (1969), in which
study animals were exposed to beryllium by inhalation at a concentration of
.35 ug/m3, 35 hours/week, for specific durations during the 24-month observation
period.
The computer program ADOLL1-83, developed by Crump and Howe (1984), has
been used to fit these data. Models with one to seven stages, and with one of
the stages affected by the dose, have been calculated. The model with the
maximum likelihood has been selected as the best-fitting model. The identified
best-fitting model has six stages, with the fifth stage dose-affected. Using
this model, the maximum likelihood estimate of the slope (linear component),
under the assumption of constant exposure, is 0.81/ug/m3. The 95 percent upper-
confidence limit for the slope is 1.05/ug/m .
A-l
-------
t"
Exposure period
TABLE A-'l. TIME-TO-DEATH-DATA3
Time-to-death
1. Control
2. 14th - 19th
month
3. llth - 16th
month
4. 8th - 13th
month
5. 5th -10th
month
6. 2nd - 8th
month
7. 8th - 19th
month
8. 2nd - 13th
month
19 , 20 (2), 21 (6), 22" (8), 24" (8)
(2>, 15, 20 (4), 20,
, 22~(5), 24~(3),
20"(2), 21"(5), 21+, 22", 22+(3), 24+(9)
13",
, 20(3),
, 24
14", 18", 19" (4), 20+(3),
' 24"(4)'
22~(4), 23", 24+(3)
, 22",
, 22+(4), 24+(2)
9. 2nd - 19th 16", 18"(4), 19"(2), 20~(5), 20+(3), 21+(3), 2l", 22+
t n and t n indicate, respectively, the time-to-death with and without
lung tumor; n is the number of replications.
All animals were exposed to beryllium at a concentration of 35 ug/m3, 35
hours/week.
*U.S. GOVERNMENT PRINTING OFFICE: 1988-5i> 8-1 5^67076
A-2
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