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Beryllium and compounds
CASRN 7440-41-7
04/03/1998
Contents
0012
Beryllium and compounds; CASRN 7440-41-7; 04/03/1998
Health assessment information on a chemical substance is included in IRIS only after a
comprehensive review of chronic toxicity data by U.S. EPA health scientists from several
Program Offices, Regional Offices, and the Office of Research and Development. The summaries
presented in Sections I and II represent a consensus reached in the review process. Background
information and explanations of the methods used to derive the values given in IRIS are provided
in the Background Documents.
STATUS OF DATA FOR Beryllium and compounds
File First On-Line 01/31/1997
| Category (section) |
Status |
Last Revised |
| ------------------------------------------------------- |
----------------- |
---------------- |
| Oral RfD Assessment (I.A.) |
On-line |
04/03/1998 |
| Inhalation RfC Assessment (I.B.) |
On-line |
04/03/1998 |
| Carcinogenicity Assessment (II.) |
On-line |
04/03/1998 |
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC
EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Beryllium and compounds
CASRN -- 7440-41-7
Last Revised -- 04/03/1998
The oral Reference Dose (RfD) is based on the assumption that thresholds exist for certain
toxic effects such as cellular necrosis. It is expressed in units of mg/kg-day. In general, the RfD
is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to
the human population (including sensitive subgroups) that is likely to be without an appreciable
risk of deleterious effects during a lifetime. Please refer to the Background Document for an
elaboration of these concepts. RfDs can also be derived for the noncarcinogenic health effects of
substances that are also carcinogens. Therefore, it is essential to refer to other sources of
information concerning the carcinogenicity of this substance. If the U.S. EPA has evaluated this
substance for potential human carcinogenicity, a summary of that evaluation will be contained in
Section II of this file.
___I.A.1. ORAL RfD SUMMARY
| Critical Effect |
Experimental Doses* |
UF |
MF |
RfD |
| ------------------------------ |
----------------------------------- |
--------- |
--------- |
------------ |
| Small intestinal lesions |
BMD10: 0.46 mg/kg-day |
300 |
1 |
2E-3 mg/kg-day |
Dog Dietary Study
Morgareidge et al., 1976
*Conversion Factors and Assumptions -- mg/kg-day doses determined from administered doses
(ppm), reported food intake of 300 g/day and TWA body weights for males and females in each
dose group. This benchmark dose (BMD10) is the dose at the 95% confidence limit of the dose-response model corresponding to a 10% increase in incidence of these effects compared with
controls. A 10% increase was chosen as the benchmark response and calculated as probability (P)
of extra risk over controls at dose (d), [P(d) - P(0)/1- P(0)]. An exponential polynomial model
was used as the dose-response model. There was good fit of the model to the data (p = 0.94), and the maximum likelihood estimate (MLE) at 10% increase in incidence is 1.4
mg/kg-day.
___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)
Morgareidge, K; Cox, GE; Gallo, MA. (1976) Chronic feeding studies with beryllium in
dogs. Food and Drug Research Laboratories, Inc. Submitted to the Aluminum Company of
America, Alcan Research & Development, Ltd., Kawecki-Berylco Industries, Inc., and Brush-Wellman, Inc.
Morgareidge et al. (1976) conducted a long-term feeding study in which groups of 5 male
and 5 female beagle dogs (aged 8 to 12 mo) were fed diets (for 1 h per day) containing 0, 5, 50,
or 500 ppm beryllium as beryllium sulfate tetrahydrate for 172 weeks. Because of overt signs of
toxicity, the 500 ppm group was terminated at 33 weeks. At this time, a group of 5 male and 5
female dogs was added to the study and fed a diet containing 1 ppm beryllium; duration of
exposure for this group was 143 weeks. Using estimated TWA body weights and the reported
average food intake of 300 g/day, the 1, 5, 50, and 500 ppm concentrations correspond to doses
of 0.023, 0.12, 1.1, and 12.2 mg/kg-day for male dogs and 0.029, 0.15, 1.3, and 17.4 mg/kg-day
for females. The following parameters were used to assess toxicity: daily observations, food
consumption, body weight, hematology and serum clinical chemistry, urinalysis, organ weights
(heart, liver, kidney, brain, spleen, pituitary, thyroids, adrenals, and gonads), and comprehensive
histopathology.
Two moribund animals in the 500 ppm group were sacrificed during week 26; the
remainder of the animals in the 500 ppm group were killed during week 33. Overt signs of
toxicity observed in the 500 ppm group included lassitude, weight loss, anorexia, and visibly
bloody feces, indicating that the MTD is <500 ppm. Four other animals died during the course of
the study or were killed moribund: two dogs died during parturition, and one male and one
female dog in the 50 ppm group died. The appearance, behavior, food intake, and body weight
gain of the animals in the other beryllium groups did not differ from controls. No beryllium-related hematological, serum chemistry, or urinalysis alterations were observed in the 1, 5, or 50
ppm groups. In the 500 ppm group, a slight anemia (slight decreases in erythrocyte, hemoglobin,
and hematocrit; statistical analysis not reported), more apparent in the females than in the males,
was observed after 3 and 6 mo of exposure; however, there were no alterations in the bone
marrow and none of the animals was seriously affected. No alterations in organ weights were
observed. All animals in the 500 ppm group showed fairly extensive erosive (ulcerative) and
inflammatory lesions in the gastrointestinal tract. These occurred predominantly in the small
intestine and to a lesser extent in the stomach and large intestine, and were regarded by the
authors as treatment related. This conclusion is supported by independent review of the study
report; the lesions are not considered to be related to some other cause such as intestinal worms
(Goodman, 1997). All of the animals with stomach or large intestinal lesions also had lesions in
the small intestine except for one animal with stomach lesions only. This animal had stomach
lesions that were very localized and not very severe. Lesions in the small intestine (4/5 males and
5/5 females) considered treatment related include: desquamation of the epithelium, edema, fibrin
thrombi, acute inflammation, subacute/chronic inflammation, necrosis and thinning/atrophy of the
epithelium, and ulceration (Goodman, 1997). High-dose animals also showed moderate to
marked erythroid hypoplasia of the bone marrow, which the authors also considered treatment
related (Goodman, 1997). Bile stasis and vasculitis in the liver and acute inflammation in the
lymph nodes occurring in these animals is attributed to a likely systemic bacterial invasion through
the damaged intestinal mucosa. A generalized low-grade septicemia likely initiated kidney
damage.
In the 50 ppm group, one female dog died after 70 weeks of treatment. This animal
showed gastrointestinal lesions, but less severe, occurring in the same locations and appearing to
be the same types of lesions as those in dogs administered 500 ppm. The authors stated the cause
of death of this animal appeared to be related to beryllium administration. Other animals in this
treatment group survived until study termination and had no remarkable gross or microscopic
findings.
Dose-response modeling of the data for small intestinal lesions in male and female dogs
(0/10, 0/10, 0/10, 1/10, 9/10) was conducted to derive a benchmark dose for beryllium. A BMD10
(the lower 95% confidence limit on the dose from the maximum likelihood estimate [MLE] of a
10% relative change) of 0.46 mg/kg-day (MLE = 1.4 mg/kg-day) was derived for this lesion and
used for further quantitation in this assessment (U.S. EPA, 1995, and Conversion Factors and
Assumptions, above).
An oral chronic study via drinking water was carried out by Schroeder and Mitchener
(1975a) using Long-Evans rats (52 weanling rats of each sex). In addition to control animals, rats
of both genders were exposed to 5 ppm beryllium as beryllium sulfate over a lifetime. No adverse
effects were observed in the beryllium-exposed rats compared to controls with respect to lifespan,
various organs (heart, kidney, liver, and spleen), urinalysis, serum glucose, cholesterol, or uric
acid. With respect to cancer, the incidence of gross or malignant tumors in the control and
beryllium-exposed rats was not significantly different. This chronic oral study served as the basis
for the previous IRIS RfD of 5E-3 mg/kg-day. The new RfD derived from the Morgareidge et al.
(1976) study of 2E-3 is not significantly different.
___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD)
UF = 300.
The following uncertainty factors are applied: 10 for extrapolation for interspecies
differences, 10 for consideration of intraspecies variation, and 3 for database deficiencies. A
partial uncertainty factor for database deficiencies is applied because while there are several
chronic oral animal studies, human toxicity data by the oral route are lacking, and
reproductive/developmental and immunotoxicologic endpoints have not been adequately assessed
in animals. Database gaps include lack of adequate studies for evaluation of reproductive and
developmental toxicity (including multigenerational studies, studies on male reproductive toxicity,
teratology, and postnatal development) owing to the possible crossing of the placenta and greater
absorption of beryllium in young animals. In addition, oral studies examining immunologic
endpoints, the most sensitive endpoint by the inhalation route, are lacking. Since the principal
study is of chronic duration and a benchmark dose is used, there are no uncertainty factors for
duration or NOAEL/LOAEL extrapolation. No modifying factor is proposed for this assessment.
MF = 1.
___I.A.4. ADDITIONAL STUDIES/COMMENTS (ORAL RfD)
No human information on the oral toxicity of this compound was located.
While each of the chronic animal studies appears to have limitations (e.g., multiple
elements in drinking water, no randomization of animals, not published in peer-reviewed journal,
no doses showing an adverse effect, and/or lack of histological examination of all animals),
collectively they establish the range of doses that is unlikely to evoke noncancer toxicity.
In a chronic toxicity study by Morgareidge et al. (1975, 1977), groups of Wistar albino
rats were fed diets containing 5, 50, or 500 ppm beryllium as beryllium sulfate tetrahydrate. The
rats were administered the beryllium-containing diet from 4 weeks of age through maturation,
mating, gestation, and lactation. Fifty male and 50 female offspring were then placed on the same
diets as the parents and fed the beryllium-containing diet for 104 weeks. Using estimated TWA
body weights of 0.467, 0.478, and 0.448 kg for males in the 5, 50, and 500 ppm groups and
0.294, 0.302, and 0.280 kg for the females, respectively, and U.S. EPA's (1988) allometric
equation of food intake, doses of 0.36, 3.6, and 37 mg/kg-day for males in the 5, 50, and 500 ppm
groups and 0.42, 4.2, and 43 mg/kg-day for females in the 5, 50, and 500 ppm groups,
respectively, were calculated. Clinical observations, body weight, food consumption, organ
weights (liver, kidney, testes, ovaries, thyroid, pituitary, adrenal), gross necropsy, and
histopathological examination of most tissues and organs (25 to 26 tissues examined) were used
to assess the toxicity and carcinogenicity of beryllium in the offspring; it does not appear that the
P0 rats were examined. Tissues from 20 rats/sex/group in the control and 500 ppm groups were
examined microscopically (the study authors did not state whether the animals undergoing
histopathological examination were randomly selected), as well as all tissues with gross
abnormalities (all groups) and tissues (excluding bone marrow, eyes, and skin) from animals found
dead or sacrificed moribund (all groups).
No overt signs of toxicity were observed, and mortality appeared to be similar in the
controls (30/50 males and 28/50 females died) and beryllium groups at 5 ppm (30/50 and 24/50,
respectively), 50 ppm (31/50 and 18/50), and 500 ppm (24/50 and 17/50) at the end of the 104
weeks of the study. During the first 40 to 50 weeks of the study, exposure to beryllium did not
appear to affect growth; slight decreases in growth (body weights of males and females in the 500
ppm group were within 10% of control body weights) were observed in the latter part of the
study; however, no statistically significant alterations were observed. Alterations in organ weights
were limited to statistically significant (p < 0.05) increases in relative kidney weight in males
exposed to 50 ppm, decreases in relative kidney and adrenal weights in 500 ppm females, and
decreases in relative testes weights in 5 and 50 ppm males. Histological examination of the major
organs and tissues did not reveal beryllium-related noncarcinogenic alterations. This study has a
NOAEL at the highest dose tested (37 mg/kg-day).
Groups of 52 male and 52 female Long-Evans rats were maintained on a low-metal diet
and given drinking water containing 0 or 5 ppm beryllium as beryllium sulfate (presumably
tetrahydrate) from weanling to natural death (Schroeder and Mitchener, 1975a). The water also
contained 5 ppm chromium III, 50 ppm zinc, 5 ppm copper, 10 ppm manganese, 1 ppm cobalt,
and 1 ppm molybdenum. Doses of 0.63 and 0.71 mg/kg-day were calculated for male and female
rats, respectively. The following parameters were used to assess toxicity: body weights; blood
glucose, cholesterol, and uric acid; urine protein, pH, and glucose; heart weight; gross pathology;
and histopathology of heart, lung, kidney, liver, spleen, and tumors. Twenty male and eight
female rats in the beryllium group died at 20 mo of age from pneumonia; a similar number of
animals in the control group also died from pneumonia. At 30 days, the male and female rats
exposed to beryllium weighed significantly more than the control animals. At 60, 90, 120, and
180 days, the beryllium-exposed male rats weighed significantly less than the controls; no
significant alterations in body weight were observed at the other time intervals (150, 360, or 540
days). No significant alterations in mortality or longevity were observed. The results of the
histological examination were not reported. Alterations in serum glucose and cholesterol levels
and urine glucose levels in beryllium-treated animals were not considered adverse because the
magnitude of the alterations was not sufficiently large to suggest an impairment in organ function.
The NOAEL for this study is 0.63 mg/kg-day, the highest dose tested.
In a lifetime exposure study, groups of 54 male and 54 female Swiss mice were
administered 0 or 5 ppm beryllium as beryllium sulfate in the drinking water from weaning to
natural death (Schroeder and Mitchener, 1975b). The mice were fed low-metal diets and the
drinking water was supplemented with 50 ppm zinc, 10 ppm manganese, 5 ppm copper, 5 ppm
chromium III, 1 ppm cobalt, and 1 ppm molybdenum. The 5 ppm water concentration is
equivalent to doses of 1.2 mg/kg-day for the male and female mice. In the beryllium group,
statistically significant alterations in body weight were observed; the alterations included heavier
male mice at 30 days and lighter female mice at 90 and 120 days. No significant alterations in
mortality or survival were observed in the beryllium-exposed mice. A NOAEL of 1.2 mg/kg-day
is established for this study.
Shorter term oral studies in rats fed up to 3% beryllium carbonate in the diet have shown
beryllium rickets (Kay and Skill, 1934) and decreases in serum phosphate and serum alkaline
phosphatase activity (480 mg/kg-day; Matsumoto et al., 1991). One hypothesis for the
development of rickets has been the deprivation of phosphate in the intestines by precipitation as
beryllium phosphate and not to any direct effects due to beryllium per se.
There are limited data on the reproductive and developmental toxicity of beryllium
compounds following oral exposure. In the chronic dog oral exposure study conducted by
Morgareidge et al. (1976), the male and female dogs exposed to 1, 5, or 50 ppm beryllium sulfate
in the diet (0.024, 0.11, and 1.1 mg/kg-day for males and 0.025, 0.15, and 1.3 mg/kg-day for the
females) were housed together, allowed to mate, and wean their pups (with the exception of the
first litter, which was killed 5 days after whelping). Beryllium did not appear to adversely affect
reproductive or developmental endpoints, but stillborn or cannibalized pups dying within the first
few postnatal days were not examined. The authors reported no gross or skeletal abnormalities in
the surviving first litter pups, but data were not shown. In addition, there was no visceral
evaluation for terata.
Several parenteral studies (as reviewed by U.S. EPA, 1991) have observed developmental
effects (increased fetal mortality, decreased fetal body weight, internal abnormalities, and delayed
neurodevelopment) in the offspring of rodents following intratracheal or intraperitoneal
administration of beryllium chloride, beryllium oxide, or beryllium sulfate during gestation. Clary
et al. (1975) conducted a continuous breeding experiment in which male and female Sprague-Dawley rats received a single intratracheal administration of 200 µg beryllium as beryllium oxide
(calcined at 960C in the first experiment and calcined at 500C in the second experiment).
There were no adverse effects of beryllium in either experiment. Mathur et al. (1987)
administered intravenous injections of 0.021 mg/kg beryllium as beryllium nitrate to mated
Sprague Dawley rats (n = 5-8/group) (1/10th the LD50) and performed laparotomies; all pups
died 2 to 3 days after birth, but these effects may have been due to the repeated surgeries.
___I.A.5. CONFIDENCE IN THE ORAL RfD
Study -- Medium
Database -- Low to Medium
RfD -- Low to Medium
The overall confidence in this RfD assessment is low to medium. The confidence in the
principal study is medium. Beryllium was administered by a relevant route (oral) at multiple dose
levels for a chronic duration, effects were demonstrated at two dose levels, and relatively
comprehensive histopathologic evaluations were conducted. However, there were small groups
of animals (5/sex/dose), early mortality at the high dose level, no evidence of randomization or
control for potential litter effects, and no measure of immune response or function, the critical
endpoint by the inhalation. Confidence in the database is low to medium because there is only one
chronic study in dogs showing adverse effect levels; other chronic studies in rodents demonstrated
NOAELs at the highest doses tested. Confidence in this assessment is improved over the earlier
version on IRIS because of the inclusion of additional chronic studies in rats and dogs.
The major areas of scientific uncertainty in this assessment are the lack of chronic oral
studies establishing LOAELs, the lack of a chronic oral study examining immunologic endpoints,
the lack of a critical effect in humans by the inhalation route as identified in dogs and the lack of
sensitive indicators for rickets, the lack of reproductive and developmental studies (including
multigenerational studies or male reproductive toxicity), and the lack of human toxicity
information. The uncertainty factors above compensate for these areas of uncertainty. The RfD
determined from the BMD10 (0.46 mg/kg-day) of small intestinal lesions in dogs (2E-3 mg/kg-day) is almost identical to the previous IRIS RfD (5E-3 mg/kg-day) derived from the NOAEL
(0.5 mg/kg-day) in the Schroeder and Mitchener (1975a) rat study. However, to SUBSTantiate the
significance of the similarities between these two RfDs, additional dose-response rat studies
would be needed to establish a LOAEL and NOAEL.
___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD
Source Document -- U.S. EPA, 1998
This assessment was peer reviewed by external scientists. Their comments have been evaluated
carefully and incorporated in finalization of this IRIS summary. A record of these comments is
included as an appendix to the Toxicological Review of Beryllium and Compounds in support of
Summary Information on the Integrated Risk Information System (IRIS) (U.S. EPA, 1998).
Other EPA Documentation -- U.S. EPA, 1987; U.S. EPA, 1991
Agency Consensus Date -- 03/26/1998
___I.A.7. EPA CONTACTS (ORAL RfD)
Please contact the Risk Information Hotline for all questions concerning this assessment or
IRIS in general at (513) 569-7254 (phone), (513) 569-7159 (fax) or
RIH.IRIS@EPAMAIL.EPA.GOV (Internet address).
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION (RfC)
Beryllium and compounds
CASRN -- 7440-41-7
Last Revised -- 04/03/1998
The inhalation Reference Concentration (RfC) is analogous to the oral RfD and is likewise
based on the assumption that thresholds exist for certain toxic effects such as cellular necrosis.
The inhalation RfC considers toxic effects for both the respiratory system (portal-of-entry) and for
effects peripheral to the respiratory system (extrarespiratory effects). It is generally expressed in units of mg/m3. In general, the RfC is an estimate (with uncertainty spanning perhaps an order of
magnitude) of a daily inhalation exposure of the human population (including sensitive subgroups)
that is likely to be without an appreciable risk of deleterious effects during a lifetime. Inhalation
RfCs were derived according to the Interim Methods for Development of Inhalation Reference
Doses (U.S. EPA, 1994). RfCs can also be derived for the noncarcinogenic health effects of
substances that are carcinogens. Therefore, it is essential to refer to other sources of information
concerning the carcinogenicity of this substance. If the U.S. EPA has evaluated this substance for
potential human carcinogenicity, a summary of that evaluation will be contained in Section II of
this file.
___I.B.1. INHALATION RfC SUMMARY
| Critical Effect |
Experimental Doses* |
UF |
MF |
RfC |
| --------------------------------- |
------------------------------------- |
-------- |
-------- |
------------ |
| Beryllium sensitization |
LOAEL: 0.55 µg/m3 |
10 |
1 |
2E-2
µg/m3 |
| and progression to CBD |
LOAEL(HEC): 0.20 µg/m3 |
|
|
|
|
|
|
|
|
| Occupational study |
|
|
|
|
| Kreiss et al., 1996 |
|
|
|
|
|
|
|
|
|
| Community exposure |
NOAEL: 0.01-0.1 µg/m3 |
|
|
|
| study |
NOAEL(HEC): 0.01-0.1 µg/m3 |
|
|
|
|
LOAEL: None |
|
|
|
Eisenbud et al., 1949
*Conversion Factors and Assumptions: MW -- 9. The occupational LOAEL is based on 8-h
TWA exposure level. Mvo = 10 m3/day, Mvh = 20 m3/day. LOAEL(ADJ) = LOAEL(HEC)
= 0.55 µg/m3 × (MVo/MVh × 5 days/7 days) = 0.20 µg/m3.
___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC)
The RfC is based on beryllium sensitization and progression to chronic beryllium disease
(CBD) identified in the co-principal studies by Kreiss et al. (1996) and Eisenbud et al. (1949).
The Kreiss et al. (1996) occupational exposure study identified a LOAEL for beryllium
sensitization in workers exposed to 0.55 µg/m3 (median of average concentrations). The
Eisenbud et al. (1949) study, using relatively insensitive screening methods, suggests a NOAEL of
0.01-0.1 µg/m3 in community residents living near a beryllium plant. The LOAEL from the Kreiss
et al. study was used for the operational derivation of the RfC because the screening method used
in the Eisenbud et al. (1949) study was less sensitive than the method used in the Kreiss et al.
(1996) study.
Chronic beryllium disease is a chronic inflammatory lung lesion that can result from
inhalation exposure to beryllium. It is characterized by the formation of granulomas (pathologic
clusters of immune cells) and involves a beryllium-specific immune response. Beryllium
sensitization of the immune system can be demonstrated using the beryllium lymphocyte
transformation test (BeLT) (reviewed by Newman, 1996). In this test, lymphocytes obtained
from bronchoalveolar lavage (BAL) fluid or from peripheral blood are cultured in vitro and then
exposed to soluble beryllium sulfate to stimulate lymphocyte proliferation. The observation of
beryllium-specific proliferation indicates beryllium sensitization.
The criteria for diagnosis of CBD have evolved with time, as more advanced diagnostic
technology became available. These varying definitions of CBD should be considered in
comparing results from different studies. More recent criteria have both higher specificity than
earlier methods and higher sensitivity identifying preclinical effects. Recent studies typically use
the following criteria: (1) history of beryllium exposure; (2) histopathological evidence of
noncaseating granulomas or mononuclear cell infiltrates; and (3) a positive blood or
bronchoalveolar lavage (BAL) lymphocyte transformation test (Newman et al., 1989).
A cross-sectional study (Kreiss et al., 1996) was conducted of 136/139 of the then-current
beryllium workers in a plant that made beryllia ceramics from beryllium oxide powder.
Measurements from 1981 and later were reviewed and included area samples, process breathing-zone samples, and personal lapel samples (the last year only). Quarterly daily-weighted average
(DWA) exposures were calculated using a formula based on all of these measurements for each
job title. General area and breathing zone samples were not recorded until the last quarter of
1985, soon after machining production was transferred to that plant, even though a limited
amount of machining had been conducted since 1982. The median breathing zone measurements
for machining was 0.6 µg/m3, and 0.3 µg/m3 for other processes. The frequency of excursions to
higher exposure levels decreased with time, with the percentage of machining breathing zone
measurements above 5 µg/m3 falling from 7.7% during early sampling years to 2.1% during later
sampling years.
Beryllium lymphocyte transformation tests were performed by two different laboratories
on blood samples collected from 136 employees. Positive results from one or both laboratories
were confirmed by analyzing a subsequent blood sample. Of 136 tested employees, 5 had
consistently abnormal blood BeLT results from the two laboratories and were diagnosed with
CBD based on observation of granulomas in lung biopsy samples. An additional two employees
had abnormal blood results from one of the two laboratories and had no granulomas in lung
biopsy samples. Both employees developed abnormal blood results in the other laboratory within
2 years. One of these two employees also developed symptoms of CBD. The other employee
declined clinical follow-up. An additional case of CBD was found during the study in an
employee hired in 1991, who had a nonhealing granulomatous response to a beryllium-contaminated skin wound. This subject had a confirmed abnormal blood test, and after several
additional months developed lung granulomas. Only one CBD case had an abnormal chest X-ray.
An additional 11 former employees had CBD, for a total prevalence of 19/709. Beryllium-sensitized cases were similar to nonsensitized ones in terms of age, ethnic background, or
smoking status, but did have significantly fewer pack-years of smoking. There was also no
significant difference in percentage exposed to beryllium dust or mist in an accident or unusual
incident, or those in areas with a posted high air count. Of the eight sensitized workers, seven
had worked in machining at some point, while one case had never worked in a production job.
The beryllium sensitization rate was 14.3% among the machinists, compared to 1.2% among all
other employees. The individual average exposures for the six CBD cases and two sensitized
cases among current employees ranged from 0.2 to 1.1 µg/m3, and the cumulative exposure
ranged from 92.6 to 1,945 µg/m3-days. Two of the seven beryllium-sensitized machinists started
machining prior to the systematic environmental monitoring, and exposure estimates for these two
subjects may have been underestimated. The median of estimated average beryllium exposure for
the sensitized cases was about 0.55 µg/m3. The sensitized cases without disease did not have
lower exposures than the CBD cases. Machinists may have been more susceptible than other
groups because of their higher overall exposure or because the particles produced during
machining were primarily respirable in size, while other exposures were to particles larger than the
respirable range (< 10 µm). Other characteristics of the machining exposure, such as the particle
morphology, particle surface properties, and adjuvants in machining fluids, may also have affected
sensitization. The study authors noted that median breathing zone levels tended to be lower than
the DWAs derived from these levels because much of the day was typically spent in high-exposure
tasks. This study identified a LOAEL of 0.55 µg/m3 and a LOAEL(HEC) adjusted for an
occupational exposure of 0.19 µg/m3.
Eisenbud et al. (1949) evaluated beryllium exposure for 11 community cases of CBD.
CBD was defined based on limited radiographic and pathologic examination. Radiologic
screening of 10,000 residents was conducted, with questionable cases undergoing clinical
evaluation. CBD was diagnosed based on radiologic and clinical findings from a consensus of
specialists, but no sensitization information. One case was exposed to beryllium dust on worker
clothes and will not be discussed further. Of the other cases, five lived within 0.25 mile of a
beryllium production plant and all lived within 0.75 mile of the plant. A follow-up to this study
reported three additional cases at less than 0.75 miles from the plant, but no additional cases of
CBD at greater than 0.75 miles (Sterner and Eisenbud, 1951). Measurements downwind from the
plant found that the beryllium concentration at 0.75 miles was about 0.045 µg/m3, and continuous
sampling stations found that the average concentration at about 700 feet from the plant (the
furthest distance within the affected area) was 0.05 µg/m3(range 0 to 0.46 µg/m3). The emitted
beryllium was primarily as beryllium oxide, although beryllium fluoride and beryl (beryllium ore)
were also present. The study authors also calculated an estimated exposure, based on emissions
levels, stack heights, and wind speed data. These estimates were generally in good agreement
with the downwind data. Based on these calculations, the authors estimated that the average
exposure levels at 0.75 miles from the plant during the period of exposure monitoring were 0.004
to 0.02 µg/m3. Averaging this value to 0.01 µg/m3, and noting that both plant production and
emissions were about 10-fold higher in earlier years, the authors estimated that the concentration
at 0.75 mile was 0.01 to 0.1 µg/m3. The similar prevalence of CBD in the community compared
to workers exposed to much higher levels (100 to 1,000 µg/m3) was attributed to the smaller
particle size of beryllium emitted to the outside air compared to beryllium particles inside the
plant. This study, although limited by classification of CBD, suggest a NOAEL(HEC) of 0.01 to
0.1 µg/m3 for the development of CBD in a population exposed to beryllium in ambient air.
Few data are available on the particle characteristics of beryllium under occupational
exposure conditions. However, Hoover et al. (1990) found that 5.7% of the particles released
during sawing beryllium metal had aerodynamic diameters smaller than 25 µm but larger than
5 µm, and 0.3% were smaller than 5 µm. For milling of beryllium metal, 12% to 28% of the
particles had aerodynamic diameters between 5 and 25 µm, and 4% to 9% were smaller than
5 µm, depending on the milling depth. More than 99% of the particles generated from operations
conducted with beryllium alloys were larger than 25 µm.
___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC)
UF = 10.
The available data suggest that only a small percentage of the population (1% to 5%)
appears to be susceptible to CBD (Kreiss et al., 1994). Because individuals developing beryllium
sensitization and CBD are the most sensitive subpopulation, an uncertainty factor of 1 was used
to account for human variability. An uncertainty factor of 1 was also used to adjust for the less-than-chronic exposure duration of the Kreiss et al. (1996) study; use of this uncertainty factor is
supported by the evidence that the occurrence of CBD does not appear to be related to exposure
duration. Because the screening method used in the Kreiss et al. (1996) study was more sensitive
than the methods used in the Eisenbud et al. (1949) study, the RfC was derived from the LOAEL
(Kreiss et al., 1996) with an uncertainty factor of 3 to account for the sensitive nature of the
subclinical endpoint (beryllium sensitization). A database uncertainty factor of 3 was used to
account for the poor quality of exposure monitoring in the co-principal studies and other
epidemiology studies that assessed the incidence of beryllium sensitization and CBD among
exposed workers and community residents. Although there are no developmental studies or 2-generation reproduction studies, a limited continuous breeding study found that beryllium does
not cause reproductive or developmental effects following intratracheal administration (Clary et
al., 1975). In addition, systemic distribution of beryllium is less than 1% (U.S. EPA, 1987), and
any systemic effects would be expected to occur at exposure levels much above the very low
levels at which CBD is observed.
MF = 1.
___I.B.4. ADDITIONAL STUDIES/COMMENTS (INHALATION RfC)
A. SUPPORTING STUDIES
Cullen et al. (1987) detected five likely cases of CBD (using the beryllium case registry
definition of CBD) in workers who were exposed to beryllium oxide fumes at a precious metals
refinery for 4 to 8 years before the development of symptoms. Time-weighted average personal
air samples for beryllium ranged from 0.22 to 42.3 µg/m3 throughout the plant, and 10% of the
samples were greater than 2.0 µg/m3. However, four of the cases worked predominantly in the
furnace area, where beryllium exposure was measured at 0.52 ± 0.44 µg/m3 (maximum
measurement 1.7 µg/m3). No additional cases were found in the screening of current workers, but
a fifth was identified after the screen. This subject worked as a crusher, where exposure was to
beryllium metal dust at 2.7 ± 7.2 µg Be/m3. The CBD cases had the classic signs of CBD,
including radiologically visible hilar adenopathy, noncaseating granuloma and pulmonary fibrosis
in biopsy samples, and decreased carbon monoxide diffusing capacity (DLCO). Symptoms
progressed even after removal from exposure. Beryllium sensitization was shown in vitro with
BAL lymphocytes. Three of the cases were considered to have CBD, while diagnosis of two
(both in the furnace area) was complicated by a history of hilar enlargement in one; the other had
schistosomiasis and no BAL stimulation data. The study authors also analyzed beryllium
exposure levels by job classification and screened 45 of 70 current workers for CBD, using
interviews and analysis of spirometry data and chest radiographs from routine testing. No in vitro
screening for beryllium sensitization was conducted on the general worker population. Noting
that the prevalence of CBD was highest at a task with lower exposure levels, the study authors
suggested that the beryllium oxide fumes to which workers were exposed in the furnace area were
more toxic than the beryllium metal dust to which workers were exposed at other tasks.
Alternative explanations for the development of disease following low-level exposure were
considered unlikely. Although sampling efficiency was low for particles < 0.8 microns, these
small particles were not considered to contribute significantly to the overall mass; however,
because of their great surface area, they may have been much more toxic than larger particles.
Although the study authors note that there were no significant changes in work practices during
the previous 20 years, it is possible that the retrospective sampling conducted in a 2-week period
may not accurately reflect past and present exposure conditions. The LOAEL in this study was
0.52 µg/m3, with a LOAEL(HEC) after adjusting for occupational exposure of 0.18 µg/m3.
CBD has resulted in death, especially in earlier years, when exposure was much higher
than it is now. In a cohort mortality study of 689 patients with CBD who were included in the
case registry, there was a high rate of deaths due to pneumoconiosis, primarily CBD (SMR =
34.23, 158 deaths) (Steenland and Ward, 1991). Similar results were observed in an earlier
analysis of deaths due to nonneoplastic respiratory disease in the beryllium case registry (Infante
et al., 1980). Deaths have also been reported in community cases of CBD, including in a 10-year-old girl (Lieben and Williams, 1969). Some of these cases have been confirmed based on
histological evidence of CBD and evidence of beryllium in the lungs.
In addition, CBD has been reported in people not occupationally exposed to beryllium,
including people living in communities near beryllium plants (Chesner, 1950; Dattoli et al., 1964;
Lieben and Metzner, 1959) and in families of beryllium workers who wore contaminated clothing
at home. These cases have been markedly reduced by better hygiene, including mandatory work
clothes exchange, but nonoccupational CBD still has been reported following low-level episodic
exposure of family members (Newman and Kreiss, 1992).
The onset of CBD from initial exposure (latency) ranges from a few months to an average
of 23.7 years (Kreiss et al., 1993); however, at the present time there is no clear relationship
between duration of exposure and the development of the disease. Some studies suggest that
early stages of CBD can be reversed (Rom et al., 1983; Sprince et al., 1978), although these
conclusions are weakened by methodological limitations of these studies (Kanarek et al., 1973;
Kriebel et al., 1988b; Rom et al., 1983); however, beryllium sensitization was observed to progress
to CBD even in the absence of continued exposure, suggesting that abnormal BeLT test findings
are predictive of future development of CBD (Kreiss et al., 1994).
A number of earlier studies have characterized the signs and symptoms of CBD. Clinical,
radiographic, and traditional spirometric signs of CBD are less sensitive than histologic findings
and immunologic screens using the BeLT. Computed tomography (CT) can identify some CBD
cases missed by chest radiography, but even CT missed 25% of histologically confirmed cases
(Newman et al., 1994). Initial symptoms of early cases of CBD typically include dyspnea, cough,
fatigue, weight loss, and chest pain (Aronchik, 1992; Hasan and Kazemi, 1974; Kriebel et al.,
1988c; Meyer, 1994; Sterner and Eisenbud, 1951; Williams, 1993). Other symptoms included
bibasilar crackles, clubbing of the fingers and skin lesions, heart failure, and an enlarged liver or
spleen. Prominent diagnostic findings are diminished vital capacity, diffuse infiltrates, and
radiographically visible hilar adenopathy. Fibrosis occurs at late stages in the disease.
Granulomatous inflammation also has been reported in extrapulmonary organs, such as
extrapulmonary lymph nodes, skin, liver, spleen, kidney, bone, myocardium, central nervous
system, and skeletal muscle.
The development of fiberoptic bronchoscopy and transbronchial biopsy methods has
allowed the identification of subclinical cases of CBD. Newman et al. (1989) evaluated
respiratory symptoms and physical examination results in 12 cases of newly identified CBD based
on (1) a history of beryllium exposure, (2) histopathological evidence of noncaseating granulomas
or mononuclear cell infiltrates, and (3) a positive blood or BAL BeLT. Based on these findings,
the authors suggested that CBD be classified into (1) sensitization, (2) subclinical beryllium
disease (sensitized subjects with histopathological evidence, but no clinical signs), and (3)
beryllium lung disease (as for [2], but with respiratory symptoms, changes on chest radiographs,
or altered pulmonary physiology).
The BeLT has allowed the identification of an exposure-response relationship for
beryllium sensitization (Kreiss et al., 1993a). Kreiss et al. (1989) used the peripheral blood BeLT
to screen occupationally exposed populations for CBD, and found that 6/51 (11.8%) of the
currently exposed workers were sensitized. No sensitized cases who had not yet developed CBD
were identified, perhaps because of the long latency period. Although subjects identified based on
BeLT test results may not have clinical signs of CBD, many do exhibit functional impairment
(Pappas and Newman, 1993).
B. GENETICS OF BERYLLIUM SENSITIVITY
Evidence from a variety of sources shows that genetic susceptibility plays a role in the
development of CBD. Early occupational studies proposed that CBD was an immune reaction
with a genetic component, based on the extreme sensitivity of certain individuals and the lack of
CBD in others who are exposed to levels several orders of magnitude higher (Sterner and
Eisenbud, 1951). Animal studies support these results. Immune granulomas are observed in
strain 2 guinea pigs, but not in strain 13 guinea pigs, which differ from strain 2 only at the MHC
Ia locus (Barna et al., 1984a). Similarly, beryllium inhalation caused immune granulomas in A/J
mice, but not in BALB/c or C57B1 mice, which have different MHC class 2 genes (Huang et al.,
1992). These studies suggest that differences in CBD susceptibility are related to differences at
the MHC locus. Saltini et al. (1989) demonstrated that T cells only respond to the antigen (in this
case, beryllium or beryllium plus some protein) in association with MHC class II molecules on the
surface of the antigen-presenting cell. Granuloma formation has been hypothesized to result from
a cytokine amplification loop involving macrophages, lymphocytes, and other factors (Newman,
1996).
Recent studies have identified a genetic marker linked to CBD susceptibility. The MHC
class II region includes the HLA-DR, DQ, and DP genes. Richeldi et al. (1993) and Stubbs et al.
(1996) reported associations between the presence of MHC class II alleles and the development
of CBD in beryllium-exposed workers. Both studies found a biased distribution of HLA-DPB1
alleles (glutamine in position 69) in beryllium-sensitized subjects. They also found a biased
distribution of the MHC class II HLA-DR gene, but found no association with specific amino acid
changes. Thus, neither of these markers are completely specific for CBD, but the data do support
a strong genetic contribution to CBD susceptibility, and the markers may be useful for screening
for sensitive workers. It is also not clear if the association between either allele and CBD is a
causal one. However, Richeldi et al. (1993) noted that structure-function studies of MHC class II
molecules indicate that the amino acid change associated with CBD may affect an amino acid that
plays a critical role in antigen binding. The more common allele of HLA-DP1 has a positively
charged amino acid (lysine) at position 69, while the glutamate-69 variant is negatively charged at
this site and could directly interact with the beryllium ion. Nonetheless, the high percentage (~
30%) of exposed workers without CBD who had this allele suggests that other factors also
contribute to the development of CBD. The beryllium exposure level plays at least some role,
since the overall prevalence of CBD in exposed workers is 2% to 5%, while the prevalence at
certain highly exposed tasks is as much as 15% (Kreiss et al., 1993a, 1996).
C. CHRONIC ANIMAL STUDIES AND MODELS
Although a number of chronic studies in laboratory animals have been conducted with
beryllium compounds, few have been done using modern criteria for high-quality toxicology
studies. In addition, whereas several laboratory animal species (such as mice, dogs, and monkeys)
respond to beryllium exposure with several features of human CBD, no laboratory animal model
fully mimics all features of human CBD. In particular, the animal models fail to demonstrate a
model that has a progressive granulomatous pulmonary response with a concomitant beryllium-specific immune response. In addition, no chronic studies are available on nonneoplastic effects
of beryllium oxide, the most environmentally relevant form.
Considerable reSEARCH has investigated the mechanism of CBD and attempted to identify
an appropriate animal model for CBD. An appropriate animal model for CBD is one that forms
immune granulomas following the inhalation of beryllium dust or fume. These immune
granulomas are distinct from granulomas formed by foreign-body reactions (Haley, 1991).
Immune granulomas result from persistent antigenic stimulation, while foreign-body granulomas
result from persistent irritation. Histologically, foreign-body granulomas consist predominantly of
macrophages and monocytes and small numbers of lymphocytes. By contrast, immune
granulomas are characterized by larger numbers of lymphocytes, primarily T lymphocytes, known
as T-cells. The studies (Haley et al., 1990; Finch et al., 1994; Haley, 1991; Sendelbach et al.,
1986; Hart et al., 1984; Sanders et al., 1975) show that acute beryllium disease occurs in the rat,
but the rat is not an appropriate model for CBD because it does not mount an immune response to
inhaled beryllium. Mice may be an appropriate model for CBD, although not all aspects of the
disease have been replicated in this species in these studies (Haung et al., 1992; Finch et al.,
1996). The guinea pig and beagle dog may be good models for CBD based on the studies by
Barna et al. (1981, 1984a,b) with respect to the guinea pig and Haley et al. (1989, 1992) with
respect to the dog. In the case of guinea pigs, intratracheal instillation of beryllium oxide can
induce both immune granulomas containing a T lymphocyte component and a beryllium-specific
immune response. However, the effect has not yet been demonstrated under physiological
conditions (inhalation exposure), and specificity for beryllium over other metals has not been
demonstrated. In the case of the beagle dog, granulomatous lesions and lung lymphocyte
responses consistent with those observed in humans with CBD were observed following a single
exposure (perinasally; 0.01 µg beryllium/m3 for 5 to 40 min) to beryllium oxide aerosol generated
from beryllium oxide calcined at 500 or 1,000C. However, Conradi et al. (1971) found no
exposure-related histological alterations in the lungs of six beagle dogs exposed to a range of
3,300 to 4,380 µg Be/m3 as beryllium oxide calcined at 1,400C for 30 min, once per month for 3
mo.
Conradi et al. (1971) found no effect in monkeys (Macaca irus) exposed via whole-body
inhalation for three 30-min monthly exposures to a range of 3,300 to 4,380 µg Be/m3 as beryllium
oxide calcined at 1,400C. On the other hand, Haley et al. (1994) showed that beryllium can
induce immune granulomas and beryllium sensitization to beryllium metal and not BeO in
monkeys, although this was not shown using a physiologically relevant route, namely,
intrabronchiolar instillation.
___I.B.5. CONFIDENCE IN THE INHALATION RfC
Study -- Medium
Database -- Medium
RfC -- Medium
The overall confidence in this RfC assessment is medium. The RfC is based on an
occupational inhalation study performed with a moderate to large group size (136 subjects
screened) in which sensitive measures were used to identify the affected population (Kreiss et al.,
1996). No NOAEL was identified in this study, but a NOAEL slightly below the LOAEL(HEC)
was suggested in a study using less sensitive methods of diagnosing CBD in a population exposed
to high levels of beryllium in ambient air (Eisenbud et al., 1949). The poor quality of the
exposure monitoring in the co-principal studies decreases the confidence in the principal studies to
medium. The confidence in the database is also medium. A common limitation in the database is
the lack of adequate exposure monitoring in the epidemiology studies and some uncertainty
regarding the mechanism (and beryllium exposure levels) associated with the progression to CBD
in beryllium-sensitized individuals. Several human and animal studies are currently being
conducted that may provide additional information on the mechanisms of action and data that
would be useful for dose-response assessment. In particular, several investigators are conducting
screening and monitoring studies of workers at the Rocky Flats Environmental Technology site
and Oak Ridge site. Although no inhalation developmental or multigenerational reproductive
studies were available for beryllium, no reproductive effects were observed in an intratracheal
reproduction study in animals at exposure levels above those causing CBD (Clary et al., 1975). In
addition, the unusually low level at which CBD occurs, together with the low systemic
distribution of inhaled beryllium, mean that any developmental effects would occur at levels much
higher than those causing CBD. Reflecting the medium confidence in the principal studies and
database, confidence in the RfC is medium.
___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC
Source Document -- U.S. EPA, 1998
This assessment was peer reviewed by external scientists. Their comments have been evaluated
carefully and incorporated in finalization of this IRIS summary. A record of these comments is
included as an appendix to the Toxicological Review of Beryllium in support of Summary
Information on the Integrated Risk Information System (IRIS) (U.S. EPA, 1998).
Other EPA Documentation -- U.S. EPA, 1987; U.S. EPA, 1991
Agency Consensus Date-- 03/26/1998
___I.B.7. EPA CONTACTS (INHALATION RfC)
Please contact the Risk Information Hotline for all questions concerning this assessment or
IRIS in general at (513) 569-7254 (phone), (513) 569-7159 (fax) or
RIH.IRIS@EPAMAIL.EPA.GOV (Internet address).
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Beryllium and compounds
CASRN -- 7440-41-7
Last Revised -- 04/03/1998
Section II provides information on three aspects of the carcinogenic assessment for the
substance in question: the weight-of-evidence judgment of the likelihood that the substance is a
human carcinogen, and quantitative estimates of risk from oral exposure and from inhalation
exposure. The quantitative risk estimates are presented in three ways. The slope factor is the
result of application of a low-dose extrapolation procedure and is presented as the risk per
(mg/kg)/day. The unit risk is the quantitative estimate in terms of either risk per µg/L drinking
water or risk per µg/m3 air breathed. The third form in which risk is presented is a concentration
of the chemical in drinking water or air providing cancer risks of 1 in 10,000, 1 in 100,000, or 1 in
1,000,000. The rationale and methods used to develop the carcinogenicity information in IRIS
are described in the Risk Assessment Guidelines of 1986 (U.S. EPA, 1986) and in the IRIS
Background Document. IRIS summaries developed since the publication of EPA's more recent
Proposed Guidelines for Carcinogen Risk Assessment also utilize those Guidelines where
indicated (U.S. EPA, 1996). Users are referred to Section I of this IRIS file for information on
long-term toxic effects other than carcinogenicity.
__II.A. EVIDENCE FOR HUMAN CARCINOGENICITY
___II.A.1. WEIGHT-OF-EVIDENCE CHARACTERIZATION
B1; probable human carcinogen. Based on the limited evidence of carcinogenicity in
humans exposed to airborne beryllium (lung cancer) and sufficient evidence of carcinogenicity in
animals (lung cancer in rats and monkeys inhaling beryllium, lung tumors in rats exposed to
beryllium via intratracheal instillation, and osteosarcomas in rabbits and possibly mice receiving
intravenous or intramedullary injection), beryllium is reclassified from a B2 (inadequate human
data) to a B1 probable human carcinogen (limited human data) using criteria of the 1986
Guidelines for Carcinogen Risk Assessment. Using the 1996 proposed Guidelines for Carcinogen
Risk Assessment, inhaled beryllium would be characterized as a "likely" carcinogen in humans,
and the human carcinogenic potential of ingested beryllium cannot be determined.
Studies regarding the potential carcinogenicity of ingested beryllium to humans were not
available. Increases in lung cancer mortality have been observed in cohort mortality studies of
beryllium processing workers (Ward et al., 1992; Wagoner et al., 1980; Mancuso, 1979, 1980)
and in studies of entrants on the BCR (Steenland and Ward, 1991; Infante et al., 1980). No
increases in other types of cancer were found, but increases in deaths from nonmalignant
respiratory disease were also observed. Newer studies, particularly the occupational study of
Ward et al. (1992), have been considered as the basis for a dose-response assessment, but share a
limitation with the Wagoner et al. (1980) study--lack of individual exposure monitoring or job
history data that would support a more definitive exposure assessment. NIOSH has recently
completed a lung cancer case-control study nested within a cohort mortality study of beryllium
manufacturing workers at the Reading beryllium processing facility. The study developed an
exposure matrix and calculated airborne beryllium exposure concentrations and thus may provide
the best available basis for a quantitative cancer estimate. Rather than calculate an interim
quantitative estimate based on the Ward et al. (1992) data and poorly defined exposure estimates,
the existing unit risk based on the Wagoner et al. (1980) study is retained until the NIOSH
assessment can be evaluated as the basis for a quantitative estimate.
Chronic oral studies of the potential carcinogenicity of beryllium in animals were
conducted at dose levels below the MTD, and therefore are inadequate for the assessment of
carcinogenicity. Beryllium has been shown to induce lung cancer in rats exposed to beryllium by
both inhalation and intratracheal instillation and in monkeys by inhalation. Osteosarcomas have
been produced in rabbits and possibly in mice by intravenous and intramedullary injection using a
variety of beryllium compounds and beryllium metal. No tumors were produced by
intracutaneous or percutaneous injections of beryllium compounds.
The majority of studies do not induce gene mutations in bacterial assays with or without
metabolic activation. Gene mutations have been observed in mammalian cells cultured with
beryllium chloride. Culturing mammalian cells with beryllium chloride, beryllium sulfate, or
beryllium nitrate has resulted in clastogenic alterations.
___II.A.2. HUMAN CARCINOGENICITY DATA
Limited. The most recently published studies are cohort mortality studies of beryllium
processing workers (Ward et al., 1992) and of entrants to the beryllium case registry (Steenland
and Ward, 1991). The Ward et al. (1992) is a follow-up to the studies by Mancuso (1979, 1980)
and Wagoner et al. (1980) and the Steenland and Ward (1991) is a follow-up to the study by
Infante et al. (1980).
Wagoner et al. (1980) conducted a cohort mortality study of 3,055 white males employed
between 1942 and 1967 at a beryllium extraction, processing, and fabrication facility in Reading,
Pennsylvania. The study cohort was followed through 1975. The total number of deaths (875)
was not significantly different from the number expected on the basis of age and calendar time
period for the general white male U.S. population (vital statistics data for the period 1965-1967
were assumed to be those of 1968-1975). Significant (p < 0.05) increases in the number of deaths
due to malignant neoplasm of trachea, bronchus, and lung (47 deaths observed versus 34.29
expected, SMR = 1.37), heart disease (SMR = 1.13), and nonneoplastic respiratory disease
(excluding influenza and pneumonia) (SMR = 1.65) were observed in the study cohort. When
deaths from lung cancer were segregated by latency (interval since onset of employment) and
duration of employment, significant increases were observed for workers with a 25-year latency
employed for < 5 years (17 observed versus 9.07 expected, SMR = 1.87) and across all
employment durations (20 observed versus 10.79 expected, SMR = 1.87). (It should be noted
that 83% of the cohort was employed for < 5 years.) When lung cancer mortalities were
partitioned based on initial date of employment, lung cancer deaths were significantly higher in
workers hired before 1950 (SMR = 1.35; p < 0.05); an increase in deaths in workers hired after
1950 was also found, but it was not statistically significant (SMR = 1.52). (Prior to 1950,
beryllium exposures were not controlled and it is likely that the workers were exposed to high
concentrations of beryllium.) Similar findings were reported when nonneoplastic respiratory
disease mortalities were segregated; a significant increase in mortality was observed in the
workers in the 25-year latency and < 5-year employment category (SMR = 2.13). In the
workers who were hired prior to 1950, a significant increase in mortality from nonneoplastic
respiratory disease was observed (SMR = 1.85). This was not observed for workers whose initial
date of employment was after 1950 (0 deaths observed versus 2.03 expected).
Wagoner et al. (1980) compared cigarette smoking histories of the cohort and the U.S.
population using smoking habit information collected during a medical survey in 1968 and
cigarette smoking data for white males from a Public Health Service Survey conducted in
1964-1965. A smaller percentage of the cohort were current smokers (49.6% never smoked or
were former smokers versus 45.2% in the U.S. population), but the percentage of current
smokers smoking more than one pack per day was higher (21.4% versus 15.3%).
Limitations of the study include the following:
1. The use of U.S. white male mortality data for the period of 1941 to 1967, which
resulted in an underestimation of the number of expected lung cancer deaths because
lung cancer death rates in the United States were increasing during the period
1968-1975. The expected number of lung cancer deaths should have been 10% to
11% higher (U.S. EPA, 1987; Saracci, 1985).
2. The inclusion of one lung cancer death of an individual who was paid for the
pre-employment physical but was not hired (U.S. EPA, 1987).
3. The exclusion of approximately 300 white males employed at the Reading
facility in similar jobs as the workers included in the cohort (U.S. EPA, 1987).
4. The inadequate discussion of confounding effects from other potential lung
carcinogens (U.S. EPA, 1987).
These limitations tended to exaggerate the risk of lung cancer in this population of workers
potentially exposed to beryllium (MacMahon, 1994; U.S. EPA, 1987).
EPA (1987) adjusted the lung cancer SMRs from the Wagoner et al. (1980) study. The
expected lung cancer deaths were increased by 11% to account for the underestimation that
occurred from using older U.S. vital statistics and by 4.1% to account for differences in smoking
habits between the beryllium cohort and the U.S. population. The one ineligible lung cancer death
was removed from the observed deaths. Although the SMRs for latency 25 years remained
elevated after this adjustment (1.42 for < 5 years employment and 1.36 across all durations of
employment), they were no longer statistically significant at p < 0.05.
Ward et al. (1992) conducted a retrospective cohort mortality study of 9,225 men (5,681
alive and 3,240 dead) employed for at least 2 days between January 1, 1940, and December 31,
1969, and followed through December 31, 1988, at any one of seven beryllium processing
facilities located in Reading, PA, Hazleton, PA, Lorain, OH, Cleveland, OH (data for Perkins and
St. Clair plants combined), Lucky, OH, and Elmore, OH. Cohort members were identified from
quarterly earning reports from the Social Security Administration and compared to personnel files.
Workers identified from quarterly earning reports without personnel files were only included in
the cohort if they appeared on at least two quarterly earning reports. Workers who worked at
more than one facility were placed into a seventh category termed "multiple plant." Vital
statistics for the workers were obtained from the Social Security Administration, Internal Revenue
Service, post office cards mailed to the last known address, Veterans Administration, Health Care
Financing Administration, and the National Death Index. Vital statistics were not located for 304
(3.3%) individuals, and death certificates were not obtained for 46 (0.4%) individuals known to
be deceased.
The workers at the beryllium processing facilities were involved in the extraction of
beryllium hydroxide from beryl ore; the production of beryllium oxide, pure beryllium metal, and
beryllium copper alloy; and the machining of beryllium-containing products. The beryllium
compounds the workers were potentially exposed to included beryllium sulfate mists and fumes,
beryllium oxide dusts, beryllium ammonium fluoride and beryllium fluoride dusts, beryllium metal,
and beryllium copper alloy dusts and fumes. In addition to exposure to beryllium, the workers
also were potentially exposed to ore dust, silicon dioxide fumes, lead sulfide, copper sulfide,
sulfur trioxide, acid fluoride mists, hydrogen fluoride, and ammonium fluoride. In addition,
according to the Beryllium Industry Scientific Advisory Committee (BISAC) (1997), exposure to
sulfuric acid mists and fumes occurred in the Lorain facility. Because no occupational history
data other than starting and ending dates of employment were coded, and no individual
monitoring data were available, the study could not address the relationship of degree of beryllium
exposure or type of beryllium compound to lung cancer risk. Ward et al. (1992) noted that prior
to 1949 when controls were not mandated, air concentrations of beryllium were very high,
frequently exceeding 1,000 µg/m3.
When mortality from all causes in the entire cohort was compared to mortality rates from
the U.S. population, a significant (p < 0.05) increase in risk was observed (SMR of 1.05, 95%
confidence interval [CI] of 1.01-1.08). Excess deaths were also observed for malignant neoplasm
of the trachea, bronchus, and lung (SMR = 1.26, 95% CI = 1.12-1.42), ischemic heart disease
(SMR = 1.08, 95% CI = 1.01 to 1.14), pneumoconiosis and other respiratory disease (SMR =
1.48, 95% CI = 1.21-1.80), and chronic and unspecified nephritis, renal failure, and other renal
sclerosis (SMR = 1.49, 95% CI = 1.00-2.12). Examination of the cause of death on a per plant
basis revealed that only the Lorain and Reading facilities (the two oldest plants) had significant
excesses in lung cancer: total SMRs of 1.69 and 1.24, respectively. In addition, the Cleveland
and Hazleton facilities had nonsignificant excesses in lung cancer (total SMRs > 1).
A significant excess of pneumoconiosis and other respiratory disease was also observed at
the Lorain facility (SMR = 1.94). Increased employment duration was not associated with an
increase in lung cancer SMR; when lung cancer mortalities were stratified by employment
duration category, the only significant increase in lung cancer SMRs was for workers employed
< 1 year. However, there was a tendency for lung cancer SMRs to increase with increasing
latency; SMRs were statistically significantly elevated in the > 30-year latency category for all
employment durations combined (SMR = 1.46) and for workers employed for < 1 year (SMR =
1.52), and in the 25- to 30-year latency category for workers employed for < 1 year.
Additionally, decade of hire influenced lung cancer mortality. The SMR (1.42) was statistically
elevated in workers hired before 1950; this was mainly influenced by mortality in the Lorain plant,
which closed in 1948. Of the other facilities in operation before 1950 (Reading and Cleveland),
an increased lung cancer rate was found at the Reading facility (SMR = 1.26 for workers hired
before 1950). With the exception of those hired before 1950 (total SMR = 1.42), no other
significant increases in lung cancer deaths were observed when workers were grouped by decade
of hire. Nonsignificant increases were seen for the 1950s decade at the Reading (SMR = 1.42),
Cleveland (SMR = 1.32), Elmore (SMR = 1.42), and Hazleton (SMR = 1.86) facilities.
Regression analysis (controlling for age, race, and calendar period of risk) showed that decade of
hire was independent of potential latency (time since first employment).
The influence of geographic variation in lung cancer mortality was evaluated comparing
lung cancer mortality found in the beryllium cohort to lung cancer rates for the cohort where most
of the workers resided. Lung cancer mortality was significantly elevated in workers at the Lorain
(SMR = 1.60, 95% CI = 1.21-2.08) and Reading (SMR = 1.42, 95% CI = 1.18-1.69) facilities as
compared to residents of Lorain County and Berks County, respectively. The investigators noted
that county residents may not serve as a better referent group than the U.S. population because
the percentage of workers at the Lorain and Reading facilities residing in an urban area was
approximately 3 times higher than the percentage of county residents living in urban areas.
Data on the smoking habits of the entire beryllium cohort were not available. Some
information was available from a 1968 Public Health Service survey conducted at the Reading,
Hazleton, Elmore, and St. Clair facilities (it included 15.9% of the cohort members). These data
were compared to smoking habits of the United States population obtained from averaging
smoking surveys conducted in 1965 (National Center for Health Statistics) and 1970 (Office of
Health Research, Statistics, and Technology). The estimated relative risk ratio for lung cancer for
the beryllium cohort to the United States population was calculated using estimated risks of 1 for
nonsmokers, 6.5 for current smokers of 1 pack per day, 13.8 for smokers of > 1 pack per day,
and 6.2 for former smokers. The relative risk ratio or smoking adjustment was 1.1323, which
indicates that smoking alone could account for an SMR of 1.13.
Using the smoking adjustment factor, smoking-adjusted SMRs were calculated for the
entire cohort and the Lorain and Reading facilities. The resultant SMRs were 1.12, 1.49, and
1.09, respectively. One process exposure, to which BISAC (1997) attributed the excess cancer
(SMR 1.49) after adjustment for smoking, and which was briefly mentioned by Ward et al.
(1992), is exposure to mists and vapors from sulfuric acid and the related sulfur oxide gases.
Such exposure, according to BISAC (1997), was very high in the Lorain plant. This was the only
plant that used a sulfuric acid-dependent process with limited ventilation (Kjellgren, 1946); at the
time, the occupational inhalation risks associated with airborne beryllium (acute pneumonitis) and
airborne sulfuric acid (respiratory cancer) had not yet been established. Because the 1968 survey
data are the only information available on the smoking habits of the beryllium cohort, an
assumption was made that the smoking habit difference between the cohort and the United States
population found in the late 1960s was the same in the 1940s and 1950s. Other investigators have
shown that increased smoking is unlikely to account for SMRs greater than 1.3 for lung cancer
and other smoking-related diseases (Siemiatycki et al., 1988).
Ward et al. (1992) examined the beryllium case registry (BCR) mortality study file to
determine how many of the members of the cohort were registered (i.e., had a history of beryllium
disease). The Lorain plant had highest percentage of registrants--8.2% (98 of 1,192 workers);
93% of these were listed as having had acute beryllium disease, which is associated with very high
exposure (Eisenbud and Lisson, 1983). The lung cancer SMR for the Lorain workers on the BCR
was 3.33 (95% CI = 1.66-5.95) compared to 1.51 (95% CI = 1.11-2.02) for the remaining Lorain
workers.
Ward et al. (1992) concluded that a plausible explanation for the observed increased lung
cancer rates is occupational exposure to beryllium. Although the results of this study are
suggestive that occupational exposure to beryllium can result in an increase in lung cancer
mortality, interpretation of this study is limited by a number of factors:
1. No data (including job history data) were available to associate beryllium exposure
levels, exposure to specific beryllium compounds, or concomitant exposure to other
chemicals with members of the cohort.
2. Because of the lack of job history data, it is possible that the cohort contained
salaried workers and other nonproduction personnel who may not have been
exposed to beryllium.
3. The limitations in the available smoking habit data, as discussed above, may
have led to an over- or underestimation of the contribution of smoking to the
lung cancer rates.
4. A large percentage (73.1%) of the workers were employed in the beryllium
industry for 5 years. This is particularly true at the Lorain facility, where
84.6% of the workers were employed for < 1 year. EPA (1987) points out
that there is a possibility that the workers were exposed to other potential
carcinogens at jobs held before or after the beryllium job; the two facilities with
the highest cancer rates (Lorain and Reading) are located in or near heavily
industrialized areas.
Regardless of the shortcomings of the epidemiological studies of beryllium exposure, the
results of the follow-up mortality studies on the same cohort and of the BCR cohort studies are
suggestive of a causal relationship between beryllium exposure and an increased risk of lung
cancer. The increased incidences of lung cancers among workers with acute beryllium disease
(presumably these workers were exposed to very high concentrations of beryllium), the higher
incidences of lung cancers among workers first employed when exposure levels were very high, a
consistent finding of lung cancer excesses in six of seven beryllium processing facilities, and the
occurrence of the highest risks for lung cancer in plants where the risk for nonmalignant
respiratory disease is the highest strengthen this conclusion.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Sufficient. Lung tumors have been induced via inhalation and intratracheal administration
to rats and monkeys, and osteosarcomas have been induced via intravenous and intramedullary
injection in rabbits and possibly in mice. The chronic oral studies did not report increased
incidences of tumors in rodents, but these were conducted at doses below the MTD.
In a chronic toxicity study by Morgareidge et al. (1975, 1977), groups of Wistar albino
rats were fed diets containing 5, 50, or 500 ppm beryllium as beryllium sulfate tetrahydrate. The
rats were administered the beryllium containing diet from 4 weeks of age through maturation,
mating, gestation, and lactation. Fifty male and 50 female offspring were then placed on the same
diets as the parents and fed the beryllium-containing diet for 104 weeks. Using estimated TWA
body weights of 0.467, 0.478, and 0.448 kg for males in the 5, 50, and 500 ppm groups and
0.294, 0.302, and 0.280 kg for the females, respectively, and U.S. EPA's (1988) allometric
equation of food intake, doses of 0.36, 3.6, and 37 mg/kg-day for males in the 5, 50, and 500 ppm
groups and 0.42, 4.2, and 43 mg/kg-day for females in the 5, 50, and 500 ppm groups,
respectively, were calculated. Clinical observations, body weight, food consumption, organ
weights (liver, kidney, testes, ovaries, thyroid, pituitary, adrenal), gross necropsy, and
histopathological examination of most tissues and organs (25 to 26 tissues examined) were used
to assess the toxicity and carcinogenicity of beryllium in the offspring; it does not appear that the
P0 rats were examined. Tissues from 20 rats/sex/group in the control and 500 ppm groups were
examined microscopically (the study authors did not state whether the animals undergoing
histopathological examination were randomly selected), as well as all tissues with gross
abnormalities (all groups) and tissues (excluding bone marrow, eyes, and skin) from animals found
dead or sacrificed moribund (all groups).
No overt signs of toxicity were observed, and mortality appeared to be similar in the
controls (30/50 males and 28/50 females died) and beryllium groups at 5 ppm (30/50 and 24/50,
respectively), 50 ppm (31/50 and 18/50), and 500 ppm (24/50 and 17/50) at the end of the 104
weeks of the study. During the first 40 to 50 weeks of the study, exposure to beryllium did not
appear to affect growth; slight decreases in growth (body weights of males and females in the 500
ppm group were within 10% of control body weights) were observed in the latter part of the
study; however, no statistically significant alterations were observed. Alterations in organ weights
were limited to statistically significant (p < 0.05) increases in relative kidney weight in males
exposed to 50 ppm, decreases in relative kidney and adrenal weights in 500 ppm females, and
decreases in relative testes weights in 5 and 50 ppm males. Histological examination of the major
organs and tissues did not reveal beryllium-related noncarcinogenic alterations. These data
suggest that the maximum tolerated dose (MTD) was not reached.
Reticulum cell sarcomas were observed in a number of tissues examined including the
lungs, lymph nodes, spleen, liver, kidneys, and pancreas; the highest incidence was in the lungs.
Because lymphomas (reticulum cell sarcoma is a type of lymphoma) are almost always detected
grossly, reticulum cell sarcoma incidences were calculated based on the number of tissues grossly
examined (all gross diagnoses were confirmed histopathologically) rather than on the number of
tissues microscopically examined. In most organs, the incidence of reticulum cell sarcomas was
not significantly higher in the beryllium-exposed rats, as compared to controls. In the lung, the
incidences of reticulum cell sarcoma were 10/50, 17/50, 16/50, and 12/50 in males and 5/50, 7/50,
7/50, and 5/50 in females exposed to 0, 5, 50, or 500 ppm beryllium, respectively. The incidences
of lung reticulum cell sarcomas in the beryllium-exposed rats were not significantly different from
controls. The incidences of reticulum cell sarcoma-bearing rats in the 0, 5, 50, and 500 ppm
groups were 12/50, 18/50, 16/50, and 13/50, respectively, for males and 8/50, 11/50, 7/50, and
8/50 for the females; no significant increases in tumor-bearing rats was found. No other
treatment-related increases in tumor incidence were observed.
In a lifetime exposure study, groups of 52 male and 52 female Long-Evans rats were
maintained on a low-metal diet and given drinking water containing 0 or 5 ppm beryllium as
beryllium sulfate (presumably tetrahydrate) from weaning to natural death (Schroeder and
Mitchener, 1975a). The water also contained 5 ppm chromium III, 50 ppm zinc, 5 ppm copper,
10 ppm manganese, 1 ppm cobalt, and 1 ppm molybdenum. Doses of 0.63 and 0.71 mg/kg-day
were calculated for male and female rats, respectively, using estimated TWA body weights of 0.42
and 0.26 kg and U.S. EPA's (1988) allometric equation for water consumption. The following
parameters were used to assess toxicity: body weights (animals weighed at weekly and monthly
intervals for the first year and at 3-mo intervals thereafter), blood glucose, cholesterol, and uric
acid (blood samples collected from 12 rats/sex after an 18-h fast), urine protein, pH, and glucose,
heart weight, gross pathology, and histopathology of heart, lung, kidney, liver, spleen, and
tumors. Twenty male and eight female rats in the beryllium group died at 20 mo of age from
pneumonia; a similar number of animals in the control group also died from pneumonia. At 30
days, the male and female rats exposed to beryllium weighed significantly more than the control
animals. At 60, 90, 120, and 180 days, the beryllium-exposed male rats weighed significantly less
than the controls; no significant alterations in body weight were observed at the other time
intervals (150, 360, or 540 days). Overall, the weight loss of less than 10% indicates that the
MTD was not achieved. No significant alterations in mortality or longevity were observed.
Glycosuria (females only) and alterations in serum glucose levels were observed in the beryllium-exposed rats. The alterations in serum glucose levels consisted of significantly lower levels in
males aged 475 days and higher levels in males and females aged 719 days. It should be noted
that the control rats were at least 50 days older than the beryllium-exposed rats when blood
samples were collected, and in the controls, blood glucose levels declined with increasing age.
Significantly increased serum cholesterol levels were observed in female rats exposed to beryllium
at ages 475 and 719 days. The results of the histological examination were not reported. The
alterations in serum glucose and cholesterol levels and urine glucose levels were not considered
adverse because the magnitude of the alterations was not sufficiently large to suggest an
impairment in organ function. The incidence of gross tumors was 4/26 (15%) and 17/24 (70%) in
the male and female control rats and 9/33 (27%) and 14/17 (82%) in the male and female rats
exposed to beryllium. The incidences of malignant tumors (tumors were considered malignant if
there were multiple tumors in the same animal) were 2/26 (7.7%) and 8/24 (33%) in the male and
female controls and 4/33 (12%) and 8/57 (14%) in the male and female beryllium-exposed rats.
The incidences of gross or malignant tumors in the control and beryllium-exposed groups was not
significantly different. It should be noted that in an unpublished report (Schroeder and Nason,
1976), the incidence of gross tumors in the male and female beryllium-exposed rats was 4/25 and
13/20 (control data the same as reported in published paper). In the published paper, this is the
tumor incidence for the tungsten-exposed male and female rats, respectively. It is difficult to
determine which is the correct tumor incidence data for the beryllium-exposed rats; however,
neither set of incidence data is statistically significantly different than controls.
In a similar lifetime exposure study, groups of 54 male and 54 female Swiss mice were
administered 0 or 5 ppm beryllium as beryllium sulfate in the drinking water from weaning to
natural death (Schroeder and Mitchener, 1975b). The mice were fed low-metal diets and the
drinking water was supplemented with 50 ppm zinc, 10 ppm manganese, 5 ppm copper, 5 ppm
chromium III, 1 ppm cobalt, and 1 ppm molybdenum. The 5 ppm water concentration is
equivalent to doses of 1.2 mg/kg-day for the male and female mice, using an estimated TWA body
weight of 0.042 and 0.035 kg and EPA's (1988) allometric equation for water consumption. In
the beryllium group, statistically significant alterations in body weight were observed; the
alterations included heavier male mice at 30 days and lighter female mice at 90 and 120 days.
Overall, the decrease in body weight was less than 10%, indicating that the MTD was not
reached. No significant alterations in mortality or survival were observed in the beryllium-exposed mice. No alterations in tumor incidence were observed.
Reeves et al. (1967) exposed 150 male and 150 female Sprague-Dawley rats for 7 h/day, 5
days/week to 34.25 µg Be/m3 as beryllium sulfate aerosol (average particle size was 0.118 µm,
electron microscopy) for up to 72 weeks, with 3 of each sex sacrificed monthly during exposure.
An equal number of control rats were exposed to distilled water aerosol. Lung weights were
markedly increased in the exposed rats, and an inflammatory lung response (characterized as a
marked accumulation of histiocytic elements and thickened and distorted alveolar septa) was
noted, accumulation of alveolar macrophages. A proliferative response was also noted,
progressing from hyperplasia to alveolar adenocarcinomas in 100% of the exposed rats at 13
months, compared to 0% of the controls. Histopathologic examination was limited to the lungs.
The authors noted that 8 male and 4 female rats in the control group and 9 male and 17 females in
the beryllium group died during the course of the study. The plateau body weight in the
beryllium-exposed female rats was approximately 25% less than found in the controls (statistical
significance not reported).
Vorwald and Reeves (1959) exposed Sherman rats (number and sex not reported) via the
inhalation route to aerosols of beryllium sulfate at 6 and 54.7 µg Be/m3 for 6 h/day, 5 days/week
for an unspecified duration. Animals were sacrificed periodically and examined
histopathologically. Initially, inflammation consisted of histiocytes, lymphocytes, and plasma cells
scattered throughout the lung parenchyma. Following more prolonged exposures, more focal
lesions consisting primarily of histiocytes were observed. Multinucleated giant cells were also
observed. Thickened alveolar walls and fibrotic changes were also observed. Lung tumors,
primarily adenomas and squamous cell cancers, were observed in the animals sacrificed after
9 months of this exposure regime.
Similar results to those of Vorwald and Reeves (1959) were observed in a study by
Reeves and Deitch (1969, as reviewed by U.S. EPA, 1987). In this study, groups of 20 to 25
Charles River CD rats were exposed to 35.66 µg Be/m3 as beryllium sulfate for 35 h/week; the
mean particle size was 0.21 µm (dae). The exposure durations were 800 h (5 groups), 1,600 h (2
groups), and 2,400 h (1 group). Age at the initiation of exposure appeared to be a more
important variable for tumor development than was exposure duration. The lung tumor incidence
(19/22, 86%) for young rats exposed for 3 mo was the same as in rats exposed for 18 mo (13/15,
86%), but was higher than in older rats exposed for 3 mo (3-10/20-25, 15-40%). Tumors were
typically observed after a latency period of 9 mo. In the beryllium-exposed rats, the epithelial
hyperplasia observed at 1 mo progressed to metaplasia at 5 to 6 mo, and anaplasia by 7 to 8 mo.
In a study to test the carcinogenicity of beryllium ores, Wagner et al. (1969) exposed
groups of 12 male squirrel monkeys (Saimiri sciurea), 60 male CR-CD rats, 30 male Greenacres
Controlled Flora (GA) rats, and 48 male Golden Syrian hamsters to 0 or 15 mg/m3 bertrandite or
beryl for 6 h/day, 5 days/week for 17 mo (rats and hamsters) or 23 mo (monkeys). The test
atmospheres generated from the bertrandite ore (Be4Si2O7[OH]2; 1.4% beryllium) and beryl ore
(B3Al2Si6O18; 4.14% beryllium) contained 210 and 620 µg Be/m3, respectively, and the geometric
mean diameters of the particles were 0.27 µm (geometric standard deviation of 2.4) and 0.64 µm
(geometric standard deviation of 2.5). Both ores contained very high silicon dioxide levels
(63.9% by weight). Exposed and control monkeys, rats, and hamsters were serially sacrificed on
completion of 6 and 12 mo of exposure; rats and hamsters at 17 months, and monkeys at 23 mo.
Five control rats and five rats from the 12- and 17-mo exposure groups were sacrificed in order to
determine the free-silica content of the lung tissue. At exposure termination, beryllium
concentrations in the lungs were 18.0 and 83 µg/g fresh tissue in the bertrandite- and beryl-exposed rats, 14.1 and 77.4 µg/g fresh tissue in the bertrandite- and beryl-exposed hamsters, and
33 and 280 µg/g fresh tissue in the bertrandite- and beryl-exposed monkeys. Free silica (SiO2)
levels in the rat lungs were 30 to 100 times higher in the beryllium ore-exposed rats than in the
controls. Increased mortality was observed in the monkeys (11%), rats (13%), and hamsters
(25%) exposed to either bertrandite or beryl ore, with the highest mortality rates in the bertrandite
ore-exposed animals (no further details provided). No significant alterations in body weight gain
were observed in the monkeys or hamsters.
In the rats, decreased body weight gains (terminal body weights were 15% lower
compared to controls) were observed beginning after 6 mo of exposure, and from 12 mo to
exposure termination at 17 mo. In the beryl-exposed rats, small foci of squamous metaplasia or
tiny epidermoid tumors were observed in the lungs of 5/11 rats killed after 12 mo of exposure. At
exposure termination, lung tumors were observed in 18/19 rats (18 had bronchiolar alveolar cell
tumors, 7 had adenomas, 9 had adenocarcinomas, and 4 had epidermoid tumors). Additional
alterations in the lungs included loose collections of foamy macrophages and cell breakdown
products, lymphocyte infiltrates around the bronchi, and polymorphonuclear leukocytes and
lymphocytes present in most of the bronchiolar-alveolar cell tumors. In the bertrandite-exposed
rats, granulomatous lesions composed of several large, tightly packed, dust-laden macrophages
were observed in all rats exposed for 6, 12, or 17 mo. No tumors were observed. Neoplastic or
granulomatous pulmonary lesions were not observed in the control rats. In the beryl- and
bertrandite-exposed monkeys, the histological alterations consisted of aggregates of dust-laden
macrophages, lymphocytes, and plasma cells near respiratory bronchioles and small blood vessels.
No tumors were found. In the bertrandite-exposed hamsters, granulomatous lesions consisting of
tightly packed, dust-laden macrophages were observed after 6 mo, and the number did not
increase after 17 mo. These alterations were not observed in the beryl-exposed or control
hamsters. Atypical proliferation and lesions, which were considered bronchiolar alveolar cell
tumors except for their size, were observed in the hamsters after 12 mo of exposure to beryl or
bertrandite. After 17 mo of exposure, these lesions became larger and more adenomatous in the
beryl-exposed hamsters. It should be noted that silicosis was not observed in any of the animals
exposed to the beryllium ores, which contained a large amount of free silica. No significant gross
or histologic alterations were observed in the thymus, spleen, liver, or kidneys of the beryllium-exposed rats, hamsters, and monkeys.
In a monkey carcinogenicity study (Vorwald, 1968), a group of 7 male and 9 female
rhesus monkeys (Macaca mulatta) (aged 18 months) were exposed to 35 µg Be/m3 beryllium
sulfate mist 6 h/day, 5 days/week. The author notes that the "exposure was interrupted, often for
considerable periods of time, in order to maintain the best possible overall well-being of the
animal, to prevent a threatening acute beryllium pneumonitis, and to favor survival to old age or
at least long enough for the inhaled beryllium to exert its maximal chronic effects in terms of
epithelial proliferation, metaplasia, and cancer." The exposure schedule was presented in a figure,
but it was difficult to determine the exposure protocol from this figure. The longest exposure was
for 4,070 h, with most of the exposure occurring during the first 4.5 years of the study with an
approximate 6-mo exposure 2.5 years later. Four animals died within the first 2 mo of the study;
the cause of death was acute chemical pneumonitis. Lung cancer was observed in 8 of the 12
remaining animals. The first tumor was observed in a monkey 8 years of age exposed for 3,241
hours. The tumors were described as a gross mass located in either the hilar area or more
peripheral portions of the lung or as small and large tumors scattered irregularly throughout the
pulmonary tissue.
A single-exposure inhalation study of beryllium metal in F344/N rats resulted in a 64%
incidence of lung carcinomas over the lifetime of the animals (Nickell-Brady et al., 1994). Groups
of 30 males and 30 females were administered a single, nose-only exposure to a beryllium metal
aerosol (MMAD = 1.4 µm, GSD = 1.9) at 500 mg/m3 for 8 min, 410 mg/m3 for 30 min, 830
mg/m3 for 48 min, or 980 mg/m3 for 39 min. Control rats were exposed to filtered air alone.
Mean lung burdens resulting from these exposures were 40, 110, 360, and 430 µg of beryllium,
respectively. Tumors became apparent by 14 mo after exposure, and the incidence (apparently for
all groups combined) was 64% over the lifetime of the rats. Multiple tumors were frequently
found, the majority were adenocarcinomas, and some were > 1 cm.
Lung tumors have been observed in rats following a single intratracheal instillation of
beryllium metal, passivated beryllium metal (99% beryllium, < 1% chromium), beryllium-aluminum alloy (62% beryllium), and beryllium hydroxide. Beryllium alloys containing 4%
beryllium did not result in increases in lung tumors. Lung tumor incidences of 11% to 51% were
observed in rats following intratracheal instillation of beryllium oxide fired at high, low, and
medium temperatures. The types of lung tumors found in animals receiving intratracheal
instillations of beryllium included adenocarcinomas, adenomas, squamous cell carcinoma, and
malignant lymphoma. Osteosarcomas have been induced by intravenous and intramedullary
injection of various beryllium compounds into rabbits, and possibly mice. The osteosarcomas in
rabbits are histologically similar to human osteosarcomas (U.S. EPA, 1987, 1991).
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
The genotoxicity of beryllium has been previously reviewed by EPA (1987) and recently
reviewed by IARC (1993). Most studies have found that beryllium chloride, beryllium nitrate,
beryllium sulfate, and beryllium oxide did not induce gene mutations in bacterial assays with or
without metabolic activation. In the case of beryllium sulfate, all mutagenicity studies (Ames
[Simmon, 1979; Dunkel et al., 1984; Arlauskas et al., 1985; Ashby et al., 1990]; E. coli pol A
[Rosenkranz and Poirer, 1979]; E. coli WP2 uvr A [Dunkel et al., 1984]) and Saccharomyces
cerevisiae (Simmon, 1979) were negative with the exception of results reported for Bacillus
subtilis rec assay (Kada et al., 1980; Kanematsu et al., 1980) and E. coli rec assay (Dylevoi,
1990). Beryllium sulfate did not induce unscheduled DNA synthesis in primary rat hepatocytes
and was not mutagenic when injected intraperitoneally in adult mice in a host-mediated assay
using Salmonella typhimurium (Williams et al., 1982).
Beryllium nitrate was negative in the Ames assay (Tso and Fung, 1981; Kuroda et al.,
1991) but positive in a Bacillus subtilis rec assay (Kuroda et al., 1991). Beryllium chloride was
negative in a variety of studies (Ames [Ogawa et al., 1987; Kuroda et al., 1991]; E. coli WP2 uvr
A [Rossman and Molina, 1986]; and Bacillus subtilis rec assay [Nishioka, 1975]). In addition,
beryllium chloride failed to induce SOS repair in E. coli (Rossman et al., 1984). However,
positive results were reported for Bacillus subtilis rec assay using spores (Kuroda et al., 1991), E.
coli KMBL 3835; lacI gene (Zakour and Glickman, 1984), and hprt locus in Chinese hamster lung
V79 cells. Beryllium oxide was negative in the Ames assay and Bacillus subtilis rec assays
(Kuroda et al., 1991).
Gene mutations have been observed in mammalian cells (V79 and CHO) cultured with
beryllium chloride (Miyaki et al., 1979; Hsie et al., 1979a,b), and culturing of mammalian cells
with beryllium chloride (Vegni-Talluri and Guiggiani, 1967), beryllium sulfate (Brooks et al.,
1989; Larramendy et al., 1981), or beryllium nitrate has resulted in clastogenic alterations.
Data on the in vivo genotoxicity of beryllium are limited to a single study that found
beryllium sulfate (1.4 and 2.3 g/kg, 50% and 80% of median lethal dose) administered by gavage
did not induce micronuclei in the bone marrow of CBA mice, although a marked depression of
erythropoiesis suggestive of bone marrow toxicity was evident 24 h after dosing. No mutations
were seen in p53 or c-raf-1 and only weak mutations were detected in K-ras in lung carcinomas
from F344/N rats given a single nose-only exposure to beryllium metal (Nickell-Brady et al.,
1994). The authors concluded that the mechanisms for the development of lung carcinomas from
inhaled beryllium in the rat do not involve gene dysfunctions commonly associated with human
non-small-cell lung cancer.
Regarding human exposure, beryllium particles produced from anthropogenic processes
almost always enter the atmosphere as BeO. Depending on the particle size, they can be
deposited near the source or transported long distances. The inhalation toxicity of insoluble
beryllium oxide, which appears to be the chemical form more likely than beryllium salts to be
present in the atmosphere, depends to a great extent on its physical and chemical properties,
which can be altered considerably, depending on production conditions. It is well known that the
toxicity of beryllium oxide is dependent on the particle size, with smaller particles (< 10 µm, dae)
able to penetrate beyond the larynx.
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL
EXPOSURE
The oral database is considered inadequate for the assessment of carcinogenicity.
The chronic oral studies did not report increased incidences of tumors in rodents, but were
conducted at doses below the MTD. The oral database, including the Schroeder and Mitchener
study (1975a) previously used in the development of the oral slope factor on IRIS, is considered
inadequate for the assessment of carcinogenicity. The basis for not using the Schroeder and
Mitchener rat study (1975a) is that the incidences of gross or malignant tumors in the control and
beryllium-exposed groups were not significantly different.
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM
INHALATION EXPOSURE
The cancer dose-response assessment based on the occupational study of Wagoner et al.
(1980) that is presented in this section was derived by EPA (1987), was verified in 1988, and
loaded on IRIS. Newer studies, particularly the occupational study of Ward et al. (1992), have
been considered as the basis for a dose-response assessment, but share a limitation with the
Wagoner et al. (1980) study--lack of individual exposure monitoring or job history data that
would support a more definitive exposure assessment. NIOSH has recently completed a lung
cancer case-control study nested within a cohort mortality study of beryllium manufacturing
workers at the Reading beryllium processing facility. The study developed an exposure matrix
and calculated airborne beryllium exposure concentrations and thus may provide the best available
basis for a quantitative cancer estimate. The study is currently in peer review. Rather than
calculate an interim quantitative estimate based on the Ward et al. (1992) data and poorly defined
exposure estimates, it is recommended that the existing unit risk based on the Wagoner et al.
(1980) study be retained until the NIOSH assessment can be evaluated as the basis for a
quantitative estimate.
___II.C.1. SUMMARY OF RISK ESTIMATES
____II.C.1.1. Air Unit Risk -- 2.4E-3 per (µg/m3)*
____II.C.1.2 Extrapolation Method -- Relative risk
Air Concentrations at Specified Risk Levels:
|
Risk Level |
Concentration |
|
------------------------- |
--------------------- |
|
E-4 (1 in 10,000) |
4E-2 per (µg/m3) |
|
E-5 (1 in 100,000) |
4E-3 per (µg/m3) |
|
E-6 (1 in 1,000,000) |
4E-4 per (µg/m3) |
*The unit risk should not be used if the air concentration exceeds 4 µg/m3, since above this
concentration the unit risk may not be appropriate.
___II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION
EXPOSURE
Tumor Type -- Lung cancer
Test Animals -- Human, male
Route -- Inhalation, occupational exposure
Reference -- Wagoner et al., 1980
| Beryllium |
Ratio of years |
|
95 percent |
|
| concentration |
of exposure |
Effective |
upper-bound |
Unit |
| in workplace |
to years at |
dose |
estimate of |
risk per |
| (µg/m3) |
risk (f/L) |
(µg/m3) |
relative risk |
(µg/m3) |
| --------------------- |
------------------- |
------------------- |
------------------- |
|
--------------- |
| 100 |
1.00 |
21.92 |
1.98 |
|
1.61E-3 |
|
|
|
2.09 |
|
1.79E-3 |
|
0.25 |
5.48 |
1.98 |
|
6.44E-3 |
|
|
|
2.09 |
|
7.16E-3 |
| 1,000 |
1.00 |
219.18 |
1.98 |
|
1.61E-4 |
|
|
|
|
|
|
|
|
|
2.09 |
|
1.79E-4 |
|
0.25 |
54.79 |
1.98 |
|
6.44E-4 |
|
|
|
2.09 |
|
7.16E-4 |
___II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION
EXPOSURE)
The epidemiology study by Wagoner et al. (1980) is used to estimate the lifetime cancer
risk from exposure to beryllium oxide based on the estimated lower and upper bounds of
exposure estimated by NIOSH; namely, 100 and 1,000 µg/m3. The effective dose was determined
by adjusting for duration of daily (8/24 h) and annual (240/365) exposure and the ratio of
exposure duration to duration at risk, i.e., f years out of a period of L years at risk (from onset of
employment to termination of follow-up). Two values of f/L were used in the calculations, f/L =
1 and 0.25. An f/L of 1.0 would avoid overestimating the risk (but could underestimate the risk)
if the observation by Reeves and Deitch (1969)--that tumor yield depends not on the length of
exposure but on age at exposure--is valid. For a given "effective" dose d and a relative risk R,
the carcinogenic potency (q1*) is calculated by the formula B =
(R - 1) × 0.036/d, where 0.036 is the estimated lung cancer mortality rate in the U.S. population.
The risk estimates were based on the data of Wagoner et al. (1980) in which the smoking-
adjusted, expected lung cancer deaths were found to range from 13.91 to 14.67, in comparison to
20 observed. Relative risk estimates of 1.36 (p > 0.05) and 1.44 (p > 0.05) were derived and the
95% upper confidence LIMITS of these estimates, 1.98 and 2.09, respectively, were used to estimate
the lifetime cancer risk (unit risk).
With the possible exception of the Wagner et al. (1969) study, the results of the animal
carcinogenicity studies are incompletely reported and the studies are not of sufficient quality to be
used as the basis of quantitative cancer risk estimates. Because Wagner et al. (1969) exposed the
rats to beryllium ores with relatively low beryllium levels and high levels of silica dioxide, this
study would not be an appropriate basis for a risk estimate for general population exposure to
beryllium.
___II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION
EXPOSURE)
The estimate for risk for inhalation was based on an epidemiologic study having several
confounding variables. The estimate of exposure levels and duration of exposure by NIOSH were
also somewhat uncertain. While a quantitative estimate based on several animal studies (U.S.
EPA, 1987) resulted in a similar estimate of risk, the epidemiological data are considered a better
basis for quantitating risk; the assessment based on the animal data is, however, supportive of the
assessment based on the human data.
The results of the epidemiological studies have been criticized (BISAC, 1997; MacMahon,
1994; U.S. EPA, 1987; Saracci, 1985). EPA (1987, 1991) considered the studies conducted prior
to 1987 to be insufficient to assess the carcinogenic potential of beryllium in humans. Although
the design of the Ward et al. (1992) study corrected a number of the shortcomings of the older
studies, the interpretation of the study results is limited by the assumption used to account for
lung cancer deaths due to cigarette smoking, the lack of job history data that would support
quantitative exposure assessment, the lack of control for potential exposure to other carcinogens,
including coexposure to sulfuric or hydrofluoric acid mists during employment in the beryllium
industry or nonconcurrent exposure to other carcinogens during employment outside of the
beryllium industry, and the relatively small increases in lung cancer risks. Exposure to sulfuric
acid mists, however, has not been strongly associated with lung cancer, but rather with laryngeal
cancer (IARC, 1992; Sathiakumar et al., 1997). Limitations in the evidence for an association
between exposure to sulfuric acid mist and lung cancer include poor or no quantitation of
exposure, possible confounding by other occupational exposures and smoking, and low SMRs.
The majority of lung cancer SMRs in the studies that reported a positive association between
exposure to sulfuric acid mists and lung cancer were in the range of 1.18 to 1.39. The studies of
lung cancer in workers exposed occupationally to beryllium and/or sulfuric acid or other acid
mists do not, for the most part, categorize the type of cancer. Thus, the data are insufficient to
determine whether different types of lung cancer may be associated with beryllium exposure
versus sulfuric acid exposure. Exposures to hydrofluoric acid and hydrogen fluoride are potential
confounders at some of the beryllium processing facilities, including the Reading plant (Ward et
al., 1992; BISAC, 1997). Information regarding the potential carcinogenicity of these compounds
was not available. IARC (1992) considered hydrofluoric acid to be a weak inorganic acid and did
not assess it in the monograph on strong inorganic acids.
IARC (1993; Vainio and Rice, 1997) considered the epidemiological data as sufficient
evidence in humans for the carcinogenicity of beryllium and compounds. IARC (1993) concluded
that the issue of adjustments for smoking had been handled adequately, and stated that a limitation
of the most recent cohort studies was the absence of discussion of potential exposure to other
lung carcinogens, although "there is no evidence that other lung carcinogens were present." The
U.S. EPA, however, considers that the issues of incomplete smoking data and exposure to other
potential lung carcinogens are not completely resolvable with the data currently available, and
therefore concludes that the evidence of carcinogenicity of beryllium and compounds is limited in
humans.
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY
ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
Source Document -- U.S. EPA, 1998
This assessment was peer reviewed by external scientists. Their comments have been evaluated
carefully and incorporated in finalization of this IRIS summary. A record of these comments is
included as an appendix to the Toxicological Review of Beryllium in support of Summary
Information on the Integrated Risk Information System (IRIS) (U.S. EPA, 1998).
Other EPA Documentation -- U.S. EPA, 1987, 1991
___II.D.2. EPA REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Consensus Date -- 03/26/1998
___II.D.3. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Please contact the Risk Information Hotline for all questions concerning this assessment or
IRIS in general at (513) 569-7254 (phone), (513) 569-7159 (fax), or
RIH.IRIS@EPAMAIL.EPA.GOV (Internet address).
_III. [RESERVED]
_IV. [RESERVED]
_V. [RESERVED]
_VI. BIBLIOGRAPHY
Beryllium and compounds
CASRN -- 7440-41-7
Last Revised --04/03/1998
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_VII. REVISION HISTORY
Beryllium and compounds
CASRN 7440-41-7
| Date |
Section |
Description |
| ------------- |
------------- |
------------------------------------------------------------------- |
| 03/01/1988 |
I.A.1. |
Reference dose table clarified |
| 03/01/1988 |
I.A.2. |
Text added |
| 09/07/1988 |
II. |
Carcinogen summary on-line |
| 01/01/1990 |
II.A.2. |
References clarified |
| 01/01/1990 |
II.A.3. |
Text revised |
| 01/01/1990 |
II.B. |
Quantitative estimate for oral exposure section added |
| 01/01/1990 |
II.C.3. |
Text revised |
| 01/01/1990 |
II.D.2. |
Work group review dates and verification date added |
| 01/01/1990 |
VI. |
Bibliography on-line |
| 02/01/1990 |
VI.A. |
Puzanova et al. 1978 citation corrected |
| 02/01/1990 |
VI.C. |
Wagner et al. 1969 citation corrected |
| 09/01/1990 |
I.A. |
Morgareidge ref. now Cox (same study-authors reversed) |
| 09/01/1990 |
IV.F.1. |
EPA contact changed |
| 09/01/1990 |
VI.A. |
Morgareidge ref. now Cox (same study-authors reversed) |
| 01/01/1991 |
II. |
Text edited |
| 01/01/1991 |
II.C.1. |
Inhalation slope factor removed (global change) |
| 01/01/1992 |
IV. |
Regulatory actions updated |
| 09/01/1992 |
II.A.3. |
U.S. EPA citation year corrected, paragraph 3 |
| 09/01/1992 |
II.D.1. |
Source document year corrected |
| 09/01/1992 |
II.D.1. |
Review statement revised |
| 09/01/1992 |
VI.C. |
U.S. EPA reference year corrected |
| 02/01/1993 |
I.A.7. |
Primary contact changed |
| 04/03/1998 |
I.A. |
Oral RfD Assessment |
| 04/03/1998 |
I.B. |
Inhalation RfC Assessment |
| 04/03/1998 |
II. |
Carcinogenicity Assessment |
_VIII. SYNONYMS
Beryllium and Compounds
CASRN -- 7440-41-7
Last Revised -- 04/03/1998
7440-41-7
Beryllium
Beryllium-9
Glucinum
RCRA waste number P015
UN 1567
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Last updated: 16 July 1998
URL: http://www.epa.gov/iris/SUBST/0012.HTM
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