(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 DNA 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). (EPA, 1998)

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 – producing breakage or disrupting
chromosomes.

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 percent and 80
percent of median lethal dose) administered by gavage did not induce
micronuclei in the bone marrow of CBA mice. However, a marked depression
of erythropoiesis (red blood cell production) was suggestive of bone
marrow toxicity which was evident 24 hours 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.  (EPA, 1998)

Human Epidemiological Studies

This section reviews in greater detail the studies used to support the
mechanistic findings for beryllium induced cancer.  Several
epidemiological cohort studies have reported excess lung cancer
mortality among employees employed in U.S. beryllium production and
processing plants during the 1930s to 1960s.  The largest and most
comprehensive study investigated the mortality experience of over 9,000
employees employed in seven different beryllium processing plants over a
30-year period (Ward et. al., 1992).  The employees at the two oldest
facilities (i.e., Lorain, OH, and Reading, PA) were found to have
significant excess lung cancer mortality relative to the U.S.
population.  These two plants were believed to have the highest
exposure levels to beryllium.  A different analysis of the lung cancer
mortality in this cohort using various local reference populations and
alternate adjustments for smoking generally found smaller,
non-significant, excess mortality among the beryllium employees (Levy et
al., 2002).  Both cohort studies are limited by a lack of job history
and air monitoring data that would allow investigation of mortality
trends with beryllium exposure.  The majority of employees at the
Lorain, OH, and Reading, PA, facilities were employed for a relatively
short period of less than one year.

Two studies evaluated participants in the BCR   ADDIN EN.CITE
<EndNote><Author>Infante</Author><Year>1980</Year><RecNum>5</RecNu
m><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><AUTHORS><AUTHOR>Infante,
PF</AUTHOR><AUTHOR>Wagoner, JK</AUTHOR><AUTHOR>Sprince,
NL</AUTHOR></AUTHORS><YEAR>1980</YEAR><TITLE>Mortality patterns from
lung cancer and nonneoplastic respiratory disease among white males in
the beryllium case registry</TITLE><SECONDARY_TITLE>Environ
Res</SECONDARY_TITLE><VOLUME>21</VOLUME><PAGES>35-43</PAGES></MDL><Author>Steenland</Author><Year>1991</Year><RecNum>26</RecNum><MD
L><REFERENCE_TYPE>0</REFERENCE_TYPE><AUTHORS><AUTHOR>Steenland,
K</AUTHOR><AUTHOR>Ward,
EM</AUTHOR></AUTHORS><YEAR>1991</YEAR><TITLE>Lung cancer incidence among
patients with beryllium disease: a cohort mortality
study</TITLE><SECONDARY_TITLE>J Natl Cancer
Inst</SECONDARY_TITLE><VOLUME>83</VOLUME><NUMBER>1380-1385</NUMBER><KEYW
ORDS><KEYWORD>2310150B</KEYWORD></KEYWORDS></MDL></EndNote>
(Infante et al., 1980; Steenland and Ward, 1991) .  Infante et al.
ADDIN EN.CITE <EndNote><Author>Infante</Author><Year>1980</Year><RecNum>5</RecN
um><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><AUTHORS><AUTHOR>Infante,
PF</AUTHOR><AUTHOR>Wagoner, JK</AUTHOR><AUTHOR>Sprince,
NL</AUTHOR></AUTHORS><YEAR>1980</YEAR><TITLE>Mortality patterns from
lung cancer and nonneoplastic respiratory disease among white males in
the beryllium case registry</TITLE><SECONDARY_TITLE>Environ
Res</SECONDARY_TITLE><VOLUME>21</VOLUME><PAGES>35-43</PAGES></MDL></EndNote> (1980)  evaluated the mortality patterns of white male
participants in the BCR diagnosed with non-neoplastic respiratory
symptoms of beryllium disease.  Of the 421 cases evaluated, 7 of the
participants had died of lung cancer.  Six of the deaths occurred more
than 15 years after initial beryllium exposure.   The duration of
exposure for 5 of the 7 participants with lung cancer was less that 1
year with the time since initial exposure ranging from 12 to 29 years.
One of the participants was exposed for 4 years with a 26 year interval
since the initial exposure.  Exposure duration for one participant
diagnosed with pulmonary fibrosis could not be determined; however, it
had been 32 years since the initial exposure.  Based on BCR records, the
participants were classified as being in the acute respiratory group,
(i.e., those diagnosed with acute respiratory illness at the time of
entry in the registry), or chronic respiratory group, (i.e., those
diagnosed with pulmonary fibrosis or some other chronic lung condition
at the time of entry into the BCR).  The 7 participants with lung cancer
were in the BCR because of diagnoses of acute respiratory illness.  For
only one of those individuals was initial beryllium exposure less than
15 years prior.  Only 1 of the 7 (with greater than 15 years since
initial exposure to beryllium) had been diagnosed with chronic
respiratory disease.   The study did not report exposure concentrations
or smoking habits.  The authors concluded that the results of this
cohort agreed with previous animal studies and with epidemiological
studies demonstrating an increased risk of lung cancer in workers
exposed to beryllium.

Steenland and Ward   ADDIN EN.CITE <EndNote><Author>Steenland</Author><Year>1991</Year><RecNum>26</R
ecNum><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><AUTHORS><AUTHOR>Steenland,
K</AUTHOR><AUTHOR>Ward,
EM</AUTHOR></AUTHORS><YEAR>1991</YEAR><TITLE>Lung cancer incidence among
patients with beryllium disease: a cohort mortality
study</TITLE><SECONDARY_TITLE>J Natl Cancer
Inst</SECONDARY_TITLE><VOLUME>83</VOLUME><NUMBER>1380-1385</NUMBER><KEYW
ORDS><KEYWORD>2310150B</KEYWORD></KEYWORDS></MDL></EndNote>
(1991)  extended the work of Infante et al.   ADDIN EN.CITE
<EndNote><Author>Infante</Author><Year>1980</Year><RecNum>5</RecN
um><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><AUTHORS><AUTHOR>Infante,
PF</AUTHOR><AUTHOR>Wagoner, JK</AUTHOR><AUTHOR>Sprince,
NL</AUTHOR></AUTHORS><YEAR>1980</YEAR><TITLE>Mortality patterns from
lung cancer and nonneoplastic respiratory disease among white males in
the beryllium case registry</TITLE><SECONDARY_TITLE>Environ
Res</SECONDARY_TITLE><VOLUME>21</VOLUME><PAGES>35-43</PAGES></MDL></EndNote> (1980)  to include females and to include 13 additional
years of follow-up.  Ninety-three percent of the women in the study had
been diagnosed with CBD while only 50 percent of the men had at the time
of entry in the BCR.  In addition, 61 percent of the women had worked in
the fluorescent tube industry and 50 percent of the men had worked in
the basic manufacturing industry.   A total of 22 males and 6 females
died of lung cancer.  Of the 28 total deaths from lung cancer, 17 had
been exposed for less than 4 years and 11 had been exposed for greater
than 4 years.  The study did not report exposure concentrations.  Survey
data collected in 1965 provided information on smoking habits for 223
cohort members (32 percent), on the basis of which the authors suggested
that the rate of smoking among workers in the cohort may have been lower
than U.S. rates.  The authors concluded that there was evidence of
increased risk of lung cancer in workers exposed to beryllium and
diagnosed with beryllium disease.

Bayliss et al.   ADDIN EN.CITE <EndNote><Author>Bayliss</Author><Year>1971</Year><RecNum>34</Rec
Num><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><AUTHORS><AUTHOR>Bayliss,
DL</AUTHOR><AUTHOR>Lainhart, WS</AUTHOR><AUTHOR>Crally,
LJ</AUTHOR></AUTHORS><YEAR>1971</YEAR><TITLE>Mortality patterns in a
groups of former beryllium workers. In: Proceedings of the American
Conference of Governmental Industrial Hygienists 33rd Annual Meeting,
Toronto, Canada</TITLE><PAGES>94-107</PAGES></MDL></EndNote>
(1971)  performed a nested cohort study of approximately 8,000 former
workers from the beryllium processing industry employed in the industry
from 1942 - 1967.  Information for the workers was collected from the
personnel files of participating companies.  Of the 8,000 employees, a
cause of death was known for 753 male workers.  The number of observed
lung cancer deaths was 36 compared to 34.06 expected for a standardized
mortality ratio (SMR) of 105.7.  When evaluated by the number of years
of employment, 24 of the 36 men were employed for less than 1 year in
the industry (SMR = 124.3), 8 were employed for 1 to 5 years (SMR
140.2), and 4 were employed for more than 5 years (SMR = 54.4).  Half of
the workers who died from lung cancer began employment in the beryllium
production industry prior to 1947.  When grouped by job classification,
over two thirds of the workers with lung cancer were in production
related jobs while the rest were classified as office workers.  The
authors concluded that while the lung cancer mortality rates were the
highest of all other mortality rates, the SMR for lung cancer was still
within range of the expected based on death rates in the United States.
The limitations of this study included the lack of information regarding
exposure concentrations, smoking habits, and the age and race of the
participants.

Mancuso   ADDIN EN.CITE <EndNote><Author>Mancuso</Author><Year>1970</Year><RecNum>12</Rec
Num><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><AUTHORS><AUTHOR>Mancuso,
TF</AUTHOR></AUTHORS><YEAR>1970</YEAR><TITLE>Relation of duration of
employment and prior respiratory illness to respiratory cancer among
beryllium workers</TITLE><SECONDARY_TITLE>Environ
Res</SECONDARY_TITLE><VOLUME>3</VOLUME><PAGES>251-275</PAGES></MDL></Cit
e><Author>Mancuso</Author><Year>1979</Year><RecNum>13</Rec
Num><MDL><REFERENCE_TYPE>31</REFERENCE_TYPE><AUTHORS><AUTHOR>Mancuso,
TF</AUTHOR></AUTHORS><YEAR>1979</YEAR><TITLE>Occupational lung cancer
among beryllium workers.  In:  Proceedings of the conference on
occuaptional exposure to fibrous and particulate dust and their
extension  into the
environment.</TITLE><SECONDARY_AUTHORS><SECONDARY_AUTHOR>Lemen,
R</SECONDARY_AUTHOR><SECONDARY_AUTHOR>Dement,
J</SECONDARY_AUTHOR></SECONDARY_AUTHORS><SECONDARY_TITLE>Dust and
Disease</SECONDARY_TITLE><PLACE_PUBLISHED>Park Forest South,
IL</PLACE_PUBLISHED><PUBLISHER>Pathotox Publishers,
Inc</PUBLISHER><PAGES>463-482</PAGES></MDL><Author>Mancuso</Author><Year>1980</Year><RecNum>14</Rec
Num><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><AUTHORS><AUTHOR>Mancuso,
TF</AUTHOR></AUTHORS><YEAR>1980</YEAR><TITLE>Motality study of beryllium
industry workers' occupational lung
cancer</TITLE><SECONDARY_TITLE>Environ
Res</SECONDARY_TITLE><VOLUME>21</VOLUME><PAGES>48-55</PAGES></MDL></EndNote> (1970; 1979; 1980)  and Mancuso and El-Attar   ADDIN EN.CITE
<EndNote><Author>Mancuso</Author><Year>1969</Year><RecNum>15</Rec
Num><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><AUTHORS><AUTHOR>Mancuso,
TF</AUTHOR><AUTHOR>El-Attar,
AA</AUTHOR></AUTHORS><YEAR>1969</YEAR><TITLE>Epidemiological study of
the beryllium industry.  Cohort methodology and mortality
studies</TITLE><SECONDARY_TITLE>J Occup
Med</SECONDARY_TITLE><VOLUME>11</VOLUME><PAGES>422-434</PAGES></MDL></Ci
te></EndNote> (1969)  performed a series of occupational cohort studies
on a group of over 3,000 workers (primarily white males) employed in the
beryllium manufacturing industry during 1937 – 1948.  The beryllium
production facilities were located in Ohio and Pennsylvania and the
records for the employees, including periods of employment, were
obtained from the Social Security Administration. These studies did not
include analyses of mortality by job title or exposure category.  In
addition, there were no exposure concentrations estimated or adjustments
for smoking. The estimated duration of employment ranged from less than
1 year to greater than 5 years.  In the most recent study (Mancuso
1980), employees from the viscose rayon industry served as a comparison
population.  There was a significant excess of lung cancer deaths based
on the total number of 80 observed lung cancer mortalities at the end of
1976 compared to an expected number of 57.06 based on the comparison
population resulting in an SMR of 140 (p < .01)   ADDIN EN.CITE
<EndNote><Author>Mancuso</Author><Year>1980</Year><RecNum>14</RecN
um><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><AUTHORS><AUTHOR>Mancuso,
TF</AUTHOR></AUTHORS><YEAR>1980</YEAR><TITLE>Motality study of beryllium
industry workers' occupational lung
cancer</TITLE><SECONDARY_TITLE>Environ
Res</SECONDARY_TITLE><VOLUME>21</VOLUME><PAGES>48-55</PAGES></MDL></EndNote> (Mancuso 1980) .  There was a statistically significant
excess in lung cancer deaths for the shortest duration of employment (<
12 months, p < .05) and the longest duration of employment (> 49 months,
p < .01).  Based on the results of this study, the author concluded that
the ability of beryllium to induce cancer in workers does not require
continuous exposure, and that it is reasonable to assume that the amount
of exposure required to produce lung cancer can occur within a few
months of exposure regardless of the length of employment.

Wagoner et al.   ADDIN EN.CITE <EndNote><Author>Wagoner</Author><Year>1980</Year><RecNum>31</Rec
Num><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><AUTHORS><AUTHOR>Wagoner,
JK</AUTHOR><AUTHOR>Infante, PF</AUTHOR><AUTHOR>Bayliss,
DL</AUTHOR></AUTHORS><YEAR>1980</YEAR><TITLE>Beryllium: An etiological
agent in the induction of lung cancer, nonneoplastic respiratory
disease, and heart disease among industrially exposed
workers</TITLE><SECONDARY_TITLE>Environ
Res</SECONDARY_TITLE><VOLUME>21</VOLUME><PAGES>15-34</PAGES></MDL></EndNote> (1980)  expanded the work of Mancuso   ADDIN EN.CITE
<EndNote><Author>Mancuso</Author><Year>1970</Year><RecNum>12</Rec
Num><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><AUTHORS><AUTHOR>Mancuso,
TF</AUTHOR></AUTHORS><YEAR>1970</YEAR><TITLE>Relation of duration of
employment and prior respiratory illness to respiratory cancer among
beryllium workers</TITLE><SECONDARY_TITLE>Environ
Res</SECONDARY_TITLE><VOLUME>3</VOLUME><PAGES>251-275</PAGES></MDL></Cit
e><Author>Mancuso</Author><Year>1979</Year><RecNum>13</Rec
Num><MDL><REFERENCE_TYPE>31</REFERENCE_TYPE><AUTHORS><AUTHOR>Mancuso,
TF</AUTHOR></AUTHORS><YEAR>1979</YEAR><TITLE>Occupational lung cancer
among beryllium workers.  In:  Proceedings of the conference on
occuaptional exposure to fibrous and particulate dust and their
extension  into the
environment.</TITLE><SECONDARY_AUTHORS><SECONDARY_AUTHOR>Lemen,
R</SECONDARY_AUTHOR><SECONDARY_AUTHOR>Dement,
J</SECONDARY_AUTHOR></SECONDARY_AUTHORS><SECONDARY_TITLE>Dust and
Disease</SECONDARY_TITLE><PLACE_PUBLISHED>Park Forest South,
IL</PLACE_PUBLISHED><PUBLISHER>Pathotox Publishers,
Inc</PUBLISHER><PAGES>463-482</PAGES></MDL><Author>Mancuso</Author><Year>1980</Year><RecNum>14</Rec
Num><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><AUTHORS><AUTHOR>Mancuso,
TF</AUTHOR></AUTHORS><YEAR>1980</YEAR><TITLE>Motality study of beryllium
industry workers' occupational lung
cancer</TITLE><SECONDARY_TITLE>Environ
Res</SECONDARY_TITLE><VOLUME>21</VOLUME><PAGES>48-55</PAGES></MDL></EndNote> (1970; 1979; 1980)  using a cohort of 3,055 white males from
the beryllium extraction, processing, and fabrication facility located
in Pennsylvania.  The men included in the study worked at the facility
sometime between 1942 and 1968, and were followed through 1976.  The
study accounted for length of employment.  Other factors accounted for
included age, smoking history, and regional lung cancer mortality.
Forty seven members of the cohort died of lung cancer compared to an
expected 34.29 based on U.S. white male lung cancer mortality rates (p <
.05).  The results of this cohort showed an excess risk of lung cancer
in beryllium-exposed workers at each duration of employment (< 5 years
and ≥ 5 years), with a statistically significant excess noted at < 5
years durations of employment and a ≥ 25 year interval since the
beginning of employment (p < .05). The study was criticized by several
epidemiologists (MacMahon 1978, 1979; Roth 1983), by a CDC Review
Committee appointed to evaluate the study, and by one of the study’s
coauthors (Bayliss 1980), for inadequate discussion of possible
alternative explanations of excess lung cancer in the cohort.  The
specific issues identified include the use of 1965-1967 U.S. white male
lung cancer mortality rates to generate expected numbers of lung cancers
in the period 1968-1975 and inadequate adjustment for smoking.

The EPA Integrated Risk Information System (IRIS), IARC, and California
EPA Office of Environmental Health Hazard Assessment (OEHHA) have all
based their cancer assessment on the prior study with supporting data
concerning exposure concentrations from Eisenbud and Lisson   ADDIN
EN.CITE <EndNote><Author>Eisenbud</Author><Year>1983</Year><RecNum>4</Rec
Num><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><AUTHORS><AUTHOR>Eisenbud,
M</AUTHOR><AUTHOR>Lisson,
J</AUTHOR></AUTHORS><YEAR>1983</YEAR><TITLE>Epidemiological aspects of
beryllium-induced nonmalignant lung disease: A 30-year
update</TITLE><SECONDARY_TITLE>J Occup
Med</SECONDARY_TITLE><VOLUME>25</VOLUME><PAGES>196-202</PAGES><KEYWORDS>
<KEYWORD>2310150B</KEYWORD></KEYWORDS></MDL></EndNote> (1983)
and NIOSH (1972), who estimated that the lower-bound estimate of the
median exposure concentration exceeded 100 µg/m3 and concentrations in
excess of 1,000 µg/m3 were commonly found.  The IRIS cancer risk
assessment recalculated expected lung cancers based on U.S. white male
lung cancer rates (including the period 1968-1975) and used an
alternative adjustment for smoking.  In addition, one individual with
lung cancer, who had not worked at the plant, was removed from the
cohort.  After these adjustments were made, an elevated rate of lung
cancer was still observed in the overall cohort (46 cases vs. 41.9
expected).  However, based on duration of employment or interval since
beginning of employment, neither the total cohort nor any of the
subgroups had a statistically significant excess in lung cancer (EPA
1987).  Based on their evaluation of this and other epidemiological
studies, the EPA characterized the human carcinogenicity data then
available as “limited” but “suggestive of a causal relationship
between beryllium exposure and an increased risk of lung cancer” (IRIS
database).   This report includes quantitative estimates of risk that
were derived using the information presented in Wagoner et al. (1980),
the expected lung cancers recalculated by the EPA, and bounds on
presumed exposure levels.

Ward et al.   ADDIN EN.CITE <EndNote><Author>Ward</Author><Year>1992</Year><RecNum>32</RecNum
><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><AUTHORS><AUTHOR>Ward,
EM</AUTHOR><AUTHOR>Aachen, A</AUTHOR><AUTHOR>Ruder,
A</AUTHOR></AUTHORS><YEAR>1992</YEAR><TITLE>A mortality study of workers
at seven beryllium processing plants.</TITLE><SECONDARY_TITLE>Am J Ind
Med</SECONDARY_TITLE><VOLUME>22</VOLUME><NUMBER>6</NUMBER><PAGES>885-904
</PAGES></MDL></EndNote> (1992)  performed a retrospective
mortality cohort study of 9,225 male workers employed at seven beryllium
processing facilities, including the Ohio and Pennsylvania facilities
studied by Mancuso and El-Attar (1969), Mancuso   ADDIN EN.CITE
<EndNote><Author>Mancuso</Author><Year>1970</Year><RecNum>12</Rec
Num><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><AUTHORS><AUTHOR>Mancuso,
TF</AUTHOR></AUTHORS><YEAR>1970</YEAR><TITLE>Relation of duration of
employment and prior respiratory illness to respiratory cancer among
beryllium workers</TITLE><SECONDARY_TITLE>Environ
Res</SECONDARY_TITLE><VOLUME>3</VOLUME><PAGES>251-275</PAGES></MDL></Cit
e><Author>Mancuso</Author><Year>1979</Year><RecNum>13</Rec
Num><MDL><REFERENCE_TYPE>31</REFERENCE_TYPE><AUTHORS><AUTHOR>Mancuso,
TF</AUTHOR></AUTHORS><YEAR>1979</YEAR><TITLE>Occupational lung cancer
among beryllium workers.  In:  Proceedings of the conference on
occuaptional exposure to fibrous and particulate dust and their
extension  into the
environment.</TITLE><SECONDARY_AUTHORS><SECONDARY_AUTHOR>Lemen,
R</SECONDARY_AUTHOR><SECONDARY_AUTHOR>Dement,
J</SECONDARY_AUTHOR></SECONDARY_AUTHORS><SECONDARY_TITLE>Dust and
Disease</SECONDARY_TITLE><PLACE_PUBLISHED>Park Forest South,
IL</PLACE_PUBLISHED><PUBLISHER>Pathotox Publishers,
Inc</PUBLISHER><PAGES>463-482</PAGES></MDL><Author>Mancuso</Author><Year>1980</Year><RecNum>14</Rec
Num><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><AUTHORS><AUTHOR>Mancuso,
TF</AUTHOR></AUTHORS><YEAR>1980</YEAR><TITLE>Motality study of beryllium
industry workers' occupational lung
cancer</TITLE><SECONDARY_TITLE>Environ
Res</SECONDARY_TITLE><VOLUME>21</VOLUME><PAGES>48-55</PAGES></MDL></EndNote> (1970; 1979; 1980) , and Wagoner et al.   ADDIN EN.CITE
<EndNote><Author>Wagoner</Author><Year>1980</Year><RecNum>31</Rec
Num><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><AUTHORS><AUTHOR>Wagoner,
JK</AUTHOR><AUTHOR>Infante, PF</AUTHOR><AUTHOR>Bayliss,
DL</AUTHOR></AUTHORS><YEAR>1980</YEAR><TITLE>Beryllium: An etiological
agent in the induction of lung cancer, nonneoplastic respiratory
disease, and heart disease among industrially exposed
workers</TITLE><SECONDARY_TITLE>Environ
Res</SECONDARY_TITLE><VOLUME>21</VOLUME><PAGES>15-34</PAGES></MDL></EndNote> (1980) .  The men were employed for no less than 2 days
between January 1940 and December 1988.  At the end of the study 61.1
percent of the cohort was known to be living and 35.1 percent was known
to be deceased.  The duration of employment ranged from 1 year or less
to greater than 10 years with the largest percentage of the cohort (49.7
percent) employed for less than one year, followed by 1 to 5 years of
employment (23.4 percent), greater than 10 years (19.1 percent), and 5
to 10 years (7.9 percent).  Of the 3,240 deaths, 280 observed deaths
were caused by lung cancer compared to 221.5 expected yielding a
statistically significant SMR of 126 (p < .01).  Information on the
smoking habits of 15.9 percent of the cohort members, obtained from a
1968 Public Health Service survey conducted at four of the plants, was
used to calculate a smoking-adjusted SMR of 112, which was not
statistically significant.  The number of deaths from lung cancer was
also examined by decade of hire.  The authors reported a relationship
between earlier decades of hire and increased lung cancer risk.

Levy et al.   ADDIN EN.CITE <EndNote><Author>Levy</Author><Year>2002</Year><RecNum>58</RecNum
><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><AUTHORS><AUTHOR>Levy,
PS</AUTHOR><AUTHOR>Roth, HD</AUTHOR><AUTHOR>May,
PT</AUTHOR><AUTHOR>Hwang, T</AUTHOR><AUTHOR>Powers,
TE</AUTHOR></AUTHORS><YEAR>2002</YEAR><TITLE>Beryllium and lung cancer:
A reanalysis of a NIOSH cohort mortality
study</TITLE><SECONDARY_TITLE>Inhalation
Toxicology</SECONDARY_TITLE><VOLUME>14</VOLUME><PAGES>1003-1015</PAGES><
/MDL></EndNote> (2002)  questioned the results of Ward et al.
ADDIN EN.CITE <EndNote><Author>Ward</Author><Year>1992</Year><RecNum>32</RecNum
><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><AUTHORS><AUTHOR>Ward,
EM</AUTHOR><AUTHOR>Aachen, A</AUTHOR><AUTHOR>Ruder,
A</AUTHOR></AUTHORS><YEAR>1992</YEAR><TITLE>A mortality study of workers
at seven beryllium processing plants.</TITLE><SECONDARY_TITLE>Am J Ind
Med</SECONDARY_TITLE><VOLUME>22</VOLUME><NUMBER>6</NUMBER><PAGES>885-904
</PAGES></MDL></EndNote> (1992)  and performed a reanalysis of
the data used by Ward et al. The Levy et al. reanalysis differed from
the Ward et al. analysis in the following significant ways.  First, Levy
et al. (2002) examined two alternative adjustments for smoking, which
were based on (1) a different analysis of the American Cancer Society
(ACS) data used by Ward et al. (1992) for their smoking adjustment, or
(2) results from a smoking/lung cancer study of veterans (Levy and
Marimont, 1998).  Second, Levy et al. (2002) also examined the impact of
computing different reference rates derived from information about the
lung cancer rates in the cities in which most of the workers at two of
the plants lived.  Finally, Levy et al. (2002) considered a
meta-analytical approach to combining the results across beryllium
facilities.  For all of the alternatives Levy et al.   ADDIN EN.CITE
<EndNote><Author>Levy</Author><Year>2002</Year><RecNum>58</RecNum
><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><AUTHORS><AUTHOR>Levy,
PS</AUTHOR><AUTHOR>Roth, HD</AUTHOR><AUTHOR>May,
PT</AUTHOR><AUTHOR>Hwang, T</AUTHOR><AUTHOR>Powers,
TE</AUTHOR></AUTHORS><YEAR>2002</YEAR><TITLE>Beryllium and lung cancer:
A reanalysis of a NIOSH cohort mortality
study</TITLE><SECONDARY_TITLE>Inhalation
Toxicology</SECONDARY_TITLE><VOLUME>14</VOLUME><PAGES>1003-1015</PAGES><
/MDL></EndNote> (2002)  considered, except the meta-analysis, the
facility-specific and combined SMRs derived were lower than those
reported by Ward et al. (1992).  Only the SMR for the Lorain, OH
facility remained statistically significantly elevated in some
reanalyses.  The SMR obtained when combining over the plants was not
statistically significant in eight of the nine approaches they examined,
leading Levy et al. (2002) to conclude that there was little evidence of
statistically significant elevated SMRs in those plants.

One occupational case-control studied evaluated lung cancer incidence in
a cohort of 3,569 male workers employed at a beryllium alloy production
plant in Reading, PA, from 1940 to 1969 and followed through 1992
ADDIN EN.CITE
<EndNote><Author>Sanderson</Author><Year>2001</Year><RecNum>22</Re
cNum><MDL><REFERENCE_TYPE>0</REFERENCE_TYPE><AUTHORS><AUTHOR>Sanderson,
WT</AUTHOR><AUTHOR>Ward, EM</AUTHOR><AUTHOR>Steenland,
K</AUTHOR></AUTHORS><YEAR>2001</YEAR><TITLE>Lung cancer case-control
study of beryllium workers</TITLE><SECONDARY_TITLE>Am J Ind
Med</SECONDARY_TITLE><VOLUME>39</VOLUME><NUMBER>133-144</NUMBER><KEYWORD
S><KEYWORD>2310150B</KEYWORD></KEYWORDS></MDL></EndNote>
(Sanderson et al., 2001) .  There were a total of 142 known lung cancer
cases and 710 controls. For each lung cancer death, 5 age- and
race-matched controls were selected by incidence density sampling.
Confounding effects of smoking were evaluated.  Job history and
historical air measurements at the plant were used to estimate
job-specific beryllium exposures from the 1930s to 1990s.
Calendar-time-specific beryllium exposure estimates were made for every
job and used to estimate workers’ cumulative, average, and maximum
exposure.  Because of the long period of time required for the onset of
lung cancer, an “exposure lag” was employed to discount recent
exposures less likely to contribute to the disease.

The cumulative, average, and maximum beryllium exposure concentration
estimates for the 142 known lung cancer cases were 46.06 ±
9.3µg/m3-days, 22.8 ± 3.4 µg/m3, and 32.4 ± 13.8 µg/m3,
respectively.  The lung cancer mortality rate was 1.22 (95 percent CI =
1.03 - 1.43).  Exposure estimates were lagged by 10 and 20 years in
order to account for exposures that did not contribute to lung cancer
because they occurred after the induction of cancer.  In the 10- and
20-year lagged exposures the geometric mean tenures and cumulative
exposures of the lung cancer mortality cases were higher than the
controls.  In addition, the geometric mean and maximum exposures of the
workers were significantly higher than controls when the exposure
estimates were lagged 10 and 20 years (p < .01).

Results of a conditional logistic regression analysis indicated that
there was an increased risk of lung cancer in workers with higher
exposures when dose estimates were lagged by 10 and 20 years.  There was
also a lack of evidence that confounding factors such as smoking
affected the results of the regression analysis.  The authors noted that
there was considerable uncertainty in the estimation of exposure in the
1940’s and 1950’s and the shape of the dose-response curve for lung
cancer.   Another analysis of the study data using a different
statistical method did not find a significantly greater relative risk of
lung cancer with increasing beryllium exposures (Levy et al., 2007).
The average beryllium air levels for the lung cancer cases were
estimated to be an order of magnitude above the current 8-hour TWA PEL
(2 μg/m3) and roughly two orders of magnitude higher than the typical
air levels in workplaces where BeS and pathological evidence of CBD have
been observed.

Schubauer-Berigan et al. reanalyzed data from the nested case-control
study of 142 lung cancer cases in the Reading, PA, beryllium processing
plant (Schubauer-Berigan, et al., 2008).  This dataset was reanalyzed
using conditional (stratified by case age) logistic regression.
Independent adjustments were made for potential confounders of birth
year and hire age.  Average and cumulative exposures were analyzed using
the values reported in the original study.  The objective of the
reanalysis was to correct for the known differences in smoking rates by
birth year.  In addition, the authors evaluated the effects of age at
hire to determine differences observed in prior by Sanderson et al.,
2001.  The effect of birth cohort adjustment on lung cancer rates in
beryllium exposed workers was evaluated by adjusting in a multivariable
model for indicator variables for the birth cohort quartiles.

Unadjusted analyses showed little evidence of lung cancer risk
associated with beryllium occupational exposure using cumulative
exposure until a 20-year lag was used.  Adjusting for either birth
cohort or hire age attenuated the risk for lung cancer associated with
cumulative exposure.  Using a 10- or 20-year lag in workers born after
1900 also showed little evidence of lung cancer risk while those born
prior to 1900 did show a slight elevation in risk.  Unlagged and lagged
analysis for average exposure showed an increase in lung cancer risk
associated with occupational exposure to beryllium.  The finding was
consistent for either workers adjusted or unadjusted for birth cohort or
hire age.  Using a 10-year lag for average exposure showed a significant
effect by birth cohort.

The authors stated that the reanalysis indicated that differences in the
hire ages among cases and controls, first noted by Deubner et al. (2001)
and Levy et al. (2007), were primarily due to the fact that birth years
were earlier among controls than among cases, resulting from much lower
baseline risk of lung cancer for men born prior to 1900
(Schuabauer-Berigan et al., 2008).  The authors went on to state that
the reanalysis of the previous NIOSH case-control study suggested the
relationship observed previously between cumulative beryllium exposure
and lung cancer was greatly attenuated by birth cohort adjustment.

Hollins et al. (2009) re-examined the weight of evidence of beryllium as
a lung carcinogen in a recent publication (Hollins et al., 2009).
Citing more than 50 relevant papers, the authors noted the
methodological shortcomings examined above, including lack of
well-characterized historical occupational exposures and inadequacy of
the availability of smoking history for workers.  They concluded that
the increase in potential risk of lung cancer was observed among those
exposed to very high levels of beryllium and that beryllium’s
carcinogenic potential in humans at exposure levels not relevant to
today’s industrial settings.  IARC did a similar re-evaluation in 2009
(IARC, 2009) and found the weight of evidence for beryllium lung
carcinogenicity that includes the animal studies described below still
warranted a Group I classification and that beryllium be considered
carcinogenic to humans.

Animal Cancer Studies

This section reviews the animal literature used to support the findings
for beryllium-induced lung cancer.  Lung tumors have been induced via
inhalation and intratracheal administration to rats and monkeys, and
osteosarcomas have been induced via intravenous and intramedullary
(inside the bone) 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 maximum tolerated
dose (MTD) (EPA, 1998).

Early animal studies revealed that some beryllium compounds are
carcinogenic when inhaled (ATSDR, 2002).  Animal experiments have shown
consistent increases in lung cancers in rats, mice and rabbits
chronically exposed to beryllium and beryllium compounds by inhalation
or intratracheal instillation.  In addition to lung cancer,
osteosarcomas have been produced in mice and rabbits exposed to various
beryllium salts by intravenous injection or implantation into the bone
(Williams and Wilkins, 1992, NIEHS, 1999).

 (1 γ Be/ft3) as an aqueous aerosol of  beryllium sulfate for 44
hours/week for 6 months, and observed the rats for 18 months after
exposure. Three to four control rats were killed every two months for
comparison purposes. Seventy-six lung neoplasms, including adenomas,
squamous-cell carcinomas, acinous adenocarcinomas, papillary
adenocarcinomas, and alveolar-cell adenocarcinomas, were observed in 52
rats exposed to beryllium sulfate aerosol.  Adenocarcinomata were the
most numerous.  Pulmonary metastases tended to localize in areas with
foam cell clustering and granulomatosis. No neoplasia was observed in
any of the control rats.  The incidence of lung tumors in exposed rats
is presented in the following Table 2:

Table 2: Neoplasm analysis

Neoplasm	No.	Metastases

Adenoma	18	--

Squamous carcinoma	5	1

Acinous adenocarcinoma	24	2

Papillary adenocarcinoma	11	1

Alveolar-cell adenocarcinoma	7	--

Mucigenous tumor	7	1

Endothelioma	1	--

Retesarcoma	3	3

Total	76	8

Schepers (1962) reviewed 38 existing beryllium studies that evaluated
seven beryllium compounds and seven mammalian species. Beryllium
sulfate, beryllium fluoride, beryllium phosphate, beryllium alloy
(BeZnMnSiO4), and beryllium oxide were proven to be carcinogenic and
have remarkable pleomorphic neoplasiogenic proclivities.  Ten varieties
of tumors were observed, with adenocarcinoma being the most common
variety.

In another study, Vorwald and Reeves (1959) exposed Sherman albino rats
via the inhalation route to aerosols of 0.006 mg Be/m3 as beryllium
oxide and 0.0547 mg Be/m3 as beryllium sulfate for 6 hours/day, 5
days/week for an unspecified duration. Lung tumors (single or
multifocal) were observed in the animals sacrificed following 9 months
of daily inhalation exposure. The histologic pattern of the cancer was
primarily adenomatous; however, epidermoid and squamous cell cancers
were also observed. Infiltrative, vascular, and lymphogenous extensions
often developed with secondary metastatic growth in the tracheobronchial
lymph nodes, the mediastinal connective tissue, the parietal pleura, and
the diaphragm.

In the first of two articles, Reeves et al. (1967a) investigated the
carcinogenic process in lungs resulting from chronic (up to 72 weeks)
beryllium sulfate inhalation. One hundred fifty male and female Sprague
Dawley C.D. strain rats were exposed to beryllium sulfate aerosol at a
mean atmospheric concentration of 34.25 μg Be/m3 (with an average
particle diameter of 0.118 µm). Prior to initial exposure and again
during the 67–68 and 75–76 week of life, the animals received
prophylactic treatments of tetracycline-HCl to combat recurrent
pulmonary infections.

The animals entered the exposure chamber at 6 weeks of age and were
exposed 7 hours per day/5 days per week for up to 2,400 hours of total
exposure time. An equal number of unexposed controls were held in a
separate chamber. Three male and three female rats were sacrificed
monthly during the 72-week exposure period. Mortality due to respiratory
or other infections did not appear until 55 weeks of age and 87 percent
of all animals survived until their scheduled sacrifices.

Average lung weight towards the end of exposure was 4.25 times normal
with progressively increasing differences between control and exposed
animals. The increase in lung weight was accompanied by notable changes
in tissue texture with two distinct pathological
processes—inflammatory and proliferative. The inflammatory response
was characterized by marked accumulation of histiocytic elements forming
clusters of macrophages in the alveolar spaces. The proliferative
response progressed from early epithelial hyperplasia of the alveolar
surfaces, through metaplasia (after 20 - 22 weeks of exposure),
anaplasia (cellular dedifferentiation) (after 32 - 40 weeks of
exposure), and finally to lung tumors.

Although the initial proliferative response occurred early in the
exposure period, tumor development required considerable time. Tumors
were first identified after nine months of beryllium sulfate exposure,
with rapidly increasing incidence until tumors were observed in 100
percent of exposed animals by 13 months. The 9- to 13-month interval is
consistent with earlier studies. The tumors showed a high degree of
local invasiveness. No tumors were observed in control rats. All 56
tumors studied appeared to be alveolar adenocarcinomas and 3
“fast-growing” tumors that reached a very large size comparatively
early. About one-third of the tumors showed small foci where the
histologic pattern differed. Most of the early tumor foci appeared to be
alveolar rather than bronchiolar, which is consistent with the expected
pathogenesis, since permanent deposition of beryllium was more likely on
the alveolar epithelium rather than on the bronchiolar epithelium.
Female rats appeared to have an increased susceptibility to Be exposure.
Not only did they have a higher mortality (control males [n = 8],
exposed males [n = 9] versus control females [n = 4], exposed females [n
= 17]) and body weight loss than male rats, but the three
“fast-growing” tumors only occurred in females.

In the second article, Reeves et al. (1967b) described the rate of
accumulation and clearance of beryllium sulfate aerosol from the same
experiment (Reeves et al., 1967a). At the time of the monthly sacrifice,
Be assays were performed on the lungs, tracheobronchial lymph nodes, and
blood of the exposed rats. The pulmonary beryllium levels of rats showed
a rate of accumulation which decreased during continuing exposure and
reached a plateau (defined as equilibrium between deposition and
clearance) of about 13.5 μg beryllium for males and 9 μg beryllium for
females in whole lungs after approximately 36 weeks. Females were
notably less efficient than males in utilizing the lymphatic route as a
method of clearance, resulting in slower removal of pulmonary beryllium
deposits, lower accumulation of the inhaled material in the
tracheobronchial lymph nodes, and higher morbidity and mortality.

showed a notable decrease (0.50 ± 0.35 μg beryllium/gram versus 1.50
± 0.55 μg beryllium/gram). This was believed to be largely a result of
the dilution factor operating in the rapidly growing tumor tissue.
Although, other factors, such as lack of continued local deposition due
to impaired respiratory function and enhanced clearance due to high
vascularity of the tumor, may also have played a role. The portion of
inhaled beryllium retained in the lungs for a longer duration, which is
in the range of one-half of the original pulmonary load, may have
significance for pulmonary carcinogenesis. This pulmonary beryllium
burden becomes localized in the cell nuclei and may be an important
factor in eliciting the carcinogenic response associated with beryllium
inhalation.

Groth et al. (1980) conducted a series of experiments to assess the
carcinogenic effects of beryllium, beryllium hydroxide, and various
beryllium alloys. For the beryllium metal/alloys experiment, 12 groups
of 3-month old female, Wistar rats (35 rats/group) were used. All rats
in each group received a single intratracheal injection of either 2.5 or
0.5 mg of one of the beryllium metals or beryllium alloys as described
in Table 3 below. These materials were suspended in 0.4 cc of isotonic
saline followed by 0.2 cc of saline. Forty control rats were injected
with 0.6 cc of saline. The geometric mean particle sizes varied from 1
to 2 µm. Rats were sacrificed and autopsied at various intervals
ranging from 1 to 18 months post-injection.

Table 3: Summary of beryllium dose from Groth et al. (1980)

Form of Be

Percent Be	Percent

Other

Compounds	Total #

Rats Autopsied	Compound Dose (mg)	Be Dose

(mg)

Be metal	100	None	16	2.5	2.5

	21	0.5	0.5

Passivated Be metal	99	0.26% Chromium	26	2.5	2.5

	20	0.5	0.5

BeAl alloy	62	38% Aluminum	24	2.5	1.55

	21	0.5	0.3

BeCu alloy	4	96% Copper	28	2.5	0.1

	24	0.5	0.02

BeCuCo alloy	2.4	0.4% Cobalt

96% Copper	33	2.5	0.06

	30	0.5	0.012

BeNi alloy	2.2	97.8% Nickel	28	2.5	0.056

	27	0.5	0.011

Lung tumors were only observed in rats exposed to Be metal, passivated
Be metal, and beryllium-aluminum alloy. Passivation refers to the
process of removing iron contamination from the surface of beryllium
metal.  As discussed, metal alloys may have a different toxicity than
beryllium alone.   Rats exposed to 100 percent beryllium exhibited
relatively high mortality rates, especially in the groups where lung
tumors were observed. Nodules varying from 1 to 10 mm in diameter were
also observed in the lungs of rats exposed to beryllium metal,
passivated beryllium metal, and beryllium-aluminum alloy. These nodules
were suspected of being malignant.

To test this hypothesis, transplantation experiments involving the
suspicious nodules were conducted in nine rats. Seven of the nine
suspected tumors grew upon transplantation.  All transplanted tumor
types metastasized to the lungs of their hosts.  Lung tumors were
observed in rats injected with both the high and low doses of beryllium
metal, passivated beryllium metal, and beryllium-aluminum alloy. No lung
tumors were observed in rats injected with the other compounds. From a
total of 32 lung tumors detected, most were adenocarcinomas and
adenomas; however, two epidermoid carcinomas and at least one poorly
differentiated carcinoma were observed. Bronchiolar alveolar cell tumors
were frequently observed in rats injected with beryllium metal,
passivated beryllium metal, and beryllium-aluminum alloy. All stages of
cuboidal, columnar, and squamous cell metaplasia were observed on the
alveolar walls in the lungs of rats injected with beryllium metal,
passivated beryllium metal, and beryllium-aluminum alloy.  These lesions
were generally reduced in size and number or absent from the lungs of
animals injected with the other alloys (BeCu, BeCuCo, BeNi).

 (p ≤ 0.008) from controls.  When autopsies were performed at the 16-
to 19-month interval, the incidence (2/6) of lung tumors in rats exposed
to 2.5 mg of beryllium-aluminum alloy was statistically significant (p =
0.004) when compared to the lung tumor incidence (0/84) in rats exposed
to BeCu, BeNi, and BeCuCo alloys, which contained much lower
concentrations of Be (Groth et al., 1980).

Finch et al. (1998b) investigated the carcinogenic effects of inhaled
beryllium on heterozygous TSG-p53 knockout mice (p53+/-) and wild-type
(p53+/+) mice.  Knockout mice can be valuable tools in determining the
role of specific genes on the toxicity of a material of interest, in
this case, beryllium.  Equal numbers of approximately 10 week old male
and female mice were used for this study. Two exposure groups were used
to provide dose-response information on lung carcinogenicity.  The
maximum initial lung burden (ILB) target of 60 µg beryllium was based
on previous acute inhalation exposure studies in mice.  The lower
exposure target level of 15 µg was selected to provide a lung burden
several times less than the high-level group, but high enough to yield
carcinogenic responses. Mice were exposed in groups to beryllium metal
or to filtered air (controls) via nose-only inhalation.  The specific
exposure parameters are presented in Table 4 below.  Mice were
sacrificed 7 days post exposure for ILB analysis, and either at 6 months
post exposure (n = 4–5 mice per group per gender) or when 10 percent
or less of the original population remained (19 months post exposure for
p53+/- knockout and 22.5 months post exposure for p53+/+ wild-type
mice).  The sacrifice time was extended in the study because a
significant number of lung tumors were not observed at 6 months post
exposure.

Table 4:  Summary of Animal data from Finch et al., 1998 b

Mouse Strain	Mean Exposure Concentration (μg Be/L)	Target Be Lung
Burden (μg)	Number of Mice	Mean daily Exposure Duration (minutes)	Mean
ILB (μg)	# of Mice with 1 or More Lung Tumors /Total # Examined

Knockout (p53+/-)	34	15	30	112 (single)	NA	0/29

	36	60	30	139‡	NA	4/28

Wild-type (p53+/+)	34	15	6*	112 (single)	12 ± 4	NA

	36	60	36†	139‡	54 ± 6	0/28

Knockout (p53+/-)	NA (air)	Control	30	60-180 (single)	NA	0/30

ILB = initial lung burden; NA = not applicable

Median aerodynamic diameter of Be aerosol = 1.4 μm (σg = 1.8)

*	Wild-type mice in the low exposure group were not evaluated for
carcinogenic effects; however ILB was analyzed in six wild-type mice.

†	Thirty wild-type mice were analyzed for carcinogenic effects; six
wild-type mice were analyzed for ILB.

‡	Mice were exposed for 2.3 hours/day for three consecutive days.

Lung burdens of beryllium measured in wild-type mice at 7 days
post-exposure were approximately 70 - 90 percent of target levels.  No
exposure-related effects on body weight were observed in mice; however,
lung weights and lung-to-body weight ratios were somewhat elevated in 60
µg target ILB p53+/- knockout mice compared to controls (0.05 < p <
0.10).  In general, p53+/+ wild-type mice survived longer than p53+/-
knockout mice and beryllium exposure tended to decrease survival time in
both groups.  The incidence of beryllium-induced lung tumors was
marginally higher in the 60 µg target ILB p53+/- knockout mice compared
to 60 µg target ILB p53+/+ wild-type mice (p = 0.056). The incidence of
lung tumors in the 60 µg target ILB p53+/- knockout mice was also
significantly higher than controls (p = 0.048). No tumors developed in
the control mice, 15 µg target ILB p53+/- knockout mice, or 60 µg
target ILB p53+/+ wild-type mice throughout the length of the study.
Most lung tumors in beryllium-exposed mice were squamous cell
carcinomas, three of four of which were poorly circumscribed and all
were associated with at least some degree of granulomatous pneumonia.
The study results suggest that having an inactivated p53 allele is
associated with lung tumor progression in p53+/- knockout mice. This is
based on the significant difference seen in the incidence of
beryllium-induced lung neoplasms for the p53+/- knockout mice compared
with the p53+/+ wild-type mice.  The authors conclude that since there
was a relatively late onset of tumors in the beryllium-exposed p53+/-
knockout mice, a 6-month bioassay in this mouse strain might not be an
appropriate model for lung carcinogenesis (Finch et al., 1998b).

 μm (σg = 1.9). The mean beryllium lung burdens for each exposure
group were 40, 110, 360, and 430 μg, respectively.

To examine genetic alterations, DNA isolation and sequencing techniques
(PCR amplification and direct DNA sequence analysis) were performed on
wild-type rat lung tissue (i.e., control samples) along with two mouse
lung tumor cell lines containing known K-ras mutations, 12 carcinomas
induced by beryllium (i.e., experimental samples), and 12 other
formalin-fixed specimens. Tumors appeared in beryllium exposed rats by
14 months and 64 percent of exposed rats developed lung tumors during
their lifetime.  Lungs frequently contained multiple tumor sites with
some of the tumors greater than 1 cm. A total of 24 tumors were
observed.  Most of the tumors (n = 22) were adenocarcinomas exhibiting a
papillary pattern characterized by cuboidal or columnar cells, although
a few had a tubular or solid pattern.  Fewer than 20 percent of the
tumors were adenosquamous (n = 1) or squamous cell (n = 1) carcinomas.

No transforming mutations of the K-ras gene (codons 12, 13, or 61) were
detected by direct sequence analysis in any of the lung tumors induced
by beryllium.  However, using a more sensitive sequencing technique (PCR
enrichment restriction fragment length polymorphism (RFLP) analysis)
resulted in the detection of K-ras codon 12 GGT to GTT transversions in
2 of 12 beryllium-induced adenocarcinomas. No p53 and c-raf-1
alterations were observed in any of the tumors induced by beryllium
exposure (i.e., no differences observed between beryllium-exposed and
control rat tissues).  The authors note that the results suggest that
activation of the K-ras proto-oncogene is both a rare and late event,
possibly caused by genomic instability during the progression of
beryllium-induced rat pulmonary adenocarcinomas.  It is unlikely that
the K-ras gene plays a role in the carcinogenicity of beryllium.  The
results also indicate that p53 mutation is unlikely to play a role in
tumor development in rats exposed to beryllium.

Belinsky et al. (1997) reviewed the findings by Nickell-Brady et al.
(1994) to further examine the role of the K-ras and p53 genes in lung
tumors induced in the F344 rat by non-mutagenic (non-genotoxic)
exposures to beryllium. Their findings are discussed along side the
results of other genomic studies that look at carcinogenic agents that
are either similarly non-mutagenic or, in other cases, mutagenic. The
authors conclude that the identification of non-ras transforming genes
in rat lung tumors induced by non-mutagenic exposures, such as
beryllium, as well as mutagenic exposures will help define some of the
mechanisms underlying cancer induction by different types of DNA damage.

The inactivation of the p16INK4a (p16) gene is a contributing factor in
disrupting control of the normal cell cycle and may be an important
mechanism of action in beryllium-induced lung tumors. Swafford et al.
(1997) investigated the aberrant methylation and subsequent inactivation
of the p16 gene in primary lung tumors induced in F344/N rats exposed to
known carcinogens via inhalation. The research involved a total of 18
primary lung tumors that developed after exposing rats to five agents,
one of which was beryllium. In this study, only one of the 18 lung
tumors was induced by beryllium exposure; the majority of the other
tumors were induced by radiation (x-rays or plutonium-239 oxide). The
authors hypothesized that if p16 inactivation plays a central role in
development of non-small-cell lung cancer, then the frequency of gene
inactivation in primary tumors should parallel that observed in the
corresponding cell lines. To test the hypothesis, a rat model for lung
cancer was used to determine the frequency and mechanism for
inactivation of p16 in matched primary lung tumors and derived cell
lines. The methylation-specific PCR (MSP) method was used to detect
methylation of p16 alleles. The results showed that the presence of
aberrant p16 methylation in cell lines was strongly correlated with
absent or low expression of the gene. The findings also demonstrated
that aberrant p16 CpG island methylation, an important mechanism in gene
silencing leading to the loss of p16 expression, originates in primary
tumors.

Building on the rat model for lung cancer and associated findings from
Swafford et al. (1997), Belinsky et al. (2002) conducted experiments in
12-week-old F344/N rats (male and female) to determine whether
beryllium-induced lung tumors involve inactivation of the p16 gene and
estrogen receptor α (ER) gene. Rats received a single nose-only
inhalation exposure to beryllium aerosol at four different exposure
levels. The mean lung burdens measured in each exposure group were 40,
110, 360, and 430 µg. The methylation status of the p16 and ER genes
was determined by MSP. A total of 20 tumors detected in
beryllium-exposed rats were available for analysis of gene-specific
promoter methylation. Three tumors were classified as squamous cell
carcinomas and the others were determined to be adenocarcinomas.
Methylated p16 was present in 80 percent (16/20) and methylated ER was
present in one-half (10/20) of the lung tumors induced by exposure to
beryllium. Additionally, both genes were methylated in 40 percent of the
tumors. The authors noted that four tumors from beryllium-exposed rats
appeared to be partially methylated at the p16 locus. Bisulfite
sequencing of exon 1 of the ER gene was conducted on normal lung DNA and
DNA from three methylated, beryllium-induced tumors to determine the
density of methylation within amplified regions of exon 1 (referred to
as CpG sites). Two of the three methylated, beryllium-induced lung
tumors showed extensive methylation with more than 80 percent of all CpG
sites methylated.

The overall findings of this study suggest that inactivation of the p16
and ER genes by promoter hypermethylation are likely to contribute to
the development of lung tumors in beryllium-exposed rats. The results
showed a correlation between changes in p16 methylation and loss of gene
transcription. The authors hypothesize that the mechanism of action for
beryllium-induced p16 gene inactivation in lung tumors may be
inflammatory mediators that result in oxidative stress. The oxidative
stress damages DNA directly through free radicals or indirectly through
the formation of 8-hydroxyguanosine DNA adducts, resulting primarily in
a single strand DNA break.

Wagner et al. (1969) studied the development of pulmonary tumors after
intermittent daily chronic inhalation exposure to beryllium ores in
three groups of male squirrel monkeys. One group was exposed to
bertrandite ore, a second to beryl ore, and the third served as
unexposed controls. Each of these three exposure groups contained 12
monkeys. Monkeys from each group were sacrificed after 6, 12, or 23
months of exposure. The 12-month sacrificed monkeys (n = 4 for
bertrandite and control groups; n = 2 for beryl group) were replaced
(i.e., a separate replacement group) to maintain a total animal
population approximating the original numbers and to provide a source of
confirming data for biologic responses that might arise following the
ore exposures. Animals were exposed to bertrandite and beryl ore
concentrations of 15 mg/m3, corresponding to 210 µg beryllium/m3 and
620 µg beryllium/m3 in each exposure chamber, respectively. The parent
ores were reduced to particles with geometric mean diameters of 0.27 µm
(± 2.4) for bertrandite and 0.64 µm (± 2.5) for beryl. Animals were
exposed for approximately 6 hours/day, 5 days/week. The histological
changes in the lungs of monkeys exposed to bertrandite and beryl ore
exhibited a similar pattern. The changes generally consisted of
aggregates of dust-laden macrophages, lymphocytes, and plasma cells near
respiratory bronchioles and small blood vessels. There were, however, no
consistent or significant pulmonary lesions or tumors observed in
monkeys exposed to either of the beryllium ores. This is in contrast to
the findings in rats exposed to beryl ore and to a lesser extent
bertrandite, where atypical cell proliferation and tumors were
frequently observed in the lungs. The authors hypothesized that the
rats’ greater susceptibility may be attributed to the spontaneous lung
disease characteristic of rats, which might have interfered with lung
clearance.

As previously described, Conradi et al. (1971) investigated changes in
the lungs of monkeys and dogs two years after intermittent inhalation
exposure to beryllium oxide calcined at 1,400°C. Five adult male and
female monkeys (Macaca irus) weighing between 3 and 5.75 kg were used in
the study. The study included two control monkeys. Beryllium
concentrations in the ambient environment of exposed monkeys varied
between 3.30 and 4.38 mg/m3. Thirty minute exposures occurred once a
month for three months, with beryllium oxide concentrations increasing
at each exposure interval. Lung tissue was investigated using electron
microscopy and morphometric methods. Be content in portions of the lungs
of five monkeys was measured two years following exposure by emission
spectrography. The reported concentrations in monkeys (82.5, 143.0, and
112.7 μg beryllium per 100 gm of wet tissue in the upper lobe, lower
lobe, and combined lobes, respectively) were higher than those in dogs.
No neoplastic or granulomatous lesions were observed in the lungs of any
exposed animals and there was no evidence of chronic proliferative lung
changes after two years.

In vitro Studies

The exact mechanism by which beryllium induces pulmonary neoplasms in
animals remains unknown (NAS 2008). Keshava et al. (2001) performed
studies to determine the carcinogenic potential of beryllium sulfate in
cultured mammalian cells. Joseph et al. (2001) investigated differential
gene expression to understand the possible mechanisms of
beryllium-induced cell transformation and tumorigenesis. Both
investigations used cell transformation assays to study the
cellular/molecular mechanisms of beryllium carcinogenesis and assess
carcinogenicity. Cell lines were derived from tumors developed in nude
mice injected subcutaneously with non-transformed BALB/c-3T3 cells that
were morphologically transformed in vitro with 50–200 µg beryllium
sulfate/ml for 72 hours. The non-transformed cells were used as
controls.

Keshava et al. (2001) found that beryllium sulfate is capable of
inducing morphological cell transformation in mammalian cells and that
transformed cells are potentially tumorigenic. A dose-dependent increase
(9–41 fold) in transformation frequency was noted. Using differential
polymerase chain reaction (PCR), gene amplification was investigated in
six proto-oncogenes (K-ras, c-myc, c-fos, c-jun, c-sis, erb-B2) and one
tumor suppressor gene (p53). Gene amplification was found in c-jun and
K-ras.  None of the other genes tested showed amplification.
Additionally, Western blot analysis showed no change in gene expression
or protein level in any of the genes examined.  Genomic instability in
both the non-transformed and transformed cell lines was evaluated using
random amplified polymorphic DNA fingerprinting (RAPD analysis). Using
different primers, 5 of the 10 transformed cell lines showed genomic
instability when compared to the non-transformed BALB/c-3T3 cells. The
results indicate that beryllium sulfate-induced cell transformation
might, in part, involve gene amplification of K-ras and c-jun and that
some transformed cells possess neoplastic potential resulting from
genomic instability.

Using the Atlas mouse 1.2 cDNA expression microarrays, Joseph et al.
(2001) studied the expression profiles of 1,176 genes belonging to
several different functional categories. Compared to the control cells,
expression of 18 genes belonging to two functional groups (nine
cancer-related genes and nine DNA synthesis, repair, and recombination
genes) was found to be consistently and reproducibly different (at least
2-fold) in the tumor cells. Differential gene expression profile was
confirmed using reverse transcription- PCR with primers specific to the
differentially expressed genes. Two of the differentially expressed
genes (c-fos and c-jun) were used as model genes to demonstrate that the
beryllium-induced transcriptional activation of these genes was
dependent on pathways of protein kinase C and mitogen-activated protein
kinase and independent of reactive oxygen species in the control cells.
These results indicate that beryllium-induced cell transformation and
tumorigenesis are associated with up-regulated expression of the
cancer-related genes (such as c-fos, c-jun, c-myc, and R-ras) and
down-regulated expression of genes involved in DNA synthesis, repair,
and recombination (such as MCM4, MCM5, PMS2, Rad23, and DNA ligase I).

Preliminary Lung Cancer Conclusions

OSHA has preliminarily determined that the weight of evidence indicates
that beryllium compounds should be regarded as potential occupational
lung carcinogens.  Other scientific organizations, including the
International Agency for Research on Cancer (IARC), the National
Toxicology Program (NTP), the U.S. Environmental Protection Agency
(EPA), the National Institute for Occupational Safety and Health
(NIOSH), and the American Conference of Governmental Industrial
Hygienists (ACGIH) have reached similar conclusions with respect to the
carcinogenicity of beryllium.

While some evidence exists for direct acting genotoxicity as a possible
mechanism for beryllium carcinogenesis the weight of evidence suggests a
possible indirect mechanism may be responsible for most tumorigenic
activity of beryllium in animal models and possibly humans.
Inflammation has been postulated to be a key contributor to many
different forms of cancer (Jackson et al., 2006; Pikarsky et al., 2004);
Greten et al., 2004; Leek RD, 2002).  In fact, chronic inflammation may
be a primary factor in the development of up to one-third of all cancers
(Ames et al., 1990; NCI, 2010).

Animal studies, as summarized above, have demonstrated a consistent
scenario of beryllium exposure resulting in chronic pulmonary
inflammation.  Studies conducted in rats have demonstrated that chronic
inhalation of materials similar in solubility to beryllium result in
increased pulmonary inflammation, fibrosis, epithelial hyperplasia, and
in some cases, pulmonary adenomas and carcinomas (Heinrich et al., 1995;
Nikula et al., 1995; NTP, 1993; Lee et al.1985; Warheit et al., 1996).
This response is generally referred to as an “overload” response or
threshold effect.  Substantial data indicate that tumor formation in the
rat after exposure to some sparingly soluble particles at doses causing
marked, chronic inflammation is due to a secondary mechanism unrelated
to the genotoxicity (or lack thereof) of the particle itself.

It has been hypothesized that the recruitment of neutrophils during the
inflammatory response and subsequent release of oxidants from these
cells have been demonstrated to play an important role in the
pathogenesis of rat lung tumors (Borm et al., 2004; Carter and Driscoll,
2001; Carter et al., 2006; Johnston et al., 2000; Knaapen et al., 2004;
Mossman BT, 2000).  Inflammatory mediators, as characterized in many of
the studies summarized above, have been shown to play a significant role
in the recruitment of cells responsible for the release of reactive
oxygen and hydrogen species.  These species have been determined to be
highly mutagenic themselves as well as mitogenic, inducing a
proliferative response (Feriola and Nettesheim, 1994; Jetten et al.1990;
Moss et al., 1994; Coussens and Werb, 2002).  The resultant effect is an
environment rich for neoplastic transformations and the progression of
fibrosis and tumor formation.  This finding does not imply no risk at
levels below an inflammatory response merely the overall weight of
evidence is suggestive of a mechanism of an indirect carcinogen at
levels where inflammation is seen.

Other Health Effects Section

Past studies on other health effects have been thoroughly reviewed by
several scientific organizations (NTP, 1999; EPA, 1998; ATSDR, 2002;
WHO, 2001; HSDB, 2005).  These include summaries of animal studies, in
vitro studies as well as human epidemiological studies associated with
cardiovascular, hematological, hepatic, renal, endocrine, reproductive
and developmental effects.  High dose exposures to beryllium have been
shown to have an adverse effect upon a variety of organs and tissues in
the body, particularly the liver.  The adverse systemic effects from
human exposures mostly occurred prior to the introduction of
occupational and environmental standards set in 1972 (AIHA, 1972; ACGIH,
1972; ANSI, 1972) and 1974 (EPA, 1974) and therefore are less relevant
today than in the past.  The available data is fairly limited.  The
hepatic, cardiovascular, and renal effects are briefly summarized below.
 Health effects in other organ systems listed above were only observed
in animal studies at very high exposure levels and are, therefore, not
discussed here.

Hepatic Effects

Beryllium has been shown to accumulate in the liver and a correlation
has been demonstrated between beryllium content and hepatic damage.
Different compounds have been shown to distribute differently within
different hepatic tissues.  For example, preformed beryllium phosphate
is accumulated almost exclusively within sinusoidal (Kupffer) cells of
the liver, while the beryllium derived from beryllium sulfate is found
mainly in parenchymal cells.  Conversely, beryllium sulphosalicyclic
acid complexes are rapidly excreted (Skillteter and Paine, 1979).

Intravenous injection of soluble beryllium compounds to rats causes
severe liver necrosis.  Death 2 or 3 days later is preceded by
biochemical disturbance which may be attributed to the progressive
destruction of liver tissue.  When beryllium is injected as suspensions
of particles of different sizes (so that it is retained by organs other
than the liver) all organs containing such beryllium are damaged (i.e.,
liver, spleen, lymph glands, bone marrow, lungs and pancreas) (Witschi
and Price, 1967).

According to a few autopsies, the beryllium poisoned liver may have
central necrosis, mild focal necrosis as well as congestion and
occasionally beryllium granuloma.

Residents near a beryllium plant may be poisoned by inhaling trace
amount of beryllium powder and different beryllium compounds may induce
different poisoning reactions

(Yian and Lin, 1982).

Cytotoxicity of particulate and soluble Be compounds to both rat liver
Kupffer cells and parenchymal cells in vitro has been demonstrated with
cells that have accumulated less than 1 nmol Be/106 cells.  In primary
culture at 37º C, both beryllium phosphate and beryllium sulphate (150
μM) cause cell damage within 10 hours as measured by detachment of the
cell monolayer and release of 51Cr in to the medium from cells
pre-labeled with the radioisotope. (Skilleter and Price, 1981)

Cardiovascular Effects

There is very limited evidence of cardiovascular effects of beryllium
and its compounds in humans. Severe cases of chronic beryllium disease
can result in cor pulmonale, which is hypertrophy of the right heart
ventricle.  In a case history study of 17 individuals exposed to
beryllium in a plant that manufactured fluorescent lamps, autopsies
revealed right atrial and ventricular hypertrophy (Hardy and Tabershaw,
1946). An increase in deaths due to heart disease or ischemic heart
disease also was found in workers at a beryllium manufacturing facility
(Ward et al., 1992).  It is not likely that the cardiac effects are due
to direct toxicity to the heart, but rather are a response to impaired
lung function.

Animal studies performed in monkeys indicate heart enlargement after
acute inhalation exposure to 13 mg beryllium/m3 as beryllium hydrogen
phosphate, 0.184 mg beryllium/m3 as beryllium fluoride, or 0.198 mg
Be/m3 as beryllium sulfate (Schepers 1964). Decreased arterial oxygen
tension was observed in dogs exposed to 30 mg beryllium/m3 beryllium
oxide for 15 days, 3.6 mg beryllium/m3 as beryllium oxide for 40 days
(Hall et al., 1950), or 0.04 mg beryllium/m3 as beryllium sulfate for
100 days (Stokinger et al., 1950).  These are expected to be indirect
effects on the heart due to pulmonary fibrosis and toxicity which can
increase arterial pressure and restrict blood flow.

Renal Effects

Renal calculi are unusually prevalent in severe cases. Renal stones
containing beryllium occur in about 10 per cent of patients so affected.
(Barnett et al., 1961)  Kidney stones were observed in 10 percent of the
CBD cases collected by the BCR up to 1959 (Hall et al., 1959).  In
addition, an excess of calcium in the blood and urine has been seen
quite frequently in patients with chronic beryllium disease. (ATSDR,
2002)

GLOSSARY

Agglomeration: a cluster of particles

Algorithm: a step-by-step problem solving procedure

Anaplasia: dedifferentiation or loss of functional and structural
differentiation of normal cells

Apoptosis: programmed cell death

Bioavailability: amount absorbed by the body

Biotransformed: process of changing one substance to another by a
biological action

Bronchoalveolar lavage fluid: fluid is directed into the lung and
recollected for examination of contents – cellular and/or biochemical

Calcination: a process of heating a material to a temperature below its
melting point to effect a thermal decomposition or a phase transition
other than melting – generally for removing water or other contaminate

CD4+: cluster of differentiation 4 – a glycoprotein expressed on the
surface of T cells, monocytes, macrophages and dendritic cells, aids in
interaction and binding with antigens presenting cell

CD28: cluster of differentiation 28 – a glycoprotein expressed on
surface of T cells that provide co-stimulatory signals

Chemokine: small cytokine secreted by cells

Clastogenic: a chemical or other agent giving rise to breakage or
disruption of chromosomes

Clustered particles: a small grouping of particles

Cor pulmonale: an alteration in the structure and function of the right
ventricle

Cytokines: signaling molecules in an inflammatory or immune response

Cytotoxicity: causing cell death

Dermal loading: skin/dermal exposure – amount of material transported
through skin

Desquamated: shedding or peeling of epithelium

DWA: daily weighted average

Edematous distension: swollen with an excessive amount of fluid –
often blood filled

Fibronodular: sharply defined circular opacities found in clusters
associated with linear opacities that distort adjacent structures;
usually indicates previous granulomatous disease

Fibrosis: formation of scar tissue

Fulminating: rapid development

Granulomas: small nodules

Granulomatous lesion: inflammatory lesion containing T cells and other
type of immune cells

GRO-1: chemokine that attracts neutrophils and other immune cells to a
site of injury or contamination

Hapten: a small molecule that can elicit an immune response only when
attached to a large carrier such as a protein

Histiocytic: pertaining to a histiocyte (a tissue macrophage)

Humoral: blood or lymph fluid, IgE antibodies

Hyperplasia: proliferation of cells within an organ or tissue

γ: Interferon gamma

IL-2: Interleukin 2

Lymphoctye: white blood cell

Macrophage: a phagocytic cell generally derived from a monocyte

MIP-1α: Monocyte Inflammatory Protein 1 alpha – a C:C cytokine
produced mainly by type 1 immune cells to recruit other inflammatory
cells

Monocyte: a type of white blood cell, part of the human body's immune
system. Monocytes have two main functions in the immune system: (1)
replenish resident macrophages and dendritic cells under normal states,
and (2) respond to inflammation signals.

Mononuclear cells: macrophages and lymphocytes

Mucociliary escalator: process to remove foreign materials from lung via
mucous-secreting ciliary cells

Neoplasia: abnormal proliferation of cells, precursor to tumor
formation.  Tumors can be benign, pre-malignant or malignant

Neutrophil: the most abundant type of white blood cell, it is generally
the first in response to a pathogen

Noncaseating granulomatous lesions: granuloma that is not necrotic
(necrotic granulomas occur in tuberculosis for example)

Nonparenchymal: non-gas exchanging structural cells in the lung

Osteosarcoma: bone cancer

Parenchymal: gas exchanging cells in the lung

Parenteral: abdominal cavity, not including the alimentary canal

Pathogenesis: development of disease condition

Percutaneous: access to inner organs or other tissue is done via
needle-puncture of the skin, rather than by using an "open" approach
where inner organs or tissue are exposed

Peribronchial: relating to, or surrounding a bronchus or the bronchi

Perinasal: relating to the nasal passage or cavity

Perivascular: relating to, or surrounding the vasculature or
arteries/veins

Phagocytosis: the process of a cell engulfing that “eating” a
foreign material or pathogen

Phagolysomal: a cellular enzyme that aids in “digestion” of
phagocytized material

Pneumonitis: inflammation of the lung

PPV: positive predictive value - refers to proportion of patients with
positive test results who are correctly diagnosed

Sarcoidosis: an inflammatory disease that affects multiple organs in the
body, but mostly the lungs and lymph glands. In patients with
sarcoidosis, granulomas consisting of inflamed tissues form in certain
organs of the body. These granulomas might alter the normal structure
and possibly the function of the affected organ(s).

Sensitization: Priming of the immune system in response to a specific
non-self antigen; a condition that involves immune memory, typically
antigen-specific T cells and/or antibodies;  beryllium sensitization
means a change in a person's responsiveness to beryllium, such that upon
subsequent exposures to beryllium there is a heightened immune response.

Sensitized: going through the sensitization response

Sn: sensitivity – refers to the proportion of actual positives which
are correctly identified

Sp: specificity – refers to the proportion of negatives which are
correctly identified

Systemic loading: systemic or total body dosing

Tem cells: T effector memory cells

TNF-α: Tumor necrosis factor alpha

Translocation: particle moving from point of entry in a body to remote
region

TWA: time weighted average REFERENCES

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 The third study (Mancuso et al.1979) restricted the cohort to workers
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  Schepers et al. (1957) reported concentrations in γ Be/ft3; however,
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  While a total of 89 tumors were observed or palpated at the time of
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midcoronal sections of both lungs were recorded.

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THIS INFORMATION IS DISTRIBUTED SOLELY FOR THE PURPOSE OF
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REPRESENT AND SHOULD NOT BE CONSTRUED TO REPRESENT ANY AGENCY
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