Document ID: OSHA-H005C-2006-0870-1271
Agency: osha
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-08-07T04:00Z

Occupational Exposure to Beryllium: 

Preliminary OSHA

Health Effects Evaluation

August 3, 2010

HEALTH EFFECTS

Beryllium is a relatively rare naturally occurring metal with an atomic
number of 4.  Beryllium, its compounds and alloys are commercially
valuable metals and gemstones with many industrial uses. 
Beryllium-associated diseases can lead to a number of highly
debilitating and life-altering conditions including pneumonitis, loss of
lung capacity (reduction in pulmonary function leading to pulmonary
dysfunction), loss of physical capacity associated with reduced lung
capacity, systemic effects related to pulmonary dysfunction, and
decreased life expectancy (National Institute for Occupational Safety
and Health (NIOSH), 1972).  OSHA considers CBD to be a progressive
illness with a continuous spectrum of symptoms ranging from no
symptomology at its earliest stage following sensitization to mild
symptoms such as a slight almost imperceptible shortness of breath, to
loss of pulmonary function, debilitating lung disease, and, in some
cases, death.  

This section presents information on beryllium and its compounds, the
fate of beryllium in the body, research that relates to its toxic
mechanisms of action, and the scientific literature on the diseases
associated with beryllium exposure, including acute beryllium disease
(ABD), beryllium sensitization (BeS), chronic beryllium disease (CBD),
and lung cancer.  This section also discusses the nature of these
illnesses, the scientific evidence that they are causally associated
with occupational exposure to beryllium, and the probable mechanism of
action.  In addition, this section reviews the mechanism underlying
these conditions as well as a more thorough review of the supporting
studies.

Beryllium and Beryllium Compounds

Particle physical/chemical properties

Beryllium (Be; CAS No. 7440-41-7) is a steel-grey, brittle metal with an
atomic number of 4 and an atomic weight of 9.01 (Group IIA of the
periodic table).  Beryllium is a relatively rate naturally occurring
element found in earth’s surface rocks at levels of approximately 1-15
mg/kg (World Health Organization (WHO), 1993).  Because of its high
reactivity, beryllium is not found as a free metal in nature; however,
there are approximately 45 mineralized forms of beryllium.  The
important beryllium minerals in the world are beryl (3BeO·Al2O3·6SiO2)
and bertrandite (Be4Si2O7(OH)2).  Beryl has been known since ancient
times as the gemstones: emerald (green), aquamarine (light blue), and
beryl (yellow) (Agency for Toxic Substances and Disease Registry
(ATSDR), 2002).  Beryllium, its compounds and alloys, are commercially
valuable metals and gemstones.  The industrial uses of beryllium are
discussed in the Preliminary Economic Assessment that is not subject to
this peer review 

Beryllium has two oxidative states: Be0 and Be2+ (ATSDR 2002). It is
most likely the Be2+ state that is most biologically reactive and able
to form a bond with peptides leading to it becoming antigenic (Lawrence
and McCabe, 2002).  This will be discussed in more detail in the
Beryllium Sensitization section below.  Beryllium has a high
charge-to-radius ratio and in addition to forming various types of ionic
bonds, beryllium has a strong tendency for covalent bond formation
(e.g., it can form organometallic compounds such as Be(CH3)2 and many
other complexes) (ATSDR), 2002; Greene et al., 1998).  However, it
appears little to no toxicity studies exist for the organometallic
compounds.  

While most beryllium compounds are non-combustible and do not burn they
may decompose upon heating to produce corrosive and/or toxic fumes. Some
beryllium compounds are oxidizers and may ignite combustibles (wood,
paper, oil, clothing, etc). Contact with metals may evolve flammable
hydrogen gas. Additional physical/chemical properties for beryllium
(ICSC 0226), beryllium oxide (ICSC 1325), beryllium sulfate (ICSC 1351),
beryllium nitrate (ICSC 1352), beryllium carbonate (ICSC 1335),
beryllium chloride (ICSC 1354), and beryllium fluoride (ICSC 1355)
obtained from their International Chemical Safety Cards is found in
Table 1 below.

Table 1: Physical/Chemical Properties of Beryllium and Compounds

	Physical Information

Compound Name	Physical Appearance	Chemical Formula	Molecular Mass	Acute
Physical Hazards	Boiling Point	Melting Point	Density	Solubility in Water
at 20°C

Insoluble/Poorly or Sparingly Compounds

Beryllium Metal	Grey to White Powder	Be	9.01	Combustible;

Finely dispersed particles - Explosive	Above 2500°C	1287°C	1.9 g/cm3
none

Beryllium Oxide	White Crystals or Powder	BeO	25.0	Not combustible or
explosive	3900°C	2530°C	3.0 g/cm3	very sparingly soluble

Beryllium Carbonate	White Powder	Be2CO3(OH)

/Be2CO5H2	181.07	Not combustible or explosive	Not reported	Not reported
Not reported	none

(decomposes in hot water)

Soluble Compounds

Beryllium Sulfate	Colorless Crystals	BeSO4	105.1	Not combustible or
explosive	Not reported	550°C	2.44 g/cm3	slightly soluble

Beryllium Nitrate	White to Yellow Solid	BeN2O6/

Be(NO3)2	133.0	Enhances combustion of other substances	100°C	60°C	1.56
g/cm3	very soluble

(1.66 x 106mg/L)

Beryllium Hydroxide	White amorphous powder or crystalline solid	Be(OH)2
43.0	Not reported	Not reported	Decom-poses when heated	1.92 g/cm3
slightly soluble

0.8 x 10-4 mol/L 

(3.44 mg/L)

Beryllium Chloride	Colorless to Yellow Crystals	BeCl2	79.9	Not
combustible or explosive	520°C	399.2°C	1.9 g/cm3	Soluble

Beryllium Fluoride	Colorless Lumps	BeF2	47.0	Not combustible or
explosive	1160°C	555°C	1.99 g/cm3	very soluble

Beryllium Phosphate	White solid	Be3(PO4)2	271.0	Not reported	Not
reported	100°C	2.44

g/cm3	Soluble

Beryllium shows a high affinity for oxygen in air and water, resulting
in a thin surface film of beryllium oxide on the bare metal.  If the
surface film is disturbed, it may become airborne or dermal exposure may
occur.  The solubility, particle surface area, and particle size of some
beryllium compounds are examined in more detail below.  These properties
have been evaluated in many toxicological studies. In particular, the
properties related to the calcination (firing temperatures) and
differences in crystal size and solubility are important aspects in
their toxicological profile. 

Factors affecting potency and effect of beryllium exposure 

The effect and potency of beryllium and its compounds, as for any
toxicant, may be dependent upon the physical state in which it is
presented to a host.  For occupational airborne materials and surface
area contaminants it is especially critical to understand those physical
parameters in order to determine the extent of exposure to the
respiratory tract and skin since these are generally the initial target
organs for this route of exposure.  

For example, large particles may have less of an effect in the lung than
smaller particles due to reduced potential to stay airborne to be
inhaled or be deposited along the respiratory tract.  In addition, once
inhalation occurs particle size is critical in determining where the
particle will deposit along the respiratory tract.  Solubility also has
an important part in determining the toxicity and bioavailability of
airborne materials as well.  Respiratory tract deposition and skin
penetration are directly influenced by the solubility and reactivity of
airborne material.  

These factors may be responsible, at least in part, to the process
leading exposed workers from BeS to CBD.  Other factors influencing
beryllium-induced toxicity include surface area and persistence in the
lung.  For skin, the physical characteristics of the particle are
important as well since those can influence skin absorption and
bioavailability.  This section addresses certain physical
characteristics (i.e., solubility, particle size, particle surface area)
that are important in influencing the toxicity of beryllium materials in
occupational settings.

Solubility

Solubility may be an important determinant of the toxicity of airborne
materials, influencing the deposition and persistence of inhaled
particles in the respiratory tract, their bioavailability, and the
likelihood of presentation to the immune system.  The ability of
airborne materials to penetrate the skin is similarly influenced by
solubility.  Some chemical agents such as certain polymers, rubber
accelerators, epoxy resins, certain solvents, perfumes and other organic
compounds can penetrate the skin to induce a toxic or immune response
such as sensitization (Boeniger, 2003).  Metals, either in the soluble
or insoluble form, can cause a similar response (Mandervelt et al.,
1997).  

This section reviews the relevant information regarding solubility, its
importance in a biological matrix and the relevance to sensitization and
beryllium lung disease.  The weight of evidence presented below suggests
that both soluble and non-soluble forms of beryllium can induce a
sensitization response and result in progression of lung disease.

・4H2O) are all water soluble.  However, soluble beryllium salts can be
converted to less soluble forms in the lung (ATSDR, 1993).  Aqueous
solutions of the soluble beryllium salts are acidic as a result of the
formation of Be(OH2)4 2+, the tetrahydrate, which will react to form
insoluble hydroxides or hydrated complexes within the general
physiological range of pH values (between 5 and 8) (US EPA, 1998).  This
may be an important factor in development of CBD since lower solubility
forms of beryllium have been shown to persist in the lung for longer
periods of time and persistence in the lung may be needed in order for
this disease to occur (NAS, 2008).

Beryllium oxide (BeO), hydroxide (Be(OH)2), carbonate (Be2CO3(OH)2), and
sulfate (anhydrous) (BeSO4) are either insoluble, slightly soluble, or
considered to be sparingly soluble (almost insoluble or extremely slow
rate of dissolution).  The solubility of beryllium oxide, which is
prepared from beryllium hydroxide by calcining (heating to a high
temperature without fusing in order to drive off volatile chemicals) at
temperatures between 500 and 1,750 °C, has an inverse relationship with
calcination temperature.  Although the solubility of the low-fired
crystals can be as much as 10 times that of the high-fired crystals,
low-fired beryllium oxide is still only sparingly soluble (Delic, 1992;
HSE, 1994).  In a study that measured the dissolution kinetics (rate to
dissolve) of beryllium compounds calcined at different temperatures,
Hoover et al. compared beryllium metals to beryllium oxide and found
them to have similar solubilities.  This was attributed to a fine layer
of beryllium oxide that coats the metal particles (Hoover et al., 1989).

Investigators have also attempted to determine how biological fluids can
dissolve beryllium materials.  In one study, insoluble beryllium, taken
up by activated phagocytes, was shown to be ionized by myeloperoxidases
(Leonard and Lauwerys, 1987; Lansdown, 1995).  The positive charge
resulting from ionization enabled the beryllium to bind to receptors on
the surface of cells such as lymphocytes or antigen presenting cells
which could make it more biologically active (NAS, 2008).   In a study
utilizing phagolysosomal-simulating fluid with a pH of 4.5, both
beryllium metal and beryllium oxide dissolved at a greater rate than
that previously reported in water or SUF (simulant fluid) (Stefaniak et
al.,  2006), and the rate of dissolution of the multi-constituent
(mixed) particles was greater than that of the single-constituent
beryllium oxide powder. The authors speculated that copper in the
particles rapidly dissolves, exposing the small inclusions of beryllium
oxide, which have higher specific surface areas (SSA) and therefore
dissolve at a higher rate. 

 on the particle size, with smaller particles (< 10 μm) able to
penetrate beyond the larynx (Stephaniak, 2008).  Most inhalation studies
and occupational exposures involve quite small (< 1-2 μm) beryllium
oxide particles that can penetrate deeply into the lungs (Stephaniak,
2008). In inhalation studies with beryllium ores, particle sizes are
generally much larger, with deposition occurring in several areas
throughout the respiratory tract for particles < 10 μm.  

The temperature at which beryllium oxide is calcined influences its
particle size, surface area, solubility, and ultimately its toxicity
(Delic, 1992).  Low-fired (500° C) beryllium oxide is predominantly
made up of poorly crystallized small particles, while higher firing
temperatures (1000 - 1750° C) result in larger particle sizes (Delic,
1992; HSE, 1994).   

In order to determine the extent to which particle size plays a role in
the toxicity of beryllium in occupational settings several key studies
are reviewed and detailed below.  The findings on particle size have
been related, where possible, to work process and biologically relevant
toxicity endpoints of either BeS or CBD.

μm or less) with 30 percent of that fraction being particles of less
than 0.6 μm.  A study by Thorat et al. (2003) found similar results
with ore mixing, crushing, powder production and machining ranging from
5.0 to 9.5 μm.  Kent et al. (2001) measured airborne beryllium using
size-selective samplers in five furnace areas at a beryllium processing
facility.  This study found a significant association between BeS and
CBD and beryllium concentration of particles less than 3.5 μm and less
than 10 μm in size (collected with a MOUDI (Micro-Orifice Uniform
Deposit Impactor)) but no association with the total mass concentration
of airborne beryllium.  The study authors suggested that the
concentration of alveolar-deposited particles (e.g., <3.5 μm) may be a
better predictor of BeS and CBD than the total mass concentration of
airborne beryllium.

Particle surface area

Surface area has been postulated as an important metric for beryllium
exposure.  Several studies have demonstrated a relationship between the
inflammatory and tumorigenic potential of ultrafine particles and their
increased surface area (Driscoll, 1996; Miller, 1997; Oberdorster et
al., 1994).  While the exact mechanism explaining how particle surface
area influences its biological activity is not known, a greater particle
surface area has been shown to increase inflammation, cytokine
production, anti-oxidant defenses and apoptosis (Elder et at., 2005;
Carter et al., 2006; Refsne et al., 2006).  

Finch et al. (1988) found that beryllium oxide calcined at 500°C had
3.3 times greater specific surface area (SSA) than beryllium oxide
calcined at 1000°C, although there was no difference in size or
structure of the particles as a function of calcining temperature.  The
beryllium-metal aerosol (airborne beryllium particles), although similar
to the beryllium oxide aerosols in aerodynamic size, had an SSA about 30
percent that of the beryllium oxide calcined at 1000°C.  As discussed
above, a later study by Delic (1992) found calcining temperatures also
had an effect on SSA but did not have an effect on particle size.  

Several studies have investigated the lung toxicity of beryllium oxide
calcined at different temperatures and generally had found that those
calcined at lower temperatures have greater toxicity and effect than
materials calcined at higher temperatures.  This may be because
beryllium oxide fired at the lower temperature has a loosely formed
crystalline structure with greater specific surface area than the fused
crystal structure of beryllium oxide fired at the higher temperature. 
For example, beryllium oxide calcined at 500° C has been found to have
stronger pathogenic effects than material calcined at 1,000° C, as
shown in several of the beagle dog, rat, mouse and guinea pig studies
discussed in the section on CBD pathogenesis that follows (Finch et al.,
1984; Polak et al., 1968; Haley et al., 1989; Haley et al., 1992; Hall
et al., 1950).  Finch et al. have also observed higher toxicity of
beryllium oxide calcined at 500° C, an observation they attribute to
the greater surface area of beryllium particles calcined at the lower
temperature (Finch et al., 1988).  These authors found that the in
vitro cytotoxicity to Chinese hamster ovary (CHO) cells and cultured
lung epithelial cells of 500° C beryllium oxide was greater than that
of 1,000° C beryllium oxide, which in turn was greater than that of
beryllium metal. However, when toxicity was expressed in terms of
particle surface area, the cytotoxicity of all three forms was similar.
Similar results were observed in a study comparing the cytotoxicity of
beryllium metal particles of various sizes to cultured rat alveolar
macrophages, although specific surface area did not entirely predict
cytotoxicity (Finch et al., 1991).  

Stefaniak et al. (2003b) investigated the particle structure and surface
area of particles (powder and process-sampled) of beryllium metal,
beryllium oxide, and copper-beryllium alloy.  Each of these samples was
separated by aerodynamic size and their chemical compositions and
structures were determined with x-ray diffraction and transmission
electron microscopy, respectively. In summary, beryllium-metal powder
varied remarkably from beryllium oxide powder and alloy particles. The
metal powder consisted of compact particles while the alloys and oxides
consisted of small primary particles in clusters.  SSA for the metal
powders varied based on production and manufacturing process with
variations of samples as high as a factor of 37.  Stephaniak et al.
(2003b) found lesser variation in SSA for the alloys or oxides.  This is
consistent with data from other studies summarized above showing that
process may affect particle size and surface area.  Particle size and/or
surface area may explain differences in the rate of BeS and CBD observed
in some epidemiological studies.  However, these properties have not
been consistently characterized in most studies.

Kinetics and Metabolism of Beryllium

Beryllium enters the body by inhalation, ingestion, or absorption
through the skin.  For occupational exposure, the airways and the skin
are the primary routes of uptake.  

Exposure via the respiratory system

The respiratory tract, especially the lung, is the primary target of
inhalation exposure in animals and humans.  Inhaled beryllium particles
are deposited along the respiratory tract in a size dependent manner. 
In general, particles less than 0.3 μm and greater than 5 μm in
aerodynamic diameter deposit along the tracheobronchial region. 
Particles ranging greater than 0.3 μm but less than 5 μm tend to
deposit in the pulmonary or alveolar region.  Particles larger than
10μm tend to deposit in the nasal region (Figures 1 and 2).  For
particles below 1 μm, regional deposition changes dramatically. 
Ultrafine particles (generally considered to be 100 nm or lower) have a
high rate of depositing in the nasal passage, where these particles can
encounter immune cells more readily.  While deposition still occurs
along the entire respiratory tract less is deposited in the alveolar
region.  However, those particles that do deposit in the alveolar region
can move into the interstitium of the lung where they may encounter
immunologic cells or may move into the vascular region where they are
free to leave the lung and can contribute to systemic beryllium
concentrations. (ICRP model, 1994 and ACGIH, 2009).

Figure 1: ACGIH model for respiratory tract deposition (2009)

The data represents the fractional deposition of particle size for each
region of the respiratory tract.  These particle sizes are based on the
International Organization 

for Standardization/European Standardization Committee (ISO/CEN).  

 

 Figure 2: ICRP model 

Beryllium is removed from the respiratory tract by various clearance
mechanisms. Soluble beryllium is removed from the respiratory tract via
absorption.  Sparingly or insoluble beryllium may remain in the lungs
for many years after exposure, as has been observed in workers (e.g.,
Schepers, 1962).  Clearance mechanisms for sparingly soluble or
insoluble beryllium particles include: in the nasal passage, sneezing,
mucociliary transport to the throat, or dissolving; in the
tracheobronchial region, mucociliary transport, coughing, phagocytosis,
or dissolving; in the pulmonary or alveolar region it is phagocytosis,
movement through the interstitium (translocation) or dissolving
(Schlesinger, 1999).  

Clearance mechanisms may occur slowly in humans, which is consistent
with some animal studies.  For example, subjects in the Beryllium Case
Registry (BCR) that identifies and track cases of acute and chronic
beryllium diseases had elevated concentrations of beryllium in lung
tissue (e.g. 0.32 pg/g in a metastinal node) more than 20 years after
termination of short-term (generally less than 2 years) occupational
exposure to beryllium (Sprince et al., 1976).  

Clearance rates may depend on the solubility, dose, and size of the
beryllium particles inhaled as well as the sex and species of the animal
tested.  More soluble beryllium compounds generally tend to be cleared
from the respiratory system and absorbed into the bloodstream more
rapidly than less soluble compounds (Van Cleave and Kaylor, 1955; Hart
et al., 1980; Finch et al., 1990).  Animal inhalation or intratracheal
instillation studies administering soluble beryllium salts demonstrated
significant absorption at approximately 20 percent of the initial lung
burden, while, sparingly soluble compounds such as beryllium oxide
demonstrated that absorption was slower and less significant (Delic,
1992; HSE, 1994).  Additional animal studies have demonstrated that
clearance of soluble and sparingly soluble beryllium compounds was
biphasic; a more rapid initial mucociliary transport phase of particles
from the tracheobronchial tree to the gastrointestinal tract, followed
by a slower phase via translocation to tracheobronchial lymph nodes,
alveolar macrophages uptake, and beryllium particles dissolution (Camner
et al., 1977; Sanders et al., 1978; Delic, 1992; HSE, 1994). 
Confirmatory studies in rats have shown the half-time for the rapid
phase was between 1 - 60 days, and the slow phase was ranged from 0.6 -
2.3 years.  It was also shown that this process was influenced by the
solubility of the beryllium compounds; weeks/months for soluble
compounds, months/years, for sparingly soluble compounds. (Reeves and
Vorwald, 1967; Reeves et al., 1967; Zorn et al., 1977; Rhoads and
Sanders, 1985).  Studies in guinea-pigs and rats indicate that 40 - 50
percent of the inhaled soluble beryllium salts are retained in the
respiratory tract.  Similar data could not be found for the sparingly or
less soluble beryllium compounds or metal administered by this exposure
route. (ATSDR, 2002)

Evidence from animal studies suggests that greater amounts of beryllium
deposited in the lung may result in slower clearance times.  A
comparative study of rats and mice using a single-dose of inhaled
aerosolized beryllium metal demonstrated that an acute inhalation
exposure to beryllium metal can slow particle clearance and induce lung
damage in rats (Haley et al., 1990) and mice (Finch et al., 1998a).  In
another study Finch et al. (1994) exposed male F344/N rats to beryllium
metal at concentrations resulting in beryllium lung burdens of 1.8, 10,
and 100 µg.  These exposure levels resulted in an estimated clearance
half-life ranging from 250 and 380 days for the three concentrations. 
For mice (Finch et al., 1998a), lung clearance half-lives were 91–150
days (for 1.7- and 2.6-μg lung burden groups) or 360–400 days (for
12- and 34-μg lung burden groups).  While the lower exposure groups
were quite different for rats and mice, the highest groups were similar
in clearance half-lives for both species. 

Beryllium absorbed from the respiratory system into the bloodstream is
mainly distributed to the tracheobronchial lymph nodes and the skeleton,
which is the ultimate site of beryllium storage (Stokinger et al., 1953;
Clary et al., 1975; Sanders et al., 1975; Finch et al., 1990).  Trace
amounts are distributed throughout the body (Zorn et al., 1977). 
Studies in rats have demonstrated accumulation of beryllium chloride in
the skeletal system following intraperitoneal injection (Crowley et al.,
1949; Scott et al., 1950) and accumulation of beryllium phosphate and
beryllium sulfate in both nonparenchymal and parenchymal cells of the
liver after intravenous administration in rats (Skilleter and Price,
1978).  Studies have also demonstrated intracellular accumulation of
beryllium oxide in bone marrow throughout the skeletal system after
intravenous administration to rabbits (Fodor, 1977).  

Systemic distribution of the more soluble compounds appears to be
greater than that of the insoluble compounds (Stokinger et al., 1953). 
Distribution has also been shown to be dose dependent in research using
intravenous administration of beryllium in rats; small doses were
preferentially taken up in the skeleton, while higher doses were
initially distributed preferentially to the liver.  Beryllium was later
mobilized from the liver and transferred to the skeleton (IARC 1993).  A
half-life of 450 days has been estimated for beryllium in the human
skeleton (ICRP, 1960).  This indicates the skeleton may serve as a
repository of beryllium that may be later reabsorbed by the circulatory
system making beryllium available to the immunological system.

Dermal exposure

The ATSDR estimated that less than 0.1 percent of beryllium compounds
are absorbed through the skin (ATSDR, 2002).  However, even minute
contact and absorption across the skin may directly elicit an
immunological sensitization response (Deubner, 2001).  Recent studies by
Tinkle et al. (2003) showed that penetration of beryllium oxide
particles was possible ex vivo for human intact skin at particle sizes
of ≤ 1μm, as confirmed by scanning electron microscopy.  Using
confocal microscopy, Tinkle et al. demonstrated that surrogate
fluorescent particles up to 1 μm in size could penetrate the mouse
epidermis and dermis layers in model designed to mimic the flexing and
stretching of human skin in motion.  Other poorly soluble particles,
such as titanium dioxide, have been shown to penetrate normal human skin
(Tan et al., 1996) suggesting the flexing and stretching motion as a
plausible mechanism for dermal penetration of beryllium as well. 

Since 1945 it has been known that beryllium can enter the body through
wounded skin (Van Ordstrand, 1945).  Introduction of soluble or
insoluble beryllium compounds into or under the skin as a result of
abrasions or cuts at work have been shown to result in chronic
ulcerations with granuloma formation (Van Orstrand et al., 1945; Lederer
and Savage 1954).  Beryllium absorption through bruises and cuts has
been demonstrated as well (Rossman et al., 1991).  In a study by
Invannikov et al. (1982), beryllium chloride was applied directly to
skin of live animals with three types of wounds: abrasions (superficial
skin trauma), cuts (skin and superficial muscle trauma), and penetration
wounds (deep muscle trauma).  The percentage of the applied dose
absorbed into the systemic circulation during a 24-hour exposure was
significant, ranging from 7.8 percent to 11.4 percent for abrasions,
from 18.3 percent to 22.9 percent for cuts, and from 34 percent to 38.8
percent for penetration wounds.  

A study by Deubner et al. (2001) conclude that exposure across damaged
skin can contribute as much systemic loading of beryllium as inhalation
(Deubner, 2001).  Deubner et al. (2001) estimated dermal loading (amount
of particles penetrating into the skin) in workers as compared to
inhalation exposure.  Deubner's calculations assume dermal loading rate
of beryllium on skin to 0.43 μg/cm2, based on the studies of loading on
skin after workers cleaned up (Sanderson et al., 1999), multiplied by a
factor of 10 to approximate the workplace concentrations and the very
low absorption rate of 0.001 percent (taken from EPA estimates).  It
should be noted these calculations did not take into account absorption
of soluble beryllium salts that might occur across nasal mucus
membranes, which may result from contact between contaminated skin and
the nose.

Oral and gastrointestinal exposure

Gastrointestinal absorption of beryllium can occur by both the
inhalation and oral routes of exposure.  In the case of inhalation, a
portion of the inhaled material is transported to the gastrointestinal
tract by the mucociliary escalator or by the swallowing of the insoluble
material deposited in the upper respiratory tract (Kjellstrom and
Kennedy, 1984).  Animal studies have shown oral administration of
beryllium compounds to result in very limited absorption and storage (as
reviewed by US EPA, 1991).  In animal ingestion studies using
radio-labeled beryllium chloride in rats, mice, dogs, and monkeys, the
vast majority of the ingested dose passed through the gastrointestinal
tract unabsorbed and was excreted in the feces.  In most studies, <1
percent of the administered radioactivity was absorbed into the
bloodstream and subsequently excreted in the urine (Crowley et al.,
1949; Furchner et al., 1973; LeFevre and Joel, 1986).  Research using
soluble beryllium sulfate has shown that as the compound passes into the
intestine, which has a higher pH than the stomach (approximate ph of 6
to 8 for the intestine, pH of 1 or 2 for the stomach), the beryllium is
precipitated as the insoluble phosphate and thus is no longer available
for absorption (Reeves, 1965).

Urinary excretion of beryllium has been shown to correlate with the
amount of occupational exposure (Klemperer et al., 1951).  Beryllium
that is absorbed into the bloodstream is excreted primarily in the urine
(Crowley et al., 1949; Scott et al., 1950; Furchner et al., 1973;
Stiefel et al., 1980), whereas excretion of unabsorbed beryllium is
primarily via the fecal route (Hart et al., 1980; Finch et al., 1990). 
A far higher percentage of the beryllium administered parenterally in
various animal species was eliminated in the urine than in the feces
(Crowley et al., 1949; Scott et al., 1950; Furchner et al., 1973),
confirming that beryllium found in the feces following oral exposure is
primarily unabsorbed material.  A study using percutaneous incorporation
of soluble beryllium nitrate in rats similarly demonstrated that more
than 90 percent of the beryllium in the bloodstream was eliminated via
urine (Zorn et al., 1977).  More than 99 percent of ingested beryllium
chloride was excreted in the feces (Mullen et al., 1972).  Elimination
half-times of 890 - 1,770 days (2.4 - 4.8 years) were calculated for
mice, rats, monkeys, and dogs injected intravenously with beryllium
chloride (Furchner et al., 1973).  Mean daily excretion of beryllium
metal was 4.6 × 10–6 percent of the dose administered by
intratracheal instillation in baboons and 3.1 × 10–6 percent in rats
(Andre et al., 1987).  

Metabolism

Beryllium and its compounds are not metabolized or biotransformed, but
soluble beryllium salts may be converted to less soluble forms in the
lung (Reeves and Vorwald, 1967).  As stated earlier, solubility is an
important factor for persistence of beryllium in the lung.  Insoluble
beryllium, engulfed by activated phagocytes, can be ionized by
myeloperoxidases (Leonard and Lauwerys, 1987; Lansdown, 1995) and this
positive charge could potentially make it more biologically reactive
because it may allow the beryllium to bind to a peptide or protein and
be presented to the T cell receptor or antigen presenting cell
(Fontenot, 2000). 

BERYLLIUM-INDUCED RESPIRATORY DISEASES

This section provides an overview of the respiratory diseases associated
with beryllium exposure and review of the scientific literature on the
immunology and pathogenesis of BeS and CBD, with particular attention to
the role of skin sensitization, particle size, beryllium compound
solubility, and genetic variability in individuals' susceptibility to
BeS and CBD.

Acute Beryllium Disease 

100μg/m3 and may be fatal in 10 percent of cases.  The disease is a
fulminating inflammatory reaction of the entire respiratory tract,
involving the nasal passages, pharynx, bronchial airways and alveoli,
and results in lung swelling, fever, and shortness of breath. Other
tissues including skin and conjunctivae may be affected as well.  The
clinical features of ABD include a nonproductive cough, chest pain,
cyanosis and a sharp drop in the vital functioning and capacity of the
lungs. Clinicians may also look for edematous distension; round cell
infiltration of the septa; proteinaceous materials, and desquamated
alveolar cells in the lung.  Monocytes, lymphocytes and plasma cells
within the alveoli are also characteristic of the acute disease process.
(Freiman and Hardy, 1970)

Two types of acute beryllium disease have been characterized in the
literature: a rapid and severe course of acute fulminating pneumonitis
generally developing within 48 hours of a massive exposure, and a second
form that takes several days to develop from exposure to lower
concentrations of beryllium (still above the levels set by regulatory
and guidance agencies) (Hall, 1950; Newman and Kreiss, 1992).  Severity
of the acute disease has been reported to have a dose-response
relationship to the concentration of beryllium (Stokinger, 1950).
Recovery from either type of ABD is generally complete after a period of
several weeks or months (DeNardi et al., 1953). However, deaths have
been reported in more severe cases (Freiman and Hardy, 1970).  There
also have been documented cases of progression to CBD (ACCP, 1965; Hall,
1950) suggesting an immune component to this disease, which would be
expected (Cummings et al., 2009).  According to the BCR, in the United
States, approximately 17 percent of ABD patients developed CBD (BCR,
2010).  The majority of ABD cases occurred between 1932 and 1970
(Eisenbud, 1983; Middleton, 1998).  ABD is extremely rare in the
workplace today due to more stringent exposure controls implemented
following occupational and environmental standards set in 1972 (AIHA,
1972; ACGIH, 1972; ANSI, 1972) and 1974 (EPA, 1974). 

Chronic Beryllium Disease

Chronic beryllium disease (CBD), formerly known as “berylliosis” or
“chronic berylliosis,” is a granulomatous disorder primarily
affecting the lungs.  CBD was recognized as early as 1951 as a chronic
disease resulting from immune sensitization to beryllium (Sterner and
Eisenbud, 1951; Curtis, 1959; Nishimura, 1966).  CBD shares many
clinical and histopathological features with pulmonary sarcoidosis, a
granulomatous lung disease of unknown cause.  This includes such
debilitating effects as obstructive functioning of the lung,
diminishment of physical capacity associated with reduced lung function,
possible depression associated with decreased physical capacity and the
possibility of decreased life expectancy.  Without appropriate
information, CBD may be difficult to distinguish from sarcoidosis.  It
is estimated that up to 6 percent of all patients diagnosed with
sarcoidosis may actually have CBD (Fireman et al., 2003; Rossman and
Kreider, 2003).  Among patients diagnosed with sarcoidosis in which
beryllium exposure can be confirmed, as many as 40 percent may actually
have CBD (Muller-Quernheim et al., 2006).  

Clinical signs and symptoms of CBD may include, but are not limited to a
simple cough and shortness of breath, fever, weight loss or anorexia,
skin lesions, clubbing of fingers, cyanosis, night sweats, cor pulmonale
(enlargement of the heart’s right ventricle caused by a disorder of
the lungs or of the pulmonary blood vessels), tachycardia, and edema. 
Changes or loss of pulmonary function also occur with CBD such as
decrease in vital capacity, reduced diffusing capacity, restrictive
breathing patterns.  The signs and symptoms of CBD constitute a
continuum of symptoms that are progressive in nature with no clear
demarcation between any stages in the disease (Rossman, 1996; NAS,
2008).

In contrast to ABD, CBD can result from inhalation exposure to beryllium
at levels below the current PEL, can take months to years after initial
beryllium exposure before signs and symptoms of CBD occur (Newman 1996,
2005 and 2007; Henneberger, 2001), and may continue to progress
following removal from beryllium exposure (Newman, 2005; Sawyer et al.,
2005).  Patients with CBD can progress to a chronic obstructive lung
disorder resulting in loss of quality of life and the potential for
decreased life expectancy (Rossman, et al., 1998).  

In contrast to some occupationally related lung diseases, the early
detection of chronic beryllium disease may be useful since treatment of
this condition can lead not only to regression of the signs and
symptoms, but also may prevent further progression of the disease in
certain individuals (Marchand-Adam, 2008; NAS, 2008).  The management of
CBD is based on the hypothesis that suppression of the hypersensitivity
reaction (i.e., granulomatous process) will prevent the development of
fibrosis.  However, once fibrosis has developed, therapy cannot reverse
the damage.  

To date, there have been no controlled studies to determine the optimal
treatment for CBD (Rossman, 1996).  Management of CBD is generally
modeled after sarcoidosis treatment.  Oral corticosteroid treatment can
be initiated in patient with evidence of disease (either by bronchoscopy
or other diagnostic measures before progression of disease or after
clinical signs of pulmonary deterioration occur).  This includes
treatment with oral corticosteroids or other anti-inflammatory agents
(NAS, 2008).  It should be noted however, that treatment with
corticosteroids has side-effects of their own that need to be measured
against the possibility of progression of disease (Gibson et al., 1996;
Zaki et al., 1987).  

Development Beryllium Sensitization (BeS)

Sensitization to beryllium is the essential first step for a worker to
develop CBD.  Sensitization to beryllium can result from inhalation
exposure to beryllium (Newman et al., 2005), and may also result from
skin exposure to beryllium (Newman et al., 1996).  Although there may be
no clinical symptoms associated with BeS, a sensitized worker's immune
function is altered such that exposure to beryllium can now trigger
serious lung disease (Kreiss et al., 1996; Kreiss et al., 1997; Kelleher
et al., 2001, and Rossman, 2001).  Since the pathogenesis of CBD
involves a beryllium-specific, cell-mediated immune response, CBD cannot
occur in the absence of sensitization (NAS 2008).  Inhalation or dermal
exposure to beryllium is one of several factors that determine whether
an individual becomes sensitized to beryllium.  It has been shown that
genetic susceptibility is another factor influencing risk of BeS and
CBD.  Skin exposure to small beryllium particles or beryllium-containing
solutions may also lead to BeS (Tinkle et al., 2003).

Sensitization occurs via the formation of a beryllium-protein complex
(an antigen) that causes an immunological response after repeated
exposure. While only very limited evidence has described humoral changes
in certain patients with CBD (Cianciara et al., 1980), clear evidence
exists for an immune cell mediated response, specifically the T-cell
(NAS, 2008).  Following inhalation or skin absorption for sensitization
to occur beryllium must complex with a protein in the body, denaturing
the protein and thereby uncovering a peptide of the protein that had not
been exposed in its previous configuration and this is known as a
“cryptic peptide.”  Because the immune system has not developed to
recognize these cryptic peptides as "self," a T-cell lymphocyte
complexes with the beryllium antigen, becoming a CD4+ T-cell with a
beryllium-specific binding site that can then identify and respond to
the beryllium antigen.  The CD4+ T-cell proliferates, creating a large
number of beryllium-specific T-cells.  At this point an individual is
immunologically sensitized to beryllium.  In the peripheral blood T
cells need a receptor site known as CD28 because the cells have not
developed a memory response (no T-effector memory cells) (Mack et al.,
2008; Fontenot et al., 2005).  However, after repeated exposures in the
lung, a mature population of T cells develop that do not require
co-stimulation by CD28 and have developed a population of T effector
memory cells (Tem cells) (Fontenot et al., 2005).  This may be one of
the mechanisms that leads to the more severe reactions observed
specifically in the lung (Fontenot et al., 2005).

To extend this observation, CBD is described as an immunologic response
characterized by the formation of an Ag-specific [beryllium acting as a
hapten, binds to peptides forming a major histocompability complex (MHC)
class II molecule (Saltini et al., 1989, 1990)]; CD4+ T cell mediated
immune response to beryllium.  CD4+ T lymphocytes created in the
sensitization process recognize the beryllium antigen, and respond by
proliferating and secreting cytokines and inflammatory mediators,
including IL-2, IFN-γ, and TNF-α (Tinkle et al., 1997a and b; Fontenot
et al., 2002) and MIP-1α and GRO-1 (Hong-Geller 2006).  This also
results in the accumulation of mononuclear cells (mostly CD4+ T cells)
in the bronchoalveolar lavage fluid (BAL fluid) (Saltini et al., 1989,
1990).  The T cells in the bronchoalveolar lavage have been shown to
express markers that are consistent with an effector-memory cell
phenotype (Fontenot et al., 2003).  The T effector-memory cells were
found to recognize beryllium in a CD28-costimulated-independent fashion,
which is unlike the beryllium reactive cells in the periphery that
require CD28 co-stimulation (Fontenot et al., 2003).  This finding is
important because it may show the progression of disease from BeS to CBD
as characterized by an increase in the frequency of beryllium specific
competent CD4+ T cells in the lung.  In other words, the memory T cells
in the lung are more differentiated than those in the periphery in
patients with CBD.  This response has the potential to be used as a
screening technique to indicate progression of disease from BeS to CBD
(see Figure 3).

 

Figure 3: Immune response to beryllium 

Source: Fontenot and Maier 2005. Reprinted with permission; 

copyright 2005, Trends in Immunology. 

Development of CBD

Following sensitization, inhaled beryllium that deposits and persists in
the lung (or that was present in the lung prior to immune sensitization)
can trigger a cell-mediated immune response (hypersensitivity reaction).
 This process is the maturation stage of disease and leads to the
activation and recruitment of Tem cells (T effector memory cells).  As
the beryllium disease progresses in the lung more Tem cells are
developed and proliferate in the lung causing an increase in the cascade
of events which lead to recruiting more inflammatory cells causing
damage to healthy tissue (Saltini et al., 1989, 1990).  This results in
the formation of a mass of immune and inflammatory cells around a
beryllium particle lodged in the interstitium of the lung, known as a
noncaseating granulomatous lesions.  A granulomatous lesion is damaged
tissue caused by an agglomeration of immune cells.  In the case of
beryllium associated granulomas or granulomatous lesions, the beryllium
is presented by mononuclear cells that may fuse together to form
multinucleated giant cells.  This also results in the accumulation of
mononuclear cells (mostly CD4+ T cells) in the BAL fluid (Saltini et
al., 1989, 1990).  

Over time, the granulomas spread and can lead to lung fibrosis and
abnormal pulmonary function, with symptoms including a persistent dry
cough and shortness of breath (Saber and Dweik, 2000).  At this point,
some people may also experience fatigue, night sweats, chest and joint
pain, clubbing of fingers (due to impaired oxygen exchange), loss of
appetite or unexplained weight loss and cor pulmonale as the disease
progresses. (Conradi et al., 1971; ACCP, 1965; Kriebel et al., 1988a and
b). While CBD primarily affects the lungs, it can also involve other
organs such as the liver, skin, spleen, and kidneys. 

Research studies suggest an apoptosis driven mechanism may be a
mechanism that enhances inflammatory cell recruitment, cytokine
production and inflammation, thus creating a scenario for progressive
granulomatous inflammation.  As the immune response in the lung
progresses, apoptosis may also play an important role in the progression
of CBD.  Macrophages and neutrophils can phagocytize beryllium particles
in an attempt to remove the beryllium from the lung.  Multiple studies
(Sawyer et al., 2004; Dettle et al., 2002) using BAL cells (mostly
macrophages and neutrophils) from patients with CBD found that in vitro
stimulation with beryllium sulfate induced the production of TNF-α (one
of many cytokines produced in response to beryllium), and that
production of TNF-α might induce apoptosis in CBD and Sarcoidosis
patients (Bost et al., 1994; Dai et al., 1999).  The stimulation of
CBD-derived macrophages by beryllium sulphate resulted in cells becoming
apoptotic, as measured by propidium iodide.  These results were
confirmed in a mouse macrophage cell-line (p388D1) (Sawyer et al.,
2000). 

imulated by beryllium to produce TNF-α and TNF-α in turns stimulates
the cells to become apoptotic the cells release beryllium back into the
lung.  Thus additional immune cells are recruited to the site where
beryllium has been reintroduced and the loop continues.  

Genetic susceptibility

Evidence from a variety of sources indicates genetic susceptibility may
play an important role in the development of CBD in certain individuals,
especially at levels low enough not to invoke a response in other
individuals (Sterner and Eisenbud, 1951).  Early occupational studies
proposed that CBD was an immune reaction with a genetic component, based
on the high susceptibility of some individuals to become sensitized and
progress to CBD and the lack of CBD in others who were exposed to levels
several orders of magnitude higher (Sterner and Eisenbud, 1951). 
Additional in vitro human research has identified genes coding for
specific protein molecules on the surface of their immune cells that
place carriers at greater risk of becoming sensitized to beryllium and
developing CBD (McCanlies et al., 2004).

One genetic marker that has been linked to CBD susceptibility is the MHC
class II region, which includes the HLA-DR, DQ, and DP genes. Fontenot
et al. (2000) demonstrated that beryllium presentation by certain
alleles of the class II human leukokyte antigen-DP (HLA-DP) to CD4+ T
cells is the mechanism underlying the development of CBD.  Richeldi et
al. (1993) reported a strong association between the MHC class II allele
HLA-DP 1, which has a glutamate at position 69, and the development of
CBD in beryllium-exposed workers from a Tucson, AZ facility.  This
marker was found in 32 of the 33 workers who developed CBD, but in only
14 of 44 similarly exposed workers without CBD.  Additional studies by
Amicosante et al. (2005) using blood lymphocytes derived from
beryllium-exposed workers found a high frequency of this gene in those
sensitized to beryllium.  In a study of 82 CBD patients (beryllium
exposed workers), Stubbs et al. (1996) also found a relationship between
the HLA-DP 1 allele and BeS. The glutamine-69 allele was present in 86
percent of sensitized subjects, but in only 48 percent of
beryllium-exposed, non-sensitized subjects. Stubbs et al. also found a
biased distribution of the MHC class II HLA-DR gene between sensitized
and non-sensitized subjects. Neither of these markers was completely
specific for CBD, as each study found BeS or CBD among individuals
without the genetic risk factor.

In a study using cells from CBD patients Saltini et al. were able to
elucidate the role of the MHC class II region in the development of CBD.
 The investigators found that MHC class II antigens and functional IL-2
receptors are needed in order for the T cells to proliferate in response
to beryllium stimulation (Saltini et al., 1989).  That is, the 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.  This requirement, known as class II
restriction, is typical of the response of CD4+ T cells to soluble
antigens, and not nonspecific mitogens, demonstrating a very specific
response to beryllium.  

There remains uncertainty as to which, if any, of the MHC class II genes
interact directly with the beryllium ion.  Antibody inhibition data
suggest that the HLA-DR gene product may be involved in the presentation
of beryllium to T lymphocytes (Amicosanti et al., 2002).  In addition,
structure-function studies of MHC class II molecules indicate that the
amino acid change that Richeldi et al. (1993) linked to CBD, a glutamate
at position 69 of the HLA-DP 1, may play a critical role in antigen
binding (Richeldi et al., 1993).  The more common allele of the HLA-DP 1
variant is negatively charged at this site and could directly interact
with the beryllium ion.  The high percentage (~30 percent) of
beryllium-exposed workers without CBD who had this allele indicates that
other factors also contribute to the development of CBD.  (EPA, 1998)  

Computational chemistry has been used to identify gene variants to the
HLA-DPB1 shown to code for Glu69 (Weston et al., 2005).  By assigning
odds ratios for specific alleles on the basis of previous studies
discussed above the researchers found a strong correlation (88 percent)
between the reported risk of CBD and the predicted surface electrostatic
potential and charge of the isotypes of the genes.  They were able to
conclude that the alleles associated with the most negatively charged
proteins carry the greatest risk of developing BeS and CBD.  This
confirms the importance of beryllium charge as a key factor in
haptogenic potential.

BeS and CBD in the Workforce

Sensitization to beryllium is currently detected in the workforce with
the beryllium lymphocyte proliferation test (BeLPT), a laboratory blood
test developed in the 1980s, also commonly referred to as the LTT or
BeLT.  In this test, lymphocytes obtained from either BAL fluid or from
peripheral blood are cultured in vitro and exposed to beryllium sulfate
to stimulate lymphocyte proliferation.  The observation of
beryllium-specific proliferation indicates beryllium sensitization. 
This test is described in more detail below.

CBD also can be detected at a subclinical stage by a number of
techniques including bronchoalveolar lavage and biopsy (Cordeiro et al.,
2007; Maier, 2001).  Bronchoalveolar lavage is a method of “washing”
the lungs with fluid inserted via a tube, removing the fluid and
analyzing the content for the inclusion of immune cells indicative of
beryllium exposure, as described earlier in this section.  Fiberoptic
bronchoscopy can be used to detect granulomatous lung inflammation prior
to the onset of CBD symptoms as well, and has been used in combination
with the BeLPT to diagnose pre-symptomatic CBD in a number of recent
screening studies of beryllium-exposed workers, which are discussed in
the following section detailing diagnostic procedures.  Of workers who
were found to be sensitized and underwent clinical evaluation, 36-100
percent of them were diagnosed with CBD (Kreiss et al., 1993; Newman et
al., 1996, 2005, 2007).  It has been estimated from ongoing surveillance
studies of sensitized individuals with an average follow-up time of 4.5
years that 37 percent of beryllium-exposed employees were estimated to
progress to CBD (Newman et al., 2005).  A study of nuclear weapons
facility employees enrolled in an ongoing medical surveillance program
found that only 20 percent of sensitized workers employed less than 5
years eventually were diagnosed with CBD, while 40 percent of sensitized
workers employed10 years or more developed CBD. (Stange et al., 2001)  

	CBD has a clinical spectrum ranging from evidence of BeS and granulomas
in the lung with little symptomology to loss of lung function and end
stage disease which may result in the need for lung transplantation and
decreased life expectancy.  Unfortunately, there are very few published
clinical studies describing the full range and progression of CBD from
the beginning to the end stages and very few of the risk factors for
progression of disease have been delineated (NAS, 2008).  Clinical
management of CBD is modeled after sarcoidosis where oral corticosteroid
treatment is initiated in patients who have evidence of progressive lung
disease, although progressive lung disease has not been well defined
(NAS, 2008).  In advanced cases of CBD corticosteroids is the standard
treatment (NAS, 2008).  No studies have been published measuring the
effect of removal of workers from beryllium exposure on BeS and CBD
(NAS, 2008)

Human Epidemiological Studies	 

This section describes the human epidemiological data supporting the
mechanistic overview of beryllium-induced disease in workers.  It is
divided into reviews of epidemiological studies performed prior to
development and implementation of the BeLPT in the late 1980s and after
wide use of the BeLPT for screening purposes.  Use of the BeLPT has
allowed investigators to screen for BeS and CBD prior to the onset of
clinical symptoms providing a more sensitive and thorough analysis of
the worker population.  The discussion of the studies is further divided
by manufacturing processes that may have similar exposure profiles.  

μg/m3.  Several studies show that the prevalence of BeS and CBD is
related to the level of airborne exposure, including a cross-sectional
survey of employees at a beryllium ceramics plant in Tucson, AZ
(Henneberger et al., 2001), and case-control studies of workers at the
Rocky Flats nuclear weapons facility (Viet et al., 2000) and workers
from a beryllium machining plant in Cullman, AL (Kelleher et al., 2001).
 The prevalence of BeS also may be related to dermal to exposure.  A
study of a comprehensive preventive program at the ceramics plant, which
included expanded respiratory protection, provided dermal protection,
and improved control of beryllium dust migration, substantially reduced
the rate of BeS among new hires (Cummings et al., 2007).   

The epidemiological evidence presented in this section demonstrates that
BeS and CBD are continuing to occur from present-day exposures below
OSHA’s PEL.  The available literature discussed below shows that
disease prevalence can be reduced by reducing inhalation exposure. 
However, epidemiological studies also indicate that it may be necessary
to minimize skin exposure to further reduce the incidence of BeS.  

Studies conducted prior to the BeLPT

First reports of CBD came from studies performed by Hardy and Tabershaw
(1946).  Cases were observed in industrial plants that were refining and
manufacturing beryllium metal and beryllium alloys and in plants
manufacturing fluorescent light bulbs (NAS, 2008).  From the late 1940s
through the 1960s clusters of CBD cases were identified around beryllium
refineries in Ohio and Pennsylvania, and outbreaks in family members of
beryllium factory workers were assumed to be from exposure to
contaminated clothes (Hardy, 1980).  It had been established that the
risk of disease among beryllium workers was variable and generally rose
with the levels of airborne concentrations (Machle et al., 1948).  And
while there was a relationship between air concentrations of beryllium
and risk of developing disease both in and surrounding these plants, the
disease rates outside the plants were higher than expected and not very
different from the rate of CBD within the plants (Eisenbud et al., 1949;
Lieben and Metzner, 1959).  There remained considerable uncertainty
regarding diagnosis due to lack of well-defined cohorts, modern
diagnostic methods, or inadequate follow-up.  In fact, many patients
with CBD may have been misdiagnosed with sarcoidosis (NAS, 2008).  

The difficulties in distinguishing lung disease caused by beryllium from
other lung diseases led to the establishment of the BCR in 1952 to
identify and track cases of ABD and CBD.  A uniform diagnostic criterion
was introduced in 1959 as a way to delineate CBD from sarcoidosis.  The
BCR listed the following criteria for diagnosing CBD: 

(1)	Establishment of significant beryllium exposure based on sound
epidemiologic history;	 

(2)	Objective evidence of lower respiratory tract disease and clinical
course consistent with beryllium disease; 

(3)	Chest X-ray films with radiologic evidence of interstitial
fibronodular disease; 

(4)	Evidence of restrictive or obstructive defect with diminished carbon
monoxide diffusing capacity (DLCO) by physiologic studies of lung
function; 

(5)	Pathologic changes consistent with beryllium disease on examination
of lung tissue; and

(6)	Presence of beryllium in lung tissue or thoracic lymph nodes. 

The criteria for entry in the BCR included either documented past
exposure to beryllium or the presence of beryllium in lung tissue as
well as clinical evidence of beryllium disease (Hardy et al., 1967). 
Cases were entered into the registry if they met at least three of the
criteria above (Hasan and Kazemi, 1974).  Patients were registered and
added to this registry from 1952 through 1983 (Eisenbud and Lisson,
1983).

Studies conducted following the development of the BeLPT

The criteria for diagnosis of CBD have evolved over time as more
advanced diagnostic technology, such as the BeLPT test, has become
available. More recent diagnostic criteria have both higher specificity
than earlier methods and higher sensitivity, identifying subclinical
effects. Recent studies typically use the following criteria (Newman et
al., 1989; Pappas and Newman 1993; Maier, et al., 1999): 

(1)	History of beryllium exposure; 

(2)	Histopathological evidence of noncaseating granulomas or mononuclear
cell infiltrates in the absence of infection; and 

(3)	Positive blood or BAL BeLPT (Newman et al., 1989). The availability
of transbronchial lung biopsy facilitates the evaluation of the second
criterion, by making histopathological confirmation possible in almost
all cases.

A significant component for the identification of CBD is the
demonstration of a confirmed abnormal BeLPT result in a blood or BAL
sample (Newman, 1996).  Since the development of the BeLPT in the 1980s,
it has been used to screen beryllium-exposed workers for sensitization
in a number of studies to be discussed below.  The BeLPT is a
non-invasive in-vitro blood test which measures the beryllium
antigen-specific T-cell mediated immune response and is the most
commonly available diagnostic tool for identifying BeS.  The test
measures the degree to which beryllium stimulates lymphocytes to
prolifereate under a specific set of conditions and is interpreted based
upon the number of stimulation indices that exceed the normal value. 
The ‘cut-off’ is based on the mean value of the peak stimulation
index among controls plus 2 or 3 standard deviations.  This methodology
was modeled into a statistical method known as the “least absolute
values” or “statistical-biological positive” method and relies on
natural log modeling of the median stimulation index values (DOE, 2001;
Frome, 2003).  In most applications, two or more stimulation indices
that exceed the cut-off constitute an abnormal test. 

Early versions of the BeLPT test had high variability, but the use of
tritiated thymidine to identify proliferating cells has led to a more
reliable test (Mroz et al., 1991; Rossman et al., 2001). In recent
years, the peripheral blood test has been found to be as sensitive as
the BAL assay, although larger abnormal responses have been observed
with the BAL assay (Kreiss et al., 1993; Pappas and Newman, 1993). 
False negative results have also been observed with the BAL BeLPT in
cigarette smokers who have marked excess of alveolar macrophages in
lavage fluid (Kreiss et al., 1993).  The BeLPT has also been a useful
tool in animal studies to identify those species with a
beryllium-specific immune response.  

Screenings for BeS have been conducted using the BeLPT in several
occupational surveys and surveillance programs, including nuclear
weapons facilities operated by the Department of Energy (Viet et al.,
2000; Strange et al., 2001; DOE/HSS Report, 2006), a beryllium ceramics
plant in Arizona (Kreiss et al., 1996; Henneberger et al., 2001;
Cummings et al., 2007), a beryllium production plant in Ohio (Kreiss et
al., 1997; Kent et al., 2001), a beryllium machining facility in Alabama
(Kelleher et al., 2001; Madl et al., 2007), a beryllium alloy plant
(Schuler et al., 2005, Thomas et al., 2009 ), and another beryllium
processing plant (Rosenman et al., 2005) in Pennsylvania.  In most of
these studies, individuals with an abnormal BeLPT result were retested
and were identified as sensitized (i.e. BeS positive) if the abnormal
result was repeated. 

Most epidemiological studies have reported rates of BeS and disease
based on a single screening of a working population ('cross-sectional'
or 'population prevalence' rates).  Studies of workers in a beryllium
machining plant and a nuclear weapons facility have included follow-up
of the population originally screened, resulting in the detection of
additional cases of beryllium BeS over several years (Newman et al.,
2001, Stange et al., 2001).  

Beryllium Mining and Extraction

Mining and extraction of beryllium usually involves the two major
beryllium minerals beryl (an aluminosilicate containing up to 4 percent
beryllium) and bertrandite (a beryllium silicate hydrate containing
generally less than 1 percent beryllium) (WHO, 2001).  The United States
is the world leader in beryllium extraction and also leads the world in
production and use of beryllium and its alloys (WHO, 2001).  Most
exposures from mining and extraction come in the form of beryllium ore,
beryllium salts, or beryllium hydroxide (NAS 2008).

Deubner et al. published a study of 75 workers employed at a beryllium
mining and extraction facility in Delta, UT (Deubner et al., 2001b).  Of
the 75 workers screened with the BeLPT, three were identified as
sensitized as confirmed by having an abnormal BeLPT.  One of those found
to be sensitized was diagnosed with CBD.  Exposures at the facility
included primarily beryllium ore and salts; workers were not exposed to
beryllium oxide.  General area (GA), breathing zone (BZ), and personal
lapel (LP) exposure samples were collected from 1970 to 1999.  Jobs
involving beryllium hydrolysis and wet-grinding activities had the
highest air concentrations, with an annual median GA concentration
ranging from 0.1 to 0.4 μg/m3.  Median BZ concentrations were higher
than either LP or GA    The average duration of exposure for beryllium
sensitized workers was 21.3 years (27.7 years for the worker with CBD),
compared to an average duration for all workers of 14.9 years.  However,
these exposures were less than either the Elmore, OH, or Tucson, AZ,
facilities described below, which also had higher reported rates of BeS
and CBD.  

There was no BeS or CBD among those who worked only at the mine where
exposure to beryllium resulted solely from working with bertrandite ore.
 The authors concluded that the results of this study indicated that
beryllium ore and salts may pose less of a hazard than beryllium metal
and beryllium hydroxide. These results are consistent with the
previously discussed animal studies examining solubility and particle
size.  

Beryllium Metal Processing and Alloy Production 

Kreiss et al. (1997) conducted a study of workers at a beryllium
production facility in Elmore, OH.  The plant, which opened in 1953 and
initially specialized in production of beryllium-copper alloy, later
expanded its operations to include beryllium metal, beryllium oxide, and
beryllium-aluminum alloy production; beryllium and beryllium alloy
machining; and beryllium ceramics production, which was moved to a
different factory in the early 1980s. Production operations included a
wide variety of jobs and processes, such as work in arc furnaces and
furnace rebuilding, alloy melting and casting, beryllium powder
processing, and work in the pebble plant.  Non-production work included
jobs in the analytical laboratory, engineering research and development,
maintenance, laundry, production-area management, and office-area
administration. While the publication refers to the use of respiratory
protection in some areas, such as the pebble plant, the extent of its
use across all jobs or time periods was not reported.  Use of dermal PPE
was not reported.

μg/m3.  Particularly high beryllium concentrations were reported in
beryllium powder production and laundry areas, alloy arc furnace
(approximately 40 percent of DWA estimates over 2.0 μg/m3) and furnace
rebuild (28.6 percent of short-term BZ samples over the OSHA STEL of 5
μg/m3). LP samples (n = 179), which were available from 1990 to 1992,
had a median value of 1 μg/m3.

Of 655 workers employed at the time of the study, 627 underwent BeLPT
screening. Blood samples were divided and split between two labs for
analysis, with repeat testing for results that were abnormal or
indeterminate. Thirty-one workers had an abnormal blood test upon
initial testing and at least one of two subsequent tests was classified
as sensitized. These workers, together with 19 workers who had an
initial abnormal result and one subsequent indeterminate result, were
offered clinical evaluation for CBD including the BAL-BeLPT and
transbronchial lung biopsy.  Nine with an initial abnormal test followed
by two subsequent normal tests were not clinically evaluated, although
four were found to be sensitized upon retesting in 1995. Of 47 workers
who proceeded with evaluation for CBD (3 declined to participate), 24
were diagnosed with CBD based on evidence of granulomas on lung biopsy
(20) or on other findings consistent with CBD (4) (Kreiss et al. p.
607). After including five workers who had been diagnosed prior to the
study, a total of 29 (4.6 percent) current workers were found to have
CBD.  In addition, the plant medical department identified 24 former
workers diagnosed with CBD before the study.

Kreiss et al. reported that the highest prevalence of BeS and CBD
occurred among workers employed in beryllium metal production, even
though the highest airborne total mass concentrations of beryllium were
generally among employees operating the beryllium alloy furnaces in a
different area of the plant (Kreiss et al., 1997).  Preliminary
follow-up investigations of particle size-specific sampling at five
furnace sites within the plant determined that the highest respirable
(e.g., particles <10 μm in diameter) and alveolar-deposited (e.g.
particles <1 μm in diameter) beryllium mass and particle number
concentrations, as collected by a general area impactor device, were
measured at the beryllium metal production furnaces rather than the
beryllium alloy furnaces (Kent et al., 2001; McCawley et al., 2001).  A
statistically significant linear trend was reported between the above
alveolar deposited particle mass concentration and prevalence of CBD and
BeS in the furnace production areas.  The authors concluded that
alveolar deposited particles may be a more relevant exposure metric for
predicting the incidence of CBD or BeS than the total mass concentration
of airborne beryllium.

Rosenman et al. (2005) studied a group of several hundred workers who
had been employed at a beryllium production and processing facility that
operated in eastern Pennsylvania between 1957 and 1978.  Of 715 former
workers located, 577 were screened for BeS with the BLPT and 544
underwent chest radiography to identify cases of beryllium BeS and CBD.
Workers were reported to have exposure to beryllium dust and fume in a
variety of chemical forms including beryl ore, beryllium metal,
beryllium fluoride, beryllium hydroxide, and beryllium oxide.

epresentative task-based IH samples ranged from 0.9 μg/m3 to 84 μg/m3
in the 1960s, falling to a range of 0.5 - 16.7 μg/m3 in the 1970s.  An
overwhelming number of workers’ mean DWA estimates (91 percent) were
above the OSHA PEL of 2.0 μg/m3, although a few workers had mean DWA
exposures between 0.2 and 2.0 μg/m3 (6 percent) or below 0.02 μg/m3 (3
percent) (Rosenman et al., Table 11).  

Blood samples for the BeLPT were collected between 1996 and 2001 and
were evaluated at a single laboratory.  Individuals with an abnormal
test result were offered repeat testing, and were classified as
sensitized if the second test was also abnormal.  Sixty workers with
two positive BeLPTs and 50 additional workers with chest radiography
suggestive of disease were offered clinical evaluation, including
bronchoscopy with bronchial biopsy and BAL-BeLPT.  Seven workers met
both criteria.  Only 56 (51 percent) of these workers proceeded with
clinical evaluation, including 57 percent of those referred on the basis
of confirmed abnormal BeLPT and 47 percent of those with abnormal
radiographs.  

Of those workers who underwent bronchoscopy, 32 (5.5 percent) with
evidence of granulomas were classified as “definite” CBD cases. 
Twelve (2.1 percent) additional workers with positive BAL-BLPT or
confirmed positive BeLPT and radiographical evidence of upper lobe
fibrosis were classified as “probable” CBD cases.  Forty workers
(6.9 percent) without upper lobe fibrosis who had confirmed abnormal
BeLPT but who were not biopsied or who underwent biopsy with no evidence
of granuloma, were classified as sensitized without disease.  It is not
clear how many of the 40 workers underwent biopsy.  Another 12 (2.1
percent) workers with upper lobe fibrosis and negative or unconfirmed
positive BeLPT were classified as “possible” CBD cases.  Nine
additional workers who were diagnosed with CBD before the screening were
included in some parts of the authors’ analysis.  

μg/m3.  Of those, 35 (8 percent) had definite or probable CBD and
another 33 (8 percent) were classified as sensitized without disease. 
The true prevalence of BeS and CBD in the group may be higher than
reported, due to the low rate of clinical evaluation among sensitized
workers.

Although most of the workers in this study had high exposures, BeS and
CBD also were observed within the small subgroup of participants
believed to have relatively low beryllium exposures.  Five cases of CBD
and four additional cases of BeS occurred among 38 workers with mean DWA
exposures below OSHA’s PEL of 2.0 µg/m3, including one case of CBD
and two sensitized-only workers with mean DWAs below 0.02 µg/m3
(Rosenman et al., Table 11).  Fifteen cases of BeS and CBD were found
among office and clerical workers, who were believed to have low
exposures (levels not reported).

Workers in this study who became sensitized during their employment had
a minimum of 20 years to develop CBD prior to screening.  In this sense
the cohort is especially well suited to compare the exposure patterns of
workers with CBD and those sensitized without disease, in contrast to
several other studies of workers with only recent beryllium exposures. 
Rosenman et al. characterized and compared the exposures of workers with
definite and probable CBD,  BeS only, and no disease or BeS using
chi-squared tests for discrete outcomes and analysis of variance (ANOVA)
for continuous variables (cumulative, mean, and peak exposure levels). 
Exposure-response relationships were further examined with logistic
regression analysis, adjusting for potential confounders including
smoking, age, and beryllium exposure from outside of the plant.  The
authors found that cumulative, peak, and duration of exposure were
significantly higher for workers with CBD than for sensitized workers
without disease (p < 0.05), suggesting that the risk of progressing from
BeS to CBD is related to the level or extent of exposure a worker
experiences.  The risk of developing CBD following BeS appeared strongly
related to exposure to insoluble forms of beryllium, which are cleared
slowly from the lung and increase beryllium lung burden more rapidly
than quickly mobilized soluble forms.  Individuals with CBD had higher
exposures to insoluble beryllium than those classified as sensitized
without disease, while exposure to soluble beryllium was higher among
sensitized individuals than those with CBD.  

Cumulative, mean, peak, and duration of exposure were found to be
comparable for workers with CBD and workers without BeS or CBD
(“normal” workers).  Cumulative, peak, and duration of exposure were
significantly lower for sensitized workers without disease than for
normal workers.  Rosenman et al. suggested that genetic predisposition
to BeS and CBD may have obscured an exposure-response relationship in
this study, and plan to control for genetic risk factors in future
studies.  Exposure misclassification from the 1950s and 1960s may have
been another limitation in this study, introducing bias that could have
influenced the lack of exposure response.  It is also unknown if the 25
percent who died from CBD-related conditions may have had higher
exposures.  

Beryllium Machining Operations

Newman et al. (2001) and Kelleher et al. (2001) studied a group of 235
workers at a beryllium metal machining plant.  Since the plant opened in
1969, its primary operations have been machining and polishing beryllium
metal and high-beryllium content composite materials, with occasional
machining of beryllium oxide/metal matrix ('E-metal'), and beryllium
alloys. Other functions include machining of metals other than
beryllium; receipt and inspection of materials; acid etching; final
inspection, quality control, and shipping of finished materials; tool
making; and engineering, maintenance, administrative and supervisory
functions (Newman et al., 2001; Madl et al., 2007). Machining
operations, including milling, grinding, lapping, deburring, lathing,
and electrical discharge machining (EDM), were performed in an
open-floor plan production area. Most non-machining jobs were located in
a separate, adjacent area; however, non-production employees had access
to the machining area.  

Engineering and administrative measures, rather than PPE, were primarily
used to control beryllium exposures at the plant (Madl, 2007).  Based on
interviews with long-standing employees of the plant, Kelleher et al.
reported that work practices were relatively stable until 1994, when a
worker was diagnosed with CBD and a new exposure control program was
initiated.  Between 1995 and 1999 new engineering and work practice
controls were implemented, including removal of pressurized air hoses
and discouragement of dry sweeping (1995), enclosure of deburring
processes (1996), mandatory uniforms (1997), and installation or
updating of local exhaust ventilation (LEV) in EDM, lapping, deburring,
and grinding processes (1998) (Madl et al., 2007).  Throughout the
plant’s history respiratory protection was used mainly for
“unusually large, anticipated exposures” to beryllium (Kelleher et
al., 2001), and was not routinely used otherwise (Newman et al., 2001). 
 

All workers at the plant participated in a beryllium disease
surveillance program initiated in 1994, and were screened for BeS with
the BeLPT beginning in 1995.  A BeLPT result was considered abnormal if
two or more of six stimulation indices exceeded the normal range (see
section on BeLPT testing above), and was considered borderline if one of
the indices exceeded the normal range. A repeat BeLPT was conducted for
workers with abnormal or borderline initial results.  Workers were
identified as beryllium sensitized and referred for a clinical
evaluation, including bronchoalveolar lavage (BAL) and transbronchial
lung biopsy, if the repeat test was abnormal.  CBD was diagnosed upon
evidence of BeS with granulomas or mononuclear cell infiltrates in the
lung tissue (Newman et al., 2001).  Following the initial plant-wide
screening, plant employees were offered BeLPT testing at 2-year
intervals.  Workers hired after the initial screening were offered a
BeLPT within 3 months of their hire date, and at 2-year intervals
thereafter (Madl et al., 2007) 

f beryllium particles less than 6 μm, particles, less than 1 μm in
diameter, and total mass.  The great majority of workers’ exposures
were below the OSHA PEL of 2 μg/m3.  However, a few higher levels were
observed in machining jobs including deburring, lathe, lapping, and
grinding.  Based on a statistical comparison between their samples and
historical data provided by the plant, the authors concluded that worker
beryllium exposures across all time periods could be approximated using
the 1996-1999 data.  They estimated workers’ cumulative and
‘lifetime weighted’ (LTW) beryllium exposure based on the exposure
samples they collected for each job in 1996-1999 and company records of
each worker’s job history.  

The case group for the case-control analysis was composed of 20 workers
who were found to be sensitized during the surveillance conducted by
Newman et al.  Thirteen of these workers were diagnosed with CBD based
on lung biopsy evidence of granulomas and/or mononuclear cell
infiltrates (11) or positive BAL results with evidence of lymphocytosis
(2).  Seven were evaluated for CBD and found to be sensitized only;
three declined evaluation.  Nine of the remaining 215 workers were
excluded due to incomplete job history information, leaving 206 workers
in the control group.  

level and other variables. Median cumulative exposures for total mass,
particles < 6 μm, and particles < 1 μm were approximately three times
higher among the cases than controls, although the relationships
observed were not statistically significant (p values ~ 0.2).  No clear
difference between cases and controls was observed for the median LTW
exposures. Odds ratios with BeS and CBD as outcomes were elevated in
high (upper third) and intermediate exposure groups relative to low
(lowest third) exposure groups for both cumulative and LTW exposure,
though the results were not statistically significant (p > 0.1). In the
logistic regression analysis, only machinist work history was a
significant predictor of case status in the final model.  Quantitative
exposure measures were not significant predictors of BeS or disease
risk.

EL of 2 μg/m3, and no cases of BeS or CBD were observed among workers
with LTW exposure < 0.02 μg/m3. Twelve (60 percent) of the 20
sensitized workers had LTW exposures > 0.20 μg/m3.

In 2007, Madl et al. published an additional study of 27 workers at the
machining plant who were found to be sensitized or diagnosed with CBD
between the start of medical surveillance in 1995 and 2005.  As
previously described, workers were offered a BeLPT in the initial 1995
screening (or within 3 months of their hire date if hired after 1995)
and at 2-year intervals after their first screening.  Workers with two
positive BeLPTs were identified as sensitized and offered clinical
evaluation for CBD, including bronchoscopy with BAL and transbronchial
lung biopsy.  The criteria for CBD in this study were somewhat stricter
than those used in the Newman et al. study, requiring evidence of
granulomas on lung biopsy or detection of X-ray or pulmonary function
changes associated with CBD, in combination with two positive BeLPTs or
one positive BAL-BeLPT.  

Based on the history of the plant’s control efforts and their analysis
of historical IH data, Madl et al. identified three “exposure control
eras”: a relatively uncontrolled period from 1980-1995; a transitional
period from 1996 to 1999; and a relatively well-controlled “modern”
period from 2000-2005.  They found that the engineering and work
practice controls instituted in the mid-1990s reduced workers' exposures
substantially, with nearly a 15-fold difference in reported exposure
levels between the pre-control and the modern period (Madl et al.,
2007).  Madl et al. estimated workers’ exposures using LP samples
collected between 1980 and 2005, including those collected by Kelleher
et al., and work histories provided by the plant.  As described more
fully in the study, they used a variety of approaches to describe
individual workers’ exposures, including approaches designed to
characterize the highest exposures workers were likely to have
experienced.  Their exposure-response analysis was based primarily on an
exposure metric they derived by identifying the year and job of each
worker’s pre-diagnosis work history with the highest reported
exposures.  They used the upper 95th percentile of the LP samples
collected in that job and year (in some cases supplemented with data
from other years) to characterize the worker's upper-level exposures.  

μg/m3 as an 8-hour TWA at some point in their history of employment in
the plant.  They also concluded that most BeS and CBD cases were likely
to have been exposed to levels greater than 0.4 μg/m3 at some point in
their work at the plant.  Madl et al. did not reconstruct exposures for
workers at the plant who did not have BeS or CBD, and therefore, could
not determine whether non-cases had upper-bound exposures lower than
these levels. They found that upper-bound exposure estimates were
generally higher for workers with CBD than for those who were
sensitized, but not diagnosed with CBD at the conclusion of the study
(Madl et al., 2007 p. 464).  Because CBD is an immunological disease and
BeS has been shown to occur within a year of exposure for some workers,
Madl et al. argued that their estimates of workers' short-term
upper-bound exposures may better capture the exposure levels that led to
BeS and disease than estimates of long-term cumulative or average
exposures such as the LTW exposure measure constructed by Kelleher et
al. (Madl et al., 2007). 

Beryllium Oxide Ceramics

Kreiss et al. (1993) conducted a screening of current and former workers
at a plant that manufactured beryllium ceramics from beryllium oxide
between 1958 and 1975, and then transitioned to metalizing circuitry
onto beryllium ceramics produced elsewhere.  Of the plant's 1,316
current and 350 retired workers, 505 participated who were not
previously diagnosed with CBD or sarcoidosis, including 377 current and
128 former workers.  Although beryllium exposure was not estimated
quantitatively in this survey, the authors conducted a questionnaire to
assess study participants' exposures qualitatively. Results showed that
55 percent of participants reported working in jobs with exposure to
beryllium dust. Close to 25 percent of participants did not know if they
had exposure to beryllium, and just over 20 percent believed they had
not been exposed.  

BeLPT tests were administered to all 505 participants in the 1989-1990
screening period and evaluated at a single lab.  Seven workers had
confirmed abnormal BeLPT results and were identified as sensitized.  All
of them also were diagnosed with CBD based on findings of granulomas
upon clinical evaluation.  Radiograph screening led to clinical
evaluation and diagnosis of two additional CBD cases, who were among
three participants with initially abnormal BeLPT results that could not
be confirmed on repeat testing.  In addition, nine workers had been
previously diagnosed with CBD, and another five were diagnosed shortly
after the screening period, in 1991-1992.

Eight (3.7 percent) of the nine CBD cases identified in the screening
population were hired before the plant stopped producing beryllium
ceramics in 1975, and were among the 216 participants who had reported
having been near or exposed to beryllium dust.  Particularly high CBD
rates of 11.1 - 15.8 percent were found among screening participants who
had worked in process development/engineering, dry pressing, and
ventilation maintenance jobs believed to have high or uncontrolled dust
exposure.  One case (0.6 percent) of CBD was diagnosed among the 171
study participants who had been hired after the plant stopped producing
beryllium ceramics.  Although this worker was hired eight years after
the end of ceramics production, he had worked in an area later found to
be contaminated with beryllium dust.  The authors concluded that the
study results suggested an exposure-response relationship between
beryllium exposure and CBD, and recommended beryllium exposure control
to reduce workers’ risk of CBD.

μg/m3, while LP and short-term BZ samples had medians of 0.3 µg/m3
respectively.  However, 3.6 percent of short-term BZ samples and 0.7
percent of GA samples exceeded 5.0 µg/mg, while LP samples ranged from
0.1 to 1.8 µg/m3.  Machining jobs had the highest beryllium exposure
levels among job tasks, with short-term BZ samples significantly higher
for machining jobs than for non-machining jobs (median 0.6 µg/m3 vs.
0.3 μg/mg, p = 0.0001).  The authors used DWA formulas provided by the
plant to estimate workers’ full-shift exposure levels, and to
calculate cumulative and average beryllium exposures for each worker in
the study.  The median cumulative exposure was 591.7 mg-days/m3 and the
median average exposure was 0.35 µg/m3.

One hundred thirty-six of the 139 workers employed at the plant at the
time of the Kreiss (1996) study underwent BeLPT screening and chest
radiographs in 1992.  Blood samples were split between two laboratories.
 If one or both test results were abnormal, an additional sample was
collected and split between the labs.  Seven workers with an abnormal
result on two draws were initially identified as sensitized.  Those with
confirmed abnormal BeLPTs or abnormal chest X-rays were offered clinical
evaluation for CBD, including transbronchial lung biopsy and BAL BeLPT. 
CBD was diagnosed based on observation of granulomas on lung biopsy, in
five of the six sensitized workers who accepted evaluation.  An eighth
case of BeS and sixth case of CBD were diagnosed in one worker hired in
October 1991 whose initial BeLPT was normal, but who was confirmed as
sensitized and found to have lung granulomas less than two years later,
after sustaining a beryllium-contaminated skin wound.  The plant medical
department reported 11 additional cases of CBD among former workers
(Kreiss et al., 1996).  The overall prevalence of BeS in the plant was
5.9 percent, with a 4.4 percent prevalence of CBD.  

Kreiss et al. reported that six (75 percent) of the eight sensitized
workers  were exposed as machinists during or before the period October
1985 – March 1988, when measurements were first available for
machining jobs.  The authors reported that 14.3 percent of machinists
were sensitized, compared to 1.2 percent of workers who had never been
machinists (p < 0.01).  Workers’ estimated cumulative and average
beryllium exposures did not differ significantly for machinists and
non-machinists, or for cases and non-cases.  As in the previous ceramics
plant study published by Kreiss et al. in 1993, one case of CBD was
diagnosed in a worker who had never been employed in a production job. 
This worker was employed in administration, a job with a median DWA of
0.1 μg/m3 (range 0.1 - 0.3).  

In 1998, Henneberger et al. conducted a follow-up cross-sectional survey
of 151 employees employed at the beryllium ceramics plant studied by
Kreiss et al. (1996) (Henneberger et al., 2001).  Employees were
eligible who either had not participated in the Kreiss et al. survey
(“short-term workers” - 74 of those studied by Henneberger), or who
had participated and were not found to have BeS or disease (“long-term
workers” -77 of those studied by Henneberger).

The authors estimated workers' cumulative, average, and peak beryllium
exposures based on the plant's formulas for estimating job-specific DWA
exposures, participants' work histories, and area and short-term
task-specific BZ samples collected from the start of full production at
the plant in 1981 to 1998.  The long-term workers, who were hired before
the 1992 study was conducted, had generally higher estimated exposures
(median of average exposures - 0.39 µg/m3; mean - 14.9 µg/m3) than the
short-term workers, who were hired after 1992 (median 0.28 µg/m3, mean
6.1 µg/m3).  

Fifteen cases of BeS were found, including eight among short-term and
seven among long-term workers.  Eight of the 15 workers were found to
have CBD. Of the workers diagnosed with CBD, seven (88 percent) were
long-term workers. One long-term worker and one sensitized long-term
worker declined clinical examination.  

Henneberger et al. reported a higher prevalence of BeS among long-term
workers with “high” (greater than median) peak exposures compared to
long-term workers with “low” exposures; however, this relationship
was not statistically significant.  No association was observed for
average or cumulative exposures.  The authors reported higher prevalence
of BeS (but not statistically significant) among short-term workers with
“high” (greater than median) average, cumulative, and peak exposures
compared to short-term workers with “low” exposures of each type.  

	Following the 1998 survey, the company continued efforts to reduce
exposures and risk of sensitization and CBD by implementing additional
engineering, administrative, and PPE measures (Cummings et al. 2007). 
Respirator use was required in production areas beginning in 1999, and
latex gloves were required beginning in 2000.  The lapping area was
enclosed in 2000, and enclosures were installed for all mechanical
presses in 2001.  Between 2000 and 2003, water-resistant or water-proof
garments, shoe covers, and taped gloves were incorporated to keep
beryllium-containing fluids from wet machining processes off the skin. 
The new engineering measures did not appear to substantially reduce
airborne beryllium levels in the plant.  LP samples collected between
2000 and 2003 had a median of 0.18 µg/m3, similar to the 1994-1999
samples.  However, respiratory protection requirements to control
workers’ airborne beryllium exposures were instituted prior to the
2000 sample collections.

To test the efficacy of the new measures instituted after 1998, in
January 2000 the company began screening new workers for sensitization
at the time of hire and at 3, 6, 12, 24, and 48 months of employment.
These more stringent measures appear to have substantially reduced the
risk of sensitization among new employees.  Of 126 workers hired
between 2000 and 2004, 93 completed BeLPT testing at hire and at least
one additional test at 3 months of employment.  One case of
sensitization was identified at 24 months of employment (1 percent). 
This worker had experienced a rash after an incident of dermal exposure
to lapping fluid through a gap between his glove and uniform sleeve,
indicating that he may have become sensitized via the skin.  He was
tested again at 48 months of employment, with an abnormal result.   

A second worker in the 2000-2004 group had two abnormal BeLPT tests at
the time of hire, and a third had one abnormal test at hire and a second
abnormal test at 3 months. Both had normal BeLPTs at 6 months, and were
not tested thereafter.  A fourth worker had one abnormal BeLPT result at
the time of hire, a normal result at 3 months, an abnormal result at 6
months, and a normal result at 12 months.  Four additional workers had
one abnormal result during surveillance, which could not be confirmed
upon repeat testing.   

Cummings et al. calculated two sensitization rates based on these
screening results: (1) a rate using only the sensitized worker
identified at 24 months, and (2) a rate including all four workers who
had repeated abnormal results.  They reported a sensitization incidence
rate (IR) of 0.7 per 1,000 person-months to 2.7 per 1,000 person-months
for the workers hired between 2000 and 2004, using the sum of
sensitization-free months of employment among all 93 workers as the
denominator.

The authors also esimated an IR of 5.6 per 1,000 person-months for
workers hired between 1993 and the 1998 survey.  This estimated IR was
based on one BeLPT screening, rather than BeLPTs conducted throughout
the workers’ employment, the denominator in this case was the total
months of employment until the 1998 screening.  Because sensitized
workers may have been sensitized prior to the screening, the denominator
may overestimate sensitization-free time in the legacy group, and the
actual sensitization IR for legacy workers may be somewhat higher than
5.6 per 1,000 person-months.  Based on comparison of the IRs, the
authors concluded that the addition of respirator use, dermal
protection, and housekeeping improvements appeared to have reduced the
risk of sensitization among workers at the plant, even though airborne
beryllium levels in some areas of the plant had not changed
significantly since the 1998 survey.

Copper-Beryllium Alloy Processing and Distribution

Schuler et al. (2005) studied a group of 152 workers at a facility
processing copper-beryllium alloys and small quantities of
nickel-beryllium alloys, and converting semi-finished alloy strip and
wire into finished strip, wire and rod.  Production activities included
annealing, drawing, straightening, point and chamfer, rod and wire
packing, die grinding, pickling, slitting, degreasing.  Periodically in
the plant’s history, they also did salt baths, cadmium plating,
welding and deburring.  Since the late 1980s, rod and wire production
processes were physically segregated from strip metal production. 
Production support jobs included mechanical maintenance, quality
assurance, shipping and receiving, inspection, and wastewater treatment.
 Administration was divided into staff primarily working within the
plant and personnel who mostly worked in office areas (Schuler, et. al.,
2005).  Workers’ respirator use was limited, mostly to occasional
tasks where high exposures were anticipated.

Following the 1999 diagnosis of a worker with CBD, the company surveyed
the workforce, offering all current employees BeLPT testing in 2000 and
offering sensitized workers clinical evaluation for CBD, including BAL
and transbronchial biopsy.  Of the facility’s 185 employees, 152
participated in the BeLPT screening. Samples were split between two
laboratories, with additional draws and testing for confirmation if
conflicting tests resulted in the initial draw.  Ten participants (7
percent) had at least two abnormal BeLPT results. The results of nine
workers who had abnormal BeLPT results from only one laboratory were not
included because the authors believed it was experiencing technical
problems with the test (Schuler et al., 2005).  CBD was diagnosed in six
workers (4 percent) on evidence of pathogenic abnormalities (e.g.,
granulomas) or evidence of clinical abnormalities consistent with CBD
based on pulmonary function testing, pulmonary exercise testing, and/or
chest radiography.  One worker diagnosed with CBD had been exposed to
beryllium during previous work at another copper-beryllium processing
facility.

measurements were below the current OSHA PEL of 2.0 μg/m3 (8-hr TWA);
93 percent were below the DOE action level of 0.2 μg/m3; and the median
value was 0.02 µg/m3.  The SD-HV BZ samples had a median value of 0.44
μg/m3, with 90 percent below the OSHA Short-Term Exposure Limit (STEL)
of 5.0 μg/m3.  The highest levels of beryllium were found in rod and
wire production, particularly in wire annealing and pickling, the only
production job with a median personal sample measurement greater than
0.1 µg/m3 (median 0.12 µg/m3; range 0.01 - 7.8 μg/m3) (Schuler et
al., Table 4).  These concentrations were significantly higher than the
exposure levels in the strip metal area (median 0.02, range 0.01 - 0.72
μg/m3), in production support jobs (median 0.02, range < 0.01 - 0.33
μg/m3), plant administration (median 0.02, range < 0.01 - 0.11 μg/m3),
and office administration jobs (median 0.01, range < 0.01 - 0.06
μg/m3).  

The authors reported that eight of the ten sensitized employees,
including all six CBD cases, had worked in both major production areas
during their tenure with the plant.  The 7 percent prevalence (6 of 81
workers) of CBD among employees who had ever worked in rod and wire was
statistically significantly elevated compared with employees who had
never worked in rod and wire (p < 0.05), while the 6 percent prevalence
(6 of 94 workers) among those who had worked in strip metal was not
significantly elevated compared to non-strip metal workers (p > 0.1). 
Based on these results, together with the higher exposure levels
reported for the rod and wire production area, Schuler et al. concluded
that work in rod and wire was a key risk factor for CBD in this
population.  Schuler et al. also found a high prevalence (13 percent) of
sensitization among workers who had been exposed to beryllium for less
than a year at the time of the screening, a rate similar to that found
by Henneberger et al. among beryllium ceramics workers exposed for one
year or less (16 percent, Henneberger et al., 2001).  All four workers
who were sensitized without disease had been exposed 5 years or less;
conversely, all six of the workers with CBD had first been exposed to
beryllium at least five years prior to the screening (Schuler et al.,
Table 2).  

μg/m3).  

μg/m3, and 59 percent below the limit of detection (LOD), which was
either 0.02 µg/m3 or 0.2 µg/m3 depending on the method of sample
analysis (Thomas et al. 2009, p. 116).  Median values below 0.03 were
reported for all processes except the wire annealing and pickling
process.  Samples for this process remained somewhat elevated, with a
median of 0.1 μg/m3.  In January 2002, the plant enclosed the wire
annealing and pickling process in a restricted access zone (RAZ),
requiring respiratory PPE in the RAZ and implementing stringent measures
to minimize the potential for skin contact and beryllium transfer out of
the zone.  While exposure samples collected by the facility were sparse
following the enclosure, they suggest exposure levels comparable to the
2000-01 samples in areas other than the RAZ.  Within the RAZ, required
use of powered-air purifier respirators indicates that respiratory
exposure was negligible. 

To test the efficacy of the new measures in preventing sensitization and
CBD, in June 2000 the facility began an intensive BeLPT screening
program for all new workers.  The company screened workers at the time
of hire; at intervals of 3, 6, 12, 24, and 48 months; and at 3-year
intervals thereafter.  Among 82 workers hired after 1999, three (3.7
percent) cases of sensitization were found.  Two (5.4 percent) of 37
workers hired prior to enclosure of the wire annealing and pickling
process were found to be sensitized within 3 and 6 months of beginning
work at the plant.  One (2.2 percent) of 45 workers hired after the
enclosure was confirmed as sensitized. 

Thomas et al. calculated a sensitization IR of 1.9 per 1,000
person-months for the workers hired after the exposure control program
was initiated in 2000 (“program workers”), using the sum of
sensitization-free months of employment among all 82 workers as the
denominator (Thomas et al., 2009).  They calculated an estimated IR of
3.8 per 1,000 person-months for 43 workers hired between 1993 and 2000
who had participated in the 2000 BeLPT screening (“legacy workers”).
 This estimated IR was based on one BeLPT screening, rather than BeLPTs
conducted throughout the legacy workers’ employment, the denominator
in this case is the total months of employment until the 2000 screening.
 Because sensitized workers may have been sensitized prior to the
screening, the denominator may overestimate sensitization-free time in
the legacy group, and the actual sensitization IR for legacy workers may
be somewhat higher than 3.8 per 1,000 person-months.  Based on
comparison of the IRs and the prevalence rates discussed previously, the
authors concluded that the combination of dermal protection, respiratory
protection, housekeeping improvements and engineering controls
implemented beginning in 2000 appeared to have reduced the risk of
sensitization among workers at the plant.  However, they noted that the
small size of the study population and the short follow-up time for the
program workers suggested that further research is needed to confirm the
program’s efficacy (Thomas et al. 2009, p. 123).

Stanton et al. (2006) conducted a study of workers in three different
copper-beryllium alloy distribution centers in the United States.  The
distribution centers, including one bulk products center established in
1963 and strip metal centers established in 1968 and 1972, sell products
received from beryllium production and finishing facilities and small
quantities of copper-beryllium, aluminum-beryllium, and nickel-beryllium
alloy materials.  Work at distribution centers does not require
large-scale heat treatment or manipulation of material typical of
beryllium processing and machining plants, but involves final processing
steps that can generate airborne beryllium.  Slitting, the main
production activity at the two strip product distribution centers,
generates low levels of airborne beryllium particles, while operations
such as tensioning and welding used more frequently at the bulk products
center can generate somewhat higher levels.  Non-production jobs at all
three centers included shipping and receiving, palletizing and wrapping,
production-area administrative work, and office-area administrative
work.  

The authors estimated workers’ beryllium exposures using IH data from
company records and job history information collected through interviews
conducted by a company occupational health nurse.  Stanton et al.
evaluated airborne beryllium levels in various jobs based on 393
full-shift LP samples collected from 1996 to 2004.  Airborne beryllium
levels at the plant were generally very low, with 54 percent of all
samples at or below the LOD, which ranged from 0.02 to 0.1 μg/m3.  The
authors reported a median of 0.03 μg/m3 and an arithmetic mean of 0.05
μg/m3 for the 393 full-shift LP samples, where samples below the LOD
were assigned a value of half the applicable LOD.  Median and geometric
mean values for specific jobs ranged from 0.01 - 0.07 and 0.02 - 0.07
µg/m3, respectively.  All measurements were below the OSHA PEL of 2.0
μg/m3 and 97 percent were below the DOE action level of 0.2 μg/m3. 
The paper does not report use of respiratory or skin protection. 
Exposure conditions may have changed somewhat over the history of the
plant due to changes in exposure control measures, including
improvements to product and container cleaning practices instituted
during the 1990s.  

Eighty-eight of the 100 workers (88 percent) employed at the three
centers at the time of the study participated in screening for BeS. 
Blood samples were collected between November 2000 and March 2001 by the
company’s medical staff.  Samples collected from employees of the
strip metal centers were split and evaluated at two laboratories, while
samples from the bulk product center workers were evaluated at a single
laboratory.  Participants were considered to be “sensitized” to
beryllium if two or more BeLPT results, from two laboratories or from
repeat testing at the same laboratory, were found to be abnormal.  One
individual was found to be sensitized and was offered clinical
evaluation, including BAL and fiberoptic bronchoscopy.  He was found to
have lung granulomas and was diagnosed with CBD.  

The worker diagnosed with CBD had been employed at a strip metal
distribution center from 1978 to 2000 as a shipper and receiver, loading
and unloading trucks delivering materials from a beryllium production
facility and to the distribution center’s customers.  Although the LP
samples collected for his job between 1996 and 2000 were generally low
(n = 35, median 0.01, range < 0.02 - 0.13 µg/m3), it is not clear
whether these samples adequately characterize his exposure conditions
over the course of his work history.  He reported that early in his work
history, containers of beryllium oxide powder were transported on the
trucks he entered.  While he did not recall seeing any breaks or leaks
in the beryllium oxide containers, some containers were known to have
been punctured by forklifts on trailers used by the company during the
period of his employment, and could have contaminated trucks he entered.
 With 22 years of employment at the facility, this worker had begun
beryllium-related work earlier and performed it longer than about 90
percent of the study population (Stanton et al. p. 208). 

Nuclear Weapons Production Facilities and Cleanup of Former Facilities

Primary exposure from nuclear weapons production facilities comes from
beryllium metal and beryllium alloys.  

A study conducted by Kreiss et al. (1989) documented beryllium BeS and
CBD among beryllium-exposed workers in the nuclear industry.  A company
medical department identified 58 workers with beryllium exposure among a
work force of 500, of whom 51 (88 percent) participated in the study. 
Twenty-four workers were involved in research and development R&D),
while the remaining 27 were production workers.  The R&D workers had a
longer tenure with a mean time from first exposure of 21.2 years,
compared to a mean time since first exposure of 5 years among the
production workers.  The number of workers with abnormal BLPT readings
was 6, with 4 being diagnosed with CBD.  This resulted in an estimated
11.8 percent prevalence of beryllium BeS.  

Kreiss et al. (1993) expanded the work of Kreiss et al. (1989) by
performing a cross-sectional study of 895 (current and former) beryllium
workers in the same nuclear weapons plant.  Participants were placed in
qualitative exposure groups (“no exposure,” “minimal exposure,”
“intermittent exposure,” and “consistent exposure”) based on
questionnaire responses.  The number of workers with abnormal BeLPT
totaled 18 with 12 being diagnosed with CBD.  Three additional workers
with BeS developed CBD over the next 2 years.  BeS occurred in all of
the qualitatively defined exposure groups.  Individuals who had worked
as machinists were statistically overrepresented among
beryllium-sensitized cases, compared with non-cases.  Cases were more
likely than non-cases to report having had a measured overexposure to
beryllium (p = 0.009), a factor which proved to be a significant
predictor of BeS in logistic regression analyses, as was exposure to
beryllium prior to 1970.  Beryllium sensitized cases were also
significantly more likely to report having had cuts that were delayed in
healing (p = 0.02).  The authors concluded that individual variability
and susceptibility along with exposure circumstances are important
factors in developing beryllium BeS and CBD.  

In 1991, the Beryllium Health Surveillance Program (BHSP) was
established at the Rocky Flats Nuclear Weapons Facility to offer BLPT
screening to current and former employees who may have been exposed to
beryllium (Stange et al., 1996).  Participants received an initial
BeLPT and follow-ups at one and three years.  Based on histologic
evidence of pulmonary granulomas and a positive BAL-BeLPT Stange et al.
published a study of 4,397 BHSP participants tested from June 1991 to
March 1995, including current employees (42.8 percent) and former
employees (57.2 percent).  Twenty-nine cases of CBD and 76 cases of BeS
were identified.  The sensitization rate for the population was 2.43
percent.  Available exposure data included FAH exposure samples
collected between 1970 and 1988 (mean concentration 0.016 µg/m3) and
personal samples collected between 1984 and 1987 (mean concentration
1.04 µg/m3).  Cases of CBD and BeS were noted in individuals in all
jobs classifications, including those believed to involve minimal
exposure to beryllium.  The authors recommended ongoing surveillance for
workers in all jobs with potential for beryllium exposure. 

Stange et al. (2001) extended the previous study, evaluating 5,173
participants in the Rocky Flats BHSP who were tested between June 1991
and December 1997.  Three-year serial testing was offered to employees
who had not been tested for three years or more and did not show BeS
during the previous study.  This resulted in 2,891 employees being
tested.  Of the 5,173 workers participating in the study, 172 were
found to have abnormal BeLPT.  Ninety-eight (3.33 percent) of the
workers were found to be sensitized (confirmed abnormal BeLPT results)
in the initial screening, conducted in 1991.  Of these workers 74 were
diagnosed with CBD (history of beryllium exposure, evidence of
noncaseating granulomas or mononuclear cell infiltrates on lung biopsy,
and a positive BeLPT or BAL-BeLPT).  A follow-up screening of 2,891
workers three years later identified an additional 56 sensitized workers
and an additional seven cases of CBD.  BeS and CBD rates were analyzed
with respect to gender, building work locations, and length of
employment.  Historical employee data included hire date, termination
date, leave of absences, and job title changes.  Exposure to beryllium
was determined by job categories and building or work area codes. 
Personal beryllium air monitoring results were used, when available,
from employees with the same job title or similar job.  However, no
quantitative information was presented in the study.  The authors
conclude that for some individuals, exposure to beryllium at levels less
that the OSHA PEL could cause BeS and CBD. 

Viet et al. (2001) conducted a case-control study of the Rocky Flats
worker population studied by Stange et al. to examine the relationship
between estimated beryllium exposure level and risk of BeS or CBD.  The
worker population included 74 beryllium-sensitized workers and 50
workers diagnosed with CBD.  Beryllium exposure levels were estimated
based on FAH airhead samples from one building, the beryllium machine
shop.  These were collected away from the BZ of the machine operator
and likely underestimated exposure.  To estimate levels in other
locations, these air sample concentrations were used to construct a job
exposure matrix that included the determination of the Building 444
exposure estimates for a 30-year period; each subject’s work history
by job location, task, and time period; and assignment of exposure
estimates to each combination of job location, task, and time period as
compared to Building 444 machinists.  The authors adjusted the levels
observed in the machine shop by factors based on interviews with former
workers.  Workers’ estimated mean exposure concentrations ranged from
0.083 µg/m3 to 0.622 µg/m3.  Estimated maximum air concentrations
ranged from 0.54 µg/m3 to 36.8 µg/m3.  Cases were matched to controls
of the same age, race, gender, and smoking status (Viet et al. 2000). 

Estimated mean and cumulative exposure levels and duration of employment
were found to be significantly higher for CBD cases than for controls. 
Estimated mean exposure levels were significantly higher for BeS cases
than for controls.  No significant difference was observed for estimated
cumulative exposure or duration of exposure.  Similar results were
found using logistic regression analysis, which identified statistically
significant relationships between CBD and both cumulative and mean
estimated exposure, but did not find significant relationships between
estimated exposure levels and BeS without CBD.  Comparing CBD with BeS
cases, Viet et al. found that workers with CBD had significantly higher
estimated cumulative and mean beryllium exposure levels than workers who
were sensitized, but did not have CBD.  

Animal Models of CBD

This section reviews the relevant animal studies supporting the
mechanisms outlined above.  Researchers have attempted to identify
animal models with which to further investigate the mechanisms
underlying the development of CBD.  A suitable animal model should
exhibit major characteristics of CBD, including the formation of immune
granulomas following inhalation exposure to beryllium, the demonstration
of a beryllium-specific immune response, and mimicking the progressive
nature of the human disease.  While exposure to beryllium has been shown
to cause chronic granulomatous inflammation of the lung in animal
studies using a variety of species, most of the granulomatous lesions
were formed by foreign-body reactions, which result from persistent
irritation and consist predominantly of macrophages and monocytes, and
small numbers of lymphocytes.  Foreign-body granulomas are distinct from
the immune granulomas of CBD, which are caused by antigenic stimulation
of the immune system and contain large numbers of lymphocytes.  Animal
studies have been useful in identifying the specific mechanistic pieces
of action for beryllium disease, however, no single model has completely
mimicked the disease process as it progresses in humans.  The following
is a discussion of the most relevant animal studies regarding the
mechanisms of BeS and CBD development in humans.

Harmesen et al. performed a study to assess whether the beagle dog could
provide an adequate model for the study of beryllium induced lung
diseases (Harmesen et al., 1985).  One group of dogs served as a control
group (air inhalation only) and four other groups received high
(approximately 50 μg/kg) and low (approximately 20 μg/kg) doses of
beryllium oxide calcined at 500° C or 1,000° C, administered as
aerosols.  As discussed above, calcining temperature controls the
solubility and SSA of beryllium particles.  Those particles calcined at
higher temperatures (e.g., 1,000° C) are less soluble and have lower
SSA than particles calcined at lower temperatures (e.g., 500°C). 
Solubility and SSA are factors in determining the toxic potential of
beryllium compounds or materials.

Cells were collected from the dogs by BAL at 30, 60, 90, 180, and 210
days after exposure, and the percentages of neutrophils and lymphocytes
were determined.  In addition, the mitogenic responses of blood
lymphocytes and lavage cells collected at 210 days were determined with
either phytohemagglutinin or beryllium sulfate as mitogen.  The
percentage of neutrophils in the lavage fluid was significantly elevated
only at 30 days with exposure to either dose of 500° C beryllium oxide.
 The percentage of lymphocytes in the fluid was significantly elevated
in samples across all times with exposure to the high dose of this
beryllium oxide form.  Beryllium oxide calcined at 1,000° C elevated
lavage lymphocytes only in high dose at 30 days.  No significant effect
of 1,000° C beryllium oxide exposure on mitogenic response of any
lymphocytes was seen.  In contrast, peripheral blood lymphocytes from
the 500° C beryllium oxide exposed groups were significantly stimulated
by beryllium sulfate compared with the phytohemagglutinin exposed cells.
 The investigators in this study were able to replicate some of the same
findings as those observed in human studies – specifically, that
beryllium in soluble and insoluble forms can be mitogenic to immune
cells, an important finding for progression of BeS and proliferation of
immune cells to developing full-blown CBD.

In another beagle study Haley et al. also found that the beagle dog
appears to model some aspects of human CBD (Haley et al., 1989).  The
authors monitored lung pathologic effects, particle clearance, and
immune sensitization of peripheral blood leukocytes following a single
exposure to beryllium oxide aerosol generated from beryllium oxide
calcined at 500° C or 1,000° C.  The aerosol was administered to the
dogs perinasally to attain initial lung burdens of 6 or 18 μg
beryllium/kg body weight.  Granulomatous lesions and lung lymphocyte
responses consistent with those observed in humans with CBD were
observed, including perivascular and peribronchiolar infiltrates of
lymphocytes and macrophages, progressing to microgranulomas with areas
of granulomatous pneumonia and interstitial fibrosis.  Beryllium
specificity of the immune response was demonstrated by positive results
in the BeLPT, although there was considerable inter-animal variation. 
The lesions declined in severity after 64 days post-exposure.  Thus,
while this model was able to mimic the formation of Be-specific immune
granulomas, it was not able to mimic the progressive nature of disease.

This study also provided an opportunity to compare the effects of
beryllium oxide calcination temperature on granulomatous disease in the
beagle respiratory system.  Haley et al. found that the percentage and
numbers of lymphocytes in BAL fluid was increased at 3 month
postexposure in dogs exposed to either dose of beryllium oxide calcined
at 500° C, but not in dogs exposed to the material calcined at the
higher temperature.  Although there was considerable inter-animal
variation, lesions were generally more severe in the dogs exposed to
material calcined at 500° C.  Positive BeLPT results were observed with
BAL lymphocytes only in the group with a high initial lung burden of the
material calcined at 500° C, but positive results with peripheral blood
lymphocytes were observed at both doses with material calcined at both
temperatures. 

The histologic and immunologic responses of canine lungs to aerosolized
beryllium oxide were investigated in another Haley et al. (1989) study. 
Beagle-dogs were exposed to high dose (50 µg/kg of body weight) or low
dose (l7 µg/kg) levels of beryllium oxide calcined at either 500° or
1000° C.  One group of dogs was examined up to 365 days after exposure
for lung histology and biochemical assay to determine the fate of
inhaled beryllium oxide.  A second group underwent BAL for lung
lymphocyte analysis for up to 22 months after exposure.  Histopathologic
examination revealed peribronchiolar and perivascular lymphocytic
histiocytic inflammation, peaking at 64 days after beryllium oxide
exposure.  Lymphocytes were initially well differentiated, but
progressed to lymphoblastic cells and aggregated in lymphofollicular
nodules or microgranulomas over time.  Alveolar macrophages were large,
and filled with intracytoplasmic material.  Cortical and paracortical
lymphoid hyperplasia of the tracheobronchial nodes was found.  Lung
lymphocyte concentrations were increased at 3 months and returned to
normal in both dose groups given 500° C treated beryllium chloride.  No
significant elevations in lymphocyte concentrations were found on dogs
given 1,000°C treated beryllium oxide.  Lung retention was higher in
the 500° C treated beryllium oxide group.  The lesions found in dog
lungs closely resembled those found in humans with CBD: severe
granulomas, lymphoblast transformation, increased pulmonary lymphocyte
concentrations and variation in beryllium sensitivity.  It was concluded
that the canine model for berylliosis may provide insight into this
disease.

4,380 μg Be/m3 as beryllium oxide calcined at 1,400° C for 30 min,
once per month for 3 months.  Because the dogs were sacrificed 2 years
post-exposure, the long time period between exposure and response may
have allowed for the reversal of any beryllium-induced changes (EPA,
1998). 

A 1994 study by Haley et al. showed that intra-bronchiolar installation
of beryllium can induce immune granulomas and BeS in monkeys.  Haley et
al. (1994) exposed male cynomolgus monkeys to either beryllium metal or
beryllium oxide calcined at 500° C by intrabronchiolar instillation as
a saline suspension.  Lymphocyte counts in BAL fluid were observed, and
were found to be significantly increased in monkeys exposed to beryllium
metal on post-exposure days 14 to 90, and on post-exposure day 60 in
monkeys exposed to beryllium oxide.  The lungs of monkeys exposed to
beryllium metal had lesions characterized by interstitial fibrosis, Type
II cell hyperplasia, and lymphocyte infiltration.  Some monkeys also
exhibited immune granulomas.  Similar lesions were observed in monkeys
exposed to beryllium oxide, but the incidence and severity were much
less.  BAL lymphocytes from monkeys exposed to Be metal, but not from
monkeys exposed to beryllium oxide, proliferated in response to
beryllium sulfate in the BeLPT (EPA, 1998).  

In an experiment similar to the one conducted with dogs, 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 3,300-4,380
μg Be/m3 as beryllium oxide calcined at 1,400° C.  The lack of effect
may have been related to the long period (2 years) between exposure and
sacrifice, or to low toxicity of beryllium oxide calcined at such a high
temperature. 

As discussed earlier in the health effects subsection, at the cellular
level, beryllium dissolution must occur for the macrophage to present
beryllium as an antigen to induce the cell-mediated CBD immune reactions
(Stefaniak et al. 2006).  Several studies have shown that low-fired
beryllium oxide, which is predominantly made up of poorly crystallized
small particles, is more immunologically reactive than beryllium oxide
calcined at higher firing temperatures that result in less reactivity
due to increasing crystal size.  As discussed previously, Haley et al.
(1989a) found more severe lung lesions and a stronger immune response in
beagle dogs receiving a single inhalation exposure to beryllium oxide
calcined at 500° C than in dogs receiving an equivalent initial lung
burden of beryllium oxide calcined at 1,000° C.  Haley et al. found
that beryllium oxide calcined at 1,000°C elicited little local
pulmonary immune response, whereas the much more soluble beryllium oxide
calcined at 500°C produced a beryllium-specific, cell-mediated immune
response in dogs (Haley, 1991). 

In a later study, beryllium metal appeared to induce a greater toxic
response than beryllium oxide following intrabronchiolar instillation in
cynomolgus monkeys, as evidenced by more severe lung lesions, a larger
effect on BAL lymphocyte counts, and a positive response in the BeLT
with BAL lymphocytes only after exposure to beryllium metal (Haley et
al., 1994).  Because an oxide layer may form on beryllium-metal surfaces
after exposure to air (Mueller and Adolphson, 1979; Harmsen et al.,
1984) dissolution of small amounts of poorly soluble beryllium compounds
in the lungs might be sufficient to allow persistent low-level beryllium
presentation to the immune system (NAS, 2008).

Preliminary Beryllium Sensitization and CBD Conclusions

It is well-established that beryllium exposure, either via inhalation or
skin, may lead to BeS, and, with inhalation exposure, may lead to the
onset and progression of CBD.  This is supported by extensive animal and
human studies.  The mechanism by which this occurs has been clearly laid
out in the previous sections.  Sensitization is a necessary first step
to the onset of CBD.  Sensitization is a change to the function of the
immune system such that a person can now develop CBD with a substantial
proportion of sensitized people progressing to this disease state.  OSHA
has made a preliminary determination to consider BeS and CBD to be
adverse events along the pathological continuum for beryllium disease,
with BeS being the necessary first step in the progression to CBD.

The epidemiological evidence presented in this section demonstrates that
BeS and CBD are continuing to occur from present-day exposures below
OSHA’s PEL.  The available literature discussed above shows that
disease prevalence can be reduced by reducing inhalation exposure. 
However, the available epidemiological studies also indicate that it may
be necessary to minimize skin exposure to further reduce the incidence
of BeS.  The preliminary risk assessment also discusses the
effectiveness of interventions to reduce beryllium exposures and the
risk of BeS and CBD.

In general, the studies demonstrate that there is substantial prevalence
of BeS and CBD in modern facilities with exposure levels below the
current PEL, that risk of BeS and CBD appears to vary across industries
and processes, and that efforts to reduce exposure have succeeded in
reducing the frequency of BeS and CBD.  

Of workers who were found to be sensitized and underwent clinical
evaluation, 36-100 percent was diagnosed with CBD (Kreiss et al., 1993;
Newman, 1996, 2005 and 2007).  Overall prevalence of CBD in
cross-sectional screenings ranges from 0.6 to 8 percent (Kreiss et al.,
2007).  It has been estimated from ongoing surveillance of sensitized
individuals, with an average follow-up time of 4.5 years, that 37
percent of beryllium-exposed employees were estimated to progress to CBD
(Newman, 2005).  A study of nuclear weapons facility employees enrolled
in an ongoing medical surveillance program found that only about 20
percent of sensitized individuals employed less than five years
eventually were diagnosed with CBD, while 40 percent of sensitized
employees employed ten years or more developed CBD (Stange et al.,
2001). 

BERYLLIUM LUNG CANCER SECTION

Beryllium exposure has been associated with a variety of adverse health
effects including lung cancer.  The potential for beryllium and its
compounds to cause cancer has been previously assessed by various other
agencies (EPA, ATSDR, NAS, NIEHS, and NIOSH).  In addition, the
International Agency for Research on Cancer (IARC) did an extensive
evaluation in 1993 and reevaluated in April 2009 (EHP, 2009).  In brief,
IARC determined beryllium and its compounds to be carcinogenic to humans
(Group 1 category), while EPA considers beryllium to be probable human
carcinogens (EPA, 1998), and the National Toxicology Program (NTP) has
determined beryllium and its compounds are reasonably expected to be
carcinogens (NTP, 1999, 2005).  OSHA has conducted an independent
evaluation of the carcinogenic potential of beryllium and these
compounds as well.  The following is a summary of the studies used to
support the Agency findings.

Genotoxicity Studies

Genotoxicity can be an important indicator for screening the potential
of a material to induce cancer and an important mechanism leading to
tumor formation and carcinogenesis.  In a review conducted by the
National Academy of Science, beryllium and its compounds have tested
positively in nearly 50 percent of the genotoxicity studies conducted
without exogenous metabolic activity, however, they were found to be
non-genotoxic in most bacterial assays (NAS, 2008).  

Gene mutations have been observed in mammalian cells cultured with
beryllium chloride in a limited number of studies (EPA, 1998; ATSDR,
2002; Gordon and Bowser, 2003).  Culturing mammalian cells with
beryllium chloride, beryllium sulfate, or beryllium nitrate has resulted
in clastogenic alterations.  However, 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).
(EPA, 1998)   eryllium 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 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><Cite><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></Cite
><Cite><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></Cite></EndNote>
(Infante et al., 1980; Steenland and Ward, 1991) .  Infante et al.  
ADDIN EN.CITE <EndNote><Cite
ExcludeAuth="1"><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></Cite
></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><Cite
ExcludeAuth="1"><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></Cite></EndNote>
(1991)  extended the work of Infante et al.   ADDIN EN.CITE
<EndNote><Cite
ExcludeAuth="1"><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></Cite
></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><Cite
ExcludeAuth="1"><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></Cite></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><Cite
ExcludeAuth="1"><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><Cite
ExcludeAuth="1"><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></Cite><Cite
ExcludeAuth="1"><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&apos; occupational lung
cancer</TITLE><SECONDARY_TITLE>Environ
Res</SECONDARY_TITLE><VOLUME>21</VOLUME><PAGES>48-55</PAGES></MDL></Cite
></EndNote> (1970; 1979; 1980)  and Mancuso and El-Attar   ADDIN EN.CITE
<EndNote><Cite
ExcludeAuth="1"><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><Cite><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&apos; occupational lung
cancer</TITLE><SECONDARY_TITLE>Environ
Res</SECONDARY_TITLE><VOLUME>21</VOLUME><PAGES>48-55</PAGES></MDL></Cite
></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><Cite
ExcludeAuth="1"><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></Cite
></EndNote> (1980)  expanded the work of Mancuso   ADDIN EN.CITE
<EndNote><Cite
ExcludeAuth="1"><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><Cite
ExcludeAuth="1"><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></Cite><Cite
ExcludeAuth="1"><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&apos; occupational lung
cancer</TITLE><SECONDARY_TITLE>Environ
Res</SECONDARY_TITLE><VOLUME>21</VOLUME><PAGES>48-55</PAGES></MDL></Cite
></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><Cite
ExcludeAuth="1"><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></Cite></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><Cite
ExcludeAuth="1"><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></Cite></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><Cite
ExcludeAuth="1"><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><Cite
ExcludeAuth="1"><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></Cite><Cite
ExcludeAuth="1"><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&apos; occupational lung
cancer</TITLE><SECONDARY_TITLE>Environ
Res</SECONDARY_TITLE><VOLUME>21</VOLUME><PAGES>48-55</PAGES></MDL></Cite
></EndNote> (1970; 1979; 1980) , and Wagoner et al.   ADDIN EN.CITE
<EndNote><Cite
ExcludeAuth="1"><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></Cite
></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><Cite
ExcludeAuth="1"><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></Cite></EndNote> (2002)  questioned the results of Ward et al.  
ADDIN EN.CITE <EndNote><Cite
ExcludeAuth="1"><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></Cite></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><Cite
ExcludeAuth="1"><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></Cite></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><Cite><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></Cite></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

Alekseeva OG (1966) Ability of beryllium compounds to cause allergy of
the delayed type. Federation proceedings, 25:843–846

American College of Chest Physicians (ACCP). (1965)  Beryllium disease:
report of the section on nature and prevalence. Dis Chest 48:550-558

American Conference of Governmental Industrial Hygienist (ACGIH). (1972)
Threshold limit values for chemical substances and physical agents and
biological exposure indices for 1971-1972. American Conference of
Governmental Industrial Hygienists, Cincinnati, OH

American Conference of Governmental Industrial Hygienist (ACGIH). (2007)
Threshold limit values for chemical substances and physical agents and
biological exposure indices. American Conference of Governmental
Industrial Hygienists, Cincinnati, OH

American Conference of Governmental Industrial Hygienist (ACGIH). (2009)
Threshold limit values for chemical substances and physical agents and
biological exposure indices. American Conference of Governmental
Industrial Hygienists, Cincinnati, OH

Agency for Toxic Substance and Disease Registry. (1993) Toxicological
Profile of Beryllium.  April, 1993

Agency for Toxic Substance and Disease Registry. (2002) Toxicological
Profile of Beryllium.  Sept, 2002

Alekseeva OG. (1966)  Ability of beryllium compounds to cause allergy of
the delayed type.  Fed Proc Transl Suppl. Sep-Oct; 25(5):843-6

Ames BN and Gold LS. (1990)  Chemical Carcinogenesis: Too many rodent
carcinogens.  Proc Natl Acad Sci U S A. Oct; 87(19):7772-6

American Industrial Hygiene Association (AIHA). The AIHA 1972 Emergency
ResponsePlanning Guidelines and Workplace Environmental Exposure Level
Guides Handbook

Amicosante M, Fontenot AP. (2006) T cell recognition in chronic
beryllium disease. Clin Immunol. Nov; 121(2):134-43

Amicosante M, Deubner D, Saltini C. (2005) Role of the
berylliosis-associated HLA-DPGlu69 supratypic variant in determining the
response to beryllium in a blood T-cells beryllium-stimulated
proliferation test. Sarcoidosis Vasc Diffuse Lung Dis. Oct; 22(3):175-9

Amicosante M, Berretta F, Rossman M, Butler RH, Rogliani P, van den
Berg-Loonen E, Saltini C. (2005)  Identification of HLA-DRPhebeta47 as
the susceptibility marker of hypersensitivity to beryllium in
individuals lacking the berylliosis-associated supratypic marker
HLA-DPGlubeta69. Respir Res. Aug 14; 6: 94 

Amicosante M, Berretta F, Franchi A, Rogliani P, Dotti C, Losi M, Dweik
R, Saltini C.  (2002) HLA-DP-unrestricted TNF-alpha release in
beryllium-stimulated peripheral blood mononuclear cells.  Eur Respir J 
Nov 20; 1174-1178

Andre SM, Metivier H, Lantenois G, Boyer M, Nolibe D, Masse R.  (1987) 
Beryllium metal solubility in the lung: comparison of metal hot-pressed
forms by in-vivo and in-vitro dissolution bioassays. Human toxicology,
6(3):233–240

American National Standards Institute (ANSI). (1970)  Acceptable
concentrations of beryllium and beryllium compounds.  (Z37.29-1970) New
York: American National Standards Institute

BA, Sun JD, eds. Annual report of the Inhalation Toxicology Research
Institute, October 1, 1985 through September 30, 1986. Lovelace
Biomedical and Environmental Research Institute, Albuquerque, New
Mexico, 291-295

Bargon J, Kronenberger H, Bergmann L, et al. (1986). Lymphocyte
transformation test in a group of foundry workers exposed to beryllium
and non-exposed controls. Eur J Respir Dis 69:211-215

Barna BP, Chiang T, Pillarisetti SG, et al. (1981) Immunological studies
of experimental beryllium lung disease in the guinea pig. Clin Immunol
Immunopathol 20:402-411

Barna BP, Deodhar SD, Chiang T, et al. (1984a) Experimental
beryllium-induced lung disease. I. Differences in immunologic response
to beryllium compounds in strains 2 and 13 guinea pigs. Int Arch Allergy
Appl Immunol 73:42-48

Barna BP, Deodhar SD, Gautam S, et al. (1984b) Experimental
beryllium-induced lung disease. II. Analyses of bronchial lavage cells
in strains 2 and 13 guinea pigs. Int Arch Allergy Appl Immunol 73:49-55

Bayliss DL, Lainhart WS, Crally LJ, et al. (1971) Mortality patterns in
a group of former beryllium workers. In: Proceedings of the American
Conference of Governmental Industrial Hygienists 33rd Annual Meeting,
Toronto, Canada, 94-107

Belinsky SA, Snow SS, Nikula KJ, Finch GL, Tellez CS, and Palmisano WA.
(2002) Aberrant CpG island methylation of the p16INK4a and estrogen
receptor genes in rat lung tumors induced by particulate carcinogens.
Carcinogenesis 23: 335-339

Belman S. Beryllium binding in epidermal constituents. (1969) J Occup
Med, Apr;11(4):175-83

Benson JM, Holmes AM, Barr EB, Nikula KJ, and March TH. (2000) Particle
clearance and histopathology in lungs of C3H/HeJ mice administered
beryllium/copper alloy by intratracheal instillation. Inhalation
Toxicology 12: 733-749

Bernard A, Torma-Krajewski J, Viet S. (1996) Retrospective beryllium
exposure assessment at the Rocky Flats Environmental Site. Am Ind Hyg
Assoc J 57:804-808

Beryllium Industry Scientific Advisory Committee. (1997) Is beryllium
carcinogenic in humans. J Occup Environ Med 39:205-208  

Boeniger MF.  The significance of skin exposure. (2003) Ann Occup Hyg.
Nov;47(8):591-593

Borm PJ, Schins RP, Albrecht C. (2004) Inhaled particles and lung
cancer. Part B:  Paradigms and risk assessments.  Int J Cancer. May
20;110(1):3-14

Bost TW, Riches DWH, Schumacher B, et al. (1994) Alveolar macrophages
from patients with beryllium disease and sarcoidosis express increased
levels of mRNA for tumor necrosis factor-alpha and interleukin-6 but not
interleukin-1beta. Am J Respir Cell Mol Biol 10(5):506-513

Carter JM, Corson N, Driscoll KE, Elder A, Finkelstein JN, Harkema JR,
Gelein R, Wade-Mercer P, Nguyen K, Oberdörster G. (2006) A Comparative
Dose-Related Response of Several Key Pro- and Anti-inflammatory
Mediators in the Lungs of Rats, Mice and Hamsters after Subchronic
Inhalation of Carbon Black. J Occup Environ Med. Dec; 48(12): 1265-1278

Carter JM and Driscoll KE.  (2001) The role of inflammation, oxidative
stress, and proliferation in silica-induced disease: a species
comparison.  J Environ Pathol Toxicol Oncol. 2001;20 Suppl 1:33-43

Camner P, Hellstrom PA, Lundborg M, Philipson K.  (1977).  Lung
clearance of 4μm particles coated with silver, carbon or beryllium.
Arch Environ Health, 32:58–62

Chiappino G, Cirla A, Vigliani EC. (1969)  Delayed-type hypersensitivity
reactions to beryllium compounds.  An experimental Study.  Arch Pathol
Feb;87(2):131-40

Cholack J, Schafer L, Yeager D. (1967)  Exposures to beryllium in a
beryllium alloying plant. Am Ind Hyg Assoc J 28:399-407 

Cianciara MJ, Volkova AP, Aizina NL, Alekseeva OG. (1980)   A study of
humoral and cellular responsiveness in a population occupationally
exposed to beryllium.  Int Arch Occup Environ Health. 1980
Jan;45(1):87-94

Clary JJ, Bland LS, Stokinger HE. (1975) The effect of reproduction and
lactation on the onset of latent chronic beryllium disease. Toxicol Appl
Pharmacol 33:214-221

Cohen BS, Harley NH, Martinelli CA, and Lippman M.  (1983)  Sampling
artifiacts in the brathing zone.  Proceedings of the International
Symposium on Aerosols in the Mining and Industrial Work Environment pp
347-360.  B. Y. H. Liu and V. A. Maples eds.  Minneapolis, MN:  Ann
Arbor Press

Conradi C, Burri PH, Kapanet Y, and Robinson FR. (1971) Lung changes
after beryllium inhalation: Ultrastructural and morphometric study. Arch
Environ Health 23: 348-358

Cordeiro CR, Jones JC, Alfaro T, Ferriera AJ.  (2007) Bronchoalveolar
lavage in occupational lung diseases.  Semin Respir Crit Care Med. 
Oct;28(5):504-13

Crowley JF, Hamilton JG, Scott KG.  (1949) The metabolism of
carrier-free radioberyllium in the rat. Journal of biological chemistry,
177:975–984

Cummings KJ, Stefaniak AB, Virji MA, Kreiss K. (2009) A
reconsiderationof acute beryllium disease. Environ Health Perspect.
Aug;117(8):1250-6

Cummings KJ, Deubner DC, Day GA, Henneberger PK, Kitt MM, Kent MS,
Kreiss K, Schuler CR. (2007) Enhanced preventive programme at a
beryllium oxide ceramics facility reduces beryllium sensitization among
workers.  Occup Environ Med. Feb;64 2):134-40

Curtis GH. (1951) Cutaneous hypersensitivity due to beryllium; A study
of thirteen cases.  AMA Arch Derm Syphiol.  Oct; 64(4):470-82

Curtis GH. (1959) The diagnosis of beryllium disease, with special
reference to the patch test.  AMA Arch Ind Health 19 (2): 150-153

Dai S, Crawford F, Marrack P, Kappler JW.  (2008)  The structure of
HLA-DR52c: comparison to other HLA-DRB3 Isotypes  PNAS 105 (33):11893-7 

Day GA, Dufresne A, Stefaniak AB, Schuler CR, Stanton ML, Miller WE,
Kent MS, 

Deubner DC, Kreiss K, Hoover MD. (2007) Exposure assessment pathway at a
copper-beryllium alloy facitilty.  Ann Occup Hyg. Jan;51(1):67-80

Day, G.A., M.D. Hoover, A.B. Stefaniak, R.M. Dickerson, E.J. Peterson,
and N.A. Esmen. (2005) Bioavailability of beryllium oxide particles: An
in vitro study in the murine J774A.1 macrophage cell line model. Exp.
Lung Res. 31(3):341-360

Delic J (1992) Toxicity Review 27 (Part 2): Beryllium and beryllium
compounds. London, Her Majesty’s Stationery Office (ISBN 0 11 886343
6)

Denardi JM, Van Ordstrand HS, Carmody MG.  (1949) Acute dermatitis and
pneumonitis in beryllium workers; review of 406 cases in 8-year period
with follow-up on recoveries.  Ohio Med. 1949 Jun; 45(6):567-75

De Nardi JM, Van Orstrand HS, Curtis GH, Zielinski J.  (1953) 
Berylliosis: Summary and survey of all clinical types observed in a
twelve-year period. American Medical Association archives of industrial
hygiene and occupational medicine, 8:1–24

Deodhar SD and BP Barna.  (1991)  Immune mechanisms in beryllium lung
disease.  Cleve Clin J Med.  Mar-Apr;58(2):157-60

Deubner DC, Goodman M, Iannuzzi J. (2001) Variability, predictive value,
and uses of the beryllium blood lymphocyte proliferation test (BLPT):
Preliminary analysis of the ongoing workforce survey. Appl Occup Environ
Hyg 16(5):521-526

Deubner D, Kelsh M, Shum M, et al. (2001) Beryllium sensitization,
chronic beryllium disease, and exposures at a beryllium mining and
extraction facility. Appl Occup Environ Hyg 16(5):579-592

DHHS (NIOSH) Publication No. 72-10268. (1972) Criteria for a Recommended
Standard: Occupational Exposure to Beryllium 

Diaconita G and Eskenasy A. (1978) Experimental aerogenic pulmonary
berylliosis in rabbits. Morphol. Embryol. 24:75-79

DOE (Department of Energy) (2001) Chronic beryllium disease prevention
program. U.S. Department of Energy. Code of Federal Regulations. 10 CFR
850.   HYPERLINK
"Http://www.access.gpo.gov/nara/waisidx_01/10cfr850_01.html" 
Http://www.access.gpo.gov/nara/waisidx_01/10cfr850_01.html . December
13, 2001

 D'Apice MR, Rogliani P, Novelli G, Saltini C, Amicosante M. (2004)
Analysis of TNF-α promoter polymorphisms in the susceptibility to
beryllium sensitization.  Sarcoidosis Vasc Diffuse Lung Dis. Mar;
21(1):29-34

Driscoll KE. (1996)  Role of inflammation in the development of rat lung
tumors in response to chronic particle exposure.  Inhal Toxicol.  8
(Suppl):  139-153

Eidson, A.F., A. Taya, G.L. Finch, M.D. Hoover, and C. Cook. (1991)
Dosimetry of beryllium in cultured canine pulmonary alveolar
macrophages. J. Toxicol. Environ. Health 34(4):433-448

Eisenbud M. (1993) Re: Lung cancer incidence among patients with
beryllium disease [Letter]. J Natl Cancer Inst 85:1697-1698

Eisnebud M, Lisson J.  (1983)  Epidemiological aspecits of
beryllium-induced non-malignant lung diseae:  A 30-year upate.  J Occup
Med 25 (3): 196-202

Eisenbud M, Wanta RC, Dustan C, Steadman LT, Harris WB, Wolf BS.  (1949)
 Non-occupational berylliosis.  J iNd Hyg Toxicol.  31: 281-294

Elder A, Gelein R, Finkelstein JN, Driscoll KE, Harkema J, Oberdörster
G.  (2005) Effects of subchronically inhaled carbon black in three
species. I. Retention kinetics, lung inflammation, and histopathology.
Toxicol Sci. Dec;88(2):614-29.

Eskenasy A. (1979) Experimental pulmonary berylliosis in rabbits
sensitized to beryllium sulfate: Contact hypersensitivity. Morphol.
Embryol. 25(3):257-262

Environmental Protection Agency (EPA). (1974) National emission
standards for hazardous air pollutants. U.S. Environmental Protection
Agency. Code of Federal Regulations 40:61.30-61.34

Environmental Protection Agency (EPA). (1987) Health Assessment Document
for Beryllium.  U. S. Environmental Protection Agency, Washington, DC

Environmental Protection Agency (EPA)(CASRN 7440-41-7). (1998)
Toxicological review of beryllium and compounds. U.S. Environmental
Protection Agency, Washington DC http://www.epa.gov/iris/subst/0012.htm

Finch, G., J. Mewhinney, A. Eidson, M. Hoover, and S. Rothenberg. (1988)
In Vitro Dissolution Characteristics of Beryllium Oxide and Beryllium
Metal Aerosols. J. Aerosol Sci. 19(3):333-342

Finch GL et al; (1986) Inhalation Toxicol Research Institute Annual
Report: The Cytotoxicity of Beryllium Compounds to Cultured Canine
Alveolar Macrophages p.286-90

Finch, G., J. Mewhinney, A. Eidson, M. Hoover, and S. Rothenberg. (1988)
In Vitro Dissolution Characteristics of Beryllium Oxide and Beryllium
Metal Aerosols. J. Aerosol Sci. 19(3):333-342

Finch GL, Mewhinney JA, Hoover MD, et al. (1990) Clearance,
translocation, and excretion of beryllium following acute inhalation of
beryllium oxide by beagle dogs. Fundam Appl Toxicol 15:231-241

Finch GL, Finch GL, Lowther WT, Hoover MD, Brooks AL. (1991) Effects of
beryllium metal particles on the viability and function of cultured rat
alveolar macrophages. J Toxicol Environ Health. Sep; 34(1):103-14

Finch GL, Hahn FF, Carlton WW, Rebar AH, Hoover MD, Griffith WC,
Mewhinney JA, and Cuddihy RG. (1994) Combined exposure of F344 rats to
beryllium metal and 239PuO2 aerosols. In Inhalation Toxicology Research
Institute Annual Report 1993-1994 (Belinsky SA, Hoover MD, and Bradley
PL, Eds.), pp 77-80. 1TRI-144, National Technical Information Service,
Springfield, VA

Finch G, March T, Hahn F, Barr E, Belinsky S, Hoover M, Lechner J,
Nikula K, Hobbs C. (1998a) Carcinogenic responses of transgenic
heterozygous p53 knockout mice to inhaled 239PuO2 or metallic beryllium.
Toxicol Pathol 26:484-491

Finch GL, Nikula KJ, Hoover MD. (1998b) Dose-response relationships
between inhaled beryllium metal and lung toxicity in C3H mice. Toxicol
Sci 42(1):36-48

Finch GL, March TH, Hahn FF, Barr EB, Belinsky SA, Hoover, MD, Lechner
JF, Nikula KJ, and Hobbs CH. (1998c) Carcinogenic responses of
transgenic heterozygous p53 knockout mice to inhaled 239PuO2 or metallic
beryllium. Toxicologic Pathology 26 (4): 484-491 

Fireman E, Haimsky E, Noiderfer M, Priel I, Lerman Y. (2003) 
Misdiagnosis of sarcoidosis in patients with chronic beryllium disease. 
Sarcoidosis Vasc Diffuse Lung Dis. Jun; 20(2):144-8

Fodor I. (1977) Histogenesis of beryllium-induced bone tumours.  Acta
Morphol Acad Sci Hung. 25(2-3): 99-105

Fontenot AP, Torres M, Marshall WH, Newman LS, Kotzin BL.  (2000)
Beryllium presentation t CD4+ T celss underlies disease-susceptibility
HLA-DP alleles in chronic beryllium Disease.  Proc Natl Acad Sci. 97
(23): 12717-12722

Fontenot AP, Canavera SJ, Gharavi L, Newman LS, Kotzin BL.  (2002)  J
Clin Invest. Nov;110(10):1473-82

Fontenot AP, Gharavi L, Bennett SR, Canavera SJ, Newman LS, and Ktzin
BL. (2003)  CD28 costimulation independence of target organ versus
circulating memory antigen-specific CD4+ T cells. J Clin Invest.  112
(5): 776-784

Fontenot AP, Palmer BE, Sullivan AK, Joslin FG, Wilson CC, Maier LA,
Newman LS, Kotzin BL. (2005) Frequency of beryllium specific, central
memory CD 4+ T cells in blood determines proliferation response.  J Clin
Invest. Oct;115(10):2886-93

Freiman DG, Hardy HL. (1970) Beryllium disease. The relation of
pulmonary pathology to clinical course and prognosis based on a study of
130 cases from the U.S. beryllium case registry.  Hum Pathol.
Mar;1(1):25-44

Frome E, Cragle D, Watkins J, Wing S, Shy C, Tankersley W, West C.
(1997) A mortality study of employees of the nuclear industry in Oak
Ridge, Tennessee. Radiat Res 148:64-80 

Frome EL, Smith MH, Littlefield LG, et al. (1996). Statistical methods
for the blood beryllium lymphocyte proliferation test. Environ Health
Perspect 104(Suppl. 5):957-968

Fuchs B and Protchard DJ.  (2002)  Etiology of Osteosarcoma.  Clin
Orthop Relat Res. 2002 Apr;(397):40-52

Furchner JE, Richmond CR, London JE. (1973). Comparative metabolism of
radionuclides in mammals.VIII. Retention of beryllium in the mouse, rat,
monkey and dog. Health Phys 24:293-300

Gelman I. (1936) Poisoning by vapors of beryllium oxyfluoride. J Ind Hyg
Toxicol 18:371±379

Gibson GJ, Prescott RJ, Muers MF, Middleton WG, Mitchell DN, Connolly
CK, Harrison BD (1996).   British Thoracic Society Sarcoidosis Study: 
effects of long-term corticosteroid treatment.  Thorax. Mar;
51(3):238-47

Gordon T and Bowser D. (2003) Beryllium: genotoxicity and
carcinogenicity.

Mutat Res. Dec 10; 533(1-2):99-105

Greene TM, Lanzisera DV, Andrews L, Downs AJ (1998) Matrix-isolation and
density functional theory study of the reactions of laser-abated
beryllium, magnesium, and calcium atoms with methane. Journal of the
American Chemical Society, 120 (24):6097–6104

Greten FR, Karin M. (2004)  The IKK/NF-kappa B activation pathway- a
target for prevention and treatment of cancer.  Cancer Lett.  Apr
8;206(2):193-9

Groth DH, Kommineni C, and Mackay GR. (1980) Carcinogenicity of
beryllium hydroxide and alloys. Environmental Research 21: 63-84.

Haley PJ, Finch GL, Mewhinney JA, et al. (1989). A canine model of
beryllium-induced granulomatous lung disease. Lab Invest 61:219-227

Haley PJ, Finch GL, Hoover, MD, et al. (1990) The acute toxicity of
inhaled beryllium metal in rats. Fundam Appl Toxicol 15:767-778

Haley PJ.  (1991)  Mechanisms of granulomatous lung disease from inhaled
beryllium: the role of antigenicity in granuloma formation.  Toxicol
Pathol, 19(4 Pt 1):514-25 

Haley PJ, Finch GL, Hoover MD, et al. (1992). Beryllium-induced lung
disease in the dog following two exposures to BeO. Environ Res
59:400-415

Haley P, Pavia KF, Swafford DS, et al. (1994) The comparative pulmonary
toxicity of beryllium metal and beryllium oxide in cynomolgus monkeys.
Immunopharmacol Immunotoxicol 16(4):627-644

Hall RH, Scott JK, Laskin S, Stroud CA, Stokinger HE.  (1950) Acute
toxicity of inhaled beryullium:  Observations correlating toxzicity with
the physicochemical properties of beryllium oxide dust.  Arch Ind Hyg
Occup Med.  2 (1): 25-48

Hanifin JM, Epstein WL and MJ Cline. (1970) In vitro studies on
granulomatous hypersensitivity to beryllium.  J Invest Derm.  Oct;
55(4):284-8

Hardy HL, Tabershaw IR. (1946) Delayed chemical pneumonitis occurring in
workers exposed to beryllium compounds. J Ind Hyg Toxicol 28:197-211

Hardy HL, Rabe EW, Lorch S. (1967).  United States Beryllium Case
Registry:  (1952-1966) Review of its methods and utility.  J Occup Med.
Jun; 9(6):271-6

Hardy HL. (1980)  Beryllium disease: a clinical perspective.  Environ
Res.  Feb;21(1):1-9

Hart BA, Bickford PC, Whatlen MC, Hemanway D (1980) Distribution and
retention of beryllium in guinea pigs after administration of a
beryllium chloride aerosol. US Department of Energy symposium series
(pulmonary toxicology of respirable particulates), 53:87–102

Hart BA, Harmsen AG, Low RB, et al. (1984) Biochemical, cytological and
histological alterations in rat lung following acute beryllium aerosol
exposure. Toxicol Appl Pharmacol 75:454-465

Hart BA, Harmsen AG, Low RB, Emerson R. (1984) Biochemical, cytological,
and histological alterations in rat lung following acute beryllium
aerosol exposure.  Toxicol Appl Pharmacol. Sep 30;75(3):454-65

Harmsen AG, Finch GL, Mewhinney JA, et al. (1986) Lung cellular response
and lymphocyte blastogenesis in beagle dogs exposed to beryllium oxide.
In: Muggenburg BA, Sun JD, eds. Annual report of the Inhalation
Toxicology Research Institute, October 1, 1985 through September 30,
1986. Lovelace Biomedical and Environmental Research Institute,
Albuquerque, New Mexico, 291-295

Heinrich U, Fuhst R, Rittenhausen S, Creutzenber O, Bellamn B, Koch W,
Levsen K.  (1995) Chronic inhalation exposure of Wistar rats and two
different strains of mice to diesel engine exhaust, carbon black, and
titanium dioxide.  Inhal Toxicol.  7: 533-556

Henneberger PK, Cumro D, Deubner DD. (2001) Beryllium sensitization and
disease among long-term and short-term workers in a beryllium ceramics
plant. Int Arch Occup Health 74:167-176

Hollins DM, McKinley MA, Williams C, Wiman A, Fillos D, Chapman PS, Madl
AK.   (2009) Beryllium and lung cancer: a weight of evidence evaluation
of the toxicological and epidemiological literature. Crit Rev Toxicol.
2009;39 Suppl 1:1-32

Hong-Geller. (2006) Chemokine response to beryllium exposure in human
peripheral blood mononuclear and dendritic cells.  Toxicology. Feb 1;
218(2-3):216-28

Hoover MD, Castorina BT, Finch GL, Rothenberg SJ. (1989) Determination
of oxide layer thickness on beryllium metal particles. Am Ind Hyg Assoc
J. Oct; 50(10):550-3 

Hoover MD, Finch GL, Mewhinney JA, Eidson AF.  (1990) Release of
aerosols during sawing and milling of beryllium exposure in human
peripheral blood mononuclear and dendritic cells.  Appl Occup Environ
Hyg 5 (11): 787-791

Hazardous Substance Database (HSDB).  (2010) Beryllium and Beryllium
compounds. 
http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~ozBARO:1

HSE (1994) EH64 summary criteria for occupational exposure standards:
Beryllium and beryllium compounds. Sudbury, Suffolk, Health and Safety
Executive Books (ISBN 0 7176 1800 5)

Huang H, Meyer KC, Kubai L, and Auerbach R. (1992) An immune model of
beryllium-induced pulmonary granulomata in mice: Histopathology, immune
reactivity, and flow-cytometric analysis of bronchoalveolar
lavage-derived cells. Lab Invest 67:138-146

Infante P, Wagoner J, Sprince N. (1980) Mortality patterns from lung
cancer and nonneoplastic respiratory disease among white males in the
Beryllium Case Registry. Environ Res 21:35-43 

International Agency for Research on Cancer (1993) Beryllium, cadmium,
mercury and exposures in the glass manufacturing industry. Monogr Eval
Carcinog Risk Hum 58:41-117 

ICRP (1960) Report of ICRP Committee II on Permissible Dose for Internal
Radiation. Health physics, 3:154–155

Jackson L, Evers BM. (2006) Chronic inflammation and pathogenesis of GI
and pancreatic cancers. Cancer Treat Res. 130:39-65

Johnson JS, Foote K, McClean M, Cogbill G. (2001) Beryllium exposure
control program at Cardiff Atomic Weapons Establishment in the United
Kingdom.  Appl Occup Environ Hyg. May;16(5):619-30

Johnston CJ, Driscoll KE, Finkelstein JN, Baggs R, O'Reilly MA, Carter
J, Gelein R, Oberdörster G. (2000)  Pulmonary chemokine and mutagenic
responses in rats after subchronic inhalation of amorphous and
crystalline silica. Toxicol Sci. 2000 Aug;56(2):405-13

Joseph, P., T. Muchnok, and T. Ong. (2001) Gene expression profile in
BALB/c-3T3 cells transformed with beryllium sulfate. Mol. Carcinog.
32(1):28-35

KanematsuN, Hara M, Kada T. (1980) Rec assay and mutagenicity studies on
metal compounds.  Mutat Res. Feb;77(2):109-16

Kang KY, Bice D, Hoffman E, D’Amato R, Ziskind M, Salviggio. (1977) J.
Allergy Clin Immunol. Jun;59(6):425-36

Kelleher PC, Martyny JW, Mroz MM, Maier LA, Ruttenber AJ, Young DA, et
al. (2001) Beryllium particulate exposure and disease relations in a
beryllium machining plant.  J Occup Environ Med 43: 238–249

Kent MS, Robins TG, Madl AK.  (2001) Is total mass or mas of alveolar
–depositied airborne particles of beryllium a better predictor of the
prevalence of disease?  A preliminary study of a beryllium processing
facility.   Appl Occup Environ Hyg.  16 (5): 539-558

Keshava, N, Zhou G, Spruill M, Ensell M, Ong TM. (2001) Carcinogenic
potential and genomic instability of beryllium sulphate in BALB/c-3T3
cells. Mol. Cell. Biochem. 222(1-2):69-76

Kjellstrom T, Kennedy P.  (1984) Criteria document for Swedish
occupational standards: Beryllium. Solna, Arbetarsdyddsstyrelsen,
Publikationsservice

Klemperer FW, Martin AP, Van Riper J. (1951)  Beryllium excretion in
humans.  A M A Arch Ind Hyg Occup Med.  Sep; 4(3):251-6

Knaapen AM, Borm PJ, Albrecht C, Schins RP. (2004)  Inhaled particles
and cancer.  Part A: Mechanisms.  Int J Cancer. May 10;109(6):799-809

Kreiss K, Newman LS, Mroz MM, Campbell PA.  (1989)  Screening blood test
identifies subclinical beryllium diease.  J Occup Med. 31 (7): 603-608

Kreiss K, Mroz MM, Zhen B, Martyny JW, Newman LS. (1993) Epidemiology of
beryllium sensitization and disease in nuclear workers. Am Rev Respir
Dis 148:985-991

Kreiss K, Wasserman S, Mroz MM, Newman LS. (1993)  Beryllium disease
screening in the ceramics industry. Blood lymphocyte test performance
and exposure-disease relations. J Occup Med 35:267-274

Kreiss K, Mroz MM, Newman LS, Martyny J, Zhen B. (1996)  Machining risk
of beryllium disease and sensitization with median exposures below 2
micrograms/m3. Am J Industrial Med 30:16-25 

Kreiss K, Mroz MM, Zhen B, Wiedemann H, Barna B.  (1997) Risks of
beryllium disease related processes at a metal, alloy, and oxide
production plant.  Occup Environ Med.  54 (8): 605-612

Kreiss K, Day GA, Schuler CR.  (2007) Beryllium: a modern industrial
hazard. Annu Rev Public Health. 28:259-77

Kriebel D, Sprince N, Eisen E, Greaves I. (1988) Pulmonary function in
beryllium workers: assessment of exposure. Br J Ind Med 45:83-92

Kriebel D, Sprince NL, Eisen EA, et al. (1988) Beryllium exposure and
pulmonary function: A cross sectional study of beryllium workers. Br J
Ind Med 45:167-173

Kriebel D, Sprince NL, Eisen EA, et al. (1988) Pulmonary function in
beryllium workers: Assessment of exposure. Br J Ind Med 45:83-92

Krivanek, Reeves.  (1972) The effects of chemical forms of beryllium on
the production of the immunological response.  Am Ind Hyg Assoc J. Jan;
33(1):45-52

Kuroda K, Endo G, Okamoto A, Yoo YS, Horiguchi S.  (1991)  Genotoxicity
of beryllium, gallium and antimony in short-term assays. Mutat Res.
Dec;264(4):163-70

Lang L. (1994) Beryllium: a chronic problem. Environ Health Perspect
102:526-531 

Lansdown ABG (1995) Physiological and toxicological changes in the skin
resulting from the action and interaction of metal ions. Critical
reviews in toxicology, 25(5):397–462

Larramendy ML, Popescu NC, DiPaolo JA. (1981)  Induction by inorganic
metal salts of sister chromatid exchanges and chromosome aberrations in
human and Syrian hamster cell strains.  Environ Mutagen.  3 (6): 597-606

Lawrence DA, McCabe MJ.  (2002)  Immunomodulation by metals.  Int
Immunopharmacol. Feb; 2 (2): 293-302

Lederer H and J Savage. (1954)  Beryllium Granuloma of the Skin. Br J
Ind Med. Jan; 11(1):45-8

Lee  KP, Trochimowicz HJ, Reinhardt CF. (1985)  Pulmonary response of
rats exposed to titanium dioxide (TiO2) by inhalation for two years. 
Toxicol Appl Pharmacol. Jun 30;79(2):179-92

Leek RD, Harris AL. (2002) Tumor-associated macrophages in breast
cancer.  J Mammary Gland Biol Neoplasia 2002 , 7:177-189

LeFevre ME, Joel DD. (1986) Distribution of label after intragastric
administration of 7Be-labeled carbon to weanling and aged mice. Proc Soc
Exp Biol Med 182:112-119

Leonard A, Lauwerys R. (1987) Mutagenicity, carcinogenicity and
teratogenicity of beryllium. Mutat Res 186:35-42

Levy PS, Roth HD, Hwang PMT, Powers TE.  (2002) Beryllium and lung
cancer: A reanalysis of a NIOSH cohort mortality study.  Inhal Toxicol.
14 (10): 1003-1015

Levy PS, Roth HD, Deubner DC.  (2007) Exposure to beryllium and
occurrence of lung cancer:  A reexamination of findings from a nested
case-control study.  J Occup Environ Med.  49 (1): 96-101

Lieben J, Metzner,F. (1959) Epidemiological findings associated with
beryllium extraction. Am IndHyg Assoc J 20(6):152

Machle W, Beyer E, Gregorious F. (1948).  Berylliosis; acute pneumonitis
and pulmonary granulomatosis of beryllium workers.  Occup Med (Chic
Ill).  Jun;5(6):671-83

Mack DG, Lanham AK, Palmer PE, Maier LA, Watts TH, Fontenot AP. (2008)
4-4BB enhances proliferation of beryllium-specific T cells in the lung
of subjects with chronic beryllium disease.  J Immunol. Sep
15;181(6):4381-8

MacMahon B. (1994)  The epidemiological evidence on the carcinogenicity
of beryllium in humans. J Occup Med 36:15-24 

Madl AK, Unice K, Brown JL, Kolanz ME, Kent MS. (2007) 
Exposure-response analysis for beryllium sensitization and chronic
beryllium disease among workers in a beryllium metal machining plant.  J
Occup Environ Hyg. Jun;4(6):448-66

Maier LA. (2001) Beryllium health effects in the era of the beryllium
lymphocyte proliferation test. Appl Occup Environ Hyg 16(5):514-520

Maier LA, Reynolds MV, Young DA, et al. (1999) Angiotensin-1 converting
enzyme polymorphisms in chronic beryllium disease. Am J Respir Crit Care
Med 159(4 Pt 1):1342-1350

Maier LA, Tinkle SS, Kittie LA, et al. (2001) IL-4 fails to regulate in
vitro beryllium-induced cytokines in berylliosis. Eur Resp J 17:403-415

Mancuso TF, El-Attar AA.  (1969) Epidemiological study of the beryllium
industry. Cohort methodology and mortality studies.  J Occup Med.
Aug;11(8):422-34

Mancuso TF. (1970) Relation of duration of employment and prior
respiratory illness to respiratory cancer among beryllium workers.
Environ. Research 3: 251-275

Mancuso TF.  (1979) Occupational lung cancer among beryllium workers. 
Dusts and Diseases, R. Lemen and JM Dement eds.  Park Forest South, Il:
Pathotox Publishers. Pp 463-471

Mancuso T. (1980)  Mortality study of beryllium industry workers'
occupational lung cancer. Environ Res 21:48-55 

Mandervelt C, Clottens FL, Demedts M, Nemery B.  (1997)  Assessment of
the sensitization potential of five metals in the murine local nymph
node assay.  Toxicology. Jun 6;120(1):65-73

Martyny J, Hoover M, Mroz M, Ellis K, Maier L, Sheff K, Newman L. (2000)
Aerosols generated during beryllium machining. J Occup Environ Med
42:8-18 

Marx JJ and R Burrell. (1973) Delayed hypersensitivity to beryllium
compounds. J Immunol.l Aug;111(2):590-8

McCanlies EC, Ensey JS, Schuler CR, Kreiss K, Weston A. (2004)  The
association between HLA-DPB1Glu69 and chronic beryllium disease and
beryllium sensitization.  Am J Ind Med.  46 (2):  95-103

McCawley MA, Kent MS, Berakis MT. (2001) Ultrafine beryllium number
concentration as a possible metric for chronic beryllium disease risk.
Appl Occup Environ Hyg 16(5):631-638

McCord DP.  (1951) Beryllium as a sensitizing agent.  Jul; 20(7):336-7

Meyer KC. (1994) Beryllium and Lung Disease. Chest 106; 942-946

Middleton DC. (1998) Chronic beryllium disease: Uncommon disease, less
common diagnosis. Environ Health Perspect 106(12):765-767

Middleton DC, Lewin MD, Kowalski PJ, Cox SS, Kleinbaum D.  (2006) The
BeLPT: algorithms and implications.  Am J Ind Med. Jan; 49(1):36-44

Misra, U.K., G. Gawdi, and S.V. Pizzo. (2002) Beryllium fluoride-induced
cell proliferation: A process requiring P21ras -dependent activated
signal transduction and NF-κB-dependent gene regulation. J. Leukoc.
Biol. 71(3):487-494

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Mroz MM, Maier LA, Strand M, Silviera L, Newman LS. (2009)  Beryllium
lymphocyte proliferation test surveillance identifies clinically
significant beryllium disease.  Am J Ind Med. Oct; 52(10):762-73

Mueller JJ, Adolphson DR.  (1979)  Corrosion/Electrochemistry of
Beryllium and Beryllium.  In Beryllium Science and Technology, Vol 2, DR
floyd and JN Lowe, eds New York: Plenum Press pp 417-433

Mullen AL, Stanley RE, Lloyd SR, Moghissi AA. (1972)  Radioberyllium
metabolism by the dairy cow. Health physics, 22:17–22

Müller-Quernheim J, Gaede KI, Fireman E, Zissel G. (2006) Diagnoses of
chronic beryllium disease with cohorts of sarcoidosis patients.  Eur
Respir J. Jun; 27(6):1190-5

National Academies of Science (NAS). (2008) Managing Health Effects of
Beryllium Exposure Committee on Beryllium Alloy Exposures. National
Research Council of the National Academies; The National Academies
Press, Washington, DC

National Cancer Institute (NCI).  Cancer Trends Progress Report –
2009/2010 Update, National Cancer Institute, NIH, DHHS, Bethesda, MD,
April 2010,   HYPERLINK "http://progressreport.cancer.gov" 
http://progressreport.cancer.gov .

National Institute of Occupational Safety and Health (NIOSH).  (1972) 
Occupational Exposure to Beryllium; Criteria for a Recommended Standard.
 DHEW (HSM) 72-10268.  US Department of Health, Education, and Welfare,
Health Services and Mental Health Administration, National Institute of
Occupational Safety and Health, Rockville, MD.

National Institute of Occupational Safety and Health (NIOSH).  (2005)
NIOSH Pocket Guide to Chemical Hazards.    HYPERLINK
"http://www.cdc.gov/niosh/npg/npgd0054.html" 
http://www.cdc.gov/niosh/npg/npgd0054.html 

Newman LS, Kreiss K.  (1992)  Nonoccupational beryllium disease
masquerading as sarcoidosis; identification by blood lymphocyte
proliferation response to beryllium.   Am Rev Respir Dis.
May;145(5):1212-4

Newman LS. (1996)  Immunology Genetics and Epidemiology of Beryllium
Disease.  Chest. 109; 40S-43S 

Newman LS, Llyody J, Daniloff E.  (1996)  The natural history of
beryllium sensitization and chronic beryllium disease.  Environ Health
Perspect. Oct;104 Suppl 5:937-43

Newman LS, Mroz MM, Maier LA, Daniloff DA, Balkissoon.  (2001) Efficacy
of serial medical surveillance from chronic beryllium disease in a
beryllium machining plant.  J Occup Environ Health.  43(3): 231-237

Newman LS, Mroz MM, Balkissoon R, Maier LA.  (2005) Beryllium
sensitization progresses to chronic beryllium disease: A longitudinal
study of disease risk.  Am J Respir Crit Care Med.  171 (1): 54-60

Nicholson W. (1976) Case study 1: asbestos-the TLV approach. Ann NY Acad
Sci 271:152-169

Nickell-Brady C, Hahn FF, Finch GL, and Belinsky SA. (1994) Analysis of
K-ras, p53, and c-raf-1 mutations in beryllium-induced rat lung tumors.
Carcinogenesis 15:257-262

Nikula KJ, Swafford DS, Hoover MD, Tohulka MD, and Finch GL. (1997)
Chronic granulomatous pneumonia and lymphocytic responses induced by
inhaled beryllium metal in A/J and C3HlHe J mice. Toxicologic Pathology
25 (1): 2-12

Nishimura M.  (1966) Clinical and experimental studies on acute
beryllium disease.  Nagoya J Med Sci. Nov; 29(1):17-44

NTP Toxicology and Carcinogenesis Studies of Talc (1993) (CAS No.
14807-96-6)(Non-Asbestiform) in F344/N Rats and B6C3F1 Mice (Inhalation
Studies).

NTP (National Toxicology Program). (2002) Tenth report on carcinogens.
U.S. Department of Health and Human Services, National Toxicology
Program, Research Triangle Park, NC

http://ntp-server.niehs.nih.gov/NewHomeROC/RAHC_list.html. July 12,
2002.

Oberdorster G. (1996) Significance of particle parameters in the
evaluation of exposure-dose-response relationships of inhaled particles.
 Inhal Toxicol. 8 Suppl:73-89.

Pappas GP, Newman LS. (1993) Early pulmonary physiologic abnormalities
in beryllium disease. American review of respiratory disease,
148:661–666

Pikaarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S,
Gutkovich-Pyest E, Urieli-Shoval S, Galun E, Ben-Neriah Y.  (2004) 
NF-kappaB functions as a tumour promoter in inflammation-associated
cancer.  Nature. Sep 23; 431(7007):461-6

Polák L, Barnes JM, Turk JL.  (1968)  The genetic control of contact
sensitization to inorganic metal compounds in guinea-pigs.  Immunology.
1968 May;14(5):707-11

Reeves AL.  (1965) The absorption of beryllium from the gastrointestinal
tract.

Arch Environ Health. Aug;11(2):209-14

Reeves AL, Vorwald AJ. (1967) Beryllium carcinogenesis. II. Pulmonary
deposition and clearance of inhaled beryllium sulfate in the rat. Cancer
Res 27:446-451

Reeves AL, Deitch D, Vorwald AJ. (1967) Beryllium carcinogenesis. I.
Inhalation exposure of rats to beryllium sulfate aerosol. Cancer Res
27:439-445

Reeves AL, Krivanek ND, Busby EK, Swanborg RH. (1972) Immunity to
pulmonary berylliosis in guinea pigs.  Int Arch Arbeitsmed. 29(3):209-20

Refsnes M, Hetland RB, Øvrevik J, Sundfør I, Schwarze PE, Låg M. 
(2006) Different particle determinants induce apoptosis and cytokine
release in primary alveolar macrophage cultures. Part Fibre Toxicol. Jun
14;3:10

Rhoads K, Sanders CL. (1985) Lung clearance, translocation, and acute
toxicity of arsenic, beryllium, cadmium, cobalt, lead, selenium,
vanadium, and ytterbium oxides following deposition in rat lung.Environ
Res 36:359-378

Richeldi L, Sorrentino R, Saltini C. (1993) HLA-DPB1 glutamate 69: a
genetic marker of beryllium disease.  Science. Oct 8;262(5131):242-4

Ritz B, Morgenstern H, Froines J, Young B. (1999)  Effects of exposure
to external ionizing radiation on cancer mortality in nuclear workers
monitored for radiation at Rocketdyne/Atomics International. Am J Ind
Med 35:21-31

Robinson FR, Schaffner F, and Trachtenburg E. (1968) Ultrastructure of
the lungs of dogs exposed to beryllium-containing dusts. Arch. Environ.
Health 16: 374-379  

Rosenkranz HS and Poirer LA. (1979) Evaluation of the mutagenicity and
DNA-modifying activity of carcinogens and noncarcinogens in microbial
systems.  J Natl Cancer Inst.  62 (4): 873-891

Rosenman K, Hertzberg V, Rice C, Reilly MJ, Aronchick J, Parker JE,
Regovich J, Rossman M.  (2005)  Chronic beryllium disease and
sensitization at a beryllium processing facility.  Environ Health
Perspect Oct;113(10):1366-72

Rossman MD, Preuss OP, Powers MB, eds.  (1991)  Beryllium:  Biomedical
and Environmental Aspects.  Baltimore, MD: Williams and Wilkins

Rossman M. (1996) Chronic beryllium disease; diagnosis and management. 
Environ Health Perspect. Oct;104 Suppl 5:945-7

Rossman MD. (2001)  Chronic beryllium disease: a hypersensitivity
disorder.

Appl Occup Environ Hyg. May;16(5):615-8.

Rossman M, Kreider. (2003) Is chronic beryllium disease sarcoidosis of
known etiology?  Sarcoidosis Vasc Diffuse Lung Dis. Jun;20(2):104-9

Roth HD.   HYPERLINK
"http://www.defendingscience.org/upload/Roth_1985_02.pdf"  Memorandum to
Brush Wellman enclosing a critique of the EPA health assessment document
for beryllium . February 22, 1985

Saber W, Dweik RA.  (2000)  A 65-year-old factory worker with dyspnea on
exertion and a normal chest x-ray.  Cleve Clin J Med. Nov; 67(11):791-2,
794, 797-8, 800

Saltini C, Winestock K, Kirby M, Pinkston P, Crystal RG. (1989)
Maintenace of alveolitis in patients with chronic beryllium disease by
beryllium-specific helper T cells.  N Engl J Med. Apr 27;320(17):1103-9

Saltini C, Kirby M, Trapnell BC, Tamura N, Crystal RG.  (1990)  Biased
accumulation of T-lymphocytes with “memory”-type CD45 leukocyte
common antigen gene expression on the epithelial surface of human lung. 
 J Exp Med. Apr 1;171(4):1123-40

Sanders CL, Cannon WC, Powers GJ, et al. (1975) Toxicology of high-fired
beryllium oxide inhaled by rodents. Arch Environ Health 30:546-551

Sanders, C.L., W.C. Cannon, and G.J. Powers. (1978) Lung carcinogenesis
induced by inhaled high-fired oxides of beryllium and plutonium. Health
Phys. 35(2):193-199

Sanderson WT, Ward EM, Steenland K, Petersen MR.  (2001)  Lung cancer
case-control study of beryllium workers.  Am J Ind Med. Feb;
39(2):133-44

Saracci R. (1991) Beryllium and lung cancer: adding another piece to the
puzzle of epidemiologic evidence. J Natl Cancer Inst 83:1362-1363

Sawyer, R.T., V.A. Fadok, L.A. Kittle, L.A. Maier, and L.S. Newman.
(2000) Beryllium-stimulated apoptosis in macrophage cell lines.
Toxicology 149(2-3):129-142

Sawyer RT, Parsons CE, Fontenot AP, Maier LA, Gillespie MM, Gottschall
EB, Silveira L, Newman LS.  (2004)   Beryllium-induced tumor necrosis
factor-alpha production by CD4+ T cells is mediated by HLA-DP.  Am J
Respir Cell Mol Biol.  Jul;31(1):122-30. 

Sawyer, R.T., D.R. Dobis, M. Goldstein, L. Velsor, L.A. Maier, A.P.
Fontenot, L. Silveira, L.S. Newman, and B.J. Day. (2005).
Beryllium-stimulated reactive oxygen species and macrophage apoptosis.
Free Radic. Biol. Med. 38(7):928-937

Schepers GW. (1962) The mineral content of the lung in chronic
berylliosis. Dis Chest. Dec; 42:600-7

Schlesinger RB, Ben-Jebria A, Dahl AR, Snipes MB, Ultman J 1997.
Disposition of inhaled toxicants. In: Handbook of Human Toxicology
(Massaro EJ, ed). New York:CRC Press, 493–550.

Schubauer-Berigan MK, Deddens JA, Steenland K, Sanderson WT, Petersen
MR.  (2008)  Adjustment for temporal confounders in a reanalysis of a
case-control study of beryllium and lung cancer.  Occup Environ Med.
Jun; 65(6):379-83

Schuler CR, Kent MS, Deubner DC, Berakis MT, McCawley M, Henneberger PK,
Rossman MD, Kreiss K.  (2005)  Process related risk of beryllium
sensitization and disease in a copper-beryllium alloy facility.  Am J
Ind Med. Mar;47(3):195-205

Scott  JK, Neumann WF, Allen R. (1950) The effect of added carrier on
the distribution and excretion of soluble beryllium.  J Biol Chem,
182:291–298

Seiler D, Rice C, Herrick R, Hertzberg V. (1996) A study of beryllium
exposure measurements: parts 1 and 2. Appl Occup Environ Hyg 11:89-102

Sendelbach LE, Witschi HP, Tryka AF. (1986) Acute pulmonary toxicity of
beryllium sulfate inhalation in rats and mice: Cell kinetics and
histopathology. Toxicol Appl Pharmacol 85:248-256

Sendelbach LE, Witschi HP. (1987) Bronchoalveolar lavage in rats and
mice following beryllium sulfate inhalation. Toxicol Appl Pharmacol
90:322-329

Sendelbach LE, Tryka AF, Witschi H. (1989) Progressive lung injury over
a one-year period after a single inhalation exposure to beryllium
sulfate. Am Rev Respir Dis 139:1003-1009

Skilleter DN, Paine AJ.  (1979)  Relative toxicities of particulate and
soluble forms of beryllium to a rat liver parenchymal cell line in
culture and possible mechanisms of uptake.  Chem Biol Interact. Jan;
24(1):19-33

Skilleter DN, Price RJ. (1981) Effects of beryllium compounds on rat
liver Kupffer cells in culture.  Toxicol Appl Pharmacol. Jun
30;59(2):279-86

Skilleter DN, Price RJ. (1988) Effects of beryllium ions on tyrosine
phosphorylation. Biochem SocTrans 16:1047-1048

Spencer HC, Sadek SE, Jones JC, et al. (1967) Toxicological studies on
beryllium oxides and beryllium containing exhaust products, technical
report. AMRL-TR-67-46. Wright Patterson Air Force Base, Aerospace
Medical Research Laboratories

Sprince NL, Kazemi H, Hardy HL. (1976) Current (1975) problem of
differentiating between beryllium disease and sarcoidosis.  Ann N Y Acad
Sci. 278:654-64

Sprince NL, Kazemi H.  (1980) U.S. beryllium case registry through 1977.
Environmental research, 21:44–47

Stange AW, Furman FJ, Hilmas DE.  (2004)  The beryllium lymphocyte
proliferation test:  Relevant issues in beryllium helath surveillance. 
Am J Ind Med.  46 (5): 453-462

Stanton ML, Henneberger PK, Kent MS, Deubner DC, Kreiss K, Schuler CR. 
(2006)  Sensitization and chronic berullium disease among workers in
copper-beryllium distribution centers.  J Occup Environ Med.  48 (2):
204-211

Steenland K, Ward E. (1991) Lung cancer incidence among patients with
beryllium disease: a cohort mortality study. J Natl Cancer Inst
83:1380-1385 

Steele VE, Wilkinson BP, Arnold JT, and Kutzman RS. (1989) Study of
beryllium oxide genotoxicity in cultured respiratory epithelial cells.
Inhalation Toxicology 1: 95-110

Stefaniak AB, Weaver VM, Cadorette M, Puckett LG, Schwartz BS, Wiggs LD,
Jankowski MD, and Breysse PN. (2003) Summary of historical beryllium
uses and airborne concentration levels at Los Alamos National
Laboratory. Appl. Occup. Environ. Hyg. 18(9):708-715

Stefaniak AB, Hoover MD, Dickerson RM, Peterson EJ, Day GA, Breysse PN,
Kent MS, Scripsick RC. (2003) Surface area of respirable beryllium
metal, oxide, and copper alloy aerosols and implications for assessment
of exposure risk of chronic beryllium disease. Am. Ind. Hyg. Assoc. J.
64(3):297-305

Stefaniak, AB, Day GA, Hoover MD, Breysse PN, Scripsick RC. (2006)
Differences in dissolution behavior in a phagolysosomal stimulant fluid
for single-constituent and multi-constituent materials associated with
beryllium sensitization and chronic beryllium disease. Toxicol. In Vitro
20(1):82-95

Stefaniak AB, Chipera SJ, Day GA, Sabey P, Dickerson RM, Sbarra DC,
Duling MG, Lawrence RB, Stanton ML, Scripsick RC. (2008) Physicochemical
characteristics of aerosol particles generated during the milling of
beryllium silicate ores: implications for risk assessment.  J Toxicol
Environ Health A. 71(22):1468-81

Stiefel T, Schultze K, Zorn H, Tolg G.  (1980)  Toxicokinetic and
toxicodynamic studies on beryllium.  Arch Toxicol. Jul; 45(2):81-92

Sterner JH and Eisenbud M.  (1951) Epidemiology of Beryllium
Intoxification.  A M A Arch Ind Hyg Occup Med. Aug; 4(2):123-51

Stokes RF, Rossman MD. (1991)  Blood cell proliferation response to
beryllium: analysis by receiver-operating characteristics.  J Occup Med.
Jan; 33(1):23-8

Stokinger HE, Sprague GF, Hall RH, et al. (1950) Acute inhalation
toxicity of beryllium. I. Four definitive studies of beryllium sulfate
at exposure concentrations of 100, 50, 10 and 1 mg per cubic meter.Arch
Ind Hyg Occup Med 1:379-397

Stokinger HE, Altman KI, Salomon K. (1953) The effect of various
pathological-conditions on in vivo hemoglobin synthesis. I. Hemoglobin
synthesis in beryllium-induced anemia as studied with alpha-14C-acetate.
 Biochim Biophys Acta. Nov; 12(3):439-44

Stubbs J, Argyris E, Lee CW, Monos D, Rossman MD.  (1996)  Genetic
markers in beryllium hypersensitization.  Chest. Mar; 109 (3 Suppl):45S

Sutton M, Burastero SR.  (2003)  Beryllium chemical speciation in
elemental human biological fluids.  Chem Res Toxicol. Sep;
16(9):1145-54.

Swafford DS, Middleton SK, Palmisano WA, Nikula KJ, Tesfaigzi J, Baylin
SB, Herman JG, and Belinsky SJ. (1997) Frequent aberrant methylation of
p16INK4a in primary rat lung tumors. Molecular and Cellular Biology 17
(3): 1366-1374

Tan MH, Commens CA, Burnett L, Snitch PJ. (1996)  A pilot study on the
percutaneous absorption of microfine titanium dioxide from sunscreens. 
Australas J Dermatol. Nov; 37(4):185-7

Tarantino LM, Hubbs AF, Hoover MD, Delano DL, Wiltshire T, and Gordon T.
 (2008) Beryllium-induced sensitization and granulomatous lung disease
in murine models. Toxicologist 102(1): 223. Conference/Symposia
Proceedings (Abstract only)

Thomas CA, Bailey RL, Kent MS, Deubner DC, Kreiss K, Schuler CR.  (2009)
Efficacy of a program to prevent beryllium sensitization among new
employees at a copper-beryllium alloy processing facility.  Public
Health Rep. Jul-Aug;124 Suppl 1:112-24

Thorat DD, Mahadevan TN, Ghosh DK.  (2003)Particle size distribution and
respioratoryt deposition estimates of beryllium aerosols in an
extraction and processing plant.  Am Ind Hyg Assoc J.  64 (4): 522-527

Tinkle SS, Antonini JM, Rich BA, Roberts JR, Salmen R, DePree K, Adkins
EJ. (2003) Skin as a route of exposure and sensitization in chronic
beryllium disease.  Environ Health Perspect. Jul; 111(9):1202-8

Tinkle SS, Newman LS. (1997)  Beryllium-stimulated release of tumor
necrosis factor-alpha, IL-6 and their soluble receptors in chronic
beryllium disease.  Am J Respir Crit Care Med. Dec; 156 (6):1884-91 

Tinkle SS, Kittle LA, Schumacher BA, Newman LS. (1997) Beryllium induces
IL-2 and IFN-gamma in berylliosis.  J Immunol. Jan 1; 158(1):518-26

Turk JL and Polak L.  (1969)  Experimental studies on metal dermatitis
in guinea pigs.  Int Arch Allergy Appl Immunol. 36(1):75-81

Vacher J.  (1972) Immunological response of guinea pigs to beryllium
salts.  J Med Microbiol. Feb; 5(1):91-108

Van Cleave CD, Kaylor CT.  (1955) Distribution, retention, and
elimination of Be in the rat after intratracheal injection. Archives of
industrial health, 11:375–392.

VanOrdstrand HS, Hughes R, DeNardi JM, et al. (1945). Beryllium
poisoning. J Am Med Assoc129:1084-1090

Vainio H, Rice J. Beryllium revisted. (1997)  J Occup Environ Med
39:203-204

Vegni-Talluri M and GuiggianiV. (1967) Action of beryllium ions on
promary cultures of swine cells.  Carlogia 20: 355-367

Viet SM, Torma-Krajewski J, Rogers J. (2000) chronic beryllium disease
and beryllium sensitization at Rocky Flats: A case-control study. Am Ind
Hyg Assoc J 61:244-254

Votto JJ, Barton RW, Gionfriddo MA, Cole SR, McCormick JR, and Thrall
RS. (1987) A model of pulmonary granulomata induced by beryllium sulfate
in the rat. Sarcoidosis 4(1):71-76

Vorwald AJ. (1968) Biologic manifestations of toxic inhalants in
monkeys. In: Vagrborg H, ed. Use of Nonhuman primates in drug
evaluation: A symposium. Southwest Foundation for Research and
Education. Austin, Texas: University of Texas Press, 222-228

Vorwald AJ, Reeves AL. (1959) Pathologic changes induced by beryllium
compounds. Arch Ind Health 19:190-199

Vourlekis JA, RT Sawyer, LS Newman. (2000) Sarcoidosis: Developments in
etiology, immunology, and therapeutics. Adv Intern Med; 45:209-257

Wagoner J, Infante P, Bayliss D. (1980) Beryllium: an etiologic agent in
the induction of lung cancer, nonneoplastic respiratory disease and
heart disease among industrially exposed workers. Environ Res 21:15-34 

Wagner WD, Groth DH, Holtz JL, Madden GE, and Stokinger HE. (1969)
Comparative chronic inhalation toxicity of beryllium ores, bertrandite
and beryl, with production of pulmonary tumors by beryl. Toxicology and
Applied Pharmacology 15: 10-29

Ward E, Okun A, Ruder A, Fingerhut M, Steenland K. (1992) A mortality
study of workers at seven beryllium processing plants. Am J Ind Med
22:885-904

Warheit DB, Yuen IS, Kelly DP, Snajdr S, Hartsky MA.  (1996) Subchronic
inhalation of high concentrations of low toxicity, low solubility
particulates produces sustained pulmonary inflammation and cellular
proliferation. Toxicol Lett. Nov; 88(1-3):249-53

Weston A, Snyder J, McCanlies EC, Schuler CR, Andrew ME, Kreiss K,
Demchuk E.  (2005) Immunogenetic factors in beryllium sensitization and
chronic beryllium disease.  Mutat Res 592 (1-2): 68-78

Williams WJ and Williams WR. (1983)  Value of beryllium lymphocyte
transformation tests in chronic beryllium disease and in potentially
exposed workers.  Thorax. Jan; 38(1):41-4

WHO (1990) Health and safety guide no. 44: Beryllium. Geneva, World 
Health Organization

WHO (2001) Concise International Chemical Assessment (CICAD) Document 32
Beryllium and Beryllium compounds.  World Health Organization

Yoshida T, Shima S, Nagaoka K, Taniwaki H, Wada A, Kurita H, Morita K.
(1997) A study on the beryllium lymphocyte transformation test and the
beryllium levels in working environment. Ind Health 35:374-379 

Zaki MH, Lyons HA, Leilop L, Huang CT. (1987) Corticosteroid therapy in
sarcoidosis. A five-year, controlled follow-up study. N Y State J Med.
Sep; 87(9):496-9

Zakour RA, Glickman BW. (1984) Metal-induced mutagenesis in the lacI
gene of Escherichia coli. Mutation research, 126:9–18

Zissu D, Binet S, Cavelier C. (1996) Patch testing with beryllium alloy
samples in guinea pigs.  Contact Dermatitis.  Mar; 34(3):196-200

Zorn H, Stiefel T, Diem H. (1977) The significance of beryllium and its
compounds in industrial medicine. Zbl Arbeitsmed 27:83-88

 The third study (Mancuso et al.1979) restricted the cohort to workers
employed between 1942 and 1948.

  Schepers et al. (1957) reported concentrations in γ Be/ft3; however,
γ/ft3 is no longer a common unit. Therefore, the concentration was
converted to mg/m3. 

  While a total of 89 tumors were observed or palpated at the time of
autopsy in the BeSO4-exposed animals, only 76 tumors are listed as
histologically neoplastic. Only the new growths identified in single
midcoronal sections of both lungs were recorded.

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THIS INFORMATION IS DISTRIBUTED SOLELY FOR THE PURPOSE OF
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