Beryllium - Toxicology of Metals - page 415

and an increase in normoblasts. Macrocytic anemia
developed in rats and rabbits exposed to 0.43 mg Be/
m 3 and dogs exposed to 0.04 mg Be/m 3 as beryllium
sulfate for 100 days (Stokinger et al ., 1950). Hemato-
logical effects were not observed in rats, hamsters,
or monkeys exposed to 0.21 or 0.62 mg Be/m 3 as
bertranite or beryl ore, respectively, for 6-23 months
(Wagner et al ., 1969).
No evidence of microscopic abnormalities of the
bone marrow or spleen was observed in rats exposed
orally to

in cancer risk, with a standardized mortality ratio
(SMR) of 1.26 (95% CI, 1.12-1.42). Steenland and Ward
et al . (1992) extended the former cohort mortality study of
Beryllium Case Registry enrollees to include women and
an additional 13 years of follow-up. A comparison of 689
patients with beryllium disease within the general U.S.
population revealed a statistically signifi cant increase in
the risk of lung cancer, with 28 cancer deaths for SMR
of 2.0 (95% CI, 1.33-2.89). An excess in lung cancer was
found for both genders and was higher for individuals
with acute beryllium disease than those with CBD. The
results of these two studies indicate beryllium dose-
response relationship for cancer. A follow-up study by
Sanderson et al . (2001) comprised 142 lung cancer cases
and 5 age- and race-matched controls for each case. The
overall lung cancer mortality rate was 1.22 (95% CI,
1.03-1.43), and no signifi cant relationship was found
between the duration of employment and cancer risk.
Several authors have criticized the conclusions of the
Steenland and Ward's (1992) and Ward's (1992) studies
mainly because of the low excess in cancer risk and inad-
equate adjustment for the smoking habit (Toxicological
Profi le, 2002).
On the basis of these investigations, the International
Agency for Research on Cancer (IARC, 1993) classifi ed
beryllium as a group 1 carcinogen (suffi cient evidence
for carcinogenicity in humans). IARC (2001) noted
that (1) the epidemiological data generally showed
increases in observed lung cancers at most of the beryl-
lium processing plants, (2) these increases were gener-
ally associated with high exposure levels that occurred
before 1950, and (3) the highest risk of lung cancer
occurred in individuals with acute beryllium disease.
IARC (2001) also noted a number of limitations with
the existing cancer database (poor exposure charac-
terization, relatively low excess cancer risk). American
Conference of Governmental Industrial Hygienists
(ACGIH) and Deutsche Forschungsgemeinshaft (DFG)
consider beryllium and its inorganic compounds as sub-
stances that cause cancer in man (groups TLV- A1 and
MAK 1, respectively) (ACGIH, 2005). US EPA (2005)
located beryllium and its compounds in group EPA-B1
(probable human carcinogen, limited evidence of car-
cinogenicity from epidemiological studies) and EPA-L
(likely to produce cancer in humans). According to US
EPA, although the results of the Ward et al . (1992) study
are suggestive that occupational exposure to beryllium
can result in an increase in lung cancer mortality, the
interpretation of these fi ndings is limited by a number of
factors. These include lack of job history data, the limi-
tations in the available smoking habit data, and a possi-
bility that the workers were exposed to other potential
carcinogens. However, regardless of the shortcomings,
the results of follow-up mortality studies on the same

31 mg Be/kg/day for 2 years (Morgareidge
et al ., 1976).

≥

7.2.3.3 Endocrine Effects
Beryllium and its compounds were found to pro-
duce effects on the endocrine system. In a study of
workers at a plant manufacturing fl uorescent lamps,
1 of 17 workers exposed to beryllium who died from
chronic beryllium disease had marked hyperemia and
vacuolization in the histology of adrenal glands (Hardy
and Tabershaw, 1946).
Histological examination of monkeys exposed to
13 mg Be/m 3 as beryllium hydrogen phosphate or
0.184 mg Be/m 3 as beryllium fl uoride revealed marked
hypoplasia and hypotrophy of the adrenal gland. The
adrenal glands of monkeys exposed to 0.196 mgBe/
m 3 as beryllium sulfate presented no abnormalities
(Schepers, 1964).
No adverse effects were observed in the adrenal, thy-
roid, pituitary, or pancreas of dogs exposed to 12 mg/
Be/kg/day as beryllium sulfate in the diet for 143-172
weeks (Morgareidge et al ., 1976) or in rats exposed to
≥

31 mg Be/kg/day as beryllium sulfate in the diet for
2 years (Morgareidge et al ., 1975).

7.3 Carcinogenic Effects
7.3.1 Humans

A number of retrospective cohort mortality studies
examining workers at beryllium facilities have been
conducted in the United States. In general, the studies
carried out before 1987 that associated beryllium expo-
sure with lung cancer had a number of defi ciencies: they
were inadequately controlled for the confounding fac-
tors such as tobacco smoking, they included workers in
beryllium industry who were not actually exposed to
beryllium, the expected number of deaths from cancer
was miscalculated, or inappropriate controls were used
(Toxicological Profi le, 2002). The more recent studies
corrected some of the methodological faults of the pre-
vious studies. Ward et al . (1992) reported on a mortality
study of 9225 male workers at seven beryllium process-
ing plants and found a statistically signifi cant increase