PRINCIPLES OF TOXICOLOGY

carcinogenic effect is increased risk of skin cancer. In addition to the risk of skin cancer, there is
mounting evidence that ingestion of arsenic may increase the risk of internal cancers.
The current daily oral reference dose (RfD) for arsenic is 3 × 10 –4 mg/kg. The USEPA has placed
inorganic arsenic in group A (known human carcinogen) for exposure by both the oral and inhalation
route, and similar designations have been assigned by the American Conference of Governmental
Industrial Hygienists (ACGIH) and the Occupational Safety and Health Administration (OSHA).
Beryllium
14.6 TOXICOLOGY OF SELECTED METALS 337
Beryllium is a hard, grayish metal that occurs as a chemical component of certain rocks, coal and oil,
soil, and volcanic dust. Most of the beryllium that is mined is converted into alloys, which are used in
making electrical or electronic parts and construction materials. Beryllium enters the environment (air,
water, and soil) as a result of natural and human activities. In general, exposure to water-soluble
beryllium compounds poses a greater threat to human health than does exposure to water-insoluble
forms.
Judging from animal studies, the several different forms of beryllium that have been studied are
poorly absorbed through both the gastrointestinal tract and the skin. The most important route by which
beryllium compounds are taken up by animals and humans is inhalation. There are very few
dose–response data regarding the health effects of beryllium and beryllium-containing compounds in
humans. Some data exist regarding decreased longevity and pulmonary effects resulting from inhalation
exposure, but dose–response relationships are not well defined.
Inhalation exposure of animals and humans to beryllium can result in two types of potentially fatal
nonneoplastic respiratory disease: acute pneumonitis and chronic beryllium disease. Lethality and
decreased longevity appear to be due to the development of chemical pneumonitis. A 1948 investigation
of acute beryllium pneumonitis in three U.S. beryllium plants reported that all of the cases of beryllium
pneumonitis studied were associated with inhalation exposures to beryllium concentrations of >0.1
mg/m 3 , primarily as beryllium sulfate or beryllium fluoride. For workers who were exposed after 1950,
beryllium pneumonitis has been virtually eliminated except in cases of accidental exposure to
concentrations above the OSHA standard of 0.002 mg/m 3 . For chronic beryllium disease, doseresponse
relationships are more difficult to determine, due to the lack of an established correlation
between exposure histories and the incidence of disease. However, the number of cases of chronic
beryllium disease has dramatically decreased in workers who were first exposed after 1950.
Several retrospective cohort studies of workers, who were exposed to beryllium from the 1940s to
the 1970s, report significantly higher mortality rates in comparison with the U.S. general mortality
rates for the time periods studied. Most of the workers reportedly experienced shortness of breath,
general weakness, and weight loss, and autopsies revealed granulomatous lung disease, lung fibrosis,
and heart enlargement.
As in humans, animal studies indicate that the respiratory tract is the primary target for inhalation
exposure to beryllium and some of its compounds. Pneumonitis, with accompanied thickening of the
alveolar walls and inflammation of the lungs, was reported in rats and mice exposed to beryllium for
one hour at ≥3.3 and 7.2 mg/m 3 (as beryllium sulfate), respectively, for 12 months or less.
Some animal species exhibit hematological effects from beryllium exposure. Acute exposure had
little hematological effect, but intermediate-duration exposure resulted in anemia in several animal
species. Weight loss has been reported in some animal species after inhalation exposure to beryllium
compounds.
No studies were discovered regarding death, systemic effects (other than some dermatological
abnormalities), immunological effects, neurological effects, developmental effects, reproductive effects,
genotoxic effects, or cancer in humans after oral or dermal exposure to beryllium or its
compounds.
A number of studies have associated inhalation exposure to beryllium with an increased incidence
of human lung cancer. In general, these studies have been judged to have limited application due to
inadequate controls in the studies related to confounding factors such as smoking, improperly