PRINCIPLES OF TOXICOLOGY - Biology East Borneo

14.6 TOXICOLOGY OF SELECTED METALS 337carcinogenic effect is increased risk of skin cancer. In addition to the risk of skin cancer, there ismounting 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 placedinorganic arsenic in group A (known human carcinogen) for exposure by both the oral and inhalationroute, and similar designations have been assigned by the American Conference of GovernmentalIndustrial Hygienists (ACGIH) and the Occupational Safety and Health Administration (OSHA).BerylliumBeryllium 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 inmaking 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-solubleberyllium compounds poses a greater threat to human health than does exposure to water-insolubleforms.Judging from animal studies, the several different forms of beryllium that have been studied arepoorly absorbed through both the gastrointestinal tract and the skin. The most important route by whichberyllium compounds are taken up by animals and humans is inhalation. There are very fewdose–response data regarding the health effects of beryllium and beryllium-containing compounds inhumans. Some data exist regarding decreased longevity and pulmonary effects resulting from inhalationexposure, but dose–response relationships are not well defined.Inhalation exposure of animals and humans to beryllium can result in two types of potentially fatalnonneoplastic respiratory disease: acute pneumonitis and chronic beryllium disease. Lethality anddecreased longevity appear to be due to the development of chemical pneumonitis. A 1948 investigationof acute beryllium pneumonitis in three U.S. beryllium plants reported that all of the cases of berylliumpneumonitis studied were associated with inhalation exposures to beryllium concentrations of >0.1mg/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 toconcentrations above the OSHA standard of 0.002 mg/m 3 . For chronic beryllium disease, doseresponserelationships are more difficult to determine, due to the lack of an established correlationbetween exposure histories and the incidence of disease. However, the number of cases of chronicberyllium 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 tothe 1970s, report significantly higher mortality rates in comparison with the U.S. general mortalityrates 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 inhalationexposure to beryllium and some of its compounds. Pneumonitis, with accompanied thickening of thealveolar walls and inflammation of the lungs, was reported in rats and mice exposed to beryllium forone 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 hadlittle hematological effect, but intermediate-duration exposure resulted in anemia in several animalspecies. Weight loss has been reported in some animal species after inhalation exposure to berylliumcompounds.No studies were discovered regarding death, systemic effects (other than some dermatologicalabnormalities), immunological effects, neurological effects, developmental effects, reproductive effects,genotoxic effects, or cancer in humans after oral or dermal exposure to beryllium or itscompounds.A number of studies have associated inhalation exposure to beryllium with an increased incidenceof human lung cancer. In general, these studies have been judged to have limited application due toinadequate controls in the studies related to confounding factors such as smoking, improperly