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Managing Health Effects of Beryllium Exposure 6 Assessment of Other Health End Points The principal health end points now of interest in connection with inhaled beryllium—beryllium sensitization, chronic beryllium disease (CBD), and lung cancer—were discussed in Chapters 3, 4, and 5. As described in Chapter 3, CBD is primarily a disease of the lungs. Other systemic effects are not common and are usually secondary to CBD or related to extrapulmonary granulomatous lesions. In deriving a reference concentration for beryllium in air based on CBD, the U.S. Environmental Protection Agency (EPA 1998a,b) noted that systemic effects of inhaled beryllium other than those seen in CBD would be expected to occur only after exposure much greater than that after which CBD is observed. The oral reference dose (RfD) derived by EPA (1998a) is based on small-intestine lesions in a long-term study of dogs fed beryllium sulfate. No human studies that could be used to derive an oral RfD were identified by EPA. This chapter examines the literature relevant to determining whether inhaled beryllium has systemic health effects other than CBD and cancer that might be critical end points for use in deriving health-based standards. The focus is on studies of reproductive and developmental effects because these are often sensitive end points. Studies of oral and parenteral exposure are also considered in some cases. The following specific questions were formulated to guide the literature review: Have any studies examined the reproductive or developmental effects of beryllium at doses relevant to current occupational exposures? Have any studies distinguished the reproductive or developmental effects of different forms of beryllium? Are any other effects of beryllium relevant to current occupational exposures? Do effects other than cancer and sensitization that leads to CBD need to be considered in establishing worker health-protection standards?
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Managing Health Effects of Beryllium Exposure Those questions are addressed in the following sections. Reproductive and developmental effects of beryllium are considered first, then other potentially relevant health end points. REPRODUCTIVE AND DEVELOPMENTAL EFFECTS Reproductive and developmental toxicity of beryllium compounds has been reviewed by EPA (1998b), the Agency for Toxic Substances and Disease Registry (ATSDR 2002), and the American Conference of Governmental Industrial Hygienists (ACGIH 2006). Animal studies have included oral and parenteral exposure but not inhalation exposure. Reproductive and developmental outcomes have not been examined in epidemiologic studies of beryllium workers, and only one study of reproductive and developmental outcomes in workers that included consideration of beryllium exposure was identified. EPA’s (1998b) review focused on hazard assessment of environmentally relevant doses and concluded that “the potential of beryllium to induce developmental and/or reproductive effects has not been adequately assessed” (p. 50). It should be noted that many of the animal studies may have been conducted at doses that result in maternal toxicity and so might not have assessed effects directly on the fetus independently of effects on the mother. The animal studies reviewed include a chronic dog-feeding study in which beryllium sulfate was mixed in the diet at three doses (from 0.023 to 1.3 mg/kg per day) and administered to males and females from before mating through weaning of pups (Morgareidge et al. 1976) and two studies previously reviewed by EPA (1991) in which beryllium compounds were administered parenterally to rats (Clary et al. 1975; Mathur et al. 1987). No adverse reproductive or developmental effects were reported in the dog study, and mixed results were reported in the rat studies. EPA also noted that no reproductive or developmental effects were reported after paternal occupational exposure to beryllium by Savitz et al. (1989), who examined the effect of parents’ occupational exposure on risk of stillbirth, preterm delivery, and small-for-gestational-age infants in a case-control study that used data from the 1980 National Natality Survey and the 1980 National Fetal Mortality Survey. For stillbirths, case groups of 2,096 mothers and 3,170 fathers were examined for associations with 18 industrial or chemical categories. No maternal cases were listed for beryllium exposure, but 127 paternal cases associated with beryllium exposure were listed with an adjusted odds ratio (OR) of 1.0 (95% confidence interval [CI], 0.7-1.3). A similar analysis of preterm deliveries (363 mothers and 552 fathers) and small-for-gestational-age infants (218 mothers and 371 fathers) yielded no cases associated with maternal beryllium exposure. For paternal exposure, 23 cases of preterm delivery were associated with beryllium exposure (OR, 1.0; 95% CI, 0.5-2.0), and 16 cases of small-for-gestational-age infants were associated with beryllium exposure (OR, 0.9; 95% CI, 0.5-1.7). Thus, this study suggested no reproductive or developmental
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Managing Health Effects of Beryllium Exposure effects associated with paternal exposure and could not assess effects of maternal exposures, because of an absence of cases. ATSDR (2002) did not identify any human studies of reproductive or developmental effects of beryllium. Its review noted that concerns about the adequacy of animal studies of reproductive and developmental effects after oral beryllium exposure were said to be mitigated by the low absorption of ingested beryllium. Inhalation studies were noted as lacking. Although neither reproductive nor developmental effects were reported in the chronic dog-feeding study (Morgareidge et al. 1976), the design was noted to be nonconventional and to warrant low confidence in interpretation of its findings. The same group also conducted a 2-year study in which beryllium sulfate was administered to rats in drinking water (Morgareidge et al. 1975) and reported no effects in reproductive organs. Neither of those studies is reported in the peer-reviewed literature. ATSDR (2002) also identified a few parenteral studies that reported developmental effects of beryllium in rats and mice. Mathur et al. (1987) exposed pregnant rats by intravenous injection to beryllium nitrate at one-tenth the dose that was lethal to 50% of the animals (that is, one-tenth the LD50). Normal pups were delivered if the dose was administered on day 1, 12, 13, 15, or 17 after coitus, but all pups died 2-3 days after delivery. If the dose was administered on day 11 after coitus, all fetuses were resorbed. Day 11 is the day before formation of the placenta but a time when the maternal circulation is supplying nutrients to the fetuses. Thus, beryllium exposure early in pregnancy when blastocysts were supported only by uterine secretions did not interfere with implantation, and exposure later in pregnancy after formation of the placenta did not appear to affect in utero development. Developmental effects occurred in pregnant rats after intratracheal injection of beryllium oxide or beryllium chloride (Selivanova and Savinova 1986), and beryllium salts injected into pregnant mice reached the fetus and caused developmental abnormalities in offspring (Bencko et al. 1979; Tsujii and Hashishima 1979). ACGIH (2006) described five animal studies (Clary et al. 1975; Morgareidge et al. 1975, 1976; Selivanova and Savinova 1986; Sharma et al. 2002) and concluded that “the doses and dose regimes are unlikely to be relevant to human occupational exposure” (p. 4). No human studies were described. No reproductive or developmental studies of beryllium that were published after the EPA, ATSDR, and ACGIH reviews were identified. Consequently, EPA’s conclusion that the potential of beryllium to induce developmental or reproductive effects has not been adequately assessed is still warranted. OTHER EFFECTS Extrapulmonary effects of beryllium compounds are not common and are most often secondary to severe lung disease or related to extrapulmonary granulomatous lesions in humans. Systemic effects of beryllium in animals are gener-
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Managing Health Effects of Beryllium Exposure ally observed only at high doses. ATSDR (2002) provides a comprehensive review of both human and animal data. Cardiovascular effects in humans (cor pulmonale) and animals (heart enlargement or decreased arterial oxygen tension) were judged to be probably secondary to lung disease. Human case studies did not report significant effects on hematologic measures, but intermediate-duration, high-dose exposures caused anemia in several species. Hepatic effects, other than granulomas, have not been reported in humans or animals. Kidney stones and increased blood and urinary calcium have been reported in people with CBD, and a cohort mortality study of beryllium workers found an increased risk of death from chronic and unspecified nephritis, renal failure, and other renal sclerosis (Ward et al. 1992). Renal effects in animals were noted by ATSDR (2002) to be minor at sublethal doses. Some adrenal effects have been reported in animals. Neurologic effects have not been noted in humans or animals after inhalation of beryllium. No literature published after the ATSDR review that would cause increased concern about extrapulmonary effects of beryllium compounds was identified. SUMMARY Studies of the extrapulmonary effects of different forms of beryllium have not comprehensively evaluated doses relevant to current occupational exposures, but there is little indication that such studies would yield useful information. Studies of reproductive and development effects and studies of other extrapulmonary effects have generally been conducted only at doses higher than the lowest doses that induce CBD or cancer. The committee concludes that effects other than cancer and sensitization that leads to CBD do not need to be considered in establishing worker health-protection standards. Protection against such health effects will be afforded by exposure guidance designed to prevent CBD or cancer.