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CALCIUM AND ZINC MOLYBDATES 192 9 Calcium and Zinc Molybdates CALCIUM and zinc molybdates readily dissociate in the body into molybdenum compounds and calcium and zinc ions. Because little data exist on calcium and zinc molydates specifically, this chapter reviews the physical and chemical properties, toxicokinetics, toxicological, epidemiological, and exposure data on molybdenum compounds and zinc. The subcommittee used that information to characterize the health risk from exposure to calcium and zinc molybdates. The subcommittee also identified data gaps and recommended research relevant for determining the health risk from exposure to calcium and zinc molybdates. PHYSICAL AND CHEMICAL PROPERTIES The physical and chemical properties of calcium and zinc molybdates are presented in Table 9â1. OCCURRENCE AND USE Calcium and zinc molybdates are used as flame retardants in cellulosic materials and other polymers. Textile applications for calcium and zinc molybdates include furniture, draperies, upholstery seating in transportation vehicles, wall coverings, and carpets (FRCA 1998). Calcium and zinc molybdates are
CALCIUM AND ZINC MOLYBDATES 193 formed when calcium oxide (CaO) or zinc oxide (ZnO) is complexed with molybdenum trioxide (MoO3). These molybdates readily dissociate in the body, resulting in molybdemum (Mo) in various valence states, along with zinc and calcium ions (Stokinger 1981). Calcium molybdate can occur naturally as the ore Powellite (Stokinger 1981). TABLE 9â1 Physical and Chemical Properties of Calcium and Zinc Molybdates Property Value Reference Calcium molybdate Chemical formula CaMoO4 Budavari et al. 1989 CAS registry # 7789â82â4 Powmet 1999 Synonym Powellite Powmet 1999 Molecular weight 200.01 Budavari et al. 1989 Physical state Solid Powmet 1999 Melting point 965Â°C Powmet 1999 Solubility 0.005 g/100 mL in H2O at 25 Â°C Tsigdinos and Moore 1981 Density 4.38â4.53 g/cm3 Powmet 1999 Zinc molybdate Chemical formula ZnMoO4 Tsigdinos and Moore 1981 CAS registry no. 13767â32â3 Powmet 1999 Synonyms zinc molybdenum oxide, molybdic acid, zinc salt, Kemguard Powmet 1999 Molecular weight 225.31 Powmet 1999 Physical state Solid Powmet 1999 Solubility 0.5g/100 mL in H2O at 25Â°C Powmet 1999 Melting point 1,020Â°C Tsigdinos and Moore 1981 Molybdenum (Mo) exists in six valence states. The most important valence states in biological systems are Mo3+, Mo4+, Mo5+, and Mo6+ (Lener and Bibr 1984). In general, higher oxidation states lead to oxygen binding while lower oxidation states favor sulfur or nitrogen binding (EPA 1979). The principal dissolved Mo species in the natural environment is molybdate (EPA 1979). The recommended daily intake of Mo is 75â250 Âµg/d (NRC 1989). Mo is important
CALCIUM AND ZINC MOLYBDATES 194 biologically to humans, as it is an essential trace element in the Mo-flavoprotein enzyme xanthine oxidase (XO), where it functions as an electron transport agent. XO permits the oxidation of hypoxanthine and xanthine to uric acid. It is also a component of several other metalloenzymes, including aldehyde oxidase and sulfite oxidase (Tsongas et al. 1980). Zinc is an essential nutrient with a recommended daily allowance of 15 mg/d for males and 12 mg/d for females (NRC 1989). The toxicity of zinc in humans is considered to be quite low; toxicity normally occurs following ingestion of >2 g of zinc (Prasad 1976, as cited in ATSDR 1994). Calcium is an essential nutrient, with a recommended daily allowance of 800â1,200 mg/d depending upon a person's age (NRC 1989). No adverse effects from consumption of levels of calcium up to 2,500 mg/d in healthy adults have been reported. High calcium intakes may induce constipation, cause increased risks of urinary stone formation in males, and may inhibit the intestinal absorption of iron, zinc, and other essential minerals. Ingestion of very large quantities of calcium may result in hypercalciuria, hypercalcemia, and deterioration of renal function in both sexes (NRC 1989). Additional toxicity data on calcium are not included in this document, because the recommended daily allowance is considerably higher than exposure estimates in flame retardants applied to upholstery fabric. TOXICOKINETICS Molybdenum Compounds There are no toxicokinetic data on Mo compounds following dermal exposure. Only limited data were located regarding the absorption, distribution, metabolism, and excretion by humans of inhaled or ingested Mo compounds. A case study of four humans injected intravenously with 99Mo showed that 5-d cumulative urinary excretion ranged from 16.6% to 27.2% of the dose (50â100 ÂµCi), with the primary excretory pathway being the kidney. Fecal excretion was found to be 6.8% in one patient and less than 1% in another after 10 d (Rosoff and Spencer 1964). Studies by Fairhall et al. (1945) showed that Mo is rapidly absorbed and eliminated by the kidneys of experimental animals following oral exposure. Six guinea pigs were administered 50 mg of Mo orally, as molybdenum trioxide in a 10% gum arabic solution, and were observed for 4, 16, and 48 hr. The highest concentrations of Mo were excreted in the urine, while much smaller quantities were found in the feces. Rats dosed orally with molybdenum trioxide were
CALCIUM AND ZINC MOLYBDATES 195 found to have Mo levels distributed uniformly in the critical organs within 4 hr, while higher levels of Mo were found in the blood and bile. Two rabbits, administered 100 mg of molybdenum trioxide each via a stomach tube, also demonstrated similar rapid absorption of Mo, with rapidly rising blood levels. Mo was found to be rapidly eliminated from the kidneys, with urinary levels returning to baseline values within 72 hr. Fecal elimination, which comprised about 50% of the urinary levels, also occurred within 72 hr. The authors noted that significant quantities of Mo were stored in the bone. Arrington and Davis (1955) studied the toxicokinetics of Mo99 (in the form of molybdenum trioxide) in Long-Evans rats (18/dose) that were consuming both normal and high-calcium diets. Rats were dosed once orally with 15 ÂµC Mo99 at least 5 wk after initiation of the high-calcium diets. No significant differences in the absorption, retention, or excretion of Mo99 were observed between the groups of rats consuming the normal versus high-calcium diets. Mo99 was eliminated primarily by the kidney and excreted rapidly. Within 6 hr of oral administration of Mo 99, about 25% of the dose was excreted in the urine. At 12 hr, 50% of the dose was present in the urine. Mo99 was distributed primarily in the kidneys and blood, with smaller amounts in the bone, liver, and muscle. Mo tissue levels were determined in guinea pigs following 25 d of inhalation exposure to calcium molybdate (121.5 mg/m3) or molybdenum trioxide (157 mg/m3) (Fairhall et al. 1945). The highest concentrations of Mo were found in lung, kidneys, spleen, and bone. Analysis 2 wk after termination of exposure to calcium molybdate showed approximately 50â75% of the Mo remained in the tissues. In contrast, 2 wk following exposure to molybdenum trioxide, 25â50% of Mo remained in the tissues. Zinc Absorption Agren (1991) (as cited in ATSDR 1994) reported that zinc was present in human interstitial fluid (site of application) following dermal application of zinc oxide (dissolved in gum resin or hydrocolloids) to human forearms. No evidence for absorption into systemic circulation was provided. Agren (1990) (as cited in ATSDR 1994) and Hallmans (1977) (as cited in ATSDR 1994) determined that zinc readily permeates intact and damaged human skin following dermal application. However, penetration of zinc into systemic circulation was not determined.
CALCIUM AND ZINC MOLYBDATES 196 Keen and Hurley (1977) (as cited in ATSDR 1994) determined that when zinc (as zinc chromate) was dissolved in oil and topically applied to rats, absorption of zinc in the bloodstream occurred. No other animal studies were identified regarding dermal absorption of zinc. Data suggest that zinc is absorbed into systemic circulation via the lungs following inhalation exposures. Hamdi (1969) (as cited in ATSDR 1994) found that zinc blood levels were elevated in workers occupationally exposed to zinc fumes. Drinker and Drinker (1928) (as cited in ATSDR 1994) determined that inhalation exposure of cats to zinc oxide fumes for up to 3.25 hr resulted in increased levels of zinc in the pancreas, kidney, and liver. In both studies, oral absorption of zinc particles following ciliary clearance and swallowing could account for all, or a significant portion, of the absorbed zinc. In the Drinker and Drinker (1928) study (as cited in ATSDR 1994), the swallowing of zinc particles during grooming activities may have also accounted for the increased tissue zinc levels. The estimated rate of oral absorption of zinc in humans is between 8% and 81%, depending on an individual's diet (ATSDR 1994). People who are not zinc-deficient will absorb about 20â30%, while individuals who are zinc-deficient absorb more (ATSDR 1994). Two studies measured the peak blood concentrations of zinc in volunteers following oral ingestion of zinc sulfate and determined that peak blood Zn2+ concentrations were reached within 3 hr (Neve et al. 1991, as cited in ATSDR 1994; Sturniolo et al. 1991, as cited in ATSDR 1994). The presence of cadmium, mercury, copper, or other trace metals can diminish zinc absorption by inhibiting zinc transport across the intestinal wall (ATSDR 1994). Zinc absorption in male Wistar rats was approximately 40â48% when diets contained 0.81 mg of radio- labeled zinc/kg as zinc chloride or zinc carbonate (Galvez-Morros et al. 1992). ATSDR (1994) noted that fractional absorption of zinc in immature organisms usually exceeds the fractional absorption of zinc in adults. Distribution No relevant human or animal studies were located that investigated the distribution of zinc following dermal exposure to zinc compounds. No inhalation studies were identified that investigated the distribution of zinc in humans. Cats exposed to zinc oxide (12â61 mg Zn2+/kg-d) for 3 hr, had increased zinc levels in the pancreas, liver, and kidneys, suggesting that absorption of zinc had taken place in the lungs (Drinker and Drinker 1928, as cited in
CALCIUM AND ZINC MOLYBDATES 197 ATSDR 1994). Oral absorption through swallowing or grooming, however, cannot be ruled out. Absorption rates were not estimated in this study. The distribution of zinc to tissues has not been measured in humans following ingestion. However, there are a number of studies in rodents that have investigated the distribution of zinc following oral exposure to zinc compounds. Weigand and Kirchgessner (1992) (as cited in ATSDR 1994) determined that rats fed 1.1 mg Zn2+/ kg-d for an unspecified amount of time, had greater amounts of zinc distributed primarily to the kidneys and pancreas than to the liver. Administration of zinc acetate to rats (191 mg Zn2+/kg-d in food for 3 mo) increased zinc levels in the heart, spleen, kidneys, liver, bone, and blood (Llobet et al. 1988). Mice fed either 76.9 mg Zn2+/ kg-d as zinc sulfate (Schiffer et al. 1991, as cited in ATSDR 1994) or 38 mg Zn2+/kg-d as zinc nitrate (Cooke et al. 1990, as cited in ATSDR 1994) for 1 mo had increased levels of Zn2+ in the kidneys and liver. Newborn, young, or adult mice that received a single oral dose of 4.6 mg Zn2+/kg as zinc chloride generally had the highest level of zinc in the liver, kidneys, lungs, bone, and muscle 1 d after dosing (He et al. 1991, as cited in ATSDR 1994). Metabolism Although zinc is not metabolized in the body, it can bind to many molecules in the body. For instance, zinc induces and binds to metallothionein (a metal binding protein) in vivo. Metallothionein therefore acts as a protective mechanism against zinc toxicity (Goyer 1996). Indirect evidence suggests that zinc also complexes with reduced glutathione in the liver in rats following intraperitoneal injection (Alexander et al. 1981, as cited in ATSDR 1994). Excretion No studies were located that investigated the excretion of zinc in humans or animals following dermal application of zinc compounds. Following inhalation exposures, elevated levels of zinc were found in the urine of workers exposed to zinc oxide fumes containing unknown levels of Zn2+(Hamdi 1969, as cited in ATSDR 1994). No other studies were identified that investigated the excretion of zinc following inhalation of zinc compounds. Following oral exposure, the primary route of zinc excretion in humans and rats is the feces. Zinc can also be excreted in the urine, saliva, hair, and sweat (ATSDR 1994). Malnutrition or low dietary levels of zinc may promote in
CALCIUM AND ZINC MOLYBDATES 198 creased levels of urinary zinc excretion and are thought to result from increased levels of tissue breakdown and catabolism (ATSDR 1994). HAZARD IDENTIFICATION1 Dermal Exposure Irritation Molybdenum Compounds No human data on the effects of dermal exposure to Mo compounds were identified. No irritation effects were seen when Mo compounds were applied to intact or abraded skin of rabbits (Stokinger 1981). Zinc There are two case studies in the scientific literature that suggest that occupational dermal exposure to zinc at high levels may cause or contribute to a skin condition referred to as âzinc oxide poxâ which is described as itchy papular-pustular eruptions that occur in the pubic region, inner surface of the thigh, axilla, and inner surface of the arms. Turner (1921) (as cited in ATSDR 1994) found that 14 out of 17 men developed zinc oxide pox at least once during their employment in the bagging or packaging of zinc oxide. The incidence of zinc oxide pox in the study by Turner (1921) (as cited in ATSDR 1994) has been attributed to poor hygiene among the workers, and not necessarily zinc oxide exposure. In a similar study, Batchelor et al. (1926) (as cited in ATSDR 1994) found that only 1 of a total of 24 workers occupationally exposed to zinc dusts developed zinc oxide pox. Agren (1990) (as cited in ATSDR 1994) reported that application of patches containing 25% zinc oxide (dose=2.9 mg Zn2+/m3) to the skin of human volunteers did not produce dermal irritation following 48 hr of exposure. The dermal irritancy of several zinc compounds in aqueous solution or suspension has been investigated in mice, rabbits, and guinea pigs (Lansdown 1991, as cited in ATSDR 1994). In this study, animals were treated topically 1In this section, the subcommittee reviewed toxicity data on calcium and zinc molybdates, including the toxicity assessment prepared by the U.S. Consumer Product Safety Commission (Hatlelid 1999).
CALCIUM AND ZINC MOLYBDATES 199 once a day for 5 consecutive days with one of the following zinc compounds (w/v): zinc oxide (20% suspension in Tween 80), zinc chloride (1% aqueous solution), zinc sulfate (1 % aqueous solution), zinc pyrithione (20% suspension), and zinc undecylenate (20% suspension). In open patch tests, zinc chloride was a potent irritant in all three species and caused the formation of epidermal hyperplasia and ulceration. All other compounds produced less severe erythema than zinc chloride, and none of the compounds caused ulceration or scaling over the 5-d test period. These compounds were also tested in a second group of rabbits using occlusive bandages at the test site. Occlusive patch testing with zinc chloride produced severe dermal irritation in rabbits within 3â5 d of application. Occlusive patch testing of zinc acetate produced moderate irritation. Occlusive patch testing with zinc oxide, sulfate, pyrithione, or undecylenate produced little dermal irritation. Histological examination of skin samples from animals treated with zinc chloride or zinc acetate showed evidence of acanthosis, parakeratosis, hyperkeratosis, and inflammatory changes in the epidermis and in the more superficial aspects of the dermis. Systemic Effects Molybdenum Compounds No data were identified on systemic effects of Mo compounds following dermal exposure. Zinc DuBray (1937) (as cited in ATSDR 1994) reported that a worker developed microcytic anemia and had low platelet counts after being exposed to zinc chloride solutions. The concentration of zinc was not reported. No systemic effects following dermal exposures of animals to zinc were identified. Inhalation Exposure Systemic Effects Molybdenum Compounds Twenty-five workers in a Mo roasting plant (where Mo sulfide is converted to molybdenum oxides) in Colorado were estimated to be exposed to soluble
CALCIUM AND ZINC MOLYBDATES 200 Mo compounds (primarily molybdenum trioxide) at a concentration of 9.5 mg/m3 for an 8-hr time-weighted average exposure. Exposure concentrations were estimated from respirable dust samples taken at the plant. Workers showed large increases in serum ceruloplasmin (50.5 mg/dL versus 30.5 mg/dL in controls) (Walravens et al. 1979). Controls consisted of 24 students and research personnel at the University of Colorado Medical Center. Workers were employed at the plant from 0.5 to 20 yr, with the average employment being 4 yr. Plasma and urine Mo levels were elevated in the workers compared with controls (0.9â36.5 Âµg/dL vs. 0â3.4 Âµg/dL in plasma and 120â11,000 Âµg/L vs. 4â347 Âµg/L in urine). No other adverse health effects were reported. The authors hypothesized that elevated serum ceruloplasmin levels stemmed from mobilization of tissue copper reserves within the hepatocyte, with subsequent ceruloplasmin synthesis and release to prevent intracellular copper toxicity. A study conducted on 73 workers from a Russian copper-molybdenum processing plant found increased levels of uric acid in the blood (Akopyan 1964). Additional details on the exposure levels of these workers were not provided. Review articles (Stokinger 1981; ACGIH 1991) reported elevated serum uric acid levels and signs of gout, including pain and deformities of joints in workers and inhabitants in Mo-rich areas in Armenia. Lener and Bibr (1984), in a review article, reported an increased incidence of nonspecific symptoms, including weakness, fatigue, headache, anorexia, and joint and muscle pains among mining and metallurgy workers exposed to 60â 600 mg/m3 Mo. No other reports of effects from industrial Mo exposure were cited. Mogilevskaya (1967) reported that 3 of 19 workers exposed to Mo compounds (Mo and molybdenum trioxide) at two industrial facilities showed early signs of pneumoconiosis on X-ray examination. These three individuals had worked at the facilities for 4â7 yr and their exposures, although variable, were reported to range from 1â19 mg/m3. Fairhall et al. (1945) observed that 5/24 guinea pigs died following exposure via inhalation to 195 mg/m3 CaMoO4 (125 mg Mo/m3) dust for 1 hr/d, 5 d/wk for 5 wk, but no other signs of toxicity were observed. Guinea pigs (51 animals, sex not reported), who were exposed to 250 mg MoO3/m3 (164 mg Mo/m3) using the same exposure regime, experienced severe eye and nasal irritation, loss of appetite and weight, diarrhea, muscular incoordination, and loss of hair. Following the 10th exposure, 26/51 animals died. Two 13-wk studies were conducted by NTP (1997) in which F-344/N rats and B6C3F1 mice (10/sex/group) were exposed to molybdenum trioxide for 6.5 hr/d, 5 d/wk at concentrations of 0, 1, 3, 10, 30, or 100 mg/m3. All rats and mice survived to the end of the study. Significant increases in liver copper concentrations were observed in female mice exposed to 30 mg/m3 and in male and female mice exposed to 100 mg/m3 (males: 11.51 Âµg/g in the 100-mg/m3 exposure group versus 8.19 Âµg/g in controls; females: 6.51 and 6.98 Âµ/g in the 30-
CALCIUM AND ZINC MOLYBDATES 201 and 100-mg/m3 dose groups, respectively, versus 5.68 Âµ/g in controls). The increased copper concentrations were not regarded as being an adverse effect relevant for deriving a LOAEL and a NOAEL. No other clinical findings were observed in either rats or mice. Additionally, no significant differences in absolute or relative organ weights, sperm counts, or motility were noted in rats or mice. In the same NTP study (1997), rats (F344/N) and mice (B6C3F1) (50/sex/ dose) exposed for 6 hr/d, 5 d/wk at concentrations of 0, 10, 30, or 100 mg/m3 molybdenum trioxide for 2 yr experienced a significant exposure- dependent increase in blood Mo concentrations. Male and female rats exposed to 30 or 100 mg/m3 experienced significantly increased incidences of chronic alveolar inflammation. Incidences of hyaline degeneration in the nasal respiratory epithelium in male rats exposed to 30 or 100 mg/m3 and in all exposed groups of females rats were significantly greater than those of the control groups. Incidences of hyaline degeneration in the nasal olfactory epithelium of all exposed groups of females were also statistically significant. For male mice, the incidences of histiocyte cellular infiltration in all exposed groups were significant. Incidences of hyaline degeneration of the respiratory epithelium of the nasal cavity in female mice at 100 mg/m3 were significantly greater than those in the controls (NTP 1997). Based on the 2-yr NTP study, the LOAEL is 10 mg/m3 for increased incidences of hyaline degeneration in the nasal respiratory epithelium and nasal olfactory epithelium in female rats. Zinc There are a number of case reports of deaths in humans following high inhalation exposures to airborne mixtures containing zinc. Ten of 70 persons died within four d following intense exposure to a smoke mixture containing approximately 33,000 mg Zn2+/kg as zinc chloride along with other compounds (Evans 1945, as cited in ATSDR 1994). These mixtures were thought to include unknown concentrations of hexachloroethane, calcium silicate, and an igniter. Milliken et al. (1963) (as cited in ATSDR 1994) describes the case of a fireman who died following exposure to a high but unknown concentration of a smoke mixture generated from a zinc chloride smoke bomb. Two soldiers developed severe respiratory distress syndrome and died 25â32 d following exposure to a high concentration of zinc chloride smoke mixture generated from a zinc chloride smoke bomb (Hjortso et al. 1988). No exposure levels were reported in this study. Autopsies performed on the soldiers revealed diffuse microvascular obliteration, widespread occlusion of the pulmonary arteries, and extensive interstitial and intra- alveolar fibrosis of the lungs. Nausea has been reported
CALCIUM AND ZINC MOLYBDATES 202 among persons following intense inhalation exposures to zinc chloride and zinc oxide (Hammond 1944, as cited in ATSDR 1994; Evans 1945, as cited in ATSDR 1994; Rohrs 1957, as cited in ATSDR 1994; Johnson and Stonehill 1961, as cited in ATSDR 1994; Schenker et al. 1981, as cited in ATSDR 1994). Routine blood chemistries and examinations revealed no liver disease among 12 workers involved in the manufacture of brass alloys, with 4â21 yr of exposure to zinc oxide (Hamdi 1969, as cited in ATSDR 1994). McCord et al. (1926) (as cited in ATSDR 1994) reported that several workers from the galvanized industry had decreased red blood cell counts. Workers investigated by Hamdi (1969) (as cited in ATSDR 1994) had normal red blood cell counts. Various adverse pulmonary effects and reduced survival rates were reported in female rodents following exposure to zinc oxide/hexachloroethane smoke (119 mg Zn2+/m3 for 1 hr/d, 5 d/wk for up to 20 wk) (Marrs et al. 1988). The authors noted that the zinc oxide/hexachloroethane smoke contained a number of toxic chemicals including carbon tetrachloride. Therefore, it is not certain whether the toxic effects observed in this study can be solely attributed to the inhalation of zinc particles. Immunological Effects Molybdenum Compounds No data were identified on the immunological effects of Mo compounds following inhalation exposure. Zinc There are three case reports in the literature that found that the inhalation of high concentrations of zinc- containing compounds appeared to stimulate changes in the immune system. Farrell (1987) reported a case study of a worker who developed hives and angioedema (suggestive of an immediate or delayed IgE response) following exposure to a low dose of zinc fumes. The signs and symptoms of toxicity were repeated in a challenge test, suggesting that the patient had developed sensitization to zinc compounds. A correlation between exposure to zinc oxide and the proportion of activated T-cells, T-helper cells, T-inducer cells, T-suppressor cells, and activated killer T-cells, was observed among 14 welders approximately 20 hr following exposure to zinc oxide (Blanc et al. 1991, as cited in ATSDR 1994). Zinc oxide exposure levels were estimated to be approximately 77â153 mg Zn2+/m3. Ameille et al. (1992) (as cited
CALCIUM AND ZINC MOLYBDATES 203 in ATSDR 1994) reported on a case of a smelter worker who had elevated levels of lymphocytes in the bronchoalveolar lavage fluid following exposure to unknown concentrations of zinc fumes. Marrs et al. (1988) did not observe any abnormalities in the lymph nodes, thymus, or spleen tissue of female rats, mice, or guinea pigs killed at 18 mo following a 20-wk exposure to zinc oxide/hexachloroethane smoke at concentrations as high as 119.3 or 121.7 mg Zn2+/m3 for 1 hr/d, 5 d/wk. Reproductive and Developmental Effects Molybdenum Compounds No data were identified on reproductive or developmental effects of Mo compounds following inhalation exposure. Zinc No studies in humans were identified regarding reproductive or developmental effects following inhalation exposures to zinc. Pathological examination 17 mo after exposure of rats, guinea pigs, and mice to zinc oxide/ hexachloroethane smoke (1 hr/d, 5 d/wk for 20 wk) at concentrations as high as 119.3 or 121.7 mg zinc/m3 produced no treatment-related abnormalities in the mammary glands, ovaries, or fallopian tubes (Marrs et al. 1988). Carcinogenicity Molybdenum Compounds Information on the carcinogenicity of calcium and zinc molybdates was not found. However, data on molybdenum trioxide are available from two chronic inhalation studies conducted in F-344/N rats and B6C3F1 mice (50/sex/group) that were exposed at concentrations of 0, 10, 30, or 100 mg/m3 of molybdenum trioxide for 6 hr/d, 5 d/wk for 103 wk (NTP 1997). Incidences of alveolar/ bronchiolar adenoma or carcinoma (combined) were increased in low-, mid-, and high-dose males (1/50, 1/50, 4/50, respectively, compared to 0/50 in controls). In the larynx, incidences of squamous metaplasia of the epithelium lining the base of the epiglottis in all exposed groups of male and female rats were
CALCIUM AND ZINC MOLYBDATES 204 significantly greater than those in the control groups and rose with increasing exposure concentration (11/50, 16/50, 39/50 males in low-, mid- and high-dose groups, respectively, vs. 0/50 in controls; 18/50, 29/50, 49/50 females in low-, mid-, and high-dose groups, respectively, vs. 0/50 in controls). The incidences of alveolar/ bronchiolar carcinoma were significantly greater in all exposed groups of male mice (16/50, 14/49, and 10/50) than in the control group (2/50). In addition, the incidences of alveolar/bronchiolar adenoma or carcinoma (combined), in male mice, exposed at concentrations of 10 or 30 mg/m3 (27/50 or 21/49), were also significantly greater than the control group (11/50), while the incidence in the 100 mg/m3 dose group (18/50) was not. In female mice, the incidence of alveolar/bronchiolar adenoma or carcinoma (combined) was significantly greater in the 100 mg/m3 dose group (15/49) than controls (3/50), but incidences in the 10 and 30 mg/m3 dose groups were not significant (6/50 and 8/49). Incidences of metaplasia of the alveolar epithelium of minimal severity in the centriacinar region of the lung were significantly increased in all exposed groups of mice. The incidences of squamous metaplasia of the epithelium lining the base of the epiglottis were significantly increased in all exposed groups of males and females. In both male and female mice, the incidences of hyperplasia of the laryngeal epithelium at level II of the larynx rose with increasing exposure concentration, but were statistically significant only in the highest dose group. Based on these results, NTP reported that there was some evidence of carcinogenicity for male and female mice, but equivocal evidence of carcinogenicity in male rats exposed for 2 yr. Zinc Excess lung cancer mortality was detected among persons living in an abandoned zinc/lead mining area in the midwestern United States as compared with state and national age- and sex-specific lung cancer rates (Neuberger and Hollowell 1982). However, it was determined that the excess mortality was not related to environmental exposure to zinc or lead. Confounding exposure factors such as smoking and occupation, that might have accounted for the observed elevation in lung cancer mortality, were not addressed. A second study by Logue et al. (1982) investigated mortality among a cohort of 4,802 male workers from two zinc refining plants and seven copper refining plants. Overall mortality and death from specific cancers was not elevated for the whole cohort. Cancer mortality rates were not computed separately for the 978 zinc refinery workers. Therefore, it cannot be determined from this study whether exposure to zinc increases cancer mortality in male zinc refinery workers.
CALCIUM AND ZINC MOLYBDATES 205 Marrs et al. (1988) found that female mice exposed to mean concentrations of zinc of 1.3, 12.8, or 121.7 as zinc oxide/hexachloroethane smoke (1 hr/d, 5 d/wk for 20 wk) had a statistically significant trend in the prevalence of alveologenic carcinoma, with the frequency of this tumor reaching significance in the high-dose group at 13 mo postexposure. No increase in tumor frequency occurred in female rats or guinea pigs exposed to similar concentrations by an identical dosing regimen. The authors noted that the zinc oxide/hexachloroethane smoke contained a number of other chemicals including carbon tretrachloride which is an animal carcinogen. Therefore, carcinogenic effects cannot be solely attributed to zinc oxide. Oral Exposure Systemic Effects Molybdenum Compounds A summary of the toxicity studies following oral exposures to Mo compounds is presented in Table 9â2. Plants in the village of the exposed population was 30 and 190 times higher, respectively, than that of the control villages. The estimated average intake levels of Mo and copper in the exposed population were 0.14â0.21 and 0.07â0.14 mg/kg-d, respectively, for a 70-kg adult; in the control population the levels were 0.01â0.03 and 0.14â0.21 mg/kg-d for Mo and copper, respectively. Three hundred villagers (84 adults) from the exposed population and 100 from the control group (78 adults) underwent medical examinations. Thirty-one percent of the exposed adult population and 17.9% of the controls demonstrated gout-like symptoms that were characterized by pain, swelling, inflammation, and deformities of the joints. All individuals had increased uric acid content of the blood. In a sub study, 52 adults from the exposed population and five of the controls underwent more detailed clinical examinations, including measurement of copper, Mo, uric acid, and xanthine oxidase concentrations in blood and Mo, copper, and uric acid concentrations in urine. Their average uric acid content was 6.2 mg in comparison to 3.8 mg in controls. Serum Mo and serum xanthine oxidase levels were positively correlated with serum uric acid levels. Increasing urinary excretion of copper was positively correlated with increasing serum levels of Mo. Based on the study findings, an intake level of 0.14 mg/kg-d was designated as the lowest observed adverse effect level (LOAEL) because of concern regarding increased serum uric acid levels (EPA 1999).
CALCIUM AND ZINC MOLYBDATES 206 TABLE 9â2 Oral Toxicity Molybdenum Compounds Species, Strain, Dose (mg/kg-d) Duration Effects NOAEL/ Reference Sex, Number LOAEL (mg/kg- d) Humans, M/F, Mo: 0.14â0.21 NS Increased serum uric LOAEL: 0.14 Kovalsky et al. 300 exposed, Cu: 0.07â0.14 acid levels 1961 100 control Humans, M, 4 Mo: up to 1,540 4d Increased urinary ND Deosthale and excretion of copper; no Gopalan 1974 effect on uric acid levels Rat, NS, 10/dose CaMoO4 4 mo LD50:101 mg/kg-d ND Fairhall et al. MoO3 LD50:125 mg/kg-d 1945 (NH4)2MoO4 LD50:333 mg/kg-d Rat, Long- Mo: <0.1 or 8 Weaning to 11 Growth retardation; LOAEL: ~2 Jeter and Davis Evans, M/F, 4 Cu: 2 wk depigmentation; male 1954 or 8/dose Mo: <0.1, 2, 8, infertility (8, 14 mg/kg- 14 d Mo) Cu: 0.5 Rat, Long- Mo: <0.1 or 8 Gestation and Decreased newborn ND Jeter and Davis Evans, F, 4 or 8/ Cu: 2 weaning weights 1954 dose Mo: <0.1, 2, 8, 14 Cu: 0.5 CaMoO4, calcium molybdate; Cu, copper; F, female; LD50, lethal dose to 50% of test animals; M, male; Mo, molybdenum; MoO3, molybdenum trioxide; (NH4)2MoO4, ammonium molybdate; ND, not determined; NS, not specified.
CALCIUM AND ZINC MOLYBDATES 207 The effects of ingestion of Mo in drinking water were investigated in residents of two Colorado cities exposed to low and high levels of Mo over a 2-yr period (EPA 1979, as reported in IRIS). The low-Mo group consisted of 42 individuals from Denver, Colorado (Mo drinking water concentrations ranged from 2 to 50 Âµg/ L). The high-Mo group consisted of 13 college students from Golden, Colorado (Mo drinking water concentrations were greater than or equal to 200 Âµg/L). Urinary Mo and copper levels, and serum levels of ceruloplasmin and uric acid were compared between the two exposure groups. Subjects in the low-exposure group exhibited no adverse effects. Subjects in the high-exposure group had higher mean urinary Mo (187 vs. 87 Âµg-d), higher mean serum ceruloplasmin (40.31 vs. 30.41 mg/mL), and lower mean serum uric acid, levels (4.35 vs. 5.34 mg/100 mL) in comparison to the low-exposure group. The authors calculated NOAELs for both the low- and high-exposure groups (incorporating in the dietary Mo) of 4 Âµg/kg-d and 8 Âµg/kg-d, respectively, assuming a 2-L/d water consumption rate and a 70 kg body weight. Deosthale and Gopalan (1974) investigated the effects of dietary Mo on uric acid and copper excretion in four adult males fed diets based on sorghum varieties containing widely varying amounts of Mo for 10 d. The urinary excretion of uric acid was unaltered at Mo intake levels up to 1,540 Âµg/d (about 0.022 mg/kg-d). Urinary excretion of copper increased in relationship to dietary Mo intake, where intake levels of 0.002 or 0.026 mg/kg-d resulted in urinary excretion of copper at 24 or 77 Âµg/d, respectively. Fairhall et al. (1945), in a series of studies in groups of 10 rats, determined that the oral LD50 for daily administration of CaMoO4 in food for approximately 4 mo was 101 mg/kg-d. Rats exhibited loss of appetite, weight loss, listlessness, and rough coat. The LD50 for MoO3 and (NH4)2MoO4 following similar dosing regimes were 125 and 333 mg/kg-d, respectively. Based on this data it appears that calcium trioxide is a reasonable surrogate for calcium molybdate. Fairhall et al. (1945) injected male guinea pigs (six or eight/group) intraperitoneally with Mo compounds in 2 mL of isotonic chloride solution and observed their mortality at 4 d, 4 wk, and 4 mo. Mortality of guinea pigs dosed with calcium molybdate, in amounts of 0.1 g Mo, reported mortality ratios of 0/6, 0/6, and 1/6 at 4 d, 4 wk, and 4 mo. In contrast, in animals dosed with Mo trioxide (0.1 g Mo), the mortality ratios were 6/8, 6/8, and 6/8 at 4 d, 4 wk, and 4 mo, respectively. No additional data were provided. Groups of guinea pigs (eight/dose) received oral doses of either molybdenum trioxide or calcium molybdate (dissolved in a 10% gum arabic solution) for approximately 95 d (Fairhall et al. 1945). Mortality rates for animals dosed with 25, 100, and 200 mg Mo/d were 1/8, 2/8, and 2/8, respectively, for calcium molybdate and 6/8, 8/8, and 8/8, respectively, for molybdate trioxide. Molybde
CALCIUM AND ZINC MOLYBDATES 208 num trioxide appeared to be more toxic than calcium molybdate. The mortality rate of animals dosed with calcium molybdate did not rise above 25% for any dose group. No additional data on the nonlethal effects of these compounds were provided. Jeter and Davis (1954) reported on the effects of Mo in the diets of male and female Long-Evans rats from weaning up to 11 wk. Rats (four or eight/sex/ group) were fed combinations of Mo (as NaMoO4Â· 2H2O) and copper (as CuSo4Â·5H20) in their diets, ad libitum, with concentrations consisting of either <1 or 80 ppm Mo and 20 ppm copper or <1, 20, 80, or 140 ppm Mo and 5 ppm copper. (These doses were equivalent to about <0.1 or 8 mg/kg-d Mo and 2 mg/kg-d copper or <0.1, 2, 8, or 14 mg/kg-d Mo and 0.5 mg/kg-d copper, as reported in EPA 1999.) The growth rates of male rats fed 5 ppm of copper and 20, 80, or 140 ppm of Mo were significantly retarded. Growth rates were significantly retarded in female rats fed 5 ppm of copper and either 80 or 140 ppm of Mo. No effects on growth were reported in rats when the copper content in diets was 20 ppm. Achromotrichia (depigmentation of the hair) and alopecia were observed in some rats fed diets containing 80 or 140 ppm of Mo. Depigmentation was occasionally observed in rats receiving approximately 20 ppm Mo. Male infertility was observed in 75% of male rats fed 80 or 140 ppm of Mo. Examination of the testes revealed degeneration of the seminiferous tubules. The 2-mg/kg-d dose represents a LOAEL in this study based on retarded growth levels in male rats and depigmentation. Zinc Zinc is an essential nutrient. The NRC (1989) has established a recommended dietary allowance for zinc of 15 mg/d for males and 12 mg/d for females (NRC 1989). However, chronic ingestion of more than 15 mg/d in addition to dietary intake is not recommended without medical supervision because of the potential of aggravating copper levels in persons who are already marginally copper deficient (NRC 1989). The toxicity of zinc in humans is considered quite low, with toxicity normally occurring following ingestion of more than 2 g of zinc (Prasad 1976, as cited in ATSDR 1994; NRC 1989). No human studies reported death following oral intake of high doses of zinc. Several LD50 values have been reported for rats and mice exposed to various zinc compounds. These LD50 values include 237, 293, 528, and 623 mg Zn/kg-d for rats and 86, 204, 605, and 390 mg Zn/kg-d for mice, following oral dosing with zinc acetate, zinc nitrate, zinc chloride, and zinc sulfate, respectively. Ingestion of zinc-containing compounds has resulted in a variety of gastrointestinal, hematological, and renal effects in humans and animals. Vomiting,
CALCIUM AND ZINC MOLYBDATES 209 abdominal cramps, and diarrhea, in several cases with blood, have been observed following ingestion of zinc sulfate. In one case report, an English school girl who ingested 440 mg zinc sulfate/d (2.6 mg Zn2+/kg-d) in capsules (a medically prescribed treatment for acne) reported epigastric discomfort (Moore 1978, as cited in ATSDR 1994). A week later she was admitted to the hospital. She was diagnosed with anemia and passed melanic stools, indicative of gastrointestinal bleeding. Gastrointestinal upset (abdominal cramps, vomiting, nausea) was reported in 26 of 47 healthy volunteers following ingestion of zinc sulfate tablets (150 mg Zn2+ in three divided doses/d, 2 mg Zn2+/kg-d) for 6 wk (Samman and Roberts 1987, as cited in ATSDR 1994). Gastrointestinal effects have also been observed in animals. Ferrets that ingested 390 mg Zn2+/kg-d as zinc oxide for 2 wk experienced intestinal hemorrhages and a 75% reduction in food intake (Straube et al. 1980, as cited in ATSDR 1994). Mice fed a diet containing 1,110 mg/kg-d developed ulcers in the forestomach. No gastrointestinal effects were observed in rats fed 565 mg Zn2+/kg-d (Maita et al. 1981). Treatment-related changes in hematological parameters have been observed in humans and animals following oral dosing with zinc. Yadrick et al. (1989) conducted a 10-wk clinical study in 18 healthy women in which they investigated the effects of oral zinc supplements on copper and iron balance. Women were given supplements (as capsules) of 50 mg Zn2+/d as zinc gluconate. Erythrocyte superoxide dismutase (ESOD) activity levels declined over the 10-wk supplementation period and at 10 wk were significantly different (p < 0.05) from values during the pretreatment period. Serum ferritin and hematocrit values were also significantly lower than pre-treatment values at 10 wk. Serum zinc was significantly increased. Ceruloplasmin levels were not altered. Fischer et al. (1984) reported on the effects of zinc supplementation in healthy adult male volunteers administered 50 mg Zn2+/d as zinc gluconate for 6 wk. Volunteers had a statistically significant decrease in ESOD activity (15%) following the 6-wk exposure. There were no differences in serum copper levels or ceruloplasmin activity in the exposed group in comparison to the controls. Serum zinc levels were significantly increased in the exposed group after 2 wk. Decreased hemoglobin, hematocrit, erythrocyte, and/or leukocyte levels have been observed in animals dosed orally with zinc compounds. Zaporowska and Wasilewski (1992) (as cited in ATSDR 1994) reported that the LOAEL in rats for decreased hemoglobin (85% of control values) was 12 mg Zn2+/kg-d as zinc chloride in a 4-wk drinking water study with 2-mo old rats. Maita et al. (1981) fed mice (12/sex/group) a diet containing zinc sulfate at 0, 300, 3,000, or 30,000 ppm (equivalent to 0, 10, 104, 1,110 mg Zn2+/kg-d) for 13 wk, observed significantly lower values in hematocrit and hemoglobin concentrations in the 3,000- and 30,000-ppm groups in comparison to controls; however, no dose
CALCIUM AND ZINC MOLYBDATES 210 response relationship was observed. The leukocyte count in male mice exposed to 30,000 ppm was decreased as well. No human studies identified renal effects following oral exposures to zinc compounds. However, several animal studies have demonstrated adverse renal effects in animals exposed to zinc oxide, zinc sulfate, and zinc acetate. Zinc sulfate caused an increase in the absolute and relative kidney weights and regressive kidney lesions (not specified) in female mice that consumed 1,110 mg Zn2+/kg-d as zinc sulfate in the diet for 13 wk, but no effects occurred in rats that consumed 565 mg Zn2+/kg-d under similar conditions (Maita et al. 1981). In rats exposed to 191 mg Zn2+/kg-d as zinc acetate for 3 mo, epithelial cell damage in the glomerulus and proximal convoluted tubules and increased plasma creatinine and urea levels were observed (Llobet et al. 1988). The NOAEL for the effects on creatinine and urea was 95 mg Zn2+/kg-d. It is unclear whether the microscopic changes were observed at lower doses. Immunological Effects Molybdenum compounds No human or animal data on immunological effects following oral exposures to Mo compounds were identified. Zinc Eleven healthy adult men who ingested 4.3 mg Zn2+/kg-d for 6 wk experienced impaired mitogenic response elicited from peripheral blood lymphocytes and impaired chemotactic and phagocytic responses of polymorphonuclear leukocytes (Chandra 1984, as cited in ATSDR 1994). No effects were observed on total numbers of lymphocytes or relative numbers of T-cells or B-cells. No studies examining the immunological effects in animals following oral dosing with zinc were identified. Neurological Effects Molybdenum compounds No data were identified on neurological effects of Mo compounds following oral exposure.
CALCIUM AND ZINC MOLYBDATES 211 Zinc Murphy (1970) (as cited in ATSDR 1994) reported on a 16-yr-old boy who ingested about 86 mg Zn2+/kg-d (as metallic zinc) over a 2-d period in an effort to promote the healing of a wound. The boy developed signs and symptoms of lethargy, light-headedness, staggering, and difficulty in writing clearly. Very limited data were located on neurological effects in animals. Rats dosed with 487 mg Zn2+/kg-d as zinc oxide for 10 d (Kozik et al. 1980, as cited in ATSDR 1994) experienced minor neuron degeneration and proliferation of oligodendroglia. Kozik et al. (1981) (as cited in ATSDR 1994) reported that rats receiving 472 mg Zn2+/kg-d for 10 d had increased levels of secretory material in the neurosecretory nuclei of the hypothalamus. Reproductive and Developmental Effects Molybdenum Compounds Long-Evans rats (four or eight/sex/dose), fed varying quantities of Mo (as NaMoO4Â· 2H2O) and copper (as CuSo4Â·5H20) in their diets (ad libitum) were mated with respective animals receiving the same doses (Jeter and Davis 1954). Concentrations of these compounds in diets consisted of either <1 or 80 ppm Mo and 20 ppm copper, respectively or <1, 20, 80, or 140 ppm Mo and 5 ppm copper. No marked effects on female fertility or gestation were observed. However, there was evidence of decreased lactation as observed by the low weaning weights of the litters, particularly for the pups of mothers fed 80 or 100 ppm Mo in their diets. No other effects on the offspring were reported. Mature virgin female rats fed 700 ppm Mo for 10 d showed irregular estrous cycles (Jeter and Davis 1954). Zinc No developmental effects were reported among newborns exposed to zinc compounds (0.06â0.3 mg zinc/kg- d) in utero during the second and third trimesters (Kynast and Saling 1986, as cited in ATSDR 1994; Mahomed et al. 1989, as cited in ATSDR 1994; Simmer et al. 1991, as cited in ATSDR 1994). Bleavins et al. (1983) (as cited in ATSDR 1994) reported no measurable effect on gestational length or litter size when female mink ingested an average dose of 20.8 mg Zn2+/kg-d as zinc sulfate. Maita et al. (1981) fed mice 1,110 mg Zn2+/kg-d for 13 wk and found no effects on the testes or ovaries.
CALCIUM AND ZINC MOLYBDATES 212 Schlicker and Cox (1968) administered 200 mg Zn2+/kg-d (as zinc oxide) in the diet of rats for 21 d prior to mating and through gestation. During gestation, the 200-mg/kg-d dose group experienced 4â29% resorptions compared with 0% in controls. When the dose was reduced to 100 mg Zn2+/kg-d (21 d prior to mating), no fetal resorptions, malformations, or growth reduction were reported. Administration of 200 mg Zn2+/kg-d to dams throughout gestation resulted in decreased growth and tissue levels of copper and iron in fetal rats (Cox et al. 1969; Schlicker and Cox 1968). During gestational d 1â18, maternal zinc levels increased in the 100- and 200-mg/kg-d dose groups. However, zinc tissue levels in the 22-d- old fetuses were not elevated in dams dosed with 100 mg/kg-d, suggesting that the placenta was able to act as a barrier to zinc at the lower dietary level. In contrast, Ketcheson et al. (1969) (as cited in ATSDR 1994) reported that newborn and 14-d old rats, from mothers who had consumed 100 mg/kg-d throughout gestation, had elevated levels of total zinc and decreased levels of iron. Cancer Molybdenum Compounds No data were identified on carcinogenic effects of Mo compounds following oral exposure. Zinc Limited human and animal data on the carcinogenicity of zinc following oral exposures exist. Two epidemiological studies reported conflicting results on the association between high zinc soil levels and cancer. In a survey of cancer registry data (1954â1978) in Shipham, Somerset (Great Britain), an area with a high soil zinc-to-copper ratio ( 17:1), Philipp et al. (1982) (as cited in ATSDR 1994) found that the gastric cancer incidence rate was significantly lower than the regional rate. In contrast, Stocks and Davies (1964) (as cited in ATSDR 1994) found an association between an excess rate of gastric cancer in people of North Wales and high zinc-to-copper ratios ( 30:1) in the soil of household gardens. It is possible that other factors, not considered by Stocks and Davies (1964) (as cited in ATSDR 1994), may have accounted for the observed association. Walters and Roe (1965) (as cited in ATSDR 1994) reported that the inci
CALCIUM AND ZINC MOLYBDATES 213 dence of tumors following exposure of mice to 951 mg Zn2+/kg-d as zinc sulfate in drinking water for 1 yr was not increased as compared to controls. However, this study lacked important details and had several limitations, including high numbers of deaths in control mice. Genotoxicity Molybdenum Compounds Calcium and zinc molybdates do not appear to be genotoxic based on limited data available. Molybdenum trioxide was reported to be negative in the Bacillus subtilis rec assay (Kada et al. 1980, as cited in NTP 1997), and not mutagenic in any of five strains of Salmonella typhimurium tested, with or without S9 metabolic activation enzymes (Zeiger et al. 1992, as reported in NTP 1997). Molybdenum trioxide did not induce sister- chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells. Zinc Bauchinger et al. (1976) found that the incidence of chromosomal aberrations was increased in 24 workers in a zinc smelting plant. However, these workers also had increased blood levels of lead and cadmium, and the authors attributed the increase in the incidence of chromosomal aberrations to cadmium exposure. A number of in vivo studies have reported that zinc salts were clastogenic when administered by various routes of exposure (see Table 9â3a). Kowalska-Wochna et al. (1988) (as cited in ATSDR 1994) found an increase in the incidence of chromosomal aberrations in rats exposed to 14.8 mg Zn2+/kg-d in their drinking water. An increase in the incidence of chromosomal aberrations was observed in mice given intraperitoneal injections of 3.6 mg Zn2+/kg-d (Gupta et al. 1991) and mice exposed to zinc oxide by inhalation (Voroshilin et al. 1978, as cited in ATSDR 1994). An increased incidence of sister-chromatid exchange was observed in bone marrow cells of rats exposed to 17.5 mg Zn2+/kg-d in drinking water (Kowalska-Wochna et al. 1988, as cited in ATSDR 1994). Zinc was negative for genotoxicity when tested in murine somatic or germ cells (Vilkina et al. 1978, as cited in ATSDR 1994). Zinc has been found to be negative for mutagenic activity in bacterial systems in vitro (see Table 9â3b). In vitro genotoxicity testing of zinc using mouse lymphocytes has resulted in inconsistent findings for mutagenicity. Limited in vitro testing suggests that zinc may have clastogenic activity in human lympho
CALCIUM AND ZINC MOLYBDATES 214 cytes (Deknudt and Deminatti 1978) and Chinese hamster ovary cells (Thompson et al. 1989, as cited in ATSDR 1994). TABLE 9â3a Genotoxicity of Zinc In Vivo Species Genotoxicity End Point Results Reference Mouse Dominant lethal mutation Negative Vilkina et al. 1978, as cited in ATSDR 1994 Mouse Micronucleus induction Positive Gocke et al. 1981 Mouse Chromosomal aberrations Positive Vilkina et al. 1978, as cited in ATSDR 1994 Mouse Chromosomal aberrations Positive Deknudt and Gerber 1979 Mouse Chromosomal aberrations Positive Gupta et al. 1991 Rat Chromosomal aberrations Positive Kowalska-Wochna 1988, as cited in ATSDR 1994 Rat Sister chromatid exchange Positive Kowalska-Wochna 1988, as cited in ATSDR 1994 Drosophila Sex-linked recessive lethal mutation Negative Gocke et al. 1981 QUANTITATIVE TOXICITY ASSESSMENT Noncancer Dermal Assessment There are inadequate dermal toxicity data to perform a dermal RfD. The limited data available suggest that calcium/zinc molybdates are not skin irritants. No irritation effects were observed when Mo compounds were applied to the intact or abraded skin of rabbits. Systemic effects following long-term dermal exposure have not been reported. Inhalation RfC The 2-yr NTP study (NTP 1997) was used for the derivation of the RfC for calcium and zinc molybdates. This study identified a LOAEL of 10 mg MoO3/m3 based on increased incidences of hyaline degeneration in the nasal respiratory epithelium and nasal olfactory epithelium in female rats. No NOAEL was identified in this study. A composite uncertainty factor of 3,000 was applied to the LOAEL that consists of a factor of 3 to account for database deficiencies including lack of
CALCIUM AND ZINC MOLYBDATES 215 a reproductive/developmental study, a factor of 10 for extrapolation from rats to humans, a factor of 10 for intraspecies differences, and a factor of 10 for extrapolation from a LOAEL to a NOAEL in a long-term study. Therefore, the RfC was determined to be 0.003 mg MoO3/m3. Since Mo comprises approximately 67%, 48%, and 43% by weight of MoO3, CaMoO4 and ZnMoO4, respectively, the RfC for MoO3 was multiplied by (0.67/0.48)â1 (for CaMoO4) or (0.67/0.43)â1 (for ZnMoO4) to yield RfCs for both calcium and zinc molybdates of 0.002 mg/m3 (see Table 9â4). Since there are few other supporting data from inhalation studies examining similar effects, confidence in the database and in the inhalation RfC are medium. TABLE 9â3b Genotoxicity of Zinc in Vitro Results Species Genotoxicity End Point With Metabolic Without Metabolic Reference Activation Activation EUKARYOTIC Mouse lymphoma cells Mutation NA Negative Amacher and Paillet 1980 Mouse lymphoma cells Mutation Positive Positive Thompson et al. 1989, as cited in ATSDR 1994 Human lymphocytes Chromosomal NA Positive Deknudt and aberrations Deminatti 1978 Chinese hamster ovary Chromosomal Positive Positive Thompson et al. cells aberrations 1989, as cited in ATSDR 1994 PROKARYOTIC Salmonella Mutation NA Negative Marzin and Phi 1985 typhimurium (TA102) Salmonella Mutation Negative Negative Wong 1988 typhimurium (TA98, TA102, TA1535, TA1537) Salmonella Mutation Negative Negative Thompson et al. typhimurium (TA98, 1989, as cited in TA100, TA1537, TA ATSDR 1994 1538) Eschericia coli Mutation NA Negative Nishioka 1975 Eschericia coli Mutation NA Negative Venitt and Levy 1974 NA, not applicable
CALCIUM AND ZINC MOLYBDATES 216 TABLE 9â4 Inhalation Reference Concentration for Calcium and Zinc Molybdates Critical effect Species Effect level (mg/m3) Uncertainty factors RfCb (mg/m3-d) Reference Increased incidences of Female rats LOAELa: 10 UFA: 10 0.002 NTP (1997) hyaline degeneration in nasal UFH: 10 respiratory epithelium and UFL: 10 olfactory epithelium UFD: 3 Total: 3,000 LOAEL, lowest-observed-adverse-effect level; RfC, reference concentration; UFA, extrapolation from animals to humans; UFH, intraspecies variability; UFL, extrapolation from a LOAEL to a NOAEL; UFD, inadequate or deficient toxicity database aLOAEL based on exposure to molybdenum trioxide. bRfC calculated based on percent by weight of molybdenum in the ratio of molybdenum trioxide to calcium molybdates or zinc molybdates (0.67/0.43 or 0.67/0.48, respectively). Oral RfD The Kovalsky et al. (1961) study was used for derivation of the oral RfD for calcium and zinc molybdates. In this epidemiological study, increases in uric acid levels and copper excretion, and elevated serum ceruloplasmin, were observed and a LOAEL of 0.14 mg/g-d Mo was identified. No NOAEL was identified in this study for Mo. The RfD was derived with consideration for the estimated safe and adequate daily intake (ESAADI) of 15â40 Âµg/d for infants, 25â150 Âµg/d for children, and 75â250 Âµg/d for adolescents and adults (NRC 1989). Data supporting selection of this key study are provided by several other epidemiological studies (Deosthale and Gopalan 1974; EPA 1979) that found an association between elevated dietary exposure to Mo and increased serum ceruloplasmin and urinary excretion of copper. The LOAEL for Mo is further supported by animal data demonstrating that the toxicological effects of Mo are more pronounced when dietary copper levels are low. The subcommittee, in calculating the oral RfD, applied an uncertainty factor of 100 to the LOAEL consisting of 10 to account for intraspecies differences and 10 to extrapolate from a LOAEL to a NOAEL in a long-term study (EPA 1999). Based on this calculation, the RfD was determined to be 1Ã10â3 mg Mo/kg-d. Since Mo comprises approximately 43% by weight of zinc molybdate (ZnMoO4) or 48% by weight of calcium molybdate (CaMoO4), the RfD for Mo
CALCIUM AND ZINC MOLYBDATES 217 was multiplied by 0.43â1 (ZnMoO4) or 0.48â1 (CaMoO4) to yield RfDs for zinc or calcium molybdates of 0.0006 mg/kg-d (see Table 9â5). TABLE 9â5 Oral Reference Dose for Calcium and Zinc Molybdates Critical effect Species Effect level (mg/kg- Uncertainty factors RfDb (mg/kg-d) Reference d) Increased uric acid Human LOAELa: 0.14 UFH: 10 0.0006 Kovalsky et al. (1961) levels UFL: 10 Total: 100 LOAEL, lowest-observed-adverse-effect level; RfD, reference dose; UFH, intraspecies variability; UFL, NOAEL for critical effect not determined aLOAEL based on exposure to molybdenum. bRfD calculated based on percent by weight of molybdenum in calcium molybdates and zinc molybdates (43% and 48%, respectively). The subcommittee selected an RfD for zinc based on a LOAEL of 1.0 mg Zn2+/kg-d for decreased erythrocyte superoxide dismutase (ESOD) activity in human adult females after 10 wk of exposure to zinc supplements (Yadrick et al. 1989). The change in enzyme activity reflects an alteration in copper levels. This study (Yadrick et al 1989) is supported by data from several other clinical studies demonstrating the effect of zinc on copper balance (Prasad et al. 1978; Fischer et al. 1984). The subcommittee, in calculating an RfD, applied an uncertainty factor of 3, based on the minimal LOAEL of 1.0 mg Zn2+/kg-d from a moderate-duration study of the most sensitive humans and with consideration that zinc is an essential dietary nutrient. Using this uncertainty factor, the RfD was determined to be 0.3 mg Zn2+/kg-d. Because zinc comprises 29% by weight of ZnMoO4, the RfD for zinc was multiplied by 0.29â1 to derive an RfD for zinc molybdate of approximately 0.10 mg/kg-d. The subcommittee selected an RfD for calcium and zinc molybdates of 0.0006 mg/kg-d, based on the toxic effects from exposure to Mo. The subcommittee believes that an RfD based on the toxicity of Mo rather than on zinc, provides a greater margin of safety, because the RfD for Mo is considerably lower than that of zinc (0.001 vs. 0.3 mg/kg-d). Confidence in the key study is medium. The study examined only gross physical effects and certain hematological parameters associated with gout (Kovalsky et al. 1961). A detailed analysis of blood chemistry and individual dietary habits was not conducted. Confidence in the database is medium because of the lack of other studies examining a broader range of hematological and clinical chemistry parameters. Therefore, confidence in the oral RfD is medium.
CALCIUM AND ZINC MOLYBDATES 218 Cancer Dermal No studies were identified regarding the carcinogenicity of calcium or zinc molybdates or other Mo compounds following dermal exposure in humans or in experimental animals. Therefore, the subcommittee concluded that the carcinogenicity of calcium and zinc molybdates cannot be determined based on available data. Inhalation Inhaled molybdenum trioxide was carcinogenic in male and female mice based on a single NTP study (NTP 1997). There was equivocal evidence for its carcinogenicity for male rats. Available data suggests that these compounds are not carcinogenic. Based on the data currently available, the subcommittee concluded that the weight of evidence suggests that calcium and zinc molybdates may be carcinogenic to humans. Therefore, the subcommittee derived a cancer slope factor for characterizing the carcinogenic risk from exposure to these chemicals. The cancer slope factor was derived using the multistage model (EPA 1996). Modeling was conducted using the adenoma/carcinoma incidence data (combined) in female mice (3/50, 6/50, 8/49, and 15/49 for the 0-, 10-, 30- and 100-mg/m3 exposure groups, respectively) (NTP 1997) (see Table 9â6). The female mice data were used instead of the male mice data because female mice were more sensitive. Exposure concentrations were normalized for continuous exposure and were converted to human equivalent concentrations (HEC) using the regional deposited dose ratios (RDDR) based on the aerodynamic particle size generated in the NTP (1997) study. Based on linear extrapolation, the unit risk of lung cancer is less than 2.6Ã10â5/Âµg/m3. Oral No studies were identified regarding the carcinogenicity of calcium or zinc molybdates or other Mo compounds following oral exposure in humans or experimental animals. Therefore, the subcommittee concluded that there are insufficient data to determine its carcinogencity.
CALCIUM AND ZINC MOLYBDATES 219 TABLE 9â6 Calculation of LED10 and 0.1/LED10 for Molybdenum Trioxide Using Incidence of Lung Carcinoma and Adenoma in Female Mice (NTP 1997) Assay concentration Assay concentration HEC (mg/m3) Tumor response LED10 (mg/ 0.1/LED10 (mg/m3)a (mg/m3), duration c (lung adenomas and m3)d (per mg/m3) adjustedb carcinomas) 0 0 0 3 3.8 0.026 10 1.75 1.8 6 30 5.25 5.4 8 100 17.5 17.7 15 HEC, human equivalent concentrations; LED10, the lower 95% confidence bound on the effective dose that causes a 10% tumor response in animals; MoO3, molybdenum trioxide. aFemale mice were exposed to air concentrations of particulate MoO3 for 6 hr/d, 5 d/wk for 103 wk. bMoO concentrations were normalized for continuous chronic exposure by multiplying by 6/24 hr and 5/7 d (EPA 1994). 3 cNormalized assay concentrations were converted to HEC using the regional deposited dose ratios for the mouse pulmonary region as recommended by EPA (1994). Particulate mass median aerodynamic diameter (MMAD) and geometric standard deviations listed for each concentration by NTP (1997) were used (Âµm): 10 mg/m3: MMAD=1.3, Ïg=1.8; 30 mg/m3: MMAD=1.4, Ïg=1.8; 100 mg/m3: MMAD=1.5, Ïg=1.8. dLED calculated using the multistage model. 10 EXPOSURE ASSESSMENT AND RISK CHARACTERIZATION Noncancer Dermal Exposure The assessment of noncancer risk for the dermal exposure route is based on the dermal exposure scenario described in Chapter 3. This exposure scenario assumes that an adult spends 1/4th of his or her time sitting on furniture upholstery treated with calcium or zinc molybdates and also assumes 1/4th of the upper torso is in contact with the upholstery and clothing presents no barrier. Calcium and zinc molybdates are considered to be ionic, and are essentially not absorbed through the skin. However, to be conservative, the subcommittee assumed that ionized calcium and zinc molybdates permeate the skin at the
CALCIUM AND ZINC MOLYBDATES 220 same rate as water, with a permeability rate of 10â3 cm/hr (EPA 1992). Using that permeability rate, the highest expected application rate for calcium and zinc molybdates (2 mg/cm3), and Equation 1 in Chapter 3, the subcommittee calculated a dermal exposure level of 6.3Ã10â3 mg/kg-d. The oral RfD for calcium and zinc molybdates (6.0Ã10â4; see Oral RfD in Quantitative Toxicity section) was used as the best estimate of the internal dose for dermal exposure. Dividing the exposure level by the oral RfD yields a hazard index of 10. Therefore it was concluded that calcium and zinc molybdates used as flame retardants in upholstery fabric may pose a non-cancer risk by the dermal route at the specified concentration and under the given worst-case exposure scenario. Inhalation Exposure Particles Inhalation exposure estimates for calcium and zinc molybdates were calculated using the exposure scenario described in Chapter 3. This scenario assumes that a person spends a quarter of his or her life in a room with low air-change rates (0.25/hr) and with a relatively large amount of fabric upholstery treated with calcium or zinc molybdate (30 m2 in a 30 m3 room), with this calcium or zinc molybdate treatment gradually being worn away over 25% of its surface to 50% of its initial quantity over the 15-yr lifetime of the fabric. A small fraction, 1%, of the worn-off calcium or zinc molybdate, is released into the indoor air as inhalable particles, and may be breathed by the occupant. Particle exposure was estimated using Equations 4 through 6 in Chapter 3. The release rate (Âµr) for calcium and zinc molybdates for upholstery, 2.3Ã 10â7/d (Equation 5), was used in conjunction with the upholstery application rate (Sa) for calcium and zinc molybdates of 2 mg/cm2 to calculate a room airborne particulate concentration of 0.76 Âµg/m3 (Equation 4). Factoring in the fraction of a day a person spends in the room containing upholstery (0.25), the time-average exposure concentration was determined to be 0.19 Âµg/m3 (Equation 6). The inhalation RfC for calcium or zinc molybdate is 2Ã10â3 mg/m3 (see Inhalation RfC section). A hazard index was calculated as the ratio of the time-averaged exposure concentration to this estimated RfC, yielding a value of 0.095. This indicates that calcium or zinc molybdates, used as upholstery flame retardants, are not likely to pose any noncancer risk via inhalation in the particulate phase.
CALCIUM AND ZINC MOLYBDATES 221 Vapors Calcium and zinc molybdates have negligible vapor pressures at ambient temperatures. Therefore calcium or zinc molybdates used as upholstery-fabric flame retardants are not likely to pose any noncancer risks, when exposure occurs in the vapor phase. Oral Exposure The assessment of the noncancer risk for the oral exposure route is based on the scenario described in Chapter 3. This scenario assumes a child is exposed to calcium and zinc molybdates through sucking on 50 cm2 of fabric daily for two yr, 1 hr/d. The dose rate to the child was calculated using Equation 15 in Chapter 3. Parameters specific to calcium and zinc molybdates that were used in this calculation included an upholstery application rate (Sa) of 2 mg/cm2 and an extraction rate (Âµa) by saliva of 0.0004/d. This extraction rate was based on data from US Borax on zinc and boron extraction from polymer films (PVC and paint film) (Borax 1996). Using these values, the average oral dose rate was estimated to be 1.7Ã10â4 mg/kg-d. The oral dose rate (1.7Ã10â4 mg/kg-d) was divided by the oral RfD of 0.0006 mg/kg-d, giving a hazard index of 0.28. The subcommittee concluded that calcium or zinc molybdate used as an upholstery fabric flame retardant is not likely to pose any noncancer risk by the oral route. Cancer Dermal Exposure Based on inadequate data on the carcinogencity of calcium and zinc molybdates via the dermal route, the subcommittee concludes that there are insufficient data to assess its carcinogencity. Inhalation Exposure Particles The average room-air concentration and average exposure concentration to calcium or zinc molybdate were obtained as described in the Noncancer sec
CALCIUM AND ZINC MOLYBDATES 222 tion. Using the inhalation unit risk of 2.6Ã10â5/Âµg/m3, the lifetime risk estimate from exposure to calcium or zinc molybdate in the particulate phase is 5.0 Ã10â6 (see Table 9â6). Vapors Calcium and zinc molybdates have negligible vapor pressures at ambient temperatures. Therefore, calcium or zinc molybdate used as an upholstery-fabric flame retardant is not likely to pose any cancer risk via inhalation in the vapor phase. Oral Exposure Based on inadequate data on the carcinogencity of calcium and zinc molybdates via the oral route, the subcommittee concludes that there are insufficient data to assess its carcinogencity. RECOMMENDATIONS FROM OTHER ORGANIZATIONS The OSHA permissible exposure limit (PEL) recommended for this compound is 5 mg/m3 for soluble compounds. The TLV-TWA (Threshold Limit Value-time weighted average) established by the American Conference of Governmental Industrial Hygienists (ACGIH) is also 5 mg/m3 (ACGIH 1991) for soluble Mo compounds. Additionally, several other countries have adopted a permissible exposure level of 5 mg/m3 for soluble Mo including Australia, Federal Republic of Germany, Sweden, and the United Kingdom. The EPA, as detailed in IRIS, has established an oral RfD of 5Ã10â3 mg/kg-d for Mo and an oral RfD for zinc of 3Ã10â1 mg/ kg-d. The National Research Council has established RDAs for Mo of 75â250 Âµg/d (1.07â3.57 Âµg/kg-d for a 70- kg person) and for zinc of 12â15 mg/d (0.17â0.21 mg/kg-d of zinc for a 70-kg person), respectively. DATA GAPS AND RESEARCH NEEDS There is a substantial amount of data available on zinc, calcium, and molybdates. For instance, the oral RfD, inhalation RfC, and cancer potency factor determined by the subcommittee for calcium and zinc molybdates are based on molybdenum. Because of the calculated inhalation lifetime cancer risk for
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