The Risk Assessment Information System

Toxicity Profiles

Formal Toxicity Summary for MOLYBDENUM

NOTE: Although the toxicity values presented in these toxicity profiles were correct at the time they were produced, these values are subject to change. Users should always refer to the Toxicity Value Database for the current toxicity values.

EXECUTIVE SUMMARY
1. INTRODUCTION
2. METABOLISM AND DISPOSITION: 2.1 ABSORPTION 2.2 DISTRIBUTION 2.3 METABOLISM 2.4 EXCRETION
3. NONCARCINOGENIC HEALTH EFFECTS: 3.1 ORAL EXPOSURES 3.2 INHALATION EXPOSURES 3.3 OTHER ROUTES OF EXPOSURE 3.4 TARGET ORGANS/CRITICAL EFFECTS
4. CARCINOGENICITY: 4.1 ORAL EXPOSURES 4.2 INHALATION EXPOSURES 4.3 OTHER ROUTES OF EXPOSURE 4.4 EPA WEIGHT-OF-EVIDENCE 4.5 CARCINOGENICITY SLOPE FACTORS
5. REFERENCES

JANUARY 1993

Prepared by: Dennis M. Opresko, Ph.D., Chemical Hazard Evaluation Group, Biomedical and Environmental Information Analysis Section, Health and Safety Research Division, *, Oak Ridge, Tennessee.

Prepared for: Oak Ridge Reservation Environmental Restoration Program.

*Managed by Martin Marietta Energy Systems, Inc., for the U.S. Department of Energy under Contract No. DE-AC05-84OR21400.

EXECUTIVE SUMMARY

Molybdenum (Mo) occurs naturally in various ores; the principal source being molybdenite (MoS₂) (Stokinger, 1981). Molybdenum compounds are used primarily in the production of metal alloys. Molybdenum is considered an essential trace element; the provisional recommended dietary intake is 75-250 g/day for adults and older children (NRC, 1989).

Water-soluble molybdenum compounds are readily taken up through the lungs and gastrointestinal tract; but insoluble compounds are not. Following absorption, molybdenum is distributed throughout the body with the highest levels generally found in the liver, kidneys, spleen, and bone (Wennig and Kirsch, 1988). Limited data suggest that 25 to 50% of an oral dose is excreted in the urine, with small amounts also eliminated in the bile. Biological half-life may vary from several hours in laboratory animals to as much as several weeks in humans (Friberg and Lener, 1986; Jarrell et al., 1980; Stokinger, 1981; Vanoeteren et al., 1982; Venugopal and Luckey, 1978).

Data documenting molybdenum toxicity in humans are limited. The physical and chemical state of the molybdenum, route of exposure, and compounding factors such as dietary copper and sulfur levels may all affect toxicity. Mild cases of molybdenosis may be clinically identifiable only by biochemical changes (eg., increases in uric acid levels due to the role of molybdenum in the enzyme xanthine oxidase). Excessive intake of molybdenum causes a physiological copper deficiency, and conversely, in cases of inadequate dietary intake of copper, molybdenum toxicity may occur at lower exposure levels.

There is no information available on the acute or subchronic oral toxicity of molybdenum in humans. In studies conducted in a region of Armenia where levels of molybdenum in the soil are high (77 mg Mo/kg), 18% of the adults examined in one town and 31% of those in another town were found to have elevated concentrations of uric acid in the blood and urine, increased blood xanthine oxidase activity, and gout-like symptoms such as arthralgia, articular deformities, erythema, and edema (Kovalskii et al., 1961). The daily molybdenum intake was estimated to be 10-15 mg. An outbreak of genu valgum (knock-knees) in India was attributed to an increase in Mo levels in sorgum, the main staple food of the region. The estimated daily Mo intake was 1.5 mg (Jarrell et al., 1980).

In animals, acutely toxic oral doses of molybdenum result in severe gastrointestinal irritation with diarrhea, coma and death from cardiac failure. Oral LD₅₀ values of 125 and 370 mg Mo/kg for molybdenum trioxide and ammonium molybdate, respectively, have been reported in laboratory rats (Venugopal and Luckey, 1978). Subchronic and chronic oral exposures can result in gastrointestinal disturbances, growth retardation, anemia, hypothyroidism, bone and joint deformities, sterility, liver and kidney abnormalities, and death (Lloyd et al., 1976; Venugopal and Luckey, 1978; Valli et al., 1969; Fairhall et al., 1945; Rana and Kumar, 1980). Fatty degeneration of the liver occurred in rabbits dosed with 50 mg/kg/day for 6 mo (Asmangulyan, 1965) and in rats dosed with 5 mg/kg/day as ammonium molybdate for 1 year (Valjcuk and Sramko, 1973). Male sterility, was reported in rats fed diets containing 80 or 140 ppm Mo (Jeter and Davis, 1954). Teratogenic effects have not been observed in mammals, but embryotoxic effects, including reduced weight gain, reduced skeletal ossification, nerve system demyelinization, and reduced survival of offspring have been reported (Wide, 1984; Earl and Vish, 1979; Schroeder and Mitchener, 1971).

The chronic oral Reference Dose (RfD) for molybdenum and molybdenum compounds is 0.005 mg/kg/day, based on biochemical indices in humans (U.S. EPA, 1992). The subchronic RfD is also 0.005 mg/kg/day (U.S. EPA, 1992).

Information on the inhalation toxicity of molybdenum in humans following acute and subchronic exposures is not available. Studies of workers chronically exposed to Mo indicate a high incidence of weakness, fatigue, headache, irritability, lack of appetite, epigastric pain, joint and muscle pain, weight loss, red and moist skin, tremor of the hands, sweating, and dizziness (Akopajan, 1964; Ecolajan, 1965; Walravens et al., 1979). Elevated levels of Mo in blood plasma and urine and high levels of ceruloplasmin and uric acid in blood serum were reported for workers exposed to Mo (8-hr TWA 9.5 mg Mo/m³) (Walravens et al., 1979). Occupational exposure to molybdenum may also result in increased serum bilirubin levels and decreased blood IgA/IgG ratios due to a rise in alpha-immunoglobulins (Avakajan, 1966b; 1968). Direct pulmonary effects of chronic exposure to Mo have been reported in only one study in which 3 of 19 workers exposed to Mo and MoO₃ (1 to 19 mg/m³) for 3-7 years were symptomatic and had X-ray findings indicative of pneumoconiosis (Mogilevskaya, 1963). Adverse reproductive or developmental effects have not been observed in molybdenum workers (Metreveli et al., 1985).

In animal studies, inhalation exposures to molybdenum compounds have resulted in respiratory tract irritation, pulmonary hemorrhages, perivascular edema, and liver and kidney damage (Mogilevskaya, 1963; Fairhall, et al., 1945). Other effects reported in animals include diarrhea, muscle incoordination, loss of hair, loss of weight (Fairhall et al., 1945), changes in ECG, increased arterial blood pressure, increased serum lactate dehydrogenase, increased cardiac adrenaline and noradrenaline levels (Babayan et al., 1984), and inflammation of the uterine horns with necrotic foci and endometrial atrophy (Metreveli and Daneliya, 1984). Some molybdenum compounds, such as molybdenum trioxide and sodium molybdate (Na₂MoO₄) are strong eye and skin irritants; however, others, such as calcium and zinc molybdates are not primary irritants.

Subchronic and chronic Reference Concentrations (RfC) for molybdenum are not available.

Information on the oral or inhalation carcinogenicity of molybdenum compounds in humans was not available, and animal data indicate that Mo may have an inhibitory effect on esophageal (Luo et al., 1983; van Rensburg et al., 1986; Komada, et al., 1990) and mammary carcinogenesis (Wei et al., 1987). However, intraperitoneal injections of MoO₃ in mice produced a significant increase in the number of lung adenomas per mouse and an insignificant increase in the number of mice bearing tumors (Stoner et al., 1976). Molybdenum is placed in EPA Group D, not classifiable as to carcinogenicity in humans (U.S. EPA, 1990) and calculation of slope factors is not possible.

1. INTRODUCTION

Molybdenum occurs naturally in various ores, the most important being molybdenite (MoS₂), which is converted to molybdenum trioxide (MoO₃) for use in ferro- and manganese alloys, chemicals, catalysts, ceramics, and pigments. Metallic molybdenum is used in electronic parts, induction heating elements, and electrodes, and molybdenum disulfide is used as a lubricant (Stokinger, 1981).

Molybdenum is considered an essential trace element. It functions as an electron transport agent in the molybdenum-flavoprotein enzyme, xanthine oxidase (Wennig and Kirsch, 1988). It is also a cofactor for aldehyde oxidase, NADH-dehydrogenase, xanthine dehydrogenase, and sulfite oxidase (Browning, 1969; Chappell, 1975; Stokinger, 1981). The provisional recommended dietary intake, based on average reported intake, is set at 75-250 g/day for adults and older children (NRC, 1989).

2. METABOLISM AND DISPOSITION

2.1. ABSORPTION

Uptake and absorption of molybdenum depend on the chemical form of the metal and on the route of exposure. Water-soluble molybdenum compounds as well as sparingly soluble compounds such as molybdenum trioxide and calcium molybdate are readily absorbed through the gastrointestinal tract, whereas the insoluble molybdenum disulfide is not (Browning, 1969). Gastrointestinal absorption rates of 38 to 77% have been reported for humans and 40-85% for animals (Friberg and Lener, 1986; U.S. EPA, 1990).

No data are available on the rates of pulmonary absorption of molybdenum compounds. As indicated by tissue distribution studies following inhalation exposures, water-soluble compounds are absorbed through the lungs, but insoluble compounds are not (Browning, 1969; Stokinger, 1981; Friberg and Lener, 1986). The latter, as well as the sparingly soluble calcium molybdate are known to have relatively long pulmonary retention times (Stokinger, 1981).

2.2. DISTRIBUTION

Molybdenum is distributed throughout the body with the highest levels generally found in the liver, kidneys, spleen, and bones (Wennig and Kirsch, 1988). Molybdenum accumulates in growth cartilage and in diaphysis spongiosis in the long bones. In the blood it is bound in the form of molybdate to ₂-macroglobulin. In erythrocytes, it is bound to proteins of the erythrocytic membrane (Friberg and Lener, 1986).

2.3. METABOLISM

No data are available regarding the metabolism of molybdenum (U.S. EPA, 1990).

2.4. EXCRETION

Following a single intravenous injection of radioactive molybdenum in two human subjects, cumulative Mo excretion over 10 days was 24% and 29%; corresponding fecal excretion was 6.8% and 1%, indicating some excretion in the bile (Rosoff and Spencer, 1964). Limited data provided by Tipton et al. (1969) suggest that 25 to 50% of an oral dose is excreted in the urine. Urinary levels of Mo average 49-71 g/day in humans. Biological half-life may vary from several hours in laboratory animals up to several weeks in humans (Friberg and Lener, 1986). Sulfate enhances the excretion of molybdenum (Friberg and Lener, 1986; Jarrell et al., 1980; Stokinger, 1981; Vanoeteren et al., 1982; Venugopal and Luckey, 1978).

3. NONCARCINOGENIC HEALTH EFFECTS

Laboratory studies have shown that the toxicity of molybdenum depends on its chemical and physical state. Water insoluble compounds are generally less toxic than water soluble compounds. Toxicity can also be altered by sulfate, Cu(+2), Zn(+2), Pb(+2), protein intake, and by the form and amount of organic sulfur, such as cystine and methionine, in the body.

Molybdenum is an important component of the flavoprotein xanthine oxidase, an enzyme involved in the breakdown of purines to uric acid. Other enzyme systems, such as succinic acid oxidase, sulfite oxidase, glutaminase, cholinesterase, and cytochrome c oxidase may be inhibited by molybdenum (Venugopal and Luckey, 1978; Stokinger, 1981).

3.1. ORAL EXPOSURES

3.1.1. Acute Toxicity

3.1.1.1. Human

Information on the acute toxicity of molybdenum and molybdenum compounds to humans was not available.

3.1.1.2. Animal

Severe gastrointestinal irritation, diarrhea, coma and death from cardiac failure are the symptoms of acute molybdenosis. Oral LD₅₀ values of 188 mg/kg (125 mg Mo/kg) for molybdenum trioxide and 680 mg/kg (370 mg Mo/kg) for ammonium molybdate have been reported for laboratory rats. Oral LD₁₀₀ values of 2200 mg/kg (1200 mg Mo/kg), 1870 mg/kg (1020 mg Mo/kg), and 2400 mg/kg (1310 mg Mo/kg) have also been reported for guinea pigs, rabbits and cats, respectively, dosed with ammonium molybdate (Venugopal and Luckey, 1978).

3.1.2. Subchronic Toxicity

3.1.2.1. Human

Information on the subchronic toxicity of molybdenum to humans was not available.

3.1.2.2. Animal

Water insoluble molybdenite (MoS₂) is practically nontoxic; rats dosed with up to 500 mg molybdenite daily for 44 days exhibited no adverse effects and continued to gain weight (Fairhall et al., 1945). In contrast, animals dosed subchronically with water soluble molybdenum compounds exhibit gastrointestinal disturbances, growth retardation, anemia, hypothyroidism, bone and joint deformities, liver and kidney abnormalities, and death. Fifty percent mortality was reported in rats maintained for 40 days on molybdenum-enhanced diets containing 125 mg Mo/kg (as molybdenum trioxide, MoO₃), 100 mg Mo/kg (as calcium molybdate, CaMoO₄), or 333 mg Mo/kg (as ammonium molybdate, (NH₄)₂MoO₄) (Fairhall et al., 1945). A dietary level of 0.1% sodium molybdate (Na₂MoO₄2H₂O) for several weeks was lethal to rabbits (Climax Molybdenum Co., 1957, 1963).

Growth retardation has been observed in rats maintained on diets containing 0.04-0.12% molybdenum ((Ostrom et al., 1961; Gray and Daniel, 1954; Johnson et al., 1969). Evidence that the toxic effects of molybdenum might be caused by a secondarily acquired copper deficiency was shown in a study by Jeter and Davis (1954) where a significant reduction in growth occurred in Long Evans rats after 11 weeks on a diet containing 20 ppm molybdenum and 5 ppm copper; whereas, growth was not affected by molybdenum dietary levels as high as 80 ppm when the dietary level of copper was increased to 20 ppm.

Hypothyroidism, as evidenced by decreased levels of plasma thyroxin, has been reported in rabbits maintained on a diet containing 0.3% Mo (as sodium molybdate) for several weeks or longer (Widjajakusuma et al., 1973).

Anemia, as well as anorexia, weight loss, alopecia, and bone deformities, occurred in young rabbits maintained for 4-17 weeks on a diet containing 0.1% molybdenum (as sodium molybdate) (Arrington and Davis, 1953). Anemia was also observed in NNRI-B rats maintained on a diet containing 0.04% Mo (as sodium molybdate) for 5 weeks (Ostrom et al., 1961), in rabbits on a dietary level of 0.2% sodium molybdate for 5 weeks (McCarter et al., 1962), and in chicks on a dietary level of 0.4% sodium molybdate for 4 weeks (Davis et al., 1960). Signs of anemia and marked erythroid hyperplasia of the bone marrow were observed in rabbits maintained for 11 days on a diet containing 0.4% sodium molybdate (equivalent to about 91 mg Mo/kg bw/day, based on a food factor of 0.049) (U.S. EPA, 1986; Valli et al., 1969).

Bone and connective tissue disorders observed in animals receiving dietary levels of molybdenum 0.04% for 4 weeks or longer include mandibular exostoses, joint deformities, detachment of tendons, epiphyseal line fractures, and epiphyseal plate widening (Lalich et al., 1965; Arrington and Davis, 1963; McCarter et al., 1962; Valli et al., 1969; Ostrom et al., 1961).

The liver can be affected to varying degrees by excessive intake of molybdenum. Significantly elevated levels of serum bilirubin were observed in dogs receiving 20 mg/kg of ammonium molybdate in their diet for 5.5 months (Avakajan, 1966a). Fatty changes in the liver occurred in rabbits dosed with 50 mg/kg/day of ammonium molybdate for 6 months (Asmangulyan, 1965) and in guinea pigs dosed with 25 mg/kg/day of molybdenum dioxide for 14 days (Fairhall et al., 1945). Histological changes in the liver and altered glycolytic enzyme activity were observed in male Wistar rats dosed with 289 mg Mo/kg/day (as ammonium molybdate) in drinking water for 28 days (Bandyopadhyay et al., 1981). Severe liver damage, consisting of perilobular necrosis, nuclear clumping and an increase in Kupfer cells, occurred in rats receiving 489 mg Mo/kg/day (as ammonium molybdate) in their diet for 20 days (Rana and Kumar, 1980). A 72% reduction in glycogen levels occurred in rats receiving the same dietary level for 30 days (Rana et al., 1985).

An increase in kidney weight and indications of mild renal failure (decreased glomerular filtration as measured by a reduction in creatinine clearance) occurred in rats dosed for 8 weeks by gastric intubation with 80 mg Mo/kg/day [as (NH₄)₆Mo₇O₂₄4H₂O] (Bompart et al., 1990). Histological changes in kidneys were also observed in male Wistar rats dosed with 289 mg Mo/kg/day (as ammonium molybdate) in drinking water for 28 days (Bandyopadhyay et al., 1981). Severe kidney damage, including glomerular shrinkage and epithelial alterations in the distal and proximal renal tubules occurred in rats receiving 1000 mg/kg/day of ammonium molybdate (489 mg Mo/kg/day) in their diet for 20 days (Rana and Kumar, 1980).

In sheep and cattle, a condition known as "teart disease" occurs when these animals graze on plants containing abnormally high amounts of molybdenum (Friberg et al., 1975). Symptoms that may occur within 24 hr include weakness and diarrhea (Lloyd et al., 1976). Longer exposure can lead to decoloration of hair, skeletal deformities, sterility due to damage to testicular interstitial cells, poor conception and deficient lactation (Lloyd et al., 1976; Venugopal and Luckey, 1978). Dietary levels of about 10 ppm molybdenum and higher can cause teart disease.

3.1.3. Chronic Toxicity

3.1.3.1. Human

Because molybdenum is important in the functioning of xanthine oxidase, an enzyme involved in the breakdown of purines to uric acid, one of the effects of prolonged exposure can be an increase in uric acid and subsequent development of gout-like diseases and other bone/joint disorders (Wennig and Kirsch, 1988). Increases in activity of blood xanthine oxidase activity, elevated levels of uric acid in the blood and urine, and symptoms of gout (arthralgia, articular deformities, erythema, and edema) occurred in 18 and 31% of the adults examined from two towns in Armenia where the soil contained 77 mg/kg of molybdenum (Kovalskii et al., 1961). Molybdenum intake was estimated to be 10-15 mg/day and copper intake 5-10 mg/day. In a control area, molybdenum intake was estimated to be 1-2 mg and copper intake 10-15 mg. In a study of a second population from an area where soil molybdenum concentrations were high but where copper intake was also high, there was no indications of elevated uric acid levels or increased incidences of gout-like disorders (Mertz, 1976).

An outbreak of genu valgum (knock-knees) in India was attributed to an increase in molybdenum levels in sorgum, the main staple food of the region. It was estimated that the daily molybdenum intake was as high as 1.5 mg for some individuals, a value almost 5 times the daily intake of 0.35 mg reported for other areas (Jarrell et al., 1980).

3.1.3.2. Animal

Few chronic animal studies have been conducted on molybdenum or molybdenum compounds; however, Valjcuk and Sramko (1973) exposed rats to ammonium molybdate for 1 year, and reported that a dose level of 5 mg/kg/day caused fatty changes in the liver. In addition, in a three generation study, Schroeder and Mitchener (1971) exposed mice to molybdenum in drinking water and evaluated the effects on reproduction. Results of this study are presented in Section 3.1.4.2.

3.1.4. Developmental and Reproductive Toxicity

3.1.4.1. Human

Information on the developmental or reproductive toxicity of molybdenum to humans as a result of oral exposures was not available.

3.1.4.2. Animal

Molybdenum was one of seven metals reported to cause abnormalities in chick embryos following injection of 4-1000 g sodium molybdate into the air sac of the egg on day 2 of incubation (Gilani and Alibai, 1990). Neck defects, hemorrhages and reduced body size were the most common abnormalities; however, there was no clear dose-response relationship.

Severe demyelinization of the central nervous system occurred in newborn lambs born to dams maintained on high-molybdenum diets during pregnancy (Earl and Vish, 1979).

Seventy-five percent of male Long Evans rats maintained on a diet containing 80 or 140 ppm Mo (as sodium molybdate dihydrate) from weaning until mating became sterile, and histological examination revealed seminiferous tubule degeneration (Jeter and Davis, 1954). Female fertility, gestation, and litter size were not affected by these dietary levels of molybdenum; however, weaning weight of offspring was reduced, indicating deficiencies in lactation. Sterility due to damage to testicular interstitial cells, poor conception, and deficient lactation have also been reported in cattle ingesting large amounts of molybdenum (Venugopal and Luckey, 1978).

In a three-generation study conducted on mice, Schroeder and Mitchener (1971) found that 10 ppm molybdenum in drinking water (1.9 mg Mo/kg/day) resulted in a significant increase in the number of dead offspring in the F₁ and F₃ generations compared to the controls. The F₃ generation totaled 123 mice compared to 230 for the controls; however, the total number of litters per generation, as well as the average litter size per generation were not affected by the molybdenum treatment.

3.1.5. Reference Dose

3.1.5.1. Subchronic

ORAL RfD: 0.005 mg/kg/day (U.S. EPA, 1992)

UNCERTAINTY FACTOR: 30

LOAEL: 0.14 mg/kg/day, humans.

3.1.5.2. Chronic

ORAL RfD: 0.005 mg/kg/day (U.S. EPA, 1992)

UNCERTAINTY FACTOR: 30

LOAEL: 0.14 mg/kg/day, humans.

CONFIDENCE:

Study: NA

Data Base: NA

RfD NA

VERIFICATION DATE: NA

PRINCIPAL STUDIES: Kovalskii et al., 1961

COMMENT: Based on changes in biochemical indices in humans. Oral RfD is under review and subject to change (U.S. EPA, 1992).

3.2. INHALATION EXPOSURES

3.2.1. Acute Toxicity

3.2.1.1. Human

Information on the toxicity of molybdenum in humans following acute inhalation exposures was not available.

3.2.1.2. Animal

Rats exposed for 1 hr to dusts of metallic molybdenum (25-30 g/m³), molybdenum trioxide (12-15 g/m³) and molybdenum dioxide (10-12 g/m³) exhibited no signs of toxicity, and those exposed to ammonium paramolybdate (3-5 g/m³) exhibited only mild upper respiratory tract irritation (Mogilevskaja, 1963).

3.2.2. Subchronic Toxicity

3.2.2.1. Human

Information on the toxicity of molybdenum in humans following subchronic inhalation exposures was not availabale.

3.2.2.2. Animal

Repeated daily exposure of rats to metallic molybdenum (12-15 g/m³, 1 hr/day for 30 days) or molybdenum dioxide (8-10 g/m³, 1 hr/day for 30 days) resulted in a slight reduction in growth, as well as slight lung and liver congestion and slight parenchymatous hypertrophy in the liver and convoluted tubules of the kidney (Mogilevskaya, 1963). Thirty-day exposure to molybdenum trioxide (8-10 g/m³) resulted in similar but more severe effects. Exposures to ammonium paramolybdate (0.5-2.5 g/m³) produced degeneration and necrosis of the liver, degeneration of the epithelium of the convoluted tubules of the kidney, and death of all the test animals. Rats exposed to 3-10 mg/m³ of a molybdenum trioxide aerosol for 2 hr/day, on alternate days for 2 months, exhibited thickened alveolar walls, interstitial pneumonia and areas of collapse and emphysema in the lungs, fatty changes and necrotic foci in the liver and dystrophic changes in the kidney (Mogilevskaya, 1963).

Repeated exposure to molybdenite dust (286 mg Mo/m³) for 1 hr/day, 5 days/wk for 5 weeks produced no adverse effects in guinea pigs (Fairhall et al., 1945). Under the same test conditions molybdenum trioxide dust (205 mg MoO₃/m³) was extremely irritating to the respiratory tract, and also caused diarrhea, muscle incoordination, loss of hair, and loss of weight. Twenty-six of 51 (51%) exposed animals died after the tenth exposure. Histopathological examination revealed slight to moderate swelling of hepatocytes with occasional necrosis and fatty infiltration, traces of fatty deposits in the kidney, and mild to moderate amounts of alveolar and bronchial exudate. Exposure to freshly generated MoO₃ fume (191 mg Mo/m³) under the same test protocol caused 8.3% mortality. An exposure level of 57 mg Mo/m³ was not lethal. Dusts of calcium molybdate (160 mg Mo/m³) produced 21% mortality (Fairhall et al., 1945).

Atrophy of the renal tubules was reported in rabbits and rats exposed to molybdenum trioxide dust (concentration cycling between 210 and 10 mg/m³ within 25 min) for 4 hr/day for 3.5 months (Lukasev et al., 1971).

Cellular exudates in the alveoli and bronchi, and diffuse pneumoconiosis occurred in rabbits exposed to powdered molybdenum (70-80 mg/kg intratracheally) for 9 mo (Browning, 1969; Stokinger, 1981; Friberg and Lener, 1986).

Inhalation of metallic molybdenum aerosol (1.65 mg/m³) for 2-4 months caused changes in ECG, increased arterial blood pressure, increased serum lactate dehydrogenase, and increased cardiac adrenaline and noradrenaline levels in rats (Babayan et al., 1984).

3.2.3. Chronic Toxicity

3.2.3.1. Human

Occupational exposure studies have identified a number of symptoms and clinical chemistry changes indicative of exposure to molybdenum; however, dose-response data for such studies are often insufficient to define minimum effect levels. In addition, the reported effects might have been due at least in part, to gastrointestinal absorption following mucociliary clearance of the molybdenum from the respiratory tract.

Direct pulmonary effects of chronic exposure to molybdenum dust have been reported in only one study in which 3 of 19 workers exposed to Mo and MoO₃ for 3-7 years were symptomatic and had X-ray findings indicative of pneumoconiosis (Mogilevskaya, 1963). The concentration of Mo in the workplace air was reported to range from 1 to 19 mg/m³.

A high incidence of weakness, fatigue, headache, irritability, lack of appetite, epigastric pain, joint and muscle pain, weight loss, red and moist skin, tremor of the hands, sweating, and dizziness were reported in Russian workers at a molybdenum mine and processing plant (Ecolajan, 1965). Joint pains, backaches, headaches, and non-specific hair and skin changes were also the most frequent complaints of 25 male workers at a U.S. molybdenum-roasting plant where the 8-hr TWA to MoO₃ and other molybdenum oxides was estimated to be about 9.5 mg Mo/m³ (Walravens et al., 1979). The dust particles had a diameter of 10 . The exposed workers, who had been employed for 0.5-20 yr, had high levels of molybdenum in the plasma and urine and significantly higher levels of serum ceruloplasmin and uric acid when compared to values for a control group. Elevated blood uric acid levels, as well as symptoms of arthalgia occurred in 34 of 37 Russian workers at a copper-molybdenum plant (Akopajan, 1964). Russian studies have also suggested that exposure to molybdenum can result in increased serum bilirubin levels and decreased blood A/G globulin ratios due to a rise in alpha-globulins (Avakajan, 1966b; 1968). The latter has been interpreted as evidence of liver dysfunction (Stokinger, 1981).

3.2.3.2. Animal

Information on the toxicity of molybdenum in animals following chronic inhalation exposures was not availabale.

3.2.4. Developmental and Reproductive Toxicity

3.2.4.1. Human

An investigation of the incidence of gynecological diseases in female workers at an integrated copper-molybdenum mill in the USSR did not reveal any evidence of molybdenum toxicosis (Metreveli et al., 1985).

3.2.4.2. Animal

Metreveli and Daneliya (1984) reported that rats exposed to molybdenum dust (19.7 mg Mo/m³, 4 hr daily for 4 months) exhibited inflammation of the uterine horns with necrotic foci and endometrial atrophy.

3.2.5. Reference Concentration

3.2.5.1. Subchronic

A subchronic Reference Concentration for molybdenum and molybdenum compounds is not available.

3.2.5.2 Chronic

A chronic Reference Concentration for molybdenum and molybdenum compounds is not available.

3.3. OTHER ROUTES OF EXPOSURE

3.3.1. Acute Toxicity

3.3.1.1. Human

Information on the acute toxicity of molybdenum or molybdenum compounds to humans by other routes of exposure was not available.

3.3.1.2. Animal

Molybdenum compounds produce varying degrees of skin and eye irritation. Calcium and zinc molybdate were reported to be non-irritating to the skin or eyes of laboratory animals; however, sodium molybdate (Na₂MoO₄) caused primary irritation in 24 hr that cleared after 72 hr (Stokinger, 1981). Molybdenum trioxide is irritating to the eyes and mucous membranes of the respiratory tract (Venugopal and Luckey, 1978).

Fairhall et al. (1945) evaluated the relative toxicity of various molybdenum compounds injected intraperitoneally in guinea pigs. A 800 mg/kg dose of MoS₂ caused 17% mortality in 4 days, while a similar dose of ammonium molybdate resulted in 100% mortality. A 400 mg/kg dose of molybdenum trioxide caused 75% mortality but the same dose of calcium molybdate was not lethal. In a similar study, Maresh et al. (1940) reported that the intraperitoneal injection of 117 mg Mo/kg (as sodium molybdate) in rats resulted in the death of the test animals within a few hours. Intraperitoneal injection of 120 mg Mo/kg/day (as ammonium molybdate) for 30 days resulted in fatty changes in the liver of rats (Rokicka, 1969).

Intratracheal administration of single doses of molybdenum dust or solution in rats and rabbits resulted in peribronchial and perivascular fibrosis and diffuse pneumoconiosis (Mogilevskaya, 1963; Dzukaev, 1970). A single i.v. dose of 25 mg/kg of sodium molybdate (Na₂MoO₄2H₂O) resulted in an increase in arterial blood pressure and a stable prolonged increase in the tonus of the nictitating membrane in cats (Cilingarajan, 1965).

3.3.2. Subchronic Toxicity

Information on the subchronic toxicity of molybdenum or molybdenum compounds to humans and animals by other routes of exposure was not available.

3.3.3. Chronic Toxicity

Information on the chronic toxicity of molybdenum or molybdenum compounds to humans or animals by other routes of exposure was not available.

3.3.4. Developmental and Reproductive Toxicity

3.3.4.1. Human

Information on the developmental and reproductive toxicity of molybdenum or molybdenum compounds to humans by other routes of exposure was not available.

3.3.4.2. Animal

Injection of female mice in the tail vein with 100 mM of sodium molybdate dihydrate (Na₂MoO₄2H₂O) either before implantation or during organogenesis (on day 8) had no effect on implantation rate or subsequent developmental stages but did cause a slight reduction in fetal weight and a significant increase in the number of fetuses with poorly developed skeletons (Wide, 1984). Intravenous injection of sodium molybdate in doses of <100 mg Mo/kg to pregnant hamsters on day 8 of gestation did not produce any developmental abnormalities (Ferm, 1972).

3.4. TARGET ORGANS/CRITICAL EFFECTS

3.4.1. Oral Exposures

3.4.1.1. Primary Target Organ(s)

1. Skeletal System: Gout-like diseases possible in humans chronically exposed. Bone and joint deformities in animals.

2. Liver: Dysfunction and fatty changes possible in humans chronically exposed; fatty changes and bilirubinemia in animals chronically exposed.

3.4.1.2. Other Target Organ(s)

1. Blood: Anemia in animals following acute to subchronic exposures.

2. Kidney: Damage to distal renal tubules in animals.

3. GI Tract: Diarrhea in cattle and sheep following acute and subchronic exposures.

4. Reproductive System: Sterility in males, deficient lactation in females, and reduced survival of offspring in animals.

5. Whole Body: Growth retardation in animals.

3.4.2. Inhalation Exposures

3.4.2.1. Primary Target Organ(s)

1. Lung: Pneumoconiosis possible in occupationally exposed humans; pneumoconiosis, pneumonia, and emphysema reported in animals subchronically exposed.

2. Skeletal System: Gout-like disorders possible in humans chronically exposed.

3.4.2.2. Other Target Organs

1. Liver: Fatty changes and necrosis in animals subchronically exposed.

2. Kidney: Dystrophic changes in animals subchronically exposed.

4. CARCINOGENICITY

There is some evidence that molybdenum may have an inhibitory effect on esophageal (Luo et al., 1983; van Rensburg et al., 1986; Komada, et al., 1990) and mammary carcinogenesis (Wei et al., 1987).

4.1. ORAL EXPOSURES

4.1.1. Human

Information on the oral carcinogenicity of molybdenum compounds in humans was not available.

4.1.2. Animal

Although of short duration (< 30 weeks), a study of male Sprague-Dawley rats receiving 2.8 mg Mo/kg/day, revealed no tumors or pretumorous lesions in the esophagus and forestomach (Luo et al., 1983).

4.2. INHALATION EXPOSURES

Information on the inhalation carcinogenicity of molybdenum compounds in humans or animals was not available.

4.3. OTHER ROUTES OF EXPOSURE

Maltoni (1973) reported that subcutaneous injections of molybdenum orange (Pb and Mo chromates) resulted in sarcomas at the injection site in 36 of 40 rats (90%) compared with 65% for rats injected with chrome yellow or chrome orange (Pb chromates). No other data were provided.

When administered to Strain A mice by intraperitoneal injection (three times weekly for 30 weeks for a total dose of 4,750 mg/kg), molybdenum trioxide produced a significant increase in the number of lung adenomas per mice and an insignificant increase in the number of mice bearing tumors (Stoner et al., 1976). Lower total doses did not result in significant changes in either parameter. Information on hexavalent molybdenum compounds was inadequate to assess carcinogenicity (Helmes et al., 1983).

4.4. EPA WEIGHT-OF-EVIDENCE

Classification --D; not classifiable as to carcinogenicity in humans (U.S. EPA, 1990).

Basis -- Existing studies are inadequate to assess the carcinogenicity of molybdenum or molybdenum compounds.

4.5. CARCINOGENICITY SLOPE FACTORS

The lack of suitable positive carcinogenic data precludes the derivation of slope factors for oral or inhalation exposures.

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