3.2.1. Inhalation Exposure

Pulmonary fibrosis, memory and sensory deficits, and increased mortality due to lung cancer have been attributed to occupational exposure to dusts generated during the manufacture or use of high tensile strength tungsten (hard metal) (see Bech 1974; Bech et al. 1962; Coates and Watson 1971; Jordan et al. 1990; Kaplun and Mezentseva 1959; Lasfargues et al. 1994; Mezentseva 1967; Miller et al. 1953; Moulin et al. 1998; Vengerskaya and Salikhodzhaev 1962; Wild et al. 2000). Hard metal is produced by sintering a mixture of powders (typically tungsten carbide and cobalt) to form a tungsten alloy. Variations can include the replacement of tungsten carbide with tungsten, the addition of other metals (yttrium, thorium, copper, nickel, iron, or molybdenum) to achieve specific metallurgical properties, and the omission of cobalt. The term “hard-metal disease” has been coined to describe pulmonary effects resulting from inhaled hard metal dust. It is generally believed that the health effects observed in hard metal workers are the result of exposure to cobalt (see Davison et al. 1983; Harding 1950) or other metals (e.g., nickel), not tungsten. Refer to the ATSDR Toxicological Profile for Cobalt (Agency for Toxic Substances and Disease Registry 2004) and the ATSDR Toxicological Profile for Nickel (Agency for Toxic Substances and Disease Registry 2005) for health effects information on cobalt and nickel, respectively. It has been suggested that tungsten carbide could increase the solubility of cobalt, effectively increasing cobalt-induced toxicity (Lasfargues et al. 1995; Lison et al. 1995, 1996), although such a mechanism has not been experimentally demonstrated.

3.2.1.2. Systemic Effects

Available information in humans is limited to occupational exposure to dusts containing tungsten and other substances such as cobalt in the hard metal industry, and reported systemic effects have been associated with cobalt rather than tungsten. Therefore, human data are not included in Table 3-1 and Figure 3-1. Reliable LOAELs for respiratory and ocular effects in animals exposed to selected tungsten compounds are recorded in Table 3-1 and plotted in Figure 3-1.

No reports were located in which cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, endocrine, or dermal effects were associated with inhalation exposure of humans or animals to tungsten or tungsten compounds.

Table 3-1

Levels of Significant Exposure to Tungsten - Inhalation.

Figure 3-1

Levels of Significant Exposure to Tungsten - Inhalation. Intermediate (15-364 days)

Respiratory Effects. Respiratory effects were reported in workers who were occupationally exposed to airborne dusts containing tungsten trioxide, tungsten dioxide, metallic tungsten, and tungsten carbide in areas where high tensile strength tungsten was prepared (Mezentseva 1967). Of 54 workers examined, 5 exhibited early radiographic signs of pulmonary fibrosis after having been employed for 2–3 years (3 workers) or 19 or 24 years. The study of Mezentseva (1967) lacks critical information regarding smoking, medical, and work histories of the examined workers. Furthermore, other potentially hazardous substances may have also been present in the workplace air. It is generally believed that the health effects observed in hard metal workers are the result of exposure to cobalt (see Davison et al. 1983; Harding 1950) or other metals (e.g., nickel), not tungsten. Refer to the ATSDR Toxicological Profile for Cobalt (Agency for Toxic Substances and Disease Registry 2004) and the ATSDR Toxicological Profile for Nickel (Agency for Toxic Substances and Disease Registry 2005) for health effects information on cobalt and nickel, respectively. See Kerley et al. (1996) and NIOSH (1977) for discussions of respiratory effects associated with the hard metal industry.

Few reports were located regarding respiratory effects in animals. Signs of mild pulmonary fibrosis were noted in rats exposed to atmospheres containing tungsten carbide at a concentration of 600 mg/m³, 1 hour/day for 5 months (Mezentseva 1967). Other rats exhibited similar signs of pulmonary fibrosis following intratracheal instillation of metallic tungsten, tungsten trioxide, or tungsten carbide and subsequent observations for up to 8 months postinstillation (Mezentseva 1967). Guinea pigs that received 3 weekly doses of tungsten metal dust or tungsten carbide and carbon dust via intratracheal instillation were examined for up to 12 months post treatment (Delahant 1955; Schepers 1955a, 1955b). Gross histological examinations of the lungs revealed pigmented lung lesions that did not appear to involve lymphoid tissue; the results were not suggestive of pulmonary fibrosis. The lungs of mice exhibited no signs of a fibrotic response following intratracheal instillation of tungsten carbide (Lardot et al. 1998).

Lasfargues et al. (1992) reported severe acute pulmonary edema in rats that had received hard metal (tungsten carbide and cobalt alloy) via intratracheal instillation, but not in rats similarly exposed to tungsten carbide or cobalt alone. In a subsequent study of repeated intratracheal instillation (Lasfargues et al. 1995), it was demonstrated that intratracheally-instilled tungsten carbide and cobalt in combination, but not alone, induced interstitial pulmonary fibrosis.

Ocular Effects. Signs of slight conjunctival irritation were noted in rabbits following single ocular instillation of 100 mg of sodium tungstate dihydrate powder or tungsten metal powder (Huntingdon Life Sciences Ltd 1999c, 2000).

3.2.2. Oral Exposure

The toxicity of ingested tungsten in humans is not known. In an early report, Kruger (1912) reported no adverse effects on patients administered 25–80 g of tungsten powder as a substitute for barium in radiological exams. Nausea, followed by seizure, 24-hour coma, temporary renal failure, and subsequent tubular necrosis and anuria were reported in a male subject who had accidentally consumed metallic tungsten in a mixture of beer and wine (Marquet et al. 1997). However, these effects could not be attributed to the consumption of tungsten per se. The toxicity of orally-administered tungsten has not been widely studied in animals. Available reports implicate reproductive, developmental, and neurological effects as end points of concern following oral exposure to tungsten (Karantassis 1924; Nadeenko 1966; Nadeenko and Lenchenko 1977; Nadeenko et al. 1977, 1978). However, these reports are lacking in some study details, thus limiting their value for purposes of quantitative risk assessment.

3.2.2.2. Systemic Effects

No human data were located in which systemic toxicity could be associated with oral exposure to tungsten or tungsten compounds. Reliable NOAELs and LOAELs for body weight changes in animals orally exposed to tungsten or tungsten compounds are recorded in Table 3-3 and plotted in Figure 3-2.

Table 3-2

Oral LD₅₀ (mg/kg) Values for Selected Tungsten Compounds.

Table 3-3

Levels of Significant Exposure to Tungsten - Oral.

Figure 3-2

Levels of Significant Exposure to Tungsten - Oral.

No reports were located in which respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, endocrine, dermal, or ocular effects were associated with oral exposure of humans or animals to tungsten or tungsten compounds.

Renal Effects. Available information in humans is restricted to an account of temporary renal failure and subsequent tubular necrosis and anuria in a male subject 1 day following the accidental consumption of metallic tungsten in a mixture of beer and wine that had been poured into the hot barrel of a 155-mm gun (Marquet et al. 1997). The author estimated the absorbed dose of tungsten to be in the range of 5–12 mg/kg. The subject fully recovered. The renal effects could not be attributed to tungsten per se, and Lison et al. (1997) suggested that nitroaromatics used as propellants for large caliber ammunition may have contributed to the renal toxicity.

No information was located regarding renal effects in animals following oral exposure to tungsten or tungsten compounds.

Body Weight Effects. No information was located regarding body weight effects in humans following oral exposure to tungsten or tungsten compounds.

Available information regarding tungsten-induced body weight effects in animals is limited to reports by a single group of investigators (Kinard and Van de Erve 1941, 1943). Reduced body weight gains were noted in rats exposed to sublethal concentrations of tungsten (0.5%, as ammonium paratungstate; 0.1%, as sodium tungstate or tungstic oxide) in the diet for 70 days (Kinard and Van de Erve 1941). Body weight gain in these treated groups ranged from 3.9 to 10.6% lower than respective controls. Weight gain in female rats, administered a diet that included 10% tungsten (as insoluble tungsten metal) for 70 days, was approximately 15.5% less than that of controls; weight gain in similarly dosed male rats was described as “normal” (Kinard and Van de Erve 1941). The authors stated that diets containing 2 or 5% tungsten (as tungsten metal) were “without marked effect” on growth. Statistically significantly increased body weights were noted at some time points in male and female rats administered tungsten (as sodium tungstate) in the drinking water at a concentration of 5 mg/L for a lifetime (Schroeder and Mitchener 1975a). Since the body weights were less than 10% higher than controls and were only seen in males at 180–540 days of treatment and in females at the 360-day examination period, the increased body weight is not considered to be biologically significant.

3.2.3. Dermal Exposure

3.2.3.2. Systemic Effects

No reports were located in which respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, endocrine, or body weight effects were associated with dermal exposure of humans or animals to tungsten or tungsten compounds.

Dermal Effects. No reports were located in which dermal exposure to tungsten compounds in humans could be associated with dermal effects. Although dermatitis has been reported among employees of the hard metal industry, results of patch testing implicated cobalt, not tungsten (Schwartz et al. 1945; Skog 1963).

In the only available report of dermal effects in animals following dermal exposure to tungsten, single or repeated dermal application of a 5% tungsten chloride solution in rabbits resulted in contact dermatitis (Dow Chemical Company 1982). The results of this study are recorded in Table 3-4.

Ocular Effects. No reports were located in which dermal exposure to tungsten compounds in humans could be associated with ocular effects.

Instillation of a 5% tungsten chloride solution into the rabbit eye resulted in conjunctivitis, iritis, and corneal haziness that resolved within 14 days postinstillation (Dow Chemical 1982). The results of this study are recorded in Table 3-4.

Table 3-4

Levels of Significant Exposure to Tungsten - Dermal.

No reports were located regarding the following health effects in humans or animals following dermal exposure to tungsten or tungsten compounds:

3.2.4. Other Routes of Exposure

No reports were located in which systemic (other than possible hematological effects), neurological, or reproductive effects were associated with exposure of humans or animals to tungsten or tungsten compounds by routes other than inhalation, oral, or dermal exposure.

Death. Parenteral injection studies that have been performed using laboratory animals were designed to establish lethal doses of tungsten compounds and to assess the efficacy of methods to reduce toxicity (see also Section 3.11). An LD₅₀ value of 500 mg/kg was reported for intraperitoneally injected tungsten metal in rats; tungsten carbide was considered to be essentially inert, although dose levels were not included in the report (Fredrick and Bradley 1946). An LD₅₀ was between 140 and 160 mg/kg for tungsten (as sodium tungstate) subcutaneously injected into 66-day-old rats; younger rats appeared to be less sensitive (Kinard and Van de Erve 1940). Intramuscular injection of a 10% aqueous solution of sodium tungstate in rats (Sivjakov and Braun 1959) and rabbits (Lusky et al. 1949) resulted in LD₅₀ values of 220.6 and 105 mg/kg, respectively.

Hematological Effects. The results of Kalinich et al. (2005) indicate the potential for tungsten alloy-induced hematotoxicity (expressed by increases in leukocyte and erythrocyte counts, hemoglobin, and hematocrit). However, since the tungsten alloy pellets consisted of nickel and cobalt in addition to tungsten, the role of tungsten in the observed effects is not known. Results of in vitro testing by one group of investigators (Miller et al. 2001, 2002) indicate the potential for synergistic effects following exposure to tungsten alloys such as tungsten-cobalt-nickel and tungsten-nickel-iron.

Immunological and Lymphoreticular Effects. The results of Kalinich et al. (2005) indicate the potential for tungsten alloy-induced immunotoxicity (expressed by increased spleen weight and decreased thymus weight). However, since the tungsten alloy pellets consisted of nickel and cobalt in addition to tungsten, the role of tungsten in the observed effects is not known. Results of in vitro testing by one group of investigators (Miller et al. 2001, 2002) indicate the potential for synergistic effects following exposure to tungsten alloys such as tungsten-cobalt-nickel and tungsten-nickel-iron.

Developmental Effects. Wide (1984) assessed the potential for tungsten to induce developmental toxicity in mice. Pregnant dams were administered a single intravenous injection (0.1 mL) of a 25 mM sodium tungstate solution on gestation day 8. Although there was no indication of tungsten-induced fetal malformations at examination on gestation day 17, a significantly increased incidence of resorptions was noted.

Cancer. Kalinich et al. (2005) recently assessed the potential health consequences of intramuscularly implanted weapons-grade tungsten alloy pellets in male F344 rats. Within 4–5 months, all of the tungsten alloy-implanted (n=92) rats developed extremely aggressive localized tumors (high-grade pleomorphic rhabdomyosarcomas) that rapidly metastasized to the lungs, necessitating euthanasia. No tumors were found in a group of 46 rats implanted with an inert control metal (tantalum), even up to 12 months postimplantation. The tungsten alloy pellets consisted of 91.1% tungsten, 6% nickel, and 2.9% cobalt. Kalinich et al. (2005) also embedded 36 rats with nickel pellets to serve as positive controls for the tungsten-alloy embedded rats since intramuscularly-injected nickel has previously been demonstrated to cause injection-site tumors (Heath and Daniel 1964). All of the nickel-embedded rats developed tumors similar to those observed in the tungsten alloy-embedded rats (Kalinich et al. 2005). Previous experiments with intramuscularly-injected cobalt have also demonstrated a carcinogenic effect (Heath 1954, 1956). Since both nickel and cobalt, components of the tungsten-alloy pellets used by Kalinich et al. (2005), are known to be carcinogenic when injected intramuscularly, the potential role of tungsten in the carcinogenic effect of the tungsten alloy pellets used by Kalinich et al. (2005) could not be determined.

3.4.1. Absorption

3.4.2. Distribution

3.4.3. Metabolism

Tungsten ion in the body is not known to be metabolized. It has been postulated that tungsten may preferentially occupy enzyme sites normally reserved for the essential element, molybdenum, because sodium tungstate has been shown to antagonize the normal metabolic action of molybdate in its role as cofactor for the enzymes xanthanine dehydrogenase (Higgins et al. 1956a, 1956b), sulfite oxidase, and aldehyde oxidase (Johnson and Rajagopalan 1974), and xanthine oxidase secretion to milk (Owen and Proudfoot 1968) in animal systems. See Section 3.5.2 for detailed information regarding mechanisms of tungsten-induced toxicity.

3.4.4. Elimination and Excretion

Elimination and excretion of tungsten is discussed without subdividing data according to route of exposure. Once tungsten has been systemically distributed following inhalation, oral, or dermal exposure or parenteral injection, the pattern of elimination is similar across exposure routes.

Information concerning elimination and excretion of tungsten in humans is limited to findings of measurable amounts of tungsten in urine of individuals exposed to tungsten either in the workplace air (see Barborik 1972; Nicolaou et al. 1987) or by controlled (Wester 1974) or accidental (Marquet et al. 1997) ingestion of tungsten.

Inhalation, oral, and parenteral injection studies in laboratory animals all indicate that absorbed tungsten is rapidly eliminated from the blood and quickly excreted in large quantities in the urine. Combined urinary and fecal excretion of radiotungsten from dogs following inhalation exposure to particulate aerosols of ¹⁸¹WO₃ was described by three exponential components (Aamodt 1975). Approximately 90% of the inhaled radioactivity was removed with a biological half-time of about 14 hours; 6% with a half-time of 5.8 days, and 4% with a half-time of 63 days. The average urine to fecal ratio was 1.14 for the 100 days of postexposure measurements, including the portion of tungsten that entered the blood directly from the lungs (approximately 33% of the deposited dose) as well as that which was deposited in the gastrointestinal tract via mucociliary clearance (approximately 66% of the initial lung burden).

Radiotungsten was rapidly excreted from rats following oral dosing (Kaye 1968). In a study of rats administered single gavage doses of ¹⁸⁵W and followed for 72 hours, approximately 40% of the administered dose of radiotungsten had been eliminated in the urine in the first 12 hours postadministration; an additional 3% was eliminated during the subsequent 60 hours. The initial rate of fecal excretion was lower than that of urinary excretion; however, by 72 hours, fecal excretion had accounted for approximately 53% of the administered dose. Thus, 72-hour urinary and fecal excretion accounted for 97% of the administered dose. Other rats were similarly administered ¹⁸⁵W and followed for up to 254 days. During the first 3 days following dosing, approximately 36 and 39% of the administered dose had been recovered in the urine and feces, respectively. By day 33 postadministration, radiotungsten could no longer be detected in the feces. Trace amounts of radiotungsten were still detected in urine analyses conducted until day 191 and correlated with slow elimination of ¹⁸⁵W from bone. In dairy cows that were orally administered radiotungsten, approximately 0.4% of the administered dose was recovered in the milk during the first 84 hours postadministration (Mullen et al. 1976).

Following intravenous injection of dogs with ¹⁸¹W (as sodium tungstate), elimination from the blood was rapid (Aamodt 1973). By 24 hours, 91% of the injected radioactivity had been excreted in the urine. An initial urinary to fecal ratio of 49 on day 1 was reduced to a constant value of 38 by day 7.

3.4.5. Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models

Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake and disposition of chemical substances to quantitatively describe the relationships among critical biological processes (Krishnan et al. 1994). PBPK models are also called biologically based tissue dosimetry models. PBPK models are increasingly used in risk assessments, primarily to predict the concentration of potentially toxic moieties of a chemical that will be delivered to any given target tissue following various combinations of route, dose level, and test species (Clewell and Andersen 1985). Physiologically based pharmacodynamic (PBPD) models use mathematical descriptions of the dose-response function to quantitatively describe the relationship between target tissue dose and toxic end points.

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to delineate and characterize the relationships between: (1) the external/exposure concentration and target tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen et al. 1987; Andersen and Krishnan 1994). These models are biologically and mechanistically based and can be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from route to route, between species, and between subpopulations within a species. The biological basis of PBPK models results in more meaningful extrapolations than those generated with the more conventional use of uncertainty factors.

The PBPK model for a chemical substance is developed in four interconnected steps: (1) model representation, (2) model parametrization, (3) model simulation, and (4) model validation (Krishnan and Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen 1994; Leung 1993). PBPK models for a particular substance require estimates of the chemical substance-specific physicochemical parameters, and species-specific physiological and biological parameters. The numerical estimates of these model parameters are incorporated within a set of differential and algebraic equations that describe the pharmacokinetic processes. Solving these differential and algebraic equations provides the predictions of tissue dose. Computers then provide process simulations based on these solutions.

The structure and mathematical expressions used in PBPK models significantly simplify the true complexities of biological systems. If the uptake and disposition of the chemical substance(s) are adequately described, however, this simplification is desirable because data are often unavailable for many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The adequacy of the model is, therefore, of great importance, and model validation is essential to the use of PBPK models in risk assessment.

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994).

PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste sites) based on the results of studies where doses were higher or were administered in different species. Figure 3-3 shows a conceptualized representation of a PBPK model.

If PBPK models for tungsten exist, the overall results and individual models are discussed in this section in terms of their use in risk assessment, tissue dosimetry, and dose, route, and species extrapolations.

International Commission for Radiological Protection (ICRP 1981) Biokinetic Model for Tungsten

The ICRP’s modular approach to biokinetic modeling.

In ICRP documents addressing occupational or environmental exposures to radionuclides, the biokinetic model for an element consists of three submodels: a respiratory tract model, a gastrointestinal tract model, and an element-specific systemic biokinetic model. For a given element, the generic respiratory tract model is used to describe the deposition and retention of inhaled material in the respiratory tract and subsequent clearance to blood or the gastrointestinal tract via mucociliary transport and swallowing. The generic gastrointestinal tract model is used to describe the movement of swallowed or endogenously secreted material through the stomach and intestines, and, together with an element-specific gastrointestinal absorption fraction (f₁ value), to describe the rate and extent of absorption of the element to blood. An element-specific systemic biokinetic model is used to describe the time-dependent distribution and excretion of the element after its absorption into blood.

The ICRP’s gastrointestinal model (ICRP 1979) as applied to tungsten (ICRP 1981).

The ICRP’s generic gastrointestinal tract model divides the gastrointestinal contents into stomach (S), small intestine (SI), upper large intestine (ULI), and lower large intestine (LLI). Material moves from S to SI at the rate of 24 day⁻¹, from SI to ULI at 6 day⁻¹, from ULI to LLI at 1.8 day⁻¹, and from LLI to feces at 1 day⁻¹. Absorption to blood is represented as transfer from SI to blood. In the absence of radioactive decay, the fraction f₁ of the ingested element moves from SI to blood and the fraction 1-f₁ moves from SI to ULI. The transfer coefficient from SI to blood is 6f₁/(1-f₁) day⁻¹. An absorption fraction f₁ of 0.3 is applied to compounds of tungsten other than tungstic acid, for which an absorption fraction of 0.1 is used.

Figure 3-3

Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for a Hypothetical Chemical Substance. Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a hypothetical chemical substance. (more...)

Differences in the values for f₁ reflect measured differences in fractional absorption of various tungsten compounds in rats (Ballou 1960; Kaye 1968).

The ICRP’s respiratory model (ICRP 1994a) as applied to tungsten (ICRP 1995).

The ICRP uses a generic respiratory model (ICRP 1994a) to describe deposition and retention of inhaled elements in the respiratory tract, absorption to blood, and transfer to the stomach via movement up the tracheobronchial tree in mucus and subsequent swallowing. The kinetics of swallowed activity is described by the gastrointestinal tract model summarized above. Elements or specific compounds of elements inhaled in particulate form are assigned to one of three “absorption types” representing the rate of transfer of material from the lungs to blood, which in turn is related to the rate of dissolution of the material in the respiratory tract. The three absorption types are Type F, representing fast absorption; Type M, representing moderately slow absorption; and Type S, representing slow absorption. There are numerous parameter values associated with each absorption type; these will not be listed here. Compounds of tungsten are assumed to be dissolved fairly rapidly in the respiratory tract and, thus, are assigned to Type F (ICRP 1994b).

The ICRP’s systemic biokinetic model for tungsten (ICRP 1981).

The ICRP uses an element-specific systemic biokinetic model to describe the kinetics of the element after its absorption to blood from the respiratory tract or gastrointestinal tract, or entry from wounds or direct injection into blood. The ICRP’s current systemic biokinetic model for tungsten (ICRP 1981) was developed in the 1970s. The model (Figure 3-4) consists of exponential curve fits to selected data on the relatively short-term behavior of tungsten in dogs, goats, and rats. In the development of the model, no attempt was made to reflect the physiological processes that control the biokinetics of tungsten or to depict actual paths of movement of this element in the body. Absorbed tungsten is assumed to enter the blood, from which 95% immediately transfers to excreta by unspecified routes, 2.5% transfers to bone mineral, 1% transfers to kidney, 1% transfers to liver, and 0.5% transfers to spleen. Tungsten in bone is removed in excretion with half-times of 4 days (20%), 100 days (10%), and 1,000 days (70%). Tungsten in any other tissue is removed to excretion with half-times of 5 days (70%) and 100 days (30%).

Figure 3-4

ICRP (1981, 2001) Biokinetics Model for Tungsten.

Validation of the model.

The extent to which the ICRP model has been validated is not described in ICRP (1981).

Risk assessment.

The model has been used to establish radiation dose equivalents (Sv/Bq) of ingested and inhaled radioactive tungsten isotopes for ages 1 day to 50 years (ICRP 2001).

Target tissues.

The model is designed to calculate intake limits for radioactive tungsten, based on radiation dose to all major organs, including the bone surfaces, bone marrow, and soft tissues.

Species extrapolation.

The model is designed for applications to human dosimetry and cannot be applied to other species without modification.

Interroute extrapolation.

The ICRP’s systemic biokinetic model for tungsten can be applied to any route of exposure (e.g., from the respiratory or GI tract, wounds, through the skin, or via intravenous injection), provided information is available on the time-course of entry of tungsten into blood.

Leggett (1997) Model of the Biokinetics of Absorbed Tungsten

Description of the model.

Leggett (1997) developed a compartmental model of the biokinetics of absorbed tungsten in adult humans that can be linked to the ICRP’s gastrointestinal tract model (ICRP 1979, 1981) or respiratory model (ICRP 1994). The model differs considerably from the ICRP’s systemic biokinetic model for tungsten with regard to structure, basis for parameter values, and predicted retention of tungsten in tissues. The model structure (Figure 3-5) is intended to depict physiologically realistic directions of movement of tungsten in the human body, including the systemic redistribution of tungsten that enters blood after removal from tissues. Model parameters are based on results of biokinetic studies of tungsten in dogs, swine, sheep, goats, cows, and rodents. Although tungsten biokinetics has been studied more frequently in rats than other species, data for rats were given low weight in selection of most parameter values because of known qualitative differences between rats and humans in the handling of molybdenum, a chemical and physiological analogue of tungsten. It is suspected that membrane transport may not distinguish between analogous compounds of tungsten and molybdenum, although biokinetic differences between tungsten and molybdenum arise, probably because molybdenum compounds are more easily reduced in biological systems (Callis and Wentworth 1977). The species differences recognized for molybdenum may apply to tungsten as well, as suggested by the much faster excretion of tungsten by rats than other studied species and apparent differences in the distribution of retained tungsten. On the other hand, some aspects of the biokinetics of tungsten or molybdenum, including long-term skeletal retention due to substitution of tungstate or molybdate for phosphate in bone, are expected to be independent of species.

The structure of the model for tungsten (Figure 3-5) is essentially the same as that applied in ICRP Publication 69 (1995) to a set of “bone-volume-seeking” elements, including calcium, strontium, barium, radium, lead, and uranium. It is assumed that the kinetics of tungsten that deposits in bone can be related to the kinetics of the major components of bone mineral, calcium, and phosphorus.

Transport of tungsten between compartments is assumed to follow first-order kinetics. Three compartments are used to describe the kinetics of circulating tungsten: (1) blood plasma, (2) red blood cells, and (3) a rapid-turnover soft-tissue compartment representing extracellular fluids. The rapid-turnover soft-tissue compartment is used to depict an early build-up of tungsten in extravascular spaces followed by relatively rapid feedback to blood. The total transfer rate from plasma to all destinations is set at 16.64 day⁻¹, corresponding to a removal half-time of 1 hour. The rapid-turnover soft-tissue compartment receives 30% of tungsten leaving plasma and returns tungsten to plasma with a half-time of 2 hours. The division of tungsten leaving the circulation, defined as atoms moving from plasma to compartments other than rapid-turnover soft-tissues, is as follows: 75% to the urinary bladder contents; 5% to kidney tissue; 5% to the contents of the upper large intestine (representing all secretions into the gastrointestinal tract); 4% to liver; 8% to bone surfaces; 2.5% to other soft tissues; and 0.5% to red blood cells. The assigned removal half-times from the various compartments within these tissues vary from 1 day (from bone surfaces) to about 23 years (from cortical bone volume). Tungsten removed from the skeleton, certain kidney tissue, liver tissue, remaining soft tissues, and red blood cells is assigned to plasma and redistributed to excretion pathways and tissues in the same ratio as the initial input into plasma. Most of the tungsten removed from kidney tissue is assigned to the urinary bladder contents.

Figure 3-5

Leggett (1997) Biokinetics Model for Tungsten. Adapted from Leggett 1997

Bone is divided into cortical and trabecular portions and each of these is further divided into a bone surface compartment and exchangeable and nonexchangeable bone volume compartments. Approximately 55% of tungsten entering the skeleton is assigned to trabecular surfaces and 45% to cortical surfaces. Tungsten is removed from bone surface with a half-time of 1 day, with 5/6 returning to plasma and 1/6 entering the corresponding exchangeable bone volume compartment. It is removed from exchangeable bone volume with a half-time of 100 days, with 60% assigned to the corresponding nonexchangeable bone volume compartment and 40% to the corresponding bone surface compartment. Removal from nonexchangeable bone to plasma occurs at the rate of bone turnover, estimated as 0.03 year⁻¹ for cortical bone (half-time of ~23 years) and 0.18 years⁻¹ for trabecular bone (half-time approximately 4 year).

The model predicts a rapid decline in body burden of tungsten after cessation of exposure; approximately 15% of the burden remains after 1 day, 5% after 1 week, 3% after 1 month, 1.6% after 1 year, and 0.4% after 10 years. The slowest component of the decline represents stores in bone volume; therefore, over time, the fraction of the body burden associated with bone increases to 60% after 1 year and 90% after 4 years. Steady state in soft tissue is predicted after approximately 300–500 days of continuous exposure, whereas, bone continues to accumulate tungsten with chronic exposure.

Validation of the model.

An evaluation of the extent to which the model has been validated was not located. Predictions from the model were compared to those from the ICRP (1981) model (Leggett 1997). Over the first few years after intake, the two models yield reasonably consistent predictions of total-body retention, but noticeably different predictions of retention in specific tissues. For example, the ratio of predicted retention values, ICRP model:Leggett model, at 1 day after acute uptake of tungsten to blood is 0.75 for the total body, but 0.44 for bone or kidney, 0.28 for liver, and 8.5 for spleen. For times greater than a few years after intake, the ICRP model predicts considerably faster decline of activity in all tissues, with the ratio ICRP model:Leggett model at 10,000 days after acute intake being <0.01 for total body or bone retention and <0.001 for retention in all other tissues. Differences in predictions of the two models result in part from differences in the databases considered, in that the ICRP restricted attention to specific data sets and relied heavily on data for rats, which were generally given low weight in the model of Leggett. Predictive differences also arise from differences in the method of extrapolation to times beyond the periods of observation of tungsten retention in laboratory animals. For example, in the ICRP model, a removal half-time from bone of 1,000 days is arbitrarily applied to represent “a very long-term component of retention in the skeleton” (ICRP 1981). In the Leggett model, long-term removal of tungsten from bone is assumed to occur at the rate at which human bone is remodeled.

Risk assessment.

The extent to which the model has been applied to risk assessment is not described in Leggett (1997). The model is configured to be applicable for estimation of time-integrated target tissue doses, blood tungsten levels, and tungsten excretion.

Target tissues.

The model output includes tungsten levels in bone, blood, kidney, liver, other soft tissues, and plasma.

Species extrapolation.

Parameter values of the model were derived for adult humans. The model structure is applicable to other mammalian species, but application to other species would require the derivation of appropriate parameter values based on species-specific information.

Interroute extrapolation.

The Leggett systemic biokinetic model for tungsten can be applied to any route of exposure (e.g., from the respiratory or gastrointestinal tract, wounds, through the skin, or via intravenous injection), provided information is available on the time-course of entry of tungsten into blood.

3.5.1. Pharmacokinetic Mechanisms

Absorption. Absorption of inhaled tungsten has been demonstrated in dogs (Aamodt 1975). Approximately one-third of a dose of radiotungsten (¹⁸¹WO₃) that was deposited in the respiratory tract was transferred to the blood. Based on relatively rapid clearance of a portion of the deposited activity from the lungs (70% was cleared with a half-time of 4 hours), diffusion may account for at least a portion of the dose entering the blood. Experimental data also indicate that tungsten particles may be dissolved within alveolar macrophages (De Sousa Pereira et al. 1992; Grande et al. 1990; Peão et al. 1993) and transported to the lymphatic system (Águas et al. 1991; Grande et al. 1990). The relative solubility of a given tungsten compound also likely dictates the degree and rate of absorption. At least a portion of tungsten inhaled as hard metal dust may be retained in lung tissue for an extended period (Cugell et al. 1990; Edel et al. 1990).

Ingested tungsten appears to be largely absorbed from the lower ileum, based on results of an in vitro study using the rat small intestine (Cardin and Mason 1976). Results of both in vitro and in vivo studies in rats indicate that gastrointestinal absorption and transport of tungsten probably occurs via the same pathways employed by the essential element molybdenum (Cardin and Mason 1976; Johnson and Rajagopalan 1974; Johnson et al. 1974). The results further indicate that a transport system common to molybdenum and tungsten is subject to competitive inhibition.

No information was located regarding mechanisms involved in absorption of tungsten through the skin. However, a report of death in rabbits following a single dermal application of a 5% tungsten chloride solution (Dow Chemical Company 1982) is evidence of absorption and systemic distribution of dermally-applied tungsten.

Distribution. Absorbed tungsten is rapidly distributed throughout the body and quickly eliminated predominantly via the urine. Mechanisms involved in the distribution of absorbed tungsten are not currently understood. However, rapid distribution via the blood and elimination via the kidney serve as indication that distribution does not likely include major binding to cellular components or proteins in blood. Retention of tungstate by the liver may be related to the findings that tungsten inhibits the binding of the essential element molybdenum to selected liver proteins (Johnson and Rajagopalan 1974). Retention of tungsten in bone has led to the suggestion that tungstate anions interact with calcium, thereby forming the relatively insoluble calcium tungstate (Wase 1955). In physiological systems such as cells and blood, molecules binding anionic forms of tungsten might release these anions to water in exchange for dissolved phosphate ion, for which they may have greater affinity, as suggested by Wide et al. (1986).

Excretion. Inhalation, oral, and parenteral injection studies in laboratory animals all indicate that absorbed tungsten is rapidly eliminated from the blood and quickly excreted in large quantities in the urine (Aamodt 1973, 1975; Kaye 1968). Specific mechanisms involved in the excretion of tungsten were not identified in available reports.

3.5.2. Mechanisms of Toxicity

Specific mechanisms of tungsten-induced toxicity have not been elucidated. Pulmonary fibrosis in hard metal workers exposed to dusts containing tungsten carbide and cobalt has been historically attributed to the presence of cobalt, not tungsten (see Davison et al. 1983; Harding 1950). Based on results of studies in which pulmonary fibrosis was induced in rats following intratracheal instillation of tungsten carbide and cobalt in combination, but not in rats exposed to tungsten carbide or cobalt alone (Lasfargues et al. 1995), it has been proposed that tungsten carbide, a relatively good conductor of electrons, may facilitate the oxidation of cobalt metal to ionic cobalt, which could increase both the solubility of cobalt and the generation of active oxygen species (Lasfargues et al. 1995; Lison et al. 1995). In vitro evidence for this mechanism includes the ability of hard metal particles, but neither cobalt nor tungsten carbide alone, to generate oxidant species and cause lipid peroxidation (Lison et al. 1995; Zanetti and Fubini 1997). Hard metal particles have also been shown to increase the levels of inducible nitric oxide synthase (iNOS); the gene for iNOS is responsive to oxidant stress (Rengasamy et al. 1999).

Leanderson and Sahle (1995) demonstrated that respirable tungsten oxide fibers, which were measured in the air of hard metal industries (80% of the fibers were ≤0.3 µm in diameter) (Sahle 1992; Sahle et al. 1994), are capable of generating hydroxyl radicals in human lung cells in vitro, and that these fibers were more cytotoxic than crocidolite asbestos. It could be argued that generation of hydroxyl radicals might contribute toward the development of pulmonary fibrosis in individuals occupationally exposed to fibrous tungsten oxide in the hard metal industry. However, any attempt to link tungsten with the development of pulmonary fibrosis via a mechanism that includes the generation of hydroxyl radicals is speculative because such a mechanism has not been demonstrated in vivo.

In animals administered high levels of tungsten in combination with low dietary levels of molybdenum, the competitive agonistic properties of the two metals can be manifested by reduced levels of molybdenum and decreased activity of enzymes such as xanthine oxidase, sulfite oxidase and aldehyde oxidase, which normally incorporate molybdenum as a metal carrier (De Renzo 1954; Higgins et al. 1956a, 1956b; Johnson and Rajagopalan 1974; Johnson et al. 1974). Although these effects can be observed following exposure to elevated levels of tungsten, only very small amounts of supplemental molybdenum are required to reverse these tungsten-induced effects. The competitive agonistic properties of tungsten and molybdenum have not been associated with any observable signs of toxicity.

3.5.3. Animal-to-Human Extrapolations

No data were located concerning major interspecies differences in pharmacokinetics or health effects associated with exposure to tungsten or tungsten compounds. However, the rat exhibits a remarkably low requirement for molybdenum, relative to other animal species (Higgins et al. 1956b). The apparently low dietary requirement of molybdenum in the rat, as well as the competitive agonistic properties of molybdenum and tungsten and their chemical similarities, is suggestive evidence of species-specific differences in the biokinetics of tungsten.

3.8.1. Biomarkers Used to Identify or Quantify Exposure to Tungsten and Tungsten Compounds

The presence of tungsten in the blood, urine, or feces serves as a biomarker of exposure to tungsten or tungsten compounds. Levels in these media may be used in conjunction with biokinetic models to estimate previous exposure levels.

3.8.2. Biomarkers Used to Characterize Effects Caused by Tungsten and Tungsten Compounds

Biomarkers of effect for tungsten or tungsten compounds were not identified in available literature.

3.11.1. Reducing Peak Absorption Following Exposure

No data were located regarding reduction of peak absorption of tungsten following exposure. Cathartics such as magnesium sulfate, as well as gastric lavage, might shorten the transit time of ingested tungsten in the gastrointestinal tract. Oral administration of activated charcoal shortly following oral exposure to tungsten might be effective in reducing peak absorption.

3.11.2. Reducing Body Burden

No data were located regarding reducing the body burden of tungsten.

3.11.3. Interfering with the Mechanism of Action for Toxic Effects

No data were located regarding reduction of the toxic effects of tungsten through interfering with mechanisms of action.

3.12.1. Existing Information on Health Effects of Tungsten and Tungsten Compounds

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to tungsten and tungsten compounds are summarized in Figure 3-6. The purpose of this figure is to illustrate the existing information concerning the health effects of tungsten and tungsten compounds. Each dot in the figure indicates that one or more studies provide information associated with that particular effect. The dot does not necessarily imply anything about the quality of the study or studies, nor should missing information in this figure be interpreted as a “data need”. A data need, as defined in ATSDR’s Decision Guide for Identifying Substance-Specific Data Needs Related to Toxicological Profiles (Agency for Toxic Substances and Disease Registry 1989), is substance-specific information necessary to conduct comprehensive public health assessments. Generally, ATSDR defines a data gap more broadly as any substance-specific information missing from the scientific literature.

Figure 3-6

Existing Information on Health Effects of Tungsten and Tungsten Compounds.

Available data regarding health effects in humans exposed to tungsten predominantly involves occupational exposure to dusts that include particles of tungsten and other metals (particularly cobalt) at facilities in which hard metal is produced. It is generally considered that cobalt is the source of adverse health effects such as pulmonary fibrosis and dermatitis in hard metal workers, not tungsten. A single case report was located concerning acute oral exposure to tungsten in a male subject. However, reported symptoms could not be specifically attributed to tungsten.

Relatively few reports were located regarding health effects in animals following acute-, intermediate-, or chronic-duration exposure to tungsten or tungsten compounds. Several early Russian reports were located, mainly originating from a single group of investigators. The reports predominantly assessed acute lethality or reproductive or developmental effects following oral exposure to soluble tungsten compounds. The carcinogenicity and genotoxicity of tungsten and tungsten compounds has not been adequately assessed in humans or animals. However, tungsten has been recently nominated by the National Center for Environmental Health for toxicological characterization including carcinogenicity (NTP 2003).

3.12.2. Identification of Data Needs

Acute-Duration Exposure. No human studies were located regarding health effects associated with acute-duration inhalation exposure to tungsten. Information in animals is restricted to exposure via intratracheal instillation of tungsten compounds. Intratracheal instillation of water-insoluble calcium tungstate crystals resulted in an inflammatory response in mice (Peão et al. 1993). Acute pulmonary edema was reported in rats that had received hard metal (tungsten carbide and cobalt alloy) via intratracheal instillation, but not in rats exposed to tungsten carbide or cobalt alone (Lasfargues et al. (1992). Due to the lack of information concerning adverse effects and targets of toxicity following acute-duration inhalation exposure to tungsten or tungsten compounds, no acute-duration inhalation MRLs were derived. Results of acute-duration inhalation toxicity studies that adequately characterize dose-response characteristics and target organs could serve as a basis to derive acute-duration inhalation MRLs for tungsten and tungsten compounds.

Information regarding health effects in humans following acute-duration oral exposure to tungsten is restricted to a single case report in which a male subject experienced neurological (nausea, seizure, and 24-hour coma) and renal (temporary renal failure, tubular necrosis, and anuria) effects following the accidental consumption of metallic tungsten in a mixture of beer and wine (Marquet et al. 1997). However, the observed effects could not be specifically attributed to tungsten. Reports of tungsten-induced adverse health effects in animals following acute-duration oral exposure to tungsten consist primarily of reports in which lethality was assessed (Karantassis 1924; Kinard and Van de Erve 1941; Nadeenko 1966; Smyth et al. 1969). Guinea pigs exhibited clinical signs that included trembling and abnormal locomotor behavior following single oral administration of sodium tungstate at ultimately lethal doses (≥780 mg/kg) (Karantassis 1924). Due to the lack of information concerning adverse effects and targets of toxicity following acute-duration oral exposure to tungsten or tungsten compounds, no acute-duration inhalation MRLs were derived. Results of acute-duration oral toxicity studies that adequately characterize dose-response characteristics and target organs could serve as a basis to derive acute-duration oral MRLs for tungsten and tungsten compounds.

Information concerning dermal effects in humans exposed to tungsten is restricted to a report of dermatitis in employees of the hard metal industry, but results of patch testing implicated cobalt, not tungsten, as the causative agent (Schwartz et al. 1945; Skog 1963). Relatively little information is available concerning adverse effects in animals following acute-duration dermal exposure to tungsten. Contact dermatitis was reported in rabbits following dermal application of a 5% tungsten chloride solution in single doses ≥100 mg/kg; doses ≥200 mg/kg also resulted in death (Dow Chemical Company 1982). Instillation of a 5% tungsten chloride solution into the rabbit eye resulted in initial ocular irritation that resolved within 14 days postinstillation (Dow Chemical Company 1982). Additional animal studies could be designed to assess the sublethal systemic toxicity of tungsten and selected tungsten compounds following acute-duration dermal exposure.

Intermediate-Duration Exposure. No human studies were located regarding health effects associated with intermediate-duration inhalation exposure to tungsten. Rats that were repeatedly exposed to atmospheres containing tungsten carbide at a concentration of 600 mg/m³ exhibited signs of pulmonary fibrosis and clinical signs that were interpreted as anxiety manifestations (Mezentseva 1967). Decreased sperm motility was noted in rats continuously repeatedly exposed to atmospheres containing sodium tungstate at concentrations ≥0.5 mg/m³ (Idiyatullina 1981). Mixed results were reported in laboratory animals following intratracheal instillation of selected tungsten compounds and examinations that spanned intermediate-duration post instillation periods. Signs of pulmonary fibrosis were reported in rats observed for up to 8 months following intratracheal instillation of metallic tungsten, tungsten trioxide, or tungsten carbide (Mezentseva 1967). Lung lesions in the absence of apparent pulmonary fibrosis were reported in guinea pigs that had received 3 weekly doses of intratracheally-instilled metallic tungsten or tungsten carbide and carbon dust, followed by up to 12 months of posttreatment examination (Delahant 1955; Schepers 1955a, 1955b). No signs of a fibrotic response were seen in the lungs of mice that had received tungsten carbide via intratracheal instillation (Lardot et al. 1998). Due to the lack of information concerning adverse effects and targets of toxicity following intermediate-duration inhalation exposure to tungsten or tungsten compounds, no intermediate-duration inhalation MRLs were derived. Results of intermediate-duration inhalation toxicity studies that adequately characterize dose-response characteristics and target organs could serve as a basis to derive intermediate-duration inhalation MRLs for tungsten and tungsten compounds.

No human studies were located regarding health effects associated with intermediate-duration oral exposure to tungsten. In rats, early reports have associated repeated oral exposure to tungsten with neurological (Karantassis 1924), reproductive (Nadeenko and Lenchenko 1977; Nadeenko et al. 1977, 1978), and developmental (Nadeenko and Lenchenko 1977; Nadeenko et al. 1977, 1978) effects. Body weight changes, in the absence of other signs of toxicity, were reported in rats following repeated oral exposure to various tungsten compounds (Kinard and Van de Erve 1941, 1943). However, the available animal studies did not include critical dose-response information and other details (including methods used in statistical analysis of data), which precludes their usefulness for the purpose of MRL derivation. Therefore, no intermediate-duration oral MRLs were derived for tungsten. Results of intermediate-duration oral toxicity studies that adequately characterize dose-response characteristics could serve as a basis to derive intermediate-duration inhalation and oral MRLs for tungsten and tungsten compounds.

No human or animal data were located regarding noncancer or cancer end points associated with intermediate-duration dermal exposure to tungsten or tungsten compounds. Intramuscularly-implanted tungsten alloy (91.1% tungsten, 6.0% nickel, and 2.9% cobalt) was recently shown to rapidly cause aggressive tumors in rats (Kalinich et al. 2005). However, since both nickel and cobalt are known to cause tumors following intramuscular injection in rats (Heath 1954, 1956; Heath and Daniel 1964), the carcinogenic role of tungsten itself was not determined.

Chronic-Duration Exposure and Cancer. Information regarding chronic exposure of humans to tungsten primarily involves respiratory effects such as pulmonary fibrosis, memory and sensory deficits, and increased mortality due to lung cancer in hard metal workers exposed to dusts that include particles of tungsten and other metals (particularly cobalt) (see Bech 1974; Bech et al. 1962; Coates and Watson 1971a, 1971b; Jordan et al. 1990; Kaplun and Mezentseva 1959; Lasfargues et al. 1994; Mezentseva 1967; Miller et al. 1953; Moulin et al. 1998; Vengerskaya and Salikhodzhaev 1962; Wild et al. 2000). It is generally considered that cobalt is the source of major toxicity concern, not tungsten (see Davison et al. 1983; Harding 1950). However, it has been suggested that tungsten oxide fibers may contribute to the development of pulmonary fibrosis in hard metal workers (Sahle 1992). No studies were located regarding chronic-duration inhalation exposure of laboratory animals to tungsten or tungsten compounds. Based on the lack of human and animal data, no chronic-duration inhalation MRLs were derived for tungsten or tungsten compounds. Results of well-designed chronic-duration inhalation studies in animals could serve as a basis to derive chronic-duration inhalation MRLs for tungsten and tungsten compounds.

No human studies were located regarding noncancer or cancer end points associated with chronic-duration oral exposure to tungsten. Information concerning health effects in animals following chronic-duration oral exposure to tungsten or tungsten compounds is restricted to reports by Schroeder and Mitchener (1975a, 1975b) in which tungsten-treated (5 ppm of tungsten as sodium tungstate in the drinking water for a lifetime) and control rats and mice exhibited similar growth patterns and incidences of gross tumors. However, these studies were limited to assessment of growth, gross tumor incidence, and longevity. Limited study design, including lack of both dose-response data and comprehensive histopathologic examinations preclude their usefulness for MRL derivation. Results of well-designed chronic-duration oral studies in animals could serve as a basis to derive chronic-duration oral MRLs for tungsten and tungsten compounds.

Recent findings of elevated tungsten body burdens in residents of Churchill County (City of Fallon), Nevada (CDC 2003b), and the discovery that a relatively limited amount of information is available concerning the potential for long-term adverse health effects following exposure to tungsten, have resulted in the nomination of tungsten by the National Center for Environmental Health (NCEH) for toxicological characterization, which includes carcinogenicity (NTP 2003).

No human or animal data were located regarding noncancer or cancer end points associated with chronic-duration dermal exposure to tungsten or tungsten compounds. Intramuscularly-implanted tungsten alloy (91.1% tungsten, 6.0% nickel, and 2.9% cobalt) was recently shown to rapidly cause aggressive tumors in rats (Kalinich et al. 2005). However, since both nickel and cobalt are known to cause tumors following intramuscular injection in rats (Heath 1954, 1956; Heath and Daniel 1964), the carcinogenic role of tungsten itself was not determined.

Genotoxicity. No information was located regarding tungsten-induced genotoxicity following inhalation, oral, or dermal exposure to tungsten or tungsten compounds in humans or laboratory animals. Sodium tungstate was found to induce mutagenic activity in a bacterial bioluminescence test (Ulitzur and Barak 1988), lambda prophage in E. coli (Rossman et al. 1984, 1991), and gene conversion and reverse mutation in Saccharomyces cerevisiae (Singh 1983). An unspecified form of tungsten enhanced mutagenic activity in Salmonella typhimurium (Miller and Page 1999). Tungstate anion induced forward mutation in Chinese hamster lung V79 cells in vitro (Zelikoff et al. 1986). Sodium tungstate did not increase sister chromatid exchanges in human whole blood cultures or cause chromosome aberrations in human lymphocytes or Syrian hamster embryo cells (Larramendy et al. 1981). Nor did sodium tungstate induce morphological transformation in Syrian hamster cells (DiPaolo and Casto 1979). Heavy metal-tungsten alloys are capable of inducing neoplastic transformation of human osteoblast cells (Miller et al. 2001). Pure tungsten is capable of inducing a similar effect (Miller et al. 2004), but at a significantly reduced magnitude relative to the heavy metal-tungsten alloys. Additional studies could be designed to further assess the potential for tungsten and tungsten compounds to induce genotoxicity.

Reproductive Toxicity. No information was located regarding reproductive toxicity in humans following inhalation exposure to tungsten or tungsten compounds. Information in animals is restricted to a single account of decreased sperm motility (10–12% lower than controls) in male rats continuously exposed to atmospheres containing sodium tungstate powder for 17 weeks at concentrations of 1.0 and 0.5 mg/m³, but not at 0.1 mg/m³ (Idiyatullina 1981).

No information was located regarding reproductive toxicity in humans following oral exposure to tungsten or tungsten compounds. Information in animals is restricted to reported embryotoxicity (expressed as increased percentages of pre- and post-implantation losses, relative to controls) following oral administration of an unspecified tungsten compound to adult female rats at a single dose level of 0.005 mg/kg for up to 8 months before and during pregnancy (Nadeenko and Lenchenko 1977; Nadeenko et al. 1977, 1978). However, deficiencies in study details regarding exposure and quantitative results render the results of these Russian studies of limited value for purposes of quantitative risk assessment. Additional well-designed animal studies would be useful to adequately assess the reproductive toxicity of orally-administered tungsten and tungsten compounds. Such studies could include standard reproductive toxicity studies as well as conventional intermediate-duration oral toxicity studies that would include an assessment of reproductive organ pathology.

No information was located regarding reproductive toxicity in humans or animals following dermal exposure to tungsten or tungsten compounds. However, inhalation is the most likely significant route of exposure to tungsten or tungsten in workers employed in industries that produce or use tungsten-containing products. Elevated levels of tungsten in groundwater, such as was detected in well water in Churchill County (City of Fallon), Nevada (CDC 2003b), indicate the potential for significant oral exposure to tungsten and tungsten compounds as well. It does not appear that additional studies of health effects associated with dermal exposure to tungsten or tungsten compounds are necessary at this time.

Developmental Toxicity. No information was located regarding developmental toxicity in humans or animals following inhalation exposure to tungsten or tungsten compounds. Animal studies could be performed to assess the potential for tungsten-induced developmental effects via the inhalation exposure route.

No information was located regarding developmental toxicity in humans following oral exposure to tungsten or tungsten compounds. Information in animals is restricted to reported delayed fetal skeletal ossification following oral administration of an identified tungsten compound to adult female rats at a single dose level of 0.005 mg/kg for up to 8 months before and during pregnancy (Nadeenko and Lenchenko 1977; Nadeenko et al. 1977, 1978). However, deficiencies in study details regarding exposure and quantitative results render the results of these Russian studies of limited value for purposes of quantitative risk assessment. Additional well-designed animal studies should be performed to adequately assess both pre- and post-natal potential for tungsten-induced developmental effects via the oral exposure route.

No information was located regarding developmental toxicity in humans or animals following dermal exposure to tungsten or tungsten compounds. However, inhalation is the most likely significant route of exposure to tungsten in workers employed in industries that produce or use tungsten-containing products. Elevated levels of tungsten in groundwater, such as was detected in well water in Churchill County (City of Fallon), Nevada (CDC 2003b), indicate the potential for significant oral exposure to tungsten and tungsten compounds as well. It does not appear that additional studies of health effects associated with dermal exposure to tungsten or tungsten compounds are necessary at this time.

Immunotoxicity. No information was located concerning tungsten-induced immunotoxicity in humans or animals following inhalation, oral, or dermal exposure to tungsten or tungsten compounds. A single report was located in which a marked inflammatory response characterized by infiltration of leukocytes in the lungs of mice following intracheal instillation of water-insoluble calcium tungstate powder (Peão et al. 1993). The inflammatory response was likely the result of local irritation rather than an adverse immunological effect. Repeated exposure animal studies by the inhalation exposure route could be designed to assess the immunotoxicity potential of tungsten.

Neurotoxicity. No human data were located in which neurological signs could be associated with inhalation, oral, or dermal exposure to tungsten. Signs of memory and sensory deficits have been reported among workers in the hard metal industry who were exposed to atmospheres of hard metal dusts (Jordan et al. 1990; Kaplun and Mezentseva 1959; Vengerskaya and Salikhodzhaev 1962); however, these effects likely reflect exposure to cobalt, not tungsten. No studies were located regarding neurological effects in animals following inhalation exposure to tungsten or tungsten compounds. Results of available animal studies indicated clinical signs of neurotoxicity following acute oral dosing at levels resulting in death (Karantassis 1924) and learning deficits and brain lesions following repeated oral dosing (Nadeenko 1966) at sublethal doses. However, clinical signs at lethal doses are not a reliable indicator of primary neurotoxicity and the report of Nadeenko (1966) was not designed to adequately assess neurotoxicity end points. Additional well-designed neurotoxicity studies in animals exposed to tungsten or tungsten compounds via inhalation or oral exposure routes might serve to adequately assess the potential for tungsten to induce neurotoxicity.

Epidemiological and Human Dosimetry Studies. Pulmonary fibrosis, memory and sensory deficits, and increased mortality due to lung cancer have been associated with occupational exposure to dusts generated in the hard metal industry (Bech 1974; Bech et al. 1962; Coates and Watson 1971a, 1971b; Jordan et al. 1990; Kaplun and Mezentseva 1959; Lasfargues et al. 1994; Mezentseva 1967; Miller et al. 1953; Moulin et al. 1998; Vengerskaya and Salikhodzhaev 1962). Hard metal is an alloy or encapsulated mixture that is composed of tungsten or tungsten carbide and cobalt (primarily, although the alloys may also contain yttrium, thorium, copper, nickel, iron, or molybdenum). Historically, the respiratory and neurological effects observed in hard metal workers have been attributed to cobalt, not tungsten (see Davison et al. 1983; Harding 1950). However, based on the presence of tungsten oxide fibers in air samples taken at some hard metal facilities (Sahle 1992; Sahle et al. 1994) and demonstrations that tungsten oxide fibers are capable of generating hydroxyl radicals in human lung cells in vitro (Leanderson and Sahle 1995), it has been suggested that tungsten oxide fibers may contribute to the development of pulmonary fibrosis in hard metal workers.

The most likely identifiable subpopulations exposed to tungsten are workers in the hard metal industry. Available human and animal data do not appear to clearly identify targets of toxicity for tungsten. Additional epidemiological studies of tungsten should attempt to identify exposure scenarios that may not be confounded by other known toxicants. Such exposure scenarios might provide valuable information regarding potential tungsten-induced toxicity. Studies of dosimetry would be useful in future epidemiological studies.

Biomarkers of Exposure and Effect.

Exposure. Tungsten can be detected in blood (Bowen 1966; Hartung 1991), urine (Paschal et al. 1998), feces , and tissue samples (Bowen 1966; Iyengar et al. 1978). Since a large percentage of absorbed tungsten is rapidly eliminated from the body, detection would be most effective within a few days following short-term exposure or termination of longer-term exposure. Additional information regarding relationships between tungsten body burden and exposure levels could improve the ability to monitor workers’ exposure to tungsten.

Effect. Biomarkers of effect for tungsten and tungsten compounds have not been definitively identified. Additional animal studies designed to assess health effects associated with tungsten should elucidate biomarkers of effect.

Absorption, Distribution, Metabolism, and Excretion. Human reports demonstrate that inhaled and ingested tungsten may be absorbed, distributed systemically, and eliminated to a large extent in the urine (Marquet et al. 1997; Nicolaou et al. 1987; Wester 1974). Animal studies support the human data and further demonstrate that distribution is rapid and widespread and that urinary excretion is also rapid (Aamodt 1975; Ballou 1960; Kaye 1968). Tungsten that is deposited in bone (Kaye 1968; Kinard and Aull 1945) may be slowly released to the blood and also eliminated mainly in the urine (Kaye 1968). Insoluble forms of orally-administered tungsten are chiefly eliminated in the feces. Tungsten has been detected in hair and nail samples of hard metal workers (Nicolaou et al. 1987). Tungsten ion in the body is not known to be metabolized as such. Additional quantitative information regarding absorption and distribution of inhaled or ingested tungsten and tungsten compounds could be used to improve existing PBPK models of the biokinetics of tungsten (ICRP 1981, 2001; Leggett 1997). Although the dermal exposure route does not appear to be a major human exposure route for tungsten, animal studies could be designed to quantify the toxicokinetics of tungsten following dermal exposure.

Comparative Toxicokinetics. Relatively little information is available regarding comparative toxicokinetics for tungsten and tungsten compounds. Available information concerning absorption, distribution, and elimination of tungsten in rats and dogs (Aamodt 1975; Ballou 1960; Kaye 1968) do not indicate major species-specific differences in biokinetics, Available toxicokinetic data in humans (Marquet et al. 1997; Nicolaou et al. 1987; Wester 1974), which have qualitatively demonstrated that airborne and ingested tungsten is absorbed and eliminated, do not indicate that the biokinetics of tungsten may differ greatly between humans and laboratory animals. Apparent species-specific differences in the dietary requirement for molybdenum (Higgins et al. 1956b), coupled with similarities in the biokinetics of molybdenum and tungsten, suggest that significant species-specific differences in the biokinetics of tungsten may exist. Additional animal toxicokinetic studies could be designed to identify species-specific differences that could serve to improve existing biokinetic models and elucidate specific mechanisms of action for tungsten.

Methods for Reducing Toxic Effects. Mechanisms concerning absorption, distribution, and toxic action of tungsten have not been studied to date; studies should be designed to identify such mechanisms. No established methods or treatments for reducing the body burden of tungsten were identified in literature searches. No information was located regarding treatments to repair damage or improve compromised function resulting from exposure to tungsten. Well-designed mechanistic studies might provide valuable information that could aid in elucidating treatments to reduce tungsten body burden or repair tungsten-induced damage.

Children’s Susceptibility. Data needs relating to both prenatal and childhood exposures, and developmental effects expressed either prenatally or during childhood, are discussed in detail in the Developmental Toxicity subsection above.

Results of studies published in Russian journals suggest that developing fetuses may be particularly sensitive to tungsten (Nadeenko and Lenchenko 1977; Nadeenko et al. 1977, 1978). However, deficiencies in study details regarding exposure and quantitative results render the results of these Russian studies of limited value for purposes of quantitative risk assessment. Tungsten has been observed to cross the placenta of pregnant rats and to be distributed to the fetus (Wide et al. 1986). Measurable amounts of tungsten have been observed in the milk of lactating cows (Mullen et al. 1976). However, no information was located regarding potentially significant age-related differences in the biokinetics of tungsten. No information was located regarding the potential for tungsten to interact with other chemicals in such a way to produce age-related differences in resulting toxicity. Based on the lack of information regarding the toxic effects of tungsten and potential for age-related differences in susceptibility, animal studies should be designed to further assess health effects that may be related to tungsten. Some of these studies could be designed to test for potential age-related differences in susceptibility and biokinetics as well.

Child health data needs relating to exposure are discussed in Section 6.8.1, Identification of Data Needs: Exposures of Children.

3.12.3. Ongoing Studies

No ongoing research has been identified in the Federal Research in Progress database (FEDRIP 2004). However, tungsten has been nominated by the National Center for Environmental Health for toxicological characterization including carcinogenicity (NTP 2003). Rationale for the nomination includes the use of tungsten in industrial materials and insufficient available data to assess human health implications of elevated urinary tungsten levels. The NTP Interagency Committee for Chemical Evaluation and Coordination (ICCEC) has recommended that toxicological studies should focus on a representative soluble tungsten compound.

The Armed Forces Radiological Research Institute (AFRRI) is currently receiving funding from the United States Army Medical Research and Material Command (USAMRMC) to assess the potential for embedded uranium and the heavy-metal tungsten alloy (tungsten/nickel/cobalt) to induce carcinogenicity and immunotoxicity in rats (principal investigator: Dr. J.F. Kalinich) and genetic damage in male mice and their offspring (principal investigator: Dr. A.C. Miller).

The following three AFFRI proposals have been submitted to the USAMRMC for review:

• Carcinogenicity of embedded tungsten alloy in mice (principal investigator: Dr. D.E. McClain). This project aims to support the findings of the earlier study in rats (Kalinich et al. 2005).
• Carcinogenicity and immunotoxicity assessment of tungsten alloy components in the rat (principal investigator: Dr. J.F. Kalinich). This project will assess the carcinogenic and immunotoxic potential of the heavy-metal tungsten alloy (tungsten/nickel/iron), as well as the individual metals of the alloy.
• Preconceptional paternal exposure to embedded tungsten alloy fragments: Lifespan study of offspring carcinogenesis (principal investigator: Dr. A.C. Miller). The objective of this study is to investigate whether paternal preconceptional exposure to embedded tungsten alloy causes neoplasia in unexposed offspring.