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4
Titanium Dioxide Smoke

Background Information

Military Applications

Titanium Dioxide (TiO2) is the proposed major component of a training grenade—XM82—under development by the U.S. Army Chemical Research Development and Engineering Center. TiO2 particles will be used to block detection of light waves in the visible portion of the electromagnetic spectrum. In using this training grenade, military personnel are likely to be exposed to airborne TiO2 particles.

Physical and Chemical Properties

TiO2 is a noncombustible, white crystalline solid. Common crystalline forms are anatase and rutile, the latter being the more thermally stable. Commercially available TiO2 products are being considered for use by the U.S. Army. The commercial products can be composed of the pure anatase or rutile forms or a mixture of both forms. Both forms of TiO2 can also occur in nature. TiO2 has a molecular weight of 79.90 and specific gravity of 3.90 (anatase) and 4.23 (rutile). The melting point for TiO2 is 1,830–1,850°C, and the boiling point is 2,500–3,000°C. TiO2 is insoluble in water, hydrochloric acid, nitric acid, or alcohol. It is soluble in hot concentrated sulfuric acid, hydrogen fluoride, or alkali. TiO2 can



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--> 4 Titanium Dioxide Smoke Background Information Military Applications Titanium Dioxide (TiO2) is the proposed major component of a training grenade—XM82—under development by the U.S. Army Chemical Research Development and Engineering Center. TiO2 particles will be used to block detection of light waves in the visible portion of the electromagnetic spectrum. In using this training grenade, military personnel are likely to be exposed to airborne TiO2 particles. Physical and Chemical Properties TiO2 is a noncombustible, white crystalline solid. Common crystalline forms are anatase and rutile, the latter being the more thermally stable. Commercially available TiO2 products are being considered for use by the U.S. Army. The commercial products can be composed of the pure anatase or rutile forms or a mixture of both forms. Both forms of TiO2 can also occur in nature. TiO2 has a molecular weight of 79.90 and specific gravity of 3.90 (anatase) and 4.23 (rutile). The melting point for TiO2 is 1,830–1,850°C, and the boiling point is 2,500–3,000°C. TiO2 is insoluble in water, hydrochloric acid, nitric acid, or alcohol. It is soluble in hot concentrated sulfuric acid, hydrogen fluoride, or alkali. TiO2 can

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--> exist as a fine-or ultrafine-sized particle.1 Fine particles are defined as material with individual particle diameters of 0.1–2.5 micrometer (µm). Ultrafine particles are defined as particles with individual diameters of <0.1 µm. Both fine and ultrafine TiO2 particles can exist as aggregates of the individual particles. Occurrence and Use TiO2 (anatase and rutile forms) is widely used as a pigment in paints, varnishes, and lacquers and as a pigment and filler for paper. It is used as an additive in polymer production and electronic-component production and as a catalyst. The anatase and rutile forms are used as a welding-rod coating and a ceramic colorant. TiO2 is used in the formulation of topical and oral pharmaceuticals and in food colorants. Toxicokinetics The clearance and distribution of TiO2 particles in rats have been examined after acute and chronic inhalation and after acute intratracheal instillation. Ferin and Oberdörster (1985) characterized lung clearance of the two most common forms of TiO2, anatase and rutile, in rats after a 7-hr exposure to anatase at 16.5 milligrams per cubic meter (mg/m3) or rutile at 19.3 mg/m3. The materials were fine-sized particles. Lung clearance half-times for anatase and rutile were 51 and 53 days, respectively. The results indicated no difference in the lung clearance of both forms of TiO2. Rats were exposed by inhalation 6 hr per day, 5 days per week for 12 weeks to ultrafine-sized (diameter 0.02 µm) and fine-sized (diameter 0.25 µm) TiO2 particles at approximately 23 mg/m3 (Ferin et al. 1992). At the end of the 12-week exposure, the total lung-particle burdens were 1   Three sizes of airborne particles are frequently described, especially for ambient particulate matter. The sizes are ultrafine (<0.1 µm), fine (0.1–2.5 µm), and coarse (>2.5 µm). For ambient particulate matter, the sizes reflect not only differences in size but also differences in formation and composition.

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--> similar for the fine and ultrafine TiO2 preparations. However, more ultrafine particles were found in the lung-associated lymph nodes and the lung interstitium. Lung-particle clearance was also significantly slower for the ultrafine TiO2 particles than for the fine; clearance half-times were 501 days and 174 days, respectively. Similar to observations made after inhalation exposure, intratracheal instillation of ultrafine and fine TiO2 particles was associated with greater interstitialization of the ultrafine particles (Ferin et al. 1992). These inhalation and intratracheal instillation studies demonstrated that the size of the TiO2 particles, particularly, ultrafine particles can influence distribution and clearance behavior in the rat lung. The distribution of fine-particle (diameter >0.1 µm) TiO2 in rats exposed for 24 months by inhalation to 10, 50, and 250 mg/m3 was described by Lee et al. (1985a). TiO2 was found throughout the respiratory tract, although the greatest accumulation was in macrophages localized at the terminal bronchioles and alveolar ducts and in lung-associated lymph nodes. Some TiO2 particles were visualized in the interstitium and in alveolar epithelial cells. TiO2 was found in the liver; the amount of material present was related to exposure concentration. The greatest amount of particles was in the peripheral hepatic lobules. The spleen also showed exposure-related dust deposition, primarily in the lymphoid tissue of the white pulp. The results of this study showed that the particles can be found throughout the respiratory tract and in extra-respiratory tissues after chronic exposure to high concentrations of TiO2. Toxicity Summary Effects in Humans Chen and Fayerweather (1988) conducted an analysis of lung-cancer mortality and incidence of nonmalignant respiratory disease in a cohort of 1,576 workers exposed to TiO2 for at least 1 year in two production facilities between 1935 and 1984. No significant association was observed between TiO2 exposure and malignant or nonmalignant respiratory disease. Time-weighted-average (TWA) exposure concentrations of TiO2 in the plants ranged from 1 to 20 mg/m3.

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--> Effects In Animals Inhalation Exposures One-Time Exposures Lethality. The lethal inhaled concentration of TiO2 in rats is reported to be >6820 mg/m3 for a 4-hr exposure (DuPont 1979). Rats exposed for 4 hr at 6820 mg/m3 exhibited irregular respiration, gasping, and lethargy; however, no deaths occurred during a 14-day observation period after exposure (DuPont 1979). Pulmonary Effects. See Table 4-1 for a summary of the nonlethal pulmonary effects of exposure to TiO2 by inhalation. Hilaski et al. (1992) exposed rats for 30 min to aerosols of fine TiO2 particles generated with a XM82 grenade. Responses were characterized by histopathological analysis and bronchoalveolar-lavage (BAL) fluid analyses and pulmonary-function tests. Two sets of high-concentration exposures of rats were performed; one set was evaluated 24 hr after exposure and the other was evaluated 14 days after exposure. In the 24-hr evaluation, the TiO2 concentrations determined 5, 15, and 25 min after detonating the grenade were 2,260, 1,506, and 1,000 mg/m 3. In the 14-day evaluation, exposure concentrations determined at 5, 15, and 25 min after detonating the grenade were 1,960, 1,300, and 964 mg/m3, respectively. The TWA concentration for the 30-min exposure in the 14-day evaluation was 1,240 mg/m3. The only consistent exposure-related response observed after 24 hr or 14 days was the presence of pigment-containing macrophages in the lung. Gases measured in the exposure chamber in the two sets of exposures included carbon monoxide (CO), carbon dioxide (CO2), nitrogen oxide (NO), formaldehyde (HCHO), and trichloroethane (CH3CCl3). The concentrations of all of them, with the exception of CO and HCHO, were below the current occupational exposure limits. CO was measured slightly above the 50 parts per million (ppm) Threshold Limit Value (TLV) TWA and the HCHO concentrations were 3 and 2.5 ppm (TLV ceiling (C) = 0.3 ppm). Ferin and Oberdörster (1985) compared the lung toxicity of anatase and rutile. Groups of rats were given a single intratracheal instillation exposure to saline or a saline suspension of 0.5 or 5 mg of anatase or rutile. Both forms of TiO2 elicited an inflammatory response in the lung assessed 24 hr after exposure by BAL-fluid analysis. No remarkable

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--> TABLE 4-1 Summary of Nonlethal Effects of Inhalation Exposure to Titanium Dioxide Smoke Species Exposure Frequency and Duration NOAEL (mg/m3) LOAEL (mg/m3) End Point and Comments Reference Rat (male F344) Single 30 min 1,240 (30 min, TWA) — TiO2 generated from a XM82 grenade; particle size, MMAD 2.0–2.2 µm; no adverse effects observed at 24 hr or 14 d after exposure Hilaski et al. 1992 Rat (female F344/N) Single 4 hr — — Particle size, MMAD 0.92–1.19 µm; lung burden was 217–252 µg/g lung; reported TiO2 relatively nontoxic; however, no data shown Yeh et al. 1990 Rat (male Long-Evans) Single 7-hr inhalation; single i.t. Inhalation: 16.5 anatase, 19.3 rutile; i.t., 0.5 anatase or rutile — Particle size, anatase MMAD 1.0 µm; rutile MMAD 0.83 µm; lung clearance half-times 51 and 53 d for anatase and ruffle, respectively; no remarkable differences observed in anatase and rutile Ferin and Oberdorster 1985 Rat (male F344) 4 hr/d, 4 d; 14 d followup — 101.5 Particle size, MMAD 1.4–1.6 µm; transient increase in BAL fluid neutrophils; no adverse effects on pulmonary function detected; response to TiO 2 less than that to graphite Thomson et al. 1988, 1990 Rat (male F344) 6 hr/d, 5 d — 51.1 Particle size, MMAD 1.0 µm; no adverse effects detected Driscoll et al. 1991 Rat (female F344) 6 hr/d, 5 d/wk, 4 wk inhalation; single i.t.; 24-wk followup Inhalation, 10; i.t., 0.75 — Particle size, MMAD 1.2–1.3 µm; fine particle size; no significant lung effects detected Henderson et al. 1995

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--> Species Exposure Frequency and Duration NOAEL (mg/m3) LOAEL (mg/m3) End Point and Comments Reference Rat (male Crl:CDBR) 6 hr/d, 5 d/wk, 4 wk 5 250 Fine-sized TiO2; inflammation and increased BrdU cell labeling observed after 250 mg/m3 but not 5 mg/m3 Warheit et al. 1996 Rat Not described — — Smoke from a TiO2/hexachloroethane mixture much less toxic than smoke from a Zn/hexachloroethane mixture Karlesson et al. 1985 Rat (F344) 7 hr/d, 5 d/wk, 1, 2, 4, 12 wk; 12-mo followup — 10 Minimal pleural fibrosis observed after 12 wk of inhalation exposure Johnson and Wagner 1989 Rat (male F344) 6 hr/d, 5 d/wk, up to 12 wk, inhalation; single 65–1,000 µg, i.t. — Inhalation: 23.5 ultrafine, 23 fine Ultrafine (i.e., <0.1 µm) and fine (1 µm) particles tested; greater retention and toxicity with ultrafine Ferin et al. 1992; Oberdorster et al. 1994a Rat (male F344) 6 hr/d, 5 d/wk, 12 wk — 23.5 ultrafine, 22.3 fine Ultrafine (~0.20 µm) and fine (0.25 µm) particles tested; ultrafine produced greater inflammation, fibrosis, and impairment of particle clearance Oberdorster et al. 1994b Rats (male and female CD) 6 hr/d, 5 d/wk, 24 mo — 10 Fine particles tested; MMAD 1.5–1.7 µm; lung burden alter 24 mo exposure 665 mg/lung at 250 mg/m3; some particles in extra-respiratory tissues; adverse effects confined to the respiratory tract and associated lymph nodes; increased lung tumors at highest exposure Lee et al. 1985a,b; 1986

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--> Species Exposure Frequency and Duration NOAEL (mg/m3) LOAEL (mg/m3) End Point and Comments Reference Rat (F344) 6 hr/d, 5 d/wk, 24 mo 5 — Fine particles tested; MMAD 1.1 µm; lung burden after 24 mo exposure 2.7 mg/lung; no adverse effects were detected by histopathology or analysis of BAL fluid Muhle et al. 1991 Rat (female Wistar) 18 hr/d, 5 d/wk, 24 mo — 10.4 Ultrafine particles (14 nm); lung burden 39.3 mg/lung; TiO2 produced epithelial hyperplasia, fibrosis, and lung tumors; similar responses in rats exposed to carbon black Heinrich et al. 1995 Rat (female Wistar) 18 hr/d, 5 d/wk, 24 mo — 10.4 Ultrafine particles (14 nm) tested; impaired alveolar clearance of tracer particles detected after TiO2, diesel soot and carbon black Creutzenberg et al. 1990 Rat (female Wistar) 18 hr/d, 5 d/wk, 24 mo — 10.4 Ultrafine particles (14 nm) tested; significant decrease in DNA adducts in lungs of rats exposed to TiO2 at average of 10 mg/m3 Gallagher et al. 1994 Rat (F344) Single i.t.; 28-d followup — 10 mg/kg body wt Ultrafine and fine particles tested; ultrafine TiO2 produced greater inflammatory response than the fine material Driscoll and Maurer 1991 Rat (male F344) Single i.t.; 28-d followup — 5 mg/kg body wt Fine particles tested; transient inflammatory response at 5 mg/kg body wt; fibrosis at 50 and 100 mg/kg; activation of macrophage cytokine release at 10, 50, and 100 mg/kg Driscoll et al. 1990a,b

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--> Species Exposure Frequency and Duration NOAEL (mg/m3) LOAEL (mg/m3) End Point and Comments Reference Rat (Sprague-Dawley) Single i.t.; 2-d followup — 10 i.t. TiO2 resulted in transient inflammation and increases in BAL fluid desmosine Li et al. 1996 Rat (F344) 10 and 100 mg/kg body wt, i.t. 10 mg/kg 100 mg/kg TiO2 at 100 mg/kg resulted in lung inflammation and increased mutation in alveolar type II cells Driscoll et al. 1997 Rat (F344) 6 hr/d, 5 d/wk, 24 mo 5 — Particle size, MMAD 1.1µm; lung burden alter 24 mo 2.7 mg/lung; no effect on the alveolar clearance of Iow solubility tracer particles Bellmann et al. 1991 Mouse (female NMRI) 18 hr/d, 5 d/wk, 13.5 mo — 10.4 Lung burden after 12 mo exposure 5.2 mg/lung; no increase in lung tumors after TiO2, diesel soot, or carbon black Heinrich et al. 1995 Mouse (CBA/ca) 20 hr/d, 2 or 4 wk 2 20 TiO2 at 20 mg/m3 for 2 or 4 wk impaired lung clearance of bacteria Pasteurella haemolytica; TiO2 at 20 mg/m3 appeared to suppress local immune responses to antigen Gilmour et al. 1989a,b Dog i.t., frequency not given; 9–15 mo observation — — TiO2 administered by i.t.; dose was not given; alveolitis, centrilobular emphysema, focal collapse of alveoli, and fibroblast hyperplasia reported Zeng et al. 1989 Human Occupational Estimated up to 20 — Epidemiological study observed no increase in cancer, nonmalignant respiratory disease, or other diseases in TiO2 exposed workers Chen and Fayerweather 1988 Abbreviations: NOAEL, no-observed-adverse-effect level; LOAEL, lowest-observed-adverse-effect level; MMAD, mass median aerodynamic diameter; TWA, time-weighted average; i.t., intratracheal instillation; BAL, bronchoalveolar lavage; BrdU, 5-bromo-2'-deoxyuridine.

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--> differences were found in the inflammatory activity of the two forms of TiO2. Driscoll et al. (1990a,b) exposed Fischer 344 (F344) rats by intratracheal instillation to TiO2 at concentrations of 5, 10, 50, and 100 milligrams per kilogram (mg/kg) of body weight (body weights ranged from 180 to 220 grams (g), resulting in burdens of approximately 1, 2, 10, and 20 mg) and characterized lung responses by BAL-fluid and histopathological analyses 1, 7, 14, and 28 days after exposure. Exposure at 50 and 100 mg/kg (lung burdens of 10 and 20 mg, respectively) resulted in lung inflammation and fibrosis, exposure at 10 mg/kg (lung burden of 2 mg) produced minimal transient inflammation, and exposure at 5 mg/kg (lung burden of 5 mg) was without significant adverse effects. In another intratracheal instillation study, Henderson et al. (1995) exposed F344 rats to TiO2 at up to 0.75 mg/ g of lung and characterized responses by BAL-fluid and histopathological analyses for 6 months following exposure. No significant effects were detected after TiO 2 exposure. Reproductive and Developmental Effects. No data are available on the reproductive and developmental effects of acute TiO2 exposure. Repeated Exposures Pulmonary Effects. Thomson et al. (1988) exposed rats to fine TiO2, particles at 101.5 mg/m3 for 4 hr per day for 4 days and examined responses by histopathological and BAL-fluid analyses and pulmonary-function tests 24 hr and 14 days after exposure. The mass median aerodynamic (MMAD) of the particles ranged from 1.39 to 1.60 µm and the standard geometric deviation ranged from 2.06 to 2.10 µm. TiO2. exposure resulted in increased BAL-fluid neutrophils and protein at 24 hr but not 14 days after exposure. No remarkable changes in pulmonary function were observed in this study, nor were any adverse histopathological changes seen in the lungs or other tissues. Driscoll et al. (1991) exposed rats via inhalation to fine TiO2 particles at 50 mg/m3 for 6 hr per day for 5 days and examined responses by analyses of BAL-fluid, alveolar macrophage-derived cytokine production, and histopathological changes in the lungs for up to 63 days after expo-

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--> sure. The MMAD of the particles was 1.0 µm and the geometric standard deviation was 2.6 µm. Lung TiO2 burdens of 1.8 mg were present at the end of the 5-day exposure. No changes in BAL-fluid indicators of injury and inflammation or in alveolar macrophage-derived cytokine production were observed. Histopathological examination revealed the presence of particle-containing macrophages but no adverse responses. Henderson et al. (1995) exposed rats to fine TiO2 particles via inhalation for 6 hr per day, 5 days per week for 4 weeks to 0.1 (MMAD was not determined), 1.0 (MMAD = 1.2 µm), or 10.0 (MMAD = 1.3 µm ± 0.01) mg/m3. Responses were determined by BAL-fluid and histopathological analyses for up to 6 months following exposure. Lung TiO2 burdens after the 4-week exposure were 4.4, 72, and 440 µg/g of lung. No adverse responses were observed in any TiO2-exposed animals at any time point examined. Warheit et al. (1996) exposed rats to fine TiO2 particles at 5 and 250 mg/m3 for 6 hr per day, 5 days per week for 4 weeks and examined inflammatory and proliferative responses in the lungs for up to 6 months following exposure. Marked and persistent lung inflammation and increased lung-cell proliferation were detected in rats exposed at 250 mg/m3. Exposure at 5 mg/m3 did not elicit any adverse effects. Johnson and Wagner (1989) exposed rats to aerosols of TiO2 at 10 mg/m3 for 7 hr per day, 5 days per week for 12 weeks. Histopathological examination was performed on some animals at the end of the 12-week inhalation exposure and other animals were examined 12 months after exposure. The only remarkable responses detected were particle-containing alveolar macrophages and some pleural fibrosis. TiO2 particles are typically fine (i.e., diameter 0.1–2.5 µm); however, some specially manufactured TiO2s are ultrafine (i.e., diameter <0.1 µm). Ferin et al. (1992), Oberdörster et al. (1994a,b) and Driscoll and Maurer (1991) examined the effects of ultrafine TiO2 particles. Ferin et al. (1992) exposed rats to aerosols of ultrafine (diameter 0.02 µm) or fine (diameter 0.25 µm) TiO2 at concentrations of 23.5 and 23.0 mg/m3, respectively. Exposures were for 6 hr per day, 5 days per week for 12 weeks. The MMAD and the geometric standard deviation of the two aerosols were similar because when aerosols are generated, the materials form aggregates that behave as particles of similar size. At the end of exposure ultrafine-and fine-particle-exposed rats had similar lung bur-

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--> dens of TiO2. BAL-fluid neutrophil numbers were increased to a significantly greater extent in rats exposed to the ultrafine particles compared with those exposed to the fine particles. Similar observations on ultrafine and fine TiO2 particles were reported by Driscoll and Maurer (1991). Briefly, exposure of rats by intratracheal instillation of ultrafine TiO2 particles at 10 mg/kg (lung burden of 1.8 mg) resulted in a marked and persistent inflammatory response in the lung. That response contrasted with the transient inflammation seen after exposure to fine TiO2 particles. A greater increase in alveolar macrophage-derived inflammatory cytokines was produced by ultrafine TiO2 particles than by fine particles, and a fibrotic response in the lung after ultrafine-particle exposure was not seen after fine-particle exposure. These studies indicate that ultrafine TiO2 particles are more toxic in the lung than fine particles. A comparison of the effects of ultrafine versus fine TiO2 particles on lung inflammation and lung-clearance retardation indicates that those responses correlate with the surface area of the TiO2 particles and not the mass (Oberdörster et al. 1994a,b). Ultrafine particles have a markedly greater surface area than fine particles and thus, are more active. Lee et al. (1985a,b) exposed rats to fine TiO2 particles at concentrations of 10, 50, and 250 mg/m3 for 6 hr per day, 5 days per week for 24 months. The MMAD of the particles was 1.5 to 1.7 µm. Lung burdens of TiO2 after 24 months of exposure were 32, 130, and 545 mg per lung in the 10-, 50-, and 250-mg/m3 exposure groups, respectively (Lee et al. 1986). Although TiO2 was found in nonrespiratory tissues, including the liver and spleen, adverse responses were confined to the respiratory tract and associated lymphatic tissues (Lee et al. 1985a). Animals exposed at 10 mg/m3 had increased numbers of particle-laden lung macrophages and minimal alveolar epithelial-cell hyperplasia. Exposure at 50 or 250 mg/m3 resulted in a dose-related increase in alveolar epithelial hyperplasia, alveolar proteinosis, and pulmonary fibrosis. Muhle et al. (1991) exposed rats to fine TiO2 particles at a concentration of 5 mg/m3 for 6 hr per day, 5 days per week for 24 months. The MMAD of the particles was 1.1 µm and the geometric standard deviation was 1.6 µm. Responses were characterized by BAL-fluid, histopathological and lung-clearance analyses. The lung burden of TiO2 at the end of exposure was 2.7 mg per lung. Slight and variable increases in BAL-fluid neutrophils and lymphocytes were detected, and no changes in

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--> inflammation (Driscoll et al. 1990a,b; Henderson et al. 1995). These studies indicate that even at the high-dose rates associated with intratracheal instillation exposure, high lung burdens of TiO2 have minimal effects on the lung. Exposure to TiO2 delivered by inhalation would not be expected to lead to a greater response compared with exposure delivered by instillation (Driscoll et al. 1991). Still, to address the potential for greater response to high-dose rate in acute inhalation exposures, the subcommittee reduced the 4-mg/g lung dose by a factor of 10 and estimated the maximal 15-min, 1-hr, and 6-hr exposure concentrations that would result in a lung dose of <0.4 mg/g of lung. Making reasonable assumptions for minute volume (43 liters/min, heavy work activity; Diem and Leather 1970), deep-lung particle deposition (35% of respirable particles; Stahlhofen et al. 1989), and lung weight (1,000 g; Diem and Lentner 1970), a 15-min exposure to approximately 1,770 mg/m3 was calculated to result in a deep-lung dose of <0.4 mg/g of lung2 and have no toxic effects. Studies that support that calculation are the 4-hr inhalation study in rats demonstrating no mortality after exposure to 6,820 mg/m3 (DuPont 1979), the intratracheal instillation studies demonstrating that bolus administration of 0.7 to 2 mg of TiO2 into rat lungs produced either no adverse effects or transient pulmonary inflammation (Driscoll et al. 1990b; Henderson et al. 1995), an acute inhalation study demonstrating no adverse effects in rats after a 30-min exposure at up to 1,240 mg/m3 (Hilaski et al. 1992), and a chronic inhalation study demonstrating minimal adverse lung effects in rats after exposure to a concentration of 250 mg/m3, which resulted in a lung dose of >10 mg/g of lung (Lee et al. 1986). Based on the above considerations, the subcommittee recommends 1,800 mg/m3 (rounded from 1,770 mg/m3) as the 15-min EEGL for TiO2. Extrapolating from the 15-min EEGL, a 1-hr EEGL of 450 mg/m3 for respirable dust and a 6-hr EEGL of 75 mg/m3 for respirable dust are recommended. 2   Calculation of 15-min exposure concentration in humans resulting in a lung TiO2 dose of 0.4 mg/g of lung. Exposure concentration = [(0.4 mg/g of lung)(1,000 g/lung]/ [(43 L/min) (15 min) (0.35) (m3/1,000)].

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--> The above recommended exposure limits are for fine-sized TiO2 particles, which are defined as particles with a diameter of 0.1–2.5 µm. Although it is expected that exposures to TiO2 from its use in military smokes and obscurants will be to fine particles, the subcommittee recognizes that there are specialized forms of TiO2 manufactured as ultrafine materials. Studies in animals indicate that ultrafine TiO2 particles (diameter <0.1 µm) have a greater toxicity in the rat lung than do fine TiO2 particles (Driscoll et al. 1991; Ferin et al. 1992; Oberdörster et al. 1994a,b; Heinrich et al. 1995). A comparison of the lung response to fine and ultrafine TiO2 particles indicate that lung inflammation and tumorigenic responses to these materials correlate with the surface area of the particles (Oberdörster and Yu 1990; Driscoll 1996). The surface area for ultrafine TiO2 particles is reported to be approximately 50 m2/g and that of fine TiO2 particles is typically 6-8 m2/g (Ferin et al. 1992; Oberdörster et al. 1994a,b; Driscoll 1996), an approximate 8-fold difference in surface area. If exposures to ultrafine TiO2 particles are of concern, an adjustment in the EEGLs based on particle surface-area differences should be considered and the EEGLs reduced by an 8-fold factor. Repeated Exposure Guidance Level (REGL) In considering an appropriate exposure limit for repeated exposure to TiO2, the subcommittee noted that chronic inhalation to high concentrations of fine or ultrafine TiO2 particles is shown to result in pulmonary inflammation, fibrosis, and lung tumors in rats (Lee et al. 1985a,b; Heinrich et al. 1995). However, an epidemiological study did not find a increased cancer risk in TiO2-exposed humans (Chen and Fayerweather 1988). As discussed above, TiO2 is not unique among particles in producing inflammatory, fibrotic, and neoplastic responses in rats but is one of a number of low-toxicity, poor-solubility particles shown to produce these adverse effects at high concentrations (Oberdörster 1994). In recommending an appropriate exposure guideline for repeated inhalation exposure to such particles, several factors that are important include the likely mechanism for the lung-tumor response and the dosimetry of the material. Increasing evidence indicates that persistent inflammation and in-

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--> creased cell proliferation play a key role in the development of lung tumors in rats after chronic inhalation at high concentrations of poorly soluble, nongenotoxic particles, such as TiO2 (Oberdörster 1994; Driscoll 1996). The release of oxidants by inflammatory cells provides a mechanism by which damage to DNA can occur after exposure to nongenotoxic particles (Ames 1983; Weitzman et al. 1985). Enhanced cell proliferation can increase the probability that a spontaneous genetic error will occur during normal cell division, resulting in mutation (Cohen and Ellwein 1991). In the presence of added oxidative stress, cell proliferation can be expected to increase the likelihood that spontaneously occurring and oxidant-induced mutations will be fixed in a proliferating cell and clonally expanded. The result is an increase in the cell population at risk for genetic changes relevant to tumorigenesis. From the perspective of recommending exposure guidelines, an important factor implicit in that mechanism is that a threshold exists, and exposure concentrations that do not produce persistent inflammation and increased cell proliferation will not carry an increased risk of lung tumors. The relation between exposure concentration and lung dose of poorly soluble particles is a key factor in recommending acceptable exposure guidelines. Several studies in rats indicate that when lung burdens of poorly soluble particles are >1–2 mg/g of lung, alveolar particle-clearance mechanisms are overloaded and particle retention is increased (Morrow et al. 1991; Oberdörster 1994). Consequently, after repeated exposure to high concentrations, accumulation of particles in the lung is disproportionate to that occurring at lower concentrations. Associated with the accumulation of lung particle burdens of >1–2 mg/g of lung in the rat is the development of adverse lung effects, including inflammation, fibrosis, and epithelial hyperplasia. Thus, the data base on chronic inhalation of low-toxicity, poorly soluble particles by rats indicates that lung burdens of >1–2 mg/g of lung carry an increased risk of adverse lung effects that might contribute to the development of lung cancer in the rat (Morrow 1992). It is further noted that the overloading of lung particle-clearance mechanisms in the rat is more closely related to the volume than the mass of particles in the lung (Morrow 1992). Because the effects of high lung doses on particle clearance have been observed in all experimental animals tested to date, it reasonable to assume that the phenomenon occurs in humans (Oberdörster 1994).

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--> Thus, the subcommittee considered that a reasonable approach to recommending a REGL for TiO2 was to estimate the exposure concentration for humans that would not overload alveolar clearance mechanisms and result in the adverse effects seen in the rat studies. That approach for developing occupational exposure limits has been described by Morrow et al. (1991) and Oberdörster (1994). Making reasonable assumptions for minute ventilation (22 liters/min, moderate work activity; Raabe 1979), the proportion of respirable particles depositing in the deep lung (35%; Stahlhofen et al. 1989), lung weight (1,000 g; Diem and Lentner 1970), and particle-clearance half-time (500 days; Bohning et al. 1982) for humans and accounting for the density of TiO2, the subcommittee estimated that chronic inhalation of poorly soluble particles at 2 mg/m3 for 8 hr per day, 5 days per week is the maximal exposure concentration that would result in a lung burden of <4 mg/g of lung.3 The calculation takes into account sources of uncertainty in lung dosimetry between rodents and humans and therefore, an additional uncertainty factor extrapolating from animals to humans was not applied. Additionally, the uncertainty factor was reduced to 1 because the rat is a more sensitive species than the human to the effects of poorly soluble particles in the lung. A REGL of 2 mg/m3 for fine TiO2 particles is supported by the epidemiological study of Chen and Fayerweather (1988) who found no increase in malignant and nonmalignant respiratory disease in workers with TWA exposures to TiO2 estimated at up to 20 mg/m3. The REGL recommended by the subcommittee is less than the 5-mg/m3 OSHA PEL for respirable TiO2. However, it should be noted that the approach used by the subcommittee (i.e., estimating the concentration that would not overload alveolar particle-clearance mechanisms) to recommend the REGL is the same as that used by the ACGIH TLV committee in developing the recently updated TLV for particles not otherwise classified (PNOC) (ACGIH 1996). 3   Calculation of exposure concentration (8 hr per day x 5 days per week) resulting in a lung TiO2 dose of 4 mg/g of lung. Exposure Concentration = [(4 mg/g of lung)] ÷ {[(22 L/min) (60 min) (8 h/d) (5 d/7 d) (m3/1,000) (0.35) (lung/1,000 g)] ÷ (ln 2/500 d]}.

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--> As discussed for EEGLs, ultrafine TiO2 particles appear to be more toxic than fine TiO2 particles in the rat lung. Because of the positive correlation between surface-area dose and biological activity of fine and ultrafine TiO2 particles, an adjustment in the REGL based on particle surface-area differences should be considered if exposures to ultrafine TiO2 particles are of concern (Oberdörster et al. 1992; Driscoll 1996). Public Exposures Short-Term Public Emergency Guidance Levels (SPEGLs) To recommend a SPEGL for TiO2, the subcommittee divided the EEGLs by an uncertainty factor of 10 to account for the potentially greater range in susceptibilities of the general public compared with healthy military personnel. Thus, the recommended 15-min SPEGL is 180 mg/m 3, the 1-hr SPEGL is 45 mg/m3, and the 6-hr SPEGL is 7.5 mg/m3 for respirable TiO2 dust. As with the EEGLs and the REGL, in the event that exposures are to ultrafine TiO2 particles, an adjustment in the SPEGLs based on particle surface-area differences can be considered. Repeated Public Exposure Guidance Level (RPEGL) The subcommittee recommends that the RPEGL be derived by incorporating an uncertainty factor of 10 into the REGL to account for the potentially greater range in susceptibilities of the general public compared with healthy military personnel. Therefore, the recommended RPEGL for TiO2 is 0.2 mg/m3 for respirable TiO2 dust. Summary Of Subcommittee Recommendations Table 4-2 summarizes the subcommittee's recommendations for exposure limits for military personnel exposed to TiO2. The subcommittee's recommendations for exposure limits for the general public are listed in Table 4-3.

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--> TABLE 4-2 EEGLs and REGL for Fine TiO2-Particle Smoke for Military Personnel Exposure Guideline Exposure Duration Exposure Guidance Level(mg/m3 respirable dust) EEGL 15 min 1800   1 hr 450   6 hr 75 REGL 8 hr/d, 5 d/wk 2 Abbreviations: EEGL, emergency exposure guidance level; REGL, repeated exposure guidance level. TABLE 4-3 SPEGL and RPEGL for Fine TiO2-Particle Smoke at the Boundaries Military-Training Facilities Exposure Guideline Exposure Duration Exposure Guidance Level(mg/m3 respirable dust) SPEGL 15 min 180   1 hr 45   6 hr 7.5 RPEGL 8 hr/d, 5 d/wk 0.2 Abbreviations: SPEGL, short-term public emergency guidance levels; RPEGL, repeated public exposure guidance level. Research Needs In the event that the military considers the use of ultrafine TiO2 particles in smokes and obscurants, research to clearly define the differences in the toxic potential of the ultrafine particles and fine particles should be considered. References ACGIH (American Conference of Governmental Industrial Hygienists). 1996. Guide to Occupational Exposure Values—1996. American Conference of Governmental Industrial Hygienists, Cincinnati, Ohio.

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--> Ames, B.N. 1983. Dietary carcinogens and anticarcinogens. Oxygen radicals and degenerative diseases. Science 221:1256–1264. Bellmann, B., H. Muhle, O. Creutzenberg, C. Dasenbrock, R. Kilpper, J.C. Mac-Kenzie, P. Morrow, and R. Mermelstein. 1991. Lung clearance and retention of toner, utilizing a tracer technique, during chronic inhalation exposure in rats. Fundam. Appl. Toxicol. 17:300–313. Bohning, D.E., H.L. Atkins, and S.H. Cohn. 1982. Long-term particle clearance in man: normal and impaired. Ann. Occup. Hyg. 26:259–271. Chen, J.L., and W.E. Fayerweather. 1988. Epidemiologic study of workers exposed to titanium dioxide. J. Occup. Med. 30:937–942. Cohen, S.M., and L.B. Ellwein. 1991. Genetic errors, cell proliferation, and carcinogenesis. Cancer Res. 51:6493–64505. Creutzenberg, O., B. Bellmann, U. Heinrich, R. Fuhst, W. Kolch, and H. Muhle. 1990. Clearance and retention of inhaled diesel exhaust particles, carbon black, and titanium dioxide in rats at lung overload conditions. J. Aerosol Sci. 21(Suppl. 1):S455–S458. Diem, K., and C. Lentner, eds. 1970. Documenta Geigy: Scientific Tables, 7th Ed. Basle, Switzerland: Ciba-Geigy. Driscoll, K.E. 1996. Role of inflammation in the development of rat lung tumors in response to chronic particle exposure. Inhalation Toxicol. 8:139–153. Driscoll, K.E., and J.K. Maurer. 1991. Cytokine and growth factor release by alveolar macrophages: Potential biomarkers of pulmonary toxicity. Toxicol. Pathol. 19(4 Pt. 1):398–405. Driscoll, K.E., R.C. Lindenschmidt, J.K. Maurer, J.M. Higgins, and G. Ridder. 1990a. Pulmonary response to silica or titanium dioxide: Inflammatory cells, alveolar macrophage-derived cytokines, and histopathology. Am. J. Respir. Cell Mol. Biol. 2:381–390. Driscoll, K.E., J.K. Maurer, R.C. Lindenschmidt, D. Romberger, S.I. Rennard, and L. Crosby. 1990b. Respiratory tract responses to dust: Relationships between dust burden, lung injury, alveolar macrophage fibronectin release, and the development of pulmonary fibrosis. Toxicol. Appl. Pharmacol. 106:88–101. Driscoll, K.E., R.C. Lindenschmidt, J.K. Maurer, L. Perkins, M. Perkins, and J. Higgins. 1991. Pulmonary response to inhaled silica or titanium dioxide. Toxicol. Appl. Pharmacol. 111:201–210. Driscoll, K.E., L.C. Deyo, J.M. Carter, B.W. Howard, D.G. Hassenbein, and T.A. Bertram. 1997. Effects of particle exposure and particle-elicited inflammatory cells on mutation in rat alveolar epithelial cells. Carcinogenesis 18:423–430. DuPont. 1979. Inhalation, Approximate Lethal Concentration—Titanium Diox-

OCR for page 68
--> ide. Rep. No. 77–79. E.I. du Pont de Nemours & Company, Wilmington, Del. Ferin, J., and G. Oberdörster. 1985. Biological effects and toxicity assessment of titanium dioxides: Anatase and rutile. Am. Ind. Hyg. Assoc. J. 46:69–72. Ferin, J., G. Oberdörster, and D.P. Penney. 1992. Pulmonary retention of ultrafine and fine particles in rats. Am. J. Respir. Cell Mol. Biol. 6:535–542. Gallagher, J., U. Heinrich, M. George, L. Hendee, D.H. Phillips, and J. Lewtas. 1994. Formation of DNA adducts in rat lung following chronic inhalation of diesel emissions, carbon black and titanium dioxide particles. Carcinogenesis 15:1291–1299. Gilmour, M.I., F.G.R. Taylor, and C.M. Wathes. 1989a. Pulmonary clearance of Pasteurella haemolytica and immune responses in mice following exposure to titanium dioxide. Environ. Res. 50:184–194. Gilmour, M.I., F.G.R. Taylor, A Baskerville, and C.M. Wathes. 1989b. The effect of titanium dioxide inhalation on the pulmonary clearance of Pasteurella haemolytica in the mouse. Environ. Res. 50:157–172. Heinrich, U., R. Fuhst, S. Rittinghausen, O. Creutzenberg, B. Bellmann, W. Koch, and K. Levsen. 1995. Chronic inhalation exposure of Wistar rats and two different strains of mice to diesel engine exhaust, carbon black, and titanium dioxide. Inhalation Toxicol. 7:533–556. Henderson, R.F., K.E. Driscoll, J.R. Harkema, R.C. Lindenschmidt, I.-Y. Chang, K.R. Maples, and E.B. Barr. 1995. A comparison of the inflammatory response of the lung to inhaled versus instilled particles in F344 rats. Fundam. Appl. Toxicol. 24:183–197. Hilaski, R.J., J.D. Bergmann, J.C. Carpin, W.T. Muse, Jr., and S.A. Thomson . 1992. Acute Inhalation Toxicity Effects of Explosively Disseminated—XM82 Grenade—Titanium Dioxide. CRDEC-TR-363. Chemical Research, Development and Engineering Center, U.S. Army Armament, Munitions and Chemical Command, Aberdeen Proving Ground, Edgewood, Md. Johnson, N.F., and J.C. Wagner. 1989. Pleural and Parenchymal Responses in Rats to Short-Term Inhalation Exposures to Erionite, Crocidolite, Chrysotile, Silica and Titanium Dioxide. Pp. 157–164 in Effects of Mineral Dusts on Cells. NATO ASI Series, Vol. H30. B.T. Mossman and R.O. Bégin, eds. Berlin: Springler-Verlag. Karlsson, N., G. Cassel, I. Fängmark, and F. Bergman. 1985. The inhalation toxicity of screening smokes [abstract]. J. Toxicol. Clin. Toxicol. 23(4–6):463. Lee, K.P., H.J. Trochimowicz, and C.F. Reinhardt. 1985a. Transmigration of titanium dioxide (TiO2) particles in rats after inhalation exposure. Exp. Mol. Pathol. 42:331–343. Lee, K.P., H.J. Trochimowicz, and C.F. Reinhardt 1985b. Pulmonary response

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--> of rats exposed to Titanium Dioxide (TiO2) by inhalation for two years. Toxicol. Appl. Pharmacol. 79:179–192. Lee, K.P., N.W. Henry III, H.J. Trochimowicz, and C.F. Reinhardt 1986. Pulmonary response to impaired lung clearance in rats following excessive titanium dioxide dust deposition. Environ. Res. 41:144–167. Li, K., B. Keeling, and A. Churg. 1996. Mineral dusts cause elastin and collagen breakdown in the rat lung: A potential mechanism of dust-induced emphysema. Am. J. Respir. Crit Care Med. 153:644–649. Mauderly, J.L., R.K. Jones, W.C. Griffith, R.F. Henderson, and R.O. McClellan. 1987. Diesel exhaust is a pulmonary carcinogen in rats exposed chronically by inhalation. Fundam. Appl. Toxicol. 9:208–221. Morrow, P.E. 1988. Possible mechanisms to explain dust overloading of the lungs. Fundam. Appl. Toxicol. 10:369–384. Morrow, P.E., H. Muhle, and R. Mermelstein. 1991. Chronic inhalation study findings as a basis for proposing a new occupational dust exposure limit. J. Am. Col. Toxicol. 10:279–289. Muhle, H., B. Bellmann, O. Creutzenberg, C. Dasenbrock, H. Ernst, R. Kilpper, J.C. MacKenzie, P. Morrow, U. Mohr, S. Takenaka, and R. Mermelstein. 1991. Pulmonary response to toner upon chronic inhalation exposure in rats. Fundam. Appl. Toxicol. 17:280–299. NCI (National Cancer Institute). 1979. Bioassay of Titanium Dioxide for Possible Carcinogenicity. NCI Carcinog. Tech. Rep. Ser. Vol. 97. National Cancer Institute, Bethesda, Md. NIOSH (National Institute for Occupational Safety and Health). 1996. Titanium dioxide. In Documentation for Immediately Dangerous to Life or Health. Online. Entry last updated Aug. 16, 1996. Available: http://www.cdc.gov/niosh/idlh/13463677.html . U.S. Department of Health and Human Services, National Institute for Occupational Safety and Health, Division of Standards Development and Technology Transfer, Cincinnati, Ohio. NTP (National Toxicology Program). 1993. TR-421 Toxicology and Carcinogenesis Studies of Talc (CAS No. 14807-96-6) (Non-Asbestiform) in F344/N Rats and B6C3F1, Mice (Inhalation Studies). TR-421. National Institute of Environmental Health Sciences, National Toxicology Program, Research Triangle Park, N.C. Available from NTIS, Springfield, Va., Doc. No. PB94-215985. Oberdörster, G. 1994. Extrapolation of results from animal inhalation studies with particles to humans. Pp. 57–73 in Toxic and Carcinogenic Effects of Solid Particles in the Respiratory Tract, D.L. Dungworth, J.L. Mauderly, and G. Oberdörster, eds. Washington, D.C.: ILSI Press. Oberdörster, G., and C.P. Yu. 1990. The carcinogenic potential of inhaled

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--> diesel exhaust: A particle effect? J. Aerosol Sci. 21(Suppl. 1):397–401. Oberdörster, G., J. Ferin, R. Gelein, S.C. Soderholm, and J. Finkelstein. 1992. Role of the alveolar macrophage in lung injury: Studies with ultrafine particles. Environ. Health Perspect. 97:193–199. Oberdörster, G., J. Ferin, and B.E. Lehnert. 1994a. Correlation between particle size, in vivo particle persistence, and lung injury. Environ. Health Perspect. 102(Suppl. 5):173–179. Oberdörster, G., J. Ferin, S. Soderholm, R. Gelein, C. Cox, R. Baggs, and P.E. Morrow. 1994b. Increased pulmonary toxicity of inhaled ultrafine particles: Due to lung overload alone? Pp. 295–302 in Proceedings of Seventh International Symposium on Inhaled Particles, J. Dogston and R.I. McCallum, eds. Oxford, U.K.: Pergamon. Raabe, O.G. 1979. Deposition and Clearance of Inhaled Aerosols. UCD-472-503. Laboratory for Energy-Related Health Research, University of California at Davis for the U.S. Department of Energy, Washington, D.C. Stahlhofen, W., G. Rudolf, and A.C. James. 1989. Intercomparison of experimental regional aerosol deposition data. J. Aerosol Med. 2(3):285–308. Thomson, S.A., J.D. Bergmann, D.C. Burnett, J.C. Carpin, C.L. Crouse, R.J. Hilaski, B. Infiesto, and E. Lawrence-Beckett. 1988. Comparative Inhalation Screen of Titanium Dioxide and Graphite Dusts. CRDEC-TR-88161. Chemical Research, Development and Engineering Center, U.S. Army Armament, Munitions and Chemical Command, Aberdeen Proving Ground, Edgewood, Md. Thomson, S.A., D.C. Burnett, J.C. Carpin, J.D. Bergmann, and R.J. Hilaski. 1990. Comparative Inhalation Hazards of Titanium Dioxide, Synthetic and Natural Graphite. Proceedings of the Seventh International Pneumonoconioses Conference. Part 2. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Atlanta, Ga. Trochimowicz, H.J., K.P. Lee, and C.F. Reinhardt. 1988. Chronic inhalation exposure of rats to titanium dioxide dust. J. Appl. Toxicol. 8:383–385. U.S. Department of Labor. 1997. Occupational Safety and Health Standards. Air Contaminants. Code of Federal Regulations, Title 29, Part 1910, Section 1910.1000. Washington, D.C.: U.S. Government Printing Office. Warheit, D.B., J.F. Hansen, I.S. Yuen, S.I. Snajdr, and M.A. Hartsky. 1996. Prolonged cellular proliferation and pulmonary inflammation are produced in rats inhaling high concentrations of low-toxicity insoluble particulates: Comparisons with cytotoxic dusts . Inhalation Toxicol. 8(Suppl.):155–167. Yeh, H.C., M.B. Snipes, A.F. Eidson, and C.H. Hobbs. 1990. Comparative evaluation of nose-only versus whole-body inhalation exposures for rats—Aerosol characteristics and lung deposition. Inhalation Toxicol. 2:205–221.

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--> Zeiger, E., B. Anderson, S. Haworth, T. Lawlor, and K. Mortelmans. 1988. Salmonella mutagenicity tests: IV. Results from the testing of 300 chemicals. Environ. Mol. Mutagen. 11(Suppl. 12):1–158. Zeng, L., Z. Zheng, and S. Zhang. 1989. Pathogenic effects of titanium dioxide dust on the lung of dogs—A histopathological and ultrastructural study [in Chinese]. J. West China Univ. Med. Sci. 20:88–91.