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Toxicity of Military Smokes and Obscurants: Volume 2 (1999)

Chapter: 4 Titanium Dioxide Smoke

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Suggested Citation:"4 Titanium Dioxide Smoke." National Research Council. 1999. Toxicity of Military Smokes and Obscurants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/9621.
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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

Suggested Citation:"4 Titanium Dioxide Smoke." National Research Council. 1999. Toxicity of Military Smokes and Obscurants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/9621.
×

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.

Suggested Citation:"4 Titanium Dioxide Smoke." National Research Council. 1999. Toxicity of Military Smokes and Obscurants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/9621.
×

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.

Suggested Citation:"4 Titanium Dioxide Smoke." National Research Council. 1999. Toxicity of Military Smokes and Obscurants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/9621.
×

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

Suggested Citation:"4 Titanium Dioxide Smoke." National Research Council. 1999. Toxicity of Military Smokes and Obscurants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/9621.
×

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

Suggested Citation:"4 Titanium Dioxide Smoke." National Research Council. 1999. Toxicity of Military Smokes and Obscurants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/9621.
×

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

Suggested Citation:"4 Titanium Dioxide Smoke." National Research Council. 1999. Toxicity of Military Smokes and Obscurants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/9621.
×

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

Suggested Citation:"4 Titanium Dioxide Smoke." National Research Council. 1999. Toxicity of Military Smokes and Obscurants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/9621.
×

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.

Suggested Citation:"4 Titanium Dioxide Smoke." National Research Council. 1999. Toxicity of Military Smokes and Obscurants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/9621.
×

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-

Suggested Citation:"4 Titanium Dioxide Smoke." National Research Council. 1999. Toxicity of Military Smokes and Obscurants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/9621.
×

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-

Suggested Citation:"4 Titanium Dioxide Smoke." National Research Council. 1999. Toxicity of Military Smokes and Obscurants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/9621.
×

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

Suggested Citation:"4 Titanium Dioxide Smoke." National Research Council. 1999. Toxicity of Military Smokes and Obscurants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/9621.
×

BAL-fluid biochemical indicators of injury or edema were seen. Histopathological examination revealed an increase in particle-laden macrophages in the lungs; no lung fibrosis or lung tumors were observed.

Heinrich et al. (1995) exposed rats and mice to ultrafine TiO2 at an average concentration of 10 mg/m3 for 18 hr per day, 5 days per week. The MMAD of the particles was 0.8 µm and the geometric standard deviation was 1.8 µm. The rats were exposed for 24 months and the mice were exposed for 13.5 months followed by 9.5 months in clean air. After 24 months of exposure, the rats had an average of 39.3 mg of TiO2 per lung and exhibited significantly increased lung weights, lower body weights, and life-time shortening compared with clean-air control animals. BAL-fluid markers of lung injury and inflammation were increased after TiO2 exposure. Histopathological examination revealed particle-laden macrophages, bronchoalveolar hyperplasia, and slight fibrosis after 6 months of exposure. After 24 months, slight-to-moderate fibrosis and bronchoalveolar hyperplasia were observed. In this study, similar histopathological effects were reported for rats exposed at a similar concentration of ultrafine carbon-black particles and diesel soot. Mice exposed to ultrafine TiO2 particles had average lung burdens of 5.2 mg per lung at the end of 12 months of exposure. Increased mortality and lung weights were observed in the exposed mice. Histopathological results were not reported.

Reproductive and Developmental Effects.

No data are available on the reproductive and developmental effects of TiO2 exposure.

Carcinogenic Effects.

Two studies observed an increased incidence of lung tumors in rats exposed by inhalation to TiO2. 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. At 250-mg/m3, a significant increase in lung adenomas and carcinomas was observed (17% of TiO2-exposed rats versus 1% of controls). The incidence of carcinomas was most prominent in females (13 of 74 females versus 1 of 77 males). An increase in lung tumors was not observed at 10 and 50 mg/m3.

Heinrich et al. (1995) reported an increased incidence of lung tumors in female rats (32% in females versus 0.5% in controls) exposed to ultrafine TiO2 particles at an average concentration of 10 mg/m3 for 18 hr per day, 5 days per week for 24 months followed by 6 months in clean air.

Suggested Citation:"4 Titanium Dioxide Smoke." National Research Council. 1999. Toxicity of Military Smokes and Obscurants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/9621.
×

In this study, no increase in lung tumors was detected in mice exposed at a similar concentration of ultrafine TiO2 for 13.5 months and held for an additional 9.5 months.

In a study by Muhle et al. (1991), no increase in lung tumors was observed in rats exposed to fine TiO2 particles at 5 mg/m3 for 6 hr per day, 5 days per week for 24 months.

The above described tumorigenic effects of TiO2 in rats are not unique to TiO2 (Driscoll 1996). Several studies have shown that chronic inhalation of poorly soluble, low-toxicity particles can result in lung adenomas and carcinomas in rats. Other particulate materials shown to cause these tumorigenic effects include diesel soot, carbon black, and talc (Mauderly et al. 1987; NTP 1993; Heinrich et al. 1995). As with TiO2, the tumorigenic response to those materials appears to be unique to the rat because hamsters and mice do not respond to similar lung burdens of those poorly soluble particles by developing lung cancer (NTP 1993; Heinrich et al. 1995). The mechanisms underlying the tumorigenic response of rats to poorly soluble particles and the relevance of that response to humans are not known. Recent analyses of the chronic inhalation data with poorly soluble particles indicate that the rat lung-tumor response correlates with the log particle surface area of the particles in the lung (Oberdörster and Yu 1990; Driscoll 1996). The correlation with surface area suggests why Heinrich et al. (1995) observed increases in rat lung tumors at an exposure concentration and lung mass burden of ultrafine TiO 2 particles that were below the concentration and mass burden for fine TiO2 particles that produced no rat lung tumors in a study by Lee et al. (1985).

Mutagenic and Genotoxic Effects.

Gallagher et al. (1994) examined lungs for the presence of DNA adducts in rats exposed chronically to ultrafine TiO2 (MMAD = 0.82 µm). DNA was isolated from rats exposed at an average concentration of 10 mg/m3 for 18 hr per day, 5 days per week for 24 months. No increase in the number or types of DNA adducts was observed in TiO2-exposed rats compared with clean-air controls. In contrast, a type of DNA adduct not observed in rat lungs chronically exposed to TiO2 or carbon black was detected in the lungs of rats exposed to diesel soot.

Driscoll et al. (1997) exposed rats via intratracheal instillation to a fine TiO2 at 10 or 100 mg/kg of body weight and characterized mutation

Suggested Citation:"4 Titanium Dioxide Smoke." National Research Council. 1999. Toxicity of Military Smokes and Obscurants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/9621.
×

in the hgprt gene of alveolar epithelial cells isolated from the animals 15 months after exposure. A slight but significant increase in hgprt mutation frequency was observed in alveolar epithelial cells from rats exposed to TiO2 at 100 mg/kg. The effect of TiO2. was remarkably less than that in rats exposed to the same concentrations of quartz or carbon black. In vitro exposure of epithelial cells to TiO2 did not result in increased hgprt mutant frequency.

Effects on Host Defense.

Gilmour et al. (1989a,b) examined the effects of TiO2 inhalation on clearance of and immune responses to Pasteurella haemolytica. Mice were exposed to an aerosol of fine TiO2 particles at 20 mg/m3 for 20 hr per day for periods of up to 7 weeks. After varying periods of exposure, mice were challenged with an aerosol of P. haemolytica , and the clearance of the bacteria was determined or the ability of the mice to mount an immune response was evaluated. Exposure to TiO2 for 2 weeks resulted in impaired lung clearance of P. haemolytica . The impaired clearance of P. haemolytica was observed in mice exposed to TiO2 immediately before or after bacterial challenge. TiO2 exposure depressed the responses of cells isolated from the mediastinal lymph nodes to bacterial antigen challenge in vitro.

Creutzenberg et al. (1990) and Heinrich et al. (1995) reported on clearance of tracer particles from the lungs of rats exposed chronically to an aerosol of ultrafine TiO2 particles. Rats were exposed at an average concentration of 10 mg/m3 for 18 hr per day, 5 day per week for 18 months with 6 months recovery in clean air. After 3, 12, and 18 months of exposure, animals were exposed to iron oxide (diameter 0.35µm) or latex (diameter 3.5 µm) tracer particles, and lung retention of the tracer material was determined. Exposure to TiO2 resulted in a significant increase in tracer-particle retention at all times examined. Average half-times of iron oxide clearance ranged from 61 to 93 days in clean-air control rats and from 208 to 368 days in TiO2-exposed rats. Clearance of the latex tracer particles was more variable; longer half-times were observed after 3 and 6 months exposure to TiO2, and shorter half-times were observed thereafter. The reason for the variability in the latex clearance was suggested to be due to the more-proximal deposition of the large latex particles (diameter 3.5 µm), a deposition that resulted from altered architecture of the rats' lungs after long-term TiO2 exposure.

Suggested Citation:"4 Titanium Dioxide Smoke." National Research Council. 1999. Toxicity of Military Smokes and Obscurants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/9621.
×
Dermal and Ocular Exposures
Lethality

The approximate lethal dose of dermally applied TiO2 (percent lethality unspecified) is reported to be >10,000 mg/kg in rabbits (Trochimowicz and Reinhardt 1988).

Skin and Eye Irritation

TiO2 is reported to be neither a dermal irritatant nor a dermal sensitizer and evoked only mild irritation in the eye (Trochimowicz and Reinhardt 1988).

In Vitro Studies

TiO2 was nonmutagenic in the Ames assay using Salmonella typhimurium strains TA100, TA1535, TA97, and TA98 with or without metabolic activation (Zeiger et al. 1988). TiO2 was tested and found to be negative in the Ames assay, the mouse lymphoma assay, and the Drosophila assay for induction of sex-linked recessive lethal mutations (NCI 1979). In Chinese hamster ovary cells, TiO2 was negative for sister chromatid exchange; the results were inconclusive for chromosomal aberrations (NCI 1979). In vitro exposure of rat lung epithelial cells to TiO2 did not increase the frequency of mutation in the hgprt locus (Driscoll et al. 1997).

Summary Of Toxicity Data

Noncancer Effects

Available data on dermal and ocular exposure are sparse; however, these data and the physical and chemical properties of TiO2 indicate a very low order of activity by those routes. After inhalation of very high concentrations of TiO2, particles have been found in nonrespiratory tissues; how-

Suggested Citation:"4 Titanium Dioxide Smoke." National Research Council. 1999. Toxicity of Military Smokes and Obscurants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/9621.
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ever, adverse effects have been confined to the respiratory tract and lung-associated lymphatic tissues (Lee et al. 1995b).

A single brief inhalation exposure of rats to fine TiO2 particles at 2260 mg/m3 has not been associated with adverse effects. In a well-described study by Hilaski et al. (1992), a single 30-min exposure to TiO2 at average concentrations of 1,240 to 830 mg/m3 produced no adverse effects. In the course of the 30-min exposure, rats experienced a 5-min average TiO2 concentration of 2,260 mg/m3 and a 5-min average of 1,506 mg/m3. In addition to this acute exposure study, the 4-hr lethal concentration for 50% of the test animals (LC50) in rats is >6,820 mg/m3 (DuPont 1979; Trochimowicz and Reinhardt, 1988).

Repeated inhalation of fine TiO2 particles at >20 mg/m3 is reported to produce inflammation, fibrosis, and epithelial hyperplasia in rat lung (Thomson et al. 1988; Ferin and Oberdörster 1992; Oberdörster et al. 1994a,b; Warheit et al. 1996). Additional effects observed after inhalation of TiO2 at >20 mg/m3 are impairment in the clearance of both viable and nonviable particles and a decreased immune response to inhaled bacteria. Overall, subchronic (Henderson et al. 1995) and chronic inhalation studies (Lee et al. 1995a,b) in rats do not demonstrate adverse effects at concentrations of 10 mg/m3 for chronic inhalation of fine TiO2 particles.

Studies using ultrafine TiO2 particles, indicate that these particles would be expected to have an effect at a lower concentration than fine particles in the rat lung (Driscoll et al. 1991; Ferin et al. 1992; Oberdörster et al. 1994a,b; Heinrich et al. 1995). The difference in activity of fine and ultrafine TiO2 particles correlates with the difference in surface area of these particles in the lung (Oberdörster et al. 1994a,b; Driscoll 1996).

Carcinogenic Effects

Data show an increase in lung-tumor incidence in rats exposed to TiO2. A significant increase in the incidence of lung adenomas and carcinomas was observed in rats exposed by inhalation to fine TiO 2 particles for 6 hr per day, 5 days per week for 24 months at a concentration of 250 mg/m3 (Lee et al. 1985a,b). No increase in the incidence of lung tumors was

Suggested Citation:"4 Titanium Dioxide Smoke." National Research Council. 1999. Toxicity of Military Smokes and Obscurants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/9621.
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reported at exposure concentrations of 10 mg/m3 and 50 mg/m3. In a study by Heinrich et al. (1995), female rats exposed by inhalation to ultrafine TiO2 particles for 6 hr per day, 5 days per week for 24 months at a concentration of 10 mg/m3 had an increased incidence of lung tumors. In addition to TiO2, other poorly soluble, low-toxicity particles have been shown to increase the incidence of lung tumors in rats. Hamsters and mice do not have an increased incidence of lung tumors even when lung burdens of poorly soluble, low-toxicity particles are similar to those of rats. The relevance of the data to humans is not known.

Previous Recommended Exposure Limits

The Occupational Safety and Health Administration (OSHA) established a permissible exposure limit (PEL) of 15 mg/m3 for total particulate TiO2 and 5 mg/m3 for respirable particulate TiO2 (U.S. Department of Labor 1997). The National Institute for Occupational Safety and Health (NIOSH) has not established a recommended exposure limit and has recommended that the TiO2 concentration be maintained as low as possible because of its recognition as a potential occupational carcinogen (NIOSH 1996). The American Conference of Governmental Industrial Hygienists (ACGIH) established a Threshold Limit Value-time-weighted average (TLV-TWA) of 10 mg/m3 for TiO2 (ACGIH 1996).

Subcommittee Evaluation And Recommendations

Military Exposures

Emergency Exposure Guidance Levels (EEGLs)

No acute toxicity information is available on human exposure to TiO 2. On the basis of animal studies, the potential for lethality from a single exposure to TiO2 is minimal. The 4-hr LC50 for TiO2 in the rat is >6,820 mg/m3 (DuPont 1979). Hilaski et al. (1992) reported that a 30-min exposure of rats to a TWA concentration of up to 1,240 mg/m3 generated from an XM82 grenade had no adverse effects characterized by

Suggested Citation:"4 Titanium Dioxide Smoke." National Research Council. 1999. Toxicity of Military Smokes and Obscurants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/9621.
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histopathological examination, BAL-fluid analysis, and pulmonary-function tests. Additional information relevant to recommending acute exposure limits for TiO2 comes from the extensive subchronic and chronic inhalation data base on TiO2 and several other poorly soluble, low-toxicity particles (e.g., talc, graphite, and carbon black). When lung burdens of poorly soluble, low-toxicity particles at >1–2 mg/g of lung tissue are obtained in the rat, considerable evidence shows that there is an overloading of alveolar-clearance mechanisms and a consequent slowing of particle clearance (Morrow et al. 1991; Oberdörster 1994). Overloading of the alveolar particle-clearance mechanisms has been observed in all experimental animals tested to date, making it reasonable to assume that the phenomenon occurs in humans (Oberdörster 1994). Associated with the alterations in particle clearance in the rat is the development of pulmonary inflammation, fibrosis, and epithelial hyperplasia; exposures resulting in lung burdens below 1–2 mg/g of lung appear to have no without adverse effects (Morrow et al. 1991; Oberdörster 1994). Overloading of the alveolar particle-clearance mechanisms has been shown to be more closely related to the volume than the mass of particles in the lung (Morrow 1988; Morrow et al. 1991). In this respect, for TiO2, the lung mass burden expected to cause particle-clearance changes and adverse lung effects would need to be increased to account for the high density of TiO2 (Morrow et al. 1991).

The approach the subcommittee used to recommend EEGLs was to estimate the maximal acute inhalation exposure concentration that would result in a lung particle dose below that associated with impairment of particle clearance and adverse lung effects. On the basis of long-term inhalation studies in rodents, a lung dose of TiO2 at <4 mg/g of lung would not be expected to alter alveolar particle clearance. The 4 mg/g lung value incorporates a correction for the average density (4 g/cm3) of the two forms of TiO2. Because the 4-mg/g lung dose is based on results of long-term inhalation studies, the subcommittee considered the possibility that the response could be greater to a dose of 4 mg/g of lung delivered by acute exposure (high-dose rate) than by chronic exposure (low-dose rate). In considering the possibility for dose-rate effects, the subcommittee noted that in intratracheal instillation studies, bolus doses of approximately 0.7 to 2 mg of TiO2 have been delivered to the lungs of rats and resulted in either no effects or transient pulmonary

Suggested Citation:"4 Titanium Dioxide Smoke." National Research Council. 1999. Toxicity of Military Smokes and Obscurants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/9621.
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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)].

Suggested Citation:"4 Titanium Dioxide Smoke." National Research Council. 1999. Toxicity of Military Smokes and Obscurants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/9621.
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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-

Suggested Citation:"4 Titanium Dioxide Smoke." National Research Council. 1999. Toxicity of Military Smokes and Obscurants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/9621.
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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).

Suggested Citation:"4 Titanium Dioxide Smoke." National Research Council. 1999. Toxicity of Military Smokes and Obscurants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/9621.
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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]}.

Suggested Citation:"4 Titanium Dioxide Smoke." National Research Council. 1999. Toxicity of Military Smokes and Obscurants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/9621.
×

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.

Suggested Citation:"4 Titanium Dioxide Smoke." National Research Council. 1999. Toxicity of Military Smokes and Obscurants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/9621.
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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.

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Suggested Citation:"4 Titanium Dioxide Smoke." National Research Council. 1999. Toxicity of Military Smokes and Obscurants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/9621.
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Suggested Citation:"4 Titanium Dioxide Smoke." National Research Council. 1999. Toxicity of Military Smokes and Obscurants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/9621.
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Suggested Citation:"4 Titanium Dioxide Smoke." National Research Council. 1999. Toxicity of Military Smokes and Obscurants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/9621.
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A variety of smokes and obscurants have been developed and are used to screen armed forces from view, signal friendly forces, and mark positions. Obscurants are anthropogenic or naturally occurring particles suspended in the air that block or weaken transmission of particular parts of the electromagnetic spectrum, such as visible and infrared radiation or microwaves. Fog, mist, and dust are examples of natural obscurants. Smokes are produced by burning or vaporizing some product. Red phosphorus smoke and graphite smoke are examples of anthropogenic obscurants.

The U.S. Army seeks to ensure that exposure to smokes and obscurants during training does not have adverse health effects on military personnel or civilians. To protect the health of exposed individuals, the Office of the Army Surgeon General requested that the National Research Council (NRC) review data on the toxicity of smokes and obscurants and recommend exposure guidance levels for military personnel in training and for the general public residing or working near military-training facilities.

The NRC assigned this project to the Committee on Toxicology (COT), which convened the Subcommittee on Military Smokes and Obscurants. The subcommittee conducted a detailed evaluation of the toxicity of four obscuring smokes: white phosphorus, brass, titanium dioxide, and graphite. The results of the subcommittee's study are presented in this report, which is the second volume in the series. Toxicity data and exposure guidance levels for diesel-fuel, fog-oil, red phosphorus, and hexachloroethane smokes were presented in Volume 1. Seven colored smokes will be reviewed in a subsequent volume.

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