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Category: Respirable, Poorly Soluble Particulates Health Only 

Definition. This category includes a variety of inorganic, poorly soluble (as designated in ILSI 

2000) particulates. Typically, they are oxides of various metals or nonmetals (i.e., silicon) 

Boundaries. Potential for respirability--that is, if there are any particles #10 : in diameter in 

the material being handled by workers. Summarized below are currently available test data on 

five different poorly soluble particulates–silica, talc, titanium dioxide, PMN 96-175 (lithium 

manganese oxide), and carbon black. The suitability of one or more of these analogues for a 

particular PMN particulate must be determined on a case-by-case basis. Risk is to be assessed 

by the margin of exposure method for the reason stated in the next paragraph. 

Hazard Concerns 

The category concerns discussed here are limited to effects on the lung as a result of inhaling the 

particles. Broadly, as shown in rat inhalation studies, these effects range from inflammation to 

fibrosis to, potentially, cancer. Because it is still not known with certainty whether high lung 

burdens of poorly soluble particulates can lead to lung cancer in humans via mechanisms similar 

to those of the rat, in the absence of mechanistic data to the contrary, it must be assumed that the 

rat model can identify potential carcinogenic hazards to humans. Since the apparent 

responsiveness of the rat model at overload is dependent on coexistent chronic active 

inflammation and cell proliferation, at lower lung doses in which chronic active inflammation 

and cell proliferation are not present, no lung cancer hazard is anticipated (ILSI 2000). 

Some of the particulates may contain metals, for example, chromium, that may present other and 

more imminent toxicities, depending on the bioavailability of the metal ions. Thus, the toxicities 

of the metal components of the particulates must also be assessed, and on a case-by-case basis. 

Lung Toxicity of Five Poorly Soluble Particulates 

1. Fibrogenicity/Carcinogenicity of Crystalline Silica 

Humans. Based on “sufficient evidence” for the carcinogenicity of inhaled crystalline silica 

from occupational sources, the International Agency for Research on Cancer (IARC, 1997) has 

classified crystalline silica as a Group 1 carcinogen in humans. According to IARC, studies of 

the following populations provided the least-confounded examinations of an association between 

silica exposure and cancer risk: gold miners, stone industry workers, granite shed and quarry 

workers, crushed stone industry workers, diatomaceous earth industry workers, refractory brick 

workers, pottery workers, and cohorts of registered silicotics. Not all of these studies 

demonstrated excess cancer risks; but, in view of the large number of epidemiological studies 

undertaken and the wide range of populations and exposure circumstances, some nonuniformity 

of results would be expected. In some studies, increasing risk gradients have been observed in 

relation to dose surrogates--cumulative exposure, duration of exposure, or the presence of 

radiographically defined silicosis--and, in one instance, to peak intensity exposure. For these 

reasons, the IARC Working Group 
concluded that overall, the epidemiological findings support increased lung cancer risks from 

inhaled crystalline silica resulting from occupational exposure. 

Animals. IARC (1997) has concluded that there is “sufficient evidence” in experimental animals 

for the carcinogenicity of crystalline silica. A number of studies (rev.in: IARC, 1997; Woo et 

al., 1988; Holland, 1990) have demonstrated that, in addition to silicosis/fibrosis, pulmonary 

tumors are induced in rats exposed to quartz (Mini-U-Sil; a common form of crystalline silica) 

by inhalation, single intrapleural, intraperitoneal, and/or intratracheal administration. In a 24-

month inhalation study in rats, the lowest tested dose of respirable crystalline silica particles to 

induce lung tumors (Lowest Observed Adverse Effect Level, or LOAEL) was 0.74 mg/m3 

. 

K Note for Cases Using Silica as Primary Analogue: For LOAEL doses, the Agency 

considers a Margin of Exposure (MOE) of 1,000 or greater as representing a low order of 

toxicity for health endpoints for which a threshold dose is deemed appropriate. In this instance, 

exposures would have to be reduced to 0.0007 mg/m3

 to achieve a MOE of 1,000, a 

concentration that is practically impossible to achieve. Because the LOAEL of 0.74 mg/m3 is 

based on test data on pure silica and because silica is considered to be a much more potent lung 

toxicant than crystalline particulates containing silica, the Agency has adopted the NIOSH 

REL (Recommended Exposure Level) for silica, 0.05 mg/m3, as a NCEL1/ (New Chemical 

Exposure Limit - see http://www.epa.gov/oppt/newchems/ncelmain.htm for more 

information) concentration that would adequately protect workers from crystalline 

particulates containing silica. This NCEL replaces the former one based on OSHA 

Permissable Exposure Limit (PEL) for silica 0.1 mg/m3

. 

2. Fibrogenicity/Carcinogenicity of Talc 

Humans. Epidemiology studies suggest an association between nonfibrous talc (a finely 

powdered hydrous magnesium silicate) and lung cancer risk. The OSHA PEL for talc is 20 

mppcf (million particles per cubic foot), and the NIOSH-recommended 8-hr TWA concentration 

is 2 mg/m3. 

Animals. In an NTP inhalation study (NTP TR 421, 1993), male and female F344 rats were 

exposed to 0, 6, or 18 mg/m3

 talc for 113 and 122 weeks, respectively. There was clear evidence 

of the carcinogenicity of talc in female rats based on the increased incidence of 

alveolar/bronchiolar adenomas and carcinomas of the lung in the 18-mg/m3

 group (LOAEL). 

The No Observed Adverse Effect Level (NOAEL) from this study is 6 mg/m3 . The NCEL 

for analogous particulates would be 0.06 mg/m3. 

3. Fibrogenicity/Carcinogenicity of Titanium Dioxide (TI) 

Humans. According to IARC (ACGIH 1993), there is inadequate evidence for the 

carcinogenicity of TI in humans. [There is limited evidence for the carcinogenicity of TI in 

experimental animals.] Overall evaluation: TI is not classifiable as to its carcinogenicity to 
humans. The OSHA PEL’s for nuisance dust (in which TI is included) are 15 mg/m3

 total 

particulates and 5 mg/m3

 respirable fraction. The ACGIH TLV-TWA is 10 mg/m3 of total dust 

containing no asbestos and <1% crystalline silica. 

The various literature case reports of lung toxicity in TI-exposed workers are generally 

inconclusive because of several factors--smoking; other conditions, such as tuberculosis; or 

incomplete data on TI exposure histories. 

In one fairly comprehensive cohort study, Chen and Fayerweather (1988, as summarized in 

ACGIH 1993) analyzed lung cancer mortality and incidence of chronic respiratory disease, chest 

x-ray abnormality, and pulmonary fibrosis among 1,576 workers exposed to TI for at least 1 yr at 

two production facilities between 1935 and 1984. Of the 211 deaths, 14 were attributed to 

respiratory cancer and 11 to nonmalignant respiratory disease compared with 18.3 and 13.8 cases 

expected, respectively, based on US mortality data. Expected deaths based on company 

mortality data since 1957 were 16.6 from respiratory cancer and 8.3 from nonmalignant 

respiratory disease. The authors concluded that the increase in deaths from nonmalignant 

respiratory disease compared with company data was not statistically significant. They further 

concluded that there was no significant association between exposure to TI and the respiratory 

diseases studied. 

Animals. There is limited evidence for the carcinogenicity of TI in experimental animals. Twoyear inhalation studies in animals are summarized below. 

(1) Lee et al. (1986, as cited in ACGIH 1993 and in USEPA 1983) exposed Charles River-CD 

rats to 0, 10, 50, or 250 mg/m3

 for 6 hr/day 5 days/wk for 2 yr. The mean respirable fractions 

were 93.7% or greater. Squamous cell carcinomas developed after exposure to the highest dose 

for the full 2 yr. The authors considered the carcinomas to be unique, experimentally induced 

tumors in rats and to be of questionable relevance to humans. Given the amount of dust in the 

rat lungs, the tumors were postulated to be the result of saturation of normal pulmonary 

clearance mechanisms. There were minute areas of lung fibrosis at the two higher exposure 

levels. 

At 50 mg/m3

, massive accumulations of dust-laden macrophages, foamy dust cells, and free 

particles were considered indicative of such an overload. At 10 mg/m3

, the architecture of the air 

spaces remained intact and there was no significant formation of scar tissue. The NOAEL is 10 

mg/m3

. 

(2) Heinrich et al. (1995, abstract only) exposed Wistar rats to diesel engine exhaust, carbon 

black, or ultrafine TI for 2 yr. Particle exposure concentrations were increased during the course 

of the experiment. The average particle concentration of TI was 10 mg/m3. Lung tumor rates 

(not given) increased with increasing cumulative particle exposure times, independent of the 

type of particle. 

(3) Trochimowicz et al. (1988, abstract only) exposed Charles River-CD rats to 10, 50, or 250 
mg/m3

 TI for 6 hr/day, 5 days/wk for 104 wk. Microscopic findings included alveolar cell 

hyperplasia, dust deposition, and minute areas of collagen fiber deposition associated with 

cholesterol giant cell granulomas. The earliest indicator of TI exposure was alveolar cell 

hyperplasia. Lung tumors were only found in rats exposed to 250 mg/m3

. The NOAEL from 

this study is 10 mg/m3. 

On the basis of the NOAEL’s from the above studies, the NCEL for analogous particulates 

would be 0.1 mg/m3. However, this would make the NCEL for TI analogues identical to that for 

silica, a highly potent lung toxicant that IARC (1997) has classified as a Group 1 carcinogen in 

humans (see section 1, above). Therefore, it was decided to use the OSHA PEL for TI, which is 

5 mg/m3 (respirable fraction), as the NCEL for TI analogues. 

4. Lung Toxicity of PMN 96-175, Lithium Manganese Oxide 

Animal Data Only. Rats were exposed by inhalation to 0 (air controls), 1, 4, or 16 mg/m3 of the 

PMN substance 6 hr/day, 5 days/wk for 90 days. At the highest concentration, rats developed 

inflammation of the lung and larynx. Similar results were seen in the 14-day range-finding study 

at concentrations ranging from 10 to 100 mg/m3

. The NOAEL from this study is 4 mg/m3. 

The NCEL for analogous particulates would be 0.04 mg/m3

. 

5. Fibrogenicity/Carcinogenicity of Carbon Black 

Chronic inhalation of carbon black produced pulmonary inflammation, fibrosis, and lung tumors 

in rats (Nikula et al. 1995, Heinrich et al. 1995). These effects were observed at dust 

concentrations of 2.5, 6.6, and approximately 10 mg/m3 carbon black. The LOAEL from these 

studies is 2.5 mg/m3. The NCEL for analogous particulates would be 0.0025 mg/m3. [The 

OSHA PEL for carbon black is 3.5 mg/m3.] 

General Testing Strategy 

A 90-day inhalation toxicity test (CFR 870.3465) in rats with special attention to histopathology 

(inflammation and cell proliferation) of the lung tissues and to various parameters of the 

bronchoalveolar lavage fluid (BALF), e.g., marker enzyme activities, total protein content, total 

cell count, cell differential, and cell viability. It is not necessary to look at internal organs. It is 

recommended that a recovery period of 60 days be included to assess the progression or 

regression of any lesions. If the results of the subchronic study indicate that the PMN particles 

have carcinogenic potential, a 2-year inhalation bioassay in rats may be warranted. 

REFERENCES 

ACGIH. 1993. American Conference of Governmental Industrial Hygienists: Threshold Limit 

Values for Chemical Substances and Physical Agents and Biological Exposure Indices, 1993-
1994. Cincinnati, Ohio: ACGIH. 

Heinrich U, Fuhst R, Rittinghausen S, Creutzenberg O, Bellmann B et al. 1995. Chronic 

inhalation exposure of Wistar rats and two different strains of mice to diesel engine exhaust, 

carbon black, and titanium dioxide. Inhal Toxicol 7:533-556. Abstract only. 

Holland LM. Reg. Toxicol. Pharmacol. 12:224-237, 1990 

IARC. 1997. International Agency for Research on Cancer. Monographs. Vol. 68, pp.41-336. 

ILSI. 2000. International Life Sciences Institute. Workshop: The relevance of the rat lung 

response to particle overload for human risk assessment. Inhal Toxicol 12: 1-17. 

Nikula KJ, Snipes MB, Griffith WC, Henderson RF, Mauderly JL. 1995. Comparative 

pulmonary toxicities and carcinogenicities of chronically inhaled diesel exhaust and carbon 

black in F344 rats. Fund Appl Toxicol 25:80-94. 

NTP. Toxicology and Carcinogenesis Studies of Talc in F334/N rats and B6C3F1 mice. National 

Toxicology Program, Technical Report No. 421, 1993. 

Trochimowicz HJ et al. 1988. J Appl Toxicol 8:383-435. Abstract only. 

USEPA. 1983. Status report for 8EHQ-1083-0497. Preliminary findings from a 2-yr rat 

inhalation study of titanium dioxide conducted by E.I. Du Pont de Nemours & Co., Inc. From 

Justine Welch, Chief, Chemical Risk Indentification Section, to Frank Kover, Chief, Chemical 

Screening Branch, Existing Chemicals Assessment Div., OPPT, USEPA. 

Woo, Y.-T., Lai, D.Y., Arcos, J.C., and Argus, M.F.: Chemical Induction of Cancer, Vol. III C, 

Academic Press, p. 508, 1988. 

October, 2002