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 m e tals or nonmetals (i.e., silicon) Boundaries. Potential f o r respirability--that is, if there are any particles 

### # 10 

### : in diameter in the m a terial being handled by workers. Summarized below are currently available test data on five different poorly soluble particulates–s ilica, talc, titanium dioxide, PMN 96-175 (lithium manganese oxide), and carbon black. The suitability of one or m o re of these analogues for a particular PMN particulate m u st be determined on a case-by-case basis. Risk is to be assessed by the m argin of exposure m e thod for the reason stated in the next paragraph. Haz a rd 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 inflamma tion 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 m e chanism s similar to those of the rat, in the absence of mechanistic data to the contrary, it m u st be assum e d 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 inflamma tion and cell proliferation, at lower lung doses in which chronic active inflamma tion and cell proliferation are not present, no lung cancer hazard is anticipated (ILSI 2000). Som e of the particulates m ay contain m e tals, for example, chrom i um, that m ay present other and mo re immi nent toxicities, depending on the bioavailability of the m e tal ions. Thus, the toxicities of the m e tal components of the particulates m u st also be assessed, and on a case-by-case basis. Lung Toxicity of Five Poorly Soluble Particulates 1. Fibrogenicity/Carcinogenicity of Crystalline Silica Hum ans . 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 m i ners, stone industry workers, granite shed and quarry workers, crushed stone industry workers, diatom aceous 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, som e nonuniformity of results would be expected. In som e 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 W o rking Groupconcluded 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 experim e ntal 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 tum o rs are induced in rats exposed to quartz (Mini-U-Sil; a comm on form of crystalline silica) by inhalation, single intrapleural, intraperitoneal, and/or intratracheal adm i nistration. In a 24- m onth inhalation study in rats, the lowest tested dose of respirable crystalline silica particles to induce lung tum o rs (Lowest Observed Adverse Effect Level, or LOAEL) w a s 0.74 mg/m 3

. 

### 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 m g /m 3 to achieve a MOE of 1,000, a concentration that is practically impossible to achieve. Because the LOAEL of 0.74 m g /m 3 is based on test data on pure silica and because silica is considered to be a m u ch m o re potent lung toxicant than crystalline particulates containing silica, the Agency has adopted the NIOSH REL (Recommended Exposure Level) for silica, 0.05 mg/m 3 , as a NCEL1/ (New Chemical Exposure Li mit - see ht tp ://www.ep a.gov/oppt/newchems/ncelmain.htm for more information) concentration that w o uld adequately protect w o rkers from crystalline particulates containing silica. This NCEL replaces the former one based on OSHA Permissable Exposure Limit (PEL) for silica 0.1 mg/m 3
.
2. Fibrogenicity/Carcinogenicity of Talc Hum ans . Epidemiology studies suggest an association between nonfibrous talc (a finely powdered hydrous m a gnesium silicate) and lung cancer risk. The OSHA PEL for talc is 20 m

ppcf (million particles per cubic foot), and the NIOSH-recomme nded 8-hr TWA concentration is 2 m g /m 3

. Animals

. In an NTP inhalation study (NTP TR 421, 1993), m a le and fem a le F344 rats were exposed to 0, 6, or 18 m g /m 3 talc for 113 and 122 weeks, respectively. There was clear evidence of the carcinogenicity of talc in fem a le rats based on the increased incidence of alveolar/bronchiolar adenomas and carcinomas of the lung in the 18-mg/m 3 group (LOAEL). The No Observed Adverse Effect Level (NOAEL) from this study is 6 mg/m 3

. The NCEL for analogous particulates would be 0.06 m g /m 3

.
3. Fibrogenicity/Carcinogenicity of Titanium Dioxide (TI) Hum ans . 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 experim e ntal animals.] Overall evaluation: TI is not classifiable as to its carcinogenicity tohumans. The OSHA PEL’s for nuisance dust (in which TI is included) are 15 m g /m 3 total particulates and 5 m g /m 3 respirable fraction. The ACGIH TLV-TWAis 10 m g /m 3 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 incom p lete data on TI exposure histories. In one fairly com p rehensive cohort study, Chen and Fayerweather (1988, as summ arized in ACGIH 1993) analyzed lung cancer m o rtality and inci dence of chronic respiratory disease, chest x-ray abnorm a lity, 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 com p ared with 18.3 and 13.8 cases expected, respectively, based on US m o rtality data. Expected deaths based on com p any mo rtality 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 com p ared with com p any data was not statistically significant. They further concluded that there was no significant associati on between exposure to TI and the respiratory diseases studied. Animals

. There is limited evidence for the carcinogenicity of TI in experim e ntal 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 m g /m 3 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, experim e ntally induced tum o rs in rats and to be of questionable relevance to humans. Given the amount of dust in the rat lungs, the tum o rs were postulated to be the result of saturation of norm a l pulmonary clearance mechanism s. There were m i nute areas of lung fibrosis at the two higher exposure levels.

At 50 m g /m 3 , m a ssive accum u lations of dust-laden macrophages, foamy dust cells, and free particles were considered indicative of such an overload. At 10 m g /m 3 , the architecture of the air spaces rem a ined intact and there was no significant formation of scar tissue. The NOAEL is 10 mg/m 3
. (2) Heinrich et al. (1995, abstract only) exposedWi star rats to diesel engine exhaust, carbon black, or ultrafine TI for 2 yr. Particle exposur e concentrations were increased during the course of the experim e nt. The average particle concentration of TI was 10 m g /m 3

. Lung tum o r rates (not given) increased with increasing cum u lative particle exposure times, independent of the type of particle. (3) Trochim o wicz et al. (1988, abstract only) exposed Charles River-CD rats to 10, 50, or 250mg /m 3 TI for 6 hr/day, 5 days/wk for 104 wk. Microscopic findings included alveolar cell hyperplasia, dust deposition, and m i nute areas of collagen fiber deposition associated with cholesterol giant cell granulomas. The earliest indicator of TI exposure was alveolar cell hyperplasia. Lung tum o rs were only found in rats exposed to 250 m g /m 3

. The NOAEL from this study is 10 mg/m 3
. On the basis of the NOAEL’s from the above studies, the NCEL for analogous particulates would be 0.1 m g /m 3

. However, this would m ake 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 m g /m 3 (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 m g /m 3 of the PMN substance 6 hr/day, 5 days/wk for 90 days. At the highest concentration, rats developed inflamma tion of the lung and larynx. Similar results were seen in the 14-day range-finding study at concentrations ranging from 10 to 100 m g /m 3

. The NOAEL from this study is 4 mg/m 3
. The NCEL for analogous particulates would be 0.04 m g /m 3

.
5. Fibrogenicity/Carcinogenicity of Carbon Black Chronic inhalation of carbon black produced pulmonary inflamma tion, fibrosis, and lung tum o rs in rats (Nikula et al. 1995, Heinrich et al . 1995). These effects were observed at dust concentrations of 2.5, 6.6, and approxim a tely 10 m g /m 3 carbon black. The LOAEL from these studies is 2.5 mg/m 3
. The NCEL for analogous particulates would be 0.0025 m g /m 3 . [The OSHA PEL for carbon black is 3.5 m g /m 3 .] General Testing Strategy A 90-day inhalation toxicity test (CFR 870.3465) in rats with special attention to histopathology (inflamma tion and cell proliferation) of the lung tissues and to various param e ters of the bronchoalveolar lavage fluid (BALF), e.g., m arker enzym e activities, total protein content, total cell count, cell differential, and cell viability. It is not necessary to look at internal organs. It is recomme nded that a recovery period of 60 days be included to assess the progression or regression of any lesions. If the results of th e subchronic study indicate that the PMN particles have carcinogenic potential, a 2-year inhalation bioassay in rats m ay be warranted.

REFERENCES ACGIH. 1993. American Conference of Governme ntal Industrial Hygienists: Threshold Lim it Values for Chemical Substances and Physi cal 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 W i star rats and two differe nt strains of m i ce to diesel engine exhaust, carbon black, and titanium dioxide. I nhal 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. Wo rkshop: The relevance of the rat lung response to particle overload for hum an risk assessment. Inhal Toxicol 12: 1-17. Nikula KJ, Snipes MB, Griffith W C , Henderson RF, Mauderly JL. 1995. Com p arative pulm onary 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 m i ce. National Toxicology Program, Technical Report No. 421, 1993. Trochim o wicz 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 W e lch, Chief, Chemical Risk Indentifi cation Section, to Frank Kover, Chief, Chemical Screening Branch, Existing Chemicals Assessment Div., OPPT, USEPA. W oo, 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