Silica Damage Progresses After Exposure Ceases

Porter, D. W.; Hubbs, A. F.; Mercer, R.; Robinson, V. A.; Ramsey, D.; McLaurin, J.; Khan, A.; Battelli, L.; Brumbaugh, K.; Teass, A., and Castranova, V.

Progression of lung inflammation and damage in rats after cessation of silica inhalation.

Toxicol Sci. 2004 Jun; 79(2):370-80.


Abstract: Human epidemiologic studies have found that silicosis may develop or progress even after occupational exposure has ended, suggesting that there is a threshold lung burden above which silica-induced pulmonary disease progresses without further exposure. We previously described the time course of rat pulmonary responses to silica inhalation as biphasic, the initial phase characterized by increased but controlled pulmonary inflammation and damage. However, after a threshold lung burden was exceeded, rapid progression of silica-induced pulmonary disease occurred. To test the hypothesis that there is a threshold lung burden above which silica-induced pulmonary disease progresses without further exposure we initiated a study to investigate the relationship between silica exposure, the initiation and progression of silica-induced pulmonary disease, and recovery. Rats were exposed to silica (15 mg/m(3), 6 h/day) for either 20, 40, or 60 days. A portion of the rats from each exposure were maintained without further exposure for 36 days to examine recovery. The major findings of this study are: (1) silica-exposed rats were not in pulmonary overload, and lung silica burden decreased with recovery; (2) pulmonary inflammation, damage and lipidosis increased with recovery for rats exposed to silica for 40 and 60 days, but not 20 days; (3) histopathology revealed changes in silica-induced alveolitis, epithelial hypertrophy and hyperplasia, and alveolar lipoproteinosis consistent with bronchoalveolar lavage (BAL) endpoints; and (4) pulmonary fibrosis developed even when exposure was stopped prior to its initial development.

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BrooklynDodger(s) comments: NIOSH labs in Morgantown produce a steady stream of "modest" size inhalation toxicology projects which really illuminate current problems of occupational exposure. For example, the only medline-accessible study of diacetyl, the active ingredient in popcorn workers lung, is from this lab. These labs are a gift from Robert Byrd, although they exist at the cost of closing NIOSH inhalation tox in Cincinnati.

It's unfortunate that these studies aren't followed up by the appropriate 2-year or lifetime bioassays, with larger groups and lower exposure levels. This study actually used substantial numbers of animals, although still modest compared to a high dollar industry bioassay [for example titanium dioxide] and only held animals for 100 days [60 days of exposure plus 36 days of recovery]

The investigators say this was "a study to investigate the relationship between initial silica exposure, the initiation and progression of silica-induced pulmonary disease, and recovery after silica exposure. Three different exposure times were used in this
study, namely 20, 40, and 60 days. These represent exposure times previously determined to result in elevated but controlled inflammation and damage without fibrosis (20 days), the tran-sition from controlled inflammation and damage to rapidly increasing inflammation and damage (40 days), and rapidly increasing inflammation and damage with fibrosis developing (60 days)." [editor could have deleted a sentence here]

The material was Min-U-Sil, particle size averaged less than 2 microns. The mass median aerodynamic diameter of the silica particles averaged 1.78 m (range 1.70 –1.89 m), and the geometric standard deviation averaged 1.93 m (range 1.87–2.00 m). Size is important should have been mentioned in the abstract.

The Dodger(s) further notes that the 15 mg/m3 exposure level must be viewed in context of resistance of the rat to particulate toxicity. The effect level for cigarette smoke carcinogenesis in the rat is about 200 mg/m3, in an extended observation study beyond the 2 year standard.

The Dodger(s) is troubled by references to a "threshold" of exposure for anything, since threshold is equally likely an artifact of small group size and population background rate of an effect. Nevertheless, the investigator's discussion is useful.

Human epidemiologic studies have
found that, even after occupational exposure has ended, silicosis
may develop or progress (Hessel and Sluis-Cremer, 1987;
Hnizdo and Murray, 1998; Hnizdo and Sluis-Cremer, 1993;
Kreiss and Zhen, 1996; Miller et al., 1998; Ng et al., 1987),
suggesting that in humans there maybe a threshold silica burden
above which silica-induced pulmonary disease would
progress without further exposure. A recent study of coal
miners who had relatively low working lifetime dust exposures,
and whose exposures were almost entirely under the
current U.S. exposure limits for coal and silica, determined that
relatively low occupational exposures to silica in mixed dust
are associated with pulmonary responses, including inflammation
and fibrosis (Kuempel et al., 2003). When considered
together, these human studies suggest that relatively low silica
exposures may pose a serious health risk because silica-induced
disease, once initiated even at low threshold lung burdens,
can progress even in the absence of further exposure. The
findings of our rat inhalation model are consistent with the
pattern of pulmonary responses reported in humans and, thus,
add support to this proposal. The similarity in the rat silica
inhalation model presented here and previously reported human
pulmonary responses suggests that this rat model can be
used in future investigations of the mechanisms which may be
responsible for these phenomena (Kuempel et al., 2002).

It's important to extend this work beyond silica to a series of other PSLT particles.