The effect of exposure pattern on the accumulation of particles and the response of the lung to inhaled particles

Abstract

We hypothesized that a rapid rate of delivery of particles to the lung would overwhelm the normal clearance mechanisms of the lung and result in a higher lung burden of particles and a greater inflammatory response than a slower rate of particle delivery. F344 N rats were exposed over a 12-week period to the same weekly concentration times time product of carbon black (CB) particles, but at three different exposure rates: 3.5 mg/m 3, 16 hr/day, 7 days/week; 13 mg/m 3, 6 hr/day, 5 days/week; or 98 mg/m 3, 4 hr/day, 1 day/week. The intermediate exposure rate was chosen to mimic an occupational work week and to give an 8-hr, time-weighted average exposure equal to the threshold limit value (TLV) for nuisance dusts of the American College of Governmental Industrial Hygienists (10 mg/m 3). Pure CB has a lower TLV, 3.5 mg/m 3, than nuisance dusts, but this is based on avoidance of excessive dirtiness in the workplace, not on the toxicity of CB. Lung burdens of CB were measured after 3, 6, 9, and 12 weeks of exposure and at 4, 8, 12, 16, and 24 weeks after the exposure ended. The inflammatory response was quantified by analysis of bronchoalveolar lavage fluid (BALF) after 6 and 12 weeks of exposure and at 1, 12, and 24 weeks after exposure. The histopathology of the lung was evaluated at the end of the exposure and at 24 weeks after the exposure. Acquired lung burdens were between 3 and 4 mg/lung at the end of the exposure. There was an approximately 20% higher lung burden in the rats exposed at the lowest rate of delivery, but this did not result in any differences among the three groups in the inflammatory response or the lesions in the lung. By 6 weeks, there was a mild inflammatory response to the particles and this response was increased by 12 weeks of exposure as indicated by an influx of neutrophils, two- to threefold increases in protein and in lactate dehydrogenase activity, and up to sixfold increases in β-glucuronidase activity in the BALF. Morphologic changes were minimal, consisting of slight thickening of the alveolar septa with hypertrophied epithelial cells, scant collagen fibers, and occasional inflammatory cells adjacent to accumulations of particles. The data support the use of time-weighted averages in regulating exposures to nuisance dusts. The results of the study indicate that exposures to a particle of relatively low toxicity at the current TLV for nuisance dusts led to pulmonary inflammation and sufficient accumulation of particles to slow lung clearance. The results suggest that the TLV for nuisance dusts may be too high.