Depleting Macrophage both Increases and Decreases Sensitization by Trimellitic Anhydride - A Lesson for Risk Assessment Models

Toxicology and Applied Pharmacology Volume 211, Issue 1 , 15 February 2006, Pages 20-29
Alveolar macrophages have a dual role in a rat model for trimellitic anhydride-induced occupational asthma
Dingena L. Valstara, Marcel A. Schijfa, Frans P. Nijkampa, Gert Stormb, Josje H.E. Artsc, C. Frieke Kuperc, Nanne Bloksmaa, d and Paul A.J. Henricksa, ,

Abstract
Occupational exposure to low molecular weight chemicals, like trimellitic anhydride (TMA), can result in occupational asthma. Alveolar macrophages (AMs) are among the first cells to encounter inhaled compounds. These cells can produce many different mediators that have a putative role in asthma. In this study, we examined the role of AMs in lung function and airway inflammation of rats exposed to TMA. Female Brown Norway rats were sensitized by dermal application of TMA or received vehicle alone on days 0 and 7. One day before challenge, rats received intratracheally either empty or clodronate-containing liposomes to deplete the lungs of AMs. On day 21, all rats were challenged by inhalation of TMA in air. Lung function parameters were measured before, during, within 1 h after, and 24 h after challenge. IgE levels and parameters of inflammation and tissue damage were assessed 24 h after challenge. Sensitization with TMA led to decreased lung function parameters during and within 1 h after challenge as compared to non-sensitized rats. AM depletion alleviated the TMA-induced drop in lung function parameters and induced a faster recovery compared to sham-depleted TMA-sensitized rats. It also decreased the levels of serum IgE 24 h after challenge, but did not affect the sensitization-dependent increase in lung lavage fluid IL-6 and tissue TNF-α levels. In contrast, AM depletion augmented the TMA-induced tissue damage and inflammation 24 h after challenge. AMs seem to have a dual role in this model for TMA-induced occupational asthma since they potentiate the immediate TMA-induced decrease in lung function but tended to dampen the TMA-induced inflammatory reaction 24 h later.
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BrooklynDodger(s) comment: Trimellitic anhydride hardens epoxy resins, particularly powdered paint. It's a sensitizer and an asthmagen.
http://www.cdc.gov/NIOSH/78121_21.html#Potential%20Occupational%20Exposures
Powdered coatings are attractive to EPA and environmental groups because of low or no VOC, but the problem in the workplace is dust (particulate) control, which is more difficult to control in spray operations than vapor.
TMA has a vapor pressure of 7.6 x 10^-5 Pa @ 25ºC, saturation vapor concentration of about .1 ppm. So we'd be talking particulate here [Can someone please check the Dodger(s) arithmatic?]

Now back to the lesson of posted abstract. Science types like to incorporate "mechanistic" data into exposure-response assessments. In a "Houdini" risk assessment, the goal is to chose a biochemical parameter in the most resistant species or subpopulation for which people are most like the resistant species, and use that parallel to argue for greater human resistence. This makes the risk disappear, or at least get smaller, and allows the regulatory agency or industry to escape from doing anything. Most of these risk assessments are untestable hypotheses, since they estimate population risks in a dose range which can't be directly observed.

An exposure response relationship in a population will be steeper - predict lower low dose risk - if the population is more homogeneous. The Dodger(s) imagine(s) that there's a range of alveolar macrophage populations in the human population. The experiment shows that depending on the end point chosen, depletion - lower levels - either reduces or enhances the gravity of the organisms response. So the assessor could chose an endpoint that either increases or decreases the estimated low dose risk, and therefore lowers or raises the appropriate PEL.