Review of the Air Quality Criteria Document for Particulate Matter

efficiencies as well as the ratio of rat to human lung surface areas. This paragraph needs to berevised.Page 7-29, lines 1 and 2: This concluding sentence stating that deposition density shouldbe considered when extrapolating health effects seen in rodent studies to the human situationneeds to be expanded in that other factors should be considered as well, such as dose in thespecific region, dose per unit surface area, dose per cell (e.g., alveolar macrophage), and alsoparticle parameters such as solubility, volume, surface area, size. Although deposition density isvery important, other factors should not be neglected.In this section on interspecies differences, it would also be useful to mention theavailability of the Multiple Path Particle Deposition model (MPPDep) which allows thecalculation of particle deposition in human and rat respiratory tracts assuming different exposurescenarios and breathing patterns and particle parameters.In general, in this section on particle deposition efficiencies in the human respiratorytract and in the rat, a figure would be useful so the reader would not have to consult otherpublications for this purpose.Page 7-31, Figure 7-3: If the size of the arrows in this figure indicates major vs. minorclearance pathways, then the arrow from phagocytosis by alveolar macrophages to passagethrough alveolar epithelium should clearly be a minor arrow since only a tiny fractionphagocytosed by macrophages takes this route (studies by Harmsen et al.), and the existence ofthis route might even be questioned. However, under particle overload conditions thetranslocation to interstitial sites via endocytosis by type I and type II alveolar cells becomes amajor pathway, but this does not occur via particle-laden alveolar macrophages.The meaning of the double-headed arrow from pulmonary capillary endothelium tophagocytosis by interstitial macrophages is not clear, does it mean that particles or interstitialmacrophages with particles are coming back from the endothelium? Also, the arrow fromphagocytosis by interstitial macrophages to pulmonary capillary endothelium is not clear: Isthere compelling evidence that, indeed, interstitial macrophages with phagocytized particles areentering the pulmonary capillary endothelium?Page 7-32, line 3: Not all solutes will be absorbed rapidly, it depends on the rate ofdissolution from a particle as well as on the molecular size of the solute and other parameters tobe discussed later.Line 10: Probably meant here is that particles re-enter the airway lumen frommucosal sites, is there any reference for that?Line 23 and 27: I don't think that the general statement can be made that the"magnitude of any increase in cell number (alveolar macrophages) is related to the number ofdeposited particles rather than to total deposition by weight". This would result in a hugeincrease in the case of deposition of ultrafine particles. Furthermore, cytotoxicity of a givenparticle is certainly a big stimulus for inflammatory cell increase, and if particles are soluble thenthe mass and not the number is the major determinant for eliciting cells. A better dosemetric torelate cellular responses to deposited poorly soluble particles would be particle surface area, andthere are a number of studies which demonstrated that specifically for ultrafine and fine particles- given that they are not chemically different - particle surface area correlates very well with theincrease in inflammatory cell numbers. Again, that applies only to poorly soluble particles andnot for soluble ones where mass is the more appropriate dosemetric.Page 7-32, line 31: This describes the pathway in Figure 7-3 of macrophages traversingthe alveolar capillary endothelium directly entering the blood stream. Again, has this beendemonstrated for macrophages with phagocytized particles?Page 7-33, lines 1-11: There are a number of statements in this paragraph which need tobe supported by appropriate references. For example, what is the evidence for macrophages withphagocytized particles traveling to extrapulmonary organs? Are these new data? What is theevidence of particles binding to macromolecules?Lines 17-29: The clearance of solutes is a bit superficially treated here, it is notthat simple. It depends on the lipophilicity vs. hydrophilicity of solutes and the molecularweight. There are also different solubilities depending on the intra- vs. extra-cellular localizationA - 66