Health Assessment Document for Diesel Emissions - NSCEP | US ...

1 · some of which can be informed choices while others are more public-health-driven policy
2 choices.
3 To recount the mode-of-action discussion earlier, at low to high doses the DE cancer
4 hazard is believed to have at least two modes. One involves mutagenic/genotoxic mechanisms
5 · associated with the organic substances adsorbed to DE particles as well as those in the gases. The
6 organics include substances that are known to be mutagenic and/or carcinogenic in animal
7 bioassays. Superoxide or hydroxal free radicals on the surface of fresh DE particles may also
8 contribute to this mode of action. The mutagenic organics are present in approximate proportion
9 to the particulate concentration, which likely varies somewhat by diesel engine circumstances.
1 0 These substances could initiate cells or be complete carcinogens. A second mode involves
11 nongenotoxic particle-specific mechanisms associated with lung particle overload, which is likely
12 to dominate at high doses, according to rat studies, by exacerbating the promotion of initiated
13 cells. The influence of the particles at low, nonoverload exposures may be limited to delivering
14 organics, but this is an unknown.
15 If we favor the organics (gases or absorbed organics on the particles) as a likely etiologic
16 agent for a suspected low-exposure carcinogenic hazard, the issue of bioavailability of the
17 organics is an important consideration. There would be little doubt about the bioavailability of
18 the gaseous-phase compounds in the DE mixture; whether they present a large enough dose to
19 make a carcinogenic response observable is a different question. The bioavailability of the
20 organics coating the particles is a more complex topic. Rat studies using radiolabeled BaP and
21 nitropyrene-coated carbon particles have. shown that lung retention time of the organic is
22 significantly increased compared to a nonparticle instillation and that the gradual elution of BaP,
23 for example, was faster than the lung clearance of the carrier particle itself. An understanding of
24 the role extracellular fluids play in extracting the organics from the particles is unclear.
25 Extraction of the organics by alveolar and other cell types is theorized but not well understood.
26 At least in the rat and mouse models, a carci_nogenic response was not seen below the whole-DE
27 exposure levels that were also associated with particle overload, implying that a dose adequate to
28 cause tumors was not present. On the other hand, one recent bioassay (Dasenbrock, 1996) has
29 shown by intratracheal instillation that rat tumor yield is decreased (from 17% to 4%) when diesel
30 particulates are stripped of their organics. Overall, limited data make it plausible to assume that
31 there is a gradual release of organics from the particles, with resulting exposure to the respiratory
32 epithelium.
33 Ideally, the dose-response curve that would be used to extrapolate from high to low
34 exposures would reflect changes in the MOAs, a result of the possible transition from primarily
35 nongenotoxic modes of action at high exposures to primarily genotoxic ones at lower exposures.
2/1/98 12-18 DRAFT--DO NOT CITE OR QUOTE