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

1 nonthreshold-mutagen driven MOA. If particle effects are assumed at all concentrations, i.e., no
2 threshold for particle effects, then the model predicts risk virtually identical to those predicted by
3 the linearized multistage model. If a threshold for particle-induced cancer effects is assumed at
4 1,000 J.l.g/m 3 , the BBDR risk estimate is about fivefold lower at a concentration of 1 J.l.g/m 3 . This
5 difference is consistent with the hypothesis that organics and oxygen radicals play a more
6 important role as concentration becomes lower. The results, however, only suggest the influence
7 of mutagenic-nonthreshold versus mutagenic-threshold modes of action, because data are
8 insufficient to validate the model.
9 There is also some debate, and hence uncertainty, regarding the biological adequacy of the
1 0 rat as a model for evaluating any human risk. This begs the question whether rats may be
11 . uniquely sensitive to particle:..induced cancer, perhaps because of their different respiratory tract
12 anatomy. Only two other rodent species have been adequately tested, hamsters and mice. The
13 response in mice was equivocal, and negative in hamsters. Hamsters, which do not respond to DE
14 exposure, are resistant to induction oflung cancer from DE. Since there is evidence for human
15 carcinogenicity of DE in epidemiologic studies, one could argue that the rat may be more
16 qualitatively similar to humans in response to this agent than are the other laboratory species. .
17 Furthermore, rats have been shown to respond similarly to humans when exposed to cigarette
18 smoke {Finch et al., 1995). Although the rat could be more sensitive from a particle standpoint,
19 we wouldn't necessarily say the same in regard to the organic components, which are playing a
20 role as well. Thus, while the use of rat data does involve uncertainty, it is not justifiable to fully
21 discount the rat as a plausible model for establishing a range of possible human risk from
22 exposure to DE.
23 A strength of rat-based risk estimates is that the studies are of good quality and provide
24 tumor responses that are in essential agreement with one another. Another strength is the ability
25 to use a sophisticated dosimetry model to derive equivalent target tissue concentrations between
26 rats and humans. However, with all statistically significant rat responses occurring at exposures
27 where particle overload is also occurring, the use of rat data to define possible risk in any manner
28 has distinct shortcomings and resulting uncertainties. For reference purposes, an LMS-derived
29 averaged risk estimate of 3.4 x 1 o-s per J.l.g/m 3 was calculated from the high-dose rat responses of
30 Mauderly, Ishinishi, and Brightwell. Use of measured rather than modeled lung particle burdens
31 from the Mauderly et al. (1987) study did not significantly affect results. As a matter of curiosity,
32 if dose equivalence is based on lung burden per unit body weight 31 \ a more traditional means of
33 species extrapolation for organics, LMS risk estimates would increase about threefold.
;34 As it turns out, all of the rat-based risk estimates are near the low end of estimated risks.
35
2/1/98 12-24 DRAFT --DO NOT CITE OR QUOTE