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

10. METABOLISM AND MECHANISM OF ACTION IN DIESEL
EMISSION-INDUCED CARCINOGENESIS
1 Considerable research has been directed toward assessing the carcinogenic potential of
2 diesel engine emissions. As indicated in Chapter 7, whole diesel exhaust (DE) is a pulmonary
3 carcinogen in rats subjected to chronic exposures at high concentrations. This response to date
4 has been clearly demonstrated only in rats, and apparently involves particle overload resulting in
5 inflammation and proliferation of alveolar epithelial cells and subsequ.ent tumor formation.
6 Studies assessing diesel exhaust-induced carcinogenicity in hamsters were negative, and studies
7 in mice were equivocal (depending on the strain). The organic components that are adsorbed to
8 the diesel exhaust particle do not appear to be required for expression of the high-dose
9 tumorigenic response in rats. Positive responses are also observed following exposure to carbon
10 black (CB) and Ti0 2 particles that lack the organic components. The organic components,
11 however, are likely to play a greater role in tumorigenic responses at lower exposure
12 concentrations. In susceptible mouse strains and in humans exposed at low concentrations,
13 genotoxic mechanisms induced by the organic components may even play a predominant role_.
14 Epidemiologic data suggest that there is a small increased cancer risk in humans following long-
15 term. occupational exposure to diesel exhaust. In examining mechanisms of diesel exhaust-
16 induced carcinogenicity, it is necessary to address several areas, including ( 1) the carcinogenic
17 potential of the carbon particle and the partiCle-overload effect, (2) the metabolism and
18 mechanism of action of known carcinogenic components such as benzo[a]pyrene (B[a]P) and
19 various nitroarenes, (3) the role of pulmonary leukocytes, and ( 4) DNA adduct formation in
20 diesel exhaust exposures.
21
22 10.1. PARTICLE-INDUCED CARCINOGENIC RESPONSE
23 DE is. a pulmonary carCinogen in rats chronically exposed to high concentrations
24 (Heinrich et al., 1986; Mauderly et al., 1987). Additional studies (Vostal, 1986; Kawabata et al.,
25 1986; Heinrich, 1990; Wolff et al., 1990; Oberdorster and Yu, 1990) provided data indicating
26 that the carbonaceous core was a major factor in this response. In addition to diesel exhaust
27 particulate matter (DPM), particle-specific pulmonary carcinogenesis in rats has been
28 demonstrated for particles with virtually no adsorbed organics, such as CB (Heinrich et al., 1994,
29 1995; Nikula et al., 1995) and particles with no organic component, such as Ti0 2 (Lee et al.,
30 1985, 1986; Heinrich et al., 1995). Results of studies (see Chapter 7) from both the Inhalation
31 Toxicology Research Institute (Nikula et al., 1995) and the Fraunhofer Institute of Toxicology
32 and Aerosol Research (Heinrich et al., 1995) have affirmed the instrumental role ofthe carbon
33 core in producing a carcinogenic response in rats chronically exposed to high concentrations (>2
2/1198 10-1 DRAFT--DO NOT CITE OR QUOTE