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

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1 U.S. Environmental Protection Agency. (1987) The risk assessment guidelines of 1986. Washington, DC: Office of 2 Health and Environmental Assessment; EPA/600/8-87/045. 211/98 9-10 DRAFT--DO NOT CITE OR QUOTE
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
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DRAFT DO NOT CITE OR QUOTE Health A
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CONTENTS (continued) 2.5.1. Volatil
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CONTENTS (continued) 11.2.1. H.fl.Z
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LIST OF TABLES (continued) 2-14. Me
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PREFACE This draft health assessmen
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AUTHORS, REVIEWERS, AND CONTRIBUTOR
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l. INTRODUCTION 1 Diesel engines ar
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1 achieved by using specific solven
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Nitro-PAH• Table 2-10. Concentrat
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1 pollutants depends on the amount
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1 For the simplest alkoxy radicals,
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1 2 3 4 5 6 7 8 9 10 11 12 13 H ON0
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1 conditions (Pitts et al., 1985c )
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Table 2-14. Mean particle, gas, and
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1 sample collection. There was no b
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1 of downtown Los Angeles (Arey et
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1 exposures. This is a complex ques
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1 Dunstan, TDJ; Mauldin, RF; Jinxia
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1 Lipkea, WH; DeJoode, AD; Christen
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1 Pitts, JN, Jr; Sweetman, JA; Ziel
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1 NOTE TO READERS CHAPTER3 2 Becaus
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1 volume basis (Table 4-1 ). This i
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1 Pritchard (1989), utilizing data
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1 4.3.3.3. Potential Mechanisms for
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1 not accurately reflect the actual
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1 Lee, PS; Chan, TL; Hering, WE. (1
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1 one-half units up to 3, strong (O
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Study Ulfvarson et a!. (1987) Batti
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N -,_. -\0 00 VI N ,_. 0 § I I 0 0
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1 control]). Heinrich et al. (1986a
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1 Heinrich et al. ( 1986a; see also
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1 thoracic area at subsequent times
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1 with matched controls for the num
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----- N \0 00 VI I 0'1 N tJ § I I
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1 In related studies, Navarro et al
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1 Mauderly et al. (1987b) evaluated
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1 pattern of adverse effects on res
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1 DPM concentrations) that resulted
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
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1 Klosterkotter, W; Blinemann, G. (
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1 Misiorowski, RL; Strom, KA; Vosta
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1 Wright, ES. (1986) Effects of sho
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1 Studies showing these effects are
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1 exposure level. In the 0.3 5 mg/m
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1 to derive the RfC. The discussion
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1 The BMC values are the lower 95%
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Table 6-5. Results of benchmark con
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1 U.S. Environmental Protection Age
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1 the latter, 16 were classified as
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
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1 burdens of the NMRI mice after 12
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1 with four to seven rings), which
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1 five daily doses of2,000 f...lg.
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1 occupations. The observed absence
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Page 356: 1 the confined space of a truck cab
Page 364 and 365: 1 The corresponding odds ratios for
Page 370 and 371: 1 Approximately 20,000 miners are e
Page 375 and 376: 1 bladder cancer was found in Canad
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Page 382 and 383: 1 Kaplan, I. (1959) Relationship of
Page 385: 9. MUTAGENICITY 1 Since 1978, more
Page 389 and 390: 1 the presence of heritable translo
Page 391 and 392: 1 9.5. REFERENCES 2 3 "Barfknecht,
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Page 399: 1 inconsequential in rats relative
Page 413: 1 response. cell injury, or cell pr
Page 418: 1 Caution must be exercised in extr
Page 424: 1 Rister, M: Baehner, RL. ( 1977) E
Page 432: 1 The potency of the other diesel e
Page 439 and 440: Table 11-2. Incidence of lung tumor
Page 441: Table 11-5. Unit risk estimates per
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
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1 to reflect the potency of several
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1 Huisingh. J; Bradow, R; Jungers,
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1 particles are fine and ultrafine
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1 are available. Exposure is most o
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1 · some of which can be informed
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1 For example, in a recent meta-ana
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1 nonthreshold-mutagen driven MOA.
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1 that their developing pulmonary a
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1 impacts. Use of these measures re
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2/1198 Appendix A Experimental Prot
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APPENDIX A. EXPERIMENTAL PROTOCOL A
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2/1198 Appendix B Alternative Model
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1 d: Dose of organics, mg/cm 2 of l
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Table B-4. Comparison of observed t
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1 uncertainties below). Based on th
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1 B.lO. RFERENCES 2 3 Bohning D., A
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1 and 2 m.(t) = (y2i - YI/exp[Ap)a/
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1 C.l. INTRODUCTION 2 As discussed
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1 For mouth breathing: 2 (DF)H . =
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TABLE C-1. LUNG MODEL FOR RATS AT T
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TABLE C-3. RATIO OF PULMONARY SURFA
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