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Table 6-3. Results of benchmark concentration analyses using the polynomial model and data from the ITRI study Benchmark Data set, model response MLE BMC Rats Male rat lung weight @ 24 mo 10 0.10 0.08 Polynomial, no threshold Female rat lung weight@ 24 mo 10 0.061 0.05 Polynomial, no threshold Rat BAL macrophages @ 24 mo, M and F combined 50 0.315 0.27 Polynomial, no threshold Rat BAL neutrophils @ 24 mo, M and F combined 200 0.0942 0.06 Polynomial, threshold Rat BAL protein @ 18 mo, M and F combined 100 0.309 0.18 Polynomial, threshold Rat BAL LDH @ 18 mo, M and F combined 100 0.221 0.15 Polynomial, no threshold Rat BAL p-glucuronidase @ 24 mo, M and F combined 100 0.172 0.05 Polynomial, threshold Rat Ga 2 0 3 clearance half-time @ 6 mo, M and F combined 20 0.262 0.15 Polynomial, no threshold Rat Ga 2o 3 clearance half-time@ 12 mo, M and F combined 20 0.168 0.10 Polynomial, no threshold Rat Ga 2 0 3 clearance half-time @ 24 mo, M and F combined 20 0.074 0.04 Polynomial, no threshold Rat Cs-FAP clearance half-time@ 24 mo, M and F combined 20 0.048 0.04 Polynomial, no threshold Rat Cs-F AP clearance, % of initial body burden after 200 days 20 0.044 0.03 Polynomial, no threshold Mice Male mouse lung weight @ 24 mo 10 0.13 0.11 Polynomial, no threshold Female mouse lung weight @ 24 mo 10 0.16 0.13 Polynomial, no threshold Mouse BAL macrophage @ 24 mo, M and F combined 10 Not able to Polynomial, no threshold converge Mouse BAL neutrophils @ 24 mo, M and F combined 200 0.640 0.47 Polynomial, no threshold Mouse BAL protein @ 18 mo, M and F combined 100 0.353 0.27 Polynomial, no threshold Mouse BAL LDH @ 18 mo, M and F combined 100 0.455 0.36 Polynomial, no threshold Mouse BAL P-glucuronidase @ 24 mo, M and F combined 100 0.112 0.11 Polynomial, threshold Source: Henderson et al. (1988) and Wolff et al. (1987). 2/1/98 6-20 DRAFT--DO NOT CITE OR QUOTE
1 The BMC values are the lower 95% confidence limit on the exposure concentration 2 predicted to result in the BMR response level.. All of the responses modeled above were data 3 presented as continuous variables, and the model was used to estimate the exposure predicted to 4 result in a predefined response magnitude, the BMR. Without any other adjustment for the 5 severity of the effect, it is implicit in the BMC approach for continuous data that BMRs are 6 assumed to represent effects of equivalent severity. Clearly, such a comparison is very subjective 7 and cannot be made precisely. Nevertheless, the judgment of the appropriate BMR is 8 fundamental to the application of the BMC approach. 9 The BMCs from the ITRI rat data were calculated using the human equivalent 10 concentration ofthe rat exposures based on the Yu and Yoon (1990) dosimetry model. The 11 NOAEL from the ITRI study was 0.35 mg/m 3 (duration-adjusted NOAEL is 0.074 mg/m 3 ) and 12 the human equivalent NOAEL is 0.042 mg/m 3 • This NOAEL (HEC) is lower than the NOAEL 13 from the Ishinishi et al. study, which was used to derive the RfC because the NOAEL and 14 LOAEL from the ITRI study differed by a factor of 10. The rat NOAEL used to derive the RfC 15 was a NOAEL (HEC) of0.155 mg/m 3 • The BMC values based on rat lung weight were below 16 the NOAEL from Ishinishi et al. (1986), suggesting that the lung weight is a sensitive effect. The 17 sensitivity of the lung weight is consistent with other chronic rat studies as well as those in mice 18 (Heinrich et al., 1995). The bronchoalveolar lavage indicators showed large variability in BMC 19 value, with macrophages, protein, and LDH having BMCs above the range of the rat NOAEL. 20 Lavagable neutrophils and p-glucuronidase, however, were quite sensitive. Measures of particle 21 clearance in rat lungs were also sensitive, resulting in a range ofBMC values between 0.033 and 22 0.146 mg/m 3 • It was noted that there are no BMC estimates based on histopathological effects, 23 even though these effects tend to be sensitive indicators of diesel exposure, because these effects 24 were not reported in an adequately quantitative manner in the various publications describing the 25 ITRi study. 26 The BMC levels based on mouse data from the ITRI study also showed a wide range, 27 with lung weight and lavage p-glucuronidase being the most sensitive. The mouse BMCs were 28 calculated using the duration-averaged exposure concentration as the dose term, so the 29 appropriate NOAEL for comparison is the duration-adjusted NOAEL from the ITRI study, which 30 was 0.074 mg/m 3 • The duration-averaged LOAEL for the same study is 0.723 mg/m 3 • All mouse 31 BMC values from the ITRI study fall between the NOAEL (HEC) and the LOAEL (HEC). 32 The basis for the RfC was the NOAEL (HEC) in the Ishinishi study, which was 0.155 33 mg/m 3 . This NOAEL (HEC) was selected because it was lower than the valid LOAELs in rats 34 from all studies considered and higher than the other NOAEL (HEC) values. The only data in 2/1/98 6-21 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
Page 201: 1 In related studies, Navarro et al
Page 210: 1 Mauderly et al. (1987b) evaluated
Page 216 and 217: 1 pattern of adverse effects on res
Page 218: 1 DPM concentrations) that resulted
Page 221: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Page 226 and 227: 1 Klosterkotter, W; Blinemann, G. (
Page 228 and 229: 1 Misiorowski, RL; Strom, KA; Vosta
Page 232: 1 Wright, ES. (1986) Effects of sho
Page 235: 1 Studies showing these effects are
Page 238: 1 exposure level. In the 0.3 5 mg/m
Page 251: 1 to derive the RfC. The discussion
Page 255: Table 6-5. Results of benchmark con
Page 262: 1 U.S. Environmental Protection Age
Page 274 and 275: 1 the latter, 16 were classified as
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Page 282: 1 burdens of the NMRI mice after 12
Page 289: 1 with four to seven rings), which
Page 298: 1 five daily doses of2,000 f...lg.
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1 occupations. The observed absence
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1 occupations). Analysis was conduc
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1 the confined space of a truck cab
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1 The corresponding odds ratios for
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1 Approximately 20,000 miners are e
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1 bladder cancer was found in Canad
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
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1 Kaplan, I. (1959) Relationship of
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9. MUTAGENICITY 1 Since 1978, more
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1 the presence of heritable translo
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1 9.5. REFERENCES 2 3 "Barfknecht,
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1 U.S. Environmental Protection Age
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
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1 inconsequential in rats relative
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1 response. cell injury, or cell pr
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1 Caution must be exercised in extr
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1 Rister, M: Baehner, RL. ( 1977) E
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1 The potency of the other diesel e
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Table 11-2. Incidence of lung tumor
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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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