Cambridge Environmental Inc 58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com



### Technical Comments on the

Primary National Ambient Air Qu ality Standard for Sulfur Dioxide. Proposed Rule

Docket No. EPA-HQ-OAR-2007-0352

by

Edmund A.C. Crouch, Ph.D. and Laura C. Green, Ph.D., D.A.B.T.

Cambridge Environmental Inc. Cambridge, Massachusetts

February 8, 2010 (Docket N o. EPA-HQ-OAR-2007-0352-1061.1)

Corrected April 6, 2010

Note: Correction of an error in one spreadshee t results in a minor change in the numbers calculated in this anal ysis, specifically inTable 4, Table 5 and Table 6. This update contains corrected entries and corrected embedded sp readsheets (“sRaw_analysis_final 2.xls” and “Exposure distributions 2.xls” have been corrected). The error was in “sRaw_analysis_final 2.xls” at DR-Analysis!AG13:AJ35, where the formul ae used the exposure concentrations in DRAnalysis!AG38:AJ38 in place of the correct ones at DR-Analysis!AG12:AJ12. In addition, the paragraphs on page 24 describing th e factors by which the EPA anal ysis is in error have been corrected to show the full ranges.Cambridge Environmental Inc Page 2

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com 

### Table of Contents

1. Executive summary........................................................................................................... .......... 3 2. Introduction................................................................................................................ ................. 4 3. The independence assumption is untenable................................................................................ 5 4. The Agency miscalculated the total number of effects............................................................... 7 5. Failure to incorporate correc tions and additional data.............................................................. 15 6. Updated calculations........................................................................................................ ......... 15 6.1. Short-period constancy of E 100 evaluations ....................................................................... 16 6.2. Independence of E 100 evaluations over long periods ......................................................... 17 6.3. Evaluation of population E 100 distribution......................................................................... 18 7. Effect of the Final REA errors on estimation of population effects ......................................... 21 8. The RIA substantially underest imates the uncertainty in hospital admissions due to SO 2 ...... 25 9. The RIA co-benefits assessment is based entirely on an incorrect assumption........................ 26 10. Erratum .................................................................................................................... ............... 29 11. Addendum................................................................................................................... ............ 29 12. Acknowledgement ............................................................................................................ ...... 30 13. References................................................................................................................. .............. 30 14. Appendix: Calculations..................................................................................................... ...... 32Cambridge Environmental Inc Page 3

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com 1. Executive summary The Proposed Rule relies heavily on the Final RE A. However, the Final REA provides estimates of potential health effect s that are completely unreliable and not scientifically based. In Section 3 we show that the fundamental assumption used in the Final REA to evaluate experimental data is incorrect. Under that assu mption, the probability for the patte rns seen in the subset of experimental data used in the Final REA is less than 1 in 10, 000,000, and considering all available experimental data th e probability for the patterns is less than 2 in 1,000,000,000. Such probabilities are so low that the assumption must be rejected. Even were the assumptions of the Final REA correct, the Final REA adds up the numb ers incorrectly. In Section 4 we demonstrate the resultant substantial errors, using more detaile d information from the computer runs used in the Final REA. Section 5 points out that the Fi nal REA failed to take account of known errors in data entry, and failed to incorporate all availabl e data. In Section 6 we update our previous demonstration of calculations usi ng a correct basic assumption about the experimental data. In Section 7 we provide a corrected accounting for th e case of transient exercise-adjusted relative sRaw increments of 100%. The bottom lines fo r number of events with this end point, taking account of both the incorrect assumptions and in correct summations of the Final REA, are (see Table 5 and Table 6):

Scenario
As Is CS 99/50 99/100 99/150 99/200 99/250 98/200 Greene County Logistic
Final REA 12500 12700 12500 12500 12500 12600 12600 12600
Best estimate of corrected results 1 49 0.1 1 5 11 22 18 Green County Probit
Final REA 1600 1800 1600 1600 1600 1600 1700 1700
Best estimate of corrected results 0.4 30 0.03 0.5 2 6 12 10 St. Louis Logistic
Final REA 65700 167200 65200 68600 76200 88000 103600 99700
Best estimate of corrected results 103 27867 47 458 1649 3968 7677 6721 St Louis Probit
Final REA 9000 93300 8600 11100 17000 26400 39200 36000
Best estimate of corrected results 25 21577 9 175 844 2381 5094 4376

Our calculations indicate that the probit model is approximately twice as likely as the logistic, based solely on the experimental data. Fina lly, although the Proposed Rule takes no account of the RIA, we argue in Sections 8 and 9 that th e RIA calculations are substantially overconfident or just plain wrong.Cambridge Environmental Inc Page 4

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com 2. Introduction These comments are directed at the Proposed Ru le for the Primary National Ambient Air Quality Standard for Sulfur Dioxide (“Pr oposed Rule”), insofar as that pr oposed rule relies on the “Risk and Exposure Assessment to S upport the Review of the SO 2 Primary National Ambient Air Quality Standards: Final Report” (EPA -452/R-09-007, July 2009, EPA-HQ-OAR-2007-0352- 0033), hereinafter “Final REA.” A second draft ve rsion of the REA was previously entered in the Docket as EPA-HQ-2007-0352-0016 (“Draft REA”).

The Proposed Rule relies heavily on the Final REA, and in particular it reli es to a large extent on the numerical estimates of the number and frac tion of asthmatics who might suffer an event consisting of a measurable transient decrement in lung function due to SO 2 exposure. For the reasons given here, the REA does not provide reliabl e or scientifically justifiable estimates for these numbers or fractions. Because of the e rrors that we have identified, the Final REA overestimates the numbers of such lung function decrements by about a factor varying from 5 to 69,000, and hence also the fraction of asthmatics potentially experienci ng such events by the same factor.

We provided technical comments on the Draft RE A and entered them in the Docket at EPA-HQOAR-2007-0352-0031.1, Attachment 1 (“Our Comments”). We specifically commented on, inter alia :

• Errors in data entry,

• Failure to incorporate all available data,

• The independence assumption underlying EPA’s an alysis of raw data on the effects of SO 2 on sRaw, and

• A miscalculation that we identified in EPA’ s summing up of the total number of effects.

and we provided corrected estimates for the tota l numbers of potential events where exercising asthmatic individuals might experience increments in exercise-corrected sRaw of more than 100% (see Our Comments for definitions of terms).

Since those original technical comments, new copi es of some of the handwritten raw data have been entered in the Docket, including individual data on an additional experiment (Linn et al
., 1983). In another Docket, (EPA- HQ-ORD-2006-0260-0036 and 0036.1 through 0036.5), EPA has now substantially improved the data entry (mi nor remaining errors that we identified in a subset of these data are given in another entry in this docket), confirmed the data entry errors we previously pointed out, and entered some of the new individual data in machine readable form.

The Final REA, however, does not respond in any meaningful way to Our Comments, which we therefore incorporate here by reference to appl y to the Final REA and to the Proposed Rule which relies on the Final REA. We also he re augment those comments and provide some stronger arguments, based on material available to EPA prior to the Draft REA and now in the Docket. We further provide some comments on the Regulatory Impact Assessment (“RIA”)Cambridge Environmental Inc Page 5

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com included in the Docket at EPA-HQ- OAR-2007-0352-0048 and 0048.1 through 0048.8), although we recognize that the RIA was not us ed in developing the Proposed Rule.

3. The independence assumption is untenable In Our Comments (Section 3, “Theoretical c onsiderations”) we pointed out that the independence assumption 1 that is the basis for the analys is methodology used in the Draft and Final REA (in Appendix C) denies the existence of individual exposure-response curves that apply across different exposures in the experiments evaluate d. We subsequently, however, demonstrated consistent dose-response cu rves between the two rounds of the Linn et al. (1987) experiment. The independence assumption of the Final REA necessarily denies the validity of the dose-response curves published by Horstman et al . (1986) 2 and featured prominently on the cover page of EPA’s 1986 Staff Paper (EPA 1986). It would also necessarily deny the validity of the published distribution of E 100 values 3 that Horstman et al . (1986) derived from those doseresponse curves, which distribution is prominen tly displayed on the cover page of the EPA 1994 Staff Paper (EPA, 1994). The approach we took fo r analysis of the experimental data in Our Comments corresponds closely wi th that published by Horstman et al . (1986); we just augmented the technical approach to provide uncertainty estima tes also. These factors alone should be sufficient to reject the independence assumption.

Quite independently, we may examine the data th emselves to see whether they are consistent with an independence hypothesis. Consider the case where the same set of individuals (numbering N ) is exposed at different times to two different concentrations of SO 2 , with R 1 responding at one dose and R 2 at the second dose, where R 2 ≥ R 1 (interchange the doses if necessary so that this is true). 4 The responders at the second dose define a partition of the N individuals into tw o groups of size R 2 and N

−

R 2 . Now partition the res ponders to the first dose into s 1 who also responded to the second and s 2 who did not, with s 1 + s 2 = R 1 . Under the independence hypothesis, the proportion of respo nders to the first dose who fall into the responder/non-responder groups at the second do se should simply be in proportion to the numbers in those responder/non- responder groups at th e second dose. The probability for any particular pattern for s 1 & s 2 can thus be simply obtained by a counting argument, and in particular, the probability for a contrast as extreme or more extreme than the observed s 1 / R 2
versus s 2 /( N

−

R 2 ) can be obtained by such a counting argumen t. Indeed, this is just the counting argument required for the Fisher Exact test. 5 Alternative hypotheses, su ch as the existence of individual dose-response relationships , lead to extreme contrasts. In that case a responder at one

1 REA, Appendix C, page 3-5, “... we assumed a single response probability (for a give n definition of response) for all individuals and treated the repeated exposures for a single subject as independent exposures in the binomial distribution.”
2 We incorporated the data used by Horstman et al. (1986) in our analysis; they are primarily those from Roger et al. (1985), but also include data at 2 ppm that were omitted in the latter paper. 3 See Our Comments for notation. The PC(SO 2 ) values defined by Horstman et al. (1986) correspond to what we call E 100 , the exposure causing 100% increase in exercise-adjusted relative sRaw.
4 The precise definition of “response” is not needed for this argument, which applies to any well-defined response.
5 The contrasts to be examined are all those of n 1 / R 2 versus n 2 /( N

−

R 2 ) subject to R 2 ≥ n 1 ≥ s 1 , N

−

R 2 ≥ n 2 ≥ 0 with fixed

n 1 + n 2 = s 1 + s 2 = R 1 , R 2 , and N

.Cambridge Environmental Inc Page 6

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com dose should also respond at a high er dose, so that the contrast observed should be extreme — all responders at one dose will also respond at the higher dose (although introduction of variability may reduce the contrast).

As an example, compare the 0.4 ppm and 0.6 ppm doses in round 1 of Linn et al . (1987). There were 40 subjects tested, of wh om 10 at 0.4 ppm and 14 at 0.6 ppm responded with exerciseadjusted relative sRaw increments greater than 100% (the “response”). Of the 10 at 0.4 ppm who responded, 9 also responded at 0.6 ppm. So the contrast here is 9/14 versus 1/26. The probability (under the independence hypothesis) for su ch a contrast or one even more extreme is 6.26 × 10 − 5 (there is only one more extreme contrast in this case, 10/14 ve rsus 0/26). Thus, based solely on round 1 of the Linn et al. (1987) experiment, it is possible to reject the independence hypothesis with very high confidence.

Applying the same analysis to all the dose-response experiment s available gives the results shown in Table 1. 6 Individual experiments (as reported in different papers) on different subjects are independent of one another; and under the independence hypothesis so are the repeated exposures (at different concentrations) on the same subjects within each experiment. The probabilities for all independent contrasts may t hus be multiplied to obtain the overall probability (under the independence hypothesis) for patterns as extreme or more extreme than observed for all experiments combined. For those experime nts included in the Final REA (“Omit L83 and L87 Round 2” in Table 1) this probability is 2.26 × 10 − 8 . Incorporating all available experiments (“Overall” in Table 1), it is 1.12 × 10 − 12 . The independence hypothesis is thus rejected with virtual certainty; the data them selves are not consistent with the independence hypothesis as used in the Draft REA and the Final REA.

Analysis of the experiments as though the obs ervations corresponded to “independent exposures in the binomial distribution” (Final REA, Appendix C, page 3-5) thus has to be rejected in favor of an analysis that can account for the non-indepe ndence. We demonstrated such an analysis in Our Comments (and update it in Section 6, belo w), where we showed that the result is a substantially steeper estimate for the slope of the resulting populat ion distribution for E 100 (the exposure causing 100% increment in exercise-corrected relative sR aw) than obtained in the Draft REA and Final REA. Similar results can be expected for other increments in sRaw, and in decrements in FEV 1 .

6 See sheet “Independence assumption” in workbook “Table 3-1 Analyses 2.xls” (see Section 14).Cambridge Environmental Inc Page 7

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com Table 1 Probabilities evalua ted under the independence hypothes is for observed patterns of response in dose-response experiments (L = Linn et al. , R = Roger et al ., 85 = 1985 etc.). Experiment Contrast Probability L83 0.2 ppm vs. 0.4 ppm 1.00E+00 a L83 0.4 ppm vs. 0.6 ppm 4.74E-02 R85 0.25 ppm vs. 0.5 ppm 1.00E+00 a R85 0.5 ppm vs. 1 ppm 4.07E-02 L87 Round 1 0.2 ppm vs 0.4 ppm 5.77E-02 L87 Round 1 0.4 ppm vs. 0.6 ppm 6.26E-05 L88 0.3 ppm vs. 0.6 ppm 3.47E-01 L90 0.3 ppm vs. 0.6 ppm 4.43E-01 L87 Round 2 0.2 ppm vs. 0.4 ppm 2.56E-01 L87 Round 2 0.4 ppm vs. 0.6 ppm 6.48E-03
Overall 1.78E-12
Omit L83 & L87 Round 2 2.26E-08

a In the implementation of the Fisher Ex act test used for these calculations any case with s 1 / R 2 ≤ s 2 /( N

−

R 2 ) was assigned probability 1. This results in a slight overestimate for the overall probability.

4. The Agency miscalculated the total number of effects We pointed out in Our Comments (Section 5.2, “Overcount due to in appropriate binning”) that if the distribution of exposure concentrations was cl ose to lognormal, as appeared plausible from previous experience, from examinat ion of distributions of actual SO 2 measurements available to us, and from the information provided in the Dr aft REA, then the calculation method illustrated in Table 3-2 of Appendix C of both the Draft RE A and the Final REA (and in Table 9-2 of the main text in both cases) results in a substantial overestimate of the numbers of events. We now demonstrate conclusively, using th e more detailed results of the APEX calculations used in the Draft REA and Final REA, that such overcounts definitely occur. 7

Section 8.8.3 of the Final REA de scribes the adjustments made to estimate and model air quality (SO 2 concentrations) for the various alternative scenarios examin ed. The assumption made is that the time pattern of relative SO 2 concentrations is invariant and corresponds to the modeling performed for the “As is” scenario, only the abso lute concentration changing between scenarios. The APEX modeling was therefore performed only once (for each of the four areas included in the examples; Greene County is treated as a single area, St. Louis as three areas, with the three

7 The results described in this Section may be found in the workbook “Exposure distributions 2.xls” (see Section 14).Cambridge Environmental Inc Page 8

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com area results combined to provide the values show n in the Final REA) to estimate exposures, and the different scenarios obtained by scaling the concentration in the resultant exposure distributions. In practice, this meant that to obtain fixed bin sizes of multiples of 50 ppb for the different scenarios (as was the aim), a larger se t of bins was used in the single APEX modeling run — Table 8-14 of the Final REA shows the bin edge concentrations used to correspond to multiples of 50 ppb in all the examined scenarios.

As a result, the APEX model 8 was actually run with more bin e dges even than indicated in Table 8-14 of the Final REA — for Greene County, APEX was run with bin edges of 0, 14.4, 16.2, 18.9, 20.3, 23.6, 27, 28.8, 31.4, 32.4, 37.7, 40.5, 43.2, 47.2, 48.6, 50, 54, 56.6, 57.6, 60.8, 62.9, 64.8, 70.8, 72, 75.5, 81, 86.4, 94.3, 97.2, 100, 100.8, 101.3, 108, 113.2, 113.4, 115.2, 117.9, 121.5, 125.8, 129.6, 132.1, 135, 141.5, 141.8, 144, 145.8, 150, 150.9, 157.2, 158.3, 162, 165.1, 169.8, 172.7, 178.2, 182.3, 187.1, 188.7, 189, 194.4, 200, 201.5, 202.5, 207.5, 210.6, 212.3, 215.9, 216, 220.1, 222.8, 226.4, 226.8, 230.3, 235.8, 243, 245.3, 250, 251.6, 259.2, 259.4, 263.3, 264.1, 270, 283, 283.5, 297, 300, 301.9, 303.8, 306.6, 314.4, 324, 330.2, 345.9, 350, 351, 353.8, 364.5, 377.3, 378, 400, 405, 408.8, 424.5, 432, 440.2, 445.5, 450, 471.7, 486, 500, 503.1, 518.8, 526.5, 550, 566, 567, 600, 607.5, 613.2, 648, 650, 660.3, 700, 707.5, 729, 750, 754.7, 800, 810, 849, 891, 943.3, 972, 1037.7, 1053, 1132, 1134, 1215, 1226.3, 1296, 1320.7, 1415, and 1509.3 ppb, while for St. Louis APEX was run with bin edges of 0, 8, 10.6, 12.7, 13.3, 15.8, 16, 17.7, 21.1, 21.2, 24, 25.3, 26.5, 31.7, 31.8, 32, 35.3, 38, 39.8, 40, 42.2, 42.4, 47.5, 48, 50, 50.7, 53, 56, 63.3, 63.6, 64, 66.3, 70.7, 72, 74.2, 76, 79.2, 79.5, 80, 84.4, 84.8, 88, 88.3, 88.7, 92.8, 95, 95.4, 96, 100, 101.3, 104, 105.6, 106, 110.8, 112, 114, 116.6, 119.3, 120, 123.7, 126.7, 127.2, 128, 132.5, 137.8, 139.3, 141.3, 142.5, 145.8, 147.8, 148.4, 150, 152, 158.3, 159, 164.7, 168.9, 169.6, 172.3, 174.2, 176.7, 177.3, 185.5, 190, 194.3, 198.8, 200, 202.7, 205.8, 211.1, 212, 221.7, 229.7, 232.2, 237.5, 238.5, 247.3, 250, 253.3, 265, 274.4, 282.7, 285, 291.5, 295.6, 300, 316.7, 318, 337.8, 344.5, 348.3, 350, 371, 380, 397.5, 400, 411.7, 424, 443.3, 450, 475, 477, 500, 506.7, 530, 550, 570, 583, 600, 633.3, 636, 650, 689, 696.7, 700, 742, 750, 760, 795, 800, 823.3, 848, 886.7, 950, and 1013.3 ppb. These values may be confirme d in the control file s for the APEX model runs (from which they were copied), and in the corresponding output files.

It is therefore possible to use al l these bins to calculate numbers of events in every scenario, rather than summing up the relevant bins to examine just bins corresponding to 50 ppb multiples in each particular scenario before calculating the numbers of events. We provide in this document the example that corresponds exactly to Table 3-2 of Appendix C of the Final REA (Table 9-2 of the main text). 9 Table 2 duplicates Table 9-2 of the Final REA, but with no

8 The APEX model and all input and output files were provided by EPA upon request. In our opinion these model files should have been provided either in the Docket or readily available on the EPA web site. The APEX model used is not that available on EPA’s web site, but is a modified version. We do not have the time or budget available for review of the model or its modifications. 9 This example calculation is in the worksheet “St. L ouis” in workbook “Exposure distributions 2.xls.” The corresponding calculations for Table 4-1 of Appendix C of the Final REA are included in the workbook “Exposure distributions 2.xls” in worksheets “Gre ene” and “St. Louis” (see Section 7 fo r summary results, and Section 14 for the workbook).Cambridge Environmental Inc Page 9

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com rounding of the output of APEX 10 and, as in Table 9-2 of the REA, summing results of APEX into the bins shown (50 ppb multiples) prio r to calculating the number of events. 11 Table 3 shows exactly the same results, but maintaining a ll the bins calculated in APEX, as adjusted for this scenario (it is the 99/100 scenario for St. Louis; for th is scenario the Final REA assumes that the ambient concentration would be 1.579 times that estimated for the “as is” scenario 12 ).

Table 2 Duplication of Table 9-2 of the Final REA, using exact output of the APEX model (no rounding). SO2 Exposure Bin (ppb) Lower Bound Upper Bound Midpoint Number o f Exposures Probability of Response at Midpoint SO 2 Level Expected Number of Occurrences of Lung

Function Response
0 50 25 16519000 0.00406 67067.1 50 100 75 136621 0.02334 3188.7 100 150 125 15760 0.05162 813.5 150 200 175 3825.5 0.08563 327.6 200 250 225 1051.4 0.123 129.3 250 300 275 413.8 0.1622 67.1 300 350 325 175.97 0.2021 35.6 350 400 375 83.54 0.2419 20.2 400 450 425 30.622 0.2806 8.6 450 500 475 23.024 0.3183 7.3 500 550 525 7.549 0.3543 2.7 550 600 575 0 0.3885 0.0 600 650 625 0 0.4209 0.0 650 700 675 7.595 0.4515 3.4 700 750 725 0 0.466 0.0 750 800 775 0 0.4938 0.0 Total number of exposures 16677000 Expected number of occurrences 71671.2

10 It is strictly incorrect to round the results from APEX, as was done in the Final REA, before doing subsequent calculations. However, the errors involved are small.
11 The calculation of the number of events involves approximating the exposure for each bin as being the concentration at the center of the bin; this is where the problem arises.
12 The concentration multipliers derived from Table 8-14 of the Final REA for the various scenarios are shown in worksheet “Factors” of workbook “Exposure distributions 2.xls” (see Section 14).Cambridge Environmental Inc Page 10

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com Table 3 Re-evaluation of Table 9-2 of the Final REA, using all availa ble bins in the output of the APEX model (no rounding; the e xposure range is truncated afte r the last non-zero number of exposures).

SO2 Exposure Bin (ppb) Probability of Response at Midpoint SO 2 Level Expected Number of Occurrences of Lung

Function Response Lower Bound Upper Bound Midpoint Number o f Exposures

0.0 12.6 6.3 13787600 0.0004446 6130.3 12.6 16.7 14.7 1088100 0.001728 1879.8 16.7 20.1 18.4 525300 0.002481 1303.4 20.1 21.0 20.5 116100 0.002959 343.5 21.0 24.9 23.0 346200 0.003545 1227.3 24.9 25.3 25.1 20700 0.004087 84.6 25.3 27.9 26.6 155000 0.004486 695.3 27.9 33.3 30.6 208600 0.005622 1172.8 33.3 33.5 33.4 4600 0.006456 29.7 33.5 37.9 35.7 108400 0.007178 778.1 37.9 39.9 38.9 37850 0.008246 312.1 39.9 41.8 40.9 29060 0.008924 259.3 41.8 50.1 45.9 91490 0.01074 983.1 50.1 50.2 50.1 1340 0.01234 16.5 50.2 50.5 50.4 2670 0.01244 33.2 50.5 55.7 53.1 35560 0.01354 481.4 55.7 60.0 57.9 21040 0.01550 326.2 60.0 62.8 61.4 11480 0.01704 195.6 62.8 63.2 63.0 1370 0.01774 24.3 63.2 66.6 64.9 11540 0.01859 214.5 66.6 66.9 66.8 980 0.01945 19.1 66.9 75.0 71.0 20750 0.02141 444.2 75.0 75.8 75.4 1830 0.02354 43.1 75.8 78.9 77.4 5340 0.02452 130.9 78.9 80.1 79.5 1770 0.02559 45.3 80.1 83.7 81.9 5270 0.02679 141.2 83.7 88.4 86.1 5360 0.02897 155.3Cambridge Environmental Inc Page 11

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com 88.4 99.9 94.2 10321 0.03335 344.2 99.9 100.4 100.2 291 0.03671 10.7 100.4 101.1 100.7 369 0.03702 13.7 101.1 104.7 102.9 2221 0.03824 84.9 104.7 111.6 108.2 3388 0.04133 140.0 111.6 113.7 112.7 868 0.04401 38.2 113.7 117.2 115.4 1347 0.04568 61.5 117.2 120.0 118.6 858 0.04761 40.8 120.0 125.1 122.5 1610 0.05006 80.6 125.1 125.5 125.3 123 0.05179 6.4 125.5 126.3 125.9 244 0.05219 12.7 126.3 133.3 129.8 1657 0.05466 90.6 133.3 133.9 133.6 146 0.05710 8.3 133.9 138.9 136.4 1028 0.05895 60.6 138.9 139.4 139.2 62 0.06077 3.8 139.4 140.1 139.7 106 0.06114 6.5 140.1 146.5 143.3 1020 0.06350 64.8 146.5 150.0 148.3 422 0.06684 28.2 150.0 150.6 150.3 107 0.06824 7.3 150.6 151.6 151.1 169 0.06878 11.6 151.6 157.9 154.7 712 0.07127 50.7 157.9 159.9 158.9 215 0.07416 15.9 159.9 164.2 162.1 444 0.07637 33.9 164.2 166.7 165.5 155 0.07876 12.2 166.7 167.4 167.1 45 0.07987 3.6 167.4 174.9 171.2 574 0.08279 47.5 174.9 176.8 175.9 99.4 0.08619 8.6 176.8 180.0 178.4 255.3 0.08802 22.5 180.0 184.1 182.1 276.1 0.09066 25.0 184.1 188.4 186.2 268.6 0.09372 25.2 188.4 189.5 188.9 45.8 0.09570 4.4 189.5 195.3 192.4 230.4 0.09827 22.6 195.3 200.1 197.7 228.9 0.1022 23.4 200.1 200.8 200.5 15.3 0.1043 1.6 200.8 202.1 201.5 31.5 0.1050 3.3Cambridge Environmental Inc Page 12

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com 202.1 209.2 205.7 208 0.1082 22.5 209.2 217.6 213.4 213.5 0.1141 24.4 217.6 220.0 218.8 38.7 0.1182 4.6 220.0 223.1 221.5 91.5 0.1203 11.0 223.1 225.0 224.1 15.5 0.1222 1.9 225.0 230.2 227.6 144.9 0.1250 18.1 230.2 233.4 231.8 76.5 0.1282 9.8 233.4 234.3 233.8 23 0.1298 3.0 234.3 236.8 235.6 38.7 0.1312 5.1 236.8 240.0 238.4 38.5 0.1334 5.1 240.0 250.0 245.0 115.8 0.1385 16.0 250.0 251.1 250.5 0 0.1429 0.0 251.1 260.1 255.6 99.1 0.1468 14.6 260.1 266.7 263.4 61 0.1530 9.3 266.7 267.8 267.2 23.6 0.1561 3.7 267.8 272.1 269.9 46 0.1582 7.3 272.1 275.1 273.6 54.17 0.1611 8.7 275.1 279.0 277.0 23.08 0.1639 3.8 279.0 280.0 279.5 0 0.1658 0.0 280.0 292.9 286.4 91.37 0.1714 15.7 292.9 300.0 296.5 15.48 0.1794 2.8 300.0 306.8 303.4 30.36 0.1849 5.6 306.8 313.9 310.3 46.33 0.1905 8.8 313.9 315.8 314.8 7.5 0.1941 1.5 315.8 320.1 317.9 0 0.1966 0.0 320.1 325.0 322.5 15.44 0.2002 3.1 325.0 333.3 329.1 30.29 0.2055 6.2 333.3 334.7 334.0 0 0.2094 0.0 334.7 350.1 342.4 46.05 0.2161 10.0 350.1 362.7 356.4 15.14 0.2272 3.4 362.7 366.6 364.7 7.55 0.2338 1.8 366.6 375.0 370.8 23.02 0.2386 5.5 375.0 376.6 375.8 7.59 0.2426 1.8 376.6 390.5 383.5 7.54 0.2486 1.9 390.5 394.7 392.6 22.7 0.2557 5.8Cambridge Environmental Inc Page 13

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com 394.7 400.0 397.3 0 0.2594 0.0 400.0 418.4 409.2 23.022 0.2686 6.2 418.4 433.3 425.8 7.6 0.2814 2.1 433.3 446.4 439.8 0 0.2921 0.0 446.4 450.0 448.2 0 0.2984 0.0 450.0 460.3 455.1 7.551 0.3036 2.3 460.3 466.7 463.5 7.878 0.3098 2.4 466.7 473.7 470.2 0 0.3148 0.0 473.7 500.1 486.9 7.595 0.3270 2.5 500.1 502.1 501.1 0 0.3373 0.0 502.1 533.4 517.7 7.549 0.3492 2.6 533.4 544.0 538.7 0 0.3638 0.0 544.0 550.0 547.0 0 0.3695 0.0 550.0 552.6 551.3 0 0.3725 0.0 552.6 585.8 569.2 0 0.3846 0.0 585.8 600.0 592.9 0 0.4002 0.0 600.0 627.6 613.8 0 0.4137 0.0 627.6 631.6 629.6 0 0.4237 0.0 631.6 650.1 640.8 0 0.4306 0.0 650.1 669.5 659.8 7.595 0.4422 3.4 669.5 700.0 684.7 0 0.4570 0.0 700.0 710.5 705.2 0 0.4688 0.0 Total number of exposures 16677000 Expected number of occurrences 19150.2

To obtain Table 3 we had to estimate the proba bility corresponding to each bin. We used a logistic curve that matched the values used in Table 2. 13 That logistic has parameters β

=

− 0.43724377, γ =

− 1.610183412 (using the notation of Appendi x C of the Final REA, with concentrations expressed in ppm).

13 See workbook “Fit_EPA_curves,” Section 14. Strictly, the probabilities may not be from a single logistic, since the values used in Table 3-2 of Appendix C of the Final REA are supposed to be the mean values from a probability distribution. However, the deviation from a single logistic are smaller than the uncertainties involved in estimating the mean values for Table 3-2 of Appendix C of the Final REA. As explained in Footnote 13 of Post and Mahoney (2009), the values shown in Table 3-2 differ slightly from those given in Table 4-1 of Appendix C of the Final REA because mean values were re-calculated after Table 3-2 was constructed, and th e difference is supposedly due to the uncertainties of calculation. The majo r difference, however (although not mentioned in Post and Mahoney, 2009), arises because Table 4-1 uses the median estimate not the mean estimate. Nevertheless, all these differences are small compared with the errors we are pointing out.Cambridge Environmental Inc Page 14

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com As can be seen, the calculation in Table 2 yiel ds an estimate (rounded) of 71,700 occurrences, in agreement with Table 9-2 of the Final REA, wh ereas the more accurate calculation of Table 3 yields an estimate of 19,150 occurrences, a fact or 3.74 difference. This was entirely to be expected based on the discussion in Our Commen ts. Examination of Table 2 and Table 3 shows that the overestimate in the former occurs becaus e of the assignation of a concentration of 25 ppb to most of the exposures (those in the lowest bin, from 0 to 50 ppb), whereas in fact most of the exposures in the first 50 ppb bi n are at concentrations much lower than 25 ppb. The same problem occurs with all the calcu lations of expected numbers of occurrences in the Final REA, and occurs even assuming everything else in the Final REA is correct (see Section 7 for the results of corresponding calculati ons for Table 4-1 of Appendix C of the Final REA). And the same problem can be expected to affect the cal culations of other end points in the Final REA (200% increment in exercise-adj usted relative sR aw, and the FEV 1 -related end points).

The most detailed results from APEX demons trate that the number of exposures versus concentration follows a distributi on that is almost exactly lognor mal over the range that can be examined (Figure 1 shows the distribution for St . Louis; Greene County is shown in Figure 6).

0 0.5

1 1.5

2 2.5

3 3.5

4 4.5

5

234567 ln(concentration/ppb)Normal ordinate

Figure 1 Cumulative distributi on of number of exposures ve rsus natural logarithm of concentration for St. Louis — APEX estimates. The dotted line is a lognormal distribution fitted to these results.Cambridge Environmental Inc Page 15

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com If this distribution continues to lower exposures , as we consider highly likely, then even the calculation shown in Table 3 sli ghtly overestimates the number of events in the lowest bin — assuming a perfect lognormal distribution (a fit to this distribution gives it a median of 3.209 ppb, and the distribution of logarithms of con centration has standard deviation 0.9693), the number of events is 17,400. 14

5. Failure to incorporate correc tions and additional data The Final REA failed to incorporate the data entry corrections that were pointed out in Our Comments and confirmed by subsequent EP A investigation (EPA -HQ-ORD-2006-0260-0036). The justification given in the Final REA (page 326-327), prior to a full investigation of the possible errors , was that the changes we indicated w ould only make small differences to the percentages of responders. No attempt was apparently made to estimate the effect on uncertainties or the effect on th e estimates of numbers of occu rrences expecte d, although this effect does indeed turn out to be small.

Moreover, the Final REA (indeed, even the Draft REA) did not attempt to incorporate all the available data. The Draft REA omitted any consideration of round 2 of the Linn et al . (1987) experiments, even though those da ta were available at the time. Table 3-1 of Appendix C of the Draft REA and the Final REA contains 334 samples su itable for analysis w ith (for an exercisecorrected sRaw increment of 100%) 99 positive re sults. Round 2 of Linn et al. (1987) would have added another 120 samples with 27 positiv e results; a substantial addition if the independence assumption were correct. The Fi nal REA also omitted to take account of the additional information available on the experiment s of Linn et al. (1983) that became available between the Draft REA and Final REA, another 69 samples with 14 positive results. The Final REA thus omits about 36% of the samples and 29% of the positive results (for an exercisecorrected sRaw increment of 100%).

These omissions do not substantially change the es timated results, but incorporating them is very simple, and would aid in reducing the s ubstantial uncertainties that remain.

6. Updated calculations The additional data entry by EPA (in EPA-HQ-ORD-2006-0260-0036 and 0036.1 through 0036.5), and the additional data (in EP A-HQ-OAR-2007-0352-0038 and 0038.1 through 0038.8) allowed us to correct a few data entry errors of our own, fully include Round 2 of Linn et al. (1987), and include the Linn et al . (1983) experiment in the analys is reported in Our Comments. The following summarizes the results, which correct the errors in the Final REA identified in Our Comments and here. Notation and term inology corresponds to those defined in Our Comments — we examine only the case of exposu res resulting in 100% increment in exercisecorrected relative sRaw (E 100 ), since this is the most sensitive end point considered. The same considerations apply to a ll the other end points exam ined in the Final REA.

14 See Section 11 for the formula required for this calculation.Cambridge Environmental Inc Page 16

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com 6.1. Short-period constancy of E 100 evaluations Figure 2 shows the comparison of E 100 estimates for Round 1 and Round 2 of Linn et al. (1987), for all 40 subjects (previously we could include only 35 of them). 15 This demonstrates the shortterm constancy of E 100 estimates, as discussed in Our Comm ents, for all but one subject. The lack of constancy for one subject shows that ev en in the relatively short term subjects can change, as we previously demonstrated for l onger periods (see also Section 6.2), but for any single experiment we still expect to be able to demonstrate individual dose-response curves (the measurements are clearly not independent as assumed in the Final REA).

0.1

1 10 100

0.1 1 10 100 E100 (ppm) Round 1E100 (ppm) Round2

Figure 2 Comparison of E 100 estimates in Round 1 and Round 2 of Linn et al. (1987). Confidence intervals are approximate ± 1 standard deviation (estimated by a change of 0.5 in profile loglikelihood).

15 The calculations for this Section are in workbook “Within study replicates 2.xls”, see Section 14.Cambridge Environmental Inc Page 17

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com 6.2. Independence of E 100 evaluations over long periods The additional data available allow adding (to the analysis we performed in Our Comments) another two subjects who took pa rt in different experiments (F igure 3; only Round 1 of Linn et al ., 1987 was included in these comparisons). 16 There is no change in interpretation from Our Comments. Three subjects (# 297, # 608, and # 611) were each tested in three experiments (Linn et al ., 1983; Linn et al ., 1987; and Linn et al ., 1988). For two of thes e subjects the estimated E 100 was similar for all three experiments (#297: 0.40, 0.39, and 0.24 ppm; # 608: 0.57, 0.34, and 0.60 ppm). However, subject 611 showed a resp onse in Linn et al . (1983) with an E 100 of about 0.45 ppm, no response in Linn et al . (1987) Round 1 and Linn et al . (1988), and a small response (E 100 estimate of 0.95 ppm) in Linn et al . (1987) Round 2.

These results and those of Secti on 6.1 correspond with the discu ssion in Our Comments — in the short term, individuals demonstrate a consistent dose-response relationshi p; but their response may change over the longer term, or perhaps in res ponse to external stimuli. Further, at any one time, not all asthmatics are hyperr esponsive to exercise plus SO 2 .

16 The calculations for this Section are in workbook “Between study replicates 2.xls,” see Section 14.Cambridge Environmental Inc Page 18

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com 0.1

1 10 100

0.1 1 10 100 E100 (ppm) Study 1E100 (ppm) Study2

Figure 3 Comparison of E100 estimates between studi es for 17 subjects. C onfidence intervals are approximate ± 1 standard deviation (estimated by a ch ange of 0.5 in profile loglikelihood).

6.3. Evaluation of population E 100 distribution Figure 4 shows all available estimates for E 100 (including subjects who di d not respond at all) taking account of corrections and new data, w ith superposed maximum likelihood estimates for the distribution of E 100 assuming probit or logis tic distributions. The distributional estimates incorporate the additional indivi dual data that do not define dose-response curves (see Our Comments for details of methods). 17 Also shown are the distribu tions derived (i ncorrectly, see Section 3) in the Final REA and used for calcula tions of Table 4-1 and 4-2 of Appendix C to the REA. The inclusion on this plot of the non-responde rs is strictly incorrec t; the distributions are for responding asthmatics and do not include th e non-responders. As discussed in Our Comments, approximately 12.5% of asthmatics ca n be expected to not respond at any time, 18

17 These calculations are all performed in workboo k “sRaw_analysis_final 2.xls,” see Section 14. 18 The failure to account for non-respon se was another problem with the Draf t REA identified in Our Comments. The same problem affects the Final REA.Cambridge Environmental Inc Page 19

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com although different individuals might be non-responde rs at different times. Figure 5 shows the same information as Figure 4, but omitting the non-responders.

-3 -2 -1 0 1 2 3

0.01 0.1 1 10 100 E100 (ppm)Normal ordinate

Data Probit_MLE Logistic_MLE EPA_Probit EPA_Logistic
Figure 4 Individual E 100 estimates with approximate ± 1 standard deviation confidence intervals, with superposed maximum likelihood estimates fo r the distribution and the Final REA estimates for the distribution.

The visual deviation of the fitted curves from the individual data points in Figure 4 and Figure 5 is due to the uncertainties in the measurements. As explained in Our Comments, the fitted curve is expected to have a steeper slope than the meas ured points, particularly at the higher estimated E 100 values where the uncertainties are largest.

It is apparent from these gra phs that the population curves used in the Final REA (EPA Probit, and EPA Logistic in Figure 4 and Figure 5) substantially overestimat e the probability for response at low exposures.Cambridge Environmental Inc Page 20

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com -3 -2 -1 0 1 2 3

0.01 0.1 1 10 100 E100 (ppm)Normal ordinate

Observed Logistic MLE Probit MLE EPA Logistic EPA Probit
Figure 5 As for Figure 4, but omitting non-responders. We use the parameterization of the Final REA (Appendix C, equations 3.1 and 3.2), that is “exposure-response” functions (actually population distributi on functions for E 100 ) given by 

## ( ) ( ) 

## ( ) ( ) () 

## ( ) 

# ( ) ( ) ln 2 1 Logistic: ; , 1 exp ln

1

Probit: ; , ln exp 2 2 P P L L L L

x
PP P P y x x
y x x t dt β λ β γ β λ

βγ β λ
π +

−∞ = + +

=Φ + = − 

# ∫

where y is the fraction of the population with E 100 less than concentration x (ppm). With this parameterization, our (maximum lik elihood) estimates for the parameters are given in Table 4. The analysis method also provide s some information on the rela tive likelihood of the probit versus the logistic distributi on shape; and the probit is fa vored by a factor of about 1.9.Cambridge Environmental Inc Page 21

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com Table 4 Maximum likelihood estimates for population distribution functions for E 100 for logistic and probit shapes. β L -2.22553

γ

L -3.37953 β

P 1.242975

γ

P 1.931819

7. Effect of the Final REA errors on estimation of population effects In Our Comments and here, we have described multiple errors in the Draft REA that were continued into the Final REA. These errors have a substantial effect on the estimated number of lung function events. We have calculated correct ed estimates for the numbers of events causing an increment in exercise-corr ected relative sRaw of 100%, 19 but the same substantial errors arise for all the other end-points.

For Greene County, Table 5 shows these correcti ons. The first lines for each dose-response shape (“Table 4-1 in Appendix C of Final REA” ) shows the entry in the Final REA. To demonstrate we know how those numbers were obtained, the second row shows a duplication of that calculation — the minor differences are due to the rounding of values in the Final REA and to our use of an exposure-response formula to esti mate the probabilities in each bin (see Footnote 13 — using the exact same probabili ties as used in the Final REA reproduces Table 4-1 exactly). The lines “Full APEX table” corresponds to the recalculation described in Section 4 (compare with Table 2 and Table 3), making use of all the output from the APEX modeling.

19 The calculations described in this Section are in workbook “Exposure distributions 2.xls,” see Section 14.Cambridge Environmental Inc Page 22

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com Table 5 Number of events (exercise-corrected relative sRaw increment of 100%) for Greene County, showing the effect of corr ecting errors in the Final REA.

Scenario
As Is CS 99/50 99/100 99/150 99/200 99/250 98/200 Logistic Table 4-1 in Appendix C of Final REA 12500 12700 12500 12500 12500 12600 12600 12600 Duplicating Table 4-1 calculation 12517 12769 12511 12518 12541 12578 12636 12615
Full APEX table 1689 12733 602 1857 3588 5723 8220 7326 Lognormal shape 145 1082 52 160 308 490 701 626 Correct E-R curve, full APEX table 2 139 0.2 3 10 27 57 45 Correct E-R curve, lognormal 1 49 0.1 1 5 11 22 18 Probit Table 4-1 in Appendix C of Final REA 1600 1800 1600 1600 1600 1600 1700 1700 Duplicating Table 4-1 calculation 1605 1798 1601 1606 1622 1650 1694 1678
Full APEX table 19 1769 2 24 111 321 709 553 Lognormal shape 9 243 1 11 33 70 124 104 Correct E-R curve, full APEX table 0.1 24 0.001 0.1 1 3 8 6 Correct E-R curve, lognormal 0.4 30 0.03 0.5 2 6 12 10

The lines “Lognormal shape” give the exact valu es that would be obtained for a lognormal distribution of concentrations fitted to the APEX results for Greene County (with median concentration 0.4233 ppb, standard deviation of the logarithm of c oncentration of 1.2827). 20 Figure 6 shows the APEX estimated cumulative distribution of exposur es, and the lognormal approximation for Greene County. Considering the still-poor coverage of the range of concentrations obtained from the APEX output (the lowest non-zero bin edge concentration output from APEX was 14.4 ppb for Greene County in the “As Is” scenario, well above the median concentration of all exposures), we consider the estimate based on a lognormal approximation to the concentrations to be the best one currently available.

The previous corrections show that the estimate s for number of events in Greene County in the Final REA are considerably in error — so mu ch so, indeed, that there is virtually no distinguishing any of the scenarios — even were th e rest of the calculations of the Final REA to be correct. As described here and previously in Our Comments, however, the exposure-response (E-R) curves used in the Final REA are very much in error. The lines “Correct E-R curve” in Table 5 incorporate the corrected exposure-res ponse curves described in Our Comments and

20 The required calculation is described in Section 11.Cambridge Environmental Inc Page 23

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com updated in Section 6, including the estimate of only 87.5% of asthmatics being hyperresponsive to SO 2 at any time.

2 2.5

3 3.5

4 4.5

5

2 2.5 3 3.5 4 4.5 5 ln(concentration/ppb)Normal ordinate

Figure 6 Cumulative distributi on of number of exposures ve rsus natural logarithm of concentration, for Greene county — APEX estimate s. The dotted line is a lognormal distribution fitted to these results. The lines “Correct E-R curve, full APEX table” co rrespond to a calculation su ch as that shown in Table 3 using the full APEX results but with probab ilities calculated using the correct E-R curve. The lines “Correct E-R curve, lognormal” co rrespond to the calculate d result, assuming a lognormal distribution of concentrations as describe d above. Again, we believe that the last lines (assuming a lognormal distribution), corre spond to the current best estimates. 21

For Greene County, if the E 100 population distribution (the “exposure-response curve”) is assumed to be probit in shape, then the lognor mal approximation actually gives slightly higher estimates for the total number of effects than using the full APEX table (compare the last two

21 It would be very straightforward for EPA to run the APEX model and obtain adequate tabular coverage of concentrations. For the four areas involved each combined run takes approximately 180 processor-hours total, based on the log files of the runs used for the Final REA, bu t we did not have time or resources to make these runs ourselves (we would also have to perform multiple cross- checks for correctness of our computer runs that EPA presumably would not, having done this already). A slig ht modification of the program might be necessary to allow for more concentration bins (we have not checked the current maximum allowable number of bins), but this should be a minor modification if the program has been correctly written. Substantially increasing the number of bins might also slow the program noticeably if it has not been carefully designed.Cambridge Environmental Inc Page 24

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com lines of Table 5). In this case, either the AP EX modeling did not involve sufficient samples to accurately capture the effect of very rare high concentrations, or the lognormal approximation is too far off for sufficiently high concentrations (there are too few APEX samples to evaluate which of these might be true).

For the three counties of St. Louis included in the APEX modeling, the corresponding results are given in Table 6. While in this case the in accurate results of the Final REA gave some discrimination between scenarios, they showed nowhere near the re lative differences actually to be expected. Once again, we believe that the mo st accurate results current ly available are given by the lines in Table 6 labeled “Correct E-R curve, lognormal”.

As can be seen, even if everything else about th e Final REA analysis were perfect (which it is not), the simple adding up of th e results performed for Table 4- 1 of Appendix C is incorrect by factors that range from about 12 to 241 for the logistic E 100 distribution in Greene County (comparing the lines “Table 4-1 in Appendix C of Final REA” and “Lognormal shape”) and 1.1 to 12 for St. Louis. For the probit shape, th e corresponding factors of error are 7 to 1194 for Greene County and 1.1 to 18 for St. Louis. Taking acc ount also of the errors in the derivation of the E 100 distributions (“exposure-response curves”), th e Final REA is in error by factors that for the logistic range from 260 to 90,940 in Greene C ounty and 6 to 1,380 in St. Louis, while for the probit the range is 60 to 56,000 in Green County and 4.3 to 982 in St. Louis.

All the estimates of total number of events in the Final REA are thus overestimates by very large factors, ranging from 60 to 90,940 in Greene C ounty and 4.3 to 1,380 in St. Louis for events corresponding to increments in exercise-corrected relative sRaw of 100% or more. We have not calculated the similar errors for increments of 20 0% or in exercise-corre cted relative sRaw, nor for the FEV 1 -related end points; however, the Final REA analysis is similarly flawed for those also, since the same erroneous assumptions are ma de and the same flawed methods are used in those analyses as in the sRaw analysis. The sa me errors also occur in the calculation of the number of asthmatics experiencing the “adverse” even ts (rather than the numb er of those events), although again we have not done the complete correct analysis. All the values in the Final REA that form the basis for the Proposed Rule ar e thus overestimates by substantial factors.Cambridge Environmental Inc Page 25

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com Table 6 Number of events (exercise-corrected relative sRaw increment of 100%) for St. Louis, showing the effect of correcti ng errors in the Final REA.

Scenario
As Is CS 99/50 99/100 99/150 99/200 99/250 98/200 Logistic Table 4-1 in Appendix C of Final REA 65700 167200 65200 68600 76200 88000 103600 99700 Duplicating Table 4-1 calculation 65842 166637 65304 68728 76334 88087 103613 99733
Full APEX table 8753 160138 5970 18288 35018 55304 78593 73175 Lognormal shape 7956 145791 5426 16628 31856 50330 71545 66609 Correct E-R curve, full APEX table 124 30204 57 550 1950 4600 8722 7669 Correct E-R curve, lognormal 103 27867 47 458 1649 3968 7677 6721 Probit Table 4-1 in Appendix C of Final REA 9000 93300 8600 11100 17000 26400 39200 36000 Duplicating Table 4-1 calculation 9012 92803 8624 11162 17044 26406 39124 35948
Full APEX table 1091 87601 557 3726 10261 20172 33281 30100 Lognormal shape 976 86532 488 3454 9771 19513 32508 29349 Correct E-R curve, full APEX table 35 24036 11 244 1121 3004 6157 5335 Correct E-R curve, lognormal 25 21577 9 175 844 2381 5094 4376

8. The RIA substantially underestimates the uncert ainty in hospital admissions due to SO 2 We have only cursorily examined the RIA, but some errors are immediately apparent. The calculation of the number of hospital admissions due to SO 2 depends entirely on a single paper (Schwartz et al ., 1996) that is not listed in any of the re ference lists in the RIA. Fortunately the Docket entry provides enough of the tit le to identify it. Examinati on of that paper shows that the coefficient used in the RIA for estimation of th e number of respiratory hospital admissions was itself estimated by using a single-pollutant model, and that coefficient is not statistically significant. Two other pollutants, O 3 and PM 10 , were more strongly statis tically associated with hospital admissions in single-pollutant models, but no multi-pollutant models were attempted (nor were single-pollutant models stratified by levels of other pollu tants, as suggested earlier in that same paper).

Since PM 2.5 is subsequently identified in the RIA (in the co-benefits assessment) also as a putative cause of hospital admissions, and because SO 2 and other pollutant concentrations are highly correlated (Schwartz et al ., 1996, under “ Multipollutant models ”), at the very least a joint analysis of the hospital admission data with both SO 2 and PM 10 or PM 2.5 or a similar PM-related variable is essential. Without such an anal ysis, any correlation between PM-related pollutantCambridge Environmental Inc Page 26

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com concentrations and SO 2 concentrations in the data evaluate d in the paper may lead to erroneous attribution of effects, and subs tantially underestimate the uncertain ties in quantitative evaluation of the coefficients (assuming that the effects examined are indeed causally related to the pollution measured examined). Further, since it is entirely plausible that O 3 and, indeed, other unmeasured components of air pollution result in respiratory-related hospital admissions, a simultaneous evaluation of at least three (SO 2 , PM, and O 3 ) pollution-related variables is essential to adequately account for uncertainties.

There appears to be no identifiable reason that EPA did not obtain the original data used for this study and perform the multi-pollutant evalua tion required for adequate evaluation of uncertainties — with the result that the uncertainty band for SO 2 -related hospital admissions is certainly much too narrow.

9. The RIA co-benefits assessment is base d entirely on an incorrect assumption
The RIA co-benefits assessment relies on the uns tated assumptions that sulfate PM can be considered equivalent to any other form of PM, and that sulfate PM, at ambient concentrations, causes disease and death. These assumptions ar e incorrect. The vast weight of scientific evidence shows that sulfate partic ulate matter at the levels encount ered in ambient air (or, for that matter, at substantially higher levels) is not harmful in any re spect. That EPA failed entirely to evaluate this evidence — even in an uncertain ty analysis — indicates an unjustified bias.

Sulfate is essential to life, and animals deficien t in sulfate fail to thrive (Markovich, 2001; Food and Nutrition Board, Institute of Medicine, 2004. Many essential biochemicals, such as chondroitin sulfate (a component of cartilage) and cerebroside sulf ate (an essential part of the nervous system), can be synthesized only if the body contains sufficient quantities of sulfate. Sulfate occurs naturally in ordinary foods and drinking water, and is also formed in vivo by oxidation of the sulfur-based amino acids, methi onine and cysteine. Su lfate in blood is freely filtered in the kidney and then reabsorbed by mean s of tubular sulfate transporters. Typically, reabsorption occurs at about the maximum rate ; therefore, any excess sulfate leaves the body via urine. In other words, body burdens of sulfat e are maintained by homeostasis, and when more sulfate is present than is needed for cell func tion and growth, this ex tra sulfate is readily excreted. On average, we ingest (and/or synthesize) about 4,000,000 micrograms of sulfate every day (Food and Nutrition Board, Institute of Medicine, 2005). Thus, to someone trained in nutrition, the idea that absorbing an ex tra 100 or so micrograms of sulfate via inhalation could be deadly is nonsensical.

Numerous experimental studies of the effects of inhaled fine and ultrafine particles (PM 2.5 ) of sulfate compounds have been conducted (revie wed by Schlesinger, 2007 and Schlesinger and Cassee, 2003; also Utell et al ., 1983; Amdur, 1989; NTP, 1996; Cassee et al ., 2002; Tunnicliffe et al ., 2003; Dorman et al ., 2005; Tapin et al ., 2006; Wallenborn et al ., 2008; and Heyder et al
., 2009). With the exception of sulfuric acid mists at high concentrations, thes e sulfates have failed to elicit significant toxic effects, much less cause death. Note that:Cambridge Environmental Inc Page 27

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com • The types of sulfates tested have include d ammonium sulfate, ammonium bisulfate, ammonium ferrosulfate, sodium sulfate, sodi um hydrogen sulfate, ferr ous sulfate, ferric sulfate, manganese sulfate, nickel sulfate, zinc sulfate, zinc ammonium sulfate, and sulfuric acid.

• Exposure concentrations have ranged from 4 to greater than 1,000,000 μg/m 3 , with almost all exposures in excess of 100 μg/m 3 , well above ambient sulfate levels (which typically are on the order of 2 – 8 μg/m 3 as an average).

• Exposure periods have ranged from about 15 minutes to a lifetime (for laboratory rodents).

• Subjects have included healthy adults, young adults with asthma, young rats, aging rats, rats with chemically induced pulmonary hype rtension, mice, rabbits, guinea pigs, guinea pigs with protein-induced asthmatic tendencies, dogs, and rhesus monkeys.

• Effects on lung function and structure, immunol ogical responses, the heart, and cancer have been examined, with lung responses of greatest interest.

These studies have indicated that the sulfate anion is remarkably nontoxic: to the extent that sulfate-based compounds do exhibi t toxicity, it is because of the cation (such as iron or hydrogen) with which sulfate combines, and not the sulfate per se . Thus, ferrous and ferric sulfates in air are moderately toxic — causing transient irritation of the upper respiratory system — but this is equally true of the other soluble ir on salts in air — such as ferrous chloride, ferric chloride, and ferric nitrate — sin ce it is the iron cation that matte rs, not the anion, whether it is sulfate, nitrate, or chloride. Si milarly, sulfuric acid is a strong acid and thus strong irritant, but, again, this is not due to th e sulfate anion, but instead to the hydrogen cations which, by definition, acidify substances (such as mucous memb ranes) with which they come into contact. Sulfuric acid mist can thus a ffect respiratory function, of asthmatics more than others, but exposures to concentrations larger than 100 μg/m 3 are required to cau se any measurable, transient changes in asthmatics (Utell et al ., 1983).

Sulfate salts, as noted above, ar e less toxic than sulfuric aci d. Rhesus monkeys exposed to 920 μg/m 3 manganese sulfate for 65 days showed no ill effects (Dorman et al ., 2005), and mice and rats exposed to nickel su lfate hexahydrate at 120 μg/m 3 (rats) or 250 μg/m 3 (for mice) for their lifetimes showed no increase in tumors or pul monary lesions (NTP, 1996). Female mice did develop atrophy of the olfactory epithelium, proba bly due to the nickel cation rather than the sulfate anion. Dogs exposed for 13 months to acidic sodium hydroge n sulfate at 4,500 μg/m 3 were extensively evaluated throughout a study by Heyder et al . (2009). Exposed animals evidenced only minor changes in lung function, no changes in the alveolar-capillary membrane system, no change in particle cl earance, and no loss of lung cell integrity. Mu cociliary clearance was increased by exposure. Changes in a few bioc hemical markers suggested marginal effects of exposure on redox balance and induction of a weak inflammatory response. The investigators deemed this chronic exposure to acidic partic les to have produced no pathophysiologic injury.

Exposures to sulfates at con centrations smaller than 100 μg/m 3 have produced inconsistent and/or ambiguous changes. Observations at the lowe r ends of exposure ranges include small and inconsistent changes in lung function in humans exposed briefly to 16 μg/m 3 zinc ammoniumCambridge Environmental Inc Page 28

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com sulfate; increases in TNF α in alveolar macrophages of rabbits exposed briefly to 75 μg/m 3 sulfuric acid (reviewed by Schlesinger and Ca ssee, 2003); and some alterations in biochemical and electrolyte parameters in ra ts exposed for 90 days to 30 μg/m 3 manganese sulfate (Tapin et al ., 2006).

The failure of controlled exposures to sulfates to produce marked toxicity in humans or in laboratory rodents accords with the occupationa l experience. Regulations and guidelines for worker exposure to chemicals are devel oped by the Occupational Safety and Health Administration (OSHA), the National Institute for Occupational Safety and Health (NIOSH), and American Conference of Governme ntal Industrial Hygienists (ACG IH). To prevent respiratory irritation, occupational exposures to ferrous su lfate and ferric sulfate are limited by OSHA, NIOSH, and ACGIH to no more than 1,000 μg/m 3 in workplace air. The same limit is set by OSHA and NIOSH for sulfuric acid; ACGI H, citing pulmonary function decrements, recommends an upper limit of 200 μg/m 3

. 22 The other sulfate salts are co nsidered to be inert, and so are limited only as generic “nui sance dusts” to levels of 5,000 μg/m 3 for respirable particles (NIOSH, 1974; NIOSH, 2005; ACGIH, 2008).

Other information casts doubt on the purported leth ality of sulfate. Various sulfate compounds — including metal sulfates, such as cupric sulfat e, ferric and ferrous sulfates, and zinc sulfate — are listed by the Food and Drug Administration (FDA) as “general ly recognized as safe” when added to food as intended. 23 Further, with regard to metal sulf ates, read the label of an ordinary, over-the-counter, multi-vitamin and mineral supplement, and you will find that some of the essential metals, such as copper, iron, and zinc, ar e supplied as sulfate salts. Thus, for example, a prenatal vitamin and mineral pill may contain 30,000 micrograms of iron, as ferrous sulfate ( http://emedicine.medscape. com/article/259059-overview ).

More than 250 sulfate compounds are approved by the FDA for use as drugs. 24 These drugs may be used chronically, such as Adderall and va rious asthma medications. Indeed, the inhaled asthma medication albuterol is formulated as th e sulfate salt, and a puff of albuterol sulfate contains thousands of micrograms of sulfate per cubi c meter (Green et al ., 2002).

None of the sulfate salts is known to be lethal: expos ure to more than 1,000,000 μg/m 3 ammonium sulfate in air for three da ys was not lethal to rats (Pepelko et al ., 1980). Sulfuric acid mist, as expected (based on its acidity), can be le thal when inhaled, but only at concentrations of about 30,000 μg/m 3 and higher (Wolff et al ., 1979).

In sum, small concentrations of sulfate compounds , such as those present in ambient air, are not known or expected to be toxic, and these compounds are benign at even much higher concentrations. Even massive concentrations of sulfates are not known to cause death, even

22 Occupational exposures to strong-inorganic-acid mists containing sulfuric acid can cause cancer in workers (IARC, 1992), but such exposures do not occur in (non-occupational) ambient air. 23 http://www.fda.gov/Food/FoodIngredientsPackaging/Ge nerallyRecognizedasSafeGRAS/GRASSubstancesSCOGS Database/default.htm
24 http://www.accessdata.fda.gov/scr ipts/cder/drugsatfda/index.cfmCambridge Environmental Inc Page 29

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com from respiratory disease. The co-benefits analysis asserts not only that airborne sulfates do cause death (at all concentrations, however small), but that they somehow cause all kinds of deaths — not only from respiratory disease, but also from heart disease, cancers of all types, strokes, diabetes, Alzheimer’s disease, influenza and pneumonia, kidney disease, and so on. 25 There is no known chemical, physical, or biological agen t, however potent, that does all this.

10. Erratum The discussion in Our Comments at page 19 contai ns an error. The seco nd equation should read:

100 2 2
4 E bb c λ λ
λ

= + + (the factor 2 in the numerator was inadvertently omitted in this description; all the calculations used the correct equation shown here — see the “P redicted” column in the relevant sheets of the workbooks).

11. Addendum For completeness, we give here the explicit formulae used for the lognormal concentration distribution case. Suppose the exposure concen tration distribution is a lognormal distribution with median concentration μ (ppm) and standard deviation σ of logarithm of concentration. Then for the logistic and probit popu lation distribution functions for E 100 given in Section 6.3, the expected fraction 26 of the population exposed to concentrations exceeding their E 100 is given by: 

# ( )
ln

2 2 Logistic: , 2;1

Probit: 1 LL L

P P

P I β γ μ σγ

μβγ

σ γ +   +   Φ   +  

where I ln is a logistic-norma l integral given by 

## ( ) 

# ( ) ( ) 2 ln 1 , ; exp 1 exp n I a b n t a bt
π ∞

−

−∞ = −+ +     

## ∫

25 Moreover, at the allowable occupational limit of 1,000 μg/m3 in workplace air for ferr ic/ferrous sulfate, the cobenefits analysis would apparently have us believe that th e total mortality rate would be increased by a factor of about 12 — which means that more than 90% of workers’ deaths would be attri butable to such exposures. This is not credible. 26 Since the relevant population is that of hyperresponsive as thmatics, the calculations fo r the “Correct E-R curve” in Table 5 and Table 6 also include the fraction 0.875 of the asthmatic population that is hyperresponsive (see Our Comments) — the APEX modeling om itted accounting for this fraction.Cambridge Environmental Inc Page 30

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com 12. Acknowledgement These comments were funded by our employer, Cambridge Environmental Inc., with the exception of Section 9, which is adapted from an expert report writte n by one of us (LCG) on behalf of Cinergy Corp. in a lawsuit involving, among other th ings, the question of whether sulfate in ambient air is lethal.

13. References

Amdur, M.O. (1989). Health effects of air poll utants: sulfuric acid, the old and the new. Environ Health Perspect 81 :109–113.
American Conference of Industria l Hygienists (ACGIH) (2008). Supplement to the 7 th Edition of Documentation of the Threshold Limit Values . Table of Contents and Entry for Sulfuric Acid . Cincinnati, OH. Cassee, F.R., Arts, JHE, Fokkens, P.H.B., Spoor, S.M., Boere, A.J.F., van Bree, L., and Dormans, J.A.M.A. (2002). Pulmonary effect s of ultrafine and fi ne ammonium salts aerosols in healthy and monoc rotaline-treated rats followi ng short-term exposure. Inhalation Toxicology 14 :1215–1229. Dorman, D.C., Struve, M.F., Gross, E.A., Wong , B.A., and Howroyd, P.C. (2005). Sub-chronic inhalation of high concentrations of manganese sulfate induces lowe r airway pathology in rhesus monkeys. Respiratory Research 6: 121. Green, L.C., Crouch, E.A.C., Ames, M.A., and Lash, T.L. (2002). What’s wrong with the National Ambient Air Quality Standard (NAAQS) for fine particulate matter (PM 2.5 )? Regul. Toxicol. Pharmacol. 35 (3):327–337. Heyder, J., Beck-Speier, I., Ferron, G.A., Jost en, M., Karg, E., Kreyling, W.G., Lenz, A-G., Maier, K.L., Reitmeier, P., Ruprecht, L., Ta kenaka, S., Wohland, T., Ziesenis, A., and Schulz, H. (2009). Long-term responses of canine lungs to acidic particles. Inhalation Toxicology 21 (11)920–932. Horstman, D., Roger, L.J., Kehrl, H., and Hazuch a, M. (1986). Airway sensitivity of asthmatics to sulfur dioxide. Toxicol. Ind. Health 2 (3):289–298. Institute of Medicine, Food and Nutrition Board (2004). Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate . Washington, DC: The National Academies Press. International Agency for Research on Cancer (IARC) (1992). IARC Monographs on the Evaluation of Carcinogenic Risks to Hum ans, Volume 54, Occupational Exposures to Mists and Vapours from Strong Inorganic Ac ids; and Other Industrial Chemicals . IARC, Lyon, France. ISBN 92 832 1254-1. Available at available at http://monographs.iarc.fr/ENG/Monographs/vol54/index.php , accessed Feb. 7, 2010.Cambridge Environmental Inc Page 31

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com Linn, W.S., Avol, E.L., Peng, R.C., Shamoo, D.A., and Hackney, J.D. (1987). Replicated exposure-response study of sulfur dioxide e ffects in normal, atopic, and asthmatic volunteers. Am. Rev. Respir. Dis. 136 :1127–1134. Linn, W.S., Avol, E.L., Shamoo, D.A., Peng, R.C., Spier, C.E., Smith, M.N., and Hackney, J.D. (1988). Effect of metaproterenol sulfate on m ild asthmatics’ response to sulfur dioxide exposure and exercise. Arch. Environ. Health 43 :399–406. Linn, W.S., Shamoo, D.A., Peng, R.C., Clark, K.W., Avol, E.L., and Hackney, J.D. (1990). Responses to sulfur dioxide and exercise by medication-dependent as thmatics: effect of varying medication levels. Arch. Environ. Health 45 :24–30. Linn, W.S., Venet, T.G., Valencia, L.M., Anzar, U.T., Spier, C.E., and Hackney, J.D. (1983). respiratory effects of sulfur dioxide in heavily exercising asthmatics. Am. Rev. Respir. Dis. 127 (3):278–283. Markovich, D. (2001). Physiological roles and regulation of mammalian sulfate transporters. Physiol Rev 81 (6):1499–1533. National Institute of Occupational Sa fety and Health (NIOSH) (1974). Criteria for a Recommended Standard: Sulfuric Acid . Cincinnati, OH:U.S. Department of Health and Human Services. National Institute of Occupational Sa fety and Health (NIOSH) (2005). NIOSH Pocket Guide to Chemical Hazards . Washington, DC.:U.S. Department of Health and Human Services. Available at http://www.cdc.gov/niosh/npg National Toxicology Program (NTP) (1996). Toxicology and Carcinoge nesis Studies of Nickel Sulfate Hexahydrate (Cas No. 10101-97-0) in F344/N rats and B6C3F 1 Mice (Inhalation Studies). Technical Report No. 454. Research Triangle Park, NC: U.S. Department of Health and Human Services. Pepelko, W.E., Mattox, J.K., and Cohen, A.L. (1980). Toxicology of ammonium sulfate in the lung. Bull. Environ. Contam. Toxicol. 24 (1):156–160. Post E, and Mahoney H. (2009). TRIM, Total Risk Integrated Methodology, Users Guide for TRIM.Risk Human Health-Probabilistic Application for the SO 2 NAAQS Risk Assessment. October 2009. Part of EPA-HQ-OAR-2007-0352-0105. Roger, L.J., Kehrl, H.R., Hazucha, M., and Horstman, D.H. (1985). Bronchoconstriction in asthmatics exposed to sulfur dioxi de during repeat ed exercise. J. Appl. Physiol. 59 (3):784–791. Schlesinger, R.B. (2007). The health imp act of common inorganic components of fine particulate matter (PM 2.5 ) in ambient air: a critical review. Inhalation Toxicology 19 (10):811–832. Schlesinger, R.B. and Cassee, F. (2003). Atmo spheric secondary inorganic particulate matter: the toxicological perspective as a basis for health effects risk assessment. Inhalation Toxicology 15 (3):197–235.Cambridge Environmental Inc Page 32

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com Schwartz, J., Spix, C., Touloumi, G., Bachár ová, L., Barumamdzadeh, T., le Tertre, A., Piekarksi, T., Ponce de Leon, A., Pönkä, A., Rossi, G., Saez, M., and Schouten, J.P. (1996). Methodological issues in studies of air pollution and daily counts of deaths or hospital admissions. J. Epidemiol. Community Health 50 (Suppl):S3–S11. Tapin, D., Kennedy, G., Lambert, J., and Zayed, J. (2006). Bioaccumulation and locomotor effects of manganese sulfate in Sprague-Da wley rats following subchronic (90 days) inhalation exposure. Toxicol. Applied Pharmacol. 211 :166–174. Tunnicliffe, W.S., Harrison, R.M., Kelly, F.J., Dunste r, C., and Ayres, J.G. (2003). The effect of sulphurous air pollutant exposures on symptoms , lung function, exhaled nitric oxide, and nasal epithelial lining fluid antioxidant concentrations in normal and asthmatic adults. Occup. Environ. Med. 60 (11):e15. U.S. Environmental Protection Agency (EPA) (1986). Review of the National Ambient Air Quality Standards for Sulfur Oxides: Updated Assessment of Scientific and Technical Information. Addendum to the 1982 OAQPS Staff Paper . EPA 450/05 86-013, December 1986. U.S. Environmental Protection Agency (EPA) (1994). Review of the National Ambient Air Quality Standards for Sulfur Oxides: Assessment of Scientific and Technical Information. Supplement to the 1986 OAQPS Staff Paper Addendum . EPA-452/R-94-013, September 1994. Utell, M.J., Morrow P.E., Speers D.M., Darling J., Hyde R.W. (1983). Airway responses to sulfate and sulfuric acid aerosols in asth matics. An exposure-response relationship. Am. Rev. Respir. Dis. 128: 444–450. Wallenborn, J.G., Evansky, P., Shannahan, J.H ., Vallanat, B., Ledbetter, A.D., Schladweiler, M.C., Richards, J.H., Gottipolu, R.R., Nyska, A., and Kadavanti, U.P. (2008). Subchronic inhalation of zinc sulfate induces cardiac ch anges in healthy rats. Toxicol. Applied Pharmacol. 232 :69–77. Wolff, R.K., Silbaugh, S.A., Brownstein, D.G., Carpenter, R.L., and Mauderly, J.L. (1979). Toxicity of 0.4- and 0.8-microm sulfur ic acid aerosols in the guinea pig. J Toxicol Environ Health 5 (6):1037–1047.

14. Appendix: Calculations Lack of time and budget prevent a de tailed description of all the calculations performed in these comments. To ensure reproducibility and allow examination of all the data and methods, we here provide copies (as embedded files within this PDF document) of the Excel workbooks used, and give a short description of them. Further information, and in particular information on practical use of the macros within these wor kbooks, may be obtained from the first author (EACC). These workbooks are generally update s of those provided with Our Comments. WARNING : all the workbooks REQUIRE the included add-in EACC_funs.xla (which is unchanged from the version embedded in Our Comm ents); in addition, several of them also contain macros [the macros are needed to re-r un the results, but are no t needed to view the results, so may be disabled on opening; the add-in is required to view the results].Cambridge Environmental Inc Page 33

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com EACC_funs.xla An add-in for Excel 2000 or 2003 (does not wo rk for Excel 2007). Required for the other workbooks to work correctly. Must be installed before opening any of the other spreadsheets. See EACC_functions.pdf for detailed instructions.

EACC_functions.pdf Instructions for installation, a nd descriptions of the functions , macros, and added menu items included with EAC_funs.xla.

gpl.txt The license under which EACC_funs .xla may be redistributed.

Raw_data 2.xls Sheets with summaries of all available individual- level data, including our en try of the individual measurements from Linn et al. (1987), and comparisons with EPA summaries. This has been updated to correct all identified e rrors, and now includes also Linn et al . (1983).

Table 3-1 Analyses 2.xls Reproduction of the EPA likelihood analysis of Table 3-1 of Appendix C of the REA (sheet “REA_Analysis”), a partially corr ected version that assumes that the entries in in Table 3-1 of Appendix C of the REA are multinomial 27 in nature but does not otherwise correct the entries there (sheet “REA_Improved”), a sheet “REA_co rrected” that incorporates all the data entry corrections in the Final REA analysis, and a sh eet “Independence assumption” that performs the calculations described in Section 3.

Within study replicates 2.xls Performs the analysis of within-study replicates described in Section 6.1

Between study replicates 2.xls Performs the analysis of between-study repli cates described in Section 6.2.

sRaw_analysis_final 2.xls Performs all the individual exposure-response calc ulations (sheet “DR-analysis”), and then the E 100 distribution parameter evalua tion (sheet “Combined”).

Fit_EPA_curves.xls Evaluates best-fit curves to Final REA & EPA tabulated “exposure-response” curves.

Exposure distributions 2.xls

27 This corresponds to each i ndividual exhibiting a dose-response curve with no variability, so that response at one dose would necessarily entail a response at every higher dose. This does not actually happen, but is closer than the “independence” assumption of the REA.Cambridge Environmental Inc Page 34

58 Charles Street Cambridge, Massachusetts 02141 617-225-0810 FAX: 617-225-0813 www.Ca mbridgeEnvironmental.com Sheet “Factors” estimates the multipliers for co ncentrations for the different scenarios from Table 8-14 of the Final REA, and fits the AP EX output results with lognormals. Sheet “Common” contains the parameters fo r the “exposure response” curves (from “Fit_EPA_curves.xls” and “sRaw_analysis_final 2. xls”) used in other sheets. Sheets “Greene” and “St. Louis” perform the calculations described in Section 7. In addition, sheet “St. Louis” has the example calculation described in Section 4.