ATTACHMENT Overview of Revisions in Second Draft PM ISA in Response to CASACPeer ReviewComments dated May 21, 2009 General ChanQes An acronym was added to the front of the ISA . When annexes or other sections were referenced in the text, theywere specified (e.g., Figures A

.2.1-1 through A .2.1-6 in Annex A)

. New studies were added that were published on or before May.15, 2009. Chapter 1_-_Introduction Further detail was added on the history of the previous PM NAAQS review in Section 1 .2. Section 1 .3 was expanded to include more information on the process of ISAdevelopment, including study selection criteria. Section 1 .5 was revised to include more specific considerations for causality determinations on PM . Additionally, consideration of publication bias was incorporated into Section 1 .5. Chapter 2 - Intesrative Overview of Health and Welfare Effects Sections 2.1 and 2.2: Concentrations and Sources of Atmospheric PM and Human Exposure ' The text was edited to reflect the larger edits made in Chapter 3. Section 2.3: Health Effects This section was reorganized to focus on the health effects evidence from studies that examined associations between morbidity and mortality and PM2,s, PMIo-2.s, and ultrafine PM . In addition, a discussion of the evidence for health outcomes that were suggestive of an association with PM was included. At the end ofthe discussion of the evidence for health effects associated with short-termand long-termexposure to a specific PM size fraction, a section was added that integrates the evidence across both exposure durations, including evidence from studies that examined the mode of action, dosimetry, atmospheric chemistry, and exposure assessment . When appropriate, figures were added that summarize the overall U .S. and Canadian epidemiologic evidence for specific size fractions and exposure durations, along with the concentrations reported in the studies. ' Section 2 .4: Policy-Relevant Considerations A new section was added that includes summaries for the evidence for susceptible subpopulations, lag structure ofassociations in epidemiologic studies, and the PM concentration- response relationship.Section 2.5: Welfare Effects A new sectionwas added to summarize the findings of the welfare effects chapter (Chapter 9) . Chapter 3 - Source to Human Exposure Section 3.2: Overviewof Basic Aerosol Properties Material was added on particle morphology. Section 3.3: Sources, Emissions and Deposition of Primary and Secondary PM The sections on sources and emissions were expanded to include mobile sources (e.g., gasoline and diesel fueled vehicles) . Discussion of deposition processes was moved into this section from Chapter 9 . Section 3 .4: Monitoring Issues The PM mass measurement sectionwas reorganized with an emphasis on addressing PM,o-2.5 measurement techniques and performance of FRMs. The PM network and siting section was reorganized and annex tables were created to compare different monitoring networks and spatial scales for PM monitoring. Asection was added on satellite determinations of surface PM2 .5. The section on measurement methods relating to climate and welfare effects was substantially increased and harmonized with the measurement section in Chapter 9 . Section 3 .5: Ambient PM Concentrations Abriefsynopsis of relevant findings fromthe 2004Air Quality Criteria Document (AQCD) for PM was added to the beginning of Section 3.5. Most ofthe figures were updated for purposes of clarity and illustration; no additional data were incorporated into the tables or figures with the exception of PM constituent trends added to Section 3.5 .2.1 . All PM size-specific discussions throughout this section were rearranged into the following order: PM2 .5, PMIO-2.s, PMto, ultrafine PM . This was done to matchthe order ofdiscussion in the rest of the document and to help clarify the fact that PM,o incorporates both PMZ.5 and PMlo-2.5. In addition, several other improvements were made to this section in response to CASACcomments including the following: added a summary of the findings fromthe PM concentration distribution tables (Tables 3.5-1 through 3.5-3) expanded the ultrafine particle discussion to include information on nucleation, spatial " " variability and chemical composition of ultrafine particles " expanded the discussion on the statistical correlations between sites as shown in the figures and tables " added studies looking at neighborhood scale variability and near-roadway environments; " added a section on trends in constituents " added a discussion on diel variability in PM constituents Section 3.6: Mathematical Modeling of PM (New Section) This sectionwas added that incorporates receptor modeling and chemistry transport modeling (topics covered in Section 3.5 of the 1S` External ReviewDraft) with expanded material requested by CASAC .Section 3.7: Background PM (Section 3.6 in lst External ReviewDraft) More data and description were provided on current and previaus methods for estimating Policy Relevant Background. Section 3 .8" Exposure Assessment (Section 3 .7 in l" External ReviewDraft) This section was reorganized in response to CASACcomments to consolidate information related to general exposure assessment concepts, relevant studies, and the effect of exposure misclassification on epidemiologic study findings. Increased attention was given to PMIO-2.s and ultrafine PM throughout the section. Descriptions of time-weighted microenvironmental and GIS-based models were added to the modeling subsection. Findings fromthe relevant studies were organized by spatial scale in part to distinguish between issues related to near road variability and issues found at the urban scale. Exposure to PM components and PM as a part of a mixture were also presented in a separate subsection. Asubsection on implications of exposure assessment for epidemiologic studies was added. Chapter 4 - Dosimetry Section 4.2 .4: Biological Factors Modulating Deposition Asubsection was added to describe the multiple influences of physical activity on particle deposition. Changes in breathing route and pattern with activity level were first presented. The discussion then shifted to the effect of these alterations in breathing on total deposition fractions and dose rates. Finally, effects on tracheobronchial and apical particle deposition with exercise were presented. In the subsection on age effects, additional discussion of breathing patterns and deposition differences between adults and children was added . Section 4 .3.1 : Clearance Mechanisms and Kinetics (poorly soluble particles) Mucociliary clearance fromthe tracheobronchial airways is generally considered to be a rapid (days) process, but a portion of the particles deposited in theseairways appear require considerably long periods (months) to clear. Discussion of this important phenomenon was expanded and updated. Section 4.3 .4" Factors Modulating Clearance (poorly soluble particles) Anew discussion on the effects ofasthma, acute inflammation, and epithelial permeability on clearance was added to the subsection on respiratory disease. . Section 4 .4.1 : Clearance Mechanisms and Kinetics (soluble constituents) The discussion of particle solubilization was expanded. Recent literature on leachable metals disposition following particle deposition was added. Chapter 5 - Mode of Action The following sections were added to the chapter: " Epigenetics (Section 5.1 .11) " Lung development (Section 5.1 .12) " Atherosclerosis (Section 5.2.3) " Acute and chronic responses (Section 5.6)Discussions on the following topics were expanded: " Neutrophilic inflammation (Section 5.1 .3, Section 5.1 .9) " Epithelial permeability (Section 5.1 .4) Factors which affect resolution of inflammation/progression or exacerbation of disease " (Section 5 .1 .9) " Role of trigeminal nerve in CNS reflexes (Section 5.3) " CNS plasticity (Section 5.3) " Translocation of PM or soluble PM components (Section 5.4) Effects on the CNS and other systems (Section 5.5) Additional gaps in knowledge (Section 5.7) " Relevant information from new studies published since the first draft and crossreferencing of all items to the appropriate sections of Chapters 6 and 7 (Section 5 .7) Paragraphs on ultrafine PM were added throughout chapter. whether health effects are similar across species, Where information was readily available on For example, it was noted that neurogenic inflammation may discussions were added to the text . However, in most cases new information was not be more important in rodents than humans. included because literature searches failed to identify publications that elucidate these topics. Chapter 6 - Integrated Health Effects of Short-TermPM Exposure For each section in Chapter 6, the causal determination for PMIOwas removed, and evidence for health effects associated with PMIo was used to support the associations with PMZ,5 and/or PM,o_ 2.5 where possible and appropriate. The discussion of cause-specific mortality has been incorporated in sections on cardiovascular and respiratory morbidity, as was done for lung cancer incidence and mortality and considered in drawing causal determinations for cardiovascular and respiratory effects. Section 6 .1 : Introduction ~ The section on The introduction was updated to reflect the changes made throughout Chapter 6 . methodological considerations was separated and moved to various sections of Chapter 1. Section 6 .2" Cardiovascular Effects Controlled human exposure and toxicological studies were reorganized by particle type or source (e.g., CAPs, diesel, gasoline, model particles, etc.) and subheadings were added. Intratracheal instillation studies were contained in their own subsection where applicable within the The summary sections were revised and condensed by removing specific toxicology sections. outcome headings and presenting the previous findings followed by new evidence in a more integrated fashion. The causal determinations for PMIO-2.s and ultrafine particles were changed frominadequate to suggestive, whereas the causal determination for PM2 .5 remained unchanged from the V ERD . Section 6 .3: Respiratory Effects The figures in Section 6 .3.1 were revised to include the results for all PM size fractions as Controlled human exposure and toxicological studies were reorganized opposedto PM2 .s alone.by particle type or source (e.g., CAPs, diesel, gasoline, model particles, etc .) and subheadings subsection where were added. Intratracheal instillation studies were contained in their own applicable within the toxicology sections. New epidemiology sections on allergic responses The summary (Section 6 .3.6.1) and host defense (Section 6 .3.7.1) were added for the 2"a ERD . sections were revised and condensed by removing specific outcome headings and presenting the previous findings followed by new evidence in a more integrated fashion . The causal determination for ultrafine particles was changed frominadequate to suggestive, whereas the causal determinations for PM2 .5 and PMIo_Z.s remained unchanged fromthe l~` ERD . Section 6 .4" Central Nervous SystemEffects studies. Toxicological studies Anew epidemiology section was added that summarized new were reorganized by particle type or source (e.g., CAPs, diesel, gasoline, model particles, etc .) and subheadings were added . Section 6 .5: Mortality Along with incorporation of recent study findings, ancillary data (i .e., empirical Bayes-adjusted city-specific estimates and ambient PM concentrations) were included fromZanobetti and Schwartz (2009) for PMz.s and PMIO-2.5. ' Attribution of Health Effects to Specific Constituents or Sources Section 6 .6: individual tables for epidemiologic, controlled human exposure, and toxicological studies were was moved to Annex F. The table that was formerly in Chapter 2 (Table 2-1 in the lst ERD) moved to this section, and includes studies fromall three disciplines grouped by source category (e.g., crustal/soil/road dust, traffic, oil combustion, etc .) . A new summary was drafted that includes paragraphs by health outcome (i .e., cardiovascular effects, respiratory effects, and source categories and constituents. mortality) for the different PM Chanter 7 - Long Term Exposure and Health Effects For each section in Chapter 7, the causal determination for PM,o was removed, and evidence for health effects associated with PM,o was used to support the associations with PM2 .5 and/or PMto_ 2.5 where possible and appropriate. The discussion of cause-specific mortality has been incorporated in sections on cardiovascular and respiratory morbidity, as was done for lung cancer incidence and mortality and considered in drawing causal determinations for cardiovascular and respiratory effects. Section 7 .2: Cardiovascular Effects The text was edited to balance the discussion of the intermediate cardiovascular outcomes so that this line of evidence was consistent with the summary sections. Text was added to the 2°d ERD to relate chronic cardiovascular health impacts with acute cardiovascular health impacts. Toxicological studies were separated by exposure atmosphere (e.g., CAPS, ambient air, wood smoke, diesel, etc.) and intratracheal instillation studies were contained in their own subsection. Consideration of evidence on cardiovascular mortality resulted in revision of the causal determination from"likely causal" to "causal ."Section 7.3: Respiratory Effects The text in this section was revised to more clearly differentiate between cross-sectional and cohort study designs. Additionally, the text was revised to ensure that the studies were The epidemiology sections on allergic characterized in a balanced and objective manner. response (Section 7.3.6.1) and host defense (Section 7.3.7.1) were expanded. Reproductive and Developmental Outcomes Section 7.4" Thetables and Several new epidemiologic studies were added to this section in the 2°d ERD . figures in this section were updated to include the newly identified studies. Section 7.5" Cancer This section was revised to include the results of epidemiologic studies examining lung cancer In the 1" ERDthis section was limited to epidemiologic studies mortality and PM concentration. that focused on cancer incidence. Rates of lung cancer incidence and mortality are similar, and A new therefore the cancer section was expanded to include studies of lung cancer mortality. table (Table 7-7) was included that shows the effect estimates fromlung cancer incidence and as well as those reviewed in previous PM AQCDs. mortality studies reviewed in the 2°d ERD The inclusion of evidence for mortality due to lung cancer associated with PM2 .5 concentrations strengthened the causal determination substantially. The section was also revised to include evidence from animal toxicological studies that has been the mutagenicity and carcinogenicity of PM in the ambient accumulating for several decades on The majority of these toxicological studies were conducted using intratracheal instillation or air. dermal routes of exposure. Generally, the toxicological evidence reviewed in the rest of the ISA was limited to inhalation studies conducted at PM concentrations <2 mg/m3. For the 2nd ERD, toxicological studies conducted at higher concentrations and using various routes of exposure were cited in order to accurately characterize the role of PM in mutagenicity, tumorogenicity, The toxicology section was reorganized such that mutagenicity and and carcinogenicity. genotoxicity studies are described first, followed by the carcinogenesis studies. Additionally, the toxicology section has new subheadings within each section for particle or source type, which is This evidence included brief consistent with toxicology sections for other health outcomes. summaries of relevant IARCand EPAdocuments on diesel exbaust, as well as reviews fromthe peer-reviewed literature. Also, a few recent studies examining the association between PM2 .5 and epigenetic changes were As a result of revisions to this section, the causal determination added to the end of the section. for PM2 .5 and cancer was changed frominadequate to suggestive. The causal determination for PM 10-2.5 and cancer remained unchanged (i .e., inadequate) fromthe ls` ERD . Section 7 .6" Mortality Several new epidemiologic studies were added to this section in the 2"d ERD, most notably the The tables results of the HEI report of the reanalysis of the ACS cohort by Krewski et al . (2009) . and figures in this section were updated to include the newly identified studies.Chapter 8 - Susceptible Subpoaulations Potentially Susceptible Subpopulations Section 8 .1 " The definition of a susceptible subpopulation was clarified based on a workshop report from The Adiscussion on effect modification was included. The American Lung Association (2001) . tablethat was originally in this section was edited to reflect the susceptibility factors examined in The table was also the health effects literature that were subsequently discussed in this chapter. revised to include the different exposure durations (short- and long-term) and PM size fractions evaluated in the studies presented in the chapter. Sections 8 .1 .1 through 8 .1.7 accurately reflect the exposure The remaining sections of this chapter were reorganized to more The susceptibility factors originally durations and size fractions where the evidence lies. were no longer characterized as included in the chapter were reconsidered and some susceptibility factors (e.g., air conditioning use and geographic location) and thus, were no longer discussed. Section 8 .1 .8 new section was included that summarizes the findings fromall of the studies evaluated in this A chapter. Chapter 9- Welfare Effects Visibility Section 9 .2

" Effects on section on Direct Optical Measurements (9.2.2 .3.) was As recommended by CASAC, a new To enhance the discussion of sense ofwell being as it relates to urban air quality, Section added. Key points of these new sections were 9

.2.2 .4. Value of Good Visual Air Quality was added . also included in the summaries in both Chapter 9 and Chapter 2 . Several figures were also revised for clarity and consistency. Section 9 .3: Effects on Climate climate was substantially, increased with more details from The section on aerosol effects on described in recent publications. Specific effects fromPM components and size fractions were detail was added to the summary' section and carried throughto more detail . In addition, more the summary in Chapter 2 . Section 9 .4" Ecological Effects types of effects (i .e., direct and indirect effects) and This section was reorganized to focus on effects of individual PM components (i .e., metals and organics) . Deposition of PM specifically related to ecosystems was merged into this section while more detailed information on The causal determination was revised fromcausal deposition processes was moved to Chapter 3 . to likely to be causal . Additionally, the introduction to the section was revised to include key conclusions from the recent NOX-SOX ISA (December 2008) .