U N I TED STATES ENVIRONMENTAL PROTECTION AGENCY WAS HI N GTO N D C 20460

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.\ir**Sci~ntitic** Adviso r) Committee I '

... Em iro nmemal Pro tec ti on Agency 1200 Pennsy lva ni a /\ve nue
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Dear Dr.**e~ .**  

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f H !: AO.\WI 'STAATOR

J' h:m!... you for you r .Ju ly 20

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. le tt e r in ''h ic.:lt Yt'U prtn idcd the Clean 1\ir 'cientilk Advisory Committee Lead Rcvic\ V Pan el's comments on t he U.S. Em ironmcn tal Protr.!ction Age nq 's Second**~\ tema/** **~1'\'iew** f)rq(t i ntegrated Scienc e
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### carc t' ull) cons i dering you r ad\ icc and nHl"ing re\'isions to 

### add r ess your com ments and**r~commendations** as \\'e l l t ho se o t TcrcJ b) 1 hc rub l ie

. l ha\'C enc losed u n O\'crv i cw or the major fl'\**isinn~** hcing in co rpo rat ed illll1 the third external fC\ 'iC\\ dra l't**ol'th~** ISA. T'hesc include :

• Increasing the syn t heo..,i s an d integration**nt'~cientitic** e\·idence**cross** <.liscip lincs a nd enhanced critical rc\' iC\\ of <; t ud ics : • l:.xpanding the cha r ach:rintiou ol**th~** !>trcngths an <.I li mi tal ions o( the epidem iologic s tud ie s by 1nc lud i ng tab l es in c hap t er 5 tha t characteri;c th t! s tati s tical me t hod s <tnd study design of the ind i\ iduul tud ics C\'a lu:llcd 111 the I S\ : • Foc us ing cri ti ca ll y o n apprais i ng groups 

# or studie s with**imil~tr** Jcs igns anJ me t hodologica l
ap pronl·hes;
• Expanding t he com prc hc n sivl! n:\'ic'' o t literature on stu d ies relevan t to u ndersta nd ing how a irrela t ed expos ure ca n con tribute lo totu l kaJ exposure: • Imp rovi ng t he cri1ica l asscssmemofthe cst immes nfthe air Pb/b loo d Ph s l ope fac to rs d is cus sed in the cha pter by ad d ing n uiscu ssio n o r the uncertnin tics in lluencing interpretat io n o f the studie s : •**ocu~i g**  on t he m ost n: l e, ·ant ecologica l endpoints sun i\'a l growth an d rcprouuction

- while**di~cussing** sub-01 gan i smal**rcspons~s** i n the con l e:>-1 

## or s upp o rting eYidencc f()r c..:\·n lum ing ecological**eiT~.!c t** **stu i~s**  in chapter 7: and
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·ul.**~ro..,, h**  ,md r...:prudm: li on in lt:rrcslrial .md uqu ,nic urganisms.

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. :.w t:'p,, tJO" RecyclediRecycta b l e • P uNcd IJ,\1 '/P·w:at !<• Q,li:J"'**n!<~** C'' lOll Post(on<;t.mcr Pr cc•"•' Chlwr,nl' I Wft Rec,c·l'd PHpe•A second key focus of revisions is itnproving the transparency \vith which the causal .fran1ework described in the preamble is applied to the health- and ccok>gical-cffccts evidence. In implementing the causal**fran1cwork~** 

## J udgmcnts will be focused on inorc specific health endpoints or groups of related health endpoints. To improve the transparency and clarity of our evaluation and conclusions, tables explicitly linking the health-effects evidence to the framework for causal determination will be included ,in chapter 5. In addition, language to further inforn1 and describe the causal**dctcrmi~a~ions** will be added to the ecological effects chapter.
The EPA's efforts to protect the environn1cnt can only be as good as the science upon which they are based. Your independent critical reviews help to ensure that we usc the best science to protect our nation's cnviromnent. Please accept my gratitude for all your hard work.

Enclosure

### Attachment Preamble and Preface
The Preamble is being revised based on comments from the Ozone and Lead CASAC panels. The Preface is being revised to include additional information on the pre-promulgation history and the initiation of the NAAQS for Lead. 

### Chaoter 1- Executive Summary
The language is being further simplified for a non-technical audience. Additional call-outs to subsequent chapters will be included to make it easier to locate more detailed discussions. Information on the reversibility of the effects of lead will be included here and in subsequent chapters of the document. 

### Chapter 2- Integrative Summary
This chapter is being revised to include additional synthesis and integration. 

### In general, revisions to the integrative summary will reflect changes made in Chapters 

### 5 and 7 as well as other sections of the document. Notably, revisions to enhance the transparency of the causal determinations will be reflected in this integrative summary. Other major revisions will include the addition of a summary on lead utilization (e.g. imports, exports and production) and an enhanced critical assessment of studies on the air lead-to-blood lead relationships.
Several revisions are being made to Section 2.9.1 (Public Health Significance). Additional discussion of Figure 2-1 as a conceptual model will be included. We are also reconsidering the evidence to give appropriate emphasis to health endpoints for which uncertainties related to public health significance are relatively low. 

### Chapter 3 - Ambient Lead: Source to Concentration Throughout Chapter 3, cross-referencing to relevant sections of Chapter 4 will be added. A map will be added to illustrate the magnitude of individual sources throughout the U.S., and this map will be used to discuss the comparison between individual source contributions for the various
source categories. More discussion of wheel weights, with attention to new references suggested by CASAC, will also be incorporated into this section.
Discussion of sampling needs and uncertainties in capturing the ambient air Pb particle size distribution will be expanded. Options for particulate matter (PM) sampling that could be utilized for Pb monitoring will be included. The section on Ambient Air Pb Concentrations is being further synthesized with extraneous material removed or transferred to the Chapter 3 Appendix. The size distribution section is being expanded. An edited version of the collocated Pb size distribution table previously removed for the Second External Review Draft will be restored with quality assurance criteria applied. The latter step will effectively remove illogical findings from

1the table. Pearson correlations will be added to the assessment, and extraneous information from the background section will be removed. 

### Chapter 4- Exposure, Toxicokinetics, and Biomarkers
The chapter is being edited to distinguish size distributions of airborne PM containing Pb from the size distribution of dust and soil containing Pb. Furthermore, cross-referencing between Chapters 3 and 4 is being expanded to emphasize where sampling and measurements of Pb concentrations and size distributions, and uncertainties therein, will affect estimation of human exposure to ambient Pb via air-related pathways. Further synthesis of the Pb exposure literature is also being incorporated. In addition, revisions include expanded description of studies that evaluate air-to-blood Pb slope factors and discussion of the air Ph-to-blood Pb relationships described in the last NAAQS review. 

### Chapter 5 - Integrated Health Effects of Lead Exposure
In the revised draft, causal determinations for health effects are being drawn for specific groups of related outcomes instead of major organ systems with a thorough consideration of the weight of evidence as outlined in the Preamble. With consultation from an outside expert on epidemiologic methods, the discussions of the causal determinations for all health endpoints are being revised to more transparently and consistently apply the causal framework by using language from the causal framework and linking it with the key supporting evidence. Further, the causal determinations will include tables that describe what lines of evidence support specific attributes for causal relationships that are described in Table II (Weight of evidence for causal determination) of the Preamble.
The discussion of the health effects of Pb are being revised to include additional details on strengths and limitations of the evidence, with respect to issues such as study design, consideration of potential confounding factors, analytical methods, and reverse causality in epidemiologic studies and Pb exposure route and concentration in toxicological studies. These issues related to study design and methodology also will be noted in the tables within the text and are more explicitly incorporated into the evaluation of the evidence for determinations of causality.
For the neurodevelopmental outcomes, experts in neuropsychology, behavioral neuroscience, and neurotoxicology are reviewing the discussion of the evidence and will advise EPA on reorganizing the discussion of the cognition-related and behavior-related outcomes into the appropriate constructs and drawing the appropriate parallels between tests**conduct~** in humans and animals.

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### Chapter 6- 

### Potentially At-Risk Populations
In order to broadly and consistently apply standard terminology and concepts across criteria pollutants for populations at-risk, a new classification system created for the third draft 

### 03 ISA is anticipated to be added to**Sec~ion** 6.3 of Chapter 6 "Potentially At-Risk Populations". We are looking forward to the CASAC comments on the 3rd draft Ozone ISA to inform the inclusion of this new approach for the Lead ISA. In addition, maternal self-esteem will be removed from discussion of stress and moved to its own section in order to better clarify the difference between the two. Also, statements are being checked for accuracy and addressed/removed. 

### Chapter 7 - Ecological Effects of Lead Chapter revisions in response to CASAC comments will include additional synthesis and technical evaluation of the available evidence on Pb effects on terrestrial, freshwater and saltwater ecosystems, and an increased emphasis on growth, reproduction, and survival as ecologically-relevant endpoints. In the terrestrial and aquatic sections, summary tables are being added for growth, reproductive, and survival endpoints. An additional table in each of these sections will summarize data from microcosm and field-studies that are referenced in the ISA. Causal determinations for aquatic plants, invertebrates and vertebrates are being divided into separate statements for freshwater and saltwater species. A new section on the fate and transport of Pb in ecosystems is being added that includes a table of current concentrations of Pb measured in different environmental media. Throughout the chapter, units will be standardized for consistent expression of exposure dose, and nominal studies, when included, will be identified. In the context of these chapter revisions, several causal determinations are being revised.

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