UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON D C 20460 

II. Christopher f rey. Ph.D. 

C c~i nnnn 

f ~aJ Rc' tl!\\' Panel 

('Jean .\ir Sci~ntitic Advisor) Committee 

I ' ... Em ironmemal Protection Agency 

1200 Pennsylvania /\venue. \\' 

\\'ashington. D.C. 20-1 60 

Dear Dr. e~ . 

SEP 1 8 2012 

fH!: AO.\WI'STAATOR 

J'h:m!... you for your .July 20. 20 l 2. letter in ''hic.:lt Yt'U prtn idcd the Clean 1\ir 'cientilk Advisory 

Committee Lead Rcvic\V Panel's comments on the U.S. Em ironmcntal Protr.!ction Agenq 's Second 

~\tema/ ~1'\'iew f)rq(t integrated Science .lsw.1smcm j;w Lead, rekasetl for publil: comment and peer 

r~\'Je\\ m h .:bruary ::w 12. We at the I· J>A v~r') much apprct:iutc..: the panel's tlmrough rcvie\\ unci 

~nnst ruet in~ thoughts. 

The t::P:\ ~ carct'ull) considering your ad\ icc and nHl"ing re\'isions to address your comments and 

r~commendations as \\'el l those otTcrcJ b) 1hc rub l ie. l ha\'C enclosed un O\'crvicw or the major 

fl'\ isinn~ hcing incorporated illll1 the third external fC\'iC\\ dra l't ol'th~ ISA. T'hesc include: 

• Increasing the syntheo..,is and integration nt'~cientitic e\·idence cross <.lisciplincs and enhanced 

critical rc\'iC\\ of <;tudics: 

• l:.xpanding the charach:rintiou ol th~ !>trcngths an <.I li mi tal ions o( the epidemiologic studies by 

1ncluding tables in chapter 5 that characteri;c tht! statistical methods <tnd study design of the 

indi\ iduul tudics C\'a lu:llcd 111 the IS\: 

• Focusing critically on appraising groups or studies with imil~tr Jcsigns anJ me thodological 

appronl·hes; 

• Expanding the comprchcnsivl! n:\'ic'' o t literature on studies relevant to understanding how airrelated exposure can contribute lo totul kaJ exposure: 

• Improving the cri1ical asscssmemofthe cstimmes nfthe air Pb/blood Ph slope fac tors discussed 

in the chapter by adding n uiscussion or the uncertnintics inlluencing interpretation of the studies: 

• ocu~i g on the most n:le,·ant ecological endpoints sun i\'a l growth and rcprouuction - while 

di~cussing sub-01 ganismal rcspons~s in the conl e:>-1 or supporting eYidencc f()r c..:\·n luming 

ecological eiT~.!c t stu i~s in chapter 7: and 

• l)...:q:luping. tabks w ntainin); :.IUJ~ dl:laib un :-.un i,·ul. ~ro..,, h ,md r...:prudm:lion in lt:rrcslrial .md 

uqu,nic urganisms. 

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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 

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the 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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