### February 2012 EPA/600/R

- 10/075B



# Integrated Science Assessment for Lead

National Center for Environmental Assessment

- RTP Division Office of Research and Development U.S. Environmental Protection Agency Research Triangle Park, NC

### February 2012 ii Draft

– Do Not Cite or Quote 

# DISCLAIMER

This document is the second external review draft for review purposes only and does not constitute

U.S. Environmental Protection Agency policy. Mention of trade names or commercial products does

not constitute endorsement or recommendation for use.

### February 2012 iii Draft

– Do Not Cite or Quote 

# CONTENTS

LEAD PROJECT TEAM

________________________________ ________________________ XXII

CLEAN AIR SCIENTIFIC ADVISORY COMMITTEE LEAD NAAQS REVIEW PA NEL

______ XXIX

ACRONYMS AND ABBREVI ATIONS

________________________________ ____________ XXXI

Table I Aspects to aid in judging causality

_______________________________ lv Table II Weight of evidence for causal determination

______________________ lvii



### CHAPTER 1 EXECUTIVE SUMMARY

________________________________ _________ 1

- 1

1.1 Introduction

________________________________ ________________________________ __ 1

- 1 1.2 Lead Sources, Fate and Transport in the Environment, Human Exposure and Dose

_________ 1

- 2 Figure 1

- 1 Conceptual model of multimedia Pb exposure.

____________________ 1

- 4 1.3 Integrative Overvi ew of Health and Ecological Effects

________________________________ _ 1

- 5 Figure 1

- 2 Schematic representation of the relationships between the various MOAs by which P b exerts its effects.

___________________________ 1

- 6 1.3.1 Health Effects of Lead

________________________________ ______________________ 1

- 6 Table 1

- 1 Summary of causal determinations between exposure to Pb and health outcomes

________________________________ ___________ 1

- 7 1.3.2 Ecological Effects of Lead

________________________________ __________________ 1

- 11 Table 1

- 2 Summary of Pb causal determinations for plants, invertebrates and vertebrates

________________________________ _______________ 1

- 12 1.4 Policy Relevant Considerations

________________________________ __________________ 1

- 15 1.5 Summary

________________________________ ________________________________ ___ 1

- 18



### CHAPTER 2 INTEGRATIVE SUMMARY

________________________________ _______ 2

- 1

2.1 ISA Development and Scope

________________________________ ____________________ 2

- 1 2.2 Ambient Lead: Source to Concentration

________________________________ ____________ 2

- 5 2.2.1 Sources, Fate and Transport of Ambient Lead

________________________________ ___ 2

- 5 2.2.2 Monitoring and Concentrations of Ambient Air Lead

_______________________________ 2

- 6 2.2.3 Ambient Lead Concentrations in Non

- Air Media and Biota

__________________________ 2

- 9 Table 2

- 1 Ambient Pb Concentrations in Non

- Air Media and Biota Considered for Ecological Assessment

________________________________ __ 2

- 10 2.3 Exposure to Ambient Lead

________________________________ _____________________ 2

- 10 2.4 Toxicokinetics

________________________________ _______________________________ 2

- 11 2.5 Lead Biomarkers

________________________________ _____________________________ 2

- 13 2.6 Health Effects

________________________________ _______________________________ 2

- 14 Table 2

- 2 Summary of causal determinations a between exposure to Pb and health outcomes

________________________________ __________ 2

- 15 2.6.1 Nervous System Effects

________________________________ ____________________ 2

- 15 2.6.2 Cardiovascular Effects

________________________________ _____________________ 2

- 18 2.6.3 Re nal Effects

________________________________ ____________________________ 2

- 19 2.6.4 Immune System Effects

________________________________ ____________________ 2

- 21 2.6.5 Heme Synthesis and Red Blood Cell Function

________________________________ __ 2

- 23 2.6.6 Reproductive and Developmental Effects

________________________________ ______ 2

- 24 2.6.7 Cancer

________________________________ ________________________________ _ 2

- 26 2.7 Ecological Effects of Lead

________________________________ ______________________ 2

- 27 2.7.1 Summary of Effects on Terrestrial Ecosystems

________________________________ __ 2

- 27 2.7.2 Summary of Effects on Aquatic Ecosystems

________________________________ ____ 2

- 31 2.7.3 Determinations of Causality for Effects on Ecosystems

___________________________ 2

- 36 Table 2

- 3 Summary of Pb causal determinations for plants, invertebrates and vertebrates

________________________________ _______________ 2

- 36 2.7.3.1 Effects on Physiological Stress

________________________________ __________ 2

- 36 2.7.3.2 Hematological Effects

________________________________ _________________ 2

- 37 2.7.3.3 Neurobehavioral Effects

________________________________ _______________ 2

- 38 2.7.3.4 Effects on Development and Reproduction

________________________________ _ 2

- 39

### February 2012 iv Draft

– Do Not Cite or Quote 2.7.3.5 Effects on Growth

________________________________ ____________________ 2

- 42 2.7.3.6 Effects on Survival

________________________________ ___________________ 2

- 43 2. 7.3.7 Community and Ecosystem Effects

________________________________ ______ 2

- 45 2.8 Integration of Health and Ecological Effects

________________________________ ________ 2

- 47 Table 2

- 4 Summary of Causal Determinations a for Health and Ecological Effects

________________________________ __________________ 2

- 48 2.8.1 Modes of Action Relevant to Downstream Health and Ecological Effects

______________ 2

- 49 Table 2

- 5 MOAs, their related health effects, and information on concentrations eliciting the MOAs

________________________________ _________ 2

- 50 2.9 Policy Relevant Considerations

________________________________ __________________ 2

- 54 2.9.1 Public Health Significance

________________________________ __________________ 2

- 54 Figure 2

- 1 The effect of a small shift in population mean on the proportion of individuals in the population diagnosed with clinical disease (i.e., the proporti on to the right of the “Critical Line.”)

_____________________ 2

- 55 Table 2

- 6 Illustrative examples contrasting the effect sizes observed in epidemiologic studies to effect sizes considered significant in a clinical setting. a

________________________________ ___________ 2

- 58 2.9.2 Air Lead

- to

- Blood Lead Relationships

________________________________ _________ 2

- 59 Table 2

- 7 Summary of Estimated Slopes for Blood Pb to Air Pb Relationships in Humans

________________________________ _______________ 2

- 61 2.9.3 Ecological Effects and Corresponding Lead Concentrations

________________________ 2

- 62 2.9.4 Concentration

- Response Functions for Health Effects

____________________________ 2

- 63 Figure 2

- 2 Comparison of association s between blood Pb and cognitive function among various blood Pb strata.

________________________ 2

- 64 2.9.5 Pb Exposure and Nervous System Effects in Childr en

____________________________ 2

- 69 2.9.6 Populations Potentially At

- Risk for Health Effects

________________________________ 2

- 71 Table 2

- 8 Factors evaluated that may determine populations potentially at increased risk from lead

________________________________ ____ 2

- 72 2.9.6.1 Age and/or Lifestage

________________________________ __________________ 2

- 73 2.9.6.2 Sex 2

- 7 5 2.9.6.3 Genes

________________________________ _____________________________ 2

- 75 2.9.6.4 Pre

- existing Conditions

________________________________ ________________ 2

- 75 2.9.6.5 Race and Ethnicity

________________________________ ___________________ 2

- 76 2.9.6.6 Socioeconomic Status

________________________________ _________________ 2

- 76 2.9.6.7 Proximity to Pb Sources and Residential Factors

____________________________ 2

- 77 2.9.6.8 Lifestyle Factors

________________________________ _____________________ 2

- 77 2.9.6.9 Nutritional Factors

________________________________ ____________________ 2

- 77 2.9.6.10 Stress and Cognitive Reserve

________________________________ ___________ 2

- 78 2.9.6.11 Co

- exposure of Lead with Meta ls and Chemicals

____________________________ 2

- 78 2.9.6.12 Summary of At

- Risk Populations

________________________________ ________ 2

- 79 Table 2

- 9 Summary of evidence for factors that potentially increase the risk of lead

- related health effects

________________________________ ___ 2

- 79 2.10 Summary

________________________________ ________________________________ ___ 2

- 80 Table 2

- 10 Summary of evidence from epidemiologic, animal toxicological and ecological studies on the effects associated with exposure to Pb

____ 2

- 80



### CHAP TER 3 AMBIENT LEAD: SOURCE TO CONCENTRATION

___________________ 3

- 1

3.1 Introduction

________________________________ ________________________________ __ 3

- 1 3.2 Sources of Atmospheric Lead

________________________________ ____________________ 3

- 1 3.2.1 National Emissions Inventory

________________________________ _________________ 3

- 2 Figure 3

- 1 Trends in Pb emissions (thousand tons) from stationary and mobile sources in the U.S., 1970

- 2008.

_______________________________ 3

- 3 Figure 3

- 2 Trends in Pb emissions (thousand tons) from stationary and mobile sources in the U.S., 1990

- 2008.

_______________________________ 3

- 4 Figure 3

- 3 Nationwide stationary and mobile source Pb emissions (tons) in the U.S. by source sector in 2008.

________________________________ 3

- 5 Figure 3

- 4 County

- level Pb emissions (tons) in the U.S. in 2008.

______________ 3

- 6 3.2.2 Anthropogenic Sources

________________________________ _____________________ 3

- 6 Table 3

- 1 Pb compounds observed in the environment

_____________________ 3

- 7 3.2.2.1 Lead Emissions from Piston

- engine Aircraft Operating on Leaded Aviation Gasoline and Other Non

- Road Sources

________________________________ _______________ 3

- 7

### February 2012 v Draft

– Do Not Cite or Quote 3.2.2.2 Emissions from Metals Processing and Mining

_______________________________ 3

- 8 3.2.2.3 Fossil Fuel Combustion

________________________________ ________________ 3

- 10 3.2.2.4 Waste Incineration

________________________________ ___________________ 3

- 11 3.2.2.5 Wood Burning

________________________________ _______________________ 3

- 12 3.2.2.6 Ro adway

- Related Sources

________________________________ _____________ 3

- 13 3.2.2.7 Deposited Lead

________________________________ ______________________ 3

- 15 Figure 3

- 5 Total U.S. Pb additives in on

- road gasoline used in on

- road vehicles, 1927

- 1995.

________________________________ ______________ 3

- 18 Figure 3

- 6 Estimated Pb aerosol inputs from on

- road gasoline into 90 U.S. urbanized areas (UAs), from 1950 through 1982.

_________________ 3

- 19 3.3 Fate and Transport of Lead

________________________________ _____________________ 3

- 19 Figure 3

- 7 Fate of atmospheric lead.

________________________________ ___ 3

- 20 3.3.1 Air 3

- 20 3.3.1.1 Transport

________________________________ ___________________________ 3

- 21 3.3.1.2 Deposition

________________________________ __________________________ 3

- 22 3.3.1.3 Resu spension of Lead from Surface Soil to Air after Deposition

________________ 3

- 24 Figure 3

- 8 Scales of turbulence within an urban environment.

________________ 3

- 26 3.3.2 Water

________________________________ ________________________________ __ 3

- 29 3.3.2.1 Lead Transport in Water and Sediment

________________________________ ___ 3

- 30 3.3.2.2 Deposition of Lead within Bodies of Water and in Sediment

___________________ 3

- 31 Table 3

- 2 Surface sediment Pb concentrations f or various continental shelves

__ 3

- 33 3.3.2.3 Flux of Lead from Sediments

________________________________ ___________ 3

- 33 3.3.2.4 Lead in Runoff

________________________________ _______________________ 3

- 35 3.3.3 So il 3

- 43 3.3.3.1 Deposition of Lead onto Soil from Air

________________________________ _____ 3

- 44 3.3.3.2 Sequestration of Lead from Water to Soil

________________________________ __ 3

- 45 3.3.3.3 Movement of Lead within the Soil Column

________________________________ _ 3

- 48 Figure 3

- 9 Schematic model summarizing the estimated flux of Pb within a typical podzol profile from northern Sweden using data from Klaminder et al. (2006a).

________________________________ ____ 3

- 50 Figure 3

- 10 Eh

- pH diagram for Pb in shooting range soils, Jefferson National Forest, VA.

________________________________ _______________ 3

- 54 3.4 Monitoring of Ambient Lead

________________________________ ____________________ 3

- 55 3.4.1 Ambient Measurement Techniques

________________________________ ___________ 3

- 55 3.4.1.1 Sample Collection

________________________________ ____________________ 3

- 55 Figure 3

- 11 Comparison of particle collection efficiency among different TSP sampler types (Modified Andersen Sampler, Hi

- volume Sampler (for different incident wind direction (45°, 0°), Prototype Dichotomous Sampler, and Original Andersen Sampler).

______________________ 3

- 56 Table 3

- 3 Airborne Pb sampling metho ds

_______________________________ 3

- 58 3.4.1.2 Sample Analysis: Federal Reference and Federal Equivalence Methods

_________ 3

- 59 3.4.1.3 Other Analysis Methods for Total Lead

________________________________ ____ 3

- 61 3.4.1.4 Sequential Extraction

________________________________ _________________ 3

- 63 3.4.1.5 Speciation Techniques

________________________________ ________________ 3

- 64 3.4.1.6 Continuous Lead Monitoring

________________________________ ____________ 3

- 67 3.4.2 Ambient Network Design

________________________________ ___________________ 3

- 68 3.4.2.1 NAAQS Monitoring Network

________________________________ ____________ 3

- 68 Figure 3

- 12 Map of Monitoring Sites in Current Pb NAAQS Monitoring Network.

__ 3

- 71 Figure 3

- 13 Fifteen U.S. locations where a study is currently being performed on airport Pb emissions.

________________________________ _______ 3

- 72 Table 3

- 4 List of 15 airports included in the airport study

___________________ 3

- 73 3.4.2.2 Other Lead Monitoring Networks

________________________________ ________ 3

- 7 3 Figure 3

- 14 Pb

- PM 2.5 monitoring sites for CSN and IMPROVE networks.

________ 3

- 75 Figure 3

- 15 Pb

- PM 10 monitoring sites for NATTS network.

___________________ 3

- 75 3.5 Ambient Air Lead Concentrations

________________________________ ________________ 3

- 76 3.5.1 Spatial Distribution of Air Lead

________________________________ _______________ 3

- 77 3.5.1.1 Variability across the U.S.

________________________________ ______________ 3

- 77 Table 3

- 5 Summary data for source

- oriented Pb monitors across the U.S., 2008

- 2010

________________________________ _______________ 3

- 79 Table 3

- 6 Summary data for sites at which source

- oriented statistics for one

month and three

- month annual site max are in the upper 90th percentile, 2008

- 2010

________________________________ ______ 3

- 79

### February 2012 vi Draft

– Do Not Cite or Quote Figure 3

- 16 Highest county

- level source

- oriented Pb

- TSP concentrations (μg/m 3 ), maximum 3

- month average, 2008

- 2010.

_________________ 3

- 80 Table 3

- 7 Summary data for non

- source

- oriented Pb monitors across the U.S., 2008

- 2010

________________________________ _______________ 3

- 82 Table 3

- 8 Summary data for sites at which non

- source

- oriented statistics for

one

- month and three

- month annual site max are in the upper 90th percentile, 2008

- 2010

________________________________ ______ 3

- 82 Figure 3

- 17 Highest county

- level non

- source

- oriented Pb

- TSP concentrations (μg/m 3 ), maximum 3

- month average, 2008

- 2010.

_________________ 3

- 83 Figure 3

- 18 Highest county

- level Pb

- PM 10 concentrations (μg/m 3 ), maximum 3

- month average, 2007

- 2009.

________________________________ 3

- 84 Figure 3

- 19 Highest county

- level Pb

- PM 2.5 concentrations (μg/m 3 ), maximum 3

- month average, 2007

- 2009.

________________________________ 3

- 85 3.5.1.2 Intra

- urban Variability

________________________________ _________________ 3

- 85 Table 3

- 9 Sample of U.S. near road Pb TSP monitors

_____________________ 3

- 87 Figure 3

- 20 Time series of monthly average Pb

- TSP concentration at five near

road monitors.

________________________________ ____________ 3

- 88 3.5.2 Temporal Variability

________________________________ _______________________ 3

- 90 3.5.2.1 Multi

- year Trends

________________________________ ____________________ 3

- 90 Figu re 3

- 21 National trends in Pb concentration (μg/m 3 ), source

- oriented FRM monitors, 1990

- 2010.

________________________________ _______ 3

- 91 Figure 3

- 22 National trends in P b concentration (μg/m 3 ), non

- source

- oriented FRM monitors, 1990

- 2010.

________________________________ __ 3

- 92 3.5.2.2 Seasonal Variations

________________________________ __________________ 3

- 93 Figure 3

- 23 Monthly source

- oriented Pb

- TSP average (μg/m 3 ) over 12 months of the year, 2008

- 2010.

________________________________ _______ 3

- 94 Figure 3

- 24 Monthly non

- source

- oriented lead

- TSP average (μg/m 3 ) over 12 months of the year, 2008

- 2010.

_______________________________ 3

- 95 Figure 3

- 25 Monthly lead

- PM 10 average (μg/m 3 ) over 12 months of the year, 2007

- 2009.

________________________________ ______________ 3

- 95 Figure 3

- 26 Monthly lead

- PM 2.5 average (μg/m 3 ) over 12 months of the year, 2007

- 2009.

________________________________ ______________ 3

- 96 3.5.3 Size D istribution of Lead

- Bearing PM

________________________________ _________ 3

- 96 3.5.3.1 Airborne Pb Near Metals Industries

________________________________ ______ 3

- 97 3.5.3.2 Airborne Pb Near Roadways

________________________________ ____________ 3

- 99 Figure 3

- 27 Comparison of urban background and near

- road size fractions of lead

- bearing PM.

________________________________ _________ 3

- 101 3.5.3.3 Airborne Pb at Other Urban and Rural Sites

_______________________________ 3

- 102 3.5.4 Lead C oncentrations in a Multipollutant Context

________________________________ 3

- 103 Figure 3

- 28 Correlations of monitored Pb

- TSP concentration with copollutant concentrations, 2007

- 2008.

________________________________ _ 3

- 104 Figure 3

- 29 Correlations of monitored Pb

- TSP concentration with co

- pollutant concentrations, 2009.

________________________________ _____ 3

- 104 Table 3

- 10 Correlations between Pb and copollutants, measured in TSP, PM 10 , and PM 2.5

________________________________ _______________ 3

- 107 Figure 3

- 30 Correlations of monitored lead

- PM 2.5 concentration with copollutant concentrations, 2007

- 2009.

________________________________ _ 3

- 108 3.5.5 Background Lead Concentrations

________________________________ ___________ 3

- 108 3.6 Ambient Lead Concentrations in Non

- Air Media and Biota

____________________________ 3

- 111 3.6.1 Soils 3

- 112 Figure 3

- 31 Map of median Pb content in soil in New Orleans.

_______________ 3

- 115 3.6.2 Sediments

________________________________ _____________________________ 3

- 118 Figure 3

- 32 WACAP data for Pb concentration in sediment at eight National Parks and/or Preserves.

________________________________ ___ 3

- 120 Table 3

- 11 Sediment concentrations in various cities, prior to 2005

___________ 3

- 122 Figure 3

- 33 Sediment core data (1992

- 1994) for the lakes and reservoirs along the Apalachicola, Chattahoochee, and Flint River Basin (ACF), which feeds from north of the Atlanta, GA metropolitan area into the Gulf of M exico at Apalachicola Bay in the Florida panhandle.

______ 3

- 122 Figure 3

- 34 Sediment core data (1975

- 1995) for the lakes and reservoirs along the Apalachicola, Chattahoochee, and Flint River Basin (ACF),

### February 2012 vii Draft

– Do Not Cite or Quote which feeds from north of the Atlanta, GA metropolitan area into the Gulf of Mexico at Apalachicola Bay in the Florida panhandle.

______ 3

- 123 3.6.3 Rain 3

- 124 Figure 3

- 35 Trends in Pb concentration in precipitation from various sites in Norway over the period 1980

- 2005.

__________________________ 3

- 125 3.6.4 Snowpack

________________________________ ______________________________ 3

- 126 Figure 3

- 36 Box plots illustrating Pb concentration in snow melt at nine National Parks and Preserves.

________________________________ _____ 3

- 128 3.6.5 Natural Waters

________________________________ __________________________ 3

- 129 Figure 3

- 37 Boxplots of Pb concentration in surface waters measured at five National Parks and Preserves.

______________________________ 3

- 130 Table 3

- 12 Pb concen trations from stream food webs in mining

- disturbed areas of Missouri and the western United States

_____________________ 3

- 132 3.6.6 Vegetation

________________________________ _____________________________ 3

- 132 Figure 3

- 38 Boxplots of Pb concentration in lichen measured at seven National Parks and Preserves.

________________________________ _____ 3

- 133 Figure 3

- 39 Trends in regional pollution near a copper smelter in Canada and Pb concentrations at the boundary of heartwood trees within roughly 75 km o f the smelter.

________________________________ ______ 3

- 135 3.6.7 Aquatic Bivalves

________________________________ _________________________ 3

- 135 3.6.8 Vertebrate Populations

________________________________ ____________________ 3

- 136 Figure 3

- 40 Boxplots of Pb concentration in fish fillet and liver measured at eight National Parks and Preserves.

______________________________ 3

- 1 37 Figure 3

- 41 Boxplots of Pb concentration in moose meat and liver measured at Denali National Park and Preserve.

__________________________ 3

- 138 3.7 Summary and Conculusions

________________________________ ___________________ 3

- 138 3.7.1 Sources of Atmospheric Lead

________________________________ ______________ 3

- 138 3.7.2 Fate and Transport of Lead

________________________________ ________________ 3

- 139 3.7.3 Ambient Lead Monitoring

________________________________ __________________ 3

- 140 3.7.4 Ambient Air Lead Concentrations

________________________________ ___________ 3

- 141 3.7.5 Ambient Lead Concentrations in Non

- Air Media and Biota

________________________ 3

- 142 3.8 Chapter 3 Appendix (Supplemental Material)

________________________________ ______ 3

- 143 3.8.1 Variability across the U.S.

________________________________ _________________ 3

- 143 Table 3

- 13 Distribution of 1

- month average Pb

- TSP concentrations ( μ g/m 3 ) nationwide, source

- oriented monitors, 2008

- 2010

_______________ 3

- 143 Table 3

- 14 Distribution of 1

- month average Pb

- TSP concentrations ( μ g/m 3 ) nationwide, non

- source

- oriented monitors, 2008

- 2010

____________ 3

- 145 Table 3

- 15 Distribution of 3

- month moving average Pb

- TSP concentrations ( μ g/m 3 ) nationwide, source

- oriented monitors, 2008

- 2010

_________ 3

- 147 Table 3

- 16 Distribution of 3

- month moving average Pb

- TSP concentrations ( μ g/m 3 ) nationwide, non

- source

- oriented monitors, 2008

- 2010

_____ 3

- 149 Table 3

- 17 Distribution of annual 1

- month site maxima TSP Pb concentrations ( μ g/m 3 ) nationwide, source

- oriented monitors, 2008

- 2010

_________ 3

- 150 Table 3

- 18 Distribution of annual 1

- month site maxima TSP Pb concentrations ( μ g/m 3 ) nationwide, non

- source

- oriented monitors, 2008

- 2010

_____ 3

- 151 Table 3

- 19 Distribution of annual 3

- month site maxima Pb

- TSP concentrations ( μ g/m 3 ) nationwide, source

- oriented monitors, 2008

- 2010

_________ 3

- 152 Table 3

- 20 Distribution of annual 3

- month site maxima Pb

- TSP concentrations ( μ g/m 3 ) nationwide, non

- source

- oriented monitors, 2008

- 2010

_____ 3

- 152 Table 3

- 21 One

- month average Pb

- TSP for individual county concentrations nationwide (μg/m 3 ), source

- oriented monitors, 2008

- 2010

_________ 3

- 154 Table 3

- 22 One

- month average Pb

- TSP for individual county concentrations nationwide ( μg/m 3 ), non

- source

- oriented monitors, 200 8

- 2010

_____ 3

- 155 Table 3

- 23 Three

- month moving average Pb

- TSP for individual county concentrations ( μg/m 3 ) nationwide, source

- oriented monitors, 2008

- 2010

________________________________ ___________________ 3

- 156 Table 3

- 24 Three

- month moving average Pb

- TSP for individual county concentrations ( μg/m 3 ) nationwide, non

- source

- oriented monitors, 2008

- 2010

________________________________ ______________ 3

- 158 3.8.2 Intra

- urban Variability

________________________________ _____________________ 3

- 159 Figure 3

- 42 Pb TSP monitor and source locations within Los Angeles County, CA (06

- 037), 2007

- 2009.

________________________________ ___ 3

- 162

### February 2012 viii Draft

– Do Not Cite or Quote Figure 3

- 43 Wind roses for Los Angeles County, CA, from meteorological data at the Los Angeles International Airport, 1961

- 1990.

_______________ 3

- 163 Figure 3

- 44 Box plots of annual and seasonal Pb TSP concentrations ( μg/m 3 ) from source

- oriented and non

- source

- oriented monitors within Los Angeles County, CA ( 06

- 037), 2007

- 2009.

_____________________ 3

- 164 Table 3

- 25 Comparisons between Pb TSP concentrations from source

- oriented and non

- source

- oriented monitors within Los Angeles County, CA (06

- 037), 2007

- 2009

________________________________ ______ 3

- 165 Figure 3

- 45 Pb TSP monitor locations within Hillsborough and Pinellas Coun ties, FL (12

- 057 and 12

- 103), 2007

- 2009.

_________________________ 3

- 167 Figure 3

- 46 Wind roses for Hillsborough/Pinellas Counties, FL, obtained from meteoro logical data at Tampa International Airport, 1961

- 1990.

____ 3

- 168 Figure 3

- 47 Box plots of annual and seasonal Pb TSP concentrations ( μg/m 3 ) from source

- oriented and non

- source

- oriented monitors within Hillsborough and Pinella s Counties, FL (12

- 057 and 12

- 103), 2007

- 2009.

________________________________ _____________ 3

- 169 Table 3

- 26 Correlations between Pb TSP concentrations from source

- oriented and non

- source

- oriented monitors within Hillsborough and Pinellas Counties, FL (12

- 057 and 12

- 103), 2007

- 2009

__________________ 3

- 170 Figure 3

- 48 Pb TSP Monitor locations within Cook County, IL (17

- 031), 2007

- 2009.

________________________________ _____________ 3

- 173 Figure 3

- 49 Wind roses for Cook County, IL, obtained from meteorological data at O’Hare International Airport, 1961

- 1990.

____________________ 3

- 174 Figure 3

- 50 Box plots of annual and seasonal Pb TSP concentrat ions ( μg/m 3 ) from source

- oriented and non

- source

- oriented monitors within Cook County, IL (17

- 031), 2007

- 2009.

_____________________________ 3

- 175 Table 3

- 27 Cor relations between Pb TSP concentrations from source

- oriented and non

- source

- oriented monitors within Cook County, IL (17

- 031), 2007

- 2009

________________________________ ______________ 3

- 176 Figure 3

- 51 Pb TSP Monitor locations within Jefferson County, MO (29

- 099), 2007

- 2009.

________________________________ _____________ 3

- 178 Figure 3

- 52 Wind roses for Jefferson County, MO, obtained from meteorological data at St. Louis/Lambert International Airport, 1961

- 1990.

________ 3

- 179 Figure 3

- 53 Bo x plots of annual and seasonal Pb TSP concentrations ( μg/m 3 ) from source

- oriented and non

- source

- oriented monitors within Jefferson County, MO (29

- 099), 2007

- 2009.

____________________ 3

- 180 Table 3

- 28 Correlations between Pb TSP concentrations from source

- oriented and non

- source

- oriented monitors within Jefferson County, MO (29

- 099), 2007

- 2009

________________________________ ______ 3

- 181 Figure 3

- 54 Pb TSP Monitor locations within Cuyahoga County, OH (39

- 035), 2007

- 2009.

________________________________ _____________ 3

- 184 Figure 3

- 55 Wind roses for Cuyahoga County, OH, obtained from meteorological data at Cleveland/Hopkins International Airport, 1961

- 90.

_________ 3

- 185 Figure 3

- 56 Box plots of annual and seasonal Pb TSP concentrations ( μg/m 3 ) from source

- oriented and non

- source

- oriented monitors within Cuyahoga County, OH (39

- 035), 2007

- 2009.

___________________ 3

- 186 Table 3

- 29 Correlations between Pb TSP concentrations from source

- oriented and non

- source

- oriented monitors within Cuyahoga County, OH (39

- 035), 2007

- 2009

________________________________ ______ 3

- 187 Figure 3

- 57 Pb TSP Monitor locations within Sullivan County, TN (47

- 163), 2008

- 20102007

- 2009.

________________________________ _____ 3

- 189 Figure 3

- 58 Wind roses for Sullivan County, TN, obtained from meteorological data at Bristol/Tri City Airport, 1961

- 90.

_______________________ 3

- 190 Figure 3

- 59 Box plots of annual and seasonal Pb TSP concentrations ( μg/m 3 ) from source

- oriented monitors within Sullivan County, TN (47

- 163), 2007

- 2009.

________________________________ _____________ 3

- 191 Table 3

- 30 Correlations between Pb TSP concentrations from source

- oriented monitors within Sullivan County, TN (47

- 163), 2007

- 2009

_________ 3

- 192 3.8.3 Lead Concentration in a Multipollutant Context

________________________________ _ 3

- 193 Figure 3

- 60 Seasonal correlations of monitored Pb

- TSP concentration with copollutant concentrations, 2007

- 2008.

_______________________ 3

- 193

### February 2012 ix Draft

– Do Not Cite or Quote Figure 3

- 61 Seasonal correlations of monitored Pb

- TSP concentration with copollutant concentrations, 2007

- 2008.

_______________________ 3

- 194 Figure 3

- 62 Seasonal correlations of monitored Pb

- TSP concentration with copollutant concentrations, 2009.

____________________________ 3

- 195 Figure 3

- 63 Seasonal correlations of monitored Pb

- TSP concentration with copollutant concentrations, 2009.

____________________________ 3

- 19 6 Figure 3

- 64 Seasonal correlations of monitored Pb

- PM 2.5 concentration with copollutant concentrations, 2007

- 2009.

_______________________ 3

- 197 Figure 3

- 65 Seasonal correlations of monitored Pb

- PM 2.5 concentration with copollutant concentrations, 2007

- 2009.

_______________________ 3

- 198 Table 3

- 31 Copollutant exposures for various trace metal studies

____________ 3

- 199



### CHAPTER 4 EXPOSURE, TOXICOKINE TICS, AND BIOMARKERS

_________________ 4

- 1

4.1 Exposure Assessment

________________________________ __________________________ 4

- 1 4.1.1 Pathways for Lead Exposure

________________________________ _________________ 4

- 1 Figure 4

- 1 Conceptual model of multimedia Pb exposure.

____________________ 4

- 3 Table 4

- 1 Estimates of Pb measurements for EPA Region 5 from the NHEXAS study

________________________________ ____________________ 4

- 5 4.1.2 Environmental Exposure Assessment Methodologies

______________________________ 4

- 7 4.1.3 Exposure Studies

________________________________ __________________________ 4

- 9 4.1.3.1 Airborne Lead Exposure

________________________________ ________________ 4

- 9 Table 4

- 2 Estimates of fixed effects multivariate modeling of Pb levels measured during the NHEXAS

- MD study

_______________________ 4

- 10 Table 4

- 3 Comparison of personal, indoor, and outdoor Pb

- PM measurements from several studies

________________________________ _______ 4

- 13 4.1.3.2 Exposure to Lead in Soil and Dust

________________________________ _______ 4

- 13 Table 4

- 4 Measurements of indoor dust Pb concentration from 2006

- 2011 studies

________________________________ __________________ 4

- 14 4.1.3.3 Dietary Lead Exposure

________________________________ ________________ 4

- 18 Figure 4

- 2 Market basket survey results for Pb concentration in foods.

_________ 4

- 19 Table 4

- 5 Pb bioaccumulation data for various plants. Bioaccumulation is expressed as percent of Pb concentration in the plant to the Pb concentration in the soil

________________________________ _____ 4

- 25 4.1.3.4 Occupational

________________________________ ________________________ 4

- 27 4.1.3.5 Exposure to Lead from Consumer Products

________________________________ 4

- 28 Table 4

- 6 Pb content in various consumer products.

______________________ 4

- 28 4.2 Kinetics

________________________________ ________________________________ ____ 4

- 30 4.2.1 Absorption

________________________________ ______________________________ 4

- 30 4.2.1.1 Inhalation

________________________________ ___________________________ 4

- 31 4.2.1.2 Inge stion

________________________________ ___________________________ 4

- 33 Figure 4

- 3 Estimated relative bioavailability (RBA, compared to Pb

- acetate) of ingested Pb in mineral groups.

_______________________________ 4

- 37 4.2.2 Distribution

________________________________ ______________________________ 4

- 39 4.2.2.1 Blood

________________________________ ______________________________ 4

- 39 Figure 4

- 4 Plot of blood and plasma Pb concentrations measured in adults and children.

________________________________ _________________ 4

- 41 Figure 4

- 5 Relationship between Pb intake and blood Pb c oncentration in infants (n = 105, age 13 weeks, formula

- fed).

____________________ 4

- 42 Figure 4

- 6 Simulation of quasi

- steady state blood and plasma Pb concentrations in a child (age 4 years) associated with varying Pb ingestion rates.

________________________________ ___________ 4

- 43 4.2.2.2 Bone 4

- 44 4.2.2.3 Soft Tissues

________________________________ _________________________ 4

- 45 4.2.2. 4 Fetus

________________________________ ______________________________ 4

- 46 4.2.2.5 Organic Lead

________________________________ ________________________ 4

- 46 4.2.3 Elimination

________________________________ ______________________________ 4

- 47 4.3 Lead Bio markers

________________________________ _____________________________ 4

- 48 4.3.1 Bone Lead Measurements

________________________________ __________________ 4

- 51 4.3.2 Blood Lead Measurements

________________________________ _________________ 4

- 53 Figure 4

- 7 Simulation of temporal relationships between Pb exposure and blood Pb concentration in children.

________________________________ _ 4

- 56

### February 2012 x Draft

– Do Not Cite or Quote 4.3.3 Urine Lead M easurements

________________________________ __________________ 4

- 57 Figure 4

- 8 Simulation of relationship between urinary Pb excretion and body burden in adults.

________________________________ __________ 4

- 58 4.3.4 Lead in Other Biomarkers

________________________________ __________________ 4

- 59 4.3.4.1 Teeth

________________________________ ______________________________ 4

- 59 4.3.4.2 Hair 4

- 60 4.3.4.3 Saliva

________________________________ ______________________________ 4

- 60 4.3.4.4 Serum δ

- ALA and ALAD

________________________________ _______________ 4

- 61 4.3.5 Relationship between Lead in Blood and Lead in Bone

___________________________ 4

- 61 4.3.5.1 Children

________________________________ ____________________________ 4

- 63 Figure 4

- 9 Simulation of relationship between blood Pb concentration and body burd en in children, with a constant Pb intake from age 2 to 5.

_______ 4

- 65 Figure 4

- 10 Simulation of relationship between time

- integrated blood Pb concentration and cumulative Pb absorption in children.

___________ 4

- 66 4.3.5.2 Adults

________________________________ _____________________________ 4

- 66 Figure 4

- 11 Simulation of relationship between blood Pb concentration, bone Pb and body burden in adults.

________________________________ __ 4

- 68 4.3.6 Relationship between Lead in Blood and Lead in Soft Tissues

______________________ 4

- 72 Figure 4

- 12 Simulation of blood and soft tissue (including brain) Pb in children and adults who experience a period of increased Pb intake.

________ 4

- 73 Figure 4

- 13 Simulation of blood and brain Pb in children and adults who experience a period of increased Pb intake.

_____________________ 4

- 75 Figure 4

- 14 Relationship between Pb in urine and Pb in blood.

________________ 4

- 77 4.4 Observational Studies of Lead Biomarker Levels

________________________________ ____ 4

- 78 4.4.1 Lead in Blood

________________________________ ____________________________ 4

- 78 Figure 4

- 15 Temporal trend in blood Pb concentration.

______________________ 4

- 79 Table 4

- 7 Blood Pb concentrations in the U.S. population.

__________________ 4

- 80 Figure 4

- 1 6 Box plots of blood Pb levels among U.S. children (1

- 5 years old) from the NHANES survey, 1988

- 2008.

_________________________ 4

- 82 Figure 4

- 17 Blood Pb cohort means versus year of exam.

____________________ 4

- 82 Figure 4

- 18 Percent distribution of blood Pb levels by race/ethnicity among U.S. children (1

- 5 years) from the NHANES survey, 1988

- 1991 (top) and 1999

- 2004 (bottom).

________________________________ _______ 4

- 83 Figure 4

- 19 Trends in 206 Pb/ 204 Pb isotope ratio in b lood Pb (a) and trends in blood Pb levels (b) among Australian study populations during the period 1990

- 2000.

________________________________ _________ 4

- 87 4.4.2 Lead in Bone

________________________________ ____________________________ 4

- 87 Table 4

- 8 Epidemiologic studies that provide bone Pb measurements for non

occupationally exposed populations

___________________________ 4

- 88 Table 4

- 9 Epidemiologic studies that provide bone Pb measurements for occupationally exposed populations

___________________________ 4

- 94 4.4.3 Lead in Urine

________________________________ ____________________________ 4

- 96 Table 4

- 10 Urine Pb concentrations in the U.S. population

___________________ 4

- 97 4.4.4 Lead in Teeth

________________________________ ____________________________ 4

- 98 Figure 4

- 20 Comparison of relative temporal changes in tooth enamel Pb concent ration.

________________________________ ____________ 4

- 99 4.5 Empirical Models of Lead Exposure

- Blood Lead Relationships

________________________ 4

- 100 4.5.1 Air Lead

- Blood Lead Relationships

________________________________ __________ 4

- 100 Table 4

- 11 Summary of estimated slopes for blood Pb to air Pb relationships in humans

________________________________ ______________ 4

- 102 Figure 4

- 21 Predicted relationship between air Pb and blood Pb based on a meta analysis of 18 studies.

________________________________ _____ 4

- 103 Figure 4

- 22 Blood Pb

– air Pb slope (μg/dL per μg/m 3 ) predicted from var ious epidemiologic studies (links available in Table 4

- 11).

_____________ 4

- 104 4.5.1.1 Children

________________________________ ___________________________ 4

- 104 Table 4

- 12 Environmental Pb levels and blood Pb levels in children in Trail, British Columbia

________________________________ _________ 4

- 105 Table 4

- 13 U.S. gasoline Pb consumption and air Pb levels

_________________ 4

- 108 Table 4

- 14 Air Pb levels and blood Pb levels in children in Mumbai, India

______ 4

- 109 Figure 4

- 23 Predicted re lationship between air Pb and blood Pb based on data from Chicago, IL in children age 0

- 5 y (1974

– 1988).

_____________ 4

- 110 4.5.1.2 Adults

________________________________ ____________________________ 4

- 110

### February 2012 xi Draft

– Do Not Cite or Quote Table 4

- 15 Significant predictors of blood Pb concentration in bridge painters

__ 4

- 111 4.5.2 Environmental Lead

- Blood Lead Relationships

________________________________ _ 4

- 112 Table 4

- 16 Linear model relating environmental Pb exposure and blood Pb concentration in children

________________________________ ___ 4

- 114 Figure 4

- 24 Predicted relationship between soil Pb concentration and blood Pb concentration in children based on data collected in the New

______ 4

- 115 Table 4

- 17 General linear model relating blood Pb concentration in children and environmental Pb levels

— Bunker Hill Superfund Site

____________ 4

- 117 4.6 Biokinetic Models of Lead Exposure

- Blood Lead Relationships

________________________ 4

- 117 4.7 Summary and Conclusions

________________________________ ____________________ 4

- 119 4.7.1 Exposure

________________________________ ______________________________ 4

- 119 4.7.2 Toxicokinetics

________________________________ ___________________________ 4

- 120 4.7.3 Le ad Biomarkers

________________________________ ________________________ 4

- 121 4.7.4 Air Lead

- Blood Lead Relationships

________________________________ __________ 4

- 123



### CHAPTER 5 INTEGRATED HEALTH EF FECTS OF LEAD EXPOSU RE

______________ 5

- 1

5.1 Introduction

________________________________ ________________________________ __ 5

- 1 5.2 Modes of A ction

________________________________ _______________________________ 5

- 2 5.2.1 Introduction

________________________________ _______________________________ 5

- 2 Figure 5

- 1 Schematic representation of the relationships between the various MOAs by which Pb exerts its health effects.

______________________ 5

- 3 5.2.2 Altered Ion Status

________________________________ __________________________ 5

- 3 5.2.2.1 Disruption of Ca 2+ Homeostasis

________________________________ __________ 5

- 3 5.2.2.2 Disruption of Ion Transport Mechanisms

________________________________ ___ 5

- 5 5.2.2.3 Displacement of Metal Ions and Perturbed Protein Function

____________________ 5

- 9 Table 5

- 1 Enzymes and proteins potentially affected by exposure to Pb and the metal cation cofactors necessary for their proper physiological activity

________________________________ __________________ 5

- 14 5.2.2.4 Mitochondrial Abnormality

________________________________ ______________ 5

- 15 5.2.3 Protein Binding

________________________________ ___________________________ 5

- 18 5.2.3.1 Intranuclear and Cytoplasmic Inclusion Bodies

_____________________________ 5

- 18 5.2.3.2 Cytosolic Lead Binding Proteins

________________________________ _________ 5

- 19 5.2.3.3 Erythrocytic Lead Bi nding Proteins

________________________________ _______ 5

- 20 5.2.3.4 Metallothionein

________________________________ ______________________ 5

- 21 5.2.4 Oxidative Stress

________________________________ __________________________ 5

- 23 5.2.4.1 δ

- ALA Oxidation

________________________________ _____________________ 5

- 23 5.2.4. 2 Membrane and Lipid Peroxidation

________________________________ _______ 5

- 24 5.2.4.3 NAD(P)H Oxidase Activation

________________________________ ___________ 5

- 25 5.2.4.4 Antioxidant Enzyme Disruption

________________________________ __________ 5

- 26 5.2.4.5 Nitric Oxide Signaling

________________________________ _________________ 5

- 28 5.2.5 Inflammation

________________________________ _____________________________ 5

- 29 5.2.5.1 Cytokine Production

________________________________ __________________ 5

- 30 5.2.6 Endocrine Disruption

________________________________ ______________________ 5

- 33 5.2.6.1 Hypothalamic

- Pituitary

- Gonadal Axis

________________________________ _____ 5

- 33 5.2.6.2 Hypothalamic

- Pituitary

- Thyroid Axis

________________________________ ______ 5

- 35 5.2.7 Cell Death and Genotoxicity

________________________________ _________________ 5

- 35 5.2.7.1 DNA Damage

________________________________ _______________________ 5

- 36 5.2.7.2 Mutagenicity

________________________________ ________________________ 5

- 39 5.2.7.3 Clastogenicity

________________________________ _______________________ 5

- 40 5.2.7.4 Epigenetic Effects

________________________________ ____________________ 5

- 4 4 5.2. 7.5 Gene Expression

________________________________ _____________________ 5

- 46 5.2.7.6 Apoptosis

________________________________ ___________________________ 5

- 47 5.2.8 Summary

________________________________ _______________________________ 5

- 48 Table 5

- 2 MOAs, their related health effects, and information on concentrations eliciting the MOAs

________________________________ _________ 5

- 49 5.3 Nervous System Effects

________________________________ _______________________ 5

- 52 5.3.1 Introduction

________________________________ ______________________________ 5

- 52 5.3.2 Cognitive Function and Learning

________________________________ _____________ 5

- 55 5.3.2.1 Epidemiologic Studies of Cognitive Function in Children

______________________ 5

- 55 Figure 5

- 2 Associations of blood P b levels with full

- scale IQ (FSIQ) among children.

________________________________ _________________ 5

- 57

### February 2012 xii Draft

– Do Not Cite or Quote Table 5

- 3 Additional characteristics and quantitative results for studies

re

presented in Figure 5

- 2

________________________________ ___ 5

- 58 Figure 5

- 3 Effect modification of the association between concurrent blood Pb level and FSIQ by blood Mn level.

_____________________________ 5

- 63 Table 5

- 4 Associations of blood Pb level with Bayley MDI in children ages 6 months to 3 years a

________________________________ _______ 5

- 67 Figure 5

- 4 Regression of fitted MDI score at 36 months on log

- transformed cord blood Pb level by sex.

________________________________ ______ 5

- 69 Figure 5

- 5 Standardized regression coefficients describing the associations of blood Pb levels with specific indices of cognitive function in children

.

_ 5

- 74 Table 5

- 5 Additional characteristics and quantitative results for studies represented in Figure 5

- 5

________________________________ ___ 5

- 75 Figure 5

- 6 Associations between childhood blood Pb levels and fourth grade End

- of

- Grade (EOG) math scores.

____________________________ 5

- 82 Figure 5

- 7 Greater reduction in EOG achievement test scores with increasing blood Pb level in lower percentiles of the test score distribution.

_____ 5

- 83 5.3.2.2 Toxicological Studies of Cognition, Memory and Learning

_____________________ 5

- 84 Figure 5

- 8 Nervous system summary array of toxicological outcomes after Pb exposure.

________________________________ ________________ 5

- 85 Table 5

- 6 Summary of findings from neurotoxicological exposure

- response array presented in Figure 5

- 8

________________________________ 5

- 86 Table 5

- 7 Summary of effects of maternal and lifetime Pb exposure on FI performance

________________________________ ___________ 5

- 91 Figure 5

- 9 Mean basal corticosterone levels of female and male offspring exposed to lifetime Pb.

________________________________ _____ 5

- 94 Figure 5

- 10 Changes in FI performance (FI overall performance, run rate, PRP ) in female offspring with maternal Pb exposure plus various stressors (restraint, cold, novelty) in adulthood.

__________________________ 5

- 97 Figure 5

- 11 Ch anges in FI performance (FI overall performance, run rate, PRP) in male offspring with maternal Pb exposure plus various stressors (restraint, cold, novelty) in adulthood.

__________________________ 5

- 98 5.3.2.3 Toxicological Studies on the Effects of Chelation

____________________________ 5

- 99 5.3.2.4 Integrated Summary of Cognitive Function in Children

______________________ 5

- 100 5.3.2.5 Epidemiologic Studies of Cognitive Function in Adults

_______________________ 5

- 103 Table 5

- 8 Associations of blood and bone Pb levels with cognitive function in adults a

________________________________ _________________ 5

- 106 Figure 5

- 12 Nonlinear association between patella Pb level and the relative change over time in response latency on the pattern comparison test.

________________________________ ___________________ 5

- 111 Figure 5

- 13 Exploration of nonlinear association of tibia Pb level with annual rate of cognitive decline, by hemochromatosis (HFE) gene variant.

_____ 5

- 112 5.3.3 Behavioral Effects

________________________________ _______________________ 5

- 118 5.3.3.1 Epidemiologic Studies of Behavioral Effects in Children

_____________________ 5

- 118 Figure 5

- 14 Associations of blood Pb levels with behavioral indices of inattention, hyperactivity, and impulsivity.

_______________________________ 5

- 124 Table 5

- 9 Additional characteristics and quantitative results for studies presented in Figure 5

- 14

________________________________ ___ 5

- 125 Table 5

- 10 Associations between blood Pb level and ADHD diagnosis or diagnostic indices in children

________________________________ 5

- 128 Figure 5

- 15 Adjusted odds ratios for Attention Deficit Hyperactivity Disorder (ADHD) among U.S. children.

_______________________________ 5

- 130 Table 5

- 11 Associations between blood Pb level and misconduct and delinquent behavior in children and young adults a

________________________ 5

- 133 5.3.3.2 Toxicological Studies of Behavior

________________________________ _______ 5

- 137 5.3.3.3 Epidemiologic Studies of Mood in Children

________________________________ 5

- 141 5.3.3.4 Epidemiologic Studies of Mood and Psychiatric Effects in Adults

______________ 5

- 143 5.3.3.5 Toxicological Studies of Mood, Emotional, and Psychotic Changes

____________ 5

- 145 Figure 5

- 16 Animal toxicology evidence of possible Pb

- induced contributors to the development of mood and psychotic disorders.

______________ 5

- 146 Figure 5

- 17 Schematic representation of the contribution of Pb exposure to the development of a phenotype consistent with schizophrenia.

_______ 5

- 148

### February 2012 xiii Draft

– Do Not Cite or Quote Figure 5

- 18 Neurogenesis (production of new cells) in the rat dentate gyrus after postnatal Pb exposure.

________________________________ ____ 5

- 149 5.3.3.6 Integrated Summary of Behavior and Mood

_______________________________ 5

- 149 5.3.4 Sensory Organ Function

________________________________ __________________ 5

- 151 5.3.4.1 Epidemiologic Studies of Sensory Organ Function in Children

________________ 5

- 151 5.3.4.2 Epidemiologic Studies of Sensory Organ Function in Adults

__________________ 5

- 152 5.3.4.3 Toxicological Studies of Sensory Organ Function

__________________________ 5

- 154 Table 5

- 12 Summary of Pb

- related retinal ERG studies

____________________ 5

- 157 Figure 5

- 19 Retinal a

- wave and b

- wave ERG amplitude in adult rodents after prenatal and early postnatal Pb exposure.

_____________________ 5

- 158 Figure 5

- 20 Retinal dopamine metabolism in adult control and gestationally lead

exposed (GLE) rats.

________________________________ ______ 5

- 160 5.3.5 Motor Function

________________________________ __________________________ 5

- 161 5.3.6 Seizures in Animals

________________________________ ______________________ 5

- 162 5.3.7 Neurodegenerative Diseases

________________________________ _______________ 5

- 163 5.3.7.1 Epidemiologic Studies of Neurodegenerative Diseases in Adults

______________ 5

- 163 5.3.7.2 Toxicological Studies of Neurodegenerative Disease

________________________ 5

- 167 5.3.8 Modes of Action for Lead Nervous System Effects

______________________________ 5

- 172 5.3.8.1 Effects on Brain Physiology and Activity

________________________________ __ 5

- 172 5.3.8.2 Oxidative Stress

________________________________ ____________________ 5

- 174 5.3. 8.3 Nitrosative Signaling and Nitrosative Stress

_______________________________ 5

- 177 5.3.8.4 Synaptic Changes

________________________________ ___________________ 5

- 177 5.3.8.5 Blood Brain Barrier

________________________________ __________________ 5

- 179 5.3.8.6 Cell Adhes ion Molecules

________________________________ ______________ 5

- 181 5.3.8.7 Glial Effects

________________________________ ________________________ 5

- 181 5.3.8.8 Neurotransmitters

________________________________ ___________________ 5

- 182 5.3. 8.9 Neurite Outgrowth

________________________________ ___________________ 5

- 187 5.3.8.10 Epigenetics

________________________________ ________________________ 5

- 188 5.3.8.11 Cholesterol and Lipid Homeostasis

________________________________ ______ 5

- 189 5.3.9 Lifestage of Lead Exposure and Neurodevelopmental Deficits

_____________________ 5

- 189 Table 5

- 13 Associations of cognitive function and behavioral outcomes with blood Pb levels mea sured at different lifestages a

________________ 5

- 192 Figure 5

- 21 Associations of cognitive function in children with different degrees of changes i n blood Pb levels over time.

_______________________ 5

- 197 Table 5

- 14 Additional characteristics and quantitative results for studies presented in Figure 5

- 21

________________________________ ___ 5

- 198 Figure 5

- 22 Estimated IQ in combined Cincinnati and Rochester cohorts, for three patterns of blood Pb level levels from 1 through 6 years of age: peak at 2 years (blue diamonds), peak at 5 years (black triangles), and constant blood Pb level (white squares).

___________________ 5

- 199 5.3.10 Examination of the Lead Concentration

- Response Relationship

____________________ 5

- 200 Figure 5

- 23 Comparison of associations between blood Pb level and cognitive function among various blood Pb strata.

_______________________ 5

- 202 Table 5

- 15 Additional characteristics and quantitative r esults for studies presented in Figure 5

- 23

________________________________ ___ 5

- 203 5.3.11 Confounding in Epidemiologic Studies of Nervous System Effects

__________________ 5

- 209 5.3.12 Public Health Significance of Associations between Lead Biomarkers and Neurodevelopmental Effects

________________________________ ________________________________ 5

- 213 Figure 5

- 24 Effect of blood Pb level on the proportion of the population with IQ levels <70 and <80 points.

________________________________ __ 5

- 216 5.3.13 Summary and Causal Determination

________________________________ _________ 5

- 217 5.3.13.1 Cognitive Function in Children

________________________________ _________ 5

- 217 5.3.13.2 Behavior in Children

________________________________ _________________ 5

- 218 5.3.13.3 Other Nervous System Effects in Children

________________________________ 5

- 219 5.3.13.4 Factors that Modify Risk in Children

________________________________ _____ 5

- 220 5.3.13.5 Nervous System Effects in Adults

________________________________ _______ 5

- 221 5.3.13.6 Neurophysiological and Neurochemical Changes

__________________________ 5

- 222 5.3.13.7 Lifestages and Duration of Lead Exposure

________________________________ 5

- 222 5.3.13.8 The Lead Concentration

- Response Relationship

___________________________ 5

- 223 5.3.13.9 Evidence that Forms the Basis of the Causal Determination

__________________ 5

- 224 5.4 Cardiovascular Effects

________________________________ ________________________ 5

- 225 5.4.1 Introduction

________________________________ _____________________________ 5

- 225

### February 2012 xiv Draft

– Do Not Cite or Quote 5.4.2 Bloo d Pressure and Hypertension

________________________________ ___________ 5

- 227 5.4.2.1 Epidemiology

________________________________ _______________________ 5

- 227 Figure 5

- 25 Concentration

- response relationships (95% CI).

_________________ 5

- 229 Table 5

- 16 Additional characteristics and quantitative data for associations of blood and bone Pb with BP measures for studies presented in Figure 5

- 25

________________________________ _____________ 5

- 230 Figure 5

- 26 Odds ratios (95% CI) for associations of blood and bone Pb with hypertension prevalence and incidence.

_______________________ 5

- 233 Table 5

- 17 Additional characteristics and quantitative data for associations of blood and bone Pb with hypertension measures for results present ed in Figure 5

- 26

________________________________ ___ 5

- 234 Figure 5

- 27 The relationship between tibia Pb and estimated systolic BP (SBP) for those with high self

- repor ted stress versus those with low self

reported stress.

________________________________ __________ 5

- 239 5.4.2.2 Toxicology

________________________________ _________________________ 5

- 241 Figure 5

- 28 Changes in BP after Pb exposure (represented as blood Pb level) in unanesthetized adult rats across studies.

______________________ 5

- 242 Table 5

- 18 Characteristics of studies of blood Pb with BP measures in animals presented in Figure 5

- 28

________________________________ ___ 5

- 243 5.4.2.3 Hypertension Modes of Action

________________________________ _________ 5

- 244 5.4.2.4 Summary of Blood Pressure and Hypertension

____________________________ 5

- 252 Figure 5

- 29 Change in systolic BP (SBP), in mmHg with 95% CI, associated with a doubling in the blood Pb concentration.

______________________ 5

- 254 Figure 5

- 30 Prospective and cross

- sectional increase in systolic BP (SBP) and diastolic BP (DBP) a nd relative risk of hypertension per 10 μg/g increase in bone Pb levels.

________________________________ _ 5

- 255 5.4.3 Vascular Effects and Cardiotoxicity

________________________________ __________ 5

- 256 5.4.3.1 Effects on Vascular Cell Types

________________________________ _________ 5

- 256 5.4.3.2 Cholesterol

________________________________ ________________________ 5

- 258 5.4.3.3 He art Rate Variability

________________________________ ________________ 5

- 259 5.4.3.4 Peripheral Artery Disease

________________________________ _____________ 5

- 261 5.4.3.5 Ischemic Heart Disease

________________________________ ______________ 5

- 262 5.4.3.6 Atherosclerosis

________________________________ _____________________ 5

- 263 Table 5

- 19 Characteristics and quantitative data for associations of blood and bone Pb with other CVD measures in epidemiologi c studies ordered as they appear in the text

________________________________ __ 5

- 264 5.4.3.7 Summary of Vascular Effects and Cardiotoxicity

___________________________ 5

- 265 5.4.4 Cardiovascular Function and Blood Pressure in Children

_________________________ 5

- 266 5.4.4.1 Introduction

________________________________ ________________________ 5

- 266 Table 5

- 20 Studies of Children Cardiovascular Endpoints and Pb Biomarkers Ordered as They Appear in the Text

__________________________ 5

- 268 5.4.4.2 Cardiovascular F unctioning in Children

________________________________ __ 5

- 269 Figure 5

- 31 Children’s adjusted total peripheral resistance (dyn

- s/cm 5 ) responses to acute stress task s, as a function of childhood Pb levels.

________ 5

- 270 5.4.4.3 Blood Pressure in Children

________________________________ ____________ 5

- 271 5.4.4.4 Summary of Child Cardiovascular Studies

________________________________ 5

- 272 5.4.5 Mortality

________________________________ _______________________________ 5

- 274 Figure 5

- 32 Multivariate adjusted relative hazards of all

- cause and cardiovascular mortality.

________________________________ ___ 5

- 276 Figure 5

- 33 Multivariate

- adjusted relative hazard (left axis) of mortality associated with blood Pb level between 1 μg/dL and 10 μg/dL.

_____ 5

- 277 Figure 5

- 34 Relative risk of all cause mortality for different blood Pb levels compared with referent level of 1.5 μg/dL (12.5th percentile).

______ 5

- 278 Figure 5

- 35 Associations between patella bone Pb level and the log of HR (logHR) for all

- cause, cardiovascular, and ischemic heart dis ease.

__ 5

- 280 Figure 5

- 36 Multivariate adjusted relative hazard (left axis) of mortality as a function of blood Pb levels between 1 μg /dL and 15 μg/dL.

________ 5

- 281 5.4.5.1 Summary of Mortality

________________________________ ________________ 5

- 281 Figure 5

- 37 Hazard ratios for associations of blood Pb (closed markers) and bone Pb (open markers) with all

- cause mortality (black diamonds) and cardiovascular mortality (blue circles).

_____________________ 5

- 283

### February 2012 xv Draft

– Do Not Cite or Quote Table 5

- 21 Additional characteristics and quantitative data for associations of blood and bone Pb wi th CVD mortality for studies presented in Figure 5

- 37

________________________________ _____________ 5

- 284 5.4.6 Air Lead

- Particulate Matter Studies

________________________________ __________ 5

- 286 5.4.6.1 Cardiovascular Morbidity

________________________________ ______________ 5

- 286 5.4.6.2 Mortality

________________________________ ___________________________ 5

- 287 5.4.7 Summar y and Causal Determination

________________________________ _________ 5

- 287 5.5 Renal Effects

________________________________ _______________________________ 5

- 292 5.5.1 Introduction

________________________________ _____________________________ 5

- 292 5.5.1.1 Ki dney Outcome Measures

________________________________ ____________ 5

- 294 5.5.2 Nephrotoxicity and Renal Pathology

________________________________ _________ 5

- 295 5.5.2.1 Toxicology

________________________________ _________________________ 5

- 295 Figure 5

- 38 Concentration

- response representation of the effect of Pb on renal outcomes in animal toxicology studies.

________________________ 5

- 296 Table 5

- 22 Additional characteristics for results of toxicological studies presented in Figure 5

- 38

________________________________ ___ 5

- 297 Table 5

- 23 Indicators of renal damage in male rats exposed to 50 ppm Pb for 40 and 65 days, starting at parturition

___________________________ 5

- 299 Table 5

- 24 Effects of Pb on the kidney/renal system related to exposure durati on

– evidence from animal toxicology studies

_______________ 5

- 306 5.5.2.2 Epidemiology in Adults

________________________________ _______________ 5

- 306 Figure 5

- 39 Kidney metric slopes for blood Pb or bone Pb.

__________________ 5

- 310 Figure 5

- 40 Percent change for kidney outcomes associated with blood Pb.

____ 5

- 312 Table 5

- 25 Additional ch aracteristics and quantitative data for associations of blood and bone Pb with kidney outcomes for results presented in Figure 5

- 39 and Figure 5

- 40

________________________________ 5

- 313 Table 5

- 26 Patient population studies: kidney function decline

_______________ 5

- 317 Table 5

- 27 Clinical randomized chelation trials in chronic kidney disease patients

________________________________ ________________ 5

- 321 Figure 5

- 41 Added variable plot of association between serum creatinine and blood Pb in 267 Korean Pb workers in the oldest age tertile.

_______ 5

- 324 5.5.2.3 Epidemiology in Children

________________________________ _____________ 5

- 325 5.5.2.4 Associations between Lead Dose and New Kidney Outcome Measures

_________ 5

- 327 5.5.2.5 Reverse Causality

________________________________ ___________________ 5

- 327 5.5.3 Modes of Action for Lead

- Induced Nephrotoxicity

_______________________________ 5

- 328 5.5.3.1 Altered Uric Acid

________________________________ ____________________ 5

- 328 5.5.3.2 Oxidative Damage

________________________________ ___________________ 5

- 329 5.5.3.3 Renal Gangliosides

________________________________ __________________ 5

- 333 5.5.3.4 Role of Metallothionein

________________________________ _______________ 5

- 333 5.5.4 Effects of Exposure to Lead Mixtures

________________________________ ________ 5

- 334 5.5.4.1 Lead and Cadmium

________________________________ __________________ 5

- 335 5.5. 4.2 Lead, Cadmium, and Arsenic

________________________________ __________ 5

- 337 5.5.4.3 Lead and Zinc

________________________________ ______________________ 5

- 337 5.5.4.4 Lead and Mercury

________________________________ ___________________ 5

- 338 5.5.5 Impact of Treatment with Antioxidants on Renal Lead Accumulation and Pathology

____ 5

- 339 5.5.5.1 Treatment with Antioxidants

________________________________ ___________ 5

- 339 5.5.5.2 Treatment with Antioxidant s plus Chelators

_______________________________ 5

- 342 5.5.6 Summary and Causal Determination

________________________________ _________ 5

- 343 5.6 Immune System Effects

________________________________ _______________________ 5

- 346 5.6.1 Introduction

________________________________ _____________________________ 5

- 346 Figure 5

- 4 2 Immunological pathways by which Pb exposure may increase risk of immune

- related diseases.

________________________________ __ 5

- 348 5.6.2 Cell

- Mediated Immunity

________________________________ ___________________ 5

- 350 5.6.2.1 T Cells

________________________________ ____________________________ 5

- 350 5.6.2.2 Lymphocyte Activation

________________________________ _______________ 5

- 353 5.6.2.3 Delayed

- type Hypersensitivity

________________________________ __________ 5

- 354 5.6.2.4 Macrophages and Monocytes

________________________________ __________ 5

- 355 5.6.2.5 Neutrophils

________________________________ ________________________ 5

- 357 5.6.2.6 Dendritic Cells

________________________________ ______________________ 5

- 359 5.6.2.7 Natural Killer Cells

________________________________ ___________________ 5

- 360 5.6.3 Humoral Immunity

________________________________ _______________________ 5

- 361

### February 2012 xvi Draft

– Do Not Cite or Quote Table 5

- 28 Comparison of serum immunoglobulin levels and B cell abun dance among various blood Pb groups

_____________________________ 5

- 364 5.6.4 Immune

- based Diseases

________________________________ __________________ 5

- 368 5. 6.4.1 Host Resistance

________________________________ ____________________ 5

- 368 5.6.4.2 Asthma and Allergy

________________________________ __________________ 5

- 369 Figure 5

- 43 Associations of blood Pb levels with asthma

- and allergy

- related conditions in children.

________________________________ _____ 5

- 370 Table 5

- 29 Additional characteristics and quantitative results for studies presented in Figure 5

- 43

________________________________ ___ 5

- 371 5.6.4.3 Other Respiratory Effects

________________________________ _____________ 5

- 374 5.6.4.4 Autoimmunity

________________________________ _______________________ 5

- 376 5.6.4.5 Specialized Cells in Other Tissues

________________________________ ______ 5

- 376 Figure 5

- 44 Specialized macrophages in nonlymphoid tissue may serve as a link between Pb exposure and disease in multiple organ systems.

_____ 5

- 377 5.6.4.6 Tumors

________________________________ ___________________________ 5

- 378 5.6.5 Modes of Action for Lead Immune Effects

________________________________ _____ 5

- 378 5.6.5.1 Infl ammation

________________________________ _______________________ 5

- 378 5.6.5.2 Increased Prostaglandin E 2 and Decreased Nitric Oxide

_____________________ 5

- 380 5.6.5.3 Cellular Death (Apoptosis, Necrosis)

________________________________ ____ 5

- 382 5.6.5.4 Cytokine Production

________________________________ _________________ 5

- 383 5.6.6 Air

- Lead Studies

________________________________ _________________________ 5

- 386 5.6.7 Immune Effects of Lead within Mixtures

________________________________ ______ 5

- 388 5.6.8 Summary and Causal Determination

________________________________ _________ 5

- 389 5.7 Effects on Heme Synthesis and Red Blood Cell Function

____________________________ 5

- 394 5.7.1 Summary of Findings from 2006 Pb AQCD

________________________________ ____ 5

- 394 5.7.2 Red Blood Cell Functions

________________________________ __________________ 5

- 396 5.7.2.1 Pb Uptake, Binding, and Transport into Red Blood Cells

_____________________ 5

- 396 5.7.2.2 Red Blood Cell Survival, Mobility, and Membrane Integrity

___________________ 5

- 397 5.7.2.3 Red Blood Cell Hematopoiesis

________________________________ _________ 5

- 404 5.7.2.4 Membrane Proteins

________________________________ __________________ 5

- 405 5.7.3 Red Blood Cell Heme Metabolism

________________________________ ___________ 5

- 406 Figure 5

- 45 Schematic representation of the enzymatic steps involved in the heme synthetic pathway.

________________________________ ___ 5

- 406 5.7.3.1 Red Blood Cell 5

- Aminolevulinic Acid Dehydratase

_________________________ 5

- 407 5.7.4 Other Heme Metabolism Enzymes

________________________________ __________ 5

- 4 08 5.7.5 Other Hematological Parameters

________________________________ ____________ 5

- 409 5.7.5.1 Energy Metabolism

________________________________ __________________ 5

- 409 5.7.5.2 Other Enzymes

________________________________ _____________________ 5

- 410 5.7.6 Red Blood Cell Oxidative Stress

________________________________ ____________ 5

- 410 5.7.6.1 Oxidative Stress, Lipid Peroxidation, and Antioxidant Enzymes

________________ 5

- 411 5.7.6.2 Antioxidant Defense

________________________________ _________________ 5

- 413 5. 7.7 Summary and Causal Determination

________________________________ _________ 5

- 414 5.8 Reproductive and Developmental Effects

________________________________ _________ 5

- 417 5.8.1 Effects on Female Reproductive Function

________________________________ _____ 5

- 418 5.8.1.1 Effects on Female Sex Endocrine System and Estrus Cycle

__________________ 5

- 418 Table 5

- 30 Summary of recent epidemiologic stu dies of associations between Pb levels and hormones for females

__________________________ 5

- 419 5.8.1.2 Effects on Fertility

________________________________ ___________________ 5

- 423 Table 5

- 31 Summary of recent epidemiologic studies of associations between Pb levels and fertility for females

_____________________________ 5

- 424 5.8.1.3 Effects on Puberty

________________________________ ___________________ 5

- 427 Table 5

- 32 Sum mary of recent epidemiologic studies of associations between Pb levels and puberty for females

____________________________ 5

- 428 Figure 5

- 46 Toxicological expo sure

- response array for reproductive effects of Pb.

________________________________ __________________ 5

- 432 Table 5

- 33 Toxicological concentration

- response array summary for reproductive effects of Pb presented in Figure 5

- 46

______________ 5

- 433 5.8.1.4 Effects on Lactation

________________________________ __________________ 5

- 435 5.8.1.5 Summary of Effects on Female Reproductive Function

______________________ 5

- 436 5.8.2 Effects on Male Reproductive Function

________________________________ _______ 5

- 436 5.8.2.1 Effects on Sperm/Semen Production, Quality, and Function

__________________ 5

- 437

### February 2012 xvii Draft

– Do Not Cite or Quote Table 5

- 34 Summary of recent epidemiologic studies of associations between Pb levels and effects on sperm and semen

____________________ 5

- 437 5.8.2.2 Effects on Hormone Levels

________________________________ ____________ 5

- 444 Table 5

- 35 Summary of recent epidemiologic studies of associations between Pb levels and hormones for males

___________________________ 5

- 445 5.8.2.3 Fertility

________________________________ ____________________________ 5

- 450 5.8.2.4 Puberty

________________________________ ___________________________ 5

- 451 Table 5

- 36 Sum mary of recent epidemiologic studies of associations between Pb levels and puberty for males

_____________________________ 5

- 452 5.8.2.5 Effects on Morphology an d Histology of Male Sex Organs

____________________ 5

- 455 5.8.2.6 Summary of Effects on Male Reproductive Function

________________________ 5

- 455 5.8.3 Effects on Ovaries, Embryo Development, Placental function, and Spontaneous Abortions 5

- 456 Table 5

- 37 Summary of recent epidemiologic studies of associations between Pb levels and spontaneous abortions

_________________________ 5

- 457 5.8.4 Infant Mortality and Embryogenesis

________________________________ __________ 5

- 460 5.8.5 Birth Defects

________________________________ ____________________________ 5

- 460 Table 5

- 38 Summary of recent epidemiologic studies of associations between P

b levels and neural tube defects

____________________________ 5

- 461 5.8.6 Preterm Birth

________________________________ ___________________________ 5

- 462 Table 5

- 39 Summary of recent epidemiologic studies of associations between Pb levels and preterm birth

________________________________ _ 5

- 463 5.8.7 Low Birth Weight/Fetal Growth

________________________________ _____________ 5

- 466 Table 5

- 40 Summary of recent epidemiologic studies of associations between Pb levels and low birth weight and fetal growth

_________________ 5

- 467 5.8.8 Effects on Postnatal Stature and Body Weight

________________________________ _ 5

- 475 Table 5

- 41 Summary of recent epidemiologic studies of associations between Pb levels and postnatal growth

______________________________ 5

- 476 5.8.9 Toxicological Studies of Developmental Effects

________________________________ 5

- 483 5.8.9.1 Developmental Effects on Blood and Liver

________________________________ 5

- 483 5.8.9.2 Developmental Effects on Skin

________________________________ _________ 5

- 484 5.8.9.3 Developmental Effects on the Retina

________________________________ ____ 5

- 484 5.8.9.4 Developmental Effects on Teeth

________________________________ ________ 5

- 485 5.8.10 Summary and Causal Determination

________________________________ _________ 5

- 485 5.9 Effects on Other Organ Systems

________________________________ ________________ 5

- 488 5.9.1 Effects on the Hepatic System

________________________________ ______________ 5

- 488 5.9.1.1 Summary of Key Findings of the Effects on the Hepatic System from the 2006 Lead AQCD

________________________________ ____________________________ 5

- 488 5.9.1.2 New Epidemiologic Studies

________________________________ ____________ 5

- 489 5.9.1.3 New Toxicological Studies

________________________________ ____________ 5

- 49 0 5.9.2 Effects on the Gastrointestinal System

________________________________ _______ 5

- 496 5.9.2.1 Summary of Key Findings on the Effects on the Gastrointestinal System from the 2006 Lead AQCD

________________________________ ________________________ 5

- 496 5.9.2.2 New Epidemiologic Studies

________________________________ ____________ 5

- 497 5.9.2.3 New Toxicological Studies

________________________________ ____________ 5

- 497 5.9.3 Effects on the Endocrine System

________________________________ ____________ 5

- 498 5.9.3.1 Summary of Key Findings of the Effects on the Endocrine System from the 2006 Lead AQCD

________________________________ ____________________________ 5

- 498 5.9.3.2 New Epidemiologic Studies

________________________________ ____________ 5

- 498 5.9.3.3 New Toxicological Studies

________________________________ ____________ 5

- 501 5.9.4 Effects on Bone and Teeth

________________________________ _________________ 5

- 501 5.9.4.1 Summary of Key Findings of the Effects on Bone and Teeth from the 2006 Lead AQCD 5

- 502 5.9.4.2 New Toxicological and Epidemiologic Studies

_____________________________ 5

- 503 5.9.5 Effects on Ocular Health

________________________________ __________________ 5

- 507 5.9.5.1 Summary of Key Findings of the Effects on Ocular Health from the 2006 Lead AQCD 5

- 507 5.9.5.2 New Toxicological and Epidemiologic Studies

_____________________________ 5

- 507 5.9.6 Effects on the Respiratory System

________________________________ ___________ 5

- 508 5.9.7 Summary

________________________________ ______________________________ 5

- 509 5.10 Cancer

________________________________ ________________________________ ____ 5

- 511 5.10.1 Cancer Incidence and Mortality

________________________________ _____________ 5

- 512 Table 5

- 42 Summary of recent epidemiologic studies a of cancer incidence and mortality

________________________________ ________________ 5

- 513 5.10.1.1 Overall Cancer Mortality

________________________________ ______________ 5

- 517

### February 2012 xviii Draft

– Do Not Cite or Quote 5.10.1.2 Lung Cancer

________________________________ _______________________ 5

- 518 5.10.1.3 Brain Cancer

________________________________ _______________________ 5

- 519 5.10.1.4 Breast Cancer

________________________________ ______________________ 5

- 520 5.10.1.5 Other Cancers

________________________________ ______________________ 5

- 521 5.10.1.6 Toxicological Models of Carcinogenicity

________________________________ __ 5

- 523 5.10.2 Cancer Biomarkers

________________________________ _______________________ 5

- 524 5.10.3 DNA and Cellular Damage

________________________________ _________________ 5

- 525 5.10.3.1 Epidemiologic E vidence for DNA and Cellular Damage

______________________ 5

- 525 5.10.3.2 Toxicological Evidence for DNA and Cellular Damage

_______________________ 5

- 526 5.10.4 Effects of Lead within Mixtures

________________________________ _____________ 5

- 533 5.10.5 Modes of Action

________________________________ _________________________ 5

- 534 5.10.5 .1 Epigenetics

________________________________ ________________________ 5

- 535 5.10.6 Summary and Causal Determination

________________________________ _________ 5

- 536



### CHAPTER 6 POTENTIALLY AT

- RISK POPULATIONS

___________________________ 6

- 1

6.1 Physiological Factors that Influence the Internal Distribution of Lead

______________________ 6

- 2 6.2 Population Characteristics Potentially Related to Differential Lead Exposure

_______________ 6

- 4 6. 2.1 Age 6

- 4 6.2.1.1 Early Childhood

________________________________ _______________________ 6

- 4 Table 6

- 1 Blood Pb levels by age and sex, 2007

- 2008 NHANES

______________ 6

- 5 Table 6

- 2 Percentage of children within six categories/brackets of blood Pb levels, 1999

- 2004 NHANES

________________________________ __ 6

- 6 6.2.1.2 Adulthood

________________________________ ___________________________ 6

- 7 6.2.2 Sex 6

- 7 6.2.3 Race and Ethnicity

________________________________ _________________________ 6

- 8 Figure 6

- 1 Percent distribution of blood Pb levels by race/ethnicity among U.S. children (1

- 5 years).

________________________________ _________ 6

- 9 Figure 6

- 2 Soil Pb concentration exposure among the population of three parishes within greater metropolitan New Orleans.

________________ 6

- 10 6.2.4 Socioeconomic Status (SES)

________________________________ ________________ 6

- 10 6.2.5 Proximity to Lead Sources

________________________________ __________________ 6

- 12 6.2.6 Residential Factors

________________________________ ________________________ 6

- 13 Table 6

- 3 Regression of log

- transformed blood Pb level of childr en 12

- 60 months old on various factors related to housing condition, from 1999

- 2004 NHANES dataset

________________________________ _ 6

- 14 6.3 Factors Potentially Rela ted to Increased Risk of Lead Induced Health Effects

_____________ 6

- 15 Table 6

- 4 Summary of evidence for factors that potentially increase the risk of lead

- related health effects

________________________________ ___ 6

- 16 6.3.1 Age 6

- 16 6.3.1.1 Children

________________________________ ____________________________ 6

- 16 6.3.1.2 Older Adults

________________________________ _________________________ 6

- 18 6.3.2 Sex 6

- 19 6.3.3 Genetics

________________________________ ________________________________ 6

- 22 6.3.3.1 Aminolevulinate Dehydratase

________________________________ ___________ 6

- 23 6.3.3.2 Vitamin D Receptor

________________________________ ___________________ 6

- 24 6.3.3.3 Methylenetetrahydrofolate reductase

________________________________ _____ 6

- 24 6.3.3.4 Apolipoprotein E

________________________________ _____________________ 6

- 25 6.3.3.5 Hemochromatosis

________________________________ ____________________ 6

- 25 6.3.3. 6 Other Genetic Polymorphisms

________________________________ __________ 6

- 25 6.3.4 Pre

- existing Diseases/Conditions

________________________________ ____________ 6

- 26 6.3.4.1 Autism

________________________________ _____________________________ 6

- 27 6.3.4.2 Atopy

________________________________ ______________________________ 6

- 27 6.3.4.3 Diabetes

________________________________ ___________________________ 6

- 27 6.3.4.4 Hypertension

________________________________ ________________________ 6

- 28 6.3.5 Smoking

________________________________ ________________________________ 6

- 29 6.3.6 Race/Ethnicity

________________________________ ___________________________ 6

- 30 6.3.7 Soci oeconomic Status

________________________________ _____________________ 6

- 31 6.3.8 Body Mass Index

________________________________ _________________________ 6

- 31 6.3.9 Alcohol Consumption

________________________________ ______________________ 6

- 32 6.3.10 Nutritional Factors

________________________________ ________________________ 6

- 32 6.3.10.1 Calcium

________________________________ ____________________________ 6

- 32

### February 2012 xix Draft

– Do Not Cite or Quote 6.3.10.2 Iro n 6

- 32 6.3.10.3 Folate

________________________________ _____________________________ 6

- 33 6.3.10.4 Protein

________________________________ _____________________________ 6

- 33 6.3.11 Stress

________________________________ ________________________________ __ 6

- 33 6.3.12 Cognitive Reserve

________________________________ ________________________ 6

- 34 6.3.13 Other Metal Exposure

________________________________ _____________________ 6

- 34 6.3.13.1 Cadmium

________________________________ ___________________________ 6

- 35 6.3.13.2 Arsenic

________________________________ ____________________________ 6

- 35 6.3.13.3 Manganese

________________________________ _________________________ 6

- 35 6.4 Summary

________________________________ ________________________________ ___ 6

- 36



### CHAPTER 7 ECOLOGIC AL EFFECTS OF LEAD

_______________________________ 7

- 1

7.1 Introduction to Ecological Concepts

________________________________ _______________ 7

- 1 7.1.1 Ecosystem Scale, Function, and Structure

________________________________ ______ 7

- 2 7.1.2 Ecosystem Services

________________________________ ________________________ 7

- 4 7.1.3 Critical Loads as an Organizing Principle for Ecological Effects of Atmospheric Deposition 7

- 5 7.1.4 Ecosystem Exposure, Lag Time and Re

- entrainment of Historically Deposited Lead

______ 7

- 6 Table 7

- 1 Comparison among several metals: Time to achieve 95% of steady state metal concentration in soil; example in a temperate system

_____ 7

- 8 7.2 Terrestrial Ecosystem Effects

________________________________ ____________________ 7

- 9 7.2.1 Introduction to Terrestrial Ecosystem Effects

________________________________ _____ 7

- 9 7.2.2 Soil Biogeochemistry and Chemical Ef fects

________________________________ _____ 7

- 10 7.2.2.1 pH, CEC and Salinity

________________________________ _________________ 7

- 10 7.2.2.2 Organic Matter

________________________________ _______________________ 7

- 11 7.2.2.3 Aging

________________________________ ______________________________ 7

- 13 7.2.3 Bioavailability in Terrestrial Systems

________________________________ __________ 7

- 14 Figure 7

- 1 Conceptual diagram for evaluating bioavailability processes and bioaccessibility for metals in soil, sediment, or aquatic systems.

_____ 7

- 16 Figure 7

- 2 Schematic diagram of the biotic ligand model.

___________________ 7

- 17 7.2.3.1 Terrestrial Plants

________________________________ _____________________ 7

- 17 7.2.3.2 Terrestrial Invertebrates

________________________________ _______________ 7

- 26 7.2.3.3 Terrestrial Vertebrates

________________________________ ________________ 7

- 30 7.2.3.4 Food Web

________________________________ __________________________ 7

- 32 7.2.4 Biological Effects

________________________________ _________________________ 7

- 35 7.2.4.1 Terrestrial Plants and Lichen

________________________________ ___________ 7

- 35 7.2.4.2 Terrestrial Invertebrates

________________________________ _______________ 7

- 40 7.2.4.3 Terrestrial Vertebrates

________________________________ ________________ 7

- 44 7.2.5 Exposure and Response of Terrestrial Species

________________________________ __ 7

- 49 7.2.6 Community and Ecosystem Effects

________________________________ ___________ 7

- 52 7.2.7 Critical Loads in Terrestrial Systems

________________________________ __________ 7

- 57 7.2.8 Soil Screening Levels

________________________________ ______________________ 7

- 59 7.2.9 Characterization of Sensitivity and Vulnerability

________________________________ _ 7

- 60 7.2.9.1 Species Sensitivity

________________________________ ___________________ 7

- 60 7.2.9.2 Nutritional Factors

________________________________ ____________________ 7

- 61 7.2.9.3 Soil Aging and Site

- Specific Bioavailability

________________________________ _ 7

- 61 7.2.9.4 Ecosystem Vulnerability

________________________________ _______________ 7

- 62 7.2.10 Ecosystem Services

________________________________ _______________________ 7

- 63 7.2.11 Summary of Effects in Terrestrial Systems

________________________________ _____ 7

- 64 7.2.11.1 Biogeochemistry and Chemical Effects

________________________________ ____ 7

- 64 7.2.11.2 Bioavailability and Uptake

________________________________ ______________ 7

- 65 7.2.11.3 Biological Effects

________________________________ _____________________ 7

- 66 7.2.11.4 Exposure Response

________________________________ __________________ 7

- 67 7.2. 11.5 Community and Ecosystem Effects

________________________________ ______ 7

- 68 7.2.11.6 Critical Loads, Sensitivity and Vulnerability

________________________________ _ 7

- 68 7.3 Aquatic Ecosystem Effects

________________________________ _____________________ 7

- 69 7.3.1 Introduction to Aquatic Ecosystem Effects

________________________________ ______ 7

- 69 7.3.2 Biogeochemistry and Chemical Effects of Pb in Freshwater and Saltwater S ystems

_____ 7

- 69 7.3.2.1 Other Metals

________________________________ ________________________ 7

- 72 7.3.2.2 Biofilm

________________________________ _____________________________ 7

- 72 7.3.2.3 Carbonate

________________________________ __________________________ 7

- 73 7.3.2.4 Dissolved Organic Matter (DOM)

________________________________ ________ 7

- 74

### February 2012 xx Draft

– Do Not Cite or Quote 7.3.2.5 Sulfides

________________________________ ____________________________ 7

- 76 7.3.3 Introduction to Bioavailability and Biological Effects of Pb in Freshwater Ecosystems

____ 7

- 76 7.3.4 Bioavailability in Freshwater Systems

________________________________ _________ 7

- 78 7.3.4.1 Freshwater Plants and Algae

________________________________ ___________ 7

- 82 7.3.4.2 Freshwater Invertebrates

________________________________ ______________ 7

- 87 7.3.4.3 Freshwater Vertebrates

________________________________ ________________ 7

- 90 7.3.4.4 Food Web

________________________________ __________________________ 7

- 97 7.3.5 Biological Effects of Pb in Freshwater Systems

________________________________ __ 7

- 99 7.3.5.1 Freshwater Plants and Algae

________________________________ __________ 7

- 100 7.3.5.2 Freshwater Invertebrates

________________________________ _____________ 7

- 103 7.3.5.3 Freshwater Vertebrates

________________________________ _______________ 7

- 107 7.3.6 Exposure and Response of Freshwater Species

________________________________ 7

- 118 7.3.7 Freshwater Community and Ecosystem Effects

________________________________ 7

- 122 7.3.8 Critical Loads in Freshwater Aquatic Systems

________________________________ __ 7

- 126 7.3.9 Characterization of Sensitivity and Vulnerability in Freshwater Systems

_____________ 7

- 127 7.3.9.1 Seasonally

- Affecte d Physiological Changes

_______________________________ 7

- 128 7.3.9.2 Increased Nutrient Uptake

________________________________ ____________ 7

- 128 7.3.9.3 Temperature and pH

________________________________ _________________ 7

- 128 7.3.9.4 Lifestage

________________________________ __________________________ 7

- 129 7.3.9.5 Spec ies Sensitivity

________________________________ __________________ 7

- 130 7.3.9.6 Ecosystem Vulnerability

________________________________ ______________ 7

- 131 7.3.10 Introduction to Bioavailability and Biological Effects of Pb in Saltwater Ecosystems

____ 7

- 132 7.3.11 Bioavailability of Pb in Saltwater Systems

________________________________ _____ 7

- 133 7.3.11.1 Saltwater Plants and Algae

________________________________ ____________ 7

- 134 7.3.11.2 Saltwater Invertebrates

________________________________ _______________ 7

- 135 7.3.11.3 Saltwater Vertebrates

________________________________ ________________ 7

- 138 7.3.11.4 Marine Food Web

________________________________ ___________________ 7

- 139 7.3.12 Biological Effects of Pb in Saltwater Systems

________________________________ __ 7

- 140 7.3.12.1 Saltwater Algae and Plants

________________________________ ____________ 7

- 140 7.3.12.2 Saltwater Invertebrates

________________________________ _______________ 7

- 141 7.3.12.3 Saltwater Vertebrates

________________________________ ________________ 7

- 143 7.3.13 Exposure and Response of Saltwater Species

________________________________ _ 7

- 145 7.3.14 Community and Ecosystem Effects in Salt water Systems

_________________________ 7

- 146 7.3.15 Characterization of Sensitivity and Vulnerability in Saltwater Species

_______________ 7

- 147 7.3.15.1 Seasonally Affected Physiological Changes

_______________________________ 7

- 148 7.3.15.2 Lifestage

________________________________ __________________________ 7

- 149 7.3.15.3 Species Sensitivity

________________________________ __________________ 7

- 149 7.3.16 Ecosystem Services Associated with Freshwater and Marine Systems

______________ 7

- 150 7.3.17 Summary of Aquatic Effects

________________________________ ________________ 7

- 151 7.3.17.1 Biogeochemistry and Chemical Effects

________________________________ ___ 7

- 152 7.3.17.2 Bioavailability

________________________________ _______________________ 7

- 152 7.3.17.3 Biological Effects

________________________________ ____________________ 7

- 154 7. 3.17.4 Exposure and Response

________________________________ ______________ 7

- 155 7.3.17.5 Community and Ecosystem Effects

________________________________ _____ 7

- 156 7.3.17.6 Critical Loads, Sensitivity and Vulnerability

________________________________ 7

- 157 7.4 Causal Determinations for Ecological Effects of Lead

_______________________________ 7

- 157 Table 7

- 2 Summary of Pb causal determinations for plants, invertebrates and vertebrates

________________________________ ______________ 7

- 15 9 7.4.1 Causal Determinations for Lead in Terrestrial Systems

___________________________ 7

- 160 7.4.1.1 Physiological Stress

- Terrestrial Biota

________________________________ ____ 7

- 160 7.4.1.2 Hematological Effects

- Terrestrial Biota

________________________________ ___ 7

- 162 7.4.1.3 Neurobehavioral Effects

- Terrestrial Biota

________________________________ _ 7

- 162 7.4.1.4 Developmental and Reproductive Effects

- Terrestrial Biota

___________________ 7

- 164 7.4.1.5 Growth Effects

- Terrestrial Biota

________________________________ ________ 7

- 166 7.4.1.6 Survival

- Terrestrial Biota

________________________________ ______________ 7

- 167 7.4.1.7 Community and Ecosystem Level Effects

- Terrestrial Biota

___________________ 7

- 168 7.4.2 Causal Determinations for Lead in Aquatic Systems

_____________________________ 7

- 171 7.4.2.1 Physiological Stress

- Aquatic Biota

________________________________ ______ 7

- 171 7.4.2.2 Hematological Effects

- Aquatic Biota

________________________________ _____ 7

- 172 7.4.2.3 Neurobehavioral Effects

- Aquatic Biota

________________________________ ___ 7

- 173 7.4.2.4 Developmental and Reproductive Effects

- Aquatic Biota

_____________________ 7

- 175 7.4.2.5 Growth Effects

- Aquatic Biota

________________________________ __________ 7

- 178

### February 2012 xxi Draft

– Do Not Cite or Quote 7.4.2.6 Survival

- Aquatic Biota

________________________________ ________________ 7

- 180 7.4.2.7 Community and Ecosystem Level Effects

- Aquatic Biota

_____________________ 7

- 182

### February 2012 xxii Draft

– Do Not Cite or Quote 

# Lead Project Team

Executive Direction Dr. John Vandenberg (Director)

— National Center for Environmental Assessment

- RTP Division, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC Ms. Debra Walsh (Deputy Director)

— National Center for Environmental Assessment

RTP Division, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC Dr. Mary Ross (Branch Chief)

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC Dr. Doug Johns (Acting Branch Chief)

— National Center for Environmental Assess ment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

Scientific Staff
Dr. Ellen Kirrane (Pb Team Leader)

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmen tal Protection Agency, Research Triangle Park, NC

Dr. James Brown

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

Mr. Allen Davis

— National Center for Environ mental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

Dr. Jean

- Jacques Dubois

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

Dr. Tara Greaver

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

Dr. Erin Hines

— National Center for Environmental Assessme nt, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

Dr. Dennis Kotchmar

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Tr iangle Park, NC

Dr. Meredith Lassiter

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

### February 2012 xxiii Draft

– Do Not Cite or Quote 

### Dr. Stephen McDow

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC Dr. Qingyu Meng

— Oak Ridge Institute for Science and Education, National Center for Environmental Assessment, Office of Research and Development, U.S. Environmenta l Protection Agency, Research Triangle Park, NC Dr. Elizabeth Oesterling Owens

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

Dr. Molini Patel

— National Cent er for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC Dr Joseph P. Pinto

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Pr otection Agency, Research Triangle Park, NC

Dr. Jennifer Richmond

- Bryant

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC Dr. Lindsay Stanek

— National Center f or Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC Dr. David Svendsgaard

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Pro tection Agency, Research Triangle Park, NC

Dr. Lisa Vinikoor

- Imler

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

Technical Support Staff

Mr. Kenneth J. Breito

– Senior Environmental Employment Program, National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC Ms. Ellen Lorang

— National Center for Environm ental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC Mr. J. Sawyer Lucy

– Student Services Authority, National Center for Environmental Assessment, Office of Research and Development, U.S. Env ironmental Protection Agency, Research Triangle Park, NC

Ms. Deborah Wales

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

Mr. Richard N. Wilson

– National Cen ter for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

### February 2012 xxiv Draft

– Do Not Cite or Quote 

### Ms. Barbara Wright

— Senior Environmental Employment Program, National Center for Environmental Assessment, Office of Resea rch and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC Authors, Contributors, and Reviewers

Authors
Dr. Ellen Kirrane (Pb Team Leader)

— National Center for Environmental Assessment, Office of Research and Development, U.S. Env ironmental Protection Agency, Research Triangle Park, NC Dr. Robyn Blain

— Energy, Environment and Transportation, Environmental Science & Policy, ICF International, Lexington, MA

Dr. James Brown

— National Center for Environmental Assessment, Office of Resea rch and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

Mr. Allen Davis

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

Dr. Ga ry Diamond

— Syracuse Research Corporation, Akron, NY Dr. Rodney Dietert

— Cornell University College of Veterinary Medicine, Veterinary Medical Center, Ithaca, NY

Dr. Jean

- Jacques Dubois

— National Center for Environmental Assessment, Office of Research and De velopment, U.S. Environmental Protection Agency, Research Triangle Park, NC

Dr. Anne Fairbrother

— Exponent, Inc., Bellevue, WA Dr. Jay Gandy

— Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR

Dr . Harvey Gonick

— David Geffen School of Medicine, University of California

- Los Angeles, Los Angeles, CA Dr. Margaret Graham

— School of Geosciences, University of Edinburgh, Edinburgh, Scotland

Dr. Tara Greaver

— National Center for Environmental Assessment, Of fice of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

Dr. Erin Hines

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park , NC

Dr. Dennis Kotchmar

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

Dr. Meredith Lassiter

— National Center for Environmental Assessment, Office of Resear ch and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

### February 2012 xxv Draft

– Do Not Cite or Quote 

### Dr. Stephen McDow

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC Dr. Qi ngyu Meng

— Oak Ridge Institute for Science and Education, National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

Dr. Bill Mendez

— Energy, Environment and Transportati on, Environmental Science & Policy, ICF International, Fairfax, VA

Dr. Howard Mielke

— Center for Bioenvironmental Research, Tulane/Xavier Universities, New Orleans, LA Ms. Chandrika Moudgal

— Energy, Environment and Transportation, Environmental Science & Po licy, ICF International, Dublin, CA Dr. Elizabeth Oesterling Owens

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC Dr. Katherine Palmquist

— Exponent, Inc., Bellevue, WA

Dr. Molini Patel

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC Dr Joseph P. Pinto

— National Center for Environmental Assessment, Office of Rese arch and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

Dr. Jennifer Richmond

- Bryant

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Pa rk, NC Dr. Stephen Rothenberg

— National Institute of Public Health, Cuernavaca, Morelos, Mexico Dr. MaryJane Selgrade

— Energy, Environment and Transportation, Environmental Science & Policy, ICF International, RTP, NC Dr. Lindsay Stanek

— National Center for E nvironmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC Dr. David Svendsgaard

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protect ion Agency, Research Triangle Park, NC

Dr. Lisa Vinikoor

- Imler

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC Dr. Virginia Weaver

— Johns Hopkins Bloomberg Sc hool of Public Health, Baltimore, MD Dr. Marc Weisskopf

— Department of Environmental Health and Department of Epidemiology, Harvard School of Public Health, Harvard University, Boston, Massachusetts

### February 2012 xxvi Draft

– Do Not Cite or Quote 

### Dr. John Pierce Wise, Sr.

— Maine Center for Toxicology an d Environmental Health, Department of Applied Medical Sciences, Portland, ME Dr. Rosalind Wright

— Harvard Medical School and School of Public Health, Harvard University, Boston, MA Dr. Robert Wright

— Harvard Medical School and School of Public Health, Harva rd University, Boston, MA

Contributors

Mr. Brian Adams

— Oak Ridge Institute for Science and Education, National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

Dr. Ha lil Cakir

— Office of Air Quality Planning and Standards, Office of Air and Radiation, U.S. Environmental Protection Agency, Research Triangle Park, NC

Ms. Ye Cao

— Oak Ridge Institute for Science and Education, National Center for Environmental Assessment, O ffice of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

Ms. Laura Datko

— Oak Ridge Institute for Science and Education, National Center for Environmental Assessment, Office of Research and Development, U.S. Enviro nmental Protection Agency, Research Triangle Park, NC

Mr. Josh Drukenbrod

— Office of Air Quality Planning and Standards, Office of Air and Radiation, U.S. Environmental Protection Agency, RTP, NC

Mr. Mark Schmidt

— Office of Air Quality Planning and Standards , Office of Air and Radiation, U.S. Environmental Protection Agency, Research Triangle Park, NC

Ms. Katie Shumake

— Oak Ridge Institute for Science and Education, National Center for Environmental Assessment, Office of Research and Development, U.S. Environm ental Protection Agency, Research Triangle Park, NC

Ms

. Kaylyn Siporin

— Oak Ridge Institute for Science and Education, National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

Ms. Lauren Tuttle

— Oak Ridge Institute for Science and Education, National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

Ms

. Adrien Wilkie

— Oak Ridge Institu te for Science and Education, National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC Ms. Brianna Young

— Oak Ridge Institute for Science and Education, National Cente r for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

Reviewers

Dr. Christal Bowman

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

### February 2012 xxvii Draft

– Do Not Cite or Quote 

### Dr. David Buchwalter

— Department of Toxicology, North Carolina State University, Raleigh, NC Dr. Barbara Buckley

— National Center for Environmental Assessment, Office of Research and Developmen t, U.S. Environmental Protection Agency, Research Triangle Park, NC

Mr. Kevin Cavender

— Office of Air Quality Planning and Standards, Office of Air and Radiation, U.S. Environmental Protection Agency, Research Triangle Park, NC

Ms

. Rebecca C. Dzubow

— Office of Children’s Health Protection, U.S. Environmental Protection Agency, Washington, DC

Dr. David DeMarini

— National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Trian gle Park, NC

Dr. Pam Factor

- Litvak

— Department of Epidemiology, Mailman School of Public Health, New York, NY Dr. Gabriel Filippelli

— Department of Earth Sciences, Indiana University

- Purdue University, Indianapolis, IN

Dr. Andrew Friedland

— Environmental Stud ies Program, Darmouth College, Hanover, NH

Dr. Barbara Glenn

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC

Dr. Jeff Herrick

— National Center for Environmental Assessmen t, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC Dr. Marion Hoyer

— Office of Transportation and Air Quality, Office of Air and Radiation, U.S. Environmental Protection Agency, Ann Arbor, MI Dr. Douglas Johns

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

Dr. Thomas Luben

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

Dr. Karen Martin

— Office of Air Quality Planning and Standards, Office of Air and Radiation, U.S. Environmental Protection Agency, Research Triangle Park, NC

Ms. Connie Meacham

— National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC Dr. Marie Lynn Miranda

— Environmental Sciences and Policy, Nicholas School of the Environment, Duke University, Durham, NC

Dr. De irdre Murphy

— Office of Air Quality Planning and Standards, Office of Air and Radiation, U.S. Environmental Protection Agency, Research Triangle Park, NC

Dr. Paul Mushak

— PB Associates, Durham NC

### February 2012 xxviii Draft

– Do Not Cite or Quote 

### Dr. Kris Novak

— National Center for Environmental Assessment, O ffice of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

Mr. David Orlin

— Air and Radiation Law Office, Office of General Counsel, U.S. Environmental Protection Agency, Washington, DC

Dr. Meredith Pedde

— Office of T ransportation and Air Quality, Office of Air and Radiation, U.S. Environmental Protection Agency, Ann Arbor, MI Dr. Pradeep Rajan

— Office of Air Quality Planning and Standards, Office of Air and Radiation, U.S. Environmental Protection Agency, Research Tria ngle Park, NC

Ms. Joanne Rice

— Office of Air Quality Planning and Standards, Office of Air and Radiation, U.S. Environmental Protection Agency, Research Triangle Park, NC Dr. Mary Ross

— National Center for Environmental Assessment, Office of Research and Dev elopment, U.S. Environmental Protection Agency, Research Triangle Park, NC

Dr. Joel Schwartz

— Department of Environmental Health, Harvard School of Public Health, Boston, MA

Mr. Jason Sacks

— National Center for Environmental Assessment, Office of Research

an d Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

Ms

. Ginger Tennant

— Office of Air Quality Planning and Standards, Office of Air and Radiation, U.S. Environmental Protection Agency, Research Triangle Park, NC Dr. Jay Turner

— En vironmental and Chemical Engineering Department, Washington University, St. Louis, MO Dr. John Vandenberg

— National Center for Environmental Assessment

- RTP Division, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC Dr. Robert W. Vanderpool

— National Exposure Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

Dr. Nosratola Vaziri

— Division of Nephrology and Hypertension, School of Medicine, University of California, Irvine

Ms. Debra Walsh

— National Center for Environmental Assessment

- RTP Division, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC

Dr. Nasser Zawia

— Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island

### February 2012 xxix Draft

– Do Not Cite or Quote 

# Clean Air Scientific Advisory Committee Lead NAAQS Review Panel

Chair of the Environmental Protection Agency’s Clean Air Scientific Advisory Committee Dr. Jonathan M. Samet*, Department of Preventive M edicine at the Keck School of Medicine, and Director of the Institute for Global Health at the University of Southern California, Los Angeles, CA

Chair of the Lead Review Panel Dr. Christopher H. Frey*, North Carolina State University, Raleigh, NC

Lead Rev iew Panel Members Dr. George A. Allen*, Northeast States for Coordinated Air Use Management (NESCAUM), Boston, MA Dr. Herbert Allen, University of Delaware, Newark, DE Dr. Richard Canfield, Cornel University, Ithaca, NY Dr. Deborah Cory

- Slechta, University of Rochester, Rochester, NY Dr. Cliff Davidson, Syracuse University, Syracuse, NY Dr. Philip E. Goodrum, Environmental Resources Management (ERM), Dewitt, NY Dr. Sean Hays, Summit Toxicology, Allenspark, CO Dr. Philip Hopke, Clarkson University, Potsdam, NY
Dr. Susan Korrick, Harvard Medical School, Boston, MA Dr. Michael Kosnett, University of Colorado Health Sciences Center, Denver, CO Dr. Roman Lanno, Ohio State University, Columbus, OH Dr. Richard L. Poirot, Vermont Agency of Natural Resources, Waterbu ry, VT
Dr. Joel Pounds, Battelle

- Pacific Northwest National Laboratory, Richland, WA Dr. Michael Rabinowitz, Harvard University, Newport, RI Dr. William Stubblefield, Oregon State University, Corvallis, OR Dr. Ian von Lindern, TerraGraphics Environmental Engineering, Inc., Moscow, ID Dr. Gail Wasserman, Columbia University, New York, NY Dr. Michael Weitzman, New York University School of Medicine, New York, NY * Members of the statutory Clean Air Scientific Advisory Committee (CASAC) appointed by the EPA A dministrator

### February 2012 xxx Draft

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### Science Advisory Board Staff Mr. Aaron Yeow, Designated Federal Officer, Office of Administration, Science Advisory Board Staff Office, U.S. Environmental Protection Agency, Washington, DC 20004. Phone: 202

- 564

- 2050, Email: yeow.aaron@epa.go v

### February 2012 xxxi Draft

– Do Not Cite or Quote 

# Acronyms and Abbreviations

α alpha

αT the extent of DNA denaturation per cell Å Ångström (10

- 10 meter)

A A African American; arachidonic acid, atomic absorption

AALM All Ages Lead Model

AAS atomic absorption (spectrophotometry, spectrometry, spectroscopy)

Ab amyloid

- beta peptide

ABL atmospheric boundary layer

ACE angiotensin converting enzyme

ACh acetylcholi ne

ACP acid phosphatase

ACR acute to chronic ratio
Acyl

- Co acyl

- coenzyme A

AD axial diffusivity

ADHD attention deficit hyperactivity disorder

ADP adenosine diphosphate

AE anion exchanger

AF absorbed fraction; absorption fraction

A/G albumin/globulin
Ag silver

A

- horizon: T opsoil horizon (surface soil)

AKI acute kidney injury

Al aluminum

ALA aminolevulinic acid

ALAD aminolevulinic acid dehydratase;

ALAD 1

- 1: aminolevulinate delta

- dehydratase 1

- 1

ALAD

- 2 aminolevulinate delta

- dehydratase

- 2

ALD aldehyde dehydrogenase

ALM Adult Lead Methodology

ALP alkaline phosphatase

ALT alanine aminotransferase

AM Alveolar macrophages

AMF arbuscular mycorrhizal fungi

AMP adenosine monophosphate ANC acid neutralizing capacity; absolute neutrophil
counts

ANF atrial natriu retic factor
AngII renal angiotensin II

ANOVA analysis of variance

ANPR advance notice of proposed rulemaking

AP

- 1 activator protein

- 1
ApaI polymorphism of the VDR in humans

APC antigen

- presenting cell

APOE Apolipoprotein E

APRT adenine phosphoribosyltransferase
AQCD Air Quality Criteria Document
AQS (U.S. EPA) Air Quality System (database)

As arsenic

AST aspartate aminotransferase

ASV anode stripping voltammetry

ATLD ataxia

- telangiectasia

- like disorder

ATOFMSaerosol time

- of

- flight mass spectrometry

ATP adenosine

- triphosphate

ATPase adenosine triphosphatase; adenosine triphosphate synthase

ATSDR Agency for Toxic Substances and Disease Research

Au gold

avg average

AVS acid

- volitile sulfides

a

- wave initial negative deflection in the electro retinogram
AWQC Ambient Water Quality Criteria β Beta; Beta coefficient; regression coefficient; standardized coefficient 3β

- HSD 3

- beta

- hydroxysteroid dehydrogenase 17β

- HSD: 17

- beta

- hydroxysteroid dehydrogenase

Ba barium

BAF bioaccumulation factors

BAL 2, 3

- dimercaptopropanol

BASC Behavior Assessment System for Children

### February 2012 xxxii Draft

– Do Not Cite or Quote BASC

- PRS: Behavior Assessment System for Children

Parent Ratings Scale

BASC

- TRS: Behavior Assessment System for Children

Teacher Rating Scale

BCB blood cerebrospinal fluid barrier

B

- cell Bone marrow

- derived lymphocytes, B lymphocyte

BCF bioconcentration factors

Bcl

- x member of the B

- cell lymphoma

- 2 protein family

Bcl

- xl B

- cell lymphoma

- extra large

B

- horizon: subsoil horizon

bio biological

Bi 2 S 3 bismuth (III) sulfide

BK biokinetics

BLM biot ic ligand model

BMD benchmark dose; bone mineral density

BMDL benchmark dose limit

BMI body mass index

BMP bone morphogenetic protein

BMS Baltimore Memory Study

BMW battery manufacturing workers

BP blood pressure

BR bronchial responsiveness

BrdU bromo

- 2’

- deoxyuridine

8

- Br

- GMPc: 8

- bromo

- cyclic guanosine monophosphate

Bs

- horizon; subsoil horizon with accumulation of sesquioxides

BSI Brief Symptom Inventory

BSID

- II Bayley Scale for Infant Development

- II

BsmI polymorphism of the VDR in humans

Bt20 birth to 20 cohort

BUN blood urea nitrogen

bw body weight

b

- wave initial positive deflection in the electroretinogram

C carbon; Celsius; soil or dry sediment Pb concentration; Caucasian; Cysteine

Ca calcium

Ca 2+ calcium ion

CAA Clean Air Act

CaBP calcium binding prot ein CaCl 2 calcium chloride

CaCO 3 calcium carbonate; calcite

CaEDTA calcium ethylenediaminetetraacetic acid

CaMKII calmodulin

- dependent protein kinase II

cAMP cyclic adenosine monophosphate

CASAC Clean Air Scientific Advisory Committee

CASM Comprehensive Aq uatic Systems Model

CaSO 4 calcium sulfate

CaSO 4 .2H 2 O : gypsum

CAT catalase

CBLI cumulative blood lead index

CBSA core based statistical area

CD cluster of differentiation

Cd cadmium
Cd(I I) cadmium (II)

Cd 2+ cadmium ion

CD3+ T lymphocyte

CD4+ T helper cell

CDC Centers for Disease Control

CEA carcinoembryonic antigen

CEC cation exchange capacity

cent central

cert. certiorari

cf correction factor; latin abbreviation for conferre (used as "compared with)

CFL contanst flux layer

CFR Code of Federal Regulations

cGMP cyclic guanosine monophosphate

ChAT chlorine acetyltranferase

CHD coronary heart disease

CHL Chinese hamster lung

CHO Chinese hamster ovary cell line

C

- horizon: S oil horizon under neath A

- and B

- horizons, may contain lumps or shelves of rock and parent material

CHV79 Chinese hamster lung cell line

CI confidence interval

Cir. circuit

CKD chronic kidney disease

CKD

- EPI: Chronic Kidney Disease Epidemiology Collaboration

### February 2012 xxxiii Draft

– Do Not Cite or Quote CL confidence l imit

Cl chlorine

Cl - chlorine ion

Cl 2 molecular chlorine

CLACE 5: F ifth Cloud and Aerosol Characterization Experiment in the Free Troposphere campaign

CLS Cincinnati Lead Study

CO carbon monoxide

CO 2 carbon dioxide

CO 3 2

- carbonate ion

Co cobalt

CoA coenzyme A

COD coefficient of difference

Coeff coefficient

COMP aT: T he percentage of sperm with increased sensitivity to DNA denaturation

Con control

Conc. concentration
Cong. congress

Corr correlation

COX cyclooxygenase; cytochrome oxidase subunits

COX

- 2 cyclooxygenase

- 2

cPLA 2 cytosolic phopholipidase A 2
CPRS

- R Conners' Parent Rating Scale

- Revised

Cr chromium; creatine

Cr III chromium III

CRAC Ca 2+ release activated calcium

CRACI calcium release activated calcium influx

CREB cyclic adenosinemonophosphate (cAMP) response element

- binding

CRP C

- reactive protein

CSF colony

- stimulating factor

CSN Chemical Speciation Network

CT zinc

- adequate control

Cu copper Cu(II) copper (II)

CV coefficient of variation

CVD cardiovasicular disease

CYP cytochrome
CYP 1A1, Cyp1A1: cytochrome P450 family 1 member A1 CYP 1A2, Cyp1A2: cytochrome P450 family 1 member A2

CYP P450: cytochrome P450

Δ delta, difference, change

Δ5

- 3β

- HSD : delta

- 5

- 3

- beta

- hydroxysteroid dehydrogenase

δ

- ALA 5

- aminolevulinic acid; delta

- aminolevulinic

a cid

δ

- ALAD : delta

- aminolevulinic acid dehydratase

D 2 , D 3 dopamine receptors

D50 size at 50% efficiency

d day(s); depth
db, dB decibel

DbH dopamine beta

- hyrdoxylase

DBP diastolic blood pressure
dep dependent

dev. deviation

DEX exogenous dexamethasone

DG degenerate gyrus

2

- dG 2

- deoxyguanosine

DHAA dehydroascorbate

diff differentiation

DIT developmental immunotoxicity

DMPS 2,3

- dimercaptopropane

- l

- sulfonic acid

DMSA dimercaptosuccinic acid

DMSO dimethyl sulfoxide

DNA deoxyribonucleic acid

DoAD development al origins of adult disease

DOC dissolved organic carbon

DOM dissolved organic matter

DP

- 109 metal chelator

DP

- 460 metal chelator

DR diet

- restricted

DRD4 dopamine 4 receptor

DRD4.7 dopamine 4 receptor repeat alleles

DRUM Davis Rotating Unit for Monitoring

D

- serine neuronal signal

DSM

- IV Diagnostic Statistical Manual

- IV

DTH delayed

- type hypersensitivity

DTPA diethylene triamine pentaacetic acid; techetium

- diethylenetriamine

- pentaacetic acid

### February 2012 xxxiv Draft

– Do Not Cite or Quote E east; expression for exposure

E2 estradiol

e exponen tial function

EC endothelial cell

EC 10 effect concentration for 10% of test population

EC 20 effect concentration for 20% of test population

EC 50 effect concentration for 50% of test population

ECG electrocardiography; electrocardiogram

ECOD 7

- ethoxycoumari n

- o

- deethylase

Eco

- SSLs: ecological soil screening levels

ED 10 effect dose for 10% of population

EDTA ethylenediaminetetraacetic acid

EFS electrical field stimulus

EGF epidermal growth factor

EGFR epidermal growth factor receptor

eGFR estimated glomerular filtration rate

Eh electrochemical potential

E

- horizon: soil horizon with eluviated or leached of mineral and/or organic content

EI

- MS electron impact ionization mass spectrometry

eNOS endothelial nitric oxide synthase

EOG end

- of

- grade

EPA U.S. Environmental Protection Agency

EPT ephemeroptera, plecoptera, trichoptera

ER endoplasmic reticulum
Erg

- 1 ether

- a

- go

- go related gene

ERG electroretinogram

ERK extracellular signal regulated kinase

ERK1/2 extracellular signal

- regulated kinases 1 and 2

ERO D 7

- ethoxyresorufin

- o

- deethylase

ESCA electron spectroscopy for chemical analysis

ESI

- MS electrospray ionization mass spectrometry

ESRD end stage renal disease

ET endothelin

ET

- 1 vasoconstrictor endothelin

- 1

ET A - type receptors : endothelin type A recepto rs

EU European Union

EURO European emission standard

eV electronvolts

EXAFS X

- ray absorption fine structure spectroscopy F 0 filial 0 generation

F 1 first offspring generation

F 2 second offspring generation

FAA Federal Aviation Agency

FAI free androgen index

FAS apoptosis stimulating fragment

Fas

- L apoptosis stimulating fragment ligand

Fe iron
Fe(III) iron III

FEM Federal equivalence method

FEV1 forced expiratory volume in 1 second

FI fixed interval

FI

- Ext fixed interval with extinction

Fl fluoride

FokI poly morphism of the VDR in humans

FR Federal Register (Notice)

FrA fractional anisotropy

FR

- FI fixed ratio

- fixed interval

FRM Federal reference method

FSH follicle

- stimulating hormone
FSIQ full scale intelligence quotient (IQ)

FT3 free triodothyronine

FT4 fr ee thyroxine

G pregnancy; guanine

G2 gap 2 Phase g, mg, kg, μg, ng, pg: G ram(s), milligram(s), microgram(s), kilogram(s), nanogram(s), picogram(s)

G93A mouse model

GABA γ

- aminobutyric acid; gamma aminobutyric acid
GABAergic: gamma aminobutyric acid

- ergic

GAD generalized anxiety disorder

GC gas chromatography

G

- CSF granulocyte colony

- stimulating factor

GD gestational day

GEE generalized estimating equations

GFAAS graphite furnace atomic absorption spectrometry

GFAP glial fibrillary acidic protein

GFR glomerular filtration rate

GGT gamma

- glutamyl transpeptidase

### February 2012 xxxv Draft

– Do Not Cite or Quote GH growth hormone

GI gastrointestinal

GIS Geographic Information System

G+L pregnancy plus lactation

GLE gestationally

- lead exposed

GM geometric mean

GMR geometric mean blood lead ratio

GnRH gon adotropin

- releasing hormone

G6PD glucose

- 6

- phosphate dehydrogenase

GPEI glutathione transferase P (GST

- P) enhancer I

GPT glutamate pyruvate transaminase

GPx glutathione peroxidase

GPX1 gene encoding for glutathione peroxidase 1

GR glutathione reductase

GRP 78 glucose

- regulated protein 78

GRP94 glucose

- regulated protein 94
Grp glucose

- regulated protein

GSD geometric standard deviation

GSH glutathione

GSSG glutathione disulfide

GST glutathione S

- transferase

GSTM1 glutathione S

- transferase Mu 1

GST

- P glutathione transferase P

GTP guanosine

- 5'

- triphosphate; guanine triphosphate

H hydrogen

H + hydrogen ion

h hour(s)

ha hectare

HAD hydroxyalkenals

Hb hemoglobin

HC 5 acute toxicity hazardous concentration for 5% of species

HC 10 acute toxicity hazardous conc entration for 10% of species

HCl hydrochloric acid

HCO 3 - bicarbonate; hydrogen carbonate

Hct hematocrit

HDL high

- density lipoprotein

HF hydrogen fluoride

HFE hemochromatosis gene HFE C282Y: hemochromatosis gene with C282Y mutation

HFE H63D : hemochromatosi s gene with H63D mutation
Hg mercury HgCl 2 mercury(II) chloride

5

- HIAA 5

- hydroxyindoleacetic acid

HIV human immunodeficiency virus

HLA

- DRB: human leukocyte antigen genes

HMEC human dermal microvascular endothelial cells

HMGR 3

- hydroxy

- 3

- methylglutaryl

- CoA reductase

HMOX

- 1: heme oxygenase

- 1

HNO 3 nitric acid

HO

- 1 heme oxygenase; heme oxidase

- 1

H 2 O water

H 2 O 2 hydrogen peroxide

HOME Home Observation for Measurement of the Environment

HPA hypothalamic

- pituitary

- adrenal
HPb, h

- Pb: high lead

HPG hypothalamic

- pitu itary

- gonadal

HPLC high

- performance liquid chromatography

HPRT hypoxanthine

- guanine phosphoribosyltransferase

HPT hyperparathyroidism; hypothalamic

- pituitary

thyroid

HR heart rate; hazard ratio

HRV heart rate variability
hsp heat shock proteins

5HT seroto nin

5

- HT 5

- hydroxytryptamine

5

- HT2B 5

- hydroxytryptamine receptor 2B

hTERT telomerase reverse transcriptase

HVA homovanillic acid

I interstate

IARC International Agency for Research on Cancer

IC 50 half maximal inhibitory concentration

ICAP inductively coupl ed argon plasma

ICP

- AES inductively coupled plasma atomic emission spectroscopy
ICPMS, ICP

- MS: I nductively coupled plasma mass spectrometry

### February 2012 xxxvi Draft

– Do Not Cite or Quote ICR imprinting control region

ICRP International Commission on Radiological Protection

ID identification

IDA iron

- deficiency anemia

IDE insulin

- degrading enzyme

IEPA Illinois Environmental Protection Agency

IEUBK Integrated Exposure Uptake Biokinetic

IFN

- γ interferon

- gamma Ig immunoglobulin
IgA immunoglobulin A
IgE immunoglobulin E

IGF

- 1 insulin

- like growth fac tor 1
IgG immunoglobulin G
IgM immunoglobulin M

IHD ischemic heart disease

IL interleukin

IL

- 1β interleukin

- 1 Beta

IL

- 2 interleukin

- 2

IL

- 4 interleukin

- 4

IL

- 5 interleukin

- 5

IL

- 6 interleukin

- 6

IL

- 8 interleukin

- 8

IL

- 10 interleukin

- 10

IL

- 12 interleukin

- 12

IMPR OVE: Interagency Monitoring of Protected Visual Environment

IMT intimal medial thickening

INL inner neuroblastic layers of the retina

iNOS inducible nitric oxide synthase
i.p. intraperitoneal (route)
IQ intelligence quotient
IQR interquartile range

IRE1 inositol

- requiring enzyme

- 1

ISA Integrated Science Assessment

ISF intake slope factor

ISL inertial sublayer

ISO International Standards Organization

i.v. intravenous

IVBA in vitro bioaccessibility IVF in vitro fertilization

JNK jun N

- terminal kinase

K Kelv in; potassium; resupsension factor

K + potassium ion

K 0.5 concentration of free metal giving half maximal metal

- dependent release

KART Karters of American Racing Triad

K d dissociation constant

Kd partition coefficient; ratio of the metal concentration in so il to that in soil solution
kDa, kD kiloDalton

KEDI

- WISC: Korean Educational Development Institute

- Wechsler Intelligence Scale for Children

6

- keto

- PGF1α: 6

- keto

- prostaglandin F1α (vasodilatory prostaglandin)

keV kiloelectron volt

Ki

- 67 antigen, cell cycle and tumor growth marker

Kim

- 1 kidney injury molecule

- 1

Kinder

- KITAP : Kinder

- Testbatterie zur Aufmerksamkeitsprüfung für Kinder

K

- ras specific protooncogene

Λ lambda; resuspension rate

L length
L, mL, dL: liter(s), milliliter(s), deciliter(s)

LA

- ICP

- MS: laser ablation inductively coupled plasma mass spectrometry

LC 50 lethal concentration (at which 50% of exposed organisms die)

LD 50 lethal dose (at which 50% of exposed organisms die)

LDH lactate dehydrogenase

LDL low

- density lipoproteins

LFH

- horizons: orga nic soil horizons located above well

drained surface soil

LF/HF low frequency to high frequency ratio

LH luteinizing hormone

LHRH luteinizing hormone releasing hormone

LINE long interspersed nuclear element

LINE

- 1 long interspersed nucleotide elements

- 1

L LNA local lymph node assay

ln natural logarithm

L

- NAME: L

- NG

- nitroarginine methyl ester

### February 2012 xxxvii Draft

– Do Not Cite or Quote L

- NOARG: L

- nitroarginine

LOEC lowest

- observed

- effect concentration
log logarithm

LPb low lead

LPS lipopolysaccharide

LSO lateral superior olive

M metal
M, mM, μM, nM : Molar, milliMolar, microMolar, nanoMolar m, cm, mm, μm, nm, km: meter(s), centimeter(s), millimeter(s), micrometer(s), nanometer(s), kilometer(s)

MAP mean arterial pressure

MAPK mitogen

- activated protein kinase(s), MAP kinase

MATC maximum acceptable toxicant concentration

max maximum, maxima

MBP myelin basic protein

MCH mean corpuscular hemoglobin

MCHC mean corpuscular hemoglobin concentration

MchDMSA: mono

- cyclohexyl dimercaptosuccinic acid

MCL maximum containment level

MCP

- 1 monocyte chemotactic pro tein

- 1

MCV mean corpuscular volume

MD mean diffusivity

MDA malondialdehyde

MDD major depressive disorder

MDI Mental Development Index

MDL method detection limit

MDRD Modification of Diet in Kidney Disease
Med, med: median

MEK1 dual specificity mitogen

- a ctivated protein kinase 1

MEK2 dual specificity mitogen

- activated protein kinase 2
Mg magnesium
Mg 2+ magnesium ion

MHC major histocompatibility complex

MI myocardial infarction, "heart attack"; myocardial ischemia

mI myoinositol

min minimum; minima; minute (s) MKK1/2 MAPK kinase 1 and 2

ML mixed layer

MMAD mass median aerodynamic diameter

MMF mycophenolate mofetil
mmHg millimeters of mercury mmol, μmol, nmol: millimole(s), micromole(s), nanomole(s)

MN micronuclei formation; mononuclear

Mn manganese

MNE micronucleated erythrocytes per thousand

MnO 2 manganese dioxide

Mo molybdenum

mo month(s)

MOUDI multi

- orifice uniform deposit impactor
MPb, m

- Pb: moderate lead

MPO myeloperoxidase

MRI magnetic resonance imaging

mRNA messenger ribonucleic acid

MRS magnetic resonance spectroscopy

MS maternal stress

MSC mesenchymal cell

MSWI municipal solid waste incineration

Mt metallothionein

MTHFR methylenetetrahydrofolate reductase

MTP mitochondrial transmembrane pore

MW molecular weight

MZ marginal zinc

N nitrogen; norma l; north; number; population

n number of observations

Na sodium

Na + sodium ion
NAAQS National Ambient Air Quality Standards

NAC N

- acetyl cysteine; nucleus accumbens

Na 2 CaEDTA: calcium disodium ethylenediaminetetraacetic acid

NaCl sodium chloride

NAD nicotinamide adenine dinucleotide

NADH nicotinamide adenine dinucleotide dehydrogenase

NADP nicotinamide adenine dinucleotide phosphate

### February 2012 xxxviii Draft

– Do Not Cite or Quote NADPH, NAD(P)H: reduced nicotinamide adenine dinucleotide phosphate

NAEC no

- adverse

- effect concentration

NAG N

- acetyl

- β

- D

- glucosaminidase; N

acetylglucosamine

NaHCO 3 sodium bicarbonate; sodium hydrogen carbonate

NANC non

- adrenergic non

- cholinergic

NAS Normative Aging Study

NASCAR: National Association for Stock Car Automobile Racing

NATTS National Air Toxics Trends Station
NAWQA National Water Quality Assessment

NCAM neural cell adhesion molecule

NCEA National Center for Environmental Assessment

NCore National Core multi

- pollutant monitoring network

N.D. not detected

NDMAR N

- nitrosodimethylamine receptor

NE norepinephrine

NECAT New England Children’s Amalgam Trial

NEI National Emissions Inventory

NFI non

- fixed interval

NF

- κB nuclear factor kappa B

NGAL neutrophil gelatinase

- associated lipocalin

NGF nerve growth factor

NH non

- hispanic

NHANES: National Health and Nutrition Examination Survey

NH 4 Cl ammonium chloride

NHEJ non

- homologous end joining
NHEXAS: National Human Exposure Assessment Survey

NH 4 OAc ammonium acetate

7

- NI 7

- nitroinidazole

Ni nickel

NICA non

- ideal competitive absorption

NIOSH National Institute for Occupat ional Safety and Health

NIST National Institute of Standards and Technology

NK natural killer

NKF

- K/DOQI: National Kidney Foundation

- Kidney Disease Outcomes Quality Initiative NMDA N

- methyl

- D

- aspartate

NMR nuclear magnetic resonance

nNOS neuronal nitric oxide synthase (NOS)

NO nitric oxide; nitrogen monoxide

NO 2 nitrogen dioxide

No. number

NOAA National Oceanic and Atmospheric Administration

NOAEL no observed adverse effect level

NOEC no

- observed

- effect concentration

NOEL no

- observed

- effect level

NOS nitr ic oxide synthase; nitric oxide systems

NO X nitrogen oxides, oxides of nitrogen (NO + NO 2 )

NP nanoparticle

NPSH nonprotein sulfhydryl
NQO1 NAD(P)H

- quinone oxidoreductase (genotype)

NRC National Research Council

NRCS Natural Resouces Conservation Service

Nrf2 nuclear factor erythroid 2

- related factor 2

NS not specified
NTPDase: nucleoside triphosphate diphosphohydrolase

NW northwest

NYC New York City

NZ New Zealand

O 2 molecular oxygen

O 2 - superoxide
O 3 ozone 9

- O

- Ac

- GD3: 9

- O

- acetylated

- GD3 OAQPS U.S. EPA Of fice of Air Quality Planning and Standards, in OAR
OAR U.S. EPA Office of Air and Radiation
OBS observations
OC organic carbon
OEPA Ohio Environmental Protection Agency
OH - hydroxide ion 1,25

- (OH) 2 D3: 1,25

- dihydroxy vitamin D
O

- horizon: horizon forest flo or, organic soil horizon (above surface soil)
OLC osteoblast

- like cells
OM organic matter
ONL outer neuroblastic layers of the retina
ONOO - peroxynitrate ion
OR odds ratio

### February 2012 xxxix Draft

– Do Not Cite or Quote ORD U.S. EPA Office of Research and Development

OS offspring stress
OSHA Occupational Safety and Health Administration
OVA ovalbumin
8

- oxo

- dG: 8

- hydroxy

- 2’

- deoxyguanosine
P percentile; phosphorus
P 0 parent generation
P450 cytochrome P450

p probability value; number of paried hourly observations; statistical significance
PAD per ipheral arterial disease PAH(s) polycyclic aromatic hydrocarbon(s)
Pb lead

203 Pb lead

- 203 radionuclide

204 Pb stable isotope of lead

- 204

206 Pb stable isotope of lead

- 206

207 Pb stable isotope of lead

- 207

208 Pb stable isotope of lead

- 208

210 Pb stable isotope of lead

- 210
Pb ++ divalent Pb ion
Pb 0 elemental lead Pb(II) lead (II)
Pb 2+ lead ion Pb(Ac) 2 lead acetate
PbB blood lead concentration
PbBrCl lead bromochloride Pb(C 2 H 3 O 2 ) 2 : lead (II) acetate
PbCl + lead chloride
PbCl 2 lead chloride
PbCl 3 lead (III) chloride; lead trichloride
PbCl 4 lead (IV) chloride; lead tetrachloride
PbCO 3 cerrusite; lead carbonate Pb(CO 3 ) 2 lead (IV) carbonate Pb(CO 3 ) 2 (OH) 2 : hydrocerussite
PbCrO 4 lead (II) chromate
PbD floor dust lead
PbFe 6 (SO 4 ) 4 (OH) 12 : plumbjarosite
PBG porphobilinogen
Pb (NO 3 ) 2 : lead(II) nitrate
Pb

- NS lead

- no stress
PbO lead oxide; litharge; massicot
PbO 2 lead dioxide Pb(IV)O 2 : lead dioxide
Pb 3 O 4 minimum or "red Pb" Pb(OH) 2 lead hydroxide
Pb 5 (PO 4 ) 3 Cl: pyromorphite
Pb 5 (PO 4 ) 3 OH: hydroxypyromorphite
PbS galena; lead sulfide; soil lead concentration PbSe lead selenide
PbSO 4 anglesite; lead sulfate
Pb 4 SO 4 (CO 3 ) 2 (OH) 3 : macphersonite
PbxS lead by stress

Pb 5 (VO 4 ) 3 Cl: vanadinite
PC12 pheochromocytoma 12 (adrenal / neuronal cell line)
PCA principal component analysis
PCE polychromatic erythrocyte
PCR polymerase chain reaction
Pct percent
PCV packed cell volume
PD Parkinson's Disease
PDI Psychomotor Development Index
PEC probable effect concentration
PEL permissible exposure limit
PER partial exfiltration reactor
PG prostaglandin
PGE 2 , PGE2: prostaglandin E 2 PGF 2 prostaglandin F2 pH relative acidity; Log of the reciprocal of the hydrogen ion concentration
PHA polyhydroxyalkanoates
PHE phenylalanine
PIH pregnancy induced hypertension PIQ performance intelligence quotient (IQ)
PIR pover ty

- income ratio
PIXE particle induced X

- Ray emission; proton

induced x

- ray emission
PKC protein kinase C
PLP proteolipid protein
PM particulate matter
PM X Particulate matter of a specific size range not defined for regulatory use. Usually X refers to the 50% cut point, the aerodynamic diameter at which the sampler collects 50% of the particles and rejects 50% of the particles. The collection efficiency, given by a penetration curve, increases for particles with smaller diameters and decreases for particles with larger diameters. The definition of PM X is sometimes abbreviated as “particles with a nominal aerodynamic diameter less than or equal to X μm” although X is usually a 50% cut point.

### February 2012 xl Draft

– Do Not Cite or Quote PM 10 In general terms, particulate matter with a nominal aerodynamic diameter less than or equal to 10 μm; a measurement of thoracic particles ( i.e., that subset of inhalable particles thought small enough to penetrate beyond the larynx into the thoracic region of the respiratory tract) in regulatory terms, particles with an upper 50% cut

- point of 10± 0.5 μm aerodynamic diameter (the 50% cut point diameter is the diameter at which the sampler collects 50% of the particles and rejects 50% of the particles) and a penetration curve as measured by a reference method based on Ap pendix J of 40 CFR Part 50 and designated in accordance with 40 CFR Part 53 or by an equivalent method designated in accordance with 40 CFR Part 53.
PM 2.5 In general terms, particulate matter with a nominal aerodynamic diameter less than or equal to 2.5 μm ; a measurement of fine particles in regulatory terms, particles with an upper 50% cut

- point of 2.5 μm aerodynamic diameter (the 50% cut point diameter is the diameter at which the sampler collects 50% of the particles and rejects 50% of the particles) and a penetration curve as measured by a reference method based on Appendix L of 40 CFR Part 50 and designated in accordance with 40 CFR Part 53, by an equivalent method designated in accordance with 40 CFR Part 53, or by an approved regional method designate d in accordance with Appendix C of 40 CFR Part 58.
PM 10

- 2.5 In general terms, particulate matter with a nominal aerodynamic diameter less than or equal to 10 μm and greater than a nominal 2.5 μm; a measurement of thoracic coarse particulate matter or the c oarse fraction of PM10 in regulatory terms, particles with an upper 50% cut

- point of 10 μm aerodynamic diameter and a lower 50% cut

- point of 2.5 μm aerodynamic diameter (the 50% cut point diameter is the diameter at which the sampler collects 50% of the pa rticles and rejects 50% of the particles) as measured by a reference method based on Appendix O of 40 CFR Part 50 and designated in accordance with 40 CFR Part 53 or by an equivalent method designated in accordance with 40 CFR Part 53.
PM 10C The PM 10

- 2.5 c oncentration of PM 10

- 2.5 measured by the 40 CFR Part 50 Appendix O reference method which consists of currently operated, collocated low

- volume (16.7 Lpm) PM 10 and PM 2.5 reference method samplers. p38MAPK: p38 mitogen

- activated protein kinase(s)
PMN polymo rphonuclear leukocyte
P5N pyrimidine 5'

- nucleotidase
PND post natal day
POC particulate organic carbon
PP polypropylene; pulse pressure ppb parts per billion

ppm parts per million
PRP post

- reinforcement pause
PS dam stress; prenatal stress; phosphatidyls erine
PSA prostate specific antigen
PSA

- NCAM: polysialylated

- neural cell adhesion molecule
PT proximal tubule
PTFE polytetrafluoroethylene
PTHrP parathyroid hormone

- related protein
PUFA polyunsaturated fatty acid
PVC polyvinyl chloride
PVD peripheral vas cular disease Q quantile; quartile; quintile QRS QRS complex in ECG QT QT interval in ECG QTc corrected QT Interval

ρ rho; bulk density; correlation ρS Pearson's r correlation coefficient
R net drainage loss out of soil depth of concern; Spearman correlation coefficient; upward resuspension flux; correlation

r Pearson correlation coefficient
R 2 multiple regression correlation coefficient

r 2 correlation coefficient
RAAS renin

- angiotensin

- aldosterone system
RAC2 gene encoding for Rac2
RBA relative b ioavailability
RBC red blood cell
RBP retinol binding protein
RD radial diffusivity
Ref reference (group)
RI

- RI concurrent random interval
RL repeated learning

220 Rn radon isotope

222 Rn stable isotope of radon

- 222
RNA ribonucleic acid
ROI reactive oxygen i ntermediate/superoxide anion; regions of interest
ROS reactive oxygen species
RR relative risk; risk ratio
RSL roughness sublayer (transition layer, wake layer, interfacial layer)
rtPCR reverse transcription polymerase chain reaction

σ sigma, standard devi ation
S south; sulfur; synthesis phase
SAB U.S. EPA Science Advisory Board

SATs Standard Assessment Tests
SBP systolic blood pressure

### February 2012 xli Draft

– Do Not Cite or Quote SCE sister chromatid exchange
Scna α

- synuclein
SD standard deviation
SDN sexually dimorphic nucleus
SE standard error
Se selenium

sec second(s)
SEM scanning electron microscopy; simultaneously extracted metal; standard error of the mean

SES socioeconomic status
Sess. session

SGA small for gestational age
sGC soluble guanylate cyclase

sGC

- β1 soluble guanylate cyclase

- beta 1
S GOT serum glutamic oxaloacetic transaminase

SGPT serum glutamic pyruvic transaminase
SHBG sex hormone binding globulin

SHM Stockholm humic model
siRNA small interfering RNA

SJW silver jewelry workers
SLAMS State and Local Air Monitoring Stations

SMC smooth muscle cells
SNAP

- 25: synaptosomal

- associated protein 25

SNARE soluble NSF attachment receptor
SNP single

- nucleotide polymorphism; sodium nitroprusside
SNS sympathetic nervous system

SO stratum oriens
SO 2 sulfur dioxide

So south
SOC superior olivary complex

SOD superoxide dismutase
SOD1 superoxide dismutase

- 1

SOF study of osteoporotic fractures
SOM self

- organizing map

SP spray painters SP1, Sp1 specificity protein 1

SPM suspended particulate matter
SPT skin prick test

SREBP

- 2: stero l regulatory element binding protein

- 2 S. Rep. Senate Report

SRIXE synchrotron radation induced X

- ray emission

StAR steroidogenic acute regulatory protein

STAT signal transducer and activator of transcription STAT3 signal transducer and activator of
transc ription 3

STAT5 signal transducer and activator of transcription 5
STD. Standard ST Interval: measured from the J point to the end of the T wave in an ECG
Syb synaptobrevin
Syn synaptophysin Syt synaptotagmin

SZn supplemental zinc T, t time
T 3 , T3 triiodothyronine

T 4 , T4 thyroxine

t 1/2 half

- life (

- lives); time required to reduce the initial concentration by 50%

TBARS thioBarbituric acid reactive substances; thiobarbituric acid

- reactive species
T cell, T

- cell: T lymphocyte

TE trace elements
TEC thre shold effect concentrations

TF ratio of the metal concentration in plant to that in soil; transferrin

TFIIIA transcription factor IIIA
Tg transgenic
TGF transforming growth factor

TGF

- β β transforming growth factor TGFβ1, TGF

- β1: β1 transforming growth fa ctor

TH tyrosine hydroxylase TH1, Th1: T

- derived lymphocyte helper 1
TH2, Th2: T

- derived lymphocyte helper 2
Th T

- helper lymphocyte

TIMP

- 1 tissue inhibitor of metalloproteinases

- 1
TIMS thermal ionization mass spectrometry

TLC Treatment of Lead

- exposed Chil dren (study)
T/LH testosterone/luteinizing hormone

- measure of Leydig cell function

TNF tumor necrosis factor ( e.g., TNF

- α)
TNP

- Ficoll: trinitrophenyl

- ficoll

TNP

- OVA: trinitrophenyl

- ovalabumin
TPR total peripheral vascular resistance

TS transferrin saturation
TSH thyroid stimulating hormone; total sulfhydryl

TSP total suspended particles
TSS total suspended solids

### February 2012 xlii Draft

– Do Not Cite or Quote TXB 2 thromboxane

UA urbanized area

UBL urban boundary layer
UCL urban canopy layer

UDPGT uridine diphosphate (UDP)

- glucuronos yltransferase(s)

U.K. United Kingdom

U.S. United States of America

USC U.S. Code

U.S. EPA: U.S. Environmental Protection Agency

USF uptake slope factor

USGS U.S. Geological Survey

USL urban surface layer

UUDS urban dynamic driving schedule

UV ultraviolet r adiation

V vanadium
V79 Chinese hamster lung cell line

VA Veterans Administration
VAChAT vesicular acetylcholine transporter

VAMP

- 2 vesicle

- associated membrane protein

- 2
VA

- NAS Veterans Administration Normative Aging Study
VDAC voltage

- dependent anion channel
VDR vitamin D receptor
VGAT vesicular gamma aminobutyric acid (GABA) transporter VGLUT1: vesicular glutamate transporter 1 VIQ verbal intelligence quotient (IQ)

VLPb very low lead

VMAT2 vesicular monoamine transporter

- 2
VO 4 3

- vanadate ion
VOC(s) vo latile organic compound(s)

vs., v. versus

VSMC vascular smooth muscle cells
WACAP Western Airborne Contaminants Assessment Project WBC white blood cell

WCST Wisconsin Card Sorting Test

WHAM Windermere humic aqueous model

WHO World Health Organization

WIA T Wechsler Individual Achievement Test

WISC Weschler Intelligence Scale for Children

WISC

- R Weschler Intelligence Scale for Children

Revised

wk week(s)

WML white matter lesions

WPPSI

- III: Wechsler Preschool and Primary Scales of Intelligence

- III

WPPSI

- R: Weschler Preschool and Primary Scale of Intelligence

- Revised

WRAT Wide Range Achievement Test

W/S winter/summer

WT wild type

wt. weight

XAFS X

- ray absorption fine structure

XANES X

- ray absorption near edge structure

XDH xanthine dehydrogenase

X ij observed hourly concentrations for time period i at site j

X ik observed hourly concentrations for time period i at site k

XPS X

- ray photoelectron spectroscopy

XRF X

- ray fluorescence

yr year(s)

Zn zinc

Zn 2+ zinc ion

ZPP zirconium

- potassium perchlorate; zinc protopo rphyrin

Z

- score standard score

### February 2012 xliii Draft

– Do Not Cite or Quote 

# PREAMBLE

Process of ISA Development

This preamble outlines the general process for developing an Integrated Science 1 

### Assessment (ISA) including the framework for evaluating weight of evidence and 2 

### drawing scientific conclusions and causal judgments. The ISA provides a concise review, 3 

### synthesis , and evaluation of the most policy

- relevant science to serve as a scientific 4 

### foundation for the review of the National Ambient Air Quality Standards (NAAQS). The 5 

### general process for NAAQS reviews is described at 6 

### http://www.epa.gov/ttn/naaqs/review.html ; information for individual NAAQS reviews is 7


### available at www.epa.gov/ttn/naaqs . This preamble is a general discussion of the basic 8 

### steps and criteria used in d eveloping an ISA; for each ISA, specific details and 9 

### considerations are included in the introductory section for that assessment. 10



### The fundamental process for developing an ISA includes: 11



###  literature searches; 12



###  study selection; 13



###  evaluation and integration of the evidence; and 14



###  development of scientific conclusions and causal judgments. 15


### An initial step in this process is publication of a call for information in the Federal 16 

### Register that invites the public to provide information rel evant to the assessment, such as 17 

### new publications on health or welfare 1 

### effects of the pollutant, or from atmospheric and 18 

### exposure sciences fields. EPA maintains an ongoing literature search process for 19 

### identification of relevant scientific studies publish ed since the last review of the NAAQS. 20 

### Search strategies are designed for pollutants and scientific disciplines and iteratively 21 

### modified to optimize identification of pertinent publications. Papers are identified for 22 

### inclusion in several additional ways: s pecialized searches on specific topics; independent 23 

### review of tables of contents for journals in which relevant papers may be published; 24 

### independent identification of relevant literature by expert scientists; review of citations in 25 

### previous assessments and identification by the public and CASAC during the external 26 

### review process. References considered for inclusion in the ISA can be found at 27 

### http://hero.epa.gov/ ; the references cited in the ISA include a hyperlink to each reference

. 28

1 Welfare effects as defined in Clean Air Act (Section 302(h) [42:U.S.C.:7602(h)]) include , but are not limited to, “effects on soils, water, crops, vegetation, man

- made materials, animals, wildlife, weather, visibility and climate, damage to and deterioration of property, and hazards to transportation, as well as effects on economic values and on personal comfort and well

- being.”

### February 2012 xliv Draft

– Do Not Cite or Quote 

### Studies that have undergone scientific peer review and have been published or accepted 1 

### for publication and reports that have undergone review are considered for inclusion in the 2 

### ISA. Analyses conducted by EPA using publicly available data are a lso considered for 3


### inclusion in the ISA. All relevant epidemiologic, controlled human exposure, 4 

### toxicological, and ecological and welfare effects studies published since the last review 5 

### are considered, including those related to exposure

- response relations hips, mode(s) of 6 

### action (MOA), and potentially at

- risk populations and lifestages. Studies on atmospheric 7 

### chemistry, environmental fate and transport, dosimetry, toxicokinetics and exposure are 8 

### also considered for inclusion in the document, as well as anal yses of air quality and 9


### emissions data. 10



### Each ISA builds upon the conclusions of previous assessments for the criteria pollutant 11 

### under review. EPA focuses on peer reviewed literature published following the 12 

### completion of the previous review and on any new i nterpretations of previous literature, 13 

### integrating the results of recent scientific studies with previous findings. Important older 14 

### studies may be discussed in detail to reinforce key concepts and conclusions or for 15 

### reinterpretation in light of newer data. Older studies also are the primary focus in some 16 

### areas of the document where research efforts have subsided, or if these older studies 17


### remain the definitive works available in the literature. 18



### Selection of studies for inclusion in the ISA is based on the general scientific quality of 19 

### the study, and consideration of the extent to which the study is informative and policy

20 

### relevant. Policy relevant and informative studies include those that provide a basis for or 21 

### describe the relationship between the criteria pollutant and effects, including studies that 22 

### offer innovation in method or design and studies that reduce uncertainty on critical issues, 23 

### such as analyses of confounding or effect modification by copollutants or other variables, 24 

### analyses of concentration

- response or dose

- response relationships, or analyses related to 25 

### time between exposure and response. Emphasis is placed on studies that examine effects 26 

### associated with pollutant concentrations relevant to current population and ecosystem 27 

### exposures, and par ticularly those pertaining to concentrations currently found in ambient 28 

### air. Other studies are included if they contain unique data, such as a previously 29 

### unreported effect or MOA for an observed effect, or examine multiple concentrations to 30 

### elucidate expos ure

- response relationships. In general, in assessing the scientific quality 31 

### and relevance of health and welfare effects studies, the following considerations have 32 

### been taken into account when selecting studies for inclusion in the ISA. 33



###  Are the study popula tions, subjects, or animal models adequately selected, and 34 

### are they sufficiently well defined to allow for meaningful comparisons between 35 

### study or exposure groups? 36

### February 2012 xlv Draft

– Do Not Cite or Quote 

###  Are the statistical analyses appropriate, properly performed, and properly 1 

### interpreted? Are likely covariates adequately controlled or taken into account in 2 

### the study design and statistical analysis? 3



###  Are the air quality data, exposure, or dose metrics of adequate quality and 4 

### sufficiently representative of information regarding ambient condition s? 5



###  Are the health, ecological or welfare effect measurements meaningful, valid and 6


### reliable? 7



###  Do the analytical methods provide adequate sensitivity and precision to support 8


### conclusions? 9


### Considerations specific to particular disciplines include the followin g. In selecting 10 

### epidemiologic studies, EPA considers whether a given study: (1) presents information on 11


### associations with short

- or long

- term pollutant exposures at or near conditions relevant to 12 

### ambient exposures; (2) addresses potential confounding by ot her pollutants; (3) assesses 13 

### potential effect modifiers; (4) evaluates health endpoints and populations not previously 14 

### extensively researched; and (5) evaluates important methodological issues related to 15 

### interpretation of the health evidence ( e.g., lag or time period between exposure and 16 

### effects, model specifications, thresholds, mortality displacement). 17



### Considerations for the selection of research evaluating controlled human exposure or 18 

### animal toxicological studies includes a focus on studies conducted us ing relevant 19 

### pollutant exposures. For both types of studies, relevant pollutant exposures are 20 

### considered to be those generally within one or two orders of magnitude of ambient 21 

### concentrations. Studies in which higher doses were used may also be considered i f they 22 

### provide information relevant to understanding MOA or mechanisms, as noted below. 23



### Evaluation of controlled human exposure studies focuses on those that approximated 24 

### expected human exposure conditions in terms of concentration and duration. Studies 25


### sh ould include control exposures to filtered air, as appropriate. In the selection of 26 

### controlled human exposure studies, emphasis is placed on studies that: (1) investigate 27 

### potentially at

- risk populations and lifestages such as people with asthma or 28


### cardiova scular diseases, children or older adults; (2) address issues such as concentration

29 

### response or time

- course of responses; and (3) have sufficient statistical power to assess 30 

### findings. 31



### Review of the animal toxicological evidence focuses on studies that app roximate 32 

### expected human dose conditions, which vary depending on the dosimetry, toxicokinetics 33 

### and biological sensitivity of the particular laboratory animal species or strains studied. 34 

### Emphasis is placed on studies that: (1) investigate animal models of d isease that can 35

### February 2012 xlvi Draft

– Do Not Cite or Quote 

### provide information on populations potentially at increased risk of effects; (2) address 1


### issues such as concentration

- response or time

- course of responses; and (3) have sufficient 2 

### statistical power to assess findings. Due to resource constr aints on exposure duration and 3 

### numbers of animals tested, animal studies typically utilize high

- concentration exposures 4 

### to acquire data relating to mechanisms and assure a measurable response. Emphasis is 5 

### placed on studies using doses or concentrations gen erally within 1

- 2 orders of magnitude 6 

### of current levels. Studies with higher concentration exposures or doses are considered to 7 

### the extent that they provide useful information to inform our understanding of 8 

### interspecies differences and potential difference s between healthy and susceptible human 9 

### populations. Results from in vitro studies may also be included if they provide 10 

### mechanistic insight or further support for results demonstrated in vivo. 11



### These criteria provide benchmarks for evaluating various studie s and for focusing on the 12 

### policy

- relevant studies in assessing the body of health, ecological and welfare effects 13 

### evidence. As stated initially, the intent of the ISA is to provide a concise review, 14 

### synthesis, and evaluation of the most policy

- relevant sci ence to serve as a scientific 15 

### foundation for the review of the NAAQS, not extensive summaries of all health, 16 

### ecological and welfare effects studies for a pollutant. Of most relevance for inclusion of 17 

### studies is whether they provide useful qualitative or qu antitative information on 18



### exposure

- effect or exposure

- response relationships for effects associated with pollutant 19 

### exposures at doses or concentrations relevant to ambient conditions that can inform 20


### decisions on whether to retain or revise the standards. 21



### In developing an ISA, EPA reviews and summarizes the evidence from: studies of 22 

### atmospheric sciences and exposure; the health effects evidence from toxicological, 23 

### controlled human exposure and epidemiologic studies; and ecological and welfare effects 24


### eviden ce. In the process of developing the first draft ISA, EPA may convene a public 25 

### workshop in which EPA and non

- EPA experts review the scientific content of 26 

### preliminary draft materials to ensure that the ISA is up to date and focused on the most 27 

### policy

- releva nt findings, and to assist EPA with integration of evidence within and across 28 

### disciplines. 29



### EPA integrates the evidence from across scientific disciplines or study types and 30 

### characterizes the weight of evidence for relationships between the pollutant and v arious 31 

### outcomes. The integration of evidence on health, and ecological or welfare effects, 32 

### involves collaboration between scientists from various disciplines. As an example, an 33 

### evaluation of health effects evidence would include the integration of the resu lts from 34 

### epidemiologic, controlled human exposure, and toxicological studies, and application of 35 

### the causal framework (described below) to draw conclusions. Using the causal 36 

### framework described in the following section, EPA scientists consider aspects such as 37

### February 2012 xlvii Draft

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### strength, consistency, coherence, and biological plausibility of the evidence, and develop 1 

### draft causality determinations on the nature of the relationships. Causality determinations 2 

### often entail an iterative process of review and evaluation of the evi dence. Two drafts of 3 

### the ISA are typically released for review by the CASAC and the public, and comments 4 

### received on the characterization of the science as well as the implementation of the causal 5 

### framework are carefully considered in revising and completi ng the final ISA. 6



# EPA Framework for Causal Determination

EPA has developed a consistent and transparent basis to evaluate the causal nature of air 7 

### pollution

- related health or welfare effects for use in developing ISAs. The framework 8


### described below establi shes uniform language concerning causality and brings more 9 

### specificity to the findings. This standardized language was drawn from sources across the 10 

### federal government and wider scientific community, especially the National Academy of 11 

### Sciences (NAS) Instit ute of Medicine (IOM) document, Improving the Presumptive 12 

### Disability Decision

- Making Process for Veterans ( 2008 )

, a comprehensive report on 13 

### evaluating causality. This framework: 14



###  describes the kinds of scientific evidence used in establishing a general causal 15 

### relationship between exposure and health effects; 16



###  characterizes the evidence necessary to reach a conclusion about the existence of 17 

### a causal relationship; 18



###  identifies issues and approaches related to uncertainty; and 19



###  provides a framework for classifying and characterizing the weight of evidence 20 

### in support of a general causal relationship. 21


### Approaches to assessing the separate and combined lines of evidence 22 

### ( e.g., epidemiologic, controlled human exposure, and animal toxicological studies) have 23 

### been formulated by a number of regulatory and science agencies, including the IOM of 24


### the NAS ( 2008 )

, International Agency for Research on Cancer ( 2006b )

, U.S. EPA 25 

### ( 200 5c )

, and Centers for Disease Control and Prevention ( 2004 )

. Causal inference criteria 26 

### have also been described for ecological effects evidence ( U.S. EPA, 1998 ; Fox, 1991 )

. 27 

### These formalized approaches offer guidance for assessing causality. The frameworks are 28 

### similar in nature, although adapted to different purposes, and have proven effective in 29 

### providing a uniform structure and language for causal determinations. 30

### February 2012 xlviii Draft

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# Evaluating Evidence for Inferring Causation

The 1964 Surgeon General’s report ( Smoking and health: Report of the advisory 1 

### committee to the surgeon general o f the public health service ) defined “cause” as a 2 

### “significant, effectual relationship between an agent and an associated disorder or disease 3


### in the host” ( HEW, 1964 )

, more generally, a caus e is defined as an agent that brings 4 

### about an effect or a result. An association is the statistical relationship among variables; 5 

### alone, however, it is in sufficient proof of a causal relationship between an exposure and a 6 

### health outcome. Unlike an association, a causal claim supports the creation of 7 

### counterfactual claims, that is, a claim about what the world would have been like under 8 

### different or changed circumstances ( Samet and Bodurow, 2008 )

. 9



### Many of the health and environmental outcomes reported in these studies have complex 10 

### etiologies. Diseases such as asthma, coronary heart disease (CHD) or cancer are typically 11 

### initiated by multiple agents. Outcomes depend on a variety of factors, such as age, 12 

### genetic susceptibility, nutritional status, immune competence, and social factors ( Samet 13 

### and Bodurow, 2008 ; Gee and Payne

- Sturges, 2004 )

. Effects on ecosys tems are often also 14 

### multifactorial with a complex web of causation. Further, exposure to a combination of 15 

### agents could cause synergistic or antagonistic effects. Thus, the observed risk may 16 

### represent the net effect of many actions and counteractions. 17



### In e stimating the causal influence of an exposure on health or environmental effects, it is 18 

### recognized that scientific findings incorporate uncertainty. “Uncertainty” can be defined 19 

### as having limited knowledge to exactly describe an existing state or future ou tcome, 20



### e.g., the lack of knowledge about the correct value for a specific measure or estimate. 21 

### Uncertainty analysis may be qualitative or quantitative in nature. In many cases, the 22 

### analysis is qualitative, and can include professional judgment or inference s based on 23 

### analogy with similar situations. Quantitative uncertainty analysis may include use of 24 

### simple measures ( e.g., ranges) and analytical techniques. Quantitative uncertainty 25 

### analysis might progress to more complex measures and techniques, if needed f or decision 26 

### support. Various approaches to evaluating uncertainty include classical statistical 27 

### methods, sensitivity analysis, or probabilistic uncertainty analysis, in order of increasing 28 

### complexity and data requirements. However, data may not be availabl e for all aspects of 29 

### an assessment and those data that are available may be of questionable or unknown 30 

### quality. Ultimately, the assessment is based on a number of assumptions with varying 31 

### degrees of uncertainty. The ISA generally evaluates uncertainties qu alitatively in 32 

### assessing the evidence from across studies; in some situations quantitative analysis 33 

### approaches, such as meta

- regression, may be used. 34



### Publication bias is a source of uncertainty regarding the magnitude of health risk 35


### estimates. It is well u nderstood that studies reporting non

- null findings are more likely to 36

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### be published than reports of null findings, and publication bias can also result in 1


### overestimation of effect estimate sizes ( Ioannidis, 2008 )

. For example, effect estimates 2 

### from single

- city epidemiologic studies have been found to be generally larger than those 3 

### from multicity studies ( Bell et al., 2005 )

. 4



# Consideration of E vidence from S cientific D isciplines

Moving from association to causation involves the elimination of alternative explanations 5 

### for the association. The ISA focuses on evaluation of the findings from the bod y of 6 

### evidence, drawing upon the results of all studies determined to meet the criteria described 7 

### previously. Causality determinations are based on the evaluation and synthesis of 8 

### evidence from across scientific disciplines. The relative importance of diffe rent types of 9 

### evidence varies by pollutant or assessment, as does the availability of different types of 10 

### evidence for causality determination. Three general types of studies inform consideration 11 

### of human health effects: controlled human exposure, epidemiol ogic and toxicological 12 

### studies. Evidence on ecological or welfare effects may be drawn from a variety of 13 

### experimental approaches ( e.g., greenhouse, laboratory, field) and numerous disciplines 14 

### ( e.g., community ecology, biogeochemistry and paleological/histo rical reconstructions). 15



### Direct evidence of a relationship between pollutant exposures and human health effects 16 

### comes from controlled human exposure studies. Controlled human exposure studies 17 

### experimentally evaluate the health effects of administered exposu res in human volunteers 18 

### under highly controlled laboratory conditions. Also referred to as human clinical studies, 19 

### these experiments allow investigators to expose subjects to known concentrations of air 20 

### pollutants under carefully regulated environmental co nditions and activity levels. In some 21 

### instances, controlled human exposure studies can also be used to characterize 22


### concentration

- response relationships at pollutant concentrations relevant to ambient 23 

### conditions. Controlled human exposures are typically co nducted using a randomized 24 

### crossover design, with subjects exposed both to the pollutant and a clean air control. In 25 

### this way, subjects serve as their own controls, effectively controlling for many potential 26 

### confounders. However, controlled human exposure studies are limited by a number of 27 

### factors, including small sample size and short exposure time. For example, exposure 28 

### patterns relevant to understanding real

- world exposures, especially long

- term exposures, 29 

### are generally not practical to replicate in a la boratory setting. In addition, although 30 

### subjects do serve as their own controls, personal exposure to pollutants in the hours and 31 

### days preceding the controlled exposures may vary significantly between and within 32 

### individuals. Finally, controlled human expos ure studies require investigators to adhere to 33 

### stringent health criteria for subjects included in the study, and therefore the results often 34 

### cannot be generalized to an entire population. Although some controlled human exposure 35


### studies have included health

- compromised individuals such as those with respiratory or 36

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### cardiovascular disease, these individuals must also be relatively healthy and may not 1 

### represent the most sensitive individuals in the population. In addition, the study design is 2 

### limited to exposur es and endpoints that are not expected to result in severe health 3 

### outcomes. Thus, not observing an effect in controlled human exposure studies does not 4 

### necessarily mean that a causal relationship does not exist. While controlled human 5 

### exposure studies prov ide important information on the biological plausibility of 6 

### associations observed in epidemiologic studies, observed effects in these studies may 7 

### underestimate the response in certain populations. 8



### Epidemiologic studies provide important information on the associations between health 9 

### effects and exposure of human populations to ambient air pollution. In epidemiologic or 10 

### observational studies of humans, the investigator generally does not control exposures or 11 

### intervene with the study population. Broadly, obse rvational studies can describe 12 

### associations between exposures and effects. These studies fall into several categories: 13



### e.g., cross

- sectional, prospective cohort, panel and time

- series studies. “Natural 14 

### experiments” offer the opportunity to investigate chan ges in health related to a change in 15 

### exposure, such as closure of a pollution source. 16



### In evaluating epidemiologic studies, consideration of many study design factors and 17 

### issues must be taken into account to properly inform their interpretation. One key 18



### co nsideration is evaluation of the potential contribution of the pollutant to a health 19 

### outcome when it is a component of a complex air pollutant mixture. Reported effect 20 

### estimates in epidemiologic studies may reflect: independent effects on health outcomes; 21 

### effects of the pollutant acting as an indicator of a copollutant or a complex ambient air 22 

### pollution mixture; effects resulting from interactions between that pollutant and 23 

### copollutants. 24



### In the evaluation of epidemiologic evidence, one important considerati on is potential 25 

### confounding. Confounding is “... a confusion of effects. Specifically, the apparent effect 26 

### of the exposure of interest is distorted because the effect of an extraneous factor is 27 

### mistaken for or mixed with the actual exposure effect (which may be null)” ( Rothman 28 

### and Greenland, 1998 )

. One approach to remove spurious associations due to possible 29 

### confounders is to control for characteristics that may differ between exposed and 30 

### unexposed persons; this is frequently termed “adjustment.” Scientific judgment is needed 31 

### to evaluate likely sour ces and extent of confounding, together with consideration of how 32 

### well the existing constellation of study designs, results, and analyses address this 33 

### potential threat to inferential validity. A confounder is associated with both the exposure 34


### and the effec t; for example, confounding can occur between correlated pollutants that are 35


### associated with the same effect. 36

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### Several statistical methods are available to detect and control for potential confounders, 1 

### with none of them being completely satisfactory. Multi variable regression models 2 

### constitute one tool for estimating the association between exposure and outcome after 3 

### adjusting for characteristics of participants that might confound the results. The use of 4 

### multipollutant regression models has been the prevail ing approach for controlling 5 

### potential confounding by copollutants in air pollution health effects studies. Finding the 6 

### likely causal pollutant from multipollutant regression models is made difficult by the 7 

### possibility that one or more air pollutants may b e acting as a surrogate for an unmeasured 8 

### or poorly measured pollutant or for a particular mixture of pollutants. In addition, more 9 

### than one pollutant may exert similar health effects, resulting in independently observed 10 

### associations for multiple pollutant s. The number and degree of diversity of covariates, as 11 

### well as their relevance to the potential confounders, remain matters of scientific 12 

### judgment. Despite these limitations, the use of multipollutant models is still the 13 

### prevailing approach employed in mo st air pollution epidemiologic studies and provides 14 

### some insight into the potential for confounding or interaction among pollutants. 15



### Confidence that unmeasured confounders are not producing the findings is increased 16 

### when multiple studies are conducted in v arious settings using different subjects or 17 

### exposures, each of which might eliminate another source of confounding from 18 

### consideration. For example, multicity studies which use a consistent method to analyze 19


### data from across locations with different levels of covariates can provide insight on 20 

### potential confounding by copollutants. Intervention studies, because of their quasi

21 

### experimental nature, can be particularly useful in characterizing causation. 22



### Another important consideration in the evaluation of epid emiologic evidence is effect 23 

### modification, which occurs when the effect differs between subgroups or strata; for 24 

### example, effect estimates that vary by age group or potential risk factor. “Effect

- measure 25 

### modification differs from confounding in several way s. The main difference is that, 26 

### whereas confounding is a bias that the investigator hopes to prevent or remove from the 27 

### effect estimate, effect

- measure modification is a property of the effect under study ... . 28


### In epidemiologic analysis one tries to eliminat e confounding but one tries to detect and 29


### estimate effect

- measure modification” ( Rothman and Greenland, 1998 )

. When a risk 30 

### factor is a confounder, it is the true cause of the association observed between the 31 

### exposure and the outcome; when a risk factor is an effect modifier, it changes the 32 

### magnitude of the association between the exposure and the outcome in stratif ied analyses. 33 

### For example, the presence of a pre

- existing disease or indicator of low socioeconomic 34 

### status may be an effect modifier in causing increased risk of effects related to air 35 

### pollution exposure. It is often possible to stratify the relationship b etween health outcome 36 

### and exposure by one or more of these potential effect modifiers. For variables that 37 

### modify the association, effect estimates in each stratum will be different from one another 38

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### and different from the overall estimate, indicating a diff erent exposure

- response 1 

### relationship may exist in populations represented by these variables. 2



### Another key consideration for ambient air pollution epidemiologic studies is exposure 3 

### measurement error. There are several components that contribute to exposure 4 

### measurement error in these epidemiologic studies, including the difference between true 5 

### and measured ambient concentrations, the difference between average personal exposure 6 

### to ambient pollutants and ambient concentrations at central monitoring sites, and the use 7 

### of average population exposure rather than individual exposure estimates. 8



### The third main type of health effects evidence, animal toxicological studies, provides 9 

### information on the pollutant’s biological action under controlled and monitored exposu re 10 

### circumstances. Taking into account physiological differences of the experimental species 11 

### from humans, these studies inform characterization of health effects of concern, 12



### exposure

- response relationships and MOAs. Further, animal models can inform 13


### determi nations of at

- risk or susceptible populations. These studies evaluate the effects of 14 

### exposures to a variety of pollutants in a highly controlled laboratory setting and allow 15 

### exploration of toxicological pathways or mechanisms by which a pollutant may cause 16 

### effects. Understanding the biological mechanisms underlying various health outcomes 17 

### can prove crucial in establishing or negating causality. In the absence of human studies 18 

### data, extensive, well

- conducted animal toxicological studies can support determina tions 19 

### of causality, if the evidence base indicates that similar responses are expected in humans 20 

### under ambient exposure conditions. 21



### Interpretations of animal toxicological studies are affected by limitations associated with 22 

### extrapolation between animal an d human responses. The differences between humans 23 

### and other species have to be taken into consideration, including metabolism, hormonal 24 

### regulation, breathing pattern, and differences in lung structure and anatomy. Also, in spite 25 

### of a high degree of homolog y and the existence of a high percentage of orthologous 26 

### genes across humans and rodents (particularly mice), extrapolation of molecular 27 

### alterations at the gene level is complicated by species

- specific differences in 28 

### transcriptional regulation. Given these differences, there are uncertainties associated with 29 

### quantitative extrapolations of observed pollutant

- induced pathophysiological alterations 30 

### between laboratory animals and humans, as those alterations are under the control of 31 

### widely varying biochemical, e ndocrine, and neuronal factors. 32



### For ecological effects assessment, both laboratory and field studies (including field 33 

### experiments and observational studies) can provide useful data for causality 34


### determination. Because conditions can be controlled in labora tory studies, responses may 35 

### be less variable and smaller differences easier to detect. However, the control conditions 36 

### may limit the range of responses ( e.g., animals may not be able to seek alternative food 37

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### sources), so they may not reflect responses that would occur in the natural environment. 1 

### In addition, larger

- scale processes are difficult to reproduce in the laboratory. 2



### Field observational studies measure biological changes in uncontrolled situations, and 3


### describe an association between a disturbance and an ecological effect. Field data can 4 

### provide important information for assessments of multiple stressors or where site

- specific 5 

### factors significantly influence exposure. They are also often useful for analyses of larger 6 

### geographic scales and higher lev els of biological organization. However, because 7 

### conditions are not controlled, variability is expected to be higher and differences harder 8 

### to detect. Field surveys are most useful for linking stressors with effects when stressor 9


### and effect levels are meas ured concurrently. The presence of confounding factors can 10 

### make it difficult to attribute observed effects to specific stressors. 11



### Intermediate between laboratory and field are studies that use environmental media 12 

### collected from the field to examine respon se in the laboratory, and experiments that are 13 

### performed in the natural environment while controlling for some environmental 14 

### conditions ( i.e., mesocosm studies). This type of study in manipulated natural 15 

### environments can be considered a hybrid between a fi eld experiment and laboratory study 16 

### since some aspects are performed under controlled conditions but others are not. They 17 

### make it possible to observe community and/or ecosystem dynamics, and provide strong 18 

### evidence for causality when combined with findings of studies that have been made 19


### under more controlled conditions. 20



# Application of Framework for Causal Determination

In its evaluation of the scientific evidence on health or welfare effects of criteria 21 

### pollutants, EPA determines the weight of evidence in s upport of causation and 22 

### characterizes the strength of any resulting causal classification. EPA also evaluates the 23 

### quantitative evidence and draws scientific conclusions, to the extent possible, regarding 24


### the concentration

- response relationships and the loa ds to ecosystems, exposure doses or 25 

### concentrations, duration and pattern of exposures at which effects are observed. 26



### To aid judgment, various “aspects” 1 

### of causality have been discussed by many 27 

### philosophers and scientists. The 1964 Surgeon General’s repor t on tobacco smoking 28 

### discussed criteria for the evaluation of epidemiologic studies, focusing on consistency, 29 

### strength, specificity, temporal relationship, and coherence ( HEW, 1964 )

. Sir Austin 30


### Bradford Hill ( 1965 ) articulated aspects of causality in epidemiology and public health 31


### that have been wide ly used ( Samet and Bodurow, 2008 ; IARC, 2006b ; U.S. EPA, 2005c ; 32 

### CDC, 2004 )

. These aspects ( Hill, 1965 ) ha ve been modified (Table I) for use in causal 33

1 The “ aspects” described by Hill ( 1965 ) have become, in the subsequent literature, more commonly described as “criteria.” The original term “aspects” is used here to avoid confusion with “ criteria ” as it is used, with d ifferent meaning, in the Clean Air Act.

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### determinations specific to health and welfare effects for pollutant exposures ( U.S. EPA, 1


### 2009 )

. 1 

### Although these aspects provide a framework for assessing the evidence, they do 2 

### not lend themselves to being considered in terms of simple formulas or fixed rules of 3 

### evidence leading to conclusions about causality ( Hill, 1965 )

. For example, one cannot 4 

### simply count the number of studies reporting statistically significant results or 5 

### statistically nonsignificant results and reach credible conclusions about the relative 6 

### weight of the evidence and the likelihood of causality. Rather, these aspects are taken into 7 

### account with the goal of producing an objective appraisal of the evidence , informed by 8 

### peer and public comment and advice, which includes weighing alternative views on 9 

### controversial issues. In addition, it is important to note that the aspects in Table I cannot 10 

### be used as a strict checklist, but rather to determine the weight o f the evidence for 11 

### inferring causality. In particular, not meeting one or more of the principles does not 12 

### automatically preclude a determination of causality [see discussion in ( CDC, 2004 ) ]

. 13

1 The Hill aspects were developed for interpretation of epidemiologic results. They have been modified here for use with a broa der array of data, i.e., epidemiologic, controlled human exposure , ecological, and animal toxicological studies, as well as in vitro data, and to be more consistent with EPA’s Guidelines for Carcinogen Risk Assessment.

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## Table I Aspects to aid in judging causality

Consistency of the observed association An inference of causality is strengthened when a pattern of elevated risks is observed across several independent studies. The reproducibility of findings constitutes one of the strongest arguments for causality. If there are discordant results among investigations, po ssible reasons such as differences in exposure, confounding factors, and the power of the study are considered.

Coherence An inference of causality from one line of evidence ( e.g., epidemiologic, clinical or animal studies) may be strengthened by other lines of evidence that support a cause

- and

- effect interpretation of the association. Evidence on ecological or welfare effects may be drawn from a variety of experimental approaches ( e.g., greenhouse, laboratory, and field) and subdisciplines of ecology ( e .g., community ecology, biogeochemistry and paleo nto logical/historical reconstructions). The coherence of evidence from various fields greatly adds to the strength of an inference of causality. In addition, there may be coherence in demonstrating effects a cross multiple study designs or related health endpoints within one scientific line of evidence.
Biological plausibility. An inference of causality tends to be strengthened by consistency with data from experimental studies or other sources demonstrating plausible biological mechanisms. A proposed mechanistic linking between an effect and exposure to the agent is an important source of support for causality, especially when data establishing the existence and functioning of those mechanistic links are avai lable.
Biological gradient (exposure

- response relationship) A well

- characterized exposure

- response relationship ( e.g., increasing effects associated with greater exposure) strongly suggests cause and effect, especially when such relationships are also ob served for duration of exposure ( e.g., increasing effects observed following longer exposure times).
Strength of the observed association The finding of large, precise risks increases confidence that the association is not likely due to chance, bias, or other factors. However, it is noted that a small magnitude in an effect estimate may represent a substantial effect in a population.

Experimental evidence Strong evidence for causality can be provided through “natural experiments” when a change in exposure is found to result in a change in occurrence or frequency of health or welfare effects.
Temporal relationship of the observed association Evidence of a temporal sequence between the introduction of an agent, and appearance of the effect, constitutes another argument in favor of causality.
Specificity of the observed association Evidence linking a specific outcome to an exposure can provide a strong argu ment for causation. However, it must be recognized that rarely, if ever, does exposure to a pollutant invariably predict the occurrence of an outcome, and that a given outcome may have multiple causes.
Analogy Structure activity relationships and informa tion on the agent’s structural analogs can provide insight into whether an association is causal. Similarly, information on mode of action for a chemical, as one of many structural analogs, can inform decisions regarding likely causality.



### Determination of Causality

In the ISA, EPA assesses the body of relevant literature, building upon evidence available 1 

### during previous NAAQS reviews, to draw conclusions on the causal relationships 2 

### between relevant pollutant exposures and health or environm ental effects. ISAs use a 3

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### five

- level hierarchy that classifies the weight of evidence for causation 1 

### . In developing 1 

### this hierarchy, EPA has drawn on the work of previous evaluations, most prominently the 2


### IOM’s Improving the Presumptive Disability Decision

- Making Process for Veterans 3 

### ( Samet and Bodurow, 2008 )

, EPA’s Guidelines for Carcinogen Risk Assessment ( U.S. 4 

### EPA, 2005c )

, and the U.S. Surgeon General’s smoking report ( CDC, 2004 )

, The Health 5 

### Consequences of Smoking: A Report of the Surgeion General . This weight of evidence 6


### evaluation is based on various lines of evidence from across the health and environmental 7 

### effects disciplines. These separate judgments are integrated into a qualitative statement 8


### about the overall weight of the evidence and causality. The five descriptors for causal 9


### determination are described in Table II. 10



### Determination of causality involves the evaluation of evidence for different types of 11 

### health, ecological or welfare effects associated w ith short

- and long

- term exposure 12 

### periods. In making determinations of causality, evidence is evaluated for major outcome 13 

### categories and then conclusions are drawn based upon the integration of evidence from 14 

### across disciplines and also across the spectrum of related endpoints. In making causal 15 

### judgments, the ISA focuses on major outcome categories ( e.g., respiratory effects, 16 

### vegetation growth), by evaluating the coherence of evidence across a spectrum of related 17 

### endpoints ( e.g., health effects ranging from inflammatory effects to respiratory mortality) 18 

### to draw conclusions regarding causality. In discussing the causal determination, EPA 19 

### characterizes the evidence on which the judgment is based, including strength of 20 

### evidence for individual endpoints within th e major outcome category. 21

1 T he Center for Disease Control ( CDC ) and IOM frameworks use a four

- category hierarchy for the strength of the evi dence. A five

- level hierarchy is used here to be consistent with the EPA Guidelines for Carcinogen Risk Assessment and to provide a more nuanced set of categories.

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## Table II Weight of evidence for causal determination

Health Effects Ecological and Welfare Effects

Causal relationship Evidence is sufficient to conclude that there is a causal relation ship with relevant pollutant exposures ( i.e., doses or exposures generally within one to two orders of magnitude of current levels). That is, the pollutant has been shown to result in health effects in studies in which chance, bias, and confounding could be ruled out with reasonable confidence. For example: a) controlled human exposure studies that demonstrate consistent effects; or b) observational studies that cannot be explained by plausible alternatives or are supported by other lines of evidence ( e.g., animal studies or mode of action inform ation). Evidence includes replica ted and consistent high

- quality studies by multiple investigators. Evidence is sufficient to conclude that there is a causal relationship with relevant pollutant exposures i.e., doses or exposures generally within one to t wo orders of magnitude of current levels). That is, the pollutant has been shown to result in effects in studies in which chance, bias, and confounding could be ruled out with reasonable confidence. Controlled exposure studies (laboratory or small

- to medi um

- scale field studies) provide the strongest evidence for causality, but the scope of inference may be limited. Generally, determination is based on multiple studies conducted by multiple research groups, and evidence that is considered sufficient to infe r a causal relationship is usually obtained from the joint consideration of many lines of evidence that reinforce each other.

Likely to be a causal relationship Evidence is sufficient to conclude that a causal relationship is likely to exist with relevant pollutant exposures, but important uncertainties remain. That is, the pollu tant has been shown to result in health effects in studies in which chance and bias can be ruled out with reasonable confidence but potential issues remain. For example: a) observ ational studies show an association, but copollutant exposures are diffi cult to address and/or other lines of evidence (controlled human exposure, animal, or mode of action information) are limited or inconsistent; or b) animal toxicological evidence from multiple studies from different laboratories that demonstrate effects, but limited or no human data are available. Evidence generally includes replicated and high

- quality studies by multiple investigators. Evidence is sufficient to conclude that there is a likely causal association with relevant pollut ant exposures. That is, an association has been observed be tween the pollutant and the outcome in studies in which chance, bias and confounding are minimized, but uncertainties remain. For example, field st udies show a relationship, but suspected interacting factors cannot be controlled, and other lines of evidence are limited or inconsistent. Generally, determination is based on multiple studies in multiple research groups.

Suggestive of a causal relations hip Evidence is suggestive of a causal relationship with relevant pollutant exposures, but is limited. For example, (a) at least one high

- quality epidemiologic study shows an association with a given health outcome but the results of other studies are inconsistent; or (b) a well

- conducted toxicological study, such as those conducted in the National Toxicology Program (NTP), shows effects in animal species. Evidence is suggestive of a causal relationship with relevant pollutant exposures, but chance, bia s and confounding cannot be ruled out. For example, at least one high

- quality study shows an effect, but the results of other studies are inconsistent.

Inadequate to infer a causal relationship Evidence is inadequate to determine that a causal relation sh ip exists with relevant pollutant exposures. The available studies are of insufficient quantity, quality, consistency or statistical power to permit a conclu sion regarding the presence or absence of an effect. The available studies are of insufficient qua lity, consistency or statistical power to permit a conclusion regarding the presence or absence of an effect.

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Not likely to be a causal relationship Evidence is suggestive of no causal relationship with relevant pollutant exposures. Several adequate studi es, covering the full range of levels of exposure that human beings are known to encounter and considering at

- risk populations, are mutually consistent in not showing an effect at any level of exposure. Several adequate studies, examining relationships wi th relevant exposures, are consistent in failing to show an effect at any level of exposure.



### In drawing judgments regarding causality for the criteria air pollutants, the ISA focuses 1 

### on evidence of effects in the range of relevant pollutant exposures or doses, and not on 2 

### determination of causality at any dose. Emphasis is placed on evidence of effects at doses 3 

### ( e.g., blood lead concentration) or exposures ( e.g., air concentrations) that are relevant to, 4 

### or somewhat above, those currently experienced by t he population. The extent to which 5 

### studies of higher concentrations are considered varies by pollutant and major outcome 6 

### category, but generally includes those with doses or exposures in the range of one to two 7 

### orders of magnitude above current or ambient conditions. Studies that use higher doses or 8 

### exposures may also be considered to the extent that they provide useful information to 9 

### inform our understanding of mode of action, interspecies differences or factors that may 10 

### increase risk of effects for a popu lation. Thus, a causality determination is based on 11 

### weight of evidence evaluation for health, ecological or welfare effects, focusing on the 12 

### evidence from exposures or doses generally ranging from current levels to one or two 13 

### orders of magnitude above curr ent levels. 14



### In addition, EPA evaluates evidence relevant to understand the quantitative relationships 15 

### between pollutant exposures and health, ecological or welfare effects. This includes 16


### evaluation of the form of concentration

- response or dose

- response rel ationships and, to 17 

### the extent possible, drawing conclusions on the levels at which effects are observed. The 18 

### ISA also draws scientific conclusions regarding important exposure conditions for effects 19 

### and populations that may be at greater risk for effects, as described in the following 20


### section. 21



### Quantitative R elationships: Effects on Human Populations

Once a determination is made regarding the causal relationship between the pollutant and 22 

### outcome category, important questions regarding quantitative relationsh ips include: 23



###  What is the concentration

- response, exposure

- response, or dose

- response 24 

### relationship in the human population? 25



###  What is the interrelationship between incidence and severity of effect? 26

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###  What exposure conditions (dose or exposure, duration and pat tern) are 1 

### important? 2



###  What populations and lifestages appear to be differentially affected ( i.e., more at 3 

### risk of experiencing effects)? 4


### To address these questions, the entirety of quantitative evidence is evaluated to 5 

### characterize pollutant concentrations and exposure durations at which effects were 6 

### observed for exposed populations, including populations and lifestages potentially at 7 

### increased risk. To accomplish this, evidence is considered from multiple and diverse 8 

### types of studies, and a study or set of studies that best approximates the concentration

9 

### response relationships between health outcomes and the pollutant may be identified. 10 

### Controlled human exposure studies provide the most direct and quantifiable exposure

11 

### response data on the human health effec ts of pollutant exposures. To the extent available, 12 

### the ISA evaluates results from across epidemiologic studies that use various methods to 13 

### characterize the form of relationships between the pollutant and health outcomes and 14 

### draws conclusions on the shape of these relationships. Animal data may also inform 15


### evaluation of concentration

- response relationships, particularly relative to MOAs and 16 

### characteristics of susceptible populations. 17



### An important consideration in characterizing the public health impacts as sociated with 18 

### exposure to a pollutant is whether the concentration

- response relationship is linear across 19 

### the range of concentrations or if nonlinear relationships exist along any part of this range. 20 

### Of particular interest is the shape of the concentration

- response curve at and below the 21 

### level of the current standards. Various sources of variability and uncertainty, such as low 22 

### data density in the lower concentration range, possible influence of exposure 23 

### measurement error, and variability between individual s in susceptibility to air pollution 24 

### health effects, tend to smooth and “linearize” the concentration

- response function, and 25 

### thus can obscure the existence of a threshold or nonlinear relationship. Since individual 26 

### thresholds vary from person to person due to individual differences such as genetic level 27 

### susceptibility or preexisting disease conditions (and even can vary from one time to 28 

### another for a given person), it can be difficult to demonstrate that a threshold exists in a 29 

### population study. These sourc es of variability and uncertainty may explain why the 30 

### available human data at ambient concentrations for some environmental pollutants 31 

### ( e.g., particulate matter [PM], ozone [O 3 

### ], lead [Pb], environmental tobacco smoke 32 

### [ETS], radiation) do not exhibit thres holds for cancer or noncancer health effects, even 33 

### though likely mechanisms include nonlinear processes for some key events. These 34 

### attributes of human population dose

- response relationships have been extensively 35 

### discussed in the broader epidemiologic liter ature ( Rothman and Greenland, 1998 )

. 36

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### Finally, identification of the population groups or lifestages that may be at greater risk of 1 

### health effects from air pollutant exposures contributes to an understanding of the public 2 

### health impact of pollutant exposures. In the ISA, the term “at

- risk population” is used to 3 

### encompass populations or lifestages that have a great er likelihood of experiencing health 4 

### effects related to exposure to an air pollutant due to a variety of factors. These factors 5 

### may be intrinsic, such as genetic or developmental factors, race, gender, lifestage, or the 6 

### presence of pre

- existing diseases, o r they may be extrinsic, such as socioeconomic status 7 

### (SES), activity pattern and exercise level, reduced access to health care, low educational 8 

### attainment, or increased pollutant exposures ( e.g., near roadways). Epidemiologic studies 9 

### can help identify pop ulations potentially at increased risk of effects by evaluating health 10 

### responses in the study population. Examples include testing for interactions or effect 11 

### modification by factors such as gender, age group, or health status. Experimental studies 12 

### using an imal models of susceptibility or disease can also inform the extent to which 13 

### health risks are likely greater in specific population groups. 14



### Quantitative R elationships: Effects on Ecosystems or Public Welfare

Key questions for understanding the quantitative relationships between exposure (or 15 

### concentration or deposition) to a pollutant and risk to ecosystems or the public welfare 16


### include: 17



###  What elements of the ecosystem ( e.g., types, regions, taxonomic groups, 18 

### populations, functions, etc.) appear to be affect ed, or are more sensitive to 19


### effects? Are there differences between locations or materials in welfare effects 20 

### responses, such as impaired visibility or materials damage? 21



###  Under what exposure conditions (amount deposited or concentration, duration 22 

### and patter n) are effects seen? 23



###  What is the shape of the concentration

- response or exposure

- response 24 

### relationship? 25


### Evaluations of causality generally consider the probability of quantitative changes in 26 

### ecological and welfare effects in response to exposure. A chall enge to the quantification 27 

### of exposure

- response relationships for ecological effects is the great regional and local 28 

### spatial variability, as well as temporal variability, in ecosystems. Thus, exposure

29 

### response relationships are often determined for a speci fic ecological system and scale, 30 

### rather than at the national or even regional scale. Quantitative relationships therefore are 31 

### available site by site and may differ greatly between ecosystems. 32

### February 2012 lxi Draft

– Do Not Cite or Quote 

### Concepts in Evaluating Adversity of Health Effects

In evaluatin g health evidence, a number of factors can be considered in delineating 1 

### between adverse and nonadverse health effects resulting from exposure to air pollution

. 2 

### Some health outcomes, such as hospitalization for respiratory or cardiovascular diseases, 3


### are cl early considered adverse. It is more difficult to determine the extent of change that 4 

### constitutes adversity in more subtle health measures. These include a wide variety of 5 

### responses, such as alterations in markers of inflammation or oxidative stress, chang es in 6 

### pulmonary function or heart rate variability, or alterations in neurocognitive function 7 

### measures. The challenge is determining the magnitude of change in these measures when 8 

### there is no clear point at which a change become adverse; for example, what percentage 9 

### change in a lung function measure represents an adverse effect. What constitutes an 10 

### adverse health effect may vary between populations. Some changes that may not be 11 

### considered adverse in healthy individuals would be potentially adverse in more 12



### s usceptible individuals. 13



### For example, the extent to which changes in lung function are adverse has been discussed 14 

### by the American Thoracic Society (ATS) in an official statement titled What Constitutes 15 

### an Adverse Health Effect of Air Pollution? ( 2000 )

. An air pollution

- induced shift in the 16 

### population distribution of a given risk factor for a health outcome was viewed as adverse, 17 

### even though it may not increase the risk of any one individual to an unacceptable level

. 18


### Fo r example, a population of asthmatics could have a distribution of lung function such 19 

### that no identifiable individual has a level associated with significant impairment. 20 

### Exposure to air pollution could shift the distribution such that no identifiable indiv idual 21 

### experiences clinically relevant effects. This shift toward decreased lung function, 22 

### however, would be considered adverse because individuals within the population would 23


### have diminished reserve function and therefore would be at increased risk to furt her 24


### environmental insult. The committee also observed that elevations of biomarkers, such as 25 

### cell number and types, cytokines and reactive oxygen species, may signal risk for ongoing 26 

### injury and clinical effects or may simply indicate transient responses th at can provide 27 

### insights into mechanisms of injury, thus illustrating the lack of clear boundaries that 28 

### separate adverse from nonadverse effects. 29



### The more subtle health outcomes may be connected mechanistically to health events that 30 

### are clearly adverse. For example, air pollution may affect markers of transient myocardial 31


### ischemia such as ST

- segment abnormalities and onset of exertional angina. These effects 32 

### may not be apparent to the individual, yet may still increase the risk of a number of 33 

### cardiac events, including myocardial infarction and sudden death. Thus, small changes in 34 

### physiological measures may not appear to be clearly adverse when considered alone, but 35 

### may be a part of a coherent and biologically plausible chain of related health outcomes 36

### February 2012 lxii Draft

– Do Not Cite or Quote 

### that ra nge up to responses that are very clearly adverse, such as hospitalization or 1 

### mortality. 2



### Concepts in Evaluating Adversity of Ecological Effects

Adversity of ecological effects can be understood in terms ranging in scale from the 3


### cellular level to the indiv idual organism and to the population, community and ecosystem 4


### levels. In the context of ecology, a population is a group of individuals of the same 5 

### species, and a community is an assemblage of populations of different species interacting 6


### with one another t hat inhabit an area. An ecosystem is the interactive system formed from 7 

### all living organisms and their abiotic (physical and chemical) environment within a given 8



### area ( IPCC, 2007 )

. The boundaries of what could be called an ecosystem are somewha t 9 

### arbitrary, depending on the focus of interest or study. Thus, the extent of an ecosystem 10 

### may range from very small spatial scales to, ultimately, the entire Earth ( IPCC, 2007 )

. 11



### Effects on an individual organism are generally not considered to be adverse to public 12 

### welfare. However if effects occur to enough individuals within a population, then 13 

### communities and ecosystems may be disrupted. Changes to populations, communities 14 

### and ecosystems can in turn result in an alteration of ecosystem process es. Ecosystem 15 

### processes are defined as the metabolic functions of ecosystems including energy flow, 16 

### elemental cycling, and the production, consumption and decomposition of organic matter 17 

### ( U.S. EPA, 2002b )

. Growth, reproduction, and mortality are species

- level endpoints that 18 

### can be clearly linked to community and ecosystem effects and are considered to be 19 

### adverse when negatively affected. Other endpoints such as changes in behavior and 20 

### physiological stress can decrease ecological fitness of an organism, but are harder to link 21 

### unequivocally to effects at the population, community and ecosyst em level. The degree to 22 

### which pollutant exposure is considered adverse may also depend on the location and its 23 

### intended use ( i.e., city park, commercial cropland). Support for consideration of adversity 24 

### beyond the species level by making explicit the linka ges between stress

- related effects at 25 

### the species and effects at the ecosystem level is found in A Framework for Assessing and 26 

### Reporting on Ecological Condition: an SAB report ( U.S. EPA, 2002b )

. Additionally, the 27 

### National Acid Precipitation Assessment Program (NAPAP) uses the following working 28


### definition of adverse ecological effects in t he preparation of reports to Congress 29 

### mandated by the Clean Air Act: “any injury (i.e. loss of chemical or physical quality or 30 

### viability) to any ecological or ecosystem component, up to and including at the regional 31 

### level, over both long and short terms.” 32



### On a broader scale, ecosystem services may provide indicators for ecological impacts. 33 

### Ecosystem services are the benefits that people obtain from ecosystems ( UNEP, 2003 )

. 34 

### According to the Millennium Ecosystem Assessment , ecosystem services include: 35

### February 2012 lxiii Draft

– Do Not Cite or Quote 

### “provisioning services such as food and water; regulating services such as regulation of 1 

### floods, drought, land degradation, and disease; supporting services such as soil formation 2 

### and nutrient cycling; and cultural services such as recreational, spiritual, religious and 3


### other nonmaterial benefits.” For example, a more subtle ecological effect of pollution 4



### exposure may result in a clearly adverse impact on ecosystem services if it results in a 5 

### population decline in a species that is recreationally or culturally important. 6

7

8



# References

ATS (American Thoracic Society). (2000). What constitutes an adverse health effect of air pollution? This official 9 statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J 10 Respir Crit Care Med 161: 665

- 673. 11

Bell, ML; Dominici, F; Samet, JM. (2005). A meta

- analysis of time

- series studies of ozone and mortality with 12 comparison to t he national morbidity, mortality, and air pollution study. Epidemiology 16: 436

- 445. 13

CDC (Centers for Disease Control and Prevention). (2004). The health conse quences of smoking: A report of the 14 Surgeon General. Washington, DC. http://www.surgeongeneral.gov/library/smokingconsequences/

. 15

Fox, GA. (1991). Practical causal inference for ecoepidemiologists. J Toxicol Environ Health A 33: 359

- 373. 16 http://dx.doi.org/10.1080/15287399109531535

. 17
Gee, GC; Payne

- Sturges, DC. (2004). Environmental health disparities: A framework integrating psychosocial and 18 environmental concepts. Environ Health Perspect 1 12: 1645

- 1653. http://dx.doi.org/10.1289/ehp.7074

. 19

HEW (U.S. Department of Health, Education and Welfare). (1964). Smoking and health: Report of the advisory 20 committee to the surgeon general of the public health service. Washington, DC. 21

Hill, AB. (1965). The environment and disease: Association or causation? Proc R Soc Med 58: 295

- 300. 22

IARC (International Agency for Re search on Cancer). (2006b). Preamble to the IARC monographs. Lyon, France. 23 http://monographs.iarc.fr/ENG/Preamble/

. 24

Ioannidis, JPA. (2008). Why most discovered true associations are inflated. Epidemiology 19: 640

- 648. 25 http://dx.doi.org/10.1097/EDE.0b013e31818131e7

. 26

IPCC (Intergovernmental Panel on Climate Change). (2007). Summary for policymakers. In: Impacts, Adaptation 27 and Vulnerability. Contribution of Working Group II to the Fourth Assessment Report of the 28 Intergovernmental Panel on Climate Change. Cambridge, UK: IPCC. 29

Rothman, KJ; Greenland, S. (1998). Modern epidemiology (2nd ed.). Philadelphia, PA: Lippinc ott, Williams, & 30 Wilkins. 31

Samet, JM; Bodurow, CC (Eds.). (2008). Improving the presumptive disability decision

- making process for 32 veterans. Washington, DC: Na tional Academies Press. 33 http://www.nap.edu/openbook.php?record_id=11908

. 34

### February 2012 lxiv Draft

– Do Not Cite or Quote U.S. EPA (U.S. Environmen tal Protection Agency). (1998). Guidelines for ecological risk assessment. (EPA/630/R

1 95/002F). Washington, DC. http://www.epa.gov/raf/publications/guidelines

- ecolo gical

- risk

2 assessment.htm

. 3

U.S. EPA (U.S. Environmental Protection Agency). (2002b). A framework for assessing and reporting on ecological 4 condition: An SAB rep ort. Washington, DC: US EPA. 5

U.S. EPA (U.S. Environmental Protection Agency). (2005c). Guidelines for carcinogen risk assessment. 6 (EPA/630/P

- 03/001F). Washington, DC. http://www.epa.gov/cancerguidelines/

. 7

U.S. EPA (U.S. Environmental Protection Agency). (2009). Integrated science assessment for particulate matter. 8 (EPA/600/R

- 08/139F). Research Triangle Park, NC. 9 http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=216546

. 10

UNEP (United Nations Environment Programme). (2003). Millennium Ecosystem Assessment: Ecosystems and 11 human well

- being: A framework for assessment. Washington, DC. 12

13

14

### February 2012 lxv Draft

– Do Not Cite or Quote 

# PREFACE

Legislative Requirements for the NAAQS Review

Two sections of the Clea n Air Act (CAA) govern the establishment and revision of the 1 

### NAAQS. Section 108 (42:U.S.C.:7408) directs the Administrator to identify and list 2 

### certain air pollutants and then to issue air quality criteria for those pollutants. The 3


### Administrator is to list those air pollutants that in her “... judgment, cause or contribute 4 

### to air pollution which may reasonably be anticipated to endanger public health or 5 

### welfare; ...” and, “... the presence of which in the ambient air results from numerous or 6


### diverse mobile or sta tionary sources;” and, “... for which ... [the Administrator] plans to 7 

### issue air quality criteria.... .” Air quality criteria are intended to “accurately reflect the 8 

### latest scientific knowledge useful in indicating the kind and extent of all identifiable 9


### effects on public health or welfare which may be expected from the presence of [a] 10 

### pollutant in the ambient air ...” (42:U.S.C.:7408([b]). Section 109 (42:U.S.C.:7409) 11 

### directs the Administrator to propose and promulgate “primary” and “secondary” NAAQS 12


### for pollutants for which air quality criteria are issued. Section 109(b)(1) defines a primary 13 

### standard as one “...the attainment and maintenance of which in the judgment of the 14 

### Administrator, based on such criteria and allowing an adequate margin of safety, are 15 

### requisite to protect the public health.” The legislative history of Section 109 indicates that 16 

### a primary standard is to be set at “... the maximum permissible ambient air level ... 17 

### which will protect the health of any [sensitive] group of the population,” and that for this 18 

### purpose “... reference should be made to a representative sample of persons comprising 19 

### the sensitive group rather than to a single person in such a group...” (S. Rep. No. 20 

### 91:1196, 91st Cong., 2d Sess. 10 [1970]). A secondary standard, as defined in Section 21 

### 109(b)(2), must “... specify a level of air quality the attainment and maintenance of 22 

### which, in the judgment of the Administrator, based on such criteria, is requisite to protect 23 

### the public welfare from any known or anticipated adverse effects ass ociated with the 24 

### presence of [the] pollutant in the ambient air.” Welfare effects (as defined in Section 25 

### 302(h); 42:U.S.C.:7602[h]) include, but are not limited to, “... effects on soils, water, 26 

### crops, vegetation, man

- made materials, animals, wildlife, weath er, visibility and climate, 27 

### damage to and deterioration of property, and hazards to transportation, as well as effects 28 

### on economic values and on personal comfort and well

- being.” 29



### The requirement that primary standards provide an adequate margin of safety w as 30


### intended to address uncertainties associated with inconclusive scientific and technical 31 

### information available at the time of standard setting. It was also intended to provide a 32 

### reasonable degree of protection against hazards that research has not yet id entified (Lead 33 

### Industries Association v. EPA, 647:F.2d:1130

- 1154 [D.C.Cir 1980]; American Petroleum 34

### February 2012 lxvi Draft

– Do Not Cite or Quote 

### Institute v. Costle, 665:F.2d:1176

- 1186 [D.C.Cir. 1981]; American Farm Bureau 1 

### Federation v. EPA, 559:F.3d:512

- 533 [D.C. Cir. 2009]; Association of Battery R ecyclers 2 

### v. EPA, 604:F.3d:613, 617

- 618 [D.C. Cir. 2010]). Both kinds of uncertainties are 3 

### components of the risk associated with pollution at levels below those at which human 4 

### health effects can be said to occur with reasonable scientific certainty. Thus, in selecting 5 

### primary standards that provide an adequate margin of safety, the Administrator is seeking 6 

### not only to prevent pollution levels that have been demonstrated to be harmful but also to 7 

### prevent lower pollutant levels that may pose an unacceptable r isk of harm, even if the risk 8 

### is not precisely identified as to nature or degree. The CAA does not require the 9 

### Administrator to establish a primary NAAQS at a zero

- risk level or at background 10 

### concentration levels (Lead Industries v. EPA, [647:F.2d:at 1156 n.51]), but rather at a 11 

### level that reduces risk sufficiently so as to protect public health with an adequate margin 12 

### of safety. 13



### In addressing the requirement for an adequate margin of safety, the EPA considers such 14 

### factors as the nature and severity of the health effects involved, the size of sensitive 15 

### population(s) at risk, and the kind and degree of the uncertainties that must be addressed. 16 

### The selection of any particular approach to providing an adequate margin of safety is a 17 

### policy choice left specifical ly to the Administrator’s judgment (Lead Industries 18 

### Association v. EPA, [647:F.2d:1161

- 1162]; Whitman v. American Trucking 19 

### Associations, [531:U.S.:457

- 495 (2001)]). 20



### In setting standards that are “requisite” to protect public health and welfare as provided in 21 

### Section 109(b), EPA’s task is to establish standards that are neither more nor less 22 

### stringent than necessary for these purposes. In so doing, EPA may not consider the costs 23 

### of implementing the standards (see generally, Whitman v. American Trucking 24


### Assoc iations, [531:U.S.:457, 465

- 472, 475

- 476 (2001)]). Likewise, “... [a]ttainability 25 

### and technological feasibility are not relevant considerations in the promulgation of 26 

### national ambient air quality standards.” (American Petroleum Institute v. Costle, 27 

### [665:F.2d :1185]). 28



### Section 109(d)(1) requires that “not later than December 31, 1980, and at 5

- year intervals 29 

### thereafter, the Administrator shall complete a thorough review of the criteria published 30 

### under section 108 and the national ambient air quality standards ... and shall make such 31 

### revisions in such criteria and standards and promulgate such new standards as may be 32 

### appropriate ... .” Section 109(d)(2) requires that an independent scientific review 33 

### committee “shall complete a review of the criteria ... and the national primary and 34 

### secondary ambient air quality standards ... and shall recommend to the Administrator any 35 

### new ... standards and revisions of existing criteria and standards as may be appropriate 36

### February 2012 lxvii Draft

– Do Not Cite or Quote 

### ... .” Since the early 1980's, this independent review function has bee n performed by the 1 

### Clean Air Scientific Advisory Committee (CASAC). 2



### History of the NAAQS for Pb

On October 5, 1978, EPA initially promulgated primary and secondary NAAQS for Pb 3 

### under Section 109 of the Act (43 FR 46246). Both primary and secondary standard s were 4


### set at a level of 1.5 micrograms per cubic meter (μg/m 3 

### ), measured as Pb in total 5 

### suspended particles (Pb

- TSP), not to be exceeded by the maximum arithmetic mean 6 

### concentration averaged over a calendar quarter. These standards were based on the 1977 7 

### Air Quality Criteria for Lead ( U.S. EPA, 1977 )

. 8



### The first review of the Pb standards was initiated in the mid

- 1980s. The scientific 9 

### assessment for that review is described in the 1986 Air Quality Criteria for Lead ( U.S. 10 

### EPA, 1986a )

, the associated Addendum ( U.S. EPA, 1986c ) and the 1990 Supplement 11 

### ( U.S. EPA, 1990a )

. As part of the review, the Agency designed and performed human 12 

### exposure and health risk analyses ( U.S. EPA, 1989 )

, the results of which were presented 13 

### in a 1990 Staff Paper ( U.S. EPA, 1990b )

. Based on the scientific assessment and the 14 

### human exposure and health risk analyses, the 1990 Staff Paper presented 15 

### recommendations for consideration by the Administ rator ( U.S. EPA, 1990b )

. After 16 

### consideration of the documents developed during the review and the significantly 17 

### changed circumstances since Pb was listed in 1976, the Agency did not propose any 18 

### revisions to the 1978 Pb NAAQS. In a parallel ef fort, the Agency developed the broad, 19


### multi

- program, multimedia, integrated U.S. Strategy for Reducing Lead Exposure ( U.S. 20 

### EPA, 1991 )

. As part of implementing this strategy, the Agency focused efforts primarily 21 

### on regulatory and remedial clean

- up actions aimed at reducing Pb exposures from a 22 

### variety of non

- air sources judged to pose more extensive public health risks to U.S. 23 

### populations, as well as on actions to reduce Pb emissions to air, such as bringing more 24 

### areas into compliance with the existing Pb NAAQS ( U.S. EPA, 1991 )

. 25



### The most recent re view of the Pb air quality criteria and standards was initiated in 26 

### November, 2004 (69 FR 64926) and the Agency’s plans for preparation of the Air 27 

### Quality Criteria Document and conduct of the NAAQS review were contained in two 28


### documents: Project Work Plan f or Revised Air Quality Criteria for Lead ( U.S. EPA, 29


### 2005e ) ; and Plan for Review of the National Ambient Air Quality Standards for Lead 30 

### ( U.S. EPA, 2006e )

. The schedule for completion of this review was governed by a 31 

### judicial order in Missouri Coalition for the Environment v. EPA (No. 4:04CV00660 32 

### ERW, Sept. 14, 2005; and amended on April 29, 2008 and July 1, 2008), which specified 33 

### a schedule for the review of duration substantially shorter than five years. 34

### February 2012 lxviii Draft

– Do Not Cite or Quote 

### The scientific assessment for the review is describ ed in the 2006 Air Quality Criteria for 1


### Lead [ 2006 Pb AQCD; ( U.S. EPA, 2006b ) ] , multiple drafts of which received review by 2 

### CASAC and the public. EPA also conducted human exposure and health risk assessments 3 

### and a pilot ecologica l risk assessment for the review, after consultation with CASAC and 4 

### receiving public comment on a draft analysis plan ( U.S. EPA, 2006d )

. Drafts of these 5 

### quantitative assessments were reviewed by C ASAC and the public. The pilot ecological 6


### risk assessment was released in December 2006 ( ICF, 2006 ) and the final health risk 7 

### assessment report was released in November 2007 ( U.S. EPA, 2007g )

. The policy 8 

### assessment based on both of these assessments, air quality analyses and key evidence 9 

### from the AQCD was presented in the Staff Paper ( U.S. EPA, 2006f )

, a draft of which also 10



### r eceived CASAC and public review. The final Staff Paper presented OAQPS staff’s 11 

### evaluation of the public health and welfare policy implications of the key studies and 12 

### scientific information contained in the 2006 Criteria Document and presented and 13 

### interpret ed results from the quantitative risk/exposure analyses conducted for this review. 14 

### Based on this evaluation, the Staff Paper presented OAQPS staff recommendations that 15 

### the Administrator give consideration to substantially revising the primary and secondary 16 

### standards to a range of levels at or below 0.2 μg/m 3



### . 17



### Immediately subsequent to completion of the Staff Paper, EPA issued an advance notice 18 

### of proposed rulemaking (ANPR) that was signed by the Administrator on December 5, 19 

### 2007 (72 FR 71488). 1 

### CASAC provi ded advice and recommendations to the 20 

### Administrator with regard to the Pb NAAQS based on its review of the ANPR and the 21 

### previously released final Staff Paper and risk assessment reports. The proposed decision 22 

### on revisions to the Pb NAAQS was signed on May 1, 2008 and published in the Federal 23 

### Register on May 20, 2008 (73 FR 29184). Members of the public provided both written 24 

### and, at two public hearings, oral comments and the CASAC Pb Panel also provided 25


### advice and recommendations to the Administrator based o n its review of the proposal 26 

### notice. The final decision on revisions to the Pb NAAQS was signed on October 15, 2008 27 

### and published in the Federal Register on November 12, 2008 (73 FR 66964). 28



### The November 2008 notice described EPA’s decision to revise the p rimary and 29 

### secondary NAAQS for Pb from a level of 1.5 μg/m 3 

### to a level of 0.15 μg/m 3 

### . EPA’s 30 

### decision on the level for the primary standard was based on the much

- expanded health 31 

### effects evidence on neurocognitive effects of Pb in children. The level of 0.15 μg/m 3 

### was 32 

### established to protect against air Pb

- related health effects, including IQ loss, in the most 33 

### highly exposed children, those exposed at the level of the standard. Results of the 34 

### quantitative risk assessment were judged supportive of the evidence

- based framework 35

1 The ANPR was one of the features of the revised NAAQS review process that EPA instituted i n 2006. :In 2009, this component of the process was replaced by reinstatement of the OAQPS policy assessment (previously termed the Staff Paper).

### February 2012 lxix Draft

– Do Not Cite or Quote 

### estimates. The averaging time was revised to a rolling three

- month period with a 1 

### maximum (not

- to

- be

- exceeded) form, evaluated over a three

- year period. As compared to 2 

### the previous averaging time of calendar quarter, this revision was consid ered to be more 3 

### scientifically appropriate and more health protective. The rolling average gives equal 4 

### weight to all three

- month periods, and the new calculation method gives equal weight to 5


### each month within each three

- month period. Further, the rolling a verage yields 12 6


### three

- month averages each year to be compared to the NAAQS versus four averages in 7 

### each year for the block calendar quarters pertaining to the previous standard. The 8


### indicator of Pb

- TSP was retained, reflecting the evidence that Pb particl es of all sizes 9 

### pose health risks. The secondary standard was revised to be identical in all respects to the 10 

### revised primary standards. 1 

### 11



### Revisions to the NAAQS were accompanied by revisions to the data handling 12 

### procedures, the treatment of exceptional even ts, and the ambient air monitoring and 13 

### reporting requirements; as well as emissions inventory reporting requirements. 2 One 14 

### aspect of the new data handling requirements is the allowance for the use of Pb

- PM 10 

### 15 

### monitoring for Pb NAAQS attainment purposes in c ertain limited circumstances at 16



### non

- source

- oriented sites. The monitoring network requirements resulted in a substantial 17 

### number of new monitors being required as of January 2010, Subsequent to the 2008 18 

### rulemaking, additional revisions were made to the moni toring network requirements, 19 

### which required additional monitors as of December 2011; the complete current 20 

### requirements are described in Section 3.4

. 21



### On February 26, 2010 (75 FR 8934), EPA formally initiated its current review of the air 22 

### quality criteria for Pb, requesting the submission of recent scientific information on 23 

### specified topics. Soon after, a science policy workshop was held to identify ke y policy 24 

### issues and questions to frame the review of the Pb NAAQS (75 FR 20843). Drawing 25 

### from the workshop discussions, a draft IRP [ Integrated Review Plan for the National 26 

### Ambient Air Quality Standards for Lead ( U.S. EPA, 2011d ) ] , was developed and made 27 

### available in late March, 2011 for public co mment and consultation with CASAC and was 28 

### discussed by the CASAC via a publicly accessible teleconference consultation on May 5, 29 

### 2011 (76 FR 20347, 76 FR 21346). The final IRP ( U.S. EPA, 2011c ) was released in 30 

### November, 2011 (76 FR 76972). 31



### As part of the science assessment phase of the current review, EPA held a wor kshop in 32 

### December 2010 (75 FR 69078) to discuss, with invited scientific experts, preliminary 33

1 The 2008 NAAQS for Pb are specified at 40 CFR 50.16. 2 The 2008 federal regulatory measurement methods for P b are specified in 40 CFR 50, Appendix G and 40 CFR part 53. Consideration of ambient air measurements with regard to judging attainment of the standards is spec ified in 40 CFR 50, Appendix R. The Pb monitoring network requireme nts are specified in 40 CFR 58, Appendix D, section 4.5. Guidance on the approach for implementation of the new standards was described in the Federal Register notices for t he proposed and final rules (73 FR 29184; 73 FR 66964).

### February 2012 lxx Draft

– Do Not Cite or Quote 

### draft materials prepared during the ongoing development of the Pb ISA. The first external 1 

### review draft ISA for Lead was released on May 6, 2011 (U.S. EPA 2011). T he CASAC 2 

### Pb Review Panel met at a public meeting on July 20, 2011 to review the draft ISA 3 

### (76 FR 36120). Subsequently, on December 9, 2011, the CASAC panel provided a 4 

### consensus letter for their review to the Administrator of the EPA (U.S. EPA 2011). The 5



### cu rrent document, the second external review draft ISA for Lead , will be discussed at a 6 

### public meeting of the CASAC Pb Review Panel, and timely public comments received 7 

### will be provided to the CASAC panel. A Federal Register notice will inform the public of 8 

### the exact date and time of that CASAC meeting. 9



# References

ICF (ICF International). (2006). Lead human exposure and health risk assessments and ecological risk assessment 10 for selected areas: Pilot phase: External review draft technical report. Research Triangle Park, NC: ICF 11 International. 12

U.S. EPA (U.S. Environmental Protection Agency). (1977). Air quality criteria for lead [EPA Report]. (EPA

- 600/8

- 13 77

- 017). Washington, DC. http://nepis.epa.gov/Exe/ZyPURL.cgi?Dockey=20013GWR.txt

. 14

U.S. EPA (U.S. Environmental Protection Agency). (1986a). Air quality criteria for lead [EPA Report]. (EPA/600/8

- 15 83/028aF

- dF). Research Triangle Park, NC. http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=32647

. 16

U.S. EPA (U.S. Environmental Protection Agency). (1986c). Lead effects on cardiovascular function, early 17 development, and stature: An addendum to U.S. EPA Air Quality Criteria for Lead (1986). (EPA

- 600/8

- 18 83/028aF ). Washington, DC: US EPA. 19

U.S. EPA (U.S. Environmental Protection Agency). (1989). Review of the national ambient air quality standards for 20 lead: Exposure anal ysis methodology and validation: OAQPS staff report. (EPA

- 450/2

- 89

- 011). Research 21 Triangle Park, NC: US EPA. 22

U.S. EPA (U.S. Environmental Protection Agency). (1 990a). Air quality criteria for lead: Supplement to the 1986 23 addendum [EPA Report]. (EPA/600/8

- 89/049F). Washington, DC. 24

U.S. EPA (U.S. Environmental Protection Agency). (1990b). Review of the national ambient air quality standards 25 for lead: Assessment of scientific and technical information: OAQPS staff paper. (EPA

- 450/2

- 89

- 022). 26 Research Triangle Park, NC: US EPA. 27

U.S. EPA (U.S. Environmental Protection Agency). (1991). Strategy for reducing lead exposures. Washington, DC: 28 US EPA. http:/ /www.epa.gov/ttn/naaqs/standards/pb/data/leadstrategy1991.pdf

. 29

U.S. EPA (U.S. Environmental Protection Agency). (2005e). Project work plan for revised air qual ity criteria for 30 lead. (NCEA

- R

- 1465). Research Triangle Park, NC. 31 http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=113963

. 32

U.S. EPA (U.S. Environmental Protection Agency). (2006b). Air quality criteria for lead: Volume I of II. 33 (EPA/600/R

- 05/144aF). Research Triangle Park, NC: US EPA. 34 http://cfpub.epa.gov/ncea/CFM/recordisplay.cfm?deid=158823

. 35

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U.S. EPA (U.S. Environmental Protection Agency). (2011c). Integrated review plan for the national ambient air 11 quality standards for lead. (EPA

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