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February 2012 ii Draft – Do Not Cite or Quote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February 2012 iii Draft – Do Not Cite or Quote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 PANEL______ XXIX

ACRONYMS AND ABBREVIATIONS____________________________________________ 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 Overview of Health and Ecological Effects _________________________________ 1-5

Figure 1-2 Schematic representation of the relationships between the various 

MOAs by which Pb 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 determinationsa 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 Renal 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 Determinationsa 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 

proportion 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 associations between blood Pb and cognitive 

function among various blood Pb strata. ________________________ 2-64

2.9.5 Pb Exposure and Nervous System Effects in Children ____________________________ 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 2-75

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 Metals 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

CHAPTER 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 Roadway-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 Resuspension 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 for 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 Soil 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 methods _______________________________ 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 ________________________________________ 3-73

Figure 3-14 Pb-PM2.5 monitoring sites for CSN and IMPROVE networks.________ 3-75

Figure 3-15 Pb-PM10 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 onemonth 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/m3

), 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/m3

), maximum 3-month average, 2008-2010._________________ 3-83

Figure 3-18 Highest county-level Pb-PM10 concentrations (μg/m3), maximum 

3-month average, 2007-2009. ________________________________ 3-84

Figure 3-19 Highest county-level Pb-PM2.5 concentrations (μg/m3), 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 nearroad monitors. ____________________________________________ 3-88

3.5.2 Temporal Variability _______________________________________________________ 3-90

3.5.2.1 Multi-year Trends ____________________________________________________ 3-90

Figure 3-21 National trends in Pb concentration (μg/m3), source-oriented FRM 

monitors, 1990-2010._______________________________________ 3-91

Figure 3-22 National trends in Pb concentration (μg/m3), 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/m3) over 12 months of 

the year, 2008-2010. _______________________________________ 3-94

Figure 3-24 Monthly non-source-oriented lead-TSP average (μg/m3) over 12 

months of the year, 2008-2010._______________________________ 3-95

Figure 3-25 Monthly lead-PM10 average (μg/m3) over 12 months of the year, 

2007-2009. ______________________________________________ 3-95

Figure 3-26 Monthly lead-PM2.5 average (μg/m3) over 12 months of the year, 

2007-2009. ______________________________________________ 3-96

3.5.3 Size Distribution 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 Concentrations 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, PM10, 

and PM2.5 _______________________________________________ 3-107

Figure 3-30 Correlations of monitored lead-PM2.5 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 Mexico 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 concentrations 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 of 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. ______________________________ 3-137

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 (μg/m3) 

nationwide, source-oriented monitors, 2008-2010 _______________ 3-143

Table 3-14 Distribution of 1-month average Pb-TSP concentrations (μg/m3) 

nationwide, non-source-oriented monitors, 2008-2010____________ 3-145

Table 3-15 Distribution of 3-month moving average Pb-TSP concentrations 

(μg/m3

) nationwide, source-oriented monitors, 2008-2010 _________ 3-147

Table 3-16 Distribution of 3-month moving average Pb-TSP concentrations 

(μg/m3

) nationwide, non-source-oriented monitors, 2008-2010 _____ 3-149

Table 3-17 Distribution of annual 1-month site maxima TSP Pb concentrations 

(μg/m3

) nationwide, source-oriented monitors, 2008-2010 _________ 3-150

Table 3-18 Distribution of annual 1-month site maxima TSP Pb concentrations 

(μg/m3

) nationwide, non-source-oriented monitors, 2008-2010 _____ 3-151

Table 3-19 Distribution of annual 3-month site maxima Pb-TSP concentrations 

(μg/m3

) nationwide, source-oriented monitors, 2008-2010 _________ 3-152

Table 3-20 Distribution of annual 3-month site maxima Pb-TSP concentrations 

(μg/m3

) nationwide, non-source-oriented monitors, 2008-2010 _____ 3-152

Table 3-21 One-month average Pb-TSP for individual county concentrations 

nationwide (μg/m3

), source-oriented monitors, 2008-2010 _________ 3-154

Table 3-22 One-month average Pb-TSP for individual county concentrations 

nationwide (μg/m3

), non-source-oriented monitors, 2008-2010 _____ 3-155

Table 3-23 Three-month moving average Pb-TSP for individual county 

concentrations (μg/m3

) nationwide, source-oriented monitors, 2008-

2010___________________________________________________ 3-156

Table 3-24 Three-month moving average Pb-TSP for individual county 

concentrations (μg/m3

) 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/m3) 

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 Counties, 

FL (12-057 and 12-103), 2007-2009. _________________________ 3-167

Figure 3-46 Wind roses for Hillsborough/Pinellas Counties, FL, obtained from 

meteorological data at Tampa International Airport, 1961-1990. ____ 3-168

Figure 3-47 Box plots of annual and seasonal Pb TSP concentrations (μg/m3)

from source-oriented and non-source-oriented monitors within 

Hillsborough and Pinellas 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 concentrations (μg/m3) 

from source-oriented and non-source-oriented monitors within Cook 

County, IL (17-031), 2007-2009. _____________________________ 3-175

Table 3-27 Correlations 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 Box plots of annual and seasonal Pb TSP concentrations (μg/m3) 

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/m3) 

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/m3) 

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
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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. ____________________________ 3-196

Figure 3-64 Seasonal correlations of monitored Pb-PM2.5 concentration with 

copollutant concentrations, 2007-2009. _______________________ 3-197

Figure 3-65 Seasonal correlations of monitored Pb-PM2.5 concentration with 

copollutant concentrations, 2007-2009. _______________________ 3-198

Table 3-31 Copollutant exposures for various trace metal studies ____________ 3-199

CHAPTER 4 EXPOSURE, TOXICOKINETICS, 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 Ingestion ___________________________________________________________ 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 concentration 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 Biomarkers _____________________________________________________________ 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 Measurements__________________________________________________ 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 

burden 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 4-16 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 206Pb/204Pb isotope ratio in blood 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 nonoccupationally 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 

concentration. ____________________________________________ 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/m3) predicted from various 

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 relationship 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 Lead Biomarkers ________________________________________________________ 4-121

4.7.4 Air Lead-Blood Lead Relationships __________________________________________ 4-123

CHAPTER 5 INTEGRATED HEALTH EFFECTS OF LEAD EXPOSURE______________5-1

5.1 Introduction __________________________________________________________________ 5-1

5.2 Modes of Action_______________________________________________________________ 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 Ca2+ 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 Binding 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 ____________________________________________________ 5-44

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 Pb 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 

represented 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 yearsa _______________________________________ 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 Changes 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 

adultsa _________________________________________________ 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 adultsa ________________________ 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 leadexposed (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 Adhesion 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 measured at different lifestagesa ________________ 5-192

Figure 5-21 Associations of cognitive function in children with different degrees 

of changes in 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 results 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 Blood 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 

presented in Figure 5-26 ___________________________________ 5-234

Figure 5-27 The relationship between tibia Pb and estimated systolic BP (SBP) 

for those with high self-reported stress versus those with low selfreported 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) and 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 Heart 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 epidemiologic 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 Functioning in Children __________________________________ 5-269

Figure 5-31 Children’s adjusted total peripheral resistance (dyn-s/cm5) responses 

to acute stress tasks, 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 disease. __ 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 with 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 Summary and Causal Determination _________________________________________ 5-287

5.5 Renal Effects _______________________________________________________________ 5-292

5.5.1 Introduction_____________________________________________________________ 5-292

5.5.1.1 Kidney 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 

duration– 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 characteristics 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 Antioxidants 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 5-42 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 abundance 

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 Inflammation _______________________________________________________ 5-378

5.6.5.2 Increased Prostaglandin E2 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 __________________________________________ 5-408

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 studies 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 Summary of recent epidemiologic studies of associations between 

Pb levels and puberty for females ____________________________ 5-428

Figure 5-46 Toxicological exposure-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 Summary of recent epidemiologic studies of associations between 

Pb levels and puberty for males _____________________________ 5-452

5.8.2.5 Effects on Morphology and 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 Abortions5-456

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 

Pb 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 ____________________________________________ 5-490

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 AQCD5-502

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 AQCD5-507

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 studiesa 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 Evidence 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 children 12-60 

months old on various factors related to housing condition, from 

1999-2004 NHANES dataset_________________________________ 6-14

6.3 Factors Potentially Related 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 Socioeconomic 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 Iron 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 ECOLOGICAL 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 Effects_____________________________________ 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 Systems _____ 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-Affected 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 Species 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 Saltwater 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______________________________________________ 7-159

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 AssessmentRTP 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 Assessment, 

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. Environmental 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 Environmental 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 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 

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. Environmental 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 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 Research 

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 Park, NC

Dr. Lindsay Stanek—National Center for 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 Protection 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 Environmental 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. Environmental 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 Center 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 Research 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. Environmental 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 Research 

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. Gary 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 Development, 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, Office 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 

Research 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. Qingyu 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 Transportation, 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 & Policy, 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 Research 

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 Park, 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 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 Protection 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 School 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 and 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, Harvard 

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. Halil 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, Office 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. Environmental 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. Environmental 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 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. Brianna Young—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

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 Development, 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 Triangle 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 Studies 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 Assessment, 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. Deirdre 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, Office 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 Transportation 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 Triangle 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 

Development, 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 

and 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—Environmental 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 Medicine 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 Review 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, Waterbury, 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 Administrator 
February 2012 xxx Draft – Do Not Cite or Quote

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.gov
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)

AA 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 acetylcholine

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: Topsoil 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 natriuretic 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 

electroretinogram

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 ChildrenParent Ratings Scale

BASC-TRS: Behavior Assessment System for ChildrenTeacher 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

Bi2S3 bismuth (III) sulfide

BK biokinetics

BLM biotic 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

Ca2+ calcium ion

CAA Clean Air Act

CaBP calcium binding protein

CaCl2 calcium chloride

CaCO3 calcium carbonate; calcite

CaEDTAcalcium ethylenediaminetetraacetic acid

CaMKII calmodulin-dependent protein kinase II

cAMP cyclic adenosine monophosphate

CASAC Clean Air Scientific Advisory Committee

CASM Comprehensive Aquatic Systems Model

CaSO4 calcium sulfate

CaSO4.2H2O : gypsum

CAT catalase

CBLI cumulative blood lead index

CBSA core based statistical area

CD cluster of differentiation

Cd cadmium

Cd(II) cadmium (II)

Cd2+ 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: Soil horizon underneath 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 limit

Cl chlorine

Cl- chlorine ion

Cl2 molecular chlorine

CLACE 5: Fifth Cloud and Aerosol Characterization 

Experiment in the Free Troposphere campaign

CLS Cincinnati Lead Study 

CO carbon monoxide

CO2 carbon dioxide 

CO3

2- carbonate ion

Co cobalt

CoA coenzyme A

COD coefficient of difference

Coeff coefficient

COMP aT: The 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

cPLA2 cytosolic phopholipidase A2

CPRS-R Conners' Parent Rating Scale-Revised

Cr chromium; creatine

Cr III chromium III

CRAC Ca2+ 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 

acid 

δ-ALAD : delta-aminolevulinic acid dehydratase

D2, D3 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 developmental 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 exponential function

EC endothelial cell

EC10 effect concentration for 10% of test population

EC20 effect concentration for 20% of test population

EC50 effect concentration for 50% of test population

ECG electrocardiography; electrocardiogram

ECOD 7-ethoxycoumarin-o-deethylase

Eco-SSLs: ecological soil screening levels

ED10 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

EROD 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 

ETA-type receptors : endothelin type A receptors

EU European Union

EURO European emission standard

eV electronvolts

EXAFS X-ray absorption fine structure spectroscopy

F0 filial 0 generation

F1 first offspring generation

F2 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 polymorphism 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 free thyroxine 

G pregnancy; guanine

G2 gap 2 Phase

g, mg, kg, μg, ng, pg: Gram(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 gonadotropin-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

GRP78 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

HC5 acute toxicity hazardous concentration for 5% 

of species

HC10 acute toxicity hazardous concentration for 10% 

of species

HCl hydrochloric acid

HCO3

- bicarbonate; hydrogen carbonate

Hct hematocrit

HDL high-density lipoprotein

HF hydrogen fluoride

HFE hemochromatosis gene

HFE C282Y: hemochromatosis gene with C282Y 

mutation

HFE H63D : hemochromatosis gene with H63D 

mutation

Hg mercury

HgCl2 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

HNO3 nitric acid

HO-1 heme oxygenase; heme oxidase-1 

H2O water

H2O2 hydrogen peroxide

HOME Home Observation for Measurement of the 

Environment

HPA hypothalamic-pituitary-adrenal

HPb, h-Pb: high lead

HPG hypothalamic-pituitary-gonadal

HPLC high-performance liquid chromatography

HPRT hypoxanthine-guanine 

phosphoribosyltransferase

HPT hyperparathyroidism; hypothalamic-pituitarythyroid 

HR heart rate; hazard ratio

HRV heart rate variability

hsp heat shock proteins

5HT serotonin

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

IC50 half maximal inhibitory concentration

ICAP inductively coupled argon plasma

ICP-AESinductively coupled plasma atomic emission 

spectroscopy

ICPMS, ICP-MS: Inductively 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 factor 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

IMPROVE: 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 Kelvin; potassium; resupsension factor

K+ potassium ion

K0.5 concentration of free metal giving half 

maximal metal-dependent release

KART Karters of American Racing Triad

Kd dissociation constant

Kd partition coefficient; ratio of the metal 

concentration in soil 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

LC50 lethal concentration (at which 50% of exposed 

organisms die)

LD50 lethal dose (at which 50% of exposed 

organisms die)

LDH lactate dehydrogenase

LDL low-density lipoproteins

LFH-horizons: organic soil horizons located above welldrained 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

LLNA 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 protein-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-activated protein 

kinase 1

MEK2 dual specificity mitogen-activated protein 

kinase 2

Mg magnesium

Mg2+ 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

MnO2 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; normal; north; number; population

n number of observations

Na sodium

Na+ sodium ion

NAAQS National Ambient Air Quality Standards

NAC N-acetyl cysteine; nucleus accumbens

Na2CaEDTA: 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; Nacetylglucosamine 

NaHCO3 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

NAWQANational 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

NDMARN-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

NH4Cl ammonium chloride

NHEJ non-homologous end joining

NHEXAS: National Human Exposure Assessment 

Survey

NH4OAc ammonium acetate

7-NI 7-nitroinidazole 

Ni nickel

NICA non-ideal competitive absorption

NIOSH National Institute for Occupational 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

NO2 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 nitric oxide synthase; nitric oxide systems

NOX nitrogen oxides, oxides of nitrogen 

(NO + NO2)

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

O2 molecular oxygen

O2

- superoxide

O3 ozone

9-O-Ac-GD3: 9-O-acetylated-GD3

OAQPS U.S. EPA Office 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)2D3: 1,25-dihydroxy vitamin D 

O-horizon: horizon forest floor, 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

P0 parent generation

P450 cytochrome P450

p probability value; number of paried hourly 

observations; statistical significance

PAD peripheral arterial disease

PAH(s) polycyclic aromatic hydrocarbon(s)

Pb lead

203Pb lead-203 radionuclide

204Pb stable isotope of lead-204

206Pb stable isotope of lead-206

207Pb stable isotope of lead-207

208Pb stable isotope of lead-208

210Pb stable isotope of lead-210

Pb++ divalent Pb ion

Pb0 elemental lead

Pb(II) lead (II)

Pb2+ lead ion

Pb(Ac)2 lead acetate

PbB blood lead concentration

PbBrCl lead bromochloride

Pb(C2H3O2)2: lead (II) acetate

PbCl+ lead chloride

PbCl2 lead chloride

PbCl3 lead (III) chloride; lead trichloride

PbCl4 lead (IV) chloride; lead tetrachloride

PbCO3 cerrusite; lead carbonate 

Pb(CO3)2lead (IV) carbonate

Pb(CO3)2(OH)2: hydrocerussite

PbCrO4 lead (II) chromate

PbD floor dust lead

PbFe6(SO4)4(OH)12: plumbjarosite

PBG porphobilinogen

Pb(NO3)2: lead(II) nitrate

Pb-NS lead-no stress

PbO lead oxide; litharge; massicot

PbO2 lead dioxide

Pb(IV)O2: lead dioxide

Pb3O4 minimum or "red Pb"

Pb(OH)2 lead hydroxide

Pb5(PO4)3Cl: pyromorphite

Pb5(PO4)3OH: hydroxypyromorphite

PbS galena; lead sulfide; soil lead concentration

PbSe lead selenide

PbSO4 anglesite; lead sulfate

Pb4SO4(CO3)2(OH)3: macphersonite

PbxS lead by stress

Pb5(VO4)3Cl: 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

PGE2, PGE2: prostaglandin E2

PGF2 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 poverty-income ratio

PIXE particle induced X-Ray emission; protoninduced x-ray emission

PKC protein kinase C

PLP proteolipid protein

PM particulate matter

PMX 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 PMX 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

PM10 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 

Appendix 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.

PM2.5 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 designated 

in accordance with Appendix C of 40 CFR Part 

58.

PM10-2.5 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 coarse 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 particles 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.

PM10C The PM10-2.5 concentration of PM10-2.5

measured by the 40 CFR Part 50 Appendix O 

reference method which consists of currently 

operated, collocated low-volume (16.7 Lpm) 

PM10 and PM2.5 reference method samplers.

p38MAPK: p38 mitogen-activated protein kinase(s)

PMN polymorphonuclear 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; phosphatidylserine

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 vascular 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

R2 multiple regression correlation coefficient 

r

2 correlation coefficient

RAAS renin-angiotensin-aldosterone system

RAC2 gene encoding for Rac2

RBA relative bioavailability

RBC red blood cell

RBP retinol binding protein

RD radial diffusivity

Ref reference (group)

RI-RI concurrent random interval

RL repeated learning

220Rn radon isotope

222Rn stable isotope of radon-222

RNA ribonucleic acid

ROI reactive oxygen intermediate/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 deviation

S south; sulfur; synthesis phase

SAB U.S. EPA Science Advisory Board

SATs Standard Assessment Tests 

SBP systolic blood pressure
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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

SGOT 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 

SO2 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: sterol 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 

transcription 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

T3, T3 triiodothyronine

T4, T4 thyroxine

t1/2 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 threshold 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 factor

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 Children (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
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TXB2 thromboxane

UA urbanized area

UBL urban boundary layer

UCL urban canopy layer

UDPGT uridine diphosphate (UDP)-

glucuronosyltransferase(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 radiation

V vanadium

V79 Chinese hamster lung cell line

VA Veterans Administration

VAChATvesicular 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

VO4

3- vanadate ion

VOC(s) volatile 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

WIAT Wechsler Individual Achievement Test

WISC Weschler Intelligence Scale for Children

WISC-R Weschler Intelligence Scale for ChildrenRevised

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

Xij observed hourly concentrations for time period 

i at site j

Xik observed hourly concentrations for time period 

i at site k

XPS X-ray photoelectron spectroscopy

XRF X-ray fluorescence

yr year(s)

Zn zinc

Zn2+ zinc ion

ZPP zirconium-potassium perchlorate; zinc 

protoporphyrin 

Z-score standard score
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PREAMBLE

Process of ISA Development

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

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

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

4 synthesis, and evaluation of the most policy-relevant science to serve as a scientific 

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

6 general process for NAAQS reviews is described at 

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

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

9 steps and criteria used in developing an ISA; for each ISA, specific details and 

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

11 The fundamental process for developing an ISA includes:

12  literature searches;

13  study selection;

14  evaluation and integration of the evidence; and 

15  development of scientific conclusions and causal judgments.

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

17 Register that invites the public to provide information relevant to the assessment, such as 

new publications on health or welfare1 18 effects of the pollutant, or from atmospheric and 

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

20 identification of relevant scientific studies published since the last review of the NAAQS. 

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

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

23 inclusion in several additional ways: specialized searches on specific topics; independent 

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

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

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

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

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

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

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

3 ISA. Analyses conducted by EPA using publicly available data are also considered for 

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

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

6 are considered, including those related to exposure-response relationships, mode(s) of 

7 action (MOA), and potentially at-risk populations and lifestages. Studies on atmospheric 

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

9 also considered for inclusion in the document, as well as analyses of air quality and 

10 emissions data.

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

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

13 completion of the previous review and on any new interpretations of previous literature, 

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

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

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

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

18 remain the definitive works available in the literature. 

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

20 the study, and consideration of the extent to which the study is informative and policy21 relevant. Policy relevant and informative studies include those that provide a basis for or 

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

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

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

25 analyses of concentration-response or dose-response relationships, or analyses related to 

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

27 associated with pollutant concentrations relevant to current population and ecosystem 

28 exposures, and particularly those pertaining to concentrations currently found in ambient 

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

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

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

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

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

34  Are the study populations, subjects, or animal models adequately selected, and 

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

36 study or exposure groups? 
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1  Are the statistical analyses appropriate, properly performed, and properly 

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

3 the study design and statistical analysis? 

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

5 sufficiently representative of information regarding ambient conditions?

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

7 reliable?

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

9 conclusions?

10 Considerations specific to particular disciplines include the following. In selecting 

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

12 associations with short- or long-term pollutant exposures at or near conditions relevant to 

13 ambient exposures; (2) addresses potential confounding by other pollutants; (3) assesses 

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

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

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

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

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

19 animal toxicological studies includes a focus on studies conducted using relevant 

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

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

22 concentrations. Studies in which higher doses were used may also be considered if they 

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

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

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

26 should include control exposures to filtered air, as appropriate. In the selection of 

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

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

29 cardiovascular diseases, children or older adults; (2) address issues such as concentration30 response or time-course of responses; and (3) have sufficient statistical power to assess 

31 findings. 

32 Review of the animal toxicological evidence focuses on studies that approximate 

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

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

35 Emphasis is placed on studies that: (1) investigate animal models of disease that can 
February 2012 xlvi Draft – Do Not Cite or Quote

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

2 issues such as concentration-response or time-course of responses; and (3) have sufficient 

3 statistical power to assess findings. Due to resource constraints on exposure duration and 

4 numbers of animals tested, animal studies typically utilize high-concentration exposures 

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

6 placed on studies using doses or concentrations generally within 1-2 orders of magnitude 

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

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

9 interspecies differences and potential differences between healthy and susceptible human 

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

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

12 These criteria provide benchmarks for evaluating various studies and for focusing on the 

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

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

15 synthesis, and evaluation of the most policy-relevant science to serve as a scientific 

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

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

18 studies is whether they provide useful qualitative or quantitative information on 

19 exposure-effect or exposure-response relationships for effects associated with pollutant 

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

21 decisions on whether to retain or revise the standards. 

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

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

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

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

26 workshop in which EPA and non-EPA experts review the scientific content of 

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

28 policy-relevant findings, and to assist EPA with integration of evidence within and across 

29 disciplines. 

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

31 characterizes the weight of evidence for relationships between the pollutant and various 

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

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

34 evaluation of health effects evidence would include the integration of the results from 

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

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

37 framework described in the following section, EPA scientists consider aspects such as 
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1 strength, consistency, coherence, and biological plausibility of the evidence, and develop 

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

3 often entail an iterative process of review and evaluation of the evidence. Two drafts of 

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

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

6 framework are carefully considered in revising and completing the final ISA.

EPA Framework for Causal Determination

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

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

9 described below establishes uniform language concerning causality and brings more 

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

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

12 Sciences (NAS) Institute of Medicine (IOM) document, Improving the Presumptive 

13 Disability Decision-Making Process for Veterans (2008), a comprehensive report on 

14 evaluating causality. This framework:

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

16 relationship between exposure and health effects; 

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

18 a causal relationship; 

19  identifies issues and approaches related to uncertainty; and

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

21 in support of a general causal relationship.

22 Approaches to assessing the separate and combined lines of evidence 

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

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

25 the NAS (2008), International Agency for Research on Cancer (2006b), U.S. EPA

26 (2005c), and Centers for Disease Control and Prevention (2004). Causal inference criteria 

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

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

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

30 providing a uniform structure and language for causal determinations.
February 2012 xlviii Draft – Do Not Cite or Quote

Evaluating Evidence for Inferring Causation 

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

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

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

4 in the host” (HEW, 1964), more generally, a cause is defined as an agent that brings 

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

6 alone, however, it is insufficient proof of a causal relationship between an exposure and a 

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

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

9 different or changed circumstances (Samet and Bodurow, 2008).

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

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

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

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

14 and Bodurow, 2008; Gee and Payne-Sturges, 2004). Effects on ecosystems are often also 

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

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

17 represent the net effect of many actions and counteractions. 

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

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

20 as having limited knowledge to exactly describe an existing state or future outcome, 

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

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

23 analysis is qualitative, and can include professional judgment or inferences based on 

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

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

26 analysis might progress to more complex measures and techniques, if needed for decision 

27 support. Various approaches to evaluating uncertainty include classical statistical 

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

29 complexity and data requirements. However, data may not be available for all aspects of 

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

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

32 degrees of uncertainty. The ISA generally evaluates uncertainties qualitatively in 

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

34 approaches, such as meta-regression, may be used.

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

36 estimates. It is well understood that studies reporting non-null findings are more likely to 
February 2012 xlix Draft – Do Not Cite or Quote

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

2 overestimation of effect estimate sizes (Ioannidis, 2008). For example, effect estimates 

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

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

Consideration of Evidence from Scientific Disciplines

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

6 for the association. The ISA focuses on evaluation of the findings from the body of 

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

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

9 evidence from across scientific disciplines. The relative importance of different types of 

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

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

12 of human health effects: controlled human exposure, epidemiologic and toxicological 

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

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

15 (e.g., community ecology, biogeochemistry and paleological/historical reconstructions).

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

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

18 experimentally evaluate the health effects of administered exposures in human volunteers 

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

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

21 pollutants under carefully regulated environmental conditions and activity levels. In some 

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

23 concentration-response relationships at pollutant concentrations relevant to ambient 

24 conditions. Controlled human exposures are typically conducted using a randomized 

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

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

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

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

29 patterns relevant to understanding real-world exposures, especially long-term exposures, 

30 are generally not practical to replicate in a laboratory setting. In addition, although 

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

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

33 individuals. Finally, controlled human exposure studies require investigators to adhere to 

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

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

36 studies have included health-compromised individuals such as those with respiratory or 
February 2012 l Draft – Do Not Cite or Quote

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

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

3 limited to exposures and endpoints that are not expected to result in severe health 

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

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

6 exposure studies provide important information on the biological plausibility of 

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

8 underestimate the response in certain populations.

9 Epidemiologic studies provide important information on the associations between health 

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

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

12 intervene with the study population. Broadly, observational studies can describe 

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

14 e.g., cross-sectional, prospective cohort, panel and time-series studies. “Natural 

15 experiments” offer the opportunity to investigate changes in health related to a change in 

16 exposure, such as closure of a pollution source. 

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

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

19 consideration is evaluation of the potential contribution of the pollutant to a health 

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

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

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

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

24 copollutants.

25 In the evaluation of epidemiologic evidence, one important consideration is potential 

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

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

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

29 and Greenland, 1998). One approach to remove spurious associations due to possible 

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

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

32 to evaluate likely sources and extent of confounding, together with consideration of how 

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

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

35 and the effect; for example, confounding can occur between correlated pollutants that are 

36 associated with the same effect. 
February 2012 li Draft – Do Not Cite or Quote

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

2 with none of them being completely satisfactory. Multivariable regression models 

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

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

5 multipollutant regression models has been the prevailing approach for controlling 

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

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

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

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

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

11 associations for multiple pollutants. The number and degree of diversity of covariates, as 

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

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

14 prevailing approach employed in most air pollution epidemiologic studies and provides 

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

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

17 when multiple studies are conducted in various settings using different subjects or 

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

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

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

21 potential confounding by copollutants. Intervention studies, because of their quasi22 experimental nature, can be particularly useful in characterizing causation. 

23 Another important consideration in the evaluation of epidemiologic evidence is effect 

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

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

26 modification differs from confounding in several ways. The main difference is that, 

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

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

29 In epidemiologic analysis one tries to eliminate confounding but one tries to detect and 

30 estimate effect-measure modification” (Rothman and Greenland, 1998). When a risk 

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

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

33 magnitude of the association between the exposure and the outcome in stratified analyses. 

34 For example, the presence of a pre-existing disease or indicator of low socioeconomic 

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

36 pollution exposure. It is often possible to stratify the relationship between health outcome 

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

38 modify the association, effect estimates in each stratum will be different from one another 
February 2012 lii Draft – Do Not Cite or Quote

1 and different from the overall estimate, indicating a different exposure-response 

2 relationship may exist in populations represented by these variables.

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

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

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

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

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

8 of average population exposure rather than individual exposure estimates. 

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

10 information on the pollutant’s biological action under controlled and monitored exposure 

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

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

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

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

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

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

17 effects. Understanding the biological mechanisms underlying various health outcomes 

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

19 data, extensive, well-conducted animal toxicological studies can support determinations 

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

21 under ambient exposure conditions. 

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

23 extrapolation between animal and human responses. The differences between humans 

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

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

26 of a high degree of homology and the existence of a high percentage of orthologous 

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

28 alterations at the gene level is complicated by species-specific differences in 

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

30 quantitative extrapolations of observed pollutant-induced pathophysiological alterations 

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

32 widely varying biochemical, endocrine, and neuronal factors.

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

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

35 determination. Because conditions can be controlled in laboratory studies, responses may 

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

37 may limit the range of responses (e.g., animals may not be able to seek alternative food 
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1 sources), so they may not reflect responses that would occur in the natural environment. 

2 In addition, larger-scale processes are difficult to reproduce in the laboratory.

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

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

5 provide important information for assessments of multiple stressors or where site-specific 

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

7 geographic scales and higher levels of biological organization. However, because 

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

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

10 and effect levels are measured concurrently. The presence of confounding factors can 

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

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

13 collected from the field to examine response in the laboratory, and experiments that are 

14 performed in the natural environment while controlling for some environmental 

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

16 environments can be considered a hybrid between a field experiment and laboratory study 

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

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

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

20 under more controlled conditions.

Application of Framework for Causal Determination

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

22 pollutants, EPA determines the weight of evidence in support of causation and 

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

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

25 the concentration-response relationships and the loads to ecosystems, exposure doses or 

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

To aid judgment, various “aspects”1 27 of causality have been discussed by many 

28 philosophers and scientists. The 1964 Surgeon General’s report on tobacco smoking 

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

30 strength, specificity, temporal relationship, and coherence (HEW, 1964). Sir Austin 

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

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

33 CDC, 2004). These aspects (Hill, 1965) have been modified (Table I) for use in causal 

 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 different meaning, in the Clean Air Act.
February 2012 liv Draft – Do Not Cite or Quote

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

2009).

1 2 Although these aspects provide a framework for assessing the evidence, they do 

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

4 evidence leading to conclusions about causality (Hill, 1965). For example, one cannot 

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

6 statistically nonsignificant results and reach credible conclusions about the relative 

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

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

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

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

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

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

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

 1 The Hill aspects were developed for interpretation of epidemiologic results. They have been modified here for use with a broader 

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, 

possible 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 

paleontological/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 across 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 available. 

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 observed 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 argument 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 information 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

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

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

3 between relevant pollutant exposures and health or environmental effects. ISAs use a 
February 2012 lvi Draft – Do Not Cite or Quote

five-level hierarchy that classifies the weight of evidence for causation1 1 . In developing 

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

3 IOM’s Improving the Presumptive Disability Decision-Making Process for Veterans

4 (Samet and Bodurow, 2008), EPA’s Guidelines for Carcinogen Risk Assessment (U.S. 

5 EPA, 2005c), and the U.S. Surgeon General’s smoking report (CDC, 2004), The Health 

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

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

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

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

10 determination are described in Table II.

11 Determination of causality involves the evaluation of evidence for different types of 

12 health, ecological or welfare effects associated with short- and long-term exposure 

13 periods. In making determinations of causality, evidence is evaluated for major outcome 

14 categories and then conclusions are drawn based upon the integration of evidence from 

15 across disciplines and also across the spectrum of related endpoints. In making causal 

16 judgments, the ISA focuses on major outcome categories (e.g., respiratory effects, 

17 vegetation growth), by evaluating the coherence of evidence across a spectrum of related 

18 endpoints (e.g., health effects ranging from inflammatory effects to respiratory mortality) 

19 to draw conclusions regarding causality. In discussing the causal determination, EPA 

20 characterizes the evidence on which the judgment is based, including strength of 

21 evidence for individual endpoints within the major outcome category.

 1 The Center for Disease Control (CDC) and IOM frameworks use a four-category hierarchy for the strength of the evidence. 

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 relationship 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 

information). Evidence includes replicated 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 two 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 medium-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 infer 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 pollutant 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) 

observational studies show an association, but 

copollutant exposures are difficult 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 pollutant 

exposures. That is, an association has been 

observed between the pollutant and the outcome 

in studies in which chance, bias and confounding 

are minimized, but uncertainties remain. For 

example, field studies 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 

relationship

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, bias 

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 

relationship exists with relevant pollutant 

exposures. The available studies are of insufficient 

quantity, quality, consistency or statistical power to 

permit a conclusion regarding the presence or 

absence of an effect.

The available studies are of insufficient quality, 

consistency or statistical power to permit a 

conclusion regarding the presence or absence of 

an effect.
February 2012 lviii Draft – Do Not Cite or Quote

Health Effects Ecological and Welfare Effects

Not likely to 

be a causal 

relationship

Evidence is suggestive of no causal relationship 

with relevant pollutant exposures. Several 

adequate studies, 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 

with relevant exposures, are consistent in failing to 

show an effect at any level of exposure.

1 In drawing judgments regarding causality for the criteria air pollutants, the ISA focuses 

2 on evidence of effects in the range of relevant pollutant exposures or doses, and not on 

3 determination of causality at any dose. Emphasis is placed on evidence of effects at doses 

4 (e.g., blood lead concentration) or exposures (e.g., air concentrations) that are relevant to, 

5 or somewhat above, those currently experienced by the population. The extent to which 

6 studies of higher concentrations are considered varies by pollutant and major outcome 

7 category, but generally includes those with doses or exposures in the range of one to two 

8 orders of magnitude above current or ambient conditions. Studies that use higher doses or 

9 exposures may also be considered to the extent that they provide useful information to 

10 inform our understanding of mode of action, interspecies differences or factors that may 

11 increase risk of effects for a population. Thus, a causality determination is based on 

12 weight of evidence evaluation for health, ecological or welfare effects, focusing on the 

13 evidence from exposures or doses generally ranging from current levels to one or two 

14 orders of magnitude above current levels.

15 In addition, EPA evaluates evidence relevant to understand the quantitative relationships 

16 between pollutant exposures and health, ecological or welfare effects. This includes 

17 evaluation of the form of concentration-response or dose-response relationships and, to 

18 the extent possible, drawing conclusions on the levels at which effects are observed. The 

19 ISA also draws scientific conclusions regarding important exposure conditions for effects 

20 and populations that may be at greater risk for effects, as described in the following 

21 section.

Quantitative Relationships: Effects on Human Populations

22 Once a determination is made regarding the causal relationship between the pollutant and 

23 outcome category, important questions regarding quantitative relationships include: 

24  What is the concentration-response, exposure-response, or dose-response 

25 relationship in the human population?

26  What is the interrelationship between incidence and severity of effect?
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1  What exposure conditions (dose or exposure, duration and pattern) are 

2 important?

3  What populations and lifestages appear to be differentially affected (i.e., more at 

4 risk of experiencing effects)?

5 To address these questions, the entirety of quantitative evidence is evaluated to 

6 characterize pollutant concentrations and exposure durations at which effects were 

7 observed for exposed populations, including populations and lifestages potentially at 

8 increased risk. To accomplish this, evidence is considered from multiple and diverse 

9 types of studies, and a study or set of studies that best approximates the concentration10 response relationships between health outcomes and the pollutant may be identified. 

11 Controlled human exposure studies provide the most direct and quantifiable exposure12 response data on the human health effects of pollutant exposures. To the extent available, 

13 the ISA evaluates results from across epidemiologic studies that use various methods to 

14 characterize the form of relationships between the pollutant and health outcomes and 

15 draws conclusions on the shape of these relationships. Animal data may also inform 

16 evaluation of concentration-response relationships, particularly relative to MOAs and 

17 characteristics of susceptible populations. 

18 An important consideration in characterizing the public health impacts associated with 

19 exposure to a pollutant is whether the concentration-response relationship is linear across 

20 the range of concentrations or if nonlinear relationships exist along any part of this range. 

21 Of particular interest is the shape of the concentration-response curve at and below the 

22 level of the current standards. Various sources of variability and uncertainty, such as low 

23 data density in the lower concentration range, possible influence of exposure 

24 measurement error, and variability between individuals in susceptibility to air pollution 

25 health effects, tend to smooth and “linearize” the concentration-response function, and 

26 thus can obscure the existence of a threshold or nonlinear relationship. Since individual 

27 thresholds vary from person to person due to individual differences such as genetic level 

28 susceptibility or preexisting disease conditions (and even can vary from one time to 

29 another for a given person), it can be difficult to demonstrate that a threshold exists in a 

30 population study. These sources of variability and uncertainty may explain why the 

31 available human data at ambient concentrations for some environmental pollutants 

32 (e.g., particulate matter [PM], ozone [O3], lead [Pb], environmental tobacco smoke 

33 [ETS], radiation) do not exhibit thresholds for cancer or noncancer health effects, even 

34 though likely mechanisms include nonlinear processes for some key events. These 

35 attributes of human population dose-response relationships have been extensively 

36 discussed in the broader epidemiologic literature (Rothman and Greenland, 1998).
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1 Finally, identification of the population groups or lifestages that may be at greater risk of 

2 health effects from air pollutant exposures contributes to an understanding of the public 

3 health impact of pollutant exposures. In the ISA, the term “at-risk population” is used to 

4 encompass populations or lifestages that have a greater likelihood of experiencing health 

5 effects related to exposure to an air pollutant due to a variety of factors. These factors 

6 may be intrinsic, such as genetic or developmental factors, race, gender, lifestage, or the 

7 presence of pre-existing diseases, or they may be extrinsic, such as socioeconomic status 

8 (SES), activity pattern and exercise level, reduced access to health care, low educational 

9 attainment, or increased pollutant exposures (e.g., near roadways). Epidemiologic studies 

10 can help identify populations potentially at increased risk of effects by evaluating health 

11 responses in the study population. Examples include testing for interactions or effect 

12 modification by factors such as gender, age group, or health status. Experimental studies 

13 using animal models of susceptibility or disease can also inform the extent to which 

14 health risks are likely greater in specific population groups.

Quantitative Relationships: Effects on Ecosystems or Public Welfare

15 Key questions for understanding the quantitative relationships between exposure (or 

16 concentration or deposition) to a pollutant and risk to ecosystems or the public welfare 

17 include: 

18  What elements of the ecosystem (e.g., types, regions, taxonomic groups, 

19 populations, functions, etc.) appear to be affected, or are more sensitive to 

20 effects? Are there differences between locations or materials in welfare effects 

21 responses, such as impaired visibility or materials damage?

22  Under what exposure conditions (amount deposited or concentration, duration 

23 and pattern) are effects seen? 

24  What is the shape of the concentration-response or exposure-response 

25 relationship? 

26 Evaluations of causality generally consider the probability of quantitative changes in 

27 ecological and welfare effects in response to exposure. A challenge to the quantification 

28 of exposure-response relationships for ecological effects is the great regional and local 

29 spatial variability, as well as temporal variability, in ecosystems. Thus, exposure30 response relationships are often determined for a specific ecological system and scale, 

31 rather than at the national or even regional scale. Quantitative relationships therefore are 

32 available site by site and may differ greatly between ecosystems. 
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Concepts in Evaluating Adversity of Health Effects

1 In evaluating health evidence, a number of factors can be considered in delineating 

2 between adverse and nonadverse health effects resulting from exposure to air pollution. 

3 Some health outcomes, such as hospitalization for respiratory or cardiovascular diseases, 

4 are clearly considered adverse. It is more difficult to determine the extent of change that 

5 constitutes adversity in more subtle health measures. These include a wide variety of 

6 responses, such as alterations in markers of inflammation or oxidative stress, changes in 

7 pulmonary function or heart rate variability, or alterations in neurocognitive function 

8 measures. The challenge is determining the magnitude of change in these measures when 

9 there is no clear point at which a change become adverse; for example, what percentage 

10 change in a lung function measure represents an adverse effect. What constitutes an 

11 adverse health effect may vary between populations. Some changes that may not be 

12 considered adverse in healthy individuals would be potentially adverse in more 

13 susceptible individuals. 

14 For example, the extent to which changes in lung function are adverse has been discussed 

15 by the American Thoracic Society (ATS) in an official statement titled What Constitutes 

16 an Adverse Health Effect of Air Pollution? (2000). An air pollution-induced shift in the 

17 population distribution of a given risk factor for a health outcome was viewed as adverse, 

18 even though it may not increase the risk of any one individual to an unacceptable level. 

19 For example, a population of asthmatics could have a distribution of lung function such 

20 that no identifiable individual has a level associated with significant impairment. 

21 Exposure to air pollution could shift the distribution such that no identifiable individual 

22 experiences clinically relevant effects. This shift toward decreased lung function, 

23 however, would be considered adverse because individuals within the population would 

24 have diminished reserve function and therefore would be at increased risk to further 

25 environmental insult. The committee also observed that elevations of biomarkers, such as 

26 cell number and types, cytokines and reactive oxygen species, may signalrisk for ongoing 

27 injury and clinical effects or may simply indicate transient responses that can provide 

28 insights into mechanisms of injury, thus illustrating the lack of clear boundaries that 

29 separate adverse from nonadverse effects.

30 The more subtle health outcomes may be connected mechanistically to health events that 

31 are clearly adverse. For example, air pollution may affect markers of transient myocardial 

32 ischemia such as ST-segment abnormalities and onset of exertional angina. These effects 

33 may not be apparent to the individual, yet may still increase the risk of a number of 

34 cardiac events, including myocardial infarction and sudden death. Thus, small changes in 

35 physiological measures may not appear to be clearly adverse when considered alone, but 

36 may be a part of a coherent and biologically plausible chain of related health outcomes 
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1 that range up to responses that are very clearly adverse, such as hospitalization or 

2 mortality.

Concepts in Evaluating Adversity of Ecological Effects

3 Adversity of ecological effects can be understood in terms ranging in scale from the 

4 cellular level to the individual organism and to the population, community and ecosystem 

5 levels. In the context of ecology, a population is a group of individuals of the same 

6 species, and a community is an assemblage of populations of different species interacting 

7 with one another that inhabit an area. An ecosystem is the interactive system formed from 

8 all living organisms and their abiotic (physical and chemical) environment within a given 

9 area (IPCC, 2007). The boundaries of what could be called an ecosystem are somewhat 

10 arbitrary, depending on the focus of interest or study. Thus, the extent of an ecosystem 

11 may range from very small spatial scales to, ultimately, the entire Earth (IPCC, 2007).

12 Effects on an individual organism are generally not considered to be adverse to public 

13 welfare. However if effects occur to enough individuals within a population, then 

14 communities and ecosystems may be disrupted. Changes to populations, communities 

15 and ecosystems can in turn result in an alteration of ecosystem processes. Ecosystem 

16 processes are defined as the metabolic functions of ecosystems including energy flow, 

17 elemental cycling, and the production, consumption and decomposition of organic matter

18 (U.S. EPA, 2002b). Growth, reproduction, and mortality are species-level endpoints that 

19 can be clearly linked to community and ecosystem effects and are considered to be 

20 adverse when negatively affected. Other endpoints such as changes in behavior and 

21 physiological stress can decrease ecological fitness of an organism, but are harder to link 

22 unequivocally to effects at the population, community and ecosystem level. The degree to 

23 which pollutant exposure is considered adverse may also depend on the location and its 

24 intended use (i.e., city park, commercial cropland). Support for consideration of adversity 

25 beyond the species level by making explicit the linkages between stress-related effects at 

26 the species and effects at the ecosystem level is found in A Framework for Assessing and 

27 Reporting on Ecological Condition: an SAB report (U.S. EPA, 2002b). Additionally, the 

28 National Acid Precipitation Assessment Program (NAPAP) uses the following working 

29 definition of adverse ecological effects in the preparation of reports to Congress 

30 mandated by the Clean Air Act: “any injury (i.e. loss of chemical or physical quality or 

31 viability) to any ecological or ecosystem component, up to and including at the regional 

32 level, over both long and short terms.” 

33 On a broader scale, ecosystem services may provide indicators for ecological impacts. 

34 Ecosystem services are the benefits that people obtain from ecosystems (UNEP, 2003).

35 According to the Millennium Ecosystem Assessment, ecosystem services include: 
February 2012 lxiii Draft – Do Not Cite or Quote

1 “provisioning services such as food and water; regulating services such as regulation of 

2 floods, drought, land degradation, and disease; supporting services such as soil formation 

3 and nutrient cycling; and cultural services such as recreational, spiritual, religious and 

4 other nonmaterial benefits.” For example, a more subtle ecological effect of pollution 

5 exposure may result in a clearly adverse impact on ecosystem services if it results in a 

6 population decline in a species that is recreationally or culturally important.

7

8

References

9 ATS (American Thoracic Society). (2000). What constitutes an adverse health effect of air pollution? This official 

10 statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J 

11 Respir Crit Care Med 161: 665-673. 

12 Bell, ML; Dominici, F; Samet, JM. (2005). A meta-analysis of time-series studies of ozone and mortality with 

13 comparison to the national morbidity, mortality, and air pollution study. Epidemiology 16: 436-445. 

14 CDC (Centers for Disease Control and Prevention). (2004). The health consequences of smoking: A report of the 

15 Surgeon General. Washington, DC. http://www.surgeongeneral.gov/library/smokingconsequences/.

16 Fox, GA. (1991). Practical causal inference for ecoepidemiologists. J Toxicol Environ Health A 33: 359-373. 

17 http://dx.doi.org/10.1080/15287399109531535.

18 Gee, GC; Payne-Sturges, DC. (2004). Environmental health disparities: A framework integrating psychosocial and 

19 environmental concepts. Environ Health Perspect 112: 1645-1653. http://dx.doi.org/10.1289/ehp.7074.

20 HEW (U.S. Department of Health, Education and Welfare). (1964). Smoking and health: Report of the advisory 

21 committee to the surgeon general of the public health service. Washington, DC.

22 Hill, AB. (1965). The environment and disease: Association or causation? Proc R Soc Med 58: 295-300. 

23 IARC (International Agency for Research on Cancer). (2006b). Preamble to the IARC monographs. Lyon, France. 

24 http://monographs.iarc.fr/ENG/Preamble/.

25 Ioannidis, JPA. (2008). Why most discovered true associations are inflated. Epidemiology 19: 640-648. 

26 http://dx.doi.org/10.1097/EDE.0b013e31818131e7.

27 IPCC (Intergovernmental Panel on Climate Change). (2007). Summary for policymakers. In: Impacts, Adaptation 

28 and Vulnerability. Contribution of Working Group II to the Fourth Assessment Report of the 

29 Intergovernmental Panel on Climate Change. Cambridge, UK: IPCC.

30 Rothman, KJ; Greenland, S. (1998). Modern epidemiology (2nd ed.). Philadelphia, PA: Lippincott, Williams, & 

31 Wilkins. 

32 Samet, JM; Bodurow, CC (Eds.). (2008). Improving the presumptive disability decision-making process for 

33 veterans. Washington, DC: National Academies Press. 

34 http://www.nap.edu/openbook.php?record_id=11908.
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1 U.S. EPA (U.S. Environmental Protection Agency). (1998). Guidelines for ecological risk assessment. (EPA/630/R2 95/002F). Washington, DC. http://www.epa.gov/raf/publications/guidelines-ecological-risk3 assessment.htm.

4 U.S. EPA (U.S. Environmental Protection Agency). (2002b). A framework for assessing and reporting on ecological 

5 condition: An SAB report. Washington, DC: US EPA.

6 U.S. EPA (U.S. Environmental Protection Agency). (2005c). Guidelines for carcinogen risk assessment. 

7 (EPA/630/P-03/001F). Washington, DC. http://www.epa.gov/cancerguidelines/.

8 U.S. EPA (U.S. Environmental Protection Agency). (2009). Integrated science assessment for particulate matter. 

9 (EPA/600/R-08/139F). Research Triangle Park, NC. 

10 http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=216546.

11 UNEP (United Nations Environment Programme). (2003). Millennium Ecosystem Assessment: Ecosystems and 

12 human well-being: A framework for assessment. Washington, DC.

13

14
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PREFACE

Legislative Requirements for the NAAQS Review

1 Two sections of the Clean Air Act (CAA) govern the establishment and revision of the 

2 NAAQS. Section 108 (42:U.S.C.:7408) directs the Administrator to identify and list 

3 certain air pollutants and then to issue air quality criteria for those pollutants. The 

4 Administrator is to list those air pollutants that in her “... judgment, cause or contribute 

5 to air pollution which may reasonably be anticipated to endanger public health or 

6 welfare; ...” and, “... the presence of which in the ambient air results from numerous or 

7 diverse mobile or stationary sources;” and, “... for which ... [the Administrator] plans to 

8 issue air quality criteria.... .” Air quality criteria are intended to “accurately reflect the 

9 latest scientific knowledge useful in indicating the kind and extent of all identifiable 

10 effects on public health or welfare which may be expected from the presence of [a] 

11 pollutant in the ambient air ...” (42:U.S.C.:7408([b]). Section 109 (42:U.S.C.:7409) 

12 directs the Administrator to propose and promulgate “primary” and “secondary” NAAQS 

13 for pollutants for which air quality criteria are issued. Section 109(b)(1) defines a primary 

14 standard as one “...the attainment and maintenance of which in the judgment of the 

15 Administrator, based on such criteria and allowing an adequate margin of safety, are 

16 requisite to protect the public health.” The legislative history of Section 109 indicates that 

17 a primary standard is to be set at “... the maximum permissible ambient air level ... 

18 which will protect the health of any [sensitive] group of the population,” and that for this 

19 purpose “... reference should be made to a representative sample of persons comprising 

20 the sensitive group rather than to a single person in such a group...” (S. Rep. No. 

21 91:1196, 91st Cong., 2d Sess. 10 [1970]). A secondary standard, as defined in Section 

22 109(b)(2), must “... specify a level of air quality the attainment and maintenance of 

23 which, in the judgment of the Administrator, based on such criteria, is requisite to protect 

24 the public welfare from any known or anticipated adverse effects associated with the 

25 presence of [the] pollutant in the ambient air.” Welfare effects (as defined in Section 

26 302(h); 42:U.S.C.:7602[h]) include, but are not limited to, “... effects on soils, water, 

27 crops, vegetation, man-made materials, animals, wildlife, weather, visibility and climate, 

28 damage to and deterioration of property, and hazards to transportation, as well as effects 

29 on economic values and on personal comfort and well-being.”

30 The requirement that primary standards provide an adequate margin of safety was 

31 intended to address uncertainties associated with inconclusive scientific and technical 

32 information available at the time of standard setting. It was also intended to provide a 

33 reasonable degree of protection against hazards that research has not yet identified (Lead 

34 Industries Association v. EPA, 647:F.2d:1130-1154 [D.C.Cir 1980]; American Petroleum 
February 2012 lxvi Draft – Do Not Cite or Quote

1 Institute v. Costle, 665:F.2d:1176-1186 [D.C.Cir. 1981]; American Farm Bureau 

2 Federation v. EPA, 559:F.3d:512-533 [D.C. Cir. 2009]; Association of Battery Recyclers 

3 v. EPA, 604:F.3d:613, 617-618 [D.C. Cir. 2010]). Both kinds of uncertainties are 

4 components of the risk associated with pollution at levels below those at which human 

5 health effects can be said to occur with reasonable scientific certainty. Thus, in selecting 

6 primary standards that provide an adequate margin of safety, the Administrator is seeking 

7 not only to prevent pollution levels that have been demonstrated to be harmful but also to 

8 prevent lower pollutant levels that may pose an unacceptable risk of harm, even if the risk 

9 is not precisely identified as to nature or degree. The CAA does not require the 

10 Administrator to establish a primary NAAQS at a zero-risk level or at background 

11 concentration levels (Lead Industries v. EPA, [647:F.2d:at 1156 n.51]), but rather at a 

12 level that reduces risk sufficiently so as to protect public health with an adequate margin 

13 of safety.

14 In addressing the requirement for an adequate margin of safety, the EPA considers such 

15 factors as the nature and severity of the health effects involved, the size of sensitive 

16 population(s) at risk, and the kind and degree of the uncertainties that must be addressed. 

17 The selection of any particular approach to providing an adequate margin of safety is a 

18 policy choice left specifically to the Administrator’s judgment (Lead Industries 

19 Association v. EPA, [647:F.2d:1161-1162]; Whitman v. American Trucking 

20 Associations, [531:U.S.:457-495 (2001)]).

21 In setting standards that are “requisite” to protect public health and welfare as provided in 

22 Section 109(b), EPA’s task is to establish standards that are neither more nor less 

23 stringent than necessary for these purposes. In so doing, EPA may not consider the costs 

24 of implementing the standards (see generally, Whitman v. American Trucking 

25 Associations, [531:U.S.:457, 465-472, 475-476 (2001)]). Likewise, “... [a]ttainability 

26 and technological feasibility are not relevant considerations in the promulgation of 

27 national ambient air quality standards.” (American Petroleum Institute v. Costle, 

28 [665:F.2d:1185]).

29 Section 109(d)(1) requires that “not later than December 31, 1980, and at 5-year intervals 

30 thereafter, the Administrator shall complete a thorough review of the criteria published 

31 under section 108 and the national ambient air quality standards ... and shall make such 

32 revisions in such criteria and standards and promulgate such new standards as may be 

33 appropriate ... .” Section 109(d)(2) requires that an independent scientific review 

34 committee “shall complete a review of the criteria ... and the national primary and 

35 secondary ambient air quality standards ... and shall recommend to the Administrator any 

36 new ... standards and revisions of existing criteria and standards as may be appropriate 
February 2012 lxvii Draft – Do Not Cite or Quote

1 ... .” Since the early 1980's, this independent review function has been performed by the 

2 Clean Air Scientific Advisory Committee (CASAC).

History of the NAAQS for Pb

3 On October 5, 1978, EPA initially promulgated primary and secondary NAAQS for Pb 

4 under Section 109 of the Act (43 FR 46246). Both primary and secondary standards were 

set at a level of 1.5 micrograms per cubic meter (μg/m3 5 ), measured as Pb in total 

6 suspended particles (Pb-TSP), not to be exceeded by the maximum arithmetic mean 

7 concentration averaged over a calendar quarter. These standards were based on the 1977 

8 Air Quality Criteria for Lead (U.S. EPA, 1977).

9 The first review of the Pb standards was initiated in the mid-1980s. The scientific 

10 assessment for that review is described in the 1986 Air Quality Criteria for Lead (U.S. 

11 EPA, 1986a), the associated Addendum (U.S. EPA, 1986c) and the 1990 Supplement

12 (U.S. EPA, 1990a). As part of the review, the Agency designed and performed human 

13 exposure and health risk analyses (U.S. EPA, 1989), the results of which were presented 

14 in a 1990 Staff Paper (U.S. EPA, 1990b). Based on the scientific assessment and the 

15 human exposure and health risk analyses, the 1990 Staff Paper presented 

16 recommendations for consideration by the Administrator (U.S. EPA, 1990b). After 

17 consideration of the documents developed during the review and the significantly 

18 changed circumstances since Pb was listed in 1976, the Agency did not propose any 

19 revisions to the 1978 Pb NAAQS. In a parallel effort, the Agency developed the broad, 

20 multi-program, multimedia, integrated U.S. Strategy for Reducing Lead Exposure (U.S. 

21 EPA, 1991). As part of implementing this strategy, the Agency focused efforts primarily 

22 on regulatory and remedial clean-up actions aimed at reducing Pb exposures from a 

23 variety of non-air sources judged to pose more extensive public health risks to U.S. 

24 populations, as well as on actions to reduce Pb emissions to air, such as bringing more 

25 areas into compliance with the existing Pb NAAQS (U.S. EPA, 1991).

26 The most recent review of the Pb air quality criteria and standards was initiated in 

27 November, 2004 (69 FR 64926) and the Agency’s plans for preparation of the Air 

28 Quality Criteria Document and conduct of the NAAQS review were contained in two 

29 documents: Project Work Plan for Revised Air Quality Criteria for Lead (U.S. EPA, 

30 2005e); and Plan for Review of the National Ambient Air Quality Standards for Lead

31 (U.S. EPA, 2006e). The schedule for completion of this review was governed by a 

32 judicial order in Missouri Coalition for the Environment v. EPA (No. 4:04CV00660 

33 ERW, Sept. 14, 2005; and amended on April 29, 2008 and July 1, 2008), which specified 

34 a schedule for the review of duration substantially shorter than five years. 
February 2012 lxviii Draft – Do Not Cite or Quote

1 The scientific assessment for the review is described in the 2006 Air Quality Criteria for 

2 Lead [2006 Pb AQCD; (U.S. EPA, 2006b)], multiple drafts of which received review by 

3 CASAC and the public. EPA also conducted human exposure and health risk assessments 

4 and a pilot ecological risk assessment for the review, after consultation with CASAC and 

5 receiving public comment on a draft analysis plan (U.S. EPA, 2006d). Drafts of these 

6 quantitative assessments were reviewed by CASAC and the public. The pilot ecological 

7 risk assessment was released in December 2006 (ICF, 2006) and the final health risk 

8 assessment report was released in November 2007 (U.S. EPA, 2007g). The policy 

9 assessment based on both of these assessments, air quality analyses and key evidence 

10 from the AQCD was presented in the Staff Paper (U.S. EPA, 2006f), a draft of which also 

11 received CASAC and public review. The final Staff Paper presented OAQPS staff’s 

12 evaluation of the public health and welfare policy implications of the key studies and 

13 scientific information contained in the 2006 Criteria Document and presented and 

14 interpreted results from the quantitative risk/exposure analyses conducted for this review. 

15 Based on this evaluation, the Staff Paper presented OAQPS staff recommendations that 

16 the Administrator give consideration to substantially revising the primary and secondary

standards to a range of levels at or below 0.2 μg/m3 17 . 

18 Immediately subsequent to completion of the Staff Paper, EPA issued an advance notice 

19 of proposed rulemaking (ANPR) that was signed by the Administrator on December 5, 

2007 (72 FR 71488).1 20 CASAC provided advice and recommendations to the 

21 Administrator with regard to the Pb NAAQS based on its review of the ANPR and the 

22 previously released final Staff Paper and risk assessment reports. The proposed decision 

23 on revisions to the Pb NAAQS was signed on May 1, 2008 and published in the Federal 

24 Register on May 20, 2008 (73 FR 29184). Members of the public provided both written 

25 and, at two public hearings, oral comments and the CASAC Pb Panel also provided 

26 advice and recommendations to the Administrator based on its review of the proposal 

27 notice. The final decision on revisions to the Pb NAAQS was signed on October 15, 2008 

28 and published in the Federal Register on November 12, 2008 (73 FR 66964). 

29 The November 2008 notice described EPA’s decision to revise the primary and 

secondary NAAQS for Pb from a level of 1.5 μg/m3 to a level of 0.15 μg/m3 30 . EPA’s 

31 decision on the level for the primary standard was based on the much-expanded health 

effects evidence on neurocognitive effects of Pb in children. The level of 0.15 μg/m3 32 was 

33 established to protect against air Pb-related health effects, including IQ loss, in the most 

34 highly exposed children, those exposed at the level of the standard. Results of the 

35 quantitative risk assessment were judged supportive of the evidence-based framework 

 

1 The ANPR was one of the features of the revised NAAQS review process that EPA instituted in 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

1 estimates. The averaging time was revised to a rolling three-month period with a 

2 maximum (not-to-be-exceeded) form, evaluated over a three-year period. As compared to 

3 the previous averaging time of calendar quarter, this revision was considered to be more 

4 scientifically appropriate and more health protective. The rolling average gives equal 

5 weight to all three-month periods, and the new calculation method gives equal weight to 

6 each month within each three-month period. Further, the rolling average yields 12 

7 three-month averages each year to be compared to the NAAQS versus four averages in 

8 each year for the block calendar quarters pertaining to the previous standard. The 

9 indicator of Pb-TSP was retained, reflecting the evidence that Pb particles of all sizes 

10 pose health risks. The secondary standard was revised to be identical in all respects to the 

revised primary standards.1 11

12 Revisions to the NAAQS were accompanied by revisions to the data handling 

13 procedures, the treatment of exceptional events, and the ambient air monitoring and 

14 reporting requirements; as well as emissions inventory reporting requirements.2 One 

15 aspect of the new data handling requirements is the allowance for the use of Pb-PM10

16 monitoring for Pb NAAQS attainment purposes in certain limited circumstances at 

17 non-source-oriented sites. The monitoring network requirements resulted in a substantial 

18 number of new monitors being required as of January 2010, Subsequent to the 2008 

19 rulemaking, additional revisions were made to the monitoring network requirements, 

20 which required additional monitors as of December 2011; the complete current 

21 requirements are described in Section 3.4.

22 On February 26, 2010 (75 FR 8934), EPA formally initiated its current review of the air 

23 quality criteria for Pb, requesting the submission of recent scientific information on 

24 specified topics. Soon after, a science policy workshop was held to identify key policy 

25 issues and questions to frame the review of the Pb NAAQS (75 FR 20843). Drawing 

26 from the workshop discussions, a draft IRP [Integrated Review Plan for the National 

27 Ambient Air Quality Standards for Lead (U.S. EPA, 2011d)], was developed and made 

28 available in late March, 2011 for public comment and consultation with CASAC and was 

29 discussed by the CASAC via a publicly accessible teleconference consultation on May 5, 

30 2011 (76 FR 20347, 76 FR 21346). The final IRP (U.S. EPA, 2011c) was released in 

31 November, 2011 (76 FR 76972).

32 As part of the science assessment phase of the current review, EPA held a workshop in 

33 December 2010 (75 FR 69078) to discuss, with invited scientific experts, preliminary 

 

1 The 2008 NAAQS for Pb are specified at 40 CFR 50.16.

2 The 2008 federal regulatory measurement methods for Pb 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 specified in 

40 CFR 50, Appendix R. The Pb monitoring network requirements 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 the proposed and final rules (73 FR 29184; 73 FR 66964).
February 2012 lxx Draft – Do Not Cite or Quote

1 draft materials prepared during the ongoing development of the Pb ISA. The first external 

2 review draft ISA for Lead was released on May 6, 2011 (U.S. EPA 2011). The CASAC 

3 Pb Review Panel met at a public meeting on July 20, 2011 to review the draft ISA 

4 (76 FR 36120). Subsequently, on December 9, 2011, the CASAC panel provided a 

5 consensus letter for their review to the Administrator of the EPA (U.S. EPA 2011). The 

6 current document, the second external review draft ISA for Lead, will be discussed at a 

7 public meeting of the CASAC Pb Review Panel, and timely public comments received 

8 will be provided to the CASAC panel. A Federal Register notice will inform the public of 

9 the exact date and time of that CASAC meeting.

References

10 ICF (ICF International). (2006). Lead human exposure and health risk assessments and ecological risk assessment 

11 for selected areas: Pilot phase: External review draft technical report. Research Triangle Park, NC: ICF 

12 International.

13 U.S. EPA (U.S. Environmental Protection Agency). (1977). Air quality criteria for lead [EPA Report]. (EPA-600/8-

14 77-017). Washington, DC. http://nepis.epa.gov/Exe/ZyPURL.cgi?Dockey=20013GWR.txt.

15 U.S. EPA (U.S. Environmental Protection Agency). (1986a). Air quality criteria for lead [EPA Report]. (EPA/600/8-

16 83/028aF-dF). Research Triangle Park, NC. http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=32647.

17 U.S. EPA (U.S. Environmental Protection Agency). (1986c). Lead effects on cardiovascular function, early 

18 development, and stature: An addendum to U.S. EPA Air Quality Criteria for Lead (1986). (EPA-600/8-

19 83/028aF). Washington, DC: US EPA.

20 U.S. EPA (U.S. Environmental Protection Agency). (1989). Review of the national ambient air quality standards for 

21 lead: Exposure analysis methodology and validation: OAQPS staff report. (EPA-450/2-89-011). Research 

22 Triangle Park, NC: US EPA.

23 U.S. EPA (U.S. Environmental Protection Agency). (1990a). Air quality criteria for lead: Supplement to the 1986 

24 addendum [EPA Report]. (EPA/600/8-89/049F). Washington, DC.

25 U.S. EPA (U.S. Environmental Protection Agency). (1990b). Review of the national ambient air quality standards 

26 for lead: Assessment of scientific and technical information: OAQPS staff paper. (EPA-450/2-89-022). 

27 Research Triangle Park, NC: US EPA.

28 U.S. EPA (U.S. Environmental Protection Agency). (1991). Strategy for reducing lead exposures. Washington, DC: 

29 US EPA. http://www.epa.gov/ttn/naaqs/standards/pb/data/leadstrategy1991.pdf.

30 U.S. EPA (U.S. Environmental Protection Agency). (2005e). Project work plan for revised air quality criteria for 

31 lead. (NCEA-R-1465). Research Triangle Park, NC. 

32 http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=113963.

33 U.S. EPA (U.S. Environmental Protection Agency). (2006b). Air quality criteria for lead: Volume I of II. 

34 (EPA/600/R-05/144aF). Research Triangle Park, NC: US EPA. 

35 http://cfpub.epa.gov/ncea/CFM/recordisplay.cfm?deid=158823.

36 U.S. EPA (U.S. Environmental Protection Agency). (2006d). Analysis plan for human health and ecological risk 

37 assessment for the review of the lead national ambient air quality standards (draft). Research Triangle Park, 

38 NC. http://www.epa.gov/ttn/naaqs/standards/pb/s_pb_cr_pd.html.
February 2012 lxxi Draft – Do Not Cite or Quote

1 U.S. EPA (U.S. Environmental Protection Agency). (2006e). Plan for review of the national ambient air quality 

2 standards for lead. Research Triangle Park, NC. 

3 http://www.epa.gov/ttn/naaqs/standards/pb/s_pb_cr_pd.html.

4 U.S. EPA (U.S. Environmental Protection Agency). (2006f). Review of the national ambient air quality standards 

5 for lead: Policy assessment of scientific and technical information: OAQPS staff paper - first draft. (EPA6 452/P-06-002). Research Triangle Park, NC: US EPA.

7 U.S. EPA (U.S. Environmental Protection Agency). (2007g). Lead: Human exposure and health risk assessments for 

8 selected case studies: Volume 1: Human exposure and health risk assessments - full-scale. (EPA-452/R-07-

9 014a). Research Triangle Park, NC: US EPA. 

10 http://www.ntis.gov/search/product.aspx?ABBR=PB2008102573.

11 U.S. EPA (U.S. Environmental Protection Agency). (2011c). Integrated review plan for the national ambient air 

12 quality standards for lead. (EPA-452/R-11-008). Research Triangle Park, NC.

13 U.S. EPA (U.S. Environmental Protection Agency). (2011d). Integrated review plan for the national ambient air 

14 quality standards for lead: External review draft. (EPA-452/D-11-001). Research Triangle Park, NC.

15