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Chapter 2 Contents

Chapter 2. Integrative Health and Ecological Effects Overview ________________________________________________ 2-1

2.1. Ambient Lead: Source to Concentration _________________________________________________________ 2-2

2.1.1. Sources, Fate and Transport of Ambient Lead _____________________________________________ 2-2

2.1.2. Monitoring and Concentrations of Ambient Air Lead _______________________________________ 2-3

2.1.3. Ambient Lead Concentrations in Non-Air Media and Biota __________________________________ 2-5

2.2. Exposure to Ambient Lead____________________________________________________________________ 2-5

2.3. Toxicokinetics _____________________________________________________________________________ 2-7

2.4. Lead Biomarkers ___________________________________________________________________________ 2-8

2.5. Health Effects______________________________________________________________________________ 2-9

Table 2-1. Summary of causal determinations between exposure to Pb and health 

outcomes ___________________________________________________________ 2-10

2.5.1. Neurological Effects________________________________________________________________ 2-10

Figure 2-1. Snapshot of evidence for the spectrum of effects to the nervous system 

associated with Pb exposure. Green=animal toxicological studies (left 

side); purple=epidemiological studies (right side).________________________2-13

2.5.2. Cardiovascular Effects ______________________________________________________________ 2-13

2.5.3. Renal Effects _____________________________________________________________________ 2-15

2.5.4. Immune System Effects _____________________________________________________________ 2-17

2.5.5. Heme Synthesis and RBC Function ____________________________________________________ 2-18

2.5.6. Reproductive Effects and Birth Outcomes _______________________________________________ 2-20

2.5.7. Effects on Other Organ Systems ______________________________________________________ 2-21

2.5.8. Cancer __________________________________________________________________________ 2-23

2.5.9. Human Health Effects and Corresponding Blood Pb Levels _________________________________ 2-24

Table 2-2. Summary of Pb-induced health effects in children and the lowest mean 

blood Pb level in the population(s) studied ______________________________2-25

Table 2-3. Summary of Pb-induced health effects in adults and the lowest mean blood 

Pb level in the population(s) studied ___________________________________2-26

2.6. Ecological Effects _________________________________________________________________________ 2-26

Table 2-4. Summary of causal determinations for Pb in plants, vertebrates and 

invertebrates _____________________________________________________2-27

2.6.1. Summary of Terrestrial Ecosystem Effects ______________________________________________ 2-28

2.6.2. Summary of Aquatic Ecosystem Effects ________________________________________________ 2-30

2.6.3. Bioaccumulation of Lead in Terrestrial and Aquatic Biota as it Affects Ecosystem Services ________ 2-33

2.6.4. Mortality_________________________________________________________________________ 2-34

2.6.5. Growth Effects ____________________________________________________________________ 2-35

2.6.6. Physiological Stress ________________________________________________________________ 2-35

2.6.7. Hematological Effects ______________________________________________________________ 2-36

2.6.8. Developmental and Reproductive Effects _______________________________________________ 2-37

2.6.9. Neurobehavioral Effects_____________________________________________________________ 2-38

2.6.10. Community and Ecosystem Level Effects _______________________________________________ 2-39

2.6.11. Ecological Effects and Corresponding Pb Concentrations ___________________________________ 2-40

2.7. Integration of Health and Ecological Effects Overview_____________________________________________ 2-41

Table 2-5. Summary of Causal Determinations for Health and Ecological Effects ________2-42

2.7.1. Modes of Action Relevant to Downstream Health and Ecological Effects ______________________ 2-42

Table 2-6. Related human health effects resulting from the MOAs of Pb and the lowest 

level eliciting the MOA _____________________________________________2-43

2.8. Policy Relevant Considerations and Human Health________________________________________________ 2-46

2.8.1. Air-to-Blood Relationships __________________________________________________________ 2-46
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Table 2-7. Summary of Estimated Slopes for Blood Pb to Air Pb Relationships in 

Children ________________________________________________________2-48

2.8.2. Concentration-Response Functions ____________________________________________________ 2-48

Figure 2-2. Comparison of associations between blood Pb and cognitive function among 

various blood Pb strata. ____________________________________________2-49

2.8.3. Timing and Duration of Exposure _____________________________________________________ 2-52

Figure 2-3. Associations of cognitive function in children with different degrees of 

changes in blood Pb levels over time. __________________________________2-53

2.8.3.1. Persistence of Effects _______________________________________________________ 2-54

2.8.4. Susceptible Populations and Lifestages _________________________________________________ 2-54

2.8.4.1. Children _________________________________________________________________ 2-55

2.8.4.2. Adults ___________________________________________________________________ 2-55

2.8.4.3. Sex _____________________________________________________________________ 2-55

2.8.4.4. Race and Ethnicity _________________________________________________________ 2-56

2.8.4.5. Socioeconomic Status_______________________________________________________ 2-56

2.8.4.6. Genes ___________________________________________________________________ 2-57

2.8.4.7. Pre-existing Conditions _____________________________________________________ 2-57

2.8.4.8. Nutrition and Lifestyle Factors________________________________________________ 2-57

2.8.4.9. Stress and Cognitive Reserve _________________________________________________ 2-58

2.8.4.10. Co-exposure of Lead with Metals or Other Chemicals______________________________ 2-58

2.9. Summary ________________________________________________________________________________ 2-59

Table 2-8. Summary of evidence from epidemiologic, animal toxicological and 

ecological studies on the effects associated with exposure to Pb______________2-60

Chapter 2 References _____________________________________________________________________________ 2-65
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Chapter 2. Integrative Health and 

Ecological Effects Overview

1 The subsequent chapters of this ISA will present the most policy relevant information related to this 

2 review of the science supporting the NAAQS for Pb. This chapter integrates the key findings from the 

3 disciplines evaluated in this current assessment of the Pb scientific literature, which includes studies of Pb 

4 sources, fate and transport of Pb, ambient air concentrations, exposure assessments, toxicokinetics, 

5 biomarkers and models of Pb burden, health (e.g., both toxicology and epidemiology), and ecological 

6 effects of Pb. The EPA framework for causal determinations described in Chapter 1 has been applied to 

7 the body of scientific evidence in order to collectively examine the health and ecological effects attributed 

8 to Pb exposure in a two-step process. The first step is to establish causal relationships followed by 

9 identification of concentration-response relationships

10 As described in Chapter 1, EPA assesses the results of recent relevant publications, building upon 

11 evidence available during the previous NAAQS reviews, to draw conclusions on the causal relationships 

12 between relevant pollutant exposures and health or environmental effects. This ISA uses a five-level 

13 hierarchy that classifies the weight of evidence for causation: 

14  Causal relationship 

15  Likely to be a causal relationship 

16  Suggestive of a causal relationship 

17  Inadequate to infer a causal relationship 

18  Not likely to be a causal relationship 

19 Beyond judgments regarding causality are questions relevant to quantifying health or 

20 environmental risks based on the understanding of the quantitative relationships between pollutant 

21 exposures and health or ecological effects. Once a determination is made regarding the causal relationship 

22 between the pollutant and outcome category, important questions regarding quantitative relationships 

23 include: 

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

25 human population?

 

Note: Hyperlinks to the reference citations throughout this document will take you to the NCEA HERO database (Health and Environmental 

Research Online) at http://epa.gov/hero. HERO is a database of scientific literature used by U.S. EPA in the process of developing science 

assessments such as the Integrated Science Assessments (ISA) and the Integrated Risk Information System (IRIS).
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1  What exposure conditions (dose or exposure, exposure pathways, duration and pattern) are 

2 important?

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

4 effects?

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

6 functions, etc.) appear to be affected or are more sensitive to effects?

7 To address these questions, in the second step of the EPA framework, the entirety of quantitative 

8 evidence is evaluated to identify and characterize potential concentration-response relationships. This 

9 requires the evaluation of the levels of the pollutant and the exposure durations at which effects were 

10 observed for exposed populations including potentially susceptible populations. 

11 This chapter summarizes and integrates the newly available scientific evidence that best informs 

12 consideration of the policy-relevant questions that frame this assessment, presented in Chapter 1. 

13 Section 2.1 discusses the trends in ambient Pb sources and concentrations, including the fate and transport 

14 of Pb in the environment, and provides a brief summary of the topics covered. Section 2.2 presents the 

15 evidence regarding exposure to ambient Pb and describes air-related Pb exposure pathways. Section 2.3 

16 provides a discussion of the toxicokinetics of Pb and Pb biomarkers are discussed in Section 2.4. 

17 Section 2.5 summarizes effects of Pb on specific health endpoints and Section 2.6 summarizes the 

18 evidence relating to the ecological effects of Pb. Section 2.7 integrates the scientific evidence across 

19 various health and ecological endpoints highlighting common modes of action where applicable. Finally, 

20 Section 2.8 provides a discussion of policy relevant considerations including air-to-blood relationships, 

21 concentration-response relationships, timing and duration of exposure and susceptible populations. 

22 Section 2.9 is a summary of the health and ecological effects of Pb.

2.1. Ambient Lead: Source to Concentration

2.1.1. Sources, Fate and Transport of Ambient Lead

23 The findings of this review with respect to sources of atmospheric Pb build upon those from the 

24 2006 Pb AQCD (U.S. EPA, 2006), which documented the decline in ambient air Pb emissions following 

25 the ban on alkyl-Pb additives for on-road gasoline. Pb emissions declined by 98% from 1970 to 1990 and 

26 then by an additional 77% from 1990 to 2008, at which time emissions were 1,200 tons per year. Data 

27 from the 2008 National Emissions Inventory (NEI) (U.S. EPA, 2011) illustrate that piston engine aircraft 

28 emissions now comprise the largest share (~49%) of total atmospheric Pb emissions; the 2008 NEI 

29 estimated that 590 tons of Pb were emitted from this source. Other sources of ambient air Pb, beginning 

30 with the largest, include metals processing, fossil fuel combustion, other industrial sources, roadway 
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1 related sources, and historic Pb. Chemical speciation of Pb had also been fairly well characterized in the 

2 2006 Pb AQCD (2006). Estimates from the 1986 Pb AQCD (U.S. EPA, 1986, 2006) for organic 

3 automotive Pb emissions provides an upper bound for organic vapor emissions of 20% of total Pb 

4 dibromide and Pb bromide emissions from piston engine aircraft. Recent speciation studies of smelting 

5 and battery-recycling operations have shown that Pb sulfide and Pb sulfates are abundant within the 

6 emissions mixture for such industrial operations. 

7 The atmosphere is the main environmental transport pathway for Pb, and on a global scale 

8 atmospheric Pb is primarily associated with fine particulate matter (PM). Global atmospheric Pb 

9 deposition peaked in the 1970s, followed by a more recent decline. On a local scale, Pb concentrations in 

10 soils (including urban areas where historic use was widespread) can be substantial, and coarse Pb-bearing 

11 PM experiences cycles of deposition and resuspension that serve to distribute it. Both wet and dry 

12 deposition are important removal mechanisms for atmospheric Pb. Because Pb in fine particles is 

13 typically fairly soluble, wet deposition is more important for fine Pb. In contrast, Pb associated with 

14 coarse particles is usually insoluble, and removed by dry deposition. However, local deposition fluxes are 

15 much higher near local industrial sources and a substantial amount of emitted Pb is deposited near 

16 sources, leading to high soil Pb concentrations. Resuspension by wind and traffic can be an important 

17 source of airborne Pb near sources where Pb occurs in substantial amounts in surface dust.

18 Environmental distribution of Pb occurs mainly through the atmosphere, from where it is deposited 

19 into surface waters and soil. Pb associated with coarse PM deposits to a great extent near sources, leading 

20 to high soil concentrations, while fine Pb-bearing PM can be transported long distances, leading to 

21 contamination of remote areas. Surface waters act as an important reservoir, with Pb lifetimes largely 

22 controlled by deposition and resuspension of Pb in sediments. Substantial amounts of Pb from vehicle 

23 wear and building materials can also be transported by runoff waters without becoming airborne. Pb 

24 containing sediment particles can be remobilized into the water column, and sediment concentrations tend 

25 to follow those in overlying waters. 

2.1.2. Monitoring and Concentrations of Ambient Air Lead

26 In recognition of the role of all PM sizes in ambient air Pb exposures, including the ingestion of 

27 particles deposited onto surfaces, the indicator for the Pb NAAQS is Pb in total suspended particulate 

28 (Pb-TSP). Although there is a lower rate of error in estimating ambient Pb from Pb-PM10 monitoring than 

29 from Pb-TSP monitoring, the Pb-TSP indicator was retained in 2008 because ingestion after deposition in 

30 the upper respiratory tract was considered an important component of Pb exposure. A new federal 

31 reference method (FRM) for Pb-PM10 has been implemented in which ambient air is drawn through an 

32 inertial particle size separator for collection on a polytetrafluoroethylene (PTFE) filter. Several FEMs 
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1 have also been approved. The FRM is based on flame AAS. ICPMS is under consideration as a new FRM 

2 for Pb-TSP.

3 Monitoring for ambient Pb levels is required for all areas where Pb levels have been shown or are 

4 expected to contribute to maximum concentrations of 0.10 μg/m3 or greater over a 3-year time period. Pb 

5 is monitored routinely at state and local air monitoring stations (SLAMS) that report data used for 

6 NAAQS compliance to the air quality system (AQS) database. Pb monitoring requirements have 

7 experienced several changes since publication of the 2006 Pb AQCD (U.S. EPA, 2006). In addition to 

8 FRM monitoring, Pb is also routinely measured in smaller particle fractions in the chemical speciation 

9 network (CSN), interagency monitoring of protected visual environment (IMPROVE), and the national 

10 air toxics trends station (NATTS) networks, and is planned for the national core multipollutant monitoring 

11 network (NCore) network. While monitoring in multiple networks provides extensive geographic 

12 coverage, measurements between networks are not directly comparable in all cases because different 

13 particle size ranges are sampled in different networks. Depending on monitoring network, Pb is monitored 

14 in TSP, PM10, or PM2.5. Monitors reporting to the AQS were considered for the purpose of this ISA to be 

15 source oriented if they were designated in AQS as source oriented, or they were located within 1 mile of a 

16 0.5 ton per year or greater source, as noted in the 2005 NEI (U.S. EPA, 2008). Non-source oriented 

17 monitors were those monitors not considered to be source oriented. 

18 Ambient air Pb concentrations have declined drastically over the period 1980-2009. The median 

annual concentrations have dropped by 97% from 0.87 μg/m3 in 1980 to 0.025 μg/m3 19 in 2009. While the 

20 sharpest drop in Pb concentration occurred during 1980-1990, a declining trend was observed between 

21 1990 and 2009. Compared to 1980-1990, a smaller reduction was observable among source oriented Pb 

22 concentration (56%) and non-source oriented Pb data (51%) for 2000-2009.

23 AQS data for source oriented and non-source oriented monitoring were analyzed for 2007-2009. 

24 For source oriented monitoring, the three-month rolling average was measured to be above the level of 

25 the NAAQS in fourteen counties across the U.S. Pb concentrations, seasonal variations, inter-monitor 

26 correlations, and wind data were analyzed for six counties: Los Angeles County, CA; 

27 Hillsborough/Pinellas Counties, FL; Cook County, IL; Jefferson County, MO; Cuyahoga County, OH; and 

28 Sullivan County, TN. Spatial and temporal variability of Pb concentrations in each county were 

29 commonly high. Meteorology, distance from sources, and positioning of sources with respect to the 

30 monitors all appeared to influence the level of concentration variability across time and space. PM size 

31 distribution also influenced how far the particle will travel upon initial emission or resuspension before 

32 being deposited. Additionally, resuspension and urban background levels of Pb were uncertain influential 

33 factors of ambient Pb concentrations. Given variability in these conditions, it was very difficult to predict 

34 how Pb concentration varies over time and space. This was consistent with field studies to characterize Pb 

35 concentrations that were described in the literature.
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1 Size distribution of Pb-bearing PM was demonstrated to vary substantially for several studies 

2 presented, depending on the nature of Pb sources and proximity of the monitors to the Pb sources. 

3 Variation in the correlation of size fractionated Pb samples among different land use types may be 

4 explained by differences in sources across land use types. Additionally, Pb concentrations exhibited 

5 varying degrees of association with other criteria pollutant concentrations. Overall, Pb was moderately 

6 associated with PM2.5, PM10 and NO2. Pb was moderately associated with CO in fall and winter only. The 

7 poorest associations were observed between Pb and O3. Among trace metals, the strongest association was 

8 with Zn. Br, Cu, and K concentrations also exhibited moderate associations with Pb concentrations. Such 

9 correlations may suggest some common sources affecting the concentrations of various pollutants.

2.1.3. Ambient Lead Concentrations in Non-Air Media and 

Biota

10 Atmospheric deposition has led to measurable Pb concentrations observed in rain, snowpack, soil, 

11 surface waters, sediments, agricultural plants, livestock, and wildlife across the world, with highest 

12 concentrations near Pb sources, such as metal smelters. After the phase-out of Pb from on-road gasoline, 

13 Pb concentrations have decreased considerably in rain, snowpack, and surface waters. Declining Pb 

14 concentrations in tree foliage, trunk sections, and grasses have also been observed. In contrast, Pb is 

15 retained in soils and sediments, where it provides a historical record of deposition and associated 

16 concentrations. In remote lakes, sediment profiles indicate higher Pb concentrations in near surface 

17 sediment as compared to pre-industrial era sediment from greater depth and indicate peak concentrations 

18 between 1960 and 1980 (when leaded on-road gasoline was at peak use). Concentrations of Pb in moss, 

19 lichens, peat, and aquatic bivalves have been used to understand spatial and temporal distribution patterns 

20 of air Pb concentrations. Ingestion and water intake are the major routes of Pb exposure for aquatic 

21 organisms, and food, drinking water, and inhalation are major routes of exposure for livestock and 

22 terrestrial wildlife. Overall, Pb concentrations have decreased substantially in media through which Pb is 

23 rapidly transported, such as air and water. Substantial Pb remains in soil and sediment sinks. Although in 

24 areas less affected by major local sources, the highest concentrations are below the surface layers and 

25 reflect the phase-out of Pb from on-road gasoline and emissions reductions from other sources. 

2.2. Exposure to Ambient Lead

26 Exposure data considered in this assessment build upon the conclusions of the 2006 Pb AQCD 

27 (2006), which found air Pb concentrations in the U.S. and associated biomarkers of exposure to have 

28 decreased substantially following the ban on Pb in gasoline as well as earlier bans on Pb in house-hold 

29 paints and solder. Pb exposure is difficult to assess because Pb has multiple sources in the environment 
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1 and passes through various media. The atmosphere is the main environmental transport pathway for Pb, 

2 and atmospheric Pb is primarily associated with fine particulate matter, which can deposit to soil and 

3 water. In addition to primary emission of particle-bearing or gaseous Pb to the atmosphere, Pb can be 

4 suspended to the air from soil or dust, and a fraction of that suspended Pb may originate from waters used 

5 to irrigate the soil. Air-related pathways of Pb exposure are the focus of this assessment. In general, air6 related pathways include those pathways where Pb passes through ambient air on its path from a source to 

7 human exposure. In addition to inhalation of Pb from ambient air, air-related Pb exposure pathways 

8 include inhalation and ingestion of Pb from indoor dust and/or outdoor soil that originated from recent or 

9 historic ambient air (e.g., air Pb that has penetrated into the residence either via the air or tracking of soil). 

10 Non-air-related exposures include occupational exposures, hand-to-mouth contact with consumer goods 

11 in which Pb has been used, or ingestion of Pb in drinking water conveyed through Pb pipes. Most Pb 

12 biomarker studies do not indicate speciation or isotopic signature, and so non-air exposures are reviewed 

13 in this section because they can also contribute to Pb body burden. 

14 Section 4.1 presents data illustrating potential exposure mechanisms. Several studies suggested that 

15 soil can act as a reservoir for historically deposited and contemporaneous Pb emissions from industrial or 

16 other activities. Exposure to soil contaminated with deposited Pb can occur through resuspended PM as 

17 well as shoe tracking and hand-to-mouth contact. In general, soil Pb concentrations tended to be higher 

18 within inner-city communities compared with suburban neighborhoods. Infiltration of Pb dust has been 

19 demonstrated, and Pb dust has been shown to persist in indoor environments even after repeated 

20 cleanings. Measurements of particle-bound Pb exposures reported in this assessment have shown that 

21 personal exposure to Pb is typically higher than indoor or outdoor ambient Pb concentrations. These 

22 findings regarding personal exposure may be related resuspension of Pb that occurs with body movement. 

23 Observational studies using biomarkers of Pb as exposure metrics are also included in Section 4.1. 

24 The median blood Pb level for the entire U.S. population is 1.2 μg/dL and the 95th percentile blood Pb 

25 level is 3.7 μg/dL, based on the 2007-2008 NHANES data (NCHS, 2010). Among children aged 1-5 

26 years, the median and 95th percentiles were slightly higher at 1.4 μg/dL and 4.1 μg/dL, respectively. 

27 Overall, trends in blood Pb levels have been decreasing among U.S. children and adults over the past 20 

28 years. Concurrent changes in isotopic ratios of blood Pb samples reflect changes in source composition 

29 over the past several decades. Several studies have regressed blood Pb as a function of environmental Pb 

30 samples such as air Pb or Pb dust fall. Recent studies have observed a relationship between blood Pb and 

31 soil Pb concentration. Studies have suggested that blood Pb is associated with exposure to Pb paints in 

32 older homes, Pb released into drinking water, and occupational work with materials containing Pb. 

33 Studies that examine blood Pb as a function of ambient air Pb measurements are discussed in Section 

34 2.8.1 that follows. 

35 Sequential extraction has been used to estimate the gastric bioavailability of particle bound Pb after 

36 exposure occurs. Findings from these studies have been mixed, ranging from 13 to 86%, but such 
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1 variation is likely a function of the particle sizes from which the Pb was extracted as well as the acid 

2 mixture used to simulate gastric juices. Estimates of bioavailability of inhaled organic Pb to the lungs are 

3 available only from older studies in the literature and suggest a that it is possible for all inhaled organic 

4 Pb to enter the blood stream (Chamberlain et al., 1975).

2.3. Toxicokinetics

5 The majority of Pb in the body is found in bone (roughly 90% in adults, 70% in children); only 

6 about 1% of Pb is found in the blood. Pb in blood is primarily (~99%) bound to red blood cells (RBCs). It 

7 has been suggested that the small fraction of Pb in plasma (<1%) may be the more biologically labile and 

8 toxicologically active fraction of the circulating Pb. Saturable binding to RBC proteins contributes to an 

9 increase in the plasma/blood Pb ratio with increasing blood Pb level concentration and curvature to the 

10 blood Pb-plasma Pb relationship. As blood Pb level increases and the higher affinity binding sites for Pb 

11 in RBCs become saturated at approximately 40 μg/dL blood, a larger fraction of the blood Pb is available 

12 in plasma to distribute to brain and other Pb-responsive tissues.

13 The burden of Pb in the body may be viewed as divided between a dominant slow compartment 

14 (bone) and a smaller fast compartment (soft tissues). Pb uptake and elimination in soft tissues is much 

15 faster than in bone. Pb accumulates in bone regions undergoing the most active calcification at the time of 

16 exposure. During infancy and childhood, bone calcification is most active in trabecular bone (e.g., 

17 patella); whereas, in adulthood, calcification occurs at sites of remodeling in cortical (e.g., tibia) and 

18 trabecular bone (Aufderheide & Wittmers, 1992). A high bone formation rate in early childhood results in 

19 the rapid uptake of circulating Pb into mineralizing bone; however, bone Pb is also recycled to other 

20 tissue compartments or excreted in accordance with a high bone resorption rate (O'Flaherty, 1995). Thus, 

21 most of the Pb acquired early in life is not permanently fixed in the bone.

22 The exchange of Pb from plasma to the bone surface is a relatively rapid process. Pb in bone 

23 becomes distributed in trabecular and the more dense cortical bone. The proportion of cortical to 

24 trabecular bone in the human body varies by age, but on average is about 80 to 20. Of the bone types, 

25 trabecular bone is more reflective of recent exposures than is cortical bone due to the slow turnover rate 

26 and lower blood perfusion of cortical bone. Some Pb diffuses to deeper bone regions where it is relatively 

27 inert, particularly in adults. These bone compartments are much more labile in infants and children than in 

28 adults as reflected by half-times for movement to the plasma (e.g., cortical half-time = 0.23 years at birth, 

29 3.7 years at 15 years of age, and 23 years in adults; trabecular half-time = 0.23 years at birth, 2.0 years at 

30 15 years of age, and 3.8 years in adults) (Leggett, 1993). Due to the more rapid turnover of bone mineral 

31 in children, changes in blood Pb concentration are thought to more closely parallel changes in total body 

32 burden. However, some Pb accumulated in bone during childhood does persist into later life. Potential 
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1 mobilization of Pb from the skeleton could occur in adults at times of physiological stress associated with 

2 enhanced bone remodeling such as during pregnancy and lactation, menopause or in older adulthood, 

3 extended bed rest, hyperparathyroidism, and weightlessness. Regardless of age, however, similar blood 

4 Pb concentrations in two individuals (or populations) do not necessarily translate to similar body burdens 

5 or similar exposure histories.

6 The kinetics of elimination of Pb from the body reflects the existence of fast and slow pools of Pb 

7 in the body. The dominant phase of Pb kinetics in the blood, exhibited shortly after a change in exposure 

8 occurs, has an elimination half-life of ~20-30 days. An abrupt change in Pb uptake gives rise to a 

9 relatively rapid change in blood Pb, to a new quasi-steady state, achieved in ~75-100 days (i.e., 3-4 times 

10 the blood elimination half-life). A slower phase may become evident with longer observation periods 

11 following a decrease in exposure due to the gradual redistribution of Pb among other compartments via 

12 the blood. Therefore, a single blood Pb concentration may reflect the near-term or longer-term history of 

13 the individual to varying degrees, depending on the relative contributions of internal (e.g., bone) and 

14 external sources of Pb to blood Pb, which in turn will depend on the exposure history and possibly age15 related and individual-specific (e.g., pregnancy, lactation) characteristics of bone turnover. In general, 

16 higher blood Pb concentrations can be interpreted as indicating higher exposures (or Pb uptakes); 

17 however, they do not necessarily predict higher body burdens, especially in adults. 

2.4. Lead Biomarkers

18 Blood Pb is dependent on both the recent exposure history of the individual, as well as the long19 term exposure history that determines body burden and Pb in bone. The contribution of bone Pb to blood 

20 Pb changes depending on the duration and intensity of the exposure, age, and various other physiological 

21 variables that may affect bone remodeling (e.g., nutritional status, pregnancy, and menopause). Blood Pb 

22 in adults is typically more an index of recent exposures than body burden, whereas bone Pb is an index of 

23 cumulative exposure and body burden. In children, due to faster exchange of Pb to and from bone, blood 

24 Pb is both an index of recent exposure and potentially an index of body burden. In some physiological 

25 circumstances (e.g., osteoporosis), bone Pb may contribute to blood Pb in adults. The disparity between 

26 blood Pb and body burden may have important implications for the interpretation of blood Pb 

27 measurements in some epidemiology studies. Conceptually, measurement of long-term Pb body burden 

28 (i.e., based on tibia Pb) may be the appropriate metric if the effects of Pb on a particular outcome are 

29 lasting and cumulative. However, if the effects of Pb on the outcome represent the acute effects of current 

30 exposure, then blood Pb may be the preferred metric. In the absence of clear evidence as to whether a 

31 particular outcome is an acute effect of recent Pb dose or a chronic effect of cumulative Pb exposure, both 

32 blood and bone metrics should be considered. 
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1 Cross-sectional studies that sample blood Pb once generally provide an index of recent exposures. 

2 In contrast, cross-sectional studies of bone Pb and longitudinal samples of blood Pb concentrations over 

3 time provide an index of cumulative exposure and are more reflective of average Pb body burdens over 

4 time. The degree to which repeated sampling will reflect the actual long-term time-weighted average 

5 blood Pb concentration depends on the sampling frequency in relation to variability in exposure. High 

6 variability in Pb exposures can produce episodic (or periodic) oscillations in blood Pb concentration that 

7 may not be captured with low sampling frequencies.

8 The concentration of Pb in urine is a function of the urinary Pb excretion and the urine flow rate. 

9 Urine flow rate requires collection of a timed urine sample, which is often problematic in epidemiologic 

10 studies. Collection of un-timed (“spot”) urine samples, a common alternative to timed samples, requires 

11 adjustment of the Pb measurement in urine to account for variation in urine flow (Diamond, 1988). 

12 Urinary Pb concentration reflects, mainly, the exposure history of the previous few months; thus, a single 

13 urinary Pb measurement cannot distinguish between a long-term low level of exposure or a higher acute 

14 exposure. Thus, a single urine Pb measurement, or a series of measurements taken over short-time span, is 

15 likely a relatively poor index of Pb body burden for the same reasons that blood Pb is not a good indicator 

16 of body burden. On the other hand, long-term average measurements of urinary Pb can be expected to 

17 better reflect body burden.

2.5. Health Effects

18 This section evaluates the evidence from toxicological and epidemiologic studies that examined the 

19 health effects associated with exposure to Pb. The results from the health studies evaluated in 

20 combination with the evidence from other disciplines (e.g., fate and transport, exposure sciences, 

21 toxicokinetics) contribute to the causal determinations (Section 1.6.4) made for the health outcomes 

22 discussed in this assessment. In the following sections a discussion of the causal determinations will be 

23 presented for the health effects for which sufficient evidence was available to conclude a causal or likely 

24 to be causal relationship (Table 2-1). Although not presented in depth in this chapter, a detailed discussion 

25 of the underlying evidence used to formulate each causal determination can be found in Chapter 5 of this 

26 document.
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Table 2-1. Summary of causal determinations between exposure to Pb and health 

outcomes

Outcome Causality Determination

Neurological Effects Causal Relationship

Cardiovascular Effects Causal Relationship

Renal Effects Causal Relationship

Immune System Effects Causal Relationship

Effects on Heme Synthesis and Red Blood Cell Function Causal Relationship

Reproductive Effects and Birth Outcomes Causal Relationship

Cancer Likely Causal Relationship

2.5.1. Neurological Effects

1 The 2006 Pb AQCD concluded that the collective body of epidemiologic studies provides clear and 

2 consistent evidence for the effects of Pb exposure on neurocognitive function in children. This conclusion 

3 was substantiated by findings in diverse populations that blood Pb levels were associated with a broad 

4 spectrum of cognitive and behavioral endpoints, including IQ, higher-order processes such as language 

5 and memory, academic achievement, behavior and conduct, sensory acuities, and changes in brain 

6 structure and activity as assessed by magnetic resonance imaging (MRI) or magnetic resonance 

7 spectroscopy (MRS). Toxicological studies not only provided coherence with similarly consistent findings 

8 for Pb-induced impairments in learning, behavior, and sensory acuities, but also provided biological 

9 plausibility by characterizing mechanisms for Pb-induced neurotoxicity. These mechanisms included Pb10 induced inhibition of neurotransmitter release and decreases in synaptic plasticity, neuronal 

11 differentiation, and blood-brain-barrier integrity. Both epidemiologic studies (in children) and 

12 toxicological studies, demonstrated neurocognitive deficits in association with blood Pb levels at and 

13 below 10 μg/dL, and evidence from both disciplines supported a nonlinear exposure-response 

14 relationship, with greater effects estimated for lower blood Pb levels. Among environmentally-exposed 

15 adults, the most consistent findings were associations between cumulative Pb exposure, as assessed by 

16 serial blood Pb or bone Pb measurements, and cognitive deficits. 

17 Building on this strong body of extant evidence, recent studies continue to demonstrate 

18 associations between Pb exposure and neurological effects. While recent epidemiologic studies in 

19 children continued to demonstrate associations with IQ, most evidence emphasized associations of blood 

20 Pb levels (as low as 2 μg/dL) with specific indices of neurocognitive function such as reading and verbal 

21 skills, memory, visuospatial processing, and academic achievement. Nonetheless, these newer findings 

22 are concordant with the previous body of evidence given that IQ is a global measure of cognitive function 

23 that reflects the integration of several neurocognitive domains. Additional coherence for findings in 
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1 children is provided by evidence in animals that blood Pb levels of 1.8 μg/dL and higher are associated 

2 with decrements in learning and memory. New findings in animals emphasized the role of stress in 

3 potentiating the low dose effects of Pb on behavior and memory. In animals, the developmental period is 

4 the most sensitive window for Pb-dependent neurotoxicity, whereas in children, concurrent blood Pb was 

5 generally found to be the best predictor of cognitive decrements. 

6 Recent studies in children continue to support associations of Pb exposure (blood Pb levels 3-11 

7 μg/dL) with a range of behavioral problems from anxiety and distractibility to conduct disorder and 

8 delinquent behavior. Whereas previous evidence was not compelling, new evidence indicates associations 

9 comparing the lowest quartiles of blood Pb level (0.8-1 μg/dL versus <0.8 μg/dL) and ADHD. These 

10 findings for ADHD are well supported by observations in animals of Pb-induced increased response rates 

11 and impulsivity. Both epidemiologic studies in children and toxicological studies demonstrate 

12 associations of Pb exposure with deficits in visual acuity and hearing and auditory processing. New 

13 evidence from toxicological studies demonstrates these effects at lower exposure levels (blood Pb levels 

14 <15 μg/dL). Combined evidence for Pb-associated neurocognitive deficits (e.g., inattention, conduct 

15 disorder, and effects on sensory function) provides plausible mechanisms by which Pb exposure may 

16 contribute to academic underachievement and to more serious problems of delinquent behavior. 

17 Studies of adults without occupational Pb exposure have not provided consistent evidence for 

18 associations between blood Pb and the range of neurological effects. One explanation for the weaker 

19 evidence may be that cognitive reserve may compensate for the effects of Pb exposure on learning new 

20 information. Compensatory mechanisms may become less effective with increasing age, explaining the 

21 consistent associations between measures of cumulative Pb exposure and neurocognitive deficits. Among 

22 recent studies of adults, blood Pb and bone Pb are associated with essential tremor and Parkinson’s 

23 disease, respectively. Consistent with these findings, toxicological studies demonstrate Pb-induced 

24 decreased dopaminergic cell activity in the substantia nigra, which contributes to the primary symptoms 

25 of Parkinson’s disease. Biological plausibility also is provided by observations of developmental Pb 

26 exposures of monkeys and rats inducing neurodegeneration in the aged brain. A recent epidemiological 

27 study indicated that early-life ALAD activity, a biomarker of Pb exposure, may be associated with 

28 schizophrenia later in adulthood. Consistent with these findings, toxicological studies have observed Pb29 induced emotional changes in males and depression in females. It is not surprising that Pb exposure may 

30 increase the risk of different neurological endpoints in children and adults given the predominance of age31 dependent neurological processes, in particular, neurogenesis and brain development in children and 

32 neurodegeneration in adults. 

33 Extensive evidence from toxicological studies, as well as evidence in some aquatic and terrestrial 

34 animal taxa (Section 2.6.9) clearly substantiates the biological plausibility for epidemiologic findings by 

35 characterizing mechanisms underlying neurological effects. Pb induces complex neurochemical changes 

36 in the brain that differ by region of the brain, neurotransmitter type, age, and sex of the organism. These 
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1 changes remain aberrant over time but are dynamic in nature. Pb exposure of animals induces changes in 

2 the transmission of dopamine, which plays a key role in cognitive functions mediated by the prefrontal 

3 cortex and in motor functions mediated by the substantia nigra. Current toxicological research has been 

4 expanded to document that early-life Pb exposure can contribute to neurodegeneration and neurofibrillary 

5 tangle formation in the aged brain. Pb exposure can affect NMDA receptors, which can contribute to 

6 mood disorders. Synapse formation, adhesion molecules, and nitrosative stress continue to be areas in 

7 which research is being conducted related to Pb-associated neurotoxicity. Finally, the new area of 

8 epigenetics shows that Pb exposure affects methylation patterns in rodent brains. These toxicological data 

9 provide coherence with epidemiologic observations, in particular, associations of Pb exposure with 

10 cognitive deficits, Parkinson’s disease, and mood disorders.

11 In summary, recent evidence substantiates and expands upon the established epidemiologic and 

12 toxicological literature demonstrating the neurological effects of Pb exposure. Both the consistency of 

13 evidence across toxicological and epidemiologic studies and the coherence of findings across the full 

14 spectrum of neurological endpoints, from mechanistic changes to impairments in cognitive function and 

15 behavior and to poorer academic achievement and delinquency, are illustrated in Figure 2-1. In 

16 epidemiologic studies of children, consistently positive associations of blood Pb levels with deficits in 

17 neurocognitive function, attention, and sensory acuities support observed associations with academic 

18 underachievement, which in turn, may explain associations with delinquent and criminal behavior. In 

19 particular, observations of cognitive and behavioral deficits in association with blood Pb levels in the 

20 range of 1-2 μg/dL indicate that a threshold may not exist for the neurological effects of Pb in children. 

21 Epidemiologic findings are strengthened by their biological plausibility in light of toxicological study 

22 findings and their coherence with toxicological findings for similar or parallel endpoints and for the 

23 mechanisms underlying the neurological effects. The collective body of evidence integrated across 

24 epidemiologic and toxicological studies and across the spectrum of neurological endpoints is sufficient to 

25 conclude that there is a causal relationship between Pb exposures and neurological effects.
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Figure 2-1. Snapshot of evidence for the spectrum of effects to the 

nervous system associated with Pb exposure. Green=animal 

toxicological studies (left side); purple=epidemiological 

studies (right side).

2.5.2. Cardiovascular Effects

1 The 2006 Pb AQCD concluded that there was a relationship between increased Pb exposure and 

2 increased adverse cardiovascular outcomes, including increased blood pressure (BP) and increased 

3 incidence of hypertension (U.S. EPA, 2006). Meta-analysis of these studies found that each doubling of 

4 blood Pb level (between 1 and >40 μg/dL) was associated with a 1 mmHg increase in systolic BP and a 
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1 0.6 mmHg increase in diastolic BP. In addition, most of the reviewed studies using cumulative Pb 

2 exposure measured by adult bone Pb levels showed increased BP. Toxicological studies provided 

3 evidence for exposure to low levels of Pb (e.g., 2 μg/dL) resulting in increased BP in experimental 

4 animals that persists long after the cessation of Pb exposure and also provided mechanistic evidence to 

5 support the biological plausibility of Pb-induced hypertension, including oxidative stress, altered 

6 sympathetic activity, and vasomodulator imbalance. Finally, limited evidence suggested a connection 

7 between Pb exposure and the development of IHD, cerebrovascular disease, peripheral vascular disease 

8 (PVD) and mortality. 

9 Building on the strong body of evidence presented in the 2006 Pb AQCD, recent studies continue 

10 to support associations between Pb exposure and exposure biomarkers and cardiovascular effects with 

11 recent epidemiologic studies informing past uncertainties (e.g., confounding, low Pb exposures). A recent 

12 study suggested that Pb has an acute effect on BP as a function of recent dose measured by blood Pb and a 

13 chronic effect on hypertension risk as a function of cumulative exposure measured by tibia Pb (Martin et 

14 al., 2006). This study also verified the magnitude of change in BP observed in the past meta-analysis. 

15 Additionally, recent epidemiologic studies provided evidence for associations between blood Pb and 

16 hypertension in adults with relatively low blood Pb levels; a positive relationship was found in the 

17 NHANES (1999-2002) data set at a geometric mean blood Pb level of 1.64 μg/dL (Muntner et al., 2005). 

18 Animal toxicological studies also provide support for effects of low blood Pb level on increased BP with 

19 statistically significant increases shown in animals with blood Pb levels as low as 2 μg/dL. New studies 

20 also demonstrate a partial reversibility of Pb-induced increased BP following Pb exposure cessation or 

21 chelation.

22 Epidemiologic studies continue to investigate the relationship between bone Pb and increased BP. 

23 Recent epidemiologic studies also emphasize the interaction between cumulative Pb exposure and factors 

24 that moderate or modify the Pb effect on BP and hypertension (e.g., chronic stress and metabolic 

25 syndrome). Further, recent epidemiologic studies found that the effects of Pb on cardiovascular endpoints 

26 (including BP, pulse pressure [PP], and QT interval) were modified by genotypes (including ALAD and 

27 genes involved in hemochromatosis or Fe metabolism). Epidemiologic and toxicological studies also 

28 provided evidence for Pb exposure to contribute to increased development of atherosclerosis, thrombosis, 

29 ischemic heart disease, peripheral artery disease, arrhythmia, and cardiac contractility. Animal 

30 toxicological evidence continues to build on the evidence supporting the biological plausibility leading to 

31 these cardiovascular alterations. New evidence extends the potential continuum of Pb-related 

32 cardiovascular effects in adults by demonstrating associations of Pb concentrations in blood and bone 

33 with both cardiovascular and all-cause mortality. 

34 In summary, new studies evaluated in the current review support or expand upon the strong body of 

35 evidence presented in the 2006 Pb AQCD that Pb exposure is causally associated with cardiovascular 

36 health effects. Both epidemiologic and toxicological studies continue to demonstrate a consistently 
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1 positive relationship between Pb exposure and increased BP or hypertension development in adults and 

2 this relationship is observed in more recent studies of adults with blood Pb levels (mean: 2 μg/dL) lower 

3 than those reported in the 2006 Pb AQCD. While some studies evaluate concentration-response 

4 relationships of blood Pb with BP or mortality, the information is inconclusive (Section 2.8.2). Recent 

5 studies investigating measures of cumulative Pb exposure measures and suggest that bone Pb related 

6 strongly to hypertension risk. Evidence of Pb increasing the risk of development of other cardiovascular 

7 diseases also is shown. By demonstrating Pb-induced oxidative stress including  ̇NO inactivation, 

8 endothelial dysfunction leading to altered vascular reactivity, activation of the RAAS, and vasomodulator 

9 imbalance, toxicological studies have characterized the mode of action of Pb and provided biological 

10 plausibility for the consistently positive associations observed in epidemiologic studies between blood 

11 and bone Pb and cardiovascular effects. These observed associations between Pb exposure and 

12 cardiovascular morbidity are supported by recent reports of increased cardiovascular mortality. 

13 Collectively, the evidence integrated across epidemiologic and toxicological studies as well as across the 

14 spectrum of cardiovascular health endpoints is sufficient to conclude that there is a causal relationship 

15 between Pb exposures and cardiovascular health effects.

2.5.3. Renal Effects

16 The 2006 Pb AQCD stated that “in the general population, both circulating and cumulative Pb was 

17 found to be associated with a longitudinal decline in renal function”, evidenced by increased serum 

18 creatinine and decreased creatinine clearance (U.S. EPA, 2006). These findings were substantiated by the 

19 coherence of effects observed across epidemiologic and toxicological studies. Toxicological studies 

20 provided mechanistic evidence to support the biological plausibility of Pb-induced renal effects, including 

21 oxidative stress leading to  ̇NO inactivation. Uncertainty remained on the implications of effects in 

22 children, confounding, hyperfiltration, and reverse causality.

23 Recent epidemiologic studies in general and patient populations of adults have, with few 

24 exceptions, been consistent in observing associations between bone or blood Pb levels and worse kidney 

25 function; and provide important evidence that nephrotoxicity occurs at current population Pb biomarker 

26 levels. Further, current evidence does not allow for the identification of a threshold for Pb-related 

27 nephrotoxicity. The odds of reduced eGFR increased by 36% (95% CI: 0.99, 1.85) at blood Pb levels as 

28 low as 1.6-2.4 μg/dL and by 56% (95% CI: 1.17, 2.08) at blood Pb >2.4 μg/dL. These studies benefit from 

29 a number of strengths that vary by study but include: comprehensive assessment of Pb dose (using bone 

30 Pb [as a measure of cumulative body burden], and chelatable Pb [as a measure of bioavailable Pb]); 

31 prospective study design; and statistical approaches that utilize a range of exposure and outcome 

32 measures, while adjusting for numerous kidney and Pb risk factors. General population studies also 

33 benefit from large populations in both Europe and the U.S. At blood Pb levels that are common in the 
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1 general U.S. population, Pb increases the risk for clinically relevant effects particularly in susceptible 

2 populations such as those with underlying chronic medical diseases that increase chronic kidney disease 

3 (CKD) risk such as diabetes mellitus and hypertension and co-exposure to other environmental 

4 nephrotoxicants. The uncertainty around the role of reverse causality, which attributes increases in blood 

5 Pb levels to compromised kidney excretion rather than as a causative factor for CKD, was reduced by 

6 evidence that the association between blood Pb and serum creatinine occurred over the entire serum 

7 creatinine range, including the normal range where reverse causality would not be expected. Further, 

8 recent studies have extended the limited body of evidence for effects of Pb on the kidney in children. 

9 Toxicological studies contribute support to effects of Pb in the early life window of exposure adding to 

10 the strength of the association between Pb and altered renal function in children.

11 CKD results in substantial morbidity and mortality and is an important risk factor for cardiac 

12 disease. As kidney dysfunction can increase BP and increased BP can lead to further damage to the 

13 kidneys, Pb-induced damage to either or both the renal and cardiovascular systems may result in a cycle 

14 of increased severity of disease. Pb exposure has been causally linked to both increased BP and other 

15 cardiovascular effects (Section 5.4) and renal dysfunction and, it is possible that the cardiovascular and 

16 renal effects of Pb observed are mechanistically linked and are contributing to the progression of the 

17 diseases. Recently available animal toxicological studies strengthen the evidence regarding the 

18 mechanisms leading to these renal alterations including oxidative stress, which is also related to CVD, 

19 infiltration of lymphocytes and macrophages associated with increased expression of NF-κB in proximal 

20 tubules and infiltrating cells, mitochondrial dysfunction, renal cell apoptosis, and glomerular hypertrophy. 

21 In summary, new studies evaluated in the current review support or expand upon the strong body of 

22 evidence presented in the 2006 Pb AQCD that Pb exposure is associated with renal health effects. 

23 Epidemiologic studies continue to demonstrate a consistently positive relationship between blood Pb level 

24 and kidney dysfunction at blood Pb levels comparable to those occurring in the current U.S. population 

25 with no evidence for a threshold across the range of levels studied. Uncertainty regarding effects in 

26 children, confounding, hyperfiltration, and reverse causality have been reduced through consideration of 

27 the recent evidence. By demonstrating Pb-induced oxidative stress and describing mechanisms of acute 

28 changes following Pb exposure, toxicological studies provide biological plausibility for the associations 

29 observed in epidemiologic studies between Pb and kidney dysfunction. Collectively, the evidence 

30 integrated across epidemiologic and toxicological studies as well as across the spectrum of kidney health 

31 endpoints is sufficient to conclude that there is a causal relationship between Pb exposures and renal 

32 health effects.
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2.5.4. Immune System Effects

1 The collective body of evidence integrated across epidemiologic and toxicological study findings 

2 consistently demonstrates that Pb exposure is associated with changes in a spectrum of immune mediators 

3 and functions. The majority of results from animal studies indicates that immune changes are observable 

4 at blood Pb levels in the range of 2 to 8 μg/dL. Likewise, in the newly expanded body of epidemiologic 

5 studies in environmentally-exposed children and adults, changes in immune function are demonstrated in 

6 association with mean blood Pb levels in the range of 1 to 10 μg/dL.

7 The strength of evidence for Pb-associated immune effects is derived not only from the consistency 

8 of associations but also from the coherence of findings between toxicological and epidemiologic studies 

9 and coherence of findings across the spectrum of related immune changes. Toxicological and 

10 epidemiologic evidence links higher Pb exposures with decreases in various T cell subtypes. These 

11 changes can affect cell-to-cell interactions that mediate acquired immunity required in subsequent 

12 memory responses to antigen exposures; however, it is unclear what effect the observed magnitudes of 

13 changes may have in attenuating acquired immunity. 

14 The key immunomodulatory effect of Pb exposure, in terms of coherence across immune endpoints 

15 and implications for developing immune-based diseases, is the skewing of immune function away from a 

16 Th1 phenotype towards a Th2 phenotype. In toxicological studies and epidemiologic studies, this shift is 

17 well demonstrated by suppressed production of Th1 cytokines (e.g., IFN-γ) and increased production of 

18 Th2 cytokines (e.g., IL-4). A recent in vitro study indicates that Pb may promote Th2 responses by acting 

19 directly on dendritic cells, the major effector in antigen response. An increase in IL-4 from activated Th2 

20 cells induces differentiation of B cells into Ab producing cells, thereby promoting the secretion of IgE, 

21 IgA, and IgG. In support of this well-established mechanism, toxicological studies describe Pb-induced 

22 changes in IgA, IgG, and IgM. Additionally, epidemiologic studies in children consistently link higher Pb 

23 exposures with increases in B cell abundance and increases in IgE. Observations of Pb-associated 

24 increases in Th2 responses and circulating IgE levels provide biological plausibility for epidemiologic 

25 observations in children of associations of blood Pb with asthma and allergic conditions. Such 

26 epidemiologic data are sparse, and additional studies with more rigorous methodology (e.g., longitudinal 

27 design and adjustment for potential confounders such as smoking, SES, and exposures to other metals) 

28 are needed to substantiate the findings.

29 Further evidence of Pb-associated suppressed Th1 activity is provided by toxicological and 

30 epidemiologic observations that Pb exposure is associated with impaired killing capacity of macrophages 

31 and neutrophils. There is toxicological and epidemiologic evidence of suppressed Th1 activity and effects 

32 on macrophage and neutrophil functional activities. This evidence provides biological plausibility for 

33 observations in animals of the Pb-induced suppression of the DTH response and the observations in both 

34 animals and humans that Pb exposure and increases the risk of infection.
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1 Toxicological studies and a limited set of epidemiologic studies demonstrate that Pb induces 

2 macrophages into a hyperinflammatory state as characterized by suppressed production of NO and 

3 enhanced production of ROS, TNF-α, and the immunosuppressive PGE2. Specialized macrophages 

4 residing in airways, reproductive organs, and in the nervous system indicate that immunomodulation may 

5 underlie the documented associations of Pb exposure with effects in these organ systems. Although 

6 limited mostly to toxicological studies, Pb has been shown to induce the generation of auto-antibodies, 

7 suggesting that Pb exposure may increase the risk of autoimmune conditions. 

8 In summary, recent toxicological and epidemiologic studies support the strong body of evidence 

9 presented in the 2006 Pb AQCD that Pb exposure is associated with a broad spectrum of changes in both 

10 cell-mediated and humoral immunity to promote a Th2 phenotype and inflammation. The consistency and 

11 coherence of findings among these related immune effects, in turn, establish the biological plausibility for 

12 Pb exposure being associated with increased susceptibility to infection, autoimmunity, allergy, and effects 

13 in other organ systems. Animal studies and to a limited extent, epidemiologic studies, demonstrate 

14 increased susceptibility of prenatal exposures and enhanced responses with co-exposures to other metals. 

15 The consistency of findings and the coherence between toxicological and epidemiologic findings across 

16 the continuum of related immune responses are sufficient to conclude that there is a causal relationship 

17 between Pb exposures and immune effects.

2.5.5. Heme Synthesis and RBC Function

18 Consistent with conclusions of the 2006 Pb AQCD as well as previous assessments, recent 

19 evidence in the toxicological and epidemiologic literature supports the longstanding relationship between 

20 Pb exposure and effects on hematological endpoints, including altered heme synthesis, decreased RBC 

21 survival and function, and increased RBC oxidative stress. 

22 Multiple occupational epidemiologic studies have shown that Pb affects several hematological 

23 parameters such as Hb, PCV, MCV, MCH, and MCHC. Although the majority of occupationally- exposed 

24 adults had blood Pb levels in excess of 20 μg/dL, decreases in Hb and PCV were also observed in an 

25 occupational cohort with a mean blood Pb level of 7 μg/dL. In addition, Pb exposure was shown to reduce 

26 Ca-ATPase and Ca-Mg-ATPase activity in RBC membranes at cord blood Pb levels of 3.54 μg/dL. 

Decreases in Ca-ATPase and Ca-Mg-ATPase activity leads to an increase in RBC [Ca2+ 27 ]i, increased 

28 membrane fragility, and abnormal morphological changes. Studies in children are less consistent than 

29 those investigating occupationally-exposed adults; this may due to the comparatively shorter duration of 

30 and magnitude of exposure experienced by children. Toxicological studies have also observed decreases 

31 in hematocrit and hemoglobin and increases in hemolysis and reticulocyte density in rats and mice with 

32 blood Pb levels as low as 6.6-7.1 μg/dL. Pb exposure has also been observed to increase PS expression on 

33 RBC membranes, leading to cell shrinkage, eryptosis, and destruction of the RBCs by macrophages. 
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1 Suggestive evidence of disrupted hematopoiesis evidenced by decreased serum erythropoietin was 

2 observed in occupationally exposed adults with blood Pb levels of 6.4 μg/dL; toxicological studies in rats 

3 also indicate that Pb is cytotoxic to RBC-progenitor cells after chronic exposure. Taken together, these 

4 studies provide consistent evidence that exposure to Pb adversely effects RBC function and survival, and 

5 leads to the reduction of RBCs in circulation. Although this decrease in RBCs may be explained by both 

6 decreased cell survival and/or disruption of hematopoiesis, the observation of increased reticulocytes 

7 seems to represent compensation for decreased RBC survival due to Pb exposure. 

8 Pb has been found to inhibit several enzymes involved in heme synthesis, namely ALAD 

9 (cytoplasmic enzyme catalyzing the second, rate-limiting, step of the heme biosynthesis pathway), 

10 coporphyrinogen oxidase (catalyses the 6th step in heme biosynthesis converting coporphyrinogen III into 

11 protoporphyrinogen IX), and ferrochelatase (catalyses the terminal step in heme synthesis converting 

12 protoporphyrin IX into heme). Recently, numerous epidemiologic studies have confirmed that decreases 

13 in RBC ALAD levels and activity are strongly associated with blood Pb levels in as low as 7.1 μg/dL in 

14 children and blood Pb levels as low as 6.4 μg/dL in adults. Decreases in blood ALAD activity were also 

15 seen in rats with blood Pb levels of 6.5 μg/dL. There is also a considerable body of evidence for a 

16 negative correlation between ALAD activity and Pb concentration in various invertebrate and vertebrate 

17 taxa (Section 2.6.7). In addition to ALAD, recent studies have shown that Pb exposure inhibits the 

18 activity of ferrochelatase, leading to increased RBC ZPP in humans and animals. Pb has also been shown 

19 to inhibit the activities of other enzymes in RBCs, including those involved in nucleotide scavenging, 

20 energy metabolism, and acid-base homeostasis.

21 Lastly, Pb exposure induces lipid peroxidation and oxidative stress in RBCs. Epidemiologic studies 

22 have observed increases in MDA in occupationally-exposed adults with blood Pb levels as low as 7.9 

23 μg/dL. Other measures of oxidative stress observed included lowered activities of SOD, GR, and CAT, 

24 and increased CRP. Indices of RBC oxidative stress were also seen in adolescents and children exposed to 

25 Pb. In vitro and in vivo studies have also demonstrated that prior, con-current, or subsequent treatment 

26 with various antioxidants has been shown to at least partially ameliorate Pb-induced oxidative stress in 

27 RBCs.

28 In conclusion, the recent epidemiologic and toxicological literature provides strong evidence that 

29 exposure to Pb is associated with numerous deleterious effects on the hematological system, including 

30 altered heme synthesis mediated through decreased ALAD and ferrochelatase activities, decreased RBC 

31 survival and function, decreased hematopoiesis, and increased oxidative stress and lipid peroxidation. The 

32 consistency of findings in the epidemiologic and toxicological literature and coherence across the 

33 disciplines is sufficient to conclude that there is a causal relationship between Pb exposure and heme 

34 synthesis and RBC function.
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2.5.6. Reproductive Effects and Birth Outcomes

1 Epidemiologic and toxicological studies of the effects of Pb on reproductive outcomes have 

2 covered outcomes such as female and male reproductive function, birth defects, spontaneous abortions, 

3 infant mortality, preterm birth, low birth weight, and developmental effects. 

4 Many of the Pb-induced effects in toxicological studies have been observed at maternal blood Pb 

5 levels that do not result in overt clinical toxicity in the dams. Recent toxicological studies have shown the 

6 effects of Pb exposure during early development to include disruption of endocrine function; delay in the 

7 onset of puberty and alteration in reproductive function later in life; and changes in morphology or 

8 histology in sex organs and placenta. Additionally, epidemiologic studies of reproductive factors among 

9 males and females investigated whether Pb levels were associated with hormone levels, fertility, and onset 

10 of puberty. Epidemiologic studies showed associations between blood Pb and hormone levels for females. 

11 Studies of Pb and fertility are limited and inconsistent for females and males. Strong and consistent

12 associations were observed between Pb levels in adult males exposed to Pb in occupational settings with 

13 blood Pb as low as 20-45 μg/dL and sperm count and quality. Decreased sperm viability and altered 

14 morphology in sperm is also observed in invertebrate species (Sections 7.2.4 and 7.3.4) Multiple studies 

15 of Pb and puberty have shown inverse associations between blood Pb levels and delayed pubertal 

16 development for girls and boys. These associations are consistently observed in multiple epidemiologic 

17 studies and demonstrate effects on pubertal development at blood Pb levels <10μg/dL. 

18 Pb-mediated changes in levels or function of reproductive and growth hormones have been 

19 demonstrated in past and more recent toxicological studies; however the findings are inconsistent. More 

20 data are needed to determine whether Pb exerts its toxic effects on the reproductive system by affecting 

21 the responsiveness of the hypothalamic-pituitary-gonad axis or by suppressing circulating hormone levels. 

22 More recent toxicological studies suggested that oxidative stress is a major contributor to the toxic effects 

23 of Pb on male and female reproductive systems. Several recent studies showed an association between 

24 increased generation of ROS and germ cell injury as evidenced by destruction of germ cell structure and 

25 function. Co-administration of Pb with various antioxidant compounds either eliminated Pb-induced 

26 injury or greatly attenuated its effects. In addition, many studies that demonstrated increased oxidative 

27 stress also reported increased apoptosis, which is likely a critical underlying mechanism in Pb-induced 

28 germ cell DNA damage and dysfunction. 

29 Overall, results of pregnancy outcomes were similar to those of the 2006 Pb AQCD; inconsistent 

30 evidence of a relationship with Pb was available for preterm birth and little evidence was available to 

31 study the associations with spontaneous abortions. The previous Pb AQCD included a few studies that 

32 reported possible associations between Pb and neural tube defects, but the recent epidemiologic studies 

33 found no association. Possible associations were observed between Pb and low birth weight when 

34 epidemiologic studies used measures of maternal bone Pb or air exposures, but the associations were less 
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1 consistent when using maternal blood Pb or umbilical cord and placenta Pb. Effects of Pb exposure 

2 during early development in toxicological studies included reduction in litter size, implantation, birth 

3 weight and postnatal growth.

4 Additional evidence for Pb exposure negatively affecting development is provided by toxicological 

5 studies demonstrating developmental Pb exposures leading to impaired development of the retina, skin, 

6 teeth and altered development of the hematopoietic and hepatic systems. In summary, the recent 

7 toxicological and epidemiologic literature provides strong evidence that Pb exposure is related to delayed 

8 onset of puberty in both males and females. Additionally, Pb exposure has been shown to have 

9 detrimental effects on sperm (at higher blood Pb levels in epidemiologic studies and lower doses in the 

10 toxicological literature). Furthermore, evidence from invertebrate and vertebrate taxa in both terrestrial 

11 and aquatic ecosystems provide additional support for reproductive and developmental effects associated 

12 with Pb exposure (Sections 2.6.8, 7.2.4, and 7.3.4). The data on preterm birth, low birth weight, 

13 spontaneous abortions, birth defects, hormonal influences, and fecundity are less consistent between the 

14 toxicological and epidemiologic literature. Despite some inconsistencies for particular endpoints, the 

15 evidence for Pb-related reproductive effects is strengthened by the coherence with similar findings in 

16 invertebrate species. The collective body of evidence integrated across epidemiologic and toxicological 

17 studies, with a focus on the strong relationship observed with negative effects on sperm and delayed 

18 pubertal onset, is sufficient to conclude that there is a causal relationship between Pb exposures and 

19 reproductive effects and birth outcomes. 

2.5.7. Effects on Other Organ Systems

20 In the 2006 Pb AQCD, exposure to Pb was shown to exert effects in organ systems not yet 

21 explicitly covered in the preceding sections of this document. These organ systems included the liver, 

22 gastrointestinal tract, endocrine system, bone and teeth. In the current document, effects on these organ 

23 systems, as well as effects on the respiratory system, have been organized in one section because the 

24 amount of new evidence appearing since the 2006 Pb AQCD is limited. The few recent studies, however, 

25 find that Pb may negatively affect the function of these systems at lower blood Pb levels than previously 

26 described.

27 There is evidence from recent epidemiologic and toxicological studies that exposure to Pb results 

28 in altered liver function and hepatic toxicity, including the observation of altered serum protein levels, 

29 increased serum enzyme activities, and altered hepatic lipid metabolism. Multiple studies in humans and 

30 animals have observed hepatic oxidative stress (generally indicated by an increase in lipid peroxidation,

31 along with a decrease in GSH levels and CAT, SOD, and GPx activities) following exposure to Pb. 

32 Effects observed in occupational cohorts of painters, battery- and jewelry-workers, as well as animal
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1 toxicological studies (applying a wide range of exposure regimens), occurred at blood Pb levels >20 

2 μg/dL.

3 Relatively few human studies have been conducted on gastrointestinal toxicity of Pb since the 

4 completion of the 2006 Pb AQCD. GI symptoms were observed in battery workers and painters exposed 

5 to Pb in India (mean blood Pb level = 42.40 ± 25.53 and 8.04 ± 5.04 μg/dL, respectively). Toxicological 

6 evidence for Pb-induced GI health effects in rats includes altered muscle relaxations and markers of 

7 oxidative stress in the gastric fundus and mucosa. The observation of oxidative stress was accompanied 

8 gastric mucosal damage following short-term, sub-chronic and chronic exposures. The anterior intestine 

9 of fish has also been identified as a target of Pb (Section 2.6.2).

10 The endocrine processes most impacted by exposure to Pb include changes in thyroid function, as 

11 well as alteration in sex and stress hormone profiles. TSH was negatively correlated with blood Pb in 

12 women that ate fish contaminated with Pb as well as other chemicals (median blood Pb level = 1.7 μg/dL,

13 less than the detection limit for the study), and FT4, but not FT3, was decreased in adolescent male auto 

14 repair workers (blood Pb level = 7.3 ± 2.92 μg/dL). Significant differences in the levels of sex hormones, 

15 including total and free testosterone, estradiol, aromatase, and luteinizing hormone, were observed in 

16 Belgian adolescents residing in areas with different levels of industrial pollution including Pb (mean 

17 blood Pb levels of 2.2 μg/dL.) Toxicological evidence for similar effects was observed in adults cow 

18 reared in an environment containing Pb and other contaminants: positive correlations were reported 

19 between blood Pb and plasma T3, T4, and estradiol levels. In study of children (mean age 9.5 years)

20 challenged with an acute stressor, increasing blood Pb was associated with significant increases in 

21 salivary cortisol responses comparing blood Pb levels of 1.1-1.4 μg/dL to blood Pb levels <1 μg/dL.

22 Multiple epidemiologic studies investigated the association between Pb exposure and bone and 

23 tooth health in adults. High blood Pb has been observed to be associated with decreased BMD in non24 Hispanic white males (blood Pb level = 4.9 μg/dL). In elderly women, blood Pb levels (≥ 8 μg/dL) were

25 associated with an increased risk of falls and fractures, including osteoporosis-related falls. Linear 

26 skeletal growth in children (7-17 years of age [mean blood Pb level = 7.7 μg/dL)]), was negatively 

27 correlated with increasing blood Pb levels. Epidemiologic studies (investigating Pb exposure and tooth 

28 loss) reported that long-term, cumulative exposure to Pb is associated with increased odds of tooth loss, 

29 periodontitis in men and women, and that periodontitis is associated with oxidative stress/damage in 

30 individuals exposed in an occupational setting.

31 New toxicology studies have reported ocular effects (i.e., retinal progenitor cell proliferation) at 

32 blood Pb levels as low as <10 μg/dL (Section 5.3.4.3), and one human study reported an association 

33 between heavy smoking, increased blood Pb, and cataracts. Investigation of the respiratory effects of Pb 

34 exposure has been limited; however, cross-sectional studies have indicated an association of increasing 

35 blood Pb with increased prevalence of respiratory tract illnesses (Section 5.6.4.1) and asthma in children 
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1 (Section 5.6.4.2). Additionally, Pb-induced production of ROS is implicated in increased BR and 

2 decrements in lung function (Section 5.6.4.3).

2.5.8. Cancer 

3 Toxicological literature on the genotoxic, mutagenic, and carcinogenic potential of Pb includes 

4 strong evidence of effects in laboratory animals. Both the International Agency for Research on Cancer 

5 (IARC) and the National Toxicology Program (NTP) have examined the role of Pb in cancer. IARC 

6 classified inorganic Pb compounds as probable human carcinogens and organic Pb compounds as not 

7 classifiable (IARC, 2006; Rousseau et al., 2005). The NTP reported Pb and Pb compounds to be 

8 ‘reasonably anticipated to be human carcinogens’(NTP, 2004).

9 In laboratory studies, high-dose Pb has been demonstrated to be an animal carcinogen. Pb is likely 

10 to be a human carcinogen based on strong evidence from animal toxicology data (IARC, 2006; Waalkes et 

11 al., 1995)and less definitive epidemiological data. Mechanistic understanding of the carcinogenicity of Pb 

12 is expanding with work on the antioxidant selenium and metallothionein, a protein that binds Pb and 

13 reduces its bioavailability. Pb is clastogenic and mutagenic in some but not all models. Clastogenicity and 

14 mutagenicity may be possible mechanisms contributing to cancer, but are not necessarily associated with 

15 the induction of cancer. Due to the disruption of metal cofactors binding to Zn-finger proteins, Pb has the 

16 potential to induce indirect effects that can contribute to carcinogenicity via interactions at hormone 

17 receptors, at cell-cycle regulatory proteins, with tumor suppressor genes like p53, with DNA repair 

18 enzymes, and with histones. These indirect effects may act at a post-translational level to alter protein 

19 structure and DNA repair. In addition, some evidence of epigenetic changes associated with Pb exposure 

20 is available in the recent literature. Epigenetic changes may further alter DNA repair or change the 

21 expression of a tumor suppressor gene or oncogene. Thus, the animal toxicology literature provides a 

22 strong base for understanding the potential contribution of Pb exposure to cancer in laboratory animals. 

23 Multiple epidemiologic studies have been performed examining the association with cancer 

24 incidence and mortality with Pb exposure assessed using biological measures and exposure databases. 

25 Mixed results have been reported for cancer mortality studies; one strong epidemiologic study of US 

26 adults (Schober et al., 2006) demonstrated a positive association between blood Pb and cancer mortality, 

27 but the other studies reported null results (Menke et al., 2006). Although the previous Pb AQCD reported 

28 that some studies were suggestive of an association between Pb exposure and lung cancer, current studies, 

29 which mostly examined occupational exposure observed no associations. Most studies of Pb and brain 

30 cancer were null among the overall study population, but positive associations were observed among 

31 individuals with certain genotypes. A limited amount of research on other types of cancer has been 

32 performed. The previous Pb AQCD reported evidence that suggested an association between Pb exposure 
May 2011 2-24 DRAFT – DO NOT CITE OR QUOTE

1 and stomach cancer, but recent studies of this association are lacking, with only one study published since 

2 the last Pb AQCD (U.S. EPA, 2006), which reported mixed results. 

3 Among epidemiologic studies on genotoxicity, positive associations were observed between high 

4 Pb blood levels and sister chromatid exchange (SCE) among adults but not children. Other epidemiologic 

5 studies of DNA damage reported inconsistent results. Consistent with previous toxicological findings, Pb 

6 does appear to have genotoxic activity inducing SCE, MN and DNA strand breaks. Only PbCrO4

7 produces chromosomal aberrations but this effect is likely due to chromate. Pb does not appear to be very 

8 mutagenic unless a cell signaling pathway was disturbed. 

9 Epigenetic effects, particularly with respect to methylation and effects on DNA repair were 

10 observed consistently. In humans, epigenetic studies examining Pb and LINE-1 and Alu consistently 

11 demonstrated an inverse association between patella Pb and global DNA LINE-1 methylation (Pilsner et 

12 al., 2009; R. O. Wright et al., 2010). Toxicological studies show that Pb can activate or interfere with a 

13 number of signaling and repair pathways, though it is unclear whether these are in response to epigenetics 

14 or genotoxicity. Thus, an underlying mechanism is still unknown, but likely involves either genomic 

15 instability or epigenetic modifications or both.

16 Overall, there is some epidemiologic evidence supporting associations between Pb and cancer. 

17 Strong evidence from toxicological studies demonstrates an association between Pb and cancer, 

18 genotoxicity/clastogenicity or epigenetic modification. The collective body of evidence integrated across 

19 epidemiologic and toxicological studies is sufficient to conclude that there is a likely causal relationship 

20 between Pb exposures and cancer.

2.5.9. Human Health Effects and Corresponding Blood Pb 

Levels

21 Tables 2-2 and 2-3 summarize the health effects in children (and adults and the lowest blood Pb 

22 level at which the weight of the evidence substantiates a causal relationship. The 2006 Pb AQCD did not 

23 identify a safe level of exposure for Pb and concluded that any threshold for Pb neurotoxicity would have 

24 to exist at levels distinctly lower than the lowest exposures examined in the epidemiologic studies 

25 included in the assessment. Recent studies continue to find associations between a wide range of health 

26 endpoints and increasingly lower levels of blood Pb. The lack of a reference population with blood Pb 

27 levels reflecting pre-industrial Pb exposures continues to limit the ability to identify a threshold. 

28 Estimates of “background” blood Pb levels have been measured in ancient bones from pre-industrialized 

29 societies. These studies suggest that the level of lead in blood in pre-industrial humans was approximately 

30 0.016 μg/dL (Flegal & Smith, 1992), approximately 65-fold lower than that currently measured in U.S. 

31 populations. In this context, a blood Pb level of 1 μg/dL is not relatively low. Further, if a threshold did 
May 2011 2-25 DRAFT – DO NOT CITE OR QUOTE

1 exist, in order to demonstrate it, the scale at which blood Pb level is measured will likely have to be 

2 adjusted to parts per million (μg/L) instead of parts per hundred thousand (μg/dL). 

Table 2-2. Summary of Pb-induced health effects in children and the lowest mean blood 

Pb level in the population(s) studied

Blood 

Pb 

Level

Neurological Effects Renal Effects Immune Effects Effects on Heme 

Synthesis and RBC 

Function

20 μg/dL • Macrophage hyperinflammationi

15 μg/dL • Lymphocyte activationj • Increased Zn protoporphyrinp

• Lipid peroxidationq

10 μg/dL • Delinquent behaviora

• Increased hearing thresholdb • Altered antioxidant enzyme activitiesr

• Decreased ALAD activitiess

• Altered hematological 

parameters (i.e., decreased 

hemoglobin)t

5 μg/dL

1 μg/dL

• Inattentionc

• Decrements in full scale IQd

• Decrements in specific 

neurocognitive domainse

• Poorer school performancef

• ADHDg

Decreased eGFRh

• Increased B cell abundancek

• Increased IgEl

• Increased risk of infectionm

• Decreased T cell abundancen

• Allergic sensitizationo

• Decreased Ca-Mg ATPase 

activityu

Note: Endpoints where the weight of the evidence, overall, substantiates the causal association with blood Pb levels in the range noted on the 

figure. Since no evident threshold has yet been clearly established for most effects, the existence of such effects at still lower blood Pb levels 

cannot be ruled out based on available information. 

Supporting references: Wright et al. (2008)

a

; Hwang et al. (2009) and Schwartz and Otto (1991)

b

; Nicolescu et al. (2010)

c

; Kim et al. (2009)

d

; Krieg

et al. (2010)

e

; Miranda et al. (2009)

f

; Braun et al. (2006) and Braun et al. (2008)

g

; Fadrowski et al. (2010)

h

; Pineda-Zavaleta et al. (2004)

I

; Lutz et al. 

(1999)

j

; Sarasua et al. (2000)

k

; Karmaus et al. (2005)

l

; Karmaus et al. (2005)

m; Karmaus et al. (2005)n

; Jedrychowski et al. (2011)

o

; Wang et al. 

(2010)

p

; Ahamed et al. (2006)

q

; Ahamed et al. (2005)

r

; Wang et al.(2010)

s

; Riddell et al. (2007)

t

; Huel et al. (2008)

u
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Table 2-3. Summary of Pb-induced health effects in adults and the lowest mean blood 

Pb level in the population(s) studied

Blood 

Pb Level

Neurological

Effects

Cardiovascular 

Effects

Renal 

Effects

Immune

Effects

Reproductive

Effects and 

Birth 

Outcomes

Effects on Heme 

Synthesis and 

RBC Function

30 μg/dL • Arrhythmiag • Decreased 

neutrophil functionp • Sperm abnormalitiesu • Decreased hematocritw

• Decreased Ca-Mg 

ATPase activityx

20 μg/dL • Impaired renal 

tubular functionn • Increased autoantibodiesq

15 μg/dL • Brain MRI 

changesa

• Increased hearing 

thresholdb

10 μg/dL

• Criminal arrestc

• Lipid peroxidationy

• Decreased

antioxidant enzyme 

activitiesy

• Altered 

hematological

parameters 

(e.g., decreased 

hemoglobin, packed 

cell volume)z

• Decreased serum 

erythropoietinaa

• Increased Zn 

protoporphyrinbb

• Altered ALAD 

activitybb

5 μg/dL

1 μg/dL

• Decrements in 

cognitive functiond

• Essential tremore

• Mood disordersf

• Mortalityh

• Decreased HRVi

• Ischemic heart 

diseasej

• Peripheral Artery 

Diseasek

• Hypertensionl

• Increased BPm

• Elevated serum creatinineo

(↓ creatinine 

clearance, GFR)

• Shift to Th2 

cytokinesr

• Increased

bronchial 

reactivitys

• Increased

inflammationt

• Delayed pubertyv

Note: Endpoints where the weight of the evidence, overall, substantiates the causal association with blood Pb levels in the range noted on the figure. Since no evident threshold has yet been clearly established for most effects, the existence of such effects at still lower blood Pb levels cannot be 

ruled out based on available information. 

Supporting references: Brubaker et al. (2010; 2009)

a

; Hwang et al. (2009) and Chuang et al. (2007)

b

; Wright et al. (2008)

c

; Krieg et al. (2009)

d

; Dogu 

et al. (2007)

e

; Bouchard et al. (2009)

f

; Reza et al. (2008)

g

; Menke et al. (2006)

h

; Park et al. (2009)

i

; Jain et al. (2007)

j

; Muntner et al. (2005)

k

; 

Scinicariello et al. (2010) and Park et al. (2009)

l

; Scinicariello et al. (2010) and Martin et al. (2006)

m; Sun et al. (2008), Lin and Tai-yi (2007) and 

Wang et al. (2010)

n

; Tsaih et al. (2004), Akesson et al. (2005) and Yu et al. (2004)

o

; Valentino et al. (1991)

p

; El-Fawal et al. (1999)

q

; Kim et al. (2007)

r

; 

Min et al. (2008)

s

; Songdej et al. (2010)

t

; Telisman et al. (2007) and Hsu et al. (2009)

u

; Hauser et al. (2008), Williams et al. (2010), Denham et al. 

(2005), Selevan et al. (2003) and Wu et al. (2003)

v

; Karita et al. (2005)

w

; Abam et al. (2008)

x

; Ergurhan-Ilhan et al. (2008)

y

; Ukaejiofo et al. (2009)

z

; 

Sakata et al. (2007)

aa; Wang (2010)bb

2.6. Ecological Effects

1 This section evaluates the evidence from studies of ecological effects associated with exposure to 

2 Pb. The results from the studies evaluated in combination with the evidence from other disciplines (e.g., 

3 fate and transport) contribute to the causal determinations for the ecological outcomes discussed in this 

4 assessment. In the following sub-sections, a discussion of the causal determinations is presented for the 
May 2011 2-27 DRAFT – DO NOT CITE OR QUOTE

1 ecological effects. Effects determined to be causal at the species level contribute to the body of evidence 

2 for causal effects at the community and ecosystem scale. Where the causal determination varies 

3 substantially between types of organisms (typically between plants and other organisms), the divergence 

4 is noted. 

5 The evidence used to formulate each causal determination is summarized here, and the 

6 corresponding detailed discussion can be found in Chapter 7 of this document. In Chapter 7, the effects on 

7 terrestrial (Section 7.2) and aquatic (Section 7.3) ecosystems are presented separately, and each of the 

8 sections first discusses effects at the species level, followed by community and ecosystem levels. In each 

9 of the two main sections, biogeochemistry and chemical effects of Pb that influence bioavailability are 

10 considered first, as Pb must first move from the environmental media (soil, water, sediment etc.) into 

11 biota. Next, uptake of Pb from soil and water are discussed, then new information on biological effects of 

12 Pb on plants, invertebrates and vertebrates, followed by data on exposure-response relationships. 

13 Ecosystem-scale responses to Pb exposure are considered along with critical loads, characterization of 

14 sensitivity and vulnerability, and the effect of Pb on ecosystem services. Finally, in Section 7.4, a 

15 synthesis of the effects of Pb observed across terrestrial and aquatic habitats is presented along with 

16 causal determinations for those effects, which are also summarized in Table 2-4 below. In this chapter, Pb 

17 effects on terrestrial and aquatic systems from Chapter 7 are summarized (Sections 2.6.1 and 2.6.2); 

18 followed by a summary of the evidence for the causal determinations (Sections 2.6.3 to 2.6.10) and 

19 consideration of atmospheric deposition of Pb as related to ecological effects (Section 2.6.11). 

Table 2-4. Summary of causal determinations for Pb in plants, vertebrates and 

invertebrates

Effect Causality Determination 

Bioaccumulation – All Organisms Causal Relationship

Mortality - Plants Inadequate to Infer Causal Relationship

Mortality - Vertebrates and Invertebrates Causal Relationship

Growth - Plants Causal Relationship

Growth - Invertebrates Causal Relationship

Growth - Vertebrates Suggestive of a Causal Relationship

Physiological Stress – All Organisms Causal Relationship

Hematological Effects – Invertebrates and Vertebrates Causal Relationship

Development and Reproduction- Invertebrates and Vertebrates Causal Relationship

Development and Reproduction-Plants Inadequate to Infer Causal Relationship

Neurobehavior – Invertebrates and Vertebrates Causal Relationship

Community and Ecosystem Level Effects Causal Relationship
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2.6.1. Summary of Terrestrial Ecosystem Effects

1 Section 7.2 focuses on the effects of Pb in terrestrial systems. Pb in terrestrial ecosystems is either 

2 deposited directly onto plant surfaces, or incorporated into soil where it can bind with organic matter or 

3 dissolve in pore water. The amount of Pb dissolved in soil pore water determines the impact of soil Pb on 

4 terrestrial ecosystems to a much greater extent than the total amount present. It has long been established 

5 that the amount of Pb dissolved in soil solution is controlled by at least six variables: (1) solubility 

6 equilibria; (2) adsorption-desorption relationship of total Pb with inorganic compounds; (3) adsorption7 desorption reactions of dissolved Pb phases on soil organic matter; (4) pH; (5) CEC; and (6) aging. Since 

8 2006, further details have been contributed to the understanding of the role of pH, cation exchange 

9 capacity (CEC), organic matter, and aging. Smolders et al. (2009) demonstrated that the two most 

10 important determinants of both Pb solubility and toxicity in soils are pH and CEC. However, they had 

11 previously shown that aging, primarily in the form of initial leaching following deposition, decreases 

12 soluble metal fraction by approximately one order of magnitude (Smolders et al., 2007). Since 2006, 

13 organic matter has been confirmed as an important influence on Pb sequestration, leading to longer-term 

14 retention in soils with higher organic matter content, and also creating the potential for later release of 

15 deposited Pb. Aging, both under natural conditions and simulated through leaching, was shown to 

16 substantially decrease bioavailability to plants, microbes, and vertebrates.

17 There is evidence over several decades of research previously reviewed in Pb AQCDs and in recent 

18 studies reviewed in this ISA that Pb bioaccumulates in plants, invertebrates and vertebrates in terrestrial 

19 systems. Studies with herbaceous species growing at various distances from smelters added to the 

20 existing strong evidence that atmospherically transported Pb is taken up by plants. These studies did not 

21 establish the relative proportion that originated from atmospheric Pb deposited in the soil, as opposed to 

22 that taken up directly from the atmosphere through the leaves. Multiple new studies showed that in trees, 

23 the latter is likely to be very substantial. One study attempted to quantify it, and suggested that 50% of the 

24 Pb contained in Scots Pine in Sweden is taken up directly from the atmosphere. Studies with herbaceous 

25 plants found that in most species tested, soil Pb taken up by the roots is not translocated into the stem and 

26 leaves. Studies with trees found that soil Pb is generally translocated from the roots. 

27 Since the 2006 Pb AQCD, various species of terrestrial snails have been found to accumulate Pb 

28 from both diet and soil. New studies with earthworms have found that both internal concentration of Pb 

29 and mortality increase with decreasing soil pH and CEC. In addition, tissue concentration differences 

30 have been found in species of earthworms that burrow in different soil layers. The rate of accumulation in 

31 each of these species may result from layer differences in interacting factors such as pH and CEC. 

32 Because earthworms often sequester Pb in granules, some authors have suggested that earthworm Pb is 

33 not bioavailable to their predators. There is some evidence that earthworm activity increases Pb 

34 availability in soil, but it is inconsistent. In various arthropods collected at contaminated sites, recent 
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1 studies found gradients in accumulated Pb that corresponded to gradients in soil with increasing distance 

2 from point sources.

3 There were a few new studies of Pb bioavailability and uptake in birds since the 2006 Pb AQCD. 

4 Several found tissue levels in birds that indicated exposure to Pb, but none of the locations for these 

5 studies was in proximity to point sources, and the origin of the Pb could not be identified. A study at the 

6 Anaconda Smelter Superfund site found increasing Pb accumulation in gophers with increasing soil Pb 

7 around the location of capture. A study of swine fed various Pb-contaminated soils showed that the form 

8 of Pb determined accumulation. New studies were able to measure Pb in the components of various food 

9 chains that included soil, plants, invertebrates, arthropods and vertebrates. They confirmed that trophic 

10 transfer of Pb is pervasive, but no consistent evidence of trophic magnification was found.

11 Evidence in this review further supports the findings of the previous Pb AQCDs that biological 

12 effects of Pb on terrestrial organisms vary with species and lifestage, duration of exposure, form of Pb, 

13 and soil characteristics. In photosynthetic organisms, experimental studies have added to the existing 

14 evidence of photosynthesis impairment in plants exposed to Pb, and have found damage to photosystem II 

15 due to alteration of chlorophyll structure, as well as decreases in chlorophyll content in diverse taxa, 

16 including lichens and mosses. A substantial amount of evidence of oxidative stress in response to Pb 

17 exposure has also been produced. Reactive oxygen species were found to increase in broad bean and 

18 tomato plants exposed to increasing concentrations of soil Pb, and a concomitant increase in superoxide 

19 dismutase, glutathione, peroxidases, and lipid peroxidation, as well as decreases in catalase were observed 

20 in the same plants. Monocot, dicot, and bryophytic taxa grown in Pb-contaminated soil or in 

21 experimentally spiked soil all responded to increasing exposure with increased antioxidant activity. In 

22 addition, reduced growth was observed in some experiments, as well as genotoxicity, decreased 

23 germination, and pollen sterility.

24 In terrestrial invertebrates, evidence for Pb effects have included neurological and reproductive 

25 endpoints. Recently published studies have shown neuronal damage in nematodes exposed to low 

26 concentrations of Pb (2.5 μM), accompanied by behavioral abnormalities. Reproductive adverse effects 

27 were found at lower exposure in younger nematodes, and effects on longevity and fecundity were shown 

28 to persist for several generations. Increased mortality was found in earthworms, but was strongly 

29 dependent on soil characteristics including pH, CEC, and aging. Snails exposed to Pb through either 

30 topical application or through consumption of Pb-exposed plants had increased antioxidant activity, and 

31 decreased food consumption, growth, and shell thickness. Effects on arthropods exposed through soil or 

32 diet varied with species and exposure conditions, and included diminished growth and fecundity, 

33 endocrine and reproductive anomalies, and body deformities. Increasing concentration of Pb in the 

34 exposure medium generally resulted in increased effects within each study, but the relationship between 

35 concentration and effects varied between studies, even when the same medium, e.g., soil, was used. 

36 Evidence suggested that aging and pH are important modifiers.
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1 Effects on amphibian and reptiles included decreased white blood cell counts, decreased testis 

2 weight, and behavioral anomalies. However, large differences in effects were observed at the same 

3 concentration of Pb in soil, depending on whether the soil was freshly amended or field-collected from 

4 contaminated areas. As in most studies where the comparison was made, effects were smaller when field5 collected soils were used. In some birds, maternal elevated blood Pb level was associated in recent studies 

6 with decreased hatching success, smaller clutch size, high corticosteroid level, and abnormal behavior. 

7 Some species evidenced little or no effect of elevated blood Pb level. Effects of dietary exposure were 

8 studied in several mammalian species, and cognitive, endocrine, immunological, and growth effects were 

9 observed. 

10 Evidence reviewed in Sections 7.2.3 and 7.2.4 demonstrates clearly that increased exposure to Pb is 

11 generally associated with negative effects in terrestrial ecosystems. It also demonstrates that many factors, 

12 including species and various soil physiochemical properties, interact strongly with Pb concentration to 

13 modify those effects. In these ecosystems, where soil is generally the main component of the exposure 

14 route, Pb aging is a particularly important factor, and one that may be difficult to reproduce 

15 experimentally. Without quantitative characterization of those interactions, characterizations of exposure16 response relationships would likely not be transferable outside of experimental settings. Since the 2006 

17 Pb AQCD, a few studies of exposure-response have been conducted with earthworms, and results have 

18 been inconsistent.

19 New evidence of effects of Pb at the community and ecosystem scale include several studies of the 

20 ameliorative effects of mycorrhizal fungi on plant growth, attributed to decreased uptake of Pb by plants, 

21 although both mycorrhizal fungus and plant were negatively affected. Most recently published research 

22 on community and ecosystem scale effects of Pb has focused on soil microbial communities, which have 

23 been shown to be impacted in both composition and activity. Many recent studies have been conducted 

24 using mixtures of metals, but have tried to separate the effects of individual metals when possible. Soil 

25 microbial activity was generally diminished, but in some cases recovered over time. Species and genotype

26 composition were consistently altered, and those changes were long-lasting or permanent. Recent studies 

27 have addressed differences in sensitivity between species explicitly, and have clearly demonstrated high 

28 variability between related species, as well as within larger taxonomic groupings. Mammalian no 

29 observed effect concentration (NOEC) values expressed as blood Pb levels were shown to vary by a 

30 factor of 8, while avian blood NOECs varied by a factor of 50 (Buekers et al., 2009). Protective effects of 

31 dietary Ca have been found in plants, birds, and invertebrates.

2.6.2. Summary of Aquatic Ecosystem Effects

32 Section 7.3 focuses on the effects of Pb in aquatic systems. Once atmospherically-derived Pb enters 

surface waters, its fate and bioavailability are influenced by Ca2+ 33 concentration, pH, alkalinity, total 
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1 suspended solids, and dissolved organic carbon (DOC, including humic acids). In sediments, Pb 

2 bioavailability may be influenced by the presence of other metals, sulfides, Fe and Mn oxides and 

3 physical disturbance. In many, but not all aquatic organisms, Pb dissolved in the water can be the primary 

4 exposure route to gills or other biotic ligands. As recognized in the 2006 Pb AQCD and further supported 

5 in this review, chronic exposures to Pb may also include dietary uptake, and there is an increasing body of 

6 evidence showing that differences in uptake and elimination of Pb vary with species. Currently available 

7 models for predicting bioavailability focus on acute toxicity and do not consider all possible routes of 

8 uptake. They are therefore of limited applicability, especially when considering species-dependent 

9 differences in uptake and bioaccumulation of Pb. 

10 According to the 2006 Pb AQCD, and further supported in this review, Pb adsorption, 

11 complexation, chelation, etc., are processes that alter bioavailability to aquatic biota. Given the low 

12 solubility of Pb in water, bioaccumulation by aquatic organisms may preferentially occur via exposure 

13 routes other than direct absorption from the water column, including ingestion of contaminated food and 

14 water, uptake from sediment pore waters, or incidental ingestion of sediment. 

15 There are considerable differences between species in the amount of Pb taken up from the 

16 environment and in the levels of Pb retained in the organism and closely related species can vary greatly 

17 in bioaccumulation of Pb and other non-essential metals. Recent studies on uptake of Pb by aquatic plants 

18 and algae support the findings of previous Pb AQCDs that all plants tend to sequester larger amounts of 

19 Pb in their roots than in their shoots, and provide additional evidence for species differences in 

20 compartmentalization of sequestered Pb and in responses to Pb in water and sediments. In invertebrates, 

21 Pb can be bioaccumulated from multiple sources, including the water column, sediment, and dietary 

22 exposure. Since the last review, new studies using stable isotopes have enabled simultaneous 

23 measurement of uptake and elimination in several aquatic organisms to assess the relative importance of 

24 water versus dietary uptake. In uptake studies of various invertebrates, Pb was mainly found in the gills 

25 and digestive gland/hepatopancreas. There is more information now on the cellular and subcellular 

26 distribution of Pb in invertebrates than there was at the time of writing the 2006 Pb AQCD. Specifically, 

27 localization of Pb at the ultrastructural level has been assessed in several species.

28 The conclusions of the 2006 Pb AQCD that the gill is a major site of Pb uptake in fish and that 

29 there are species differences in the rate of Pb accumulation and distribution of Pb within the organism are 

30 supported in this review. The anterior intestine has been newly identified as a site of uptake of Pb through 

31 dietary exposure studies. There are few new studies on Pb uptake by amphibians and mammals. At the 

32 time of the publication of the 2006 Pb AQCD, trophic transfer of Pb through aquatic food chains was 

33 considered to be negligible. Measured concentrations of Pb in the tissues of aquatic organisms were 

34 generally higher in algae and benthic organisms than in higher trophic-level consumers, indicating that Pb 

35 was bioconcentrated but not biomagnified. Some studies published since the 2006 Pb AQCD support the 
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1 potential for transfer of Pb in aquatic food webs, while other studies indicate that Pb concentration 

2 decreases with increasing trophic level (biodilution). 

3 Evidence in this ISA further supports the findings of the previous Pb AQCDs that waterborne Pb is 

4 highly toxic to aquatic organisms, with toxicity varying with species and lifestage, duration of exposure, 

5 form of Pb, and water quality characteristics. Effects of Pb on algae reported in the 2006 Pb AQCD are 

6 further supported by evidence from additional species in this review. They include decreased growth, 

7 deformation and disintegration of cells, and blocking of the pathways that lead to pigment synthesis, thus 

8 affecting photosynthesis. Effects on plants supported by additional evidence in this review include 

9 oxidative damage, decreased photosynthesis and reduced growth. The mechanism of Pb toxicity in plants 

10 is likely mediated by damage to photosystem II through alteration of chlorophyll structure. Elevated 

11 levels of antioxidant enzymes are commonly observed in aquatic plant, algae, and moss species exposed 

12 to Pb. 

13 Since the 2006 Pb AQCD, there is additional evidence for Pb effects on antioxidant enzymes, lipid 

14 peroxidation, stress response and osmoregulation in aquatic invertebrates. Studies of reproductive and 

15 developmental effects of Pb in this review provide further support for findings in the 2006 Pb AQCD. 

16 These new studies include reproductive endpoints for rotifers and freshwater snails as well as 

17 multigenerational effects of Pb in mosquito larvae. Growth effects are observed at lower concentrations in 

18 some aquatic invertebrates since in the 2006 Pb AQCD, including juveniles of the freshwater snail 

19 Lymnaea stagnalis where growth is affected at <4 μg Pb/L (Grosell et al., 2006). Behavioral effects of Pb 

20 in aquatic invertebrates reviewed in this ISA include decreased valve closing speed in scallops and slower 

21 feeding rate in blackworms.

22 Evidence in this ISA supports the findings of reproductive, behavioral, and growth effects in 

23 previous Pb AQCDs, as well as effects on blood parameters in vertebrates. Additional mechanisms of Pb 

24 toxicity have been elucidated in the gill and the renal system of fish since the 2006 Pb AQCD. 

Furthermore, the mitogen-activated protein kinases, ERK1/2 and p38MAPK 25 were identified for the first 

26 time as possible molecular targets for Pb neurotoxicity in a teleost (Leal et al., 2006). In the 2006 Pb 

27 AQCD, amphibians were considered to be relatively tolerant to Pb. Observed responses to Pb exposure 

28 included decreased enzyme activity (e.g., ALAD reduction) and changes in behavior. Since the 2006 Pb 

29 AQCD, studies conducted at concentrations approaching environmental levels of Pb have indicated 

30 sublethal effects on tadpole endpoints including growth, deformity, and swimming ability.

31 Concentration-response data from plants, invertebrates and vertebrates is consistent with findings 

32 in previous AQCDs of species differences in sensitivity to Pb in aquatic systems. In this ISA (and 

33 previous AQCDs), aquatic plant growth was shown to be adversely affected by Pb exposure. The lowest 

34 EC50 for growth observed in marine microalgae and freshwater microalgae was in the range of 100 μg 

35 Pb/L. In the 2006 Pb AQCD, concentrations at which effects were observed in aquatic invertebrates 

36 ranged from 5 to 8,000 μg/L. Several studies in this review have provided evidence of effects at lower 
May 2011 2-33 DRAFT – DO NOT CITE OR QUOTE

1 concentrations. Among the most sensitive species, growth of juvenile freshwater snails (L. stagnalis) was 

2 inhibited at an EC20 of <4 μg Pb/L. (Grosell & Brix, 2009; Grosell et al., 2006). A chronic value of 10 μg 

3 Pb/L obtained in 28-day exposures of 2-month-old Lampsilis siliquoidea juveniles was the lowest genus 

4 mean chronic value ever reported for Pb (N. Wang et al., 2010). In the 2006 Pb AQCD, adverse effects 

5 were found in freshwater fish at concentrations ranging from 10 to >5,400 μg Pb/L, generally depending 

6 on water quality variables (e.g., pH, hardness, salinity). Additional testing of Pb toxicity under conditions 

7 of varied alkalinity, DOC, and pH has been conducted since the last review. However, adverse effects in 

8 fish observed in recent studies fall within the range of concentrations observed in the previous Pb AQCD.

9 Since the 2006 Pb AQCD, additional evidence for community and ecosystem level effects of Pb 

10 have been observed primarily in microcosm studies or field studies with other metals present. Ecological 

11 effects associated with Pb, reported in previous Pb AQCDs, include alteration of predator-prey dynamics, 

12 species richness, species composition, and biodiversity. New studies in this ISA provide evidence in 

13 additional habitats for these community and ecological-scale effects, specifically in aquatic macrophyte 

14 communities and sediment-associated communities. Different species may exhibit different responses to 

15 Pb-impacted ecosystems dependent not only upon other environmental factors (e.g., temperature, pH), but 

16 also on the species sensitivity, lifestage, or seasonally-affected physiological state.

2.6.3. Bioaccumulation of Lead in Terrestrial and Aquatic 

Biota as it Affects Ecosystem Services

17 Pb deposited on the surface of, or taken up by organisms has the potential to alter the services 

18 provided by terrestrial and aquatic biota to humans. Ecosystem services are the benefits people obtain 

19 from ecosystems. They include supporting, provisioning, regulating and cultural services that are vital for 

20 the functioning of the biosphere and provide the basis for the delivery of tangible benefits to human 

21 society. There is compelling evidence over several decades of research and in recent studies reviewed in 

22 this ISA (Sections 7.2.3 and 7.3.3.) that Pb bioaccumulates in plants, invertebrates and vertebrates in 

23 terrestrial and aquatic systems. Generally, there are considerable differences between species in the 

24 amount of Pb taken up from the environment, and in the amounts of Pb retained in the organism. In order 

25 for Pb to reach a biological receptor, the metal must first cross the membranes of organisms to reach the 

26 target organ or site of storage. This process varies between plants, invertebrates and vertebrates, and 

27 furthermore, uptake and sequestration are at times similar in unrelated species, while substantially 

28 different between related ones. Uptake of Pb from environmental media is dependent upon the 

29 bioaccessibility of Pb (reviewed in Chapter 3) which is influenced by many factors including, but not 

30 limited to, temperature, pH, presence of humic acid and dissolved organic matter, presence of other 

31 metals, and speciation of Pb. 
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1 Pb is bioaccumulated in plants, invertebrates and vertebrates inhabiting terrestrial and aquatic 

2 systems that receive Pb from atmospheric deposition. This represents a potential route for Pb mobilization 

3 into the food web or into food products. For example, Pb bioaccumulation in leaves and roots of an edible 

4 plant may represent an adverse impact to the provisioning of food, an essential ecosystem service. Recent 

5 research has suggested that dietary Pb (i.e., Pb adsorbed to sediment, particulate matter, and food) may 

6 contribute to exposure and toxicity in primary and secondary order consumers (including humans). 

7 Although there is no consistent evidence of trophic magnification, there is substantial evidence of trophic 

8 transfer. It is through consumption of Pb-exposed prey or Pb-contaminated food that atmospherically 

9 deposited Pb reaches species that may have very little direct exposure to it. Overall, based on the 

10 consistency of findings across taxa, the evidence is sufficient to conclude that there is a causal 

11 relationship between Pb exposures and bioaccumulation of Pb that affects ecosystem services 

12 associated with terrestrial and aquatic biota.

2.6.4. Mortality

13 The relationship between Pb exposure and mortality has been well demonstrated in terrestrial and 

14 aquatic species as presented in Sections 7.2.5 and 7.3.5 of this ISA and in the previous Pb AQCDs. 

15 Toxicological studies have established LC50 values for some species of plants, invertebrates and 

16 vertebrates. From the LC50 data on Pb in this review and previous Pb AQCDs a wide range of sensitivity 

17 to Pb is evident across taxa. However, the LC50 is usually much higher than current environmental levels 

18 of Pb, even though physiological dysfunction that adversely impacts the fitness of an organism often 

19 occurs well below concentrations that result in mortality. 

20 Pb is generally not phytotoxic to plants at concentrations found in the environment away from 

21 point-sources, probably due to the fact that plants often sequester large amounts of Pb in roots, and that 

22 translocation to other parts of the plant is limited. Invertebrates are generally more sensitive to Pb 

23 exposure than other taxa, with survival adversely impacted in a few species at concentrations occurring 

24 near point-sources, or at concentrations near ambient levels. These impacted species may include 

25 candidate or endangered species. The freshwater mussel Lampsilis rafinesqueana (Neosho mucket), is a 

26 candidate for the endangered species list. The EC50 for foot movement (a measure of viability) for newly 

27 transformed juveniles of this species was 188 μg Pb/L. Other invertebrates such as odonates may be 

28 tolerant of Pb concentrations that greatly exceed environmental levels. 

29 Thirty day LC50 values for larval fathead minnows ranged from 39 to 1,903 μg/L in varying 

30 concentrations of DOC, CaSO4 and pH. (Grosell et al., 2006). In a recent study of rainbow trout fry at 2-4 

31 weeks post-swim up, the 96-hour LC50 was 120 μg Pb/L at a hardness of 29 mg/L as CaCO3, a value 

32 much lower than in testing with older fish (Mebane et al., 2008). 
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1 The evidence is inadequate to conclude that there is a causal relationship between Pb and 

2 mortality in plants.

3 The evidence is sufficient to conclude that there is a causal relationship between Pb exposures 

4 and mortality in sensitive terrestrial and aquatic animal taxa.

2.6.5. Growth Effects

5 Evidence for Pb effects on growth is strongest in plants, with limited information in invertebrates 

6 and vertebrates. There is evidence over several decades of research that Pb inhibits photosynthesis and 

7 respiration in plants, both of which reduce growth (U.S. EPA, 1977, 2006). Many laboratory and 

8 greenhouse toxicity studies have reported effects on plants, and there are few field toxicity studies. Pb has 

9 been shown to affect photosystem II with the hypothesized mechanism being that Pb may replace either 

10 Mg or Ca in chlorophyll, altering the pigment structure and decreasing the efficiency of visible light 

11 absorption by affected plants. Decreases in chlorophyll a and b content have been observed in various 

12 algal and plant species. The lowest 72-hour EC50 for growth inhibition reported for algae was 105 μg Pb/L 

13 in Chaetoceros sp. Most primary producers experience EC50 values for growth in the range of 1,000 to 

14 100,000 μg Pb/L (U.S. EPA, 2006). 

15 In previous Pb AQCDs, growth effects of Pb have been reported in fish (growth inhibition), birds 

16 (changes in juvenile weight gain), and frogs (delayed metamorphosis, smaller larvae). Growth effects 

17 observed in invertebrates and vertebrates underscore the importance of lifestage to overall Pb 

18 susceptibility. In general, juvenile organisms are more sensitive than adults. Several studies since the last 

19 review have demonstrated effects of Pb on growth at lower concentrations than in previous literature. 

20 Among the animal taxa tested, aquatic invertebrates were the most sensitive to the effect of Pb, with 

21 adverse effects being reported as low as 4 μg Pb/L. Growth of juvenile freshwater snails L. stagnalis was 

22 inhibited at EC20 <4 μg Pb/L (Grosell & Brix, 2009; Grosell et al., 2006). In the freshwater mussel, 

23 fatmucket (L. siliquoidea) juveniles were the most sensitive lifestage (N. Wang et al., 2010). A chronic 

24 value of 10 μg Pb/L in a 28-day exposure of 2-month-old fatmucket juveniles was the lowest genus mean 

25 chronic value ever reported for Pb. 

26 Evidence is sufficient to conclude that there is a causal relationship between Pb exposures and 

27 growth effects in plants and invertebrates. Evidence is suggestive of a causal relationship between 

28 Pb exposures and growth effects in vertebrates. 

2.6.6. Physiological Stress

29 In this ISA and previous Pb AQCDs, there is consistent and coherent evidence of upregulation of 

30 antioxidant enzymes and increased lipid peroxidation associated with Pb exposure in many species of 

31 plants, invertebrates and vertebrates. In plants, increases of antioxidant enzymes with Pb exposure occur 
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1 in algae, aquatic mosses, floating and rooted aquatic macrophytes, and terrestrial species. There is 

2 considerable evidence for antioxidant activity in invertebrates, including gastropods, mussels, and 

3 crustaceans, in response to Pb exposure. Upregulation of antioxidant enzymes are also observed in fish. 

4 Across all biota, there are differences in the induction of antioxidant enzymes that appear to be species5 dependent.

6 Additional stress responses observed in terrestrial and aquatic invertebrates include elevated heat 

7 shock proteins, osmotic stress and decreased glycogen levels. Heat shock protein induction by Pb 

8 exposure has been observed in zebra mussels and mites. Tissue volume regulation is adversely affected in 

9 freshwater crabs. Glycogen levels in the freshwater snail Biomphalaria glabrata were significantly 

10 decreased at near environmentally-relevant concentrations (50 μg Pb/L and higher) (Ansaldo et al., 2006). 

11 Upregulation of antioxidant enzymes and increased lipid peroxidation are considered to be reliable 

12 biomarkers of stress, and suggest that Pb exposure induces a stress response in those organisms, which 

13 may increase susceptibility to other stressors and reduce individual fitness. 

14 Evidence is sufficient to conclude that there is a causal relationship between Pb exposures and 

15 physiological stress in plants, invertebrates and vertebrates. 

2.6.7. Hematological Effects

16 Hematological responses are commonly reported effects of Pb exposure in invertebrates and 

17 vertebrates in both aquatic and terrestrial systems. In environmental assessments of metal-impacted 

18 habitats, ALAD is a recognized biomarker of Pb exposure (U.S. EPA, 2006). ALAD activity is negatively 

19 correlated with total Pb concentration in bivalves. Lower ALAD activity has been significantly correlated 

20 with elevated blood Pb levels in fish and mammals as well. In the 1986 Pb AQCD, decreases in RBC 

21 ALAD activity following Pb exposure were well documented in birds and mammals. Further evidence 

22 from the 2006 Pb AQCD and this review for Pb effects on ALAD enzymatic activity including effects in 

23 bacteria, amphibians and additional field and laboratory studies on fish suggest this enzyme is an 

24 indicator for Pb exposure across a wide range of taxa. Limited evidence of Pb effects on other blood 

25 parameters including altered serum profiles and changes in white blood cell counts in fish and amphibians 

26 support the finding of the hematological system as a target for Pb in natural systems. This evidence is 

27 strongly coherent with observations from human epidemiologic and animal toxicology studies where a 

28 causal relationship was identified between exposure to Pb and hematological effects in humans and 

29 laboratory animals (Sections 2.5.5 and 5.7). Based on observations in both terrestrial and aquatic 

30 organisms and additionally supported by toxicological and epidemiological findings in laboratory animals 

31 and humans, evidence is sufficient to conclude that there is a causal relationship between Pb exposures 

32 and hematological effects in invertebrates and vertebrates. 
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2.6.8. Developmental and Reproductive Effects

1 Evaluation of the literature on Pb effects in aquatic and terrestrial species indicates that exposure to 

2 Pb is associated with adverse effects on development and reproduction. Evidence in this review and the 

3 previous Pb AQCDs from invertebrate and vertebrate studies indicate that Pb is adversely affecting 

4 reproductive performance in multiple species. In plants, few studies are available that specifically address 

5 reproductive effects of Pb exposure. 

6 Several new studies of snails, clams and rotifers support previous findings of adverse impacts to 

7 embryonic development. In addition to affecting the embryo, Pb can alter developmental timing, sperm 

8 morphology and hormone homeostasis. In fruit flies, Pb exposure increased time to pupation and 

9 decreased pre-adult development. Sperm morphology was altered in earthworms exposed to Pb10 contaminated soils. Pb may also disrupt hormonal homeostasis in invertebrates as studies with moths have 

11 suggested. 

12 Reproductive effects have also been observed in multi-generational studies. Larval settlement rate 

13 and rate of population increase was adversely impacted in rotifers. Rotifers have decreased fertilization 

14 rate associated with Pb exposure that appeared to be due to decreased viability of sperm and eggs. 

15 Evidence of multi-generational toxicity of Pb is also present in terrestrial invertebrates, specifically 

16 springtails, mosquitoes, carabid beetles and nematodes where decreased fecundity in progeny of Pb17 exposed individuals was observed. 

18 In aquatic vertebrates there is evidence for reproductive and developmental effects of Pb. Pb19 exposure in frogs has been demonstrated to delay metamorphosis, decrease larval size and produce subtle 

20 skeletal malformations. Previous Pb AQCDs have reported developmental effects in fish, specifically 

21 spinal deformities in larvae. In the 2006 Pb AQCD, decreased spermatocyte development in rainbow trout 

22 was observed at 10 μg Pb/L and in fathead minnow testicular damage occurred at 500 μg Pb/L. In fish, 

23 there is new evidence in this ISA of Pb effects on steroid profiles. Reproduction in fathead minnows was 

24 affected in breeding exposures following 300-day chronic toxicity testing. However, reproductive 

25 performance was unaffected in zebrafish (Danio rerio) exposed to Pb-contaminated prey. Additional 

26 reproductive parameters in fish observed to be impacted by Pb include decreased oocyte diameter and 

27 density in toadfish associated with elevated Pb levels in gonad.

28 In terrestrial vertebrates, evidence from Chapter 7 and in previous Pb AQCDs indicates an 

29 association between observed adverse reproductive effects and Pb exposure. Decreased testis weight was 

30 observed in lizards. In mammals, few studies in the field have addressed Pb specifically, due to most 

31 available data in wild or grazing animals being from near smelters, where animals are co-exposed to other 

32 metals. Other reproductive endpoints including spontaneous abortions, pre-term birth, embryo 

33 development, placental development, low birth weight, subfecundity, hormonal changes, and teratology 

34 were also affected, but less consistently. New toxicological data support trans-generational effects, a 
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1 finding that is also an area of emerging interest in the ecology. The evidence presented in Section 5.8 is 

2 sufficient to conclude that there is a causal relationship between Pb exposure and reproductive effects in 

3 humans and laboratory animals. The strongest and most consistent evidence, which was coherent across 

4 epidemiologic and toxicological studies, was for effects of Pb on sperm and the onset of puberty in males 

5 and females.

6 Adverse effects of Pb on reproduction in invertebrates and vertebrates indicate that Pb is likely 

7 affecting fecundity of Pb-exposed organisms in both aquatic and terrestrial habitats, and the evidence is 

8 sufficient to conclude that there is a causal relationship between Pb exposures and reproductive 

9 effects in terrestrial and aquatic invertebrates and vertebrates. In plants, the evidence is inadequate 

10 to conclude a causal relationship between Pb exposures and plant reproductive effects.

2.6.9. Neurobehavioral Effects

11 Evidence from laboratory studies and limited data from field studies reviewed in Chapter 7 have 

12 shown adverse effects of Pb on neurological endpoints in both aquatic and terrestrial animal taxa. These 

13 include changes in behaviors that may decrease the overall fitness of the organism. There is also evidence 

14 from both invertebrate and vertebrate studies that Pb adversely affects behaviors that may decrease the 

15 ability of an organism to escape predators or capture prey.

16 Central nervous system effects in fish recognized in previous Pb AQCDs include effects on spinal 

neurons and brain receptors. New evidence from this review identifies the MAPKs ERK1/2 and p38MAPK 17

18 as possible molecular targets for Pb neurotoxicity in catfish (Leal et al., 2006). Additionally, there is new 

19 evidence for neurotoxic action of Pb in invertebrates with exposure to Pb observed to cause changes in 

20 the morphology of GABA motor neurons in nematodes (C. elegans) (Du & Wang, 2009).

21 Decreased food consumption of Pb-contaminated diet has been demonstrated in some invertebrates 

22 (snails) and vertebrates (lizards, pigs). Pb may also decrease the ability of an organism to capture prey or 

23 escape predation. For example, Pb exposure has been demonstrated to adversely affect prey capture 

24 ability of certain fungal and fish species, and the motility of nematodes was adversely affected in Pb25 contaminated soils (Wang & Xing, 2008). In a laboratory study, Pb-exposed gull chicks exhibited 

26 abnormal behaviors such as decreased walking, erratic behavioral thermoregulation and food begging that 

27 could make them more vulnerable in the wild (Burger & Gochfeld, 2005). Lizards exposed to Pb through 

28 diet in the laboratory exhibited abnormal coloration and posturing behaviors. Other behavioral effects 

29 affected by Pb exposure include increased hyperactivity in fish and hypoxia-like behavior in frogs. 

30 These findings are coherent with findings from studies in laboratory animals described in Sections 

31 2.5.1 and 5.3 of the ISA that show that Pb induces changes in attention, increased response rates and 

32 motor function. The evidence presented in those sections is sufficient to conclude that there is a causal 

33 relationship between Pb exposure and neurobehavioral effects (Section 5.3). These data from laboratory 
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1 toxicology studies, especially neurobehavioral findings and structural changes are highly coherent with 

2 data from ecological studies. Overall, the evidence from aquatic and terrestrial systems is sufficient to 

3 conclude that there is a causal relationship between Pb exposures and neurobehavioral effects in 

4 invertebrates and vertebrates.

2.6.10. Community and Ecosystem Level Effects

5 Uptake of Pb into aquatic and terrestrial organisms and subsequent effects on survival, 

6 reproduction, growth, behavior and other physiological variables at the species scale are likely to result in 

7 effects at the population, community and ecosystem scale. The effects may include alteration of predator8 prey dynamics, species richness, species composition, and biodiversity. There are few field studies that 

9 directly consider effects of Pb on these measures of ecosystem health. Ecosystem-level studies are 

10 complicated by the confounding of Pb exposure with other factors such as trace metals and acidic 

11 deposition. In natural systems, Pb is often found co-existing with other stressors, and observed effects 

12 may be due to cumulative toxicity.

13 Most direct evidence of community and ecosystem level effects is from near point sources. For 

14 terrestrial systems evidence of impacts on natural ecosystems near smelters, mines, and other industrial 

15 sources of Pb has been assembled in previous decades. Those impacts include decreases in species 

16 diversity and changes in floral and faunal community composition. For aquatic systems, the literature 

17 focuses on evaluating ecological stress from Pb originating from urban and mining effluents rather than 

18 atmospheric deposition. In laboratory studies and simulated ecosystems, where it is possible to isolate the 

19 effect of Pb, this metal has been shown to alter competitive behavior of species, predator-prey interactions 

20 and contaminant avoidance. These dynamics may change species abundance and community structure at 

21 higher levels of ecological organization. Effects of Pb on mortality, growth, physiological stress, blood, 

22 neurobehavioral and developmental and reproductive endpoints at the individual level are expected to 

23 have ecosystem level consequences, and thus provide consistency and plausibility for causality in 

24 ecosystem level effects.

25 Avoidance response to Pb exposure varies widely in different species and this could affect 

26 community composition. For example, frogs and toads lack avoidance response while snails and fish 

27 avoid higher concentrations of Pb. New evidence, published since the 2006 Pb AQCD indicates that some 

28 species of worms will avoid Pb-contaminated soils (Langdon et al., 2005).

29 In terrestrial ecosystems, most studies show decreases in microorganism abundance, diversity, and 

30 function with increasing soil Pb concentration. Specifically, shifts in nematode communities, bacterial 

31 species, and fungal diversity have been observed. Furthermore, presence of arbuscular mycorrhizal fungi 

32 may protect plants growing in Pb-contaminated soils. Increased plant diversity ameliorated effects of Pb 

33 contamination on a microbial community. 
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1 Since the 2006 Pb AQCD, there is further evidence for effects of Pb in sediment-associated 

2 communities. Exposure to three levels of sediment Pb contamination (322, 1,225, and 1,465 μg Pb/g dry 

3 weight) in a microcosm experiment significantly reduced nematode diversity and resulted in profound 

4 restructuring of the community structure (Mahmoudi et al., 2007). Sediment-bound Pb contamination 

5 appears to differentially affect members of the benthic invertebrate community, potentially altering 

6 ecosystems dynamics in small urban streams (Kominkova & Nabelkova, 2005). Although surface water 

7 Pb concentrations in monitored streams were determined to be very low, concentrations of the metal in 

8 sediment were high enough to pose a risk to the benthic community (e.g., 34-101 mg Pb/kg). These risks 

9 were observed to be linked to benthic invertebrate functional feeding group, with collector-gatherer 

10 species exhibiting larger body burdens of heavy metals than benthic predators and collector-filterers.

11 In a new study conducted since the 2006 Pb AQCD, changes to aquatic plant community 

12 composition have been observed in the presence of elevated surface water Pb concentrations at three lake 

13 sites impacted by mining effluents. The site with highest Pb concentration (103-118 μg Pb/L) had the 

14 lowest number of resident aquatic plant species when compared to sites with lower Pb concentrations (78-

15 92 μg Pb/L) (Mishra et al., 2008). This shift toward more Pb-tolerant species is also observed in terrestrial 

16 plant communities near smelter sites (U.S. EPA, 2006). Certain types of plants such as rooted and 

17 submerged aquatic plants may be more susceptible to aerially-deposited Pb resulting in shifts in Pb 

18 community composition. High Pb sediment concentrations are linked to shifts in amphipod communities 

19 inhabiting plant structures. 

20 In many cases, it is difficult to characterize the nature and magnitude of effects and to quantify 

21 relationships between ambient concentrations of Pb and ecosystem response due to existence of multiple 

22 stressors in natural systems. However, the evidence for Pb effects at higher levels of ecological 

23 organization is sufficient to conclude that there is a causal relationship between Pb exposures and the 

24 alteration of species richness, species composition and biodiversity in terrestrial and aquatic 

25 ecosystems. 

2.6.11. Ecological Effects and Corresponding Pb 

Concentrations

26 There is limited evidence to relate ambient air concentrations of Pb to levels of deposition onto 

27 terrestrial and aquatic ecosystems and subsequent movement of atmospherically-deposited Pb though 

28 environmental compartments (e.g., soil, sediment, water, biota). Current evidence indicates that Pb is 

29 bioaccumulated in biota; however, the sources of Pb in biota have only been identified in a few studies, 

30 and the relative contribution of Pb from all sources is usually not known. There are large differences in 

31 species sensitivity to Pb, and many environmental variables (e.g., pH, organic matter) determine the 

32 bioavailability and toxicity of Pb. However, the proportion of observed effects of Pb attributable to Pb 
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1 from atmospheric sources is difficult to assess due to a lack of information not only on bioavailability, as 

2 affected by the specific characteristics of the receiving ecosystem, but also on deposition, and on kinetics 

3 of Pb distribution in ecosystems in long-term exposure scenarios. 

4 Threshold levels for Pb in terrestrial and aquatic systems may serve as a tool for interpreting the 

5 effects of atmospherically deposited Pb as a component of total Pb loading. For soils, ecological soil 

6 screening levels (Eco-SSLs) have been developed by the EPA for Pb. Eco-SSLs are maximum 

7 contaminant concentrations in soils that are predicted to result in little or no quantifiable effect on 

8 terrestrial receptors. The Pb Eco-SSL values for terrestrial birds, mammals, plants and invertebrates are 

9 11, 56, 120 and 1,700 mg Pb/kg soil (dry weight), respectively. In aquatic systems, national recommended 

10 ambient water quality criteria have been developed by the EPA Office of Water to protect aquatic life and 

11 human health in surface waters. The ambient water quality criteria for Pb are expressed as a criteria 

12 maximum concentration (CMC) for acute toxicity and criteria continuous concentration (CCC) for 

13 chronic toxicity. In freshwater, the CMC is 65 μg Pb/L and the CCC is 2.5 μg Pb/L at a hardness of 100 

14 mg/L. In saltwater, these values are 210 μg Pb/L CMC and 8.1 μg Pb/L CCC, respectively. These U.S. 

15 EPA Office of Water criteria were published pursuant to Section 304(a) of the Clean Water Act, and 

16 provide guidance to states and tribes to use in adopting water quality standards.

2.7. Integration of Health and Ecological Effects 

Overview

17 The health and ecological effects considered for causal determination are summarized in the Table 

18 2-5. The health endpoints include neurological, cardiovascular, renal, immune, hematological and 

19 reproductive effects as well as cancer. The ecological endpoints considered for causal determination are 

20 bioaccumulation, mortality, growth, physiological stress, hematological effects, developmental and 

21 reproductive effects, neurobehavioral effects, and community and ecosystem level effects. The substantial 

22 overlap between the ecological and health endpoints considered in the causal determinations allowed for 

23 the integration of the evidence across these disciplines. 
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Table 2-5. Summary of Causal Determinations for Health and Ecological Effects

Outcome Human Health 

Causal Determination

Ecological Receptors

Causal Determination

Neurological Effectsa Causal Relationship Causal Relationship: Invertebrates and Vertebrates

Cardiovascular Effects Causal Relationship N/A

Renal Effects Causal Relationship N/A

Immune System Effects Causal Relationship N/A

Heme Synthesis and 

RBC Functionb Causal Relationship Causal Relationship: Invertebrates and Vertebrates

Reproductive Effects

and Birth Outcomec Causal Relationship Causal Relationship: Invertebrates and VertebratesInadequate to Infer Causal Relationship: Plants

Cancer Likely to be a causal relationship N/A

Bioaccumulation The causal determination for bioaccumulation 

was developed respective to the impact of 

bioaccumulation on ecosystem services. Thus, 

although Pb bioaccumulates in all organisms 

including humans, causality was not applicable 

to bioaccumulation in humans.

Causal Relationship 

Mortality The strongest evidence of Pb-induced mortality 

in humans was observed for cardiovascular 

disease related mortality.

Causal Relationship: Invertebrates and Vertebrates

Inadequate to Infer Causal Relationship: Plants

Growth N/A Causal Relationship: Plants and Invertebrates

Suggestive of a Causal Relationship: Vertebrates

Physiological Stress In Human Health, oxidative stress was 

considered as a upstream event in the modes 

of action of Pb, leading downstream to various 

effects. Ecological literature commonly uses 

oxidative stress as a proxy indicator of overall 

fitness, and thus treats it as an effect.

Causal Relationship 

Community and 

Ecosystem Level Effects

N/A Causal Relationship

a In ecological receptors, the causal determination was developed considering neurobehavioral effects that can be observed in toxicological studies 

of animal models and studies of ecological effects in vertebrates and invertebrates. The human epidemiologic evidence evaluated included a wider 

range of health endpoints such as cognition. 

b

The health hematological effects considered in the determination of causality were primarily heme synthesis and RBC function. The ecological 

evidence considered for the causal determination included heme synthesis, blood cell count, and altered serum profiles. 

c Reproductive health effects, including effects on sperm, as well as birth outcomes such as spontaneous abortion, were considered in the causal 

determination. In the ecological literature, a wide range of endpoints, including embryonic development, multigenerational studies, delayed 

metamorphosis, and altered steroid profiles, were considered.

2.7.1. Modes of Action Relevant to Downstream Health and 

Ecological Effects

1 The diverse health and ecological effects of Pb are mediated through multiple, interconnected 

2 modes of action. This section summarizes the principle modes of action of human health endpoints 

3 associated with Pb exposure and the concentrations at which those effects are observed. Then, effects of 

4 Pb observed in organisms in aquatic and terrestrial ecosystems (Section 2.6) are evaluated along with 

5 evidence from human and laboratory animals to determine the extent to which common modes of action 
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1 can be inferred from the observed effects. The rationale for this approach is that the mechanism of Pb 

2 toxicity is likely conserved from invertebrates to vertebrates to humans in some organ systems. 

3 Each of the modes of action discussed in Section 5.2 has the potential to contribute to the 

4 development of a number of Pb-induced health effects (Table 2-6). Evidence for the majority of these 

5 modes of action is observed at low blood Pb levels in humans and laboratory animals, between 2 and 5 

6 μg/dL, and at doses as low as the picomolar range in animals and cells. Dose captures Pb exposure 

7 concentrations in in vitro systems or in animal models when no blood Pb level was reported. The 

8 observable effect levels in humans reported in Table 2-6 are limited by the data and methods available and 

9 do not imply that these modes of action are not acting at lower exposure levels or that these doses 

10 represent the threshold of the effect.

Table 2-6. Related human health effects resulting from the MOAs of Pb and the lowest 

level eliciting the MOA

Mode of Action Related Health Effects 

(ISA Section)

Lowest Level at which MOA 

Observed

References

Blood Pba Dosea

Altered Ion Status All Heath Effects of Pb 3.5 μg/dL 50 pM, acute Huel et al. (2008); Kern et al. (2000)

Protein Binding Renal (5.5), Heme Synthesis and RBC 

Function (5.7)

6.4 μg/dL 50 μM, acute Chen et al. (2010); Klann and 

Shelton (1989)

Oxidative Stress All Heath Effects of Pb 5-10 μg/dL 10 μM, acute Quinlan et al. (1988); Ahamed et al. 

(2006); Yiin and Lin (1995)

Inflammation Neurological ( 5.3), Cardiovascular (5.4), 

Renal (5.5), Immune (5.6), Respiratory 

(5.6.4), Hepatic (5.9.1)

3 μg/dL 0.01 μM, acute Kim et al. (2007); Chetty et al. (2005)

Endocrine Disruption Reproductive Effects and Birth Outcomes 

(5.9), Bone and Teeth (5.9.4), Endocrine 

System (5.9.3)

2 μg/dL 20 ppm, acute Krieg (2007); Wiebe and Barr (1988)

Cell 

Death/Genotoxicity

Cancer (5.10), Reproductive Effects and Birth 

Outcomes (5.8), Bone and Teeth (5.9.4)

3.1 μg/dL 50 nM, acute Van et al. (2004); Bonacker et al. 

(2005)

a

Reported as blood Pb level and dose delivered (human, laboratory animal, and in vitro data).

11 Ecological studies have presented evidence for the occurrence of many of these modes of action in 

12 animals, and to some degree in plants, however the connection to ecological outcomes must usually be 

13 inferred because ecological studies are typically not designed to address mode of action directly. The level 

14 at which Pb elicits a specific effect is more difficult to establish in terrestrial and aquatic systems due to 

15 the influence of environmental variables on Pb bioavailability and toxicity and substantial species 

16 differences in Pb susceptibility. 

The alteration of cellular ion status (including disruption of Ca2+ 17 homeostasis, altered ion transport 

18 mechanisms, and perturbed protein function through displacement of metal cofactors) appears to be the 

19 major unifying mode of action underlying all subsequent modes of action in plants, animals, and humans 

20 (Figure 5-1). Pb will interfere with endogenous cation homeostasis, necessary as a cell signal carrier 
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mediating normal cellular functions. Pb is able to displace metal ions, such as Zn, Mg, and Ca2+ 1 , from 

2 proteins due to the flexible coordination numbers and multiple ligand binding ability of Pb, leading to 

3 abnormal conformational changes to proteins and altered protein function. Disruption of ion transport 

leading to increased intracellular Ca2+ 4 levels is due in part to the alteration of the activity of transport 

channels and proteins, such as Na+-K+ ATPase and voltage-sensitive Ca2+ 5 channels. Pb can interfere with 

6 these proteins through direct competition between Pb and the native metals present in the protein metal 

7 binding domain or through disruption of proteins important in calcium-dependent cell signaling, such as 

8 PKC or calmodulin. 

9 This competition between metals has been reported not only in human systems, but also in fish, 

snails, and plants. Altered Ca2+ channel activity and binding of Pb with Na+-K+ 10 ATPase in the gills of fish 

disrupts the Na+ and Cl- homeostasis, which may lead to ionoregulatory failure and death. Ca2+ 11 influx and 

12 ionoregulation has also been shown to be inhibited by Pb exposure in a sensitive species of snail, leading 

13 to a reduction in snail growth. In plants, substitution of the central atom of chlorophyll, Mg, by Pb 

14 prevents light-harvesting, resulting in a breakdown of photosynthesis. Pb-exposed animals also have 

15 decreased cellular energy production due to perturbation of mitochondrial function.

Disruption of ion transport not only leads to altered Ca2+ 16 homeostasis, but can also result in 

17 perturbed neurotransmitter function. Pb-exposure decreases evoked release of neurotransmitters, while 

simultaneously increasing spontaneous release of neurotransmitters through Ca2+ 18 mimicry. Evidence for 

19 these effects in Pb-exposed experimental animals and cell cultures have been linked to altered 

20 neurobehavioral endpoints and other neurotoxicity. Neurobehavioral changes that may decrease the 

21 overall fitness of the organism have also been observed in aquatic and terrestrial invertebrate and 

22 vertebrate studies. There is evidence in tadpoles and fish to suggest Pb may alter neurotransmitter 

23 concentrations, possibly resulting in some of these neurobehavioral changes.

24 Altered cellular ion status following Pb exposure is also responsible for the inhibition of heme 

25 synthesis. Pb exposure is commonly associated with altered hematological responses in aquatic and 

26 terrestrial invertebrates, experimental animals, and human subjects. The proteins affected by Pb are highly 

27 conserved across species accounting for the common response seen in human health and ecological 

28 studies. This evolutionarily conserved response to Pb is likely the result of the competition of Pb with the 

29 necessary metal cofactors in the proteins involved in heme synthesis. 

30 Although Pb will bind to proteins within cells through interactions with side group moieties, thus 

31 potentially disrupting cellular function, protein binding of Pb may represent a mechanism by which cells 

32 protect themselves against the toxic effects of Pb. Intranuclear and intracytosolic inclusion body 

33 formation has been observed in the kidney, liver, lung, and brain following Pb exposure to experimental 

34 animals. A number of unique Pb binding proteins have been detected, constituting the observed inclusion 

35 bodies. The major Pb binding protein in blood is ALAD with carriers of the ALAD-2 allele potentially 

36 exhibiting higher Pb binding affinity. Additionally, metallothionein is an important protein in the 
May 2011 2-45 DRAFT – DO NOT CITE OR QUOTE

1 formation of inclusion bodies and mitigation of the toxic effects of Pb. Protein binding of Pb is a 

2 recognized mechanism of Pb detoxification in some terrestrial and aquatic biota. For example, plants can 

3 sequester Pb through binding with phytochelatin and some fish have the ability to store accumulated Pb in 

4 heat-stable proteins. 

5 A second major mode of action of Pb is the development of oxidative stress, due in many instances 

6 to the antagonism of normal metal ion functions. Disturbances of the normal redox state of tissues can 

7 cause toxic effects and is involved in the majority of health and ecological outcomes observed after Pb 

8 exposure. The origin of oxidative stress produced after Pb exposure is likely a multi-pathway process. 

9 Studies in humans and experimental animals provide evidence to conclude that oxidative stress results 

10 from oxidation of δ-ALA, NAD(P)H oxidase activation, membrane and lipid peroxidation, and 

11 antioxidant enzyme depletion. Evidence of increased lipid peroxidation associated with Pb exposure 

12 exists for many species of plants, invertebrates, and vertebrates. Enhanced lipid peroxidation can also 

result from Pb potentiation of Fe2+ 13 initiated lipid peroxidation and alteration of membrane composition 

after Pb exposure. Increased Pb-induced ROS will also sequester and inactivate biologically active • 14 NO, 

15 leading to the increased production of the toxic product nitrotyrosine, increased compensatory NOS, and 

16 decreased sGC protein. Pb-induced oxidative stress not only results from increased ROS production but 

17 also through the alteration and reduction in activity of the antioxidant defense enzymes. The biological 

18 actions of a number of these enzymes are antagonized due to the displacement of the protein functional 

19 metal ions by Pb. Increased ROS are often followed by a compensatory and protective upregulation in 

20 antioxidant enzymes, such that this observation is indicative of oxidative stress conditions. A number of 

21 studies in plants, invertebrates, and vertebrates present evidence of increased antioxidant enzymes with 

22 Pb exposure. Additionally, continuous ROS production may overwhelm this defensive process leading to 

23 decreased antioxidant activity and further oxidative stress and injury.

24 In a number of organ systems Pb-induced oxidative stress is accompanied by misregulated 

25 inflammation. Pb exposure will modulate inflammatory cell function, production of proinflammatory 

26 cytokines and metabolites, inflammatory chemical messengers, and proinflammatory signaling cascades. 

27 Cytokine production is skewed toward the production of proinflammatory cytokines like TNF-α and IL-6 

28 as well as leading to the promotion of Th2 response and suppression of Th1cytokines and Th1-related 

29 responses.

30 Pb is a potent endocrine disrupting chemical. Steroid receptors and some endocrine signaling 

31 pathways are known to be highly conserved over a broad expanse of animal phylogeny. Pb will disrupt 

32 the HPG axis evidenced in humans, other mammals, and fish, by a decrease in serum hormone levels, 

33 such as FSH, LH, testosterone, and estradiol. Pb interacts with the hypothalamic-pituitary level hormone 

34 control causing a decrease in pituitary hormones, altered growth dynamics, inhibition of LH secretion, 

35 and reduction in StAR protein. Pb has also been shown to alter hormone receptor binding likely due to 

36 interference of metal cations in secondary messenger systems and receptor ligand binding and through 
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1 generation of ROS. Pb disrupts hormonal homeostasis in invertebrates necessary for reproduction and 

2 development. Pb also may disrupt the HPT axis by alteration of a number of thyroid hormones, possibly 

3 due to oxidative stress. These studies have been conducted in humans and animals, including cattle. 

4 However the results of these studies are mixed and require further investigation.

5 Genotoxicity and cell death has been investigated after Pb exposure in humans, animals, plants, and 

6 cell models. High level Pb exposure to humans leads to increased DNA damage, however lower blood Pb 

7 levels have caused these effects in experimental animals and cells. Reports vary on the effect of Pb on 

8 DNA repair activity, however a number of studies report decreased repair processes following Pb 

9 exposure. There is some evidence in plants, earthworms, freshwater mussels and fish for DNA damage 

10 associated with Pb exposure. There is evidence of mutagenesis and clastogenicity in highly exposed 

11 humans, however weak evidence has been shown in animals and cells based systems. Human 

12 occupational studies provide limited evidence for micronucleus formation (>10 μg/dL), supported by Pb13 induced effects in both animal and cell studies. Micronucleus formation has also been reported in 

14 amphibians. Animal and plant studies have also provided evidence for Pb-induced chromosomal 

15 aberrations. The observed increases in clatogenicity may be the result of increased oxidative damage to 

16 DNA due to Pb exposure, as co-exposures with antioxidants ameliorate the observed toxicities. Limited 

17 evidence of epigenetic effects is available, including DNA methylation, mitogenesis, and gene expression. 

18 Altered gene expression may come about through Pb displacing Zn from multiple transcriptional factors, 

19 and thus perturbing their normal cellular activities. Consistently positive results have provided evidence 

20 of increased apoptosis following Pb exposure. 

21 Overall, Pb-induced health and ecological effects can occur through a number of interconnected 

22 and evolutionarily well conserved modes of action that generally originate with the alteration of ion 

23 status.

2.8. Policy Relevant Considerations and Human 

Health

2.8.1. Air-to-Blood Relationships

24 The 1986 Pb AQCD described epidemiological studies of relationships between air Pb and blood 

25 Pb. Much of the pertinent earlier literature described in the 1986 Pb AQCD was drawn from a meta26 analysis by Brunekreef (1984). In addition to the meta-analysis of Brunekreef (1984), seven more recent 

27 studies have provided data from which estimates of the blood Pb-air Pb slope can be derived for children 

(Table 2-7). The range of estimates from these seven studies is 1-9 μg/dL per μg/m3 28 , which encompasses 

the estimate from the Brunekreef (1984) meta-analysis of (3-6 μg/dL per μg/m3 29 ). The Schnaas (2004) had 
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1 a particularly strong experimental design in that is the only longitudinal study in which blood Pb 

2 concentration was monitored repeatedly in individual children from age 6 months to 10 years. For 

children who experienced the largest declines in air Pb (i.e., from 2.8 to <0.1 μg/m3 3 ), the predicted blood 

4 Pb-air Pb slope (adjusted for age, year of birth, SES, and use of glazed pottery) was 0.213 ln[μg/dL 

blood] per ln[μg/m3 5 air]. The cross-sectional study done by Ranft (2008) attempted to account for 

6 potential covariates that influence blood Pb (e.g., soil Pb concentration, gender, environmental tobacco 

7 smoke, fossil heating system and parental education). It is the only study that reported a logarithmic blood 

8 Pb-linear air Pb relationship, which results in an upward curvature of the blood Pb-air Pb relationship 

9 (i.e., the blood Pb-air Pb slope increases with increasing air Pb concentration). In other studies (or based 

10 on other studies), the blood Pb-air Pb relationship was either log-log (Brunekreef, 1984; Hayes et al., 

11 1994; Schnaas et al., 2004), which predicts an increase in the blood Pb-air Pb slope with decreasing air Pb 

12 concentration or linear (Hilts, 2003; Schwartz & Pitcher, 1989; Tripathi et al., 2001), which predicts a 

13 constant blood Pb-air Pb slope across all air Pb concentrations. These differences may simply reflect 

14 model selection by the investigators; alternative models are not reported in these studies. Because air Pb 

15 contributes to Pb in soil and indoor dusts, adjustment for the correlated covariates such as soil Pb would 

16 introduce a downward bias in the slope estimate.
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Table 2-7. Summary of Estimated Slopes for Blood Pb to Air Pb Relationships in 

Children

Reference Study Methods Model Description Blood Pb – Air Pb Slope 

(μg/dL per μg/m3)

Brunekreef et al. (1984) Location: Various countries

Years: 1974-1983

Subjects: Children (varying age 

ranges)

Analysis: Meta analysis of 18 studies

Model: Log-Log

Blood Pb: 5-41 μg/dL (mean range for 

studies)

Air Pb: 0.2-10 μg/m3 (mean range for 

studies)

All children: 18a, 6.1b

Children <20 μg/dL: 13a, 3.0b

Hayes et al. (1994) Location: Chicago, IL

Years: 1974-1988

Subjects: 0.5-6 yr (9,604 blood Pb 

measurements)

Analysis: Regression of blood Pb 

screening and quarterly average air Pb 

Model: Log-Log

Blood Pb: 12-30 μg/dL (annual GM range)

Air Pb: 0.5-1.2 μg/m3 (annual GM range)

24a, 5.7b

Hilts et al. (2003) Location: Trail, BC

Years: 1989-2001

Subjects: 0.5-6 yr (292-536 blood Pb 

measurements/yr)

Analysis: Regression of blood Pb 

screening and community air Pb 

following upgrading of a local smelter

Model: Linear

Blood Pb: 4.7-11.5 μg/dL (annual median 

range)

Air Pb: 0.03-1.1 μg/m3 (annual median 

range)

6.5

Ranft et al. (2008) Location: Germany

Years: 1983-2000

Subjects: 6-11 yr (n = 843) 

Analysis: Pooled regression 5 cross- sectional studies

Model: Log-Linear

Blood Pb: 2.2-13.6 μg/dL (5th-95th 

percentile)

Air Pb: 0.03-0.47 μg/m3 (5th-95th 

percentile)

3.2c

Schnaas et al. (2004)

Location: Mexico City

Years: 1987-2002

Subjects: 0.5-10 yr (n = 321)

Analysis: Regression of longitudinal 

blood Pb measurements and annual 

average air Pb data

Model: Log-Log

Blood Pb: 5-12 μg/dL (annual GM range)

Air Pb: 0.7-2.8 μg/m3 (annual mean range)

4.8a, 1.1b

Schwartz and Pitcher 

(1989), U.S. EPA (1986)

Location: U.S.

Years: 1976-1980

Subjects: 0.5-7 yr (n = 7,000)

Analysis: NHANES blood Pb, gasoline 

consumption data and Pb 

concentrations in gasoline

Model: Linear

Blood Pb: 11-18 μg/dL (mean range)

Air Pb: 0.36-1.22 μg/m3 (annual maximum 

quarterly mean) 

9.3

Schwartz and Pitcher 

(1989), U.S. EPA (1986)

Location: Chicago, IL

Years: 1976-1980

Subjects: 0-5 yr (n = 7,000)

Analysis: Chicago blood Pb screening, 

gasoline consumption data, and Pb 

concentrations in gasoline

Model: Linear

Blood Pb: 18-27 μg/dL (mean range)

Air Pb: 0.36-1.22 μg/m3 (annual maximum 

quarterly mean)

7.7

Tripathi et al. (2001) Location: Mumbai, India

Years: 1984-1996

Subjects: 6-10 yr (n = 544)

Analysis: Regression of blood Pb and 

air Pb data

Model: Linear

Blood Pb: 8.6-14.4 μg/dL (regional GM 

range)

Air Pb: 0.11-1.18 μg/m3 (regional GM 

range)

3.6

a

At an air concentration of 0.15 μg/m3

b

At an air concentration of 1 μg/m3

c For a change in air Pb concentration from 0.025 to 0.465 μg/m3

GM, geometric mean

2.8.2. Concentration-Response Functions

1 With each successive assessment to-date, the epidemiologic and toxicological study findings show 

2 that progressively lower blood Pb levels are associated with cognitive deficits and behavioral impairments 
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1 as well as other outcomes (U.S. EPA, 2006) (Tables 2-2 and 2-3). Furthermore, in the 2006 Pb AQCD, 

2 compelling evidence for a steeper slope for the relationship between blood Pb level and children’s IQ at 

3 lower blood Pb levels was presented based on the international pooled analysis of seven prospective 

4 cohort studies by Lanphear et al. (2005), a subsequent reanalysis of these data focusing on the shape of 

5 the concentration response function (Rothenberg & Rothenberg, 2005), and several individual studies. 

6 This body of with the addition of more recent studies is presented Figure 2-2. The majority of the 

7 epidemiologic evidence from stratified analyses comparing the lower and the higher ends of the blood Pb 

8 distributions indicates larger slopes at lower blood Pb levels. Relatively few studies examined the 

9 concentration-response relationship between Pb in blood or bone and neurocognitive effects in adults. Of 

10 the studies that did examine this relationship, findings were mixed with some studies reporting a linear 

11 relationship with cognition and others reporting non-linear relationships.

Reference Exposure Period Outcome Blood Pb strata

Lanphear et al. (2000) Concurrent Reading score All

<10

<7.5

<5

<2.5

Bellinger and Needleman (2003) Early childhood FSIQ >10

<10

Canfield et al. (2003) Lifetime avg FSIQ All

<10

Tellez-Rojo et al. (2006) Concurrent Bayley MDI ≥10

<10

5-10

<5

Hu et al. (2006) Prenatal Bayley MDI/10 >1.226a

<1.226a

Kordas et al. (2006) Concurrent Math score All

<10

Lanphear et al. (2005) Concurrent FSIQ ≥10

<10

≥7.5

<7.5

Schwartz (1994) Early childhood FSIQ >15

≤15

Change in Cognitive Score (95% CI)

Note: a = Pb levels measured in plasma of maternal blood during 1st trimester of pregnancy. FSIQ = full-scale IQ, MDI = mental development index. Effect estimates are 

standardized to a 1 μg/dL increase in blood Pb level. Black symbols represent effect estimates among all subjects or in highest blood Pb stratum. Red symbols represent effect 

estimates in lower blood Pb strata. Effect estimates without error bars are from studies that did not provide sufficient information in order to calculate 95% CIs.

Figure 2-2. Comparison of associations between blood Pb and cognitive 

function among various blood Pb strata. 

12 Concentration-response relationships were examined in several epidemiologic studies of blood 

13 pressure and mortality. In a study of Korean workers, the Pb-induced increase in systolic blood pressure 

14 was better described by a log linear function of blood Pb level than by a linear function (Weaver, 2010). 
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1 Animal toxicological studies provide support for this concentration response relationship. Few studies 

2 that focused on Pb-induced hypertension in experimental animals have included more than two exposure 

3 concentrations; however these few studies appear to have a supralinear (concave downward) dose 

4 response and do not conflict with the epidemiologic findings.

5 Studies investigating both all-cause and cardiovascular mortality report both linear and non-linear 

6 relationships. Findings from NHANES analyses were mixed with Schober et al. (2006), reporting a linear 

7 association between the relative hazard for all cause mortality with blood Pb, and Menke et al. (2006),

8 reporting a non-linear relationships between blood Pb level and the hazard ratio for all cause, MI, stroke, 

9 and cancer mortality. This latter analysis provided evidence for an association between blood Pb and 

10 cardiovascular mortality in the NHANES population, where the mean blood Pb level was 2.58 μg/dL, and 

11 the hazard ratio of Pb with cardiovascular mortality reached its maximum at blood Pb levels between of 6 

12 and 7 μg/dL. Non-linear relationships between patella bone Pb and log HR for all-cause, cardiovascular, 

13 and IHD mortality were reported by Weisskopf et al. (2009). 

14 Concentration response information was provided in a small number of studies of Pb-related 

15 nephrotoxicity in the occupational setting (Ehrlich et al., 1998; Weaver et al., 2003). Data in 267 Korean 

16 Pb workers in the oldest age tertile (mean age = 52 years) revealed no threshold for a Pb effect (beta = 

17 0.0011, p = <0.05; regression and lowess lines shown), however the mean blood Pb level in this 

18 population was 32 μg/dL (Weaver et al., 2003).

19 Non-linear concentration/exposure response relationships or attenuation of these relationships at 

20 higher exposure levels is reported in the occupational literature for a variety of exposures. Explanations 

21 for this phenomenon include greater exposure measurement error, competing risks, and saturation of 

22 biological mechanisms at higher exposure levels, and exposure-dependent variation in other risk factors 

23 (Stayner et al., 2003). Non-linear concentration response functions are reported in the air pollution 

24 literature (Smith & Peel, 2010). With respect to Pb exposure, different biological mechanisms may 

25 operate at different exposure levels and/or there may be a lower incremental effect of Pb due to covarying 

26 risk factors such as low SES, poorer caregiving environment, and other higher environmental exposures. 

27 In addition, the 2006 Pb AQCD considered the explanation for the supralinear concentration response 

28 function postulated by Bowers and Beck (2006), who stated that “a supralinear slope is a required 

29 outcome of correlations between a data distribution where one is log-normally distributed and the other is 

30 normally distributed.” The 2006 Pb AQCD determined that, while the conclusions drawn by Bowers and 

31 Beck may be true under certain conditions, their assumptions (e.g., that IQ are scores forced into a normal 

32 distribution) were not generally the case in the epidemiologic analyses showing a supralinear 

33 concentration response function. To support this conclusion, the 2006 Pb AQCD cited Hornung et al. 

34 (2006), which provided evidence that the IQ data used in the pooled analysis of seven studies by 

35 Lanphear et al. (2005) were not normalized and a log-linear model (a linear relationship between IQ and 

36 the log of blood Pb) provided the best fit. 
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1 The current body of evidence on the effects of Pb allows critical evaluation of several of the 

2 aforementioned explanations for the supralinear curve concentration response function in epidemiological 

3 studies. For example, in several populations, higher blood Pb levels have been measured in susceptible 

4 groups such as those with higher poverty, greater exposure to tobacco smoke, lower parental education, 

5 and lower birth weight (Lanphear et al., 2000; Lanphear et al., 2005). It has been suggested that in 

6 populations of low SES, poorer caregiving environment, and greater social stress, the incremental effect 

7 of Pb exposure may be attenuated due to the overwhelming effects of these other risk factors (Schwartz, 

8 1994). Several studies have found significant associations of these sociodemographic risk factors with 

9 neurocognitive deficits, and Miranda et al. (2009) found that indicators of SES (i.e., parental education 

10 and enrollment in a free/reduced fee lunch program) accounted for larger decrements in EOG scores than 

11 did blood Pb level (Figure 5-10). Few studies have compared Pb effect estimates among groups in 

12 different sociodemographic strata, and the limited data are mixed. Some have found greater Pb-associated 

13 neurocognitive deficits in low-SES groups (Bellinger et al., 1990; Schwartz, 1994). In a meta-analysis of 

14 eight studies, Schwartz (1994) found a smaller decrement in IQ per 1 μg/dL increase in blood Pb level for 

15 studies in disadvantaged populations (-2.7 points [95% CI: -5.3, -0.07]) than for studies in 

16 nondisadvantaged populations (-4.5 points [95% CI: -5.6, -2.8]). It is important to note that blood Pb is 

17 associated with deficits in neurocognitive function in both higher and lower SES groups; however, it is 

18 unclear what differences there are between groups in the decrement per unit increase in blood Pb and 

19 whether these differences can explain the nonlinear dose-response relationship.

20 Although, the 2006 Pb AQCD did not identify a biological mechanism for a steeper slope at lower 

21 than at higher blood Pb levels such a mechanism was not ruled out. In fact, several lines of evidence 

22 support the possibility of low-dose and high dose-Pb acting through different mechanisms. For example, 

23 in mice, lower-dose Pb is associated with differential responses of the neurotransmitters dopamine and 

24 norepinephrine compared with control treatment and higher doses (Leasure et al., 2008; Virgolini et al., 

25 2005). These differential responses of neurotransmitter systems to low-dose Pb versus a higher-dose Pb 

26 may provide mechanistic understanding of the nonlinearity of Pb-induced behavioral changes in animals 

27 and may also explain the nonlinear blood Pb-neurocognitive and neurobehavioral associations reported 

28 widely among children. Additional evidence points to differences in hormonal homeostasis by Pb 

29 exposure level. In male mice with chronic Pb exposure (PND21 to 9 months of age), basal corticosterone 

30 levels are significantly lower in the 50 ppm exposure group versus control or 150 ppm Pb.

31 Additional mechanistic understanding comes from differences in histological changes found in Pb32 exposed animals. Compared with high-dose Pb, low-dose Pb stimulates greater induction of c-fos, a 

33 marker of neuronal activation and action potential firing (Lewis & Pitts, 2004). These findings may 

34 underlie the nonlinear association between Pb exposure and learning and the U-shaped behavioral dose35 responsiveness seen with amphetamine-induced motor activity in males after GLE (Leasure et al., 2008).
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1 Sensory organ findings also show vastly different outcomes with low versus higher doses of Pb. 

2 High-dose Pb produces subnormal retinal ERGs and low-dose Pb produces supernormal ERGs in both 

3 children (Rothenberg et al., 2002) and rodents (Fox & Chu, 1988; Fox & Farber, 1988; Fox et al., 1991). 

4 Inverted U-shaped dose-response curves have been seen for rod photoreceptor numbers or neurogenesis 

5 (Giddabasappa et al., 2011), retinal thickness (Fox et al., 2010), and rod cell proliferation (Giddabasappa 

6 et al., 2011). Thus, these dichotomous histological findings are coherent with the functional retinal test or 

7 the ERG where high-dose Pb produces subnormal ERGs and low-dose Pb produces supernormal ERGs.

8 Hierarchical enzyme activity also may explain nonlinear Pb dose-response relationships. The 

9 phosphatase enzyme calcineurin has been shown to be inhibited by high dose Pb exposure and stimulated 

10 by low dose Pb exposure (Kern & Audesirk, 2000). At low doses of Pb, Pb displaces calcium at its 

11 binding sites on calmodulin and by acting as a calmodulin agonist at calcineurin’s catalytic A subunit, 

12 stimulates calcineurin activity. At high Pb doses, Pb can bind directly to a separate calcium-binding B 

13 subunit, overriding the calmodulin-dependent effect and turning off the activity of calcineurin. 

14 Interestingly, mice with modulated calcineurin expression exhibit aberrant behavior related to 

15 schizophrenia (Miyakawa et al., 2003) or impaired synaptic plasticity and memory (Zeng et al., 2001). 

16 This example of the stimulatory effects of Pb at low doses and inhibitory effects of Pb at high doses gives 

17 another example of biological plausibility for the non-monotonic dose response of Pb reported in multiple 

18 studies.

2.8.3. Timing and Duration of Exposure

19 Epidemiologic studies reviewed in the 2006 Pb AQCD observed neurocognitive deficits in 

20 association with prenatal, peak childhood, cumulative childhood, and concurrent blood Pb levels. Among 

21 longitudinal studies that examined blood Pb level at multiple time points, several found that concurrent 

22 blood Pb was associated with the largest decrement in IQ. A common limitation of epidemiologic studies 

23 was the high correlation among Pb exposure metrics at different ages, making it difficult to distinguish 

24 among effects of Pb exposure at different ages and to ascertain which developmental time periods of Pb 

25 exposure were associated with the greatest risk of neurodevelopmental morbidity. Although prospective 

26 cohort studies have provided valuable information on the effects of Pb exposure at different periods of 

27 development, including the prenatal period and early childhood, the limitations noted in the previous 2006 

28 Pb AQCD remain. Collectively, the epidemiologic evidence has not identified one unique time window of 

29 exposure that poses the greatest risk to cognitive function in children (Figure 2-3). However, toxicological 

30 studies included in the 2006 Pb AQCD demonstrated that developmental exposure to Pb was the most 

31 sensitive window for Pb-dependent neurotoxicity and recent toxicological studies continue to support this 

32 finding. 
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Reference Outcome Blood Pb Variable Examined

Tong et al. (1998) FSIQ, 11-13 yr. < 10.2 decline age 2 to 11-13

10.2-16.2 decline age 2 to 11-13

> 16.2 decline, age 2 to 11-13

Bellinger et al. (1990) GCI, 24 and 57 mo Concurrent, Prenatal < 3a

Concurrent, Prenatal 3-10a

Concurrent, Prenatal ≥ 10a

Chen et al. (2005) FSIQ, 7 yr. Low 2 yr, (<24.9), Low 7 yr, (<7.2)

Low 2 yr, (<24.9), High 7 yr, (≥ 7.2)

High 2 yr, (≥ 24.9), Low 7 yr, (<7.2)

High 2 yr, (≥ 24.9), High 7 yr, (≥ 7.2)

Hornung et al. (2009) FSIQ, 6 yr. 0.5 ratio age 6 to 2 yr b

2.0 ratio age 6 to 2 yr b

Change in Cognitive Score (95% CI)

Note: aEffect estimates represent associations between concurrent blood Pb level and cognitive 

function (standardized to standard deviation) in children categorized by prenatal blood Pb level. 

b

Values represent the ratio of blood Pb level at age 6 years to that at age 2 years. FSIQ = Fullscale IQ, GCI = General Cognitive Index. Cognitive function scores were standardized to their 

standard deviation. Effect estimates in red represent blood Pb level variables associated with the 

greater decrease in cognitive function.

Figure 2-3. Associations of cognitive function in children with different 

degrees of changes in blood Pb levels over time.

1 The 2006 Pb AQCD noted the importance of the duration of exposure in animal studies of a wide 

2 array of effects including neurological, cardiovascular, renal, immune and reproductive effects of Pb. 

3 Generally, epidemiologic studies of the effect of Pb exposure on human health have not been designed to 

4 assess duration of exposure needed to induce those effects. Some exceptions are cohort studies with 

5 repeated blood Pb measurements and cognitive assessments within short intervals of time during 

6 pregnancy and in the first year of life (every 3 months). Studies have reported associations between 

7 prenatal blood Pb levels and decrements in mental development (Bayley MDI) in children assessed 

8 between 3 and 6 months (Bellinger et al., 1984; Dietrich et al., 1986; Dietrich et al., 1987; Shen et al., 

9 1998). In particular, Rothenberg et al. (1989) observed that maternal blood Pb levels from week 36 of 

10 pregnancy to delivery was associated with less ability of infants to self-quiet in the first 30 days of life. 

11 Additionally, in the Cincinnati cohort, blood Pb levels measured at neonatal day 10 also were associated 
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1 with MDI decrements at age 3 and 6 months (Dietrich et al., 1986; Dietrich et al., 1987). Consistent with 

2 the neurotoxicology literature, findings from these studies indicate that short-duration Pb exposure during 

3 critical periods of in utero or neonatal development are associated with cognitive impairments in young 

4 infants.

2.8.3.1. Persistence of Effects

5 The issue of persistence of the neurodevelopmental effects of low-level Pb exposure was also 

6 considered in the 2006 Pb AQCD, with some evidence suggesting that the effects of Pb on 

7 neurodevelopmental outcomes persisted into adolescence and young adulthood. However, in these 

8 studies, blood Pb levels remained relatively stable over time. Thus, the effect of concurrent exposures was 

9 not ruled out. In addition, the persistence of effect appears to depend on the duration of exposure as well 

10 as other factors that may affect an individual’s ability to recover from an insult. Toxicological studies 

11 from the 2006 Pb AQCD highlighted the importance of Pb exposure in early life in promoting 

12 Alzheimer’s like pathologies in the adult brain, demonstrating Pb-induced neurodegeneration and 

13 formation of neurofibrillary tangles. Recent toxicological studies continue to point to an early life window 

14 in which Pb exposure can contribute to pathological brain changes consistent with Alzheimer’s disease. 

15 Blood Pb generally is not associated with Alzheimer’s disease in epidemiological studies of adults. 

16 However, recent evidence indicates associations between early life ALAD activity, a biomarker of Pb 

17 exposure, and schizophrenia later in adulthood. Consistent with these findings, toxicological studies have 

18 observed Pb-induced emotional changes in males and depression changes in females.

2.8.4. Susceptible Populations and Lifestages

19 Potential susceptibility factors examined in Chapter 6 of this document include lifestage, sex, 

20 genes, pre-existing diseases/conditions, race and ethnicity, SES, BMI, nutrition, stress, cognitive reserve 

21 (e.g., the resilience of the mind), and co-exposure to other metals/toxicants. Studies are included in 

22 Chapter 6 if the findings for the susceptible population or lifestage were compared across strata with and 

23 without the potential susceptibility factor. By virtue of their design some cohort studies, including cohort 

24 studies of pregnant women or other populations or lifestages with no comparison group, are discussed in 

25 the endpoint-specific sections rather than in Chapter 6. This integrative summary, however, draws on 

26 evidence relating to potentially susceptible populations and lifestages appearing throughout this 

27 document. Also in Chapter 6, separate discussions of studies that evaluate factors that influence Pb 

28 exposure and uptake, and studies that examine the modification of the association of Pb with health 

29 endpoints by a possible susceptibility factor are presented. In this integrative summary both types of 

30 studies are considered together. 
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2.8.4.1. Children

1 Children may be more highly exposed to Pb compared to adults without occupational exposure to 

2 Pb, through their behaviors (e.g., hand-to-mouth contact). Blood Pb levels are highest among the 

3 youngest children and decrease with increasing age of the child (Table 6-1). Biokinetic factors that vary 

4 by age, including bone turnover and absorption, also affect blood Pb levels. Childhood, as a susceptibility 

5 factor related to Pb exposure and dose, is discussed in more detail in sectin 6.1.1.1. The kinetics of Pb, 

6 and how absorption, distribution, and elimination may vary depending on lifestage, is discussed in 

7 Section 4.2. 

8 It is recognized that Pb can cross the placenta to affect the developing nervous system of the fetus 

9 (Sections 4.2.2.4, 5.3.2.1) and there is evidence of increased susceptibility to the neurocognitive effects of 

10 Pb exposure during several lifestages throughout childhood and into adolescence (for more detail, see 

11 Section 5.3.2.1). Further, Pb exposure is associated with effects on the renal (Section 5.5.2.3), immune 

12 (Section 5.6) and heme synthesis and RBC function (Section 5.7) of children. A limited number of studies 

13 of immune parameters, transferring saturation, and iron-deficiency anemia that stratified children by age 

14 report stronger associations among the youngest children. Childhood, as a susceptibility factor related to 

15 Pb-induced health effects, is discussed in more detail in Section 6.2.1.1.

2.8.4.2. Adults

16 There is evidence that both recent and/or cumulative exposure to Pb may result in health outcomes 

17 during adulthood, as indicated by consistent associations of blood Pb or bone Pb with cardiovascular 

18 diseases and mortality, renal, immune, hematological, and reproductive effects. Blood Pb and bone Pb 

19 levels tend to be higher in older adults (>65 years) compared with the general population. Mobilization 

20 (Section 4.2.2.2) of Pb from the bone stores may occur during periods of physiological stress, including 

21 older adulthood (Section 6.1.1.2). In recent studies, age was specifically examined as an effect modifier of 

22 the association of Pb with mortality, cognition and blood pressure in adults; findings for mortality were 

23 mixed while little evidence of modification by age was reported for the other specific outcomes. 

24 Toxicological studies support the plausibility of differences in susceptibility to health effects depending 

25 on lifestage.

2.8.4.3. Sex 

26 In a recent NHANES analysis and several other studies, gender-based differences in blood Pb level 

27 were observed among the adolescent and adult age groups, with higher blood Pb levels among males. The 

28 gender-based differences were not substantial among the youngest age groups (1-5 years old and 6-11 

29 years old). Studies of effect measure modification of the association of Pb and various health endpoints 

30 including neurological effects such as cognition, kidney function blood pressure immune effects and 
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1 cancer by sex were conducted. Overall, findings were mixed with the most consistent evidence reported 

2 for neurological endpoints. Recent epidemiologic evidence increased the consistency of collective 

3 evidence base and pointed to males having increased susceptibility for Pb-associated neurotoxicity. 

4 Toxicological studies continue to demonstrate increased susceptibility of males for endpoints such as 

5 sensory function, balance, stress hormone homeostasis, and brain membrane composition. Sex differences 

6 were also observed in toxicological studies across a wide array of endpoints including of behavior, 

7 memory, gross motor skills, obesity, and retinal decrements. See Section 6.1.2 and 6.2.2 for more details.

8 Hormone levels may affect susceptibility to Pb-related health effects and associations among 

9 females may vary based on hormonal status, such as menopause or ovary removal. Toxicological and 

10 epidemiologic evidence supports the potential susceptibility to Pb effects based on hormonal status with 

11 findings on delayed onset of puberty and changes to the female reproductive tract.

2.8.4.4. Race and Ethnicity 

12 Higher blood Pb and bone Pb levels among African Americans have been documented and recent 

13 studies continue support previous findings. Further, larger proportions of both non-Hispanic blacks and 

14 Mexican American children have blood Pb levels exceeding 5 μg/dL of blood. The 2006 Pb AQCD noted 

15 that a clear downward temporal trend was apparent in NHANES data during the previous two decades but 

16 that blood Pb level was declining at different rates for groups within the population, which were defined 

17 by race, as well as income and demographic factors include age of housing. Recent data suggest that the 

18 gap in Pb exposure between African American and White subjects is decreasing, but African Americans 

19 still tend to have higher blood Pb levels. Evidence of increased association of Pb with cardiovascular 

20 outcomes among non Hispanic blacks and Mexican Americans was reported for the NHANES population. 

21 Results of other recent epidemiological studies suggest that there may be race related susceptibility for 

22 additional outcomes but the evidence is limited and confounding or modification by other factors, such as 

23 SES, may be present. See Sections 6.1.3 and 6.2.7 for additional details.

2.8.4.5. Socioeconomic Status

24 The 2006 Pb AQCD noted that the geometric mean blood Pb concentration varied with SES and 

25 other demographic characteristics that have been linked to Pb exposure. The gap between SES groups 

26 with respect to Pb level appears to be diminishing, with Pb level being higher but not significantly higher 

27 among lower income subjects. Lower SES individuals appear to represent a susceptible population. For 

28 example, a study of Pb and IQ reported greater inverse associations among those in the lowest SES 

29 groups. There is also evidence that some cognitive effects of prenatal Pb exposure may be transient and 

30 that recovery is greater among children reared in households with more optimal caregiving characteristics 

31 and in children whose concurrent blood Pb levels were low (Bellinger et al., 1990). In contrast, there is 
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1 some evidence that Pb-associated neurocognitive effects may be larger in magnitude among higher SES 

2 populations. In a meta-analysis, Schwartz (1994) found that in studies in higher SES populations, blood 

3 Pb was associated with a greater decrement in IQ than in low SES populations. See Sections 6.1.4 and 

4 6.2.8 for additional details.

2.8.4.6. Genes

5 Several genes were examined as potential modifiers the associations between Pb and health effects. 

6 Epidemiologic and toxicological studies reported ALAD and VDR variants may be health-related 

7 susceptibility factors. Although limited, evidence suggests that risk of Pb-associated neurocognitive 

8 deficits in children also may be modified by variants in genes for APOE, MTHFR, and dopamine 

9 receptors. Other genes examined that may also affect susceptibility to Pb-related health effects were 

10 DRD4, GSTM1, TNF-alpha, eNOS, and HFE. See Section 6.2.4 for additional details.

2.8.4.7. Pre-existing Conditions

11 Pre-existing diseases/conditions also have the potential to affect the association of Pb exposure 

12 with health endpoints have been studied in relation to autism, diabetes, and hypertension. Recent 

13 epidemiologic studies did not support modification of Pb and health endpoints by diabetes; however, past 

14 studies have found diabetics to be a more susceptible population with regard to effects on renal function. 

15 Recent epidemiological studies support finding from the 2006 Pb AQCD that hypertension is observed to 

16 be a susceptibility factor i with both renal effects and heart rate variability demonstrating stronger 

17 associations among hypertensive individuals compared to those that are normotensive. Although the 

18 evidence is limited, current research has shown that in autistic children, blood Pb level is differentially 

19 correlated with expression of immune-related genes. See Section 6.2.5 for additional details.

2.8.4.8. Nutrition and Lifestyle Factors

20 Body mass index (BMI), alcohol consumption, and nutritional factors were examined in recent 

21 epidemiologic and toxicological studies. Modification of associations between Pb and various health 

22 effects (mortality and heart rate variability) was not observed by BMI or obesity. Also, no modification 

23 was observed in an epidemiologic study of renal function examining alcohol consumption as a modifier, 

24 but a toxicological study supported the possibility of alcohol as a susceptibility factor. Among nutritional 

25 factors, those with iron deficiencies were observed to be a susceptible population for Pb-related health 

26 effects in both epidemiologic and toxicological studies. Other nutritional factors, such as calcium, zinc, 

27 and protein, demonstrated the potential to modify associations between Pb and health effects in 

28 toxicological studies. Recent epidemiologic studies of these factors were either not performed or observed 

29 no modification. Folate was also examined in a recent epidemiologic study of birth size but no interaction 
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1 was reported between Pb and folate. Further study of these and other nutritional factors will be useful in 

2 determining susceptibility among individuals with various nutritional levels/deficiencies. See Sections 

3 4.2, 6.2.9, 6.2.10, and 6.2.11 for additional details.

2.8.4.9. Stress and Cognitive Reserve

4 Animal toxicology findings described in the 2006 Pb AQCD demonstrated interactions between Pb 

5 exposure and stress. Namely, Pb-exposed animals reared in cages with enriched environments (toys) 

6 perform better in the Morris water maze than their Pb-exposed littermates who were reared in isolation. 

7 New findings indicate a potentiating effect of stress on behavior and memory at low-dose Pb exposures. 

8 In comparison, epidemiologic evidence for such interactions has been sparse. However, consistent with 

9 historical animal studies, a recent epidemiological study indicated that positive social environment of 

10 children as characterized by maternal self-esteem, may lessen the impact of Pb exposure on 

11 neurodevelopment. Self-perceived stress was shown to modify the association of bone Pb with 

12 hypertension. In addition, a greater association of Pb with cognitive function was found in workers with 

13 lower cognitive reserve (Sections 6.2.12 and 6.2.13).

2.8.4.10. Co-exposure of Lead with Metals or Other Chemicals 

14 The 2006 Pb AQCD reported that the majority of studies examined other chemicals as confounders 

15 and not effect measure modifiers (U.S. EPA, 2006). Although the body of evidence remains limited, 

16 recent epidemiologic studies have begun to explore the possible interaction between Pb and other metals 

17 or chemical agents. These studies report some stronger associations between Pb and various health 

18 endpoints with co-exposure to Cd, As, Mn, fluoride, tobacco smoke and urban pollutants.

19 Epidemiologic and toxicological studies have reported increased susceptibility to Pb-related health 

20 effects among those with high Cd levels. Modification of associations of Pb with levels of reproductive 

21 hormones and renal dysfunction were reported in epidemiologic studies. Toxicological evidence of a

22 synergism between Pb and Cd with regard to renal toxicity supported the epidemiological evidence. In 

23 addition, exposure to Pb and As was associated with effects on immune function in children living near a 

24 smelter and a statistical interaction between the metals was observed. Studies suggest that co-exposure to 

25 As may increase the bioavailability of Pb establishing the plausibility of increased susceptibility of Pb26 related health effects when co-exposed to As. An interaction was also reported between Pb and Mn (Y. 

27 Kim et al., 2009) in a study of IQ. Fl has been identified as a potential susceptibility factor in a 

28 toxicological study but has not yet been explored in epidemiologic studies. The toxicological reported that 

29 co-exposure of Pb and Fl increased Pb deposition in calcified tissues. Since Pb is acid soluble, 

30 fluoridation may increase Pb concentration in water through leaching from pipes and Pb solder.

31 Additional details of the studies summarized, are found in Sections 6.2.14 and 6.2.15.
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1 Recent studies suggested that Pb-associated neurotoxicity in children are exacerbated with 

2 co-exposures to environmental tobacco smoke but findings from recent epidemiologic studies examining 

3 modification by smoking for other outcomes are mixed. Exposure to urban areas with larger industrial 

4 sources and higher traffic has been suggested to increase Pb body burden and risk of Pb exposure. An 

5 ecological study reports an association of accumulated metals in the soil (e.g., Pb, Zn, Cd, Ni, Mn, Cu, 

6 Co, Cr and V) with reduced learning achievement among the students at the school (Mielke et al., 2005). 

2.9. Summary

7 This section summarizes the main conclusions of this assessment regarding the health and 

8 ecological effects of Pb and, for health outcomes, the concentrations at which those effects are observed. 

9 The conclusions from the 2006 Pb AQCD and the causality determinations for the health and ecological 

10 effects of Pb exposure from this review are summarized in Table 2-8. 

11 The 2006 Pb AQCD reviewed a strong body of evidence clearly substantiating the health effects of 

12 Pb at contemporary exposure levels. Neurological effects in children and cardiovascular effects in adults 

13 were the effects that were best substantiated as occurring at blood Pb concentrations as low as 5 to 10 

14 μg/dL. Other newly demonstrated immune and renal system effects among general population groups 

15 were also emerging as low-level Pb-exposure effects of potential public health concern. New 

16 epidemiologic and toxicological studies support the findings of the previous assessement and provide 

17 additional evidence for these effects at increasingly lower levels.

18 The major conclusions reached in the 2006 Pb AQCD for terrestrial ecosystems focused on 

19 evidence from smelter sites or other industrial point sources with elevated levels of Pb where death of 

20 vegetation was found to cause a near-complete collapse of the detrital food web, creating a terrestrial 

21 ecosystem in which energy and nutrient flows were minimal. In aquatic ecosystems, the best documented 

22 links between Pb and effects on the environment were with effects on individual organisms. 

23 Bioaccumulation of Pb in aquatic organisms was shown to alter the aquatic environment. Further, it was 

24 noted that alteration of ecological interactions (e.g., species competitive behaviors, predator-prey 

25 interactions, and contaminant avoidance behaviors) may have negative effects on species abundance and 

26 community structure. However, the fact that both terrestrial and aquatic systems frequently contain 

27 multiple metals and other stressors made it difficult to attribute observed adverse effects to Pb. 

28 The current document presents detailed reviews of the scientific literature on the effects of Pb in 

29 aquatic and terrestrial ecosystems, but, also integrates the evidence of effects across aquatic and terrestrial 

30 habitats. The ecological endpoints considered for causal determination are bioaccumulation, mortality, 

31 growth, physiological stress, hematological effects, developmental and reproductive effects, and 

32 neurobehavioral effects. The substantial overlap between the ecological and health endpoints considered 
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1 in the causal determinations allowed the integration of the evidence across these disciplines. This 

2 organizational scheme represents an evolution from the structure of the 2006 Pb AQCD and lends 

3 additional weight to the ecological evidence by reducing the uncertainty associated with attributing 

4 ecosystem effects to Pb rather than other metals or toxicants that co-occur with Pb since much of the 

5 evidence documenting the effects and modes of action of Pb comes from controlled animal experiments.

Table 2-8. Summary of evidence from epidemiologic, animal toxicological and ecological 

studies on the effects associated with exposure to Pb

Health Outcome Conclusions from the 2006 Pb 

AQCD

Conclusions from the 2011 Ist Draft Pb 

ISA

Neurological 

Effects

Causal relationship

Neurocognitive 

Function and 

Learning

The collective body of epidemiologic 

studies provided clear and consistent 

evidence for the effects of Pb exposure 

on decreasing neurocognitive function in 

children.

Recent epidemiologic studies in children continue 

to demonstrate associations with IQ; most 

evidence emphasizes associations of blood Pb 

levels as low as 2 μg/dL with specific indices of 

neurocognitive function (e.g., verbal skills, 

memory, learning visuospatial processing). Among 

environmentally exposed adults, the most 

consistent findings were associations of 

cumulative Pb exposure metrics with cognitive 

deficits.

Neurobehavioral 

Effects

Several epidemiologic studies reported 

associations between Pb exposure and 

that ranged from inattentiveness to selfreported delinquent behaviors to criminal 

activities. Uncertainty remained 

regarding the critical time period of Pb 

exposure. In addition, uncertainties 

remained regarding whether Pb 

exposure was an independent predictor 

of neurobehavioral effects. Results from 

studies of ADHD were inconclusive. 

Suggestive relationship for both blood 

and bone Pb with depression and 

anxiety symptoms.

Recent studies in children continue to support 

associations of Pb exposure (blood Pb levels 3-11 

μg/dL) with a range of effects from anxiety and 

distractibility to conduct disorder and delinquent 

behavior. New evidence indicates associations 

between blood Pb levels as low as 1 μg/dL and 

ADHD diagnosis and contributing diagnostic 

indices. 

Sensory Organ 

Function

The selective action of Pb on retinal rod 

cells and bipolar cells is well 

documented in earlier AQCDs. There 

was coherence between the animal and 

the human literature on the effects of 

chronic Pb exposure on auditory 

function. 

No new epidemiologic studies on sensory organ 

function. Recent toxicological studies find retinal 

effects in male rodents at lower blood Pb levels 

(~12 μg/dL)
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Neurodegenerative 

Diseases

Several epidemiologic studies of Pb 

exposure and Alzheimer’s disease, or 

dementia did not report associations 

association, but each study had sufficient 

limitations.

Recent epidemiological studies report associations 

with PD and essential tremor. Emerging 

toxicological evidence suggests that early life 

exposure may be associated with 

neurodegeneration in adult animals. 

Cardiovascular 

Effects

Epidemiologic studies consistently 

demonstrated associations between Pb 

exposure and increased risk of CVD 

outcomes. Experimental toxicology 

confirmed Pb effects on the 

cardiovascular system observed in 

epidemiologic studies.

Causal relationship

Blood Pressure A doubling of blood Pb level was 

associated with a 1 mmHg increase in 

systolic blood pressure and a 0.6 mmHg 

increase in diastolic blood pressure.

Recent studies confirm these findings. 

Associations of increased BP with Pb exposure 

observed at blood Pb levels < 2 μg/dL. 

Hypertension Suggestive evidence that cumulative Pb 

exposure may be associated with 

hypertension. Animal studies 

demonstrated that long-term exposure to 

Pb resulted in hypertension that 

persisted after cessation of exposure.

Recent studies, including those using bone Pb as 

a metric of cumulative exposure, confirm and add 

weight to previous findings. Associations of 

hypertension with Pb exposure observed at blood 

Pb levels < 2 μg/dL. Recent studies have 

emphasized the interaction of cumulative 

exposure to Pb with other factors including stress.

Cardiovascular 

Mortality

Limited evidence in support of 

cardiovascular mortality.

Recent studies including an NHANES analysis of 

the association of blood Pb with cause-specific 

mortality and study of older adults, which used 

bone Pb as an exposure metric, addressed 

limitations of previous studies and provide 

additional evidence for an association of Pb with 

cardiovascular mortality.

Renal Effects Circulating and cumulative Pb exposure 

was associated with longitudinal decline 

in renal function. Experimental studies 

demonstrated that initial accumulation of 

absorbed Pb occurred primarily in the 

kidneys and hyperfiltration phenomenon 

during the first 3 months of exposure 

was noted. 

Causal relationship 

Recent studies expand upon the strong body of 

evidence that Pb exposure is associated with 

kidney dysfunction including increased serum 

creatinine and decreased creatinine clearance at 

blood Pb levels < 5 μg/dL.

Immune System 

Effects

Epidemiologic studies suggested that Pb 

exposure may be associated with effects 

on cellular and humoral immunity 

including changes in serum 

immunoglobulin E levels in children. 

Toxicological evidence supported these 

findings and provided evidence for 

effects on downstream events such as 

inflammation and decreased host 

resistance.

Causal relationship

Recent studies support the strong body of 

evidence that Pb exposure is associated with both 

cell-mediated and humoral immunity. The 

consistency and coherence of findings among 

related immune effects establishes the biological 

plausibility for epidemiologic observations of 

associations with infection, allergy and effects in 

other organ systems. 
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Heme Synthesis 

and RBC Function

Pb exposure was associated with 

disruption in heme synthesis in both 

children and adults. Toxicological studies 

demonstrated that Pb interferes with red 

blood cell survival and mobility. 

Causal relationship

Recent epidemiologic and toxicological studies 

provide strong evidence that exposure to Pb is 

associated with numerous deleterious effects on 

the hematological system including altered heme 

synthesis mediated through decreased ALD and 

ferrochelatase activities, decreased RBC survival 

and function, decreased hematopoiesis and 

increased oxidative stress and lipid peroxidation. 

Reproductive 

Effects and Birth 

Outcomes

Epidemiologic evidence suggested small 

associations between Pb exposure and 

male reproductive outcomes including 

perturbed semen quality and increased 

time to pregnancy. Associations between 

Pb exposure and male reproductive 

endocrine status were not observed in 

the occupational populations studied. 

Toxicological studies provided evidence 

that Pb produced effects on male and 

female reproductive junction and 

development and disrupts endocrine 

function. 

Causal relationship

Recent toxicological and epidemiologic studies 

provide strong evidence for delayed onset of 

puberty in males and females as well as effects on 

sperm. Evidence on pregnancy outcomes was 

inconsistent and less coherent across disciplines 

for preterm birth, spontaneous abortion, low birth 

weight, birth defects, hormonal influence and 

fecundity. 

Cancer Epidemiologic studies of highly exposed 

workers suggested a relationship 

between Pb and cancers of the lung and 

the stomach; the evidence was limited by 

confounding by metal co-exposures 

(e.g., to As,Cd), smoking, and dietary 

habits. The 2003 NTP and 2004 IARC 

reviews concluded that Pb and Pb 

compounds were probable carcinogens, 

based on limited evidence in humans 

and sufficient evidence in animals. 

Based on animal data and inadequate 

human data Pb and Pb compounds 

would be classified as likely carcinogens 

according to the EPA Cancer 

Assessment Guidelines for Carcinogen 

Risk Assessment.

Likely causal relationship

Some epidemiologic evidence supporting 

associations between Pb and cancer with the 

strongest evidence from animal toxicology 

between Pb and cancer, 

genotoxicity/clastogenicity, or epigenetic 

modification.
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Ecological/ Welfare 

Effect

Findings from 2006 Pb AQCD Conclusions in the 2011 1st Draft ISA

Bioaccumulation 

as it affects 

Ecosystem 

Services

Atmospheric Pb pollution has resulted in 

accumulation of Pb in terrestrial and 

aquatic systems throughout the world. In 

field studies in aquatic systems, Pb has 

been shown to significantly alter the 

aquatic environment through 

bioaccumulation and alterations of 

community structure and function. Due to 

low solubility of Pb in water, dietary Pb 

(i.e., Pb absorbed to sediment, 

particulate matter and food) may 

contribute substantially to exposure and 

toxicity.

Causal relationship

There is compelling evidence from several 

decades of research and in recent studies that Pb 

bioaccumulates in plants, invertebrates and 

vertebrates in terrestrial and aquatic ecosystems. 

Pb deposited on the surface of, or taken up by 

organisms has the potential to contribute to 

exposure and toxicity in primary and secondary 

order consumers and alter the services provided 

by ecosystems (i.e., provisioning services).

Mortality No information on mortality in plants. 

Effects of Pb on invertebrates and 

vertebrates include decreased survival. 

Inadequate to infer a causal relationship for plants

Insufficient evidence for mortality in plants.

Causal relationship in vertebrates and 

invertebrates

Recent studies provide additional evidence for Pb 

effects on mortality in invertebrates and 

vertebrates. 

Growth Evidence of growth effects in algae, 

aquatic plants, soil invertebrates and 

aquatic invertebrates. Limited evidence 

in avian and mammalian consumers.

Causal relationship in plants and invertebrates

Recent studies on growth in algae and 

invertebrates find effects of Pb at lower 

concentrations than previously, and additional 

evidence for growth effects in plants. 

Suggestive causal relationship in vertebrates

Limited studies considered effects on growth in 

vertebrates.

Physiological 

Stress

Pb exposure may cause lipid 

peroxidation and changes in glutathione 

concentrations. There are species 

differences in resistance to oxidative 

stress.

Causal relationship

Recent studies support the strong body of 

evidence for upregulation of antioxidant enzymes 

and increased lipid peroxidation associated with 

Pb exposure in many species of plants, 

invertebrates and vertebrates.

Hematological 

Effects

Pb effects on heme synthesis were 

documented in the 1986 AQCD and 

continue to be studied in aquatic and 

terrestrial biota. Changes in ALAD are 

not always related to adverse effects but 

may simply indicate exposure. 

Numerous studies have reported the 

effects of Pb exposure on blood 

chemistry in aquatic and terrestrial biota.

Causal relationship

Recent studies expand the evidence for Pb effects 

on ALAD enzyme activity in bacteria, 

invertebrates, and vertebrates and altered serum 

profiles and blood cell counts in vertebrates.
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Development and 

Reproduction

No information on reproduction in plants. 

Limited new evidence in invertebrates 

and vertebrates.

Inadequate to infer a causal relationship for plants 

There are an insufficient number of studies that 

consider Pb effects on plant reproduction.

Causal relationship in invertebrates and 

vertebrates

Recent studies expand the evidence for Pb effects 

on embryonic development as well as for multigenerational effects in invertebrates. In 

vertebrates, there is new evidence for delayed 

metamorphosis and altered steroid profiles in the 

few species studied.

Neurobehavior Exposure to Pb has been shown to affect 

brain receptors in fish. Exposure to Pb in 

laboratory studies and simulated 

ecosystems may alter species 

competitive behaviors, predator-prey 

interactions and contaminant avoidance 

behaviors.

Causal relationship

Recent studies identify possible molecular targets

for Pb neurotoxicity in invertebrates and fish. 

There is new evidence in a few invertebrate and 

vertebrate species for behavioral effects 

associated with Pb exposure.

Community and 

Ecosystem Level

Effects of Pb difficult to interpret because 

of the presence of other stressors 

including metals.

Causal Relationship

Uptake of Pb into aquatic and terrestrial organisms 

and subsequent effects on survival, reproduction, 

growth, behavior and other physiological variables 

at the species scale is likely to lead to effects at 

the population, community and ecosystem scale. 

There is additional evidence for effects of Pb in 

soil microbial communities, and in sedimentassociated and aquatic plant communities.
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