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CHAPTER 1 EXECUTIVE SUMMARY

1.1 Introduction

1 This Integrated Science Assessment (ISA) is a synthesis and evaluation of the most 

2 policy-relevant science that forms the scientific foundation for the review of the primary 

3 (health-based) and secondary (welfare-based) national ambient air quality standard 

4 (NAAQS) for Lead (Pb). In 2008, the levels of the the primary and secondary NAAQS 

for Pb were lowered ten-fold, from the 1978 level of 1.5 μg/m3, to a level of 0.15 μg/m3 5 .

6 The averaging time was revised to a rolling three-month period with a maximum (not-to7 be-exceeded) form, evaluated over a three-year period. EPA’s decision on the level for 

8 the primary standard was based on the much-expanded health effects evidence on 

9 neurocognitive effects of Pb in children. The revised standard was established to protect 

10 against air Pb-related health effects, including IQ loss, in the most highly exposed 

11 children. 

12 EPA has developed a process for evaluating the scientific evidence and drawing 

13 conclusions and causal judgments regarding air pollution-related health and 

14 environmental effects. The ISA development process includes literature search strategies, 

15 criteria for selecting and evaluating studies, approaches for evaluating weight of the 

16 evidence, and a framework for making causality determinations. The ISA uses a 

17 five-level hierarchy that classifies the weight of evidence for causation: 

18  Causal relationship 

19  Likely to be a causal relationship 

20  Suggestive of a causal relationship 

21  Inadequate to infer a causal relationship 

22  Not likely to be a causal relationship 

23 The process and causality framework are described in more detail in the Preamble to the 

24 ISA. Considerations that are specific to the causal determinations drawn for the health 

25 and ecological effects of Pb are described in Section 2.1 of the document.
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1.2 Lead Sources, Fate and Transport in the Environment, Human 

Exposure and Dose

1 Emissions of Pb to ambient air have declined by more than two orders of magnitude over 

2 the period 1970 to 2008 following the ban on alkyl-Pb additives for on-road gasoline and 

3 tightened industrial standards. Emissions were estimated to be 970 tons in 2008, with 

4 more than half emitted from piston-engine aircraft. Other sources of ambient air Pb 

5 (beginning with the largest) include metals processing, fossil fuel combustion, other 

6 industrial sources, roadway related sources, and historic Pb. During the same period that 

7 saw this dramatic decrease in Pb emissions, ambient air Pb concentrations have also 

declined. The median annual concentrations in 2010 (0.03 μg/m3 8 ) were approximately 

9 thirty times lower than they were in 1980. The sharpest drop in Pb concentration occurred 

10 during 1980-1990 and concentrations continued to decline through 2010. Concentrations 

11 near Pb sources as well as concentrations away from Pb sources have shown a sharp

12 decline (Section 2.2.2). 

13 The indicator for the Pb NAAQS is Pb in total suspended particles (Pb-TSP). The Pb14 TSP indicator was retained in 2008 in recognition of the role of all PM sizes in ambient 

15 air Pb exposures. The Federal Reference Method (FRM) Pb-TSP sampler’s size selective 

16 performance is known to be affected by wind speed and direction, and collection 

17 efficiency has been demonstrated to decline with particle size. The size distribution of 

18 Pb-bearing particulate matter (PM) varies substantially depending on the nature of Pb 

19 sources and proximity of the monitors to the Pb sources. Coarse Pb-bearing PM deposits 

20 to a great extent near its source, contributing to local soil Pb concentrations, while fine 

21 Pb-bearing PM (e.g. aircraft emissions) can be transported long distances, potentially 

22 contributing Pb to remote areas. Depending on local conditions, deposited particles may 

23 be resuspended and redeposited multiple times before further transport becomes unlikely. 

24 In regulatory Pb monitoring, ambient Pb sampled using the FRM for Pb-PM10 is allowed 

25 in certain instances where the expected Pb concentration does not approach the NAAQS 

26 and no sources of ultracoarse Pb are nearby.

27 Atmospheric deposition has led to measurable Pb concentrations observed in rain, 

28 snowpack, soil, surface waters, sediments, agricultural plants, livestock, and wildlife 

29 across the world, with the highest concentrations near Pb sources, such as metal smelters. 

30 After the phase-out of Pb from on-road gasoline, Pb concentrations have decreased 

31 considerably in rain, snowpack, and surface waters. In contrast, Pb is retained in soils and 

32 sediments, where it provides a historical record of deposition and associated 

33 concentrations. In remote lakes, sediment profiles indicate higher Pb concentrations in 

34 near surface sediment as compared to pre-industrial era sediment from greater depth and 

35 indicate peak concentrations between 1960 and 1980 (when leaded on-road gasoline was 
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1 at peak use). Ingestion and water intake are the major routes of Pb exposure for aquatic 

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

3 livestock and terrestrial wildlife.

4 Human exposure to Pb involves multiple pathways (Figure 1-1) and is difficult to assess 

5 because Pb has multiple sources in the environment. Air-related pathways of Pb exposure 

6 are the focus of this assessment. In addition to inhalation of Pb from ambient air, air7 related Pb exposure pathways include inhalation and ingestion of Pb from indoor dust 

8 and/or outdoor soil that originated from recent or historic ambient air. Non-air-related 

9 exposures to humans include occupational exposures, hand-to-mouth contact with Pb10 containing consumer goods, hand-to-mouth contact with dust or chips of peeling Pb11 containing paint, or ingestion of Pb in drinking water conveyed through Pb pipes. Soil 

12 can act as a reservoir for deposited Pb emissions and exposure to soil contaminated with 

13 deposited Pb can occur through resuspended PM as well as shoe tracking and hand-to14 mouth contact, which is the main pathway of childhood exposure to Pb. Infiltration of Pb 

15 dust into indoor environments has been suggested, and Pb dust has been shown to persist 

16 in indoor environments even after repeated cleanings. Measurements of particle-bound 

17 Pb exposures reported in this assessment have shown that personal exposure 

18 measurements of Pb concentration are typically higher than are indoor or outdoor 

19 ambient Pb concentrations. 
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Note: The Venn diagram is used to illustrate the passage of Pb through multiple environmental media compartments through which 

exposure can occur. 

Figure 1-1 Conceptual model of multimedia Pb exposure.

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

2 only about 1% of Pb is found in the blood. Pb in blood is primarily (~99%) bound to 

3 RBCs. The burden of Pb in the body may be viewed as that divided between a dominant 

4 slow compartment (bone) and smaller fast compartment(s) (soft tissues). Pb uptake and 

5 elimination in soft tissues is much faster than it is in bone. Pb accumulates in bone 

6 regions undergoing the most active calcification at the time of exposure. Pb in bone 

7 becomes distributed in trabecular (e.g. patella) and the more dense cortical bone (e.g. 

8 tibia). 

9 Blood Pb is the most common metric of Pb dose or exposure used in epidemiologic 

10 studies of Pb health effects. Overall, blood Pb levels have been decreasing among U.S. 

11 children and adults over the past twenty years. The median blood Pb level for the entire 

12 U.S. population is 1.2 μg/dL with a 95th percentile blood Pb level of 3.7 μg/dL based on 

13 the 2007-2008 NHANES (National Health and Nutrition Examination Survey) data. 

14 Among children aged 1-5 years, the median and 95th percentiles are slightly higher at 1.4 

15 μg/dL and 4.1 μg/dL, respectively. Other common metrics of Pb dose or exposure used in 
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1 epidemiologic studies are Pb in bone (a metric of cumulative exposure) and Pb cord 

2 blood (a metric of prenatal exposure). 

3 Blood Pb is dependent on both the recent exposure history of the individual, as well as 

4 the long-term exposure history that determines body burden and Pb in bone. The 

5 contribution of bone Pb to blood Pb changes in an individual depending on the duration 

6 and intensity of the exposure, age, and various other physiological stressors that may 

7 affect bone remodeling (e.g., nutritional status, pregnancy, menopause, extended bed rest, 

8 hyperparathyroidism) beyond that which normally and continuously occurs. In children, 

9 largely due to faster exchange of Pb to and from bone, blood Pb is both an index of recent 

10 exposure and potentially an index of body burden. In adults and children whose current 

11 exposure to Pb has effectively ceased or greatly decreased, a slow decline in blood Pb 

12 concentrations mainly reflects the gradual release of Pb from bone. Generally, bone Pb is 

13 an index of cumulative exposure and body burden. Pb is sequestered in two bone 

14 compartments; with Pb in trabecular bone exchanging more rapidly with the blood, than 

15 Pb in cortical bone. Therefore, Pb in cortical bone a better marker of cumulative exposure 

16 and Pb in trabecular bone more likely to be correlated with blood Pb, in adults and 

17 children. There is evidence for maternal-to-fetal transfer of Pb in humans. Transplacental 

18 transfer of Pb may be facilitated by an increase in the plasma/blood Pb concentration 

19 ratio during pregnancy. Maternal-to-fetal transfer of Pb appears to be related partly to the 

20 mobilization of Pb from the maternal skeleton.

1.3 Integrative Overview of Health and Ecological Effects

21 There is substantial overlap between the ecological and health endpoints related to Pb 

22 exposure in that they can be mediated through multiple, interconnected modes of action 

23 (Table 2-5). The principal cellular/subcellular effects contributing to modes of action for 

24 human health and ecological endpoints are altered ion status, protein binding, oxidative 

25 stress, inflammation, endocrine disruption and cell death/genotoxicity (Figure 1-2). The 

26 commonalities with regard to the endpoints and modes of action allowed the integration 

27 of the evidence across disciplines (Table 2-4). The mechanisms of Pb toxicity are likely 

28 conserved from invertebrates to vertebrates, including humans in some organ systems. 

29 See Section 2.8.1 for additional details.
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Note: The subsections where these MOAs are discussed are indicated in parentheses.

Figure 1-2 Schematic representation of the relationships between the 

various MOAs by which Pb exerts its effects.

1.3.1 Health Effects of Lead

1 Evidence from epidemiologic and toxicological studies was considered in combination 

2 with the evidence from other disciplines such as exposure sciences and toxicokinetics in 

3 determining the causal relationships for the health outcomes discussed in this assessment. 

4 The evidence related to the specific endpoints comprising the weight of the evidence for 

5 the organ system-specific causal determination are summarized in Table 1-1 below. Table 

6 1-1 also specifies the sections sections in Chapter 2 and Chapter 5 where detailed

7 information can be found.
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Table 1-1 Summary of causal determinations between exposure to Pb and 

health outcomes

Outcomea Causality Determination

Nervous System Effects (Section 2.6.1) Causal Relationship

Cardiovascular Effects (Section 2.6.2) Causal Relationship

Renal Effects (Section 2.6.3) Causal Relationship

Immune System Effects (Section 2.6.4) Causal Relationship

Effects on Heme Synthesis and Red Blood Cell Function (Section 2.6.5) Causal Relationship

Reproductive and Developmental Effects (Section 2.6.6) Causal Relationship

Cancer (Section 2.6.7) Likely Causal Relationship

a

Based upon the framework described in the Preamble, a determination of causality was made for a broad outcome category (e.g., nervous system effects) 

by evaluating the coherence of evidence across disciplines and across a spectrum of related endpoints. However, the evidence on which the causal 

judgment is based, including the strength of evidence for the individual endpoints within the major outcome category, is characterized within the discussion. 

Causal determinations were made within approximately 1-2 orders of magnitude of current levels.

Nervous System Effects

1 Recent epidemiologic and toxicological studies substantiated the strong body of evidence 

2 presented in the 2006 Pb AQCD that Pb exposure is associated with nervous system 

3 effects. The weight of evidence clearly supports associations of increases in blood Pb 

4 levels with decrements in cognitive function in children, i.e., full-scale IQ and various 

5 measures of learning and memory. Several studies find that there is a larger incremental 

6 effect of Pb on cognition at lower blood Pb levels. Studies have not provided evidence of 

7 a threshold for Pb-related impaired cognition. Epidemiologic and toxicological evidence 

8 also clearly demonstrates Pb-associated increases in behavioral problems, in particular, 

9 inattention and impulsivity in children. In epidemiologic studies, associations with 

10 cognitive function and behavior were observed after adjustment for a range of potential 

11 confounding variables, but most commonly, parental IQ, parental education, and other 

12 SES-related variables. In children, the weight of evidence supports cognitive function 

13 decrements and behavioral problems in association with concurrent blood Pb levels. 

14 Associations also are observed with prenatal, early childhood, and childhood average 

15 blood Pb levels, thus uncertainty remains regarding the lifestage of exposure within

16 childhood that is associated with the greatest risk. The weight of toxicological evidence 

17 demonstrates neurodevelopmental effects with prenatal and early postnatal Pb exposures 

18 that can have effects persisting to adulthood. The biological plausibility for

19 epidemiologic and toxicological findings for effects on cognitive function and behavior is 

20 provided by evidence characterizing underlying mechanisms, including Pb-induced 
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1 changes in neurogenesis, synaptogenesis and synaptic pruning, long term potentiation, 

2 and neurotransmitter function. Based most heavily on cognitive function decrements and 

3 inattention in children, the collective body of evidence integrated across epidemiologic 

4 and toxicological studies is sufficient to conclude that there is a causal relationship 

5 between Pb exposures and nervous system effects (Section 2.6.1).

Cardiovascular Effects

6 The 2006 Pb AQCD concluded that there was a relationship between blood Pb and bone 

7 Pb and cardiovascular effects in adults, in particular increased blood pressure (BP) and 

8 increased incidence of hypertension. Building on this strong body of evidence, recent 

9 epidemiologic and toxicological studies substantiated the evidence that long-term Pb 

10 exposure is associated with cardiovascular effects in adults with the largest body of 

11 evidence demonstrating associations of Pb with increased BP and hypertension. The 

12 epidemiologic evidence is strengthened by several recent prospective studies that find 

13 associations between biomarkers of Pb and BP and hypertension and by effect estimates 

14 that are observed after adjustment for multiple potential confounding factors. However, 

15 there is uncertainty regarding the level, timing, frequency, and duration of Pb exposure 

16 contributing to the observed associations since the populations studied were likely to 

17 have higher past than recent Pb exposure. Animal toxicological studies provide

18 mechanistic evidence to support the biological plausibility of Pb-induced hypertension, 

19 including Pb-induced oxidative stress, activation of renin-angiotensin aldosterone system 

20 (RAAS), altered sympathetic activity, and vasomodulator imbalance. Collectively, the 

21 evidence integrated across epidemiologic and toxicological studies as well as across the 

22 spectrum of other cardiovascular endpoints examined is sufficient to conclude that there 

23 is a causal relationship between Pb exposures and cardiovascular health effects 

24 (Section 2.6.2). 

Renal Effects

25 New epidemiologic and toxicological studies evaluated in the current review support or 

26 expand upon the strong body of older evidence on the effect of Pb on the renal system

27 presented in the 2006 Pb AQCD. The weight of epidemiologic evidence consistently 

28 demonstrates a relationship between higher blood Pb level and kidney dysfunction 

29 (e.g., lower creatinine clearance, higher serum creatinine, and lower glomerular filtration 

30 rate [GFR]) in nonoccupationally-exposed adults. Associations between Pb biomarker 

31 levels and renal function are observed after adjustment for multiple potential confounding 

32 factors such as age, sex, comorbid cardiovascular conditions, body mass index, smoking, 

33 and alcohol use; however, there is uncertainty regarding the level, timing, frequency, and 
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1 duration of Pb exposure contributing to the observed associations, since the populations 

2 studied were likely to have higher past exposure than recent exposure. Coherence for 

3 epidemiologic findings is provided by observations from animal models that Pb exposure 

4 for longer than 6 months decreases GFR and increases serum creatinine. The weight of 

5 evidence from animal studies indicates that Pb induces histopathological changes, 

6 including tubular atrophy and sclerosis. By demonstrating Pb-induced renal oxidative 

7 stress, inflammation, mitochondrial dysfunction, apoptosis, and glomerular hypertrophy, 

8 toxicological studies provide biological plausibility for the associations observed in 

9 epidemiologic studies between blood Pb levels and kidney dysfunction. Collectively, the 

10 evidence integrated across epidemiologic and toxicological studies as well as across the 

11 spectrum of renal outcomes is sufficient to conclude that there is a causal relationship 

12 between Pb exposures and renal health effects (Section 2.6.3).

Immune System Effects

13 As described in the 2006 Pb AQCD, rather than producing overt cytotoxicity or 

14 pathology, Pb exposure was found to be associated with alterations in several subclinical 

15 parameters related to cellular and humoral immunity (Figure 5-42). The principal 

16 findings are Pb-induced increased production of Th2 cytokines, suppressed production of 

17 Th1 cytokines, increased inflammation, and elevated IgE, with the weight of evidence 

18 provided by toxicological studies. Collectively, these findings are coherent with the 

19 observed effects of Pb exposure on decreasing responses to antigens (e.g., DTH, bacterial 

20 resistance) in animals. Both toxicological studies in animals and epidemiologic studies in 

21 children provide evidence for Pb-associated increases in IgE. The toxicological and 

22 epidemiologic findings for the Pb-induced effects on Th2 cytokines, IgE, and 

23 inflammation provide biological plausibility for the associations observed for blood Pb 

24 levels with asthma and allergic conditions in children. Associations with asthma and 

25 allergy were observed after considering potential confounding by several factors, 

26 including, SES and allergen exposure. The blood Pb levels and Pb exposure lifestage, 

27 magnitude, frequency, and duration associated with immune effects are not well 

28 characterized in children or adults. Epidemiologic studies of children and adults primarily 

29 examined concurrent blood Pb levels. The consistency and coherence of findings across 

30 the continuum of related immune parameters that demonstrate a stimulation of Th2 

31 responses in toxicological studies combined with the supporting epidemiologic evidence 

32 in children are sufficient to conclude that there is a causal relationship between Pb 

33 exposures and immune system effects (Section 2.6.4).
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Heme Synthesis and Red Blood Cell Function

1 Recent epidemiologic and toxicological studies support findings from the 2006 Pb 

2 AQCD which concluded that Pb exposure was associated with effects on developing red 

3 blood cells (RBCs) as well as heme synthesis in children and occupationally exposed 

4 adults. The principal findings for RBC survival and function from recent studies are the 

5 consistent Pb-induced alterations in several inter-connected hematological parameters 

6 such as hemoglobin (Hb), hematocrit (Hct), and mean corpuscular volume (MCV) 

7 observed across multiple studies. The effects on heme synthesis occurred through the 

8 inhibition of multiple key enzymes, most notably aminolevulinic acid dehydratase 

9 (ALAD), the enzyme that catalyzes the second, rate-limiting step in heme biosynthesis. 

10 For heme synthesis, the largest body of evidence indicates decreased ALAD activity in 

11 association with Pb exposure or blood Pb levels in occupationally-exposed adults or in 

12 children (3-12 years old), respectively. Evidence for oxidative stress, an important mode 

13 of action by which Pb may exert effects, primarily comes from studies of occupationally14 exposed adults and of children. the level, frequency, timing and duration of exposure 

15 associated with altered RBC survival and function, heme synthesis, or the state of 

16 oxidative stress in RBCs is uncertain in both adults and in children. The consistency of 

17 findings in epidemiologic studies investigating effects in occupationally-exposed adults 

18 and children, and the coherence of findings in the toxicological literature and coherence 

19 across the disciplines is sufficient to conclude that there is a causal relationship exists 

20 between Pb exposures and effects on heme synthesis and RBC function (Section 2.6.5). 

Reproductive and Developmental Effects

21 Supporting conclusions from the 2006 Pb AQCD, recent toxicological and epidemiologic 

22 literature provides strong evidence that Pb exposure is associated with effects on 

23 reproduction and development, and expands evidence for additional endpoints. The 

24 weight of the evidence supports the association of Pb exposure with delayed onset of 

25 puberty in both males and females; and detrimental effects on sperm and semen quality in 

26 occupationally-exposed males and in laboratory animals. In cross-sectional 

27 epidemiologic studies of girls (ages 6-18 years) consistent associations with delayed 

28 pubertal development (measured by age at menarche, pubic hair development, and breast 

29 development) were observed. In boys (ages 8-15 years), fewer studies were conducted 

30 but associations with delayed puberty were observed in most. There is uncertainty with 

31 regard to the exposure frequency, timing, duration and level that contributed to these 

32 observed association in studies of adolescents. The collective body of evidence integrated 

33 across epidemiologic and toxicological studies (which examined Pb-induced detrimental 

34 effects on sperm and on delayed onset of puberty), is sufficient to conclude that there is a
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1 causal relationship between Pb exposures and reproductive and developmental effects 

2 (Section 2.6.6).

Cancer

3 The previous epidemiologic studies included in the 2006 Pb AQCD provided very limited 

4 evidence suggestive of Pb exposure associations with cancers of the lung and stomach 

5 and genotoxic effects in humans. The conclusions of the 2006 Pb AQCD were consistent 

6 with those of International Agency for Research on Cancer (IARC) and the National 

7 Toxicology Program. The animal toxicological literature continues to provide the 

8 strongest evidence for an association between cancer and Pb exposure, with some 

9 supporting evidence provided by the epidemiologic literature. Evidence from 

10 toxicological studies demonstrates a relationship between Pb and cancer, 

11 genotoxicity/clastogenicity or epigenetic modification. Carcinogenicity in previous

12 animal toxicology studies with Pb exposure has been reported in the kidneys, testes, 

13 brain, adrenals, prostate, pituitary, and mammary gland, albeit at high doses of Pb. 

14 Epidemiologic studies of cancer incidence and mortality reported inconsistent results. 

15 Recent occupational studies of Pb exposure and lung cancer reported no associations. The 

16 majority of epidemiologic studies of brain cancer had null results overall, but positive 

17 associations between Pb exposure and brain cancer were observed among individuals 

18 with certain genotypes (e.g. ALAD2). The collective body of evidence integrated across 

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

20 causal relationship between Pb exposure and cancer (Section 2.6.7). 

1.3.2 Ecological Effects of Lead

21 The 2006 Pb AQCD and previous assessments found that the most commonly observed 

22 effects in terrestrial organisms included decreased survival, reproduction and growth as 

23 well as development and behavior. In aquatic invertebrates, effects of Pb exposures 

24 included inhibition of ALAD, reduced reproduction, growth and survival. Evidence of 

25 toxicity to fish (e.g. heme formation, alterations in brain receptors, effects on blood 

26 chemistry and hormonal systems, and decreases in some enzyme activities) was also 

27 observed. The effects of Pb can be observed in endpoints common to both terrestrial and 

28 aquatic biota. These effects can be observed at multiple levels of biological organization, 

29 starting at the cellular and subcellular level, then at the whole organism level, and finally 

30 at the community and ecosystem level. Effects of Pb on physiological stress, blood, and 

31 neurobehavior may increase susceptibility to other stressors and impact fitness of 

32 individual organisms. Effects on development, reproduction, growth and survival may 
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1 lead to effects on communities and ecosystems. The relationship of exposure and 

2 responses is difficult to quantitatively characterize because of the influence of multiple 

3 environmental variables on both Pb bioavailability and toxicity, and the substantial 

4 species and lifestage differences in Pb sensitivity. 

5 A brief discussion of the conclusions regarding Pb effects on physiological stress, 

6 hematology, neurobehavior, development, reproduction, growth, survival and community 

7 and ecosystem level effects is provided below and summarized in Table 1-2. Causal 

8 determinations were based on consideration and integration of information on 

9 biogeochemistry, bioavailability, biological effects, and exposure-response relationships 

10 of Pb in terrestrial and aquatic environments. A detailed discussion for all relevant 

11 welfare effects is provided in Chapters 2 and 7.

Table 1-2 Summary of Pb causal determinations for plants, invertebrates and 

vertebrates

Effecta Terrestrial Aquaticb

Physiological Stress-All organisms (Section 2.7.3.1) Causal Causal

Hematological Effects-Invertebrates (Section 2.7.3.2) Inadequate Causal

Hematological Effects-Vertebrates (Section 2.7.3.2) Causal Causal

Neurobehavioral Effects-Invertebrates and Vertebrates (Section 2.7.3.3) Likely Causal Likely Causal

Developmental and Reproductive Effects-Plants (Section 2.7.3.4) Inadequate Inadequate

Developmental and Reproductive Effects-Invertebrates and Vertebrates (Section 2.7.3.4) Causal Causal

Growth-Plants (Section 2.7.3.5) Causal Causal

Growth-Invertebrates (Section 2.7.3.5) Inadequate Causal

Growth-Vertebrates (Section 2.7.3.5) Inadequate Inadequate 

Survival-Plants (Section 2.7.3.6) Inadequate Inadequate

Survival- Invertebrates and Vertebrates (Section 2.7.3.6) Causal Causal 

Community and Ecosystem Level Effects (Section 2.7.3.7) Likely Causal Likely Causal

a

Effects observed at or near ambient levels of Pb were emphasized, and studies generally within 1-2 orders of magnitude above current conditions

were considered in the body of evidence for terrestrial and aquatic ecosystems.

b

Causal determinations for aquatic biota are based primarily on evidence from freshwater organisms.

Effects on physiological stress

12 Upregulation of antioxidant enzymes and increased lipid peroxidation are considered to 

13 be reliable biomarkers of stress. Alterations in these biomarkers are associated with Pb 

14 exposure in plants, invertebrates and vertebrates, and they may be indicative of increased 

15 susceptibility to other stressors, and of reduction in individual fitness. Markers of 

16 oxidative damage and antioxidant activity have been observed in a wide range of species 
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1 in terrestrial and aquatic environments when Pb is present, and following laboratory 

2 exposures. Evidence is sufficient to conclude that there is a causal relationship between 

3 Pb exposures and physiological stress in terrestrial and aquatic plants, invertebrates and 

4 vertebrates (Section 2.7.3.1). 

Hematological Effects

5 Changes in hematological variables including ALAD activity, blood cell counts and 

6 serum profiles are associated with Pb exposure in both aquatic and terrestrial animal taxa. 

7 Evidence from both field and laboratory studies suggest that ALAD is an indicator for Pb 

8 exposure across a wide range of biota, and it is commonly recognized as such. Studies 

9 conducted across the last two decades have indicated that hematological responses are 

10 associated with Pb in the environment. Evidence is sufficient to conclude that there is a 

11 causal relationship between Pb exposures and hematological effects in aquatic 

12 invertebrates and vertebrates. Evidence is inadequate to establish a causal relationship 

13 between Pb exposures and hematological effects in terrestrial invertebrates

14 (Section 2.7.3.2). 

Neurobehavioral Effects

15 Historical and recent evidence from Pb-exposed animals indicates that Pb affects 

16 behaviors such as food consumption, avoidance and escape from predators, behavioral 

17 thermoregulation, and prey capture. Alterations to these behaviors may decrease the 

18 overall fitness of the organism. Evidence from laboratory studies has shown effects of Pb 

19 on nervous system endpoints in both aquatic and terrestrial animal taxa. Overall, the 

20 evidence from terrestrial and aquatic systems is sufficient to conclude that there is a 

21 likely causal relationship between Pb exposures and neurobehavioral effects in terrestrial 

22 and aquatic invertebrates and vertebrates (Section 2.7.3.3).

Effects on Development and Reproduction

23 Various endpoints measured in multiple taxa of terrestrial and aquatic organisms have 

24 documented effects of Pb on development, fecundity and hormone homeostasis. In plants, 

25 few studies have addressed reproductive effects of Pb exposure. Decreased reproduction 

26 at the organismal level can result in declining abundance and/or extirpation of 

27 populations, decreased taxa richness, and decreased relative or absolute abundance at the 

28 community level. Among the animal species tested, aquatic invertebrates were the most 

29 sensitive to Pb with respect to reproduction. Effects of Pb on reproduction in 

30 invertebrates and vertebrates indicate that Pb is affecting fecundity of Pb-exposed 
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1 organisms in both aquatic and terrestrial habitats, and the evidence is sufficient to 

2 conclude that there is a causal relationship between Pb exposures and reproductive effects 

3 in terrestrial and aquatic invertebrates and vertebrates. The evidence is inadequate to 

4 conclude that there is a causal relationship between Pb exposures and reproductive effects 

5 in plants (Section 2.7.3.4).

Effects on Growth

6 Effects on growth observed at the species level may translate into effects at the ecosystem 

7 level. Exposure to Pb has been shown to have effects on growth in plants and in some 

8 species of invertebrates and vertebrates. Evidence for effects of Pb on growth is strongest 

9 in plants, although they are typically observed in laboratory studies with high exposure 

10 concentrations or in field studies near point sources. Evidence for Pb effects on growth in 

11 invertebrates has been observed most extensively in freshwater aquatic taxa, with 

12 inhibition in sensitive species occurring near the current range of Pb in surface waters. In 

13 general, juvenile organisms are more sensitive than are adults. There are limited data on 

14 growth effects in vertebrates. Evidence is sufficient to conclude that there is a causal 

15 relationship between Pb exposures and growth effects in aquatic and terrestrial plants and 

16 aquatic invertebrates. Evidence is inadequate to to conclude that there is a causal 

17 relationship between Pb exposures and growth effects in terrestrial invertebrates and in 

18 terrestrial and aquatic vertebrates (Section 2.7.3.5).

Effects on Survival 

19 Decreased survival of individuals within a population can have ecosystem-level impacts. 

20 Pb is generally not toxic to aquatic or terrestrial plants at concentrations found in the 

21 environment away from point sources, probably due to the fact that plants often sequester 

22 large amounts of Pb in roots, with little translocation to other parts of the plant. Aquatic 

23 invertebrates are generally more sensitive to Pb exposure than other taxa, with survival 

24 adversely impacted in a few species at concentrations occurring near point sources, or at 

25 concentrations near common ambient levels. Terrestrial invertebrates typically tolerate 

26 higher concentrations of Pb. Limited studies with vertebrates indicated adverse effects of 

27 Pb on survival at concentrations typically higher than ambient Pb in the environment, 

28 although juvenile organisms appear to be more sensitive than adults. The evidence is 

29 inadequate to conclude that there is a causal relationship between Pb exposure and 

30 survival in terrestrial and aquatic plants. Evidence is sufficient to conclude that there is a 

31 causal relationship between Pb exposures and survival in terrestrial and aquatic 

32 invertebrates and vertebrates (Section 2.7.3.6).
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Community and Ecosystem Effects

1 At higher levels of ecological organization, exposure to Pb may alter community and 

2 ecosystem structure and function. Decreases in abundance, reduced species diversity and 

3 shifts in community composition have been observed following Pb exposure in 

4 laboratory and field experiments, but considerable uncertainties exist in generalizing to 

5 natural ecosystem level effects. Assessment of Pb-specific exposure-response 

6 relationships is difficult at the whole ecosystem level because potential confounders such 

7 as other metals, physico-chemical variables, or various stressors cannot be controlled. 

8 These factors make it difficult to quantify relationships between ambient concentrations 

9 of Pb and ecosystem responses. The cumulative evidence that has been reported for 

10 effects of Pb at the highest levels of ecological organization, and for species-level 

11 endpoints with direct relevance to population and ecosystem level effects 

12 (i.e., development and reproduction, growth, survival) is sufficient to conclude that there 

13 is a likely causal relationship between Pb exposures and the alteration of species richness, 

14 species composition and biodiversity in terrestrial and aquatic ecosystems 

15 (Section 2.7.3.7).

1.4 Policy Relevant Considerations

Public Health Significance

16 The concept of population risk is relevant to the interpretation of findings for the 

17 continuously-distributed subclinical health endpoints frequently studied in association 

18 with Pb biomarkers in the assessment of their public health significance. A seemingly 

19 small increase in the mean of a continuously distributed health index may push the most 

20 susceptible group in the population above a critical cut point on the continuum of disease 

21 development, such that their condition meets the clinical definition of a disease. 

22 Moreover, small changes at the population level could translate into large numbers of 

23 clinical events if a large population is affected. Pb-associated changes in subclinical 

24 indices of disease may also increase an individual’s risk for health effects that are of 

25 greater clinical consequence, thus of greater public health concern. For example, a 

26 downward shift in the mean IQ value can also reduce the proportion of the population 

27 achieving very high IQ scores. Additional small increases in blood pressure or decreases 

28 in renal function that are associated with Pb biomarkers, may shift the population mean 

29 resulting in a larger proportion of the population that is diagnosed with hypertension or 

30 chronic kidney disease, respectively. 
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Air Lead-to-Blood Lead Relationships

1 A limited number of epidemiological studies evaluated relationships between air Pb and 

2 blood Pb (Section 2.9.2). Much of the pertinent earlier literature described in the 1986 Pb 

3 AQCD and more recent studies provide data from which estimates of the blood Pb-air Pb 

4 slope can be derived for children. The range of estimates from these studies is 

2 to 9 μg/dL per μg/m3 5 . The differences in the estimates across studies may reflect model 

6 selection by the investigators (e.g., some models predict an increase in the blood Pb-air 

7 Pb slope with decreasing air Pb concentration while other models predict a constant 

8 blood Pb-air Pb slope across all air Pb concentrations) as well as inclusion parameters 

9 (e.g. soil Pb) that may account for some of the variation in blood Pb that is attributable to 

10 air Pb. Other factors that may explain the variation in the derived blood Pb-air Pb slope 

11 include differences in the populations examined and Pb sources (e.g. leaded gasoline or 

12 smelter).

Ecological Effects and Corresponding Lead Concentrations

13 There is limited evidence to relate ambient air concentrations of Pb to levels of deposition 

14 onto terrestrial and aquatic ecosystems and to subsequent movement of atmospherically15 deposited Pb through environmental compartments (e.g., soil, sediment, water, and biota) 

16 (Section 2.9.3). Therefore, the connection between air concentration and ecosystem 

17 exposure continues to be poorly characterized for Pb and the contribution of atmospheric 

18 Pb to specific sites is not clear. Furthermore, the level at which Pb elicits a specific effect 

19 is difficult to establish in terrestrial and aquatic systems, due to the influence of other 

20 environmental variables on both Pb bioavailability and toxicity, and also to substantial 

21 species differences in Pb susceptibility. Current evidence indicates that Pb is 

22 bioaccumulated in biota; however, the sources of Pb in biota have only been identified in 

23 a few studies, and the relative contribution of Pb from all sources is usually not known. In 

24 addition, there are large differences in species sensitivity to Pb, and many environmental 

25 variables (e.g., pH, organic matter) determine the bioavailability and toxicity of Pb. 

Concentration-Response Relationships for Health Effects

26 With each successive assessment to-date, the epidemiologic and toxicological study 

27 findings show that progressively lower blood Pb levels or Pb exposures are associated 

28 with cognitive deficits and behavioral impairments (Section 2.9.4). Compelling evidence 

29 for a steeper slope for the relationship between blood Pb level and children’s IQ at lower 

30 blood Pb levels was presented in the 2006 Pb AQCD based on the international pooled 

31 analysis of seven prospective cohort studies. A subsequent reanalysis of these data 

32 focusing on the shape of the concentration-response function and several recent studies 
February 2012 1-17 Draft – Do Not Cite or Quote

1 support these findings. The majority of the epidemiologic evidence from stratified 

2 analyses comparing the lower and the higher ends of the blood Pb distributions indicates 

3 larger negative slopes at lower blood Pb levels (Figure 2-2). Several lines of toxicological 

4 evidence support the possibility of lower and higher Pb exposures acting through 

5 differential activation of mechanisms underlying cognition. The shapes of concentration6 response relationships were examined in a more limited number epidemiologic studies of 

7 other effects and findings were mixed (Section 2.9.4).

Pb Exposure and Nervous System Effects in Children

8 Young children, do not have lengthy exposure histories and consequently the 

9 interpretation of associations with blood Pb levels for this age group may be less 

10 complicated compared to older age groups. Several lines of evidence inform the 

11 interpretation of study findings as they relate to aspects of exposure that can be attributed 

12 to the cognitive and behavioral effects of Pb observed in young children (Section 2.9.5). 

13 Epidemiologic studies find associations of cognitive function and behavior with prenatal, 

14 early-childhood, lifetime average, and concurrent blood Pb levels as well as with 

15 childhood tooth Pb levels. However, the weight of epidemiologic evidence supports 

16 associations of concurrent blood Pb level. Studies of children up to three years of age that 

17 found associations with concurrent blood Pb levels also tended to find associations with 

18 prenatal cord or maternal blood Pb levels. Thus, both postnatal child and maternal Pb 

19 exposures may contribute to lower cognitive function in young children. Exposures that 

20 are reflected by concurrent blood Pb measured when children are older, by cumulative 

21 blood Pb levels or by tooth Pb levels have also been demonstrated to be associated with 

22 neurodevelopmental deficits throughout school-age and into adolescence. These findings 

23 are consistent with the understanding that the nervous system continues to develop 

24 throughout childhood. 

Potentially At-Risk Populations

25 The NAAQS are intended to provide an adequate margin of safety for both the population 

26 as a whole and those groups with unique factors that make them potentially at increased 

27 risk for health effects in response to ambient air pollutant exposure. The most well28 substantiated at-risk population for the effects of Pb exposure is children. Among 

29 children, the youngest age groups were observed to be most at risk of elevated blood Pb 

30 levels, with levels decreasing with increasing age of the children. Recent epidemiologic 

31 studies of infants/children detected increased risk of Pb-related health effects, and this 

32 was supported by toxicological studies. Synaptic pruning, which is active throughout 

33 early childhood (ages 1-4 years), may underlie the elevated risk of neurodevelopmental 
February 2012 1-18 Draft – Do Not Cite or Quote

1 effects in young children. Evidence is less consistent for other factors that may increase 

2 Pb-related risk including sex, genetics, pre-existing disease (e.g., hypertension), 

3 race/ethnicity, SES, nutrition, stress and co-exposure to other metals (Table 2-9).

1.5 Summary

4 Overall, the evidence evaluated for the current review expands upon findings of the 2006 

5 Pb AQCD, which concluded that there was a strong body of evidence substantiating the 

6 health effects of Pb and strong evidence of effects on some ecological endpoints. Table 

7 2-10 of Chapter 2 summarizes the main conclusions from the 2006 Pb AQCD and 

8 compares them to the findings from this assessment, including causality determinations, 

9 regarding the health and ecological effects of Pb. 

10 Nervous system effects, specifically cognition and behavior, in children are the effects 

11 that are best substantiated as occurring at the lowest blood lead concentrations. Some new 

12 epidemiologic and toxicological findings indicate that some effects (e.g., behavioral 

13 impairments) are observed in populations of children with lower mean blood lead levels 

14 than in previous assessments (e.g. <2 μg/dL). Causal relationships were also determined 

15 between Pb exposure and several adult outcomes including renal and cardiovascular 

16 effects, for which the evidence strongly suggests that cumulative exposure plays a role. 

17 As lead exposures were generally higher in the past than they are today, uncertainties 

18 exist, regarding the relative importance of recent versus past exposure in the development 

19 of the lead-related health effects in the adult populations studied. 

20 With regard to the ecological effects of Pb at or near concentrations currently present in 

21 the environment, there is new evidence to support previous findings of effects on growth 

22 and on reproduction and development in aquatic invertebrates as well as effects on 

23 survival in both invertebrate and vertebrate aquatic biota. These effects are observed at or 

24 near ambient levels of Pb in only a few species with greater toxicity generally associated 

25 with early lifestages. Hematological and stress related responses were also associated 

26 with elevated Pb levels in polluted areas in some terrestrial and aquatic species. In both 

27 aquatic and terrestrial systems, uptake of Pb into flora and fauna and subsequent effects 

28 on reproduction, growth and survival at the species level are likely to lead to effects at the 

29 population, community and ecosystem level of biological organization.