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# CHAPTER 1 EXECUTIVE SUMMARY

1.1 Introduction

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



### policy

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



### (health

- based) and secondary (welfare

- based) national ambient air quality standard 3



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



### for Pb were lowered ten

- fold, from the 1978 level of 1.5 μg/m 3 

### , to a level of 0.15 μg/m 3



### . 5



### The averaging time was revised to a rolling three

- month period with a maximum (not

- to

6



### be

- exceeded) form, evaluated over a three

- year period. EPA’s decision on the level for 7



### the primary standard was based on the much

- expanded health effects evidence on 8



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



### ag ainst air Pb

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



### children. 11



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



### conclusions and causal judgments regarding air pollution

- related health and 13



### environ mental effects. The ISA development process includes literature search strategies, 14



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



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



### five

- lev el hierarchy that classifies the weight of evidence for causation: 17



###  Causal relationship 18



###  Likely to be a causal relationship 19



###  Suggestive of a causal relationship 20



###  Inadequate to infer a causal relationship 21



###  Not likely to be a causal relationship 22



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



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



### and ecological effects of Pb are described in Section 2.1 of the document. 25February 2012 1

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

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



### the period 1970 to 2008 following the ban on alkyl

- Pb additives for on

- road gasoline and 2



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



### more than half emitted from piston

- engine aircraft. Other sources of ambient air Pb 4



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



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



### saw this dramatic decrease in Pb emissions, ambient air Pb concentrations hav e also 7



### declined. The median annual concentrations in 2010 (0.03 μg/m 3 

### ) were approximately 8



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



### during 1980

- 1990 and concentrations continued to decline through 20 10. C once ntrations 10



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



### decline (Section 2.2.2 ). 12



### The indicator for the Pb NAAQS is Pb in total suspended particles (Pb

- TSP). The Pb

13



### TSP indicator was retained in 2008 in recognition of the role of all PM sizes in ambient 14



### air Pb exposures. The Federal Reference Method (FRM) Pb

- TSP sampler’s size selective 15



### performance is known to be af fected by wind speed and direction, and collection 16



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



### Pb

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



### sources and proximity of the m onitors to the Pb sources. Coarse Pb

- bearing PM deposits 19



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



### Pb

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



### contributing Pb to r emote areas. Depending on local conditions, deposited particles may 22



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



### In regulatory Pb monitoring , ambient Pb sampled using the FRM for Pb

- PM 10 

### is allowed 24



### in certain ins tances where the expected Pb concentration does not approach the NAAQS 25



### and no sources of ultracoarse Pb are nearby. 26



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



### snowpack, soil, surface waters, sediments, agricultural pla nts, livestock, and wildlife 28



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



### After the phase

- out of Pb from on

- road gasoline, Pb concentrations have decreased 30



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



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



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



### near surface sediment as compared to pre

- industrial era sediment from greater depth and 34



### indicate peak concentrations between 1960 and 1980 (when leaded on

- road gasoline was 35February 2012 1

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### at peak use). Ingestion and water intake are the major routes of Pb exposure for aquatic 1



### organisms, and food, drinking water, and inha lation are major routes of exposure for 2



### livestock and terrestrial wildlife. 3



### Human exposure to Pb involves multiple pathways ( Figure 1

- 1 ) and is difficult to assess 4



### because Pb has multiple sources in the environment. Air

- related pathways of Pb exposure 5



### are the focus of this assessment. In addition to inhalation of Pb from ambient air, air

6



### related Pb exposure pathways include inhalation and ingestion of Pb from indoor dust 7



### and/or outdoor soil that originated from recent or historic ambient air. Non

- air

- related 8



### exposures to humans include occupational exposures, hand

- to

- mouth contact with Pb

9



### containing consumer goods, hand

- to

- mouth contact wi th dust or chips of peeling Pb

10



### containing paint, or ingestion of Pb in drinking water conveyed through Pb pipes. Soil 11



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



### deposited Pb can occur through resuspended PM as well as shoe tracking and hand

- to

13



### mouth contact, which is the main pathway of childhood exposure to Pb. Infiltration of Pb 14



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



### in indoor environments even after repeated cl eanings. Measurements of particle

- bound 16



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



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



### ambient Pb concentrations. 19February 2012 1

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exposure can occur.



### Figure 1

- 1 Conceptual model of multimedia Pb exposure.

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



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



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



### slow compartment (bone) and small er fast compartment(s) (soft tissues). Pb uptake and 4



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



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



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



### tibia). 8



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



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



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



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



### the 2007

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



### Among children aged 1

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



### μg/dL and 4.1 μg/dL, respectively. Other common metrics of Pb dose or exposure used in 15February 2012 1

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### epidemiologic studies are Pb in bone (a metric of cumulative exposure) and Pb cord 1



### blood (a metric of p renatal exposure). 2



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



### the long

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



### contribution of bone Pb to blood Pb changes in an individual dependin g on the duration 5



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



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



### hyperparathyroidism) beyond that which normally and continuo usly occurs . In children, 8



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



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



### exposure to Pb has effectively ceased or greatly dec reased, a slow decline in blood Pb 11



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



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



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



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



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



### children. There is evidence for maternal

- to

- fet al transfer of Pb in humans. Transplacental 17



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



### ratio during pregnancy. Maternal

- to

- fetal transfer of Pb appears to be related partly to the 19



### mobilization of Pb from the mater nal skeleton. 20



## 1.3 Integrative Overview of Health and Ecological Effects

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



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



### ( Table 2

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



### human health and ecological endpoints are altered ion status, protein bi nding, oxidative 24



### stress, inflammation, endocrine disruption and cell death/genotoxicity ( Figure 1

- 2 ). The 25



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



### of the evidence across disciplines ( Table 2

- 4 ). The mechanisms of Pb toxicity are likely 27



### conserved from invertebrates to vert ebrates, including humans in some organ systems. 28



### See Section 2.8.1 for additional detail s

. 29February 2012 1

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### Figure 1

- 2 Schematic representation of the relat ionships between the

various MO As by which Pb exerts its effects.

1.3.1 Health Effects of Lead

Evidence from epidemiologic and toxicological studies was considered in combination 1



### with the evidence from other disciplines such as exposure sciences and toxicokineti cs in 2



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



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



### the organ system

- specific causal determination are summarized in Tabl e 1

- 1 below. Tabl e 5



### 1

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



### information can be found. 7February 2012 1

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### Tabl e 1

- 1 Summary of causal determinations between exposure to Pb and

health outcomes

Outcome a 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 f or 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

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



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



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



### levels with decreme nts in cognitive function in children, i.e., full

- scale IQ and various 4



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



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



### a thre shold for Pb

- related impaired cognition. Epidemiologic and toxicological evidence 7



### also clearly demonstrates Pb

- associated increases in behavioral problems, in particular, 8



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



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



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



### SES

- related variables. In children, the weight of evidence supports cognitive funct ion 12



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



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



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



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



### demonstrates neurodevelopmental effects with prenatal and early postnatal Pb exposures 17



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



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



### provided by evidence characterizing underlying mechanisms, including Pb

- induced 20February 2012 1

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### changes in neurogenesis, synaptogenesis and synaptic pruning, long term potentiation

, 1



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



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



### and toxicological studies is sufficient to conclude that there is a causal rel ationship 4



### between Pb exposures and nervous system effects (Section 2.6 .1 ). 5



### Cardiovascular Effects

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



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



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



### epidemiologic and toxicological studies substantiated the evidence that long

- term Pb 9



### exposure is associated with cardiovascular effects in adults with the largest b ody of 10



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



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



### associations between biomarkers of Pb and BP and hypertension and by effect esti mates 13



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



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



### contributing to the observed associations since the populations studied w ere likely to 16



### have higher past than recent Pb exposure. Anima l toxicological studies provide 17



### mechanistic evidence to support the biological plausibility of Pb

- induced hypertension, 18



### including Pb

- induced oxidative stress, activation of renin

- angiotensin aldo sterone system 19



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



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



### spectrum of other cardiovascular endpoints examined is sufficient t o conclude that there 22



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



### (Section 2.6.2 ). 24



### Renal Effects

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



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



### presented in the 2006 Pb AQCD

. The weight of epidemiologic evidence consistently 27



### demonstrates a r elationship between higher blood Pb level and kidney dysfunction 28



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



### rate [GFR]) in nonoccupationally

- exposed adults. Associations between Pb biomarker 30



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



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



### and alcohol use; however, there is uncertainty regarding the level, timing, frequency, and 33February 2012 1

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### du ration of Pb exposure contributing to the observed associations, since the populations 1



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



### epidemiologic finding s is provided by observations from animal m odels that Pb exposu re 3



### for long er than 6 months decreases GFR and increases serum creat inine. The weight of 4



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



### including tubular atrophy and sclerosis. By demonstrating Pb

- induced renal oxidative 6



### s tress, inflammation, mitochondrial dysfunction, apoptosis, and glomerular hypertrophy, 7



### toxicological studies provide biological plausibility for the associations observed in 8



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



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



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



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



### Immune System Effects

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



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



### parameters related to cellular and humoral immunity ( Figure 5

- 42 ). The principal 15



### findings are Pb

- induced increased production of Th2 cytokines, suppressed production of 16



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



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



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



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



### children provide evidence for Pb

- associated increases in IgE. The toxicological and 21



### epidemiologic findings for the Pb

- induced effects on Th2 cytokines, IgE, and 22



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



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



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



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



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



### characterized in children or adults. E pidemiologic studies of children and adults primarily 28



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



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



### responses in toxicological studies combined with the supporting epidemiologic evidence 31



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



### exposures and immune system effects (Section 2.6.4 ). 33February 2012 1

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### Heme Synthesis and Red Blood Cell Function

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



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



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



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



### consistent Pb

- induced alterations in several inter

- connected hematological parameters 5



### su ch as hemoglobin (Hb), hematocrit (Hct), and mean corpuscular volume (MCV) 6



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



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



### (ALAD), the enz yme that catalyzes the second, rate

- limiting step in heme biosynthesis. 9



### For heme synthesis, th e largest body of evidence indicates decreased ALAD activity in 10



### association with Pb exposure or blood Pb levels in occupationally

- exposed adults or in 11



### children (3

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



### of action by which Pb may exert effects, primarily comes from studies of occupationally

13



### exposed adults and of children. the level, frequency, timing and duration of exposure 14



### ass ociated with altered RBC survival and function, heme synthesis, or the state of 15



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



### findings in epidemiologic studies investigating effects in occupationally

- exposed adult s 17



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



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



### between Pb exposures and effects on heme synthesis and RBC function (Sec tion 2.6.5 ). 20



### Reproductive and Developmental Effects

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



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



### reproduction and development

, and expand s evidence for additional endpoints. The 23



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



### puberty in both m ales and females ; and detrimental effects on sperm and semen quality in 25



### occupationally

- exposed males and in laboratory animals. In cross

- sectional 26



### epidemiologic studies of girls (ages 6

- 18 years) consistent associations with delayed 27



### pubertal development (m easured by age at menarche, pubic hair development, and breast 28



### development) were observed. In boys (ages 8

- 15 years), fewer studies were conducted 29



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



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



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



### across epidemiologic and toxicological studies (which examined Pb

- induced detrimental 33



### effects on spe rm and on delayed onset of puberty), is sufficient to conclude that there is a 34February 2012 1

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### causal relationship between Pb exposures and reproductive and developmental effects 1



### (Section 2.6.6 ). 2



### Cancer

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



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



### and genotoxic effects in humans. The conclus ions of the 2006 Pb AQCD were consistent 5



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



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



### strongest evidence for an association between cancer and Pb exposure

, with some 8



### supporting evidence provided by the epidemiologic literature. Evidence from 9



### toxicological studies demonstrates a relationship between Pb and cancer, 10



### genotoxicity/clastogenicity or epigenetic modificatio n. Carcinogenicity in previous 11



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



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



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



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



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



### associations between Pb exposure and brain cancer were observed amon g individuals 17



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



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



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



### 1.3.2 Ecological Effects of Lead

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



### effects in terrestrial organisms incl uded decreased survival, reproduction and growth as 22



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



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



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



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



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



### aquatic biota. These effects can b e observed at multiple levels of biological organization, 28



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



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



### neurobehavior ma y increase susceptibility to other stressors and impact fitness of 31



### individual organisms. Effects on development, reproduction, growth and survival may 32February 2012 1

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### lead to effects on communities and ecosystems. The relationship of exposure and 1



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



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



### species and lifestage differences in Pb sensitivity. 4



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



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



### and ecosystem level effects is provided below and summarized in Table 1

- 2 . Causal 7



### determinations were based on consideration and integration of information on 8



### biogeochemistry, bioavailability, biological effects, and exposure

- response relationships 9



### of Pb in terrestrial and aquatic environ ments. A detailed discussion for all relevant 10



### welfare effects is provided in Chapters 2 and 7. 11



### Table 1

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

vertebrates

Effect a Terrestrial Aquati c b

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

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



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



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



### susceptibility to other stressors

, and of reduction in individual fitness. Markers of 15



### oxidative damage and ant ioxidant activity have been observed in a wide range of species 16February 2012 1

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### in terrestrial and aquatic environments when Pb is present, and following laboratory 1



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



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



### vertebrates (Section 2.7.3.1 ). 4



### Hematological Effects

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



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



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



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



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



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



### causal relationship between Pb exposures and hematological effects in aquatic 11



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



### between Pb exposures and hematological effects in terrestrial invertebrates 13



### (Section 2.7.3.2 ). 14



### Neurobehavioral Effects

Historical and recent evidence from Pb

- exposed animals indicates that Pb affects 15



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



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



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



### on nervous system endpoints in bot h aquatic and terrestrial animal taxa. Overall, the 19



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



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



### and aquatic invertebrates and vertebrates (Section 2.7.3.3 ). 22



### Effects on Development and Reproduction

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



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



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



### at the organismal level can result in declining abundance and/or ex tirpation of 26



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



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



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



### invertebrates and vertebrates indicate that Pb is affecting fecundity of Pb

- exposed 30February 2012 1

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### organisms in both aquatic and terrestrial habitats, and the evidence is sufficient to 1



### conclude that there is a causal relationship between Pb exposures and repr oductive effects 2



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



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



### in plants (Section 2.7.3.4 ). 5



### Effects on Growth

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



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



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



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



### concentrations or in field studies near point sources. Evid ence for Pb effects on growth in 10



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



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



### general, juvenile organisms are more sensitive t han are adults. There are limited data on 13



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



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



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



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



### terrestrial and aquatic vertebrates (Section 2.7.3.5 ). 18



### Effects on Survival

Decreased survival of individuals within a population can have ecosystem

- level impacts. 19



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



### environmen t away from point sources, probably due to the fact that plants often sequester 21



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



### invertebrates are generally more sensitive to Pb exposure than other taxa, with sur vival 23



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



### concentrations near common ambient levels. Terrestrial invertebrates typically tolerate 25



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



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



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



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



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



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



### invertebrates and vertebrates (Section 2.7.3.6 ). 32February 2012 1

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### Community and Ecosystem Effects

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



### ecosystem structure and function. Decreases i n abundance, reduced species diversity and 2



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



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



### natural ecosystem level effects. Assessment of Pb

- specific exposure

- response 5



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



### as other metals, physico

- chemical variables, or various stressors cannot be controlled. 7



### These factors make it difficult to quantify rel ationships between ambient concentrations 8



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



### effects of Pb at the highest levels of ecological organization, and for species

- level 10



### endpoints with direct relevance to population and ecosystem level effects 11



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



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



### species composition and biodiversity in ter restrial and aquatic ecosystems 14



### (Section 2.7.3.7 ). 15



## 1.4 Policy Relevant Considerations

Public Health Significance

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



### continuously

- distributed subclinical health endpoints frequently studied in association 17



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



### small increase in the mean of a cont inuously distributed health index may push the most 19



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



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



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



### clinical events if a large population is affected. Pb

- associated changes in subclinical 23



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



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



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



### achieving very high IQ scores. Additional s mall increases in blood pressure or decreases 27



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



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



### chronic k idney disease , respectively. 30February 2012 1

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### Air Lead

- to

- Blood Lead Relationships

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



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



### AQCD and more recent studies provide data from which estimates of the blood Pb

- air Pb 3



### slope can be derived for children. The range of estimates from these st udies is 4



### 2 to 9 μg/dL per μg/m 3 

### . The differences in the estimates across studies may reflect model 5



### sel ection by the investigators ( e.g., some models predict an increase in the blood Pb

- air 6



### Pb slope with decreasing air Pb concentration while other models pr edict a constant 7



### blood Pb

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



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



### air Pb. Other factors that may explain the variation in t he derived blood Pb

- air Pb slope 10



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



### smelter). 12



### Ecological Effects and Corresponding Lead Concentrations

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



### onto terrestrial and aquatic ecosystems and to subsequent movement of atmospherically

14



### deposited Pb through environmental compartments ( e.g., soil, sediment, water, and biota) 15



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



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



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



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



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



### species dif ferences in Pb susceptibility. Current evidence indicates that Pb is 21



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



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



### addi tion, there are large differences in species sensitivity to Pb, and many environmental 24



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



### Concentration

- Response Relationships for Health Effects

With each successive asse ssment to

- date, the epidemiologic and toxicological study 26



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



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



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



### blood Pb levels was presented in the 2006 Pb AQCD based on the international poo led 30



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



### focusing on the shape of the concentration

- response function and several recent studies 32February 2012 1

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### support these findings. The majority of the epidemiologic evidence from stratifi ed 1



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



### larger negative slopes at lower blood Pb levels ( Fi gure 2

- 2 ). Several lines of toxicological 3



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



### differential activation of mechanisms underlying cognition. The shapes of con centration

5



### response relationships were examined in a more limited number epidemiologic studies of 6



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



### Pb Exposure and Nervous System Effects in Children

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



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



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



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



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



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



### early

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



### childhoo d tooth Pb levels. However, the weight of epidemiologic evidence supports 15



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



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



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



### exposures may contribute to lower cognitive function in young children. E xposures that 19



### are reflected by concurrent blood Pb measured when children are older, by cumulativ e 20



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



### neurodevelopmental deficits throughout school

- age and into adolescence. These findings 22



### are consistent with the understanding that the nervous system continues to deve lop 23



### throughout childhood. 24



### Potentially At

- Risk Populations

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



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



### risk for health effect s in response to ambient air pollutant exposure. The most well

27



### substantiated at

- risk population for the effects of Pb exposure is children. Among 28



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



### levels, with levels de creasing with increasing age of the children. Recent epidemiologic 30



### studies of infants/children detected increased risk of Pb

- related health effects, and this 31



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



### early childho od (ages 1

- 4 years), may underlie the elevated risk of neurodevelopmental 33February 2012 1

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



### Pb

- related risk including sex, genetics, pre

- existing disease ( e.g., hypertension), 2



### race/et hnicity, SES, nutrition, stress and co

- exposure to other metals ( Table 2

- 9 ). 3



## 1.5 Summary

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



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



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



### 2

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



### compares th em to the findings from this assessment, including causality determinations, 8



### regarding the health and ecological effects of Pb. 9



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



### that are best substantiated as occurri ng at the lowest blood lead concentrations. Some new 11



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



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



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



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



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



### As lead exposures were gene rally higher in the past than they are today, uncertainties 17



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



### of the lead

- related health effects in the adult populations studied. 19



### With regard to the ecological effec ts of Pb at or near concentrations currently present in 20



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



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



### survival in both invertebrat e and vertebrate aquatic biota. These effects are observed at or 23



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



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



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



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



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



### population, community and ecosystem level of biological organization. 29