Health Effects of Lead Exposure

Susan K. Cummins, MD, MPHSenior Science Advisor

Pediatric & Maternal Health StaffOffice of New Drugs

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Today’s Talk

• Blood lead distribution & trends over time

• Trends in measurement and modeling of exposure

• Health effects in children and adults

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Lead in Arctic Snow Strata

Year

Per

cen

t o

f C

urr

ent

Co

nce

ntr

atio

n

0%

20%

40%

60%

80%

100%

120%

1750 1820 1930 1950 1975

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Geometric Mean Blood Lead Levels by Gender & Age

NHANES III, 1991 to 1994

00.5

11.5

22.5

33.5

44.5

5

1-2 3-5 6-11 12-19 20-29 30-39 40-49 50-59 60-69 >=70

Age (years)

Ge

om

etr

ic m

ean

b

loo

d le

ad

leve

l (u

g/d

L)

Env Health Perspect, 1998

Females

Males

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Geometric Mean Blood Lead Levels in Children 1 to 5 years

National Health & Nutrition Surveys

0

2

4

6

8

10

12

14

16

1976-1980 1988-1991 1991-1994 1999-2000

Geo

met

ric M

ean

Blo

od L

ead

Leve

ls

in u

g/dL

who

le b

lood

NHANES II NHANES III NHANES III NHANES IV

Source: CDC

14.9

3.62.7 2.2

6

13 ug/dL

3 ug/dL2 ug/dL

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Common Lead Sources• Children

– Deteriorated paint– Contaminated dust,

water, soil, food– Occupational take-

home exposure– Folk remedies– Imported ceramic

pots, toys– Many others

• Adults– Occupational (90%)– Hobbies (stained

glass, packing shot)– Folk remedies– Imported ceramic

pots– Contaminated food– Many others

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Uptake, Distribution, Metabolism and Excretion

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Primary Routes of Lead Exposure

• Inhalation

– Only particles of respirable size (< 1um)

• Ingestion

– Inhaled lead particles > 2.5 um in diameter

– Absorption influenced by:

• Presence of other nutrients (iron, zinc, calcium)

• Age—Children ~ 50% Adults ~ 10-20%

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Exposure Scenarios

Time

Blood Lead Level

Brief Acute Exposure

Long Term Chronic Exposure

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Lead Uptake, Deposition & Excretion

Source: EPA

Blood

Bone

Soft Tissue

Kidney

Urine

Humans

InhailedAir

Ingested Dust, Food & Water

Feces, Sweat,Hair, Nails

Bone Lead Body BurdenAdults – 90-95%

Children – 80-95%

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Circulating Lead Increases with:

• Physiologic states that heighten bone resorption--

– Pregnancy & lactation– Prolonged bed rest (fracture in traction)– Postmenopausal osteoporosis– Hyperthyroidism– Weightlessness

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Measuring Human Lead Exposure and Body Burden

• Blood Lead Level – If brief exposure – half-time 35 days– If long term exposure – slower clearance, ongoing lead

exposure equilibrates with stores in soft tissue & bone

• Bone Lead Level -- by K X-Ray Florescence – Measures cumulative body burden

• Cortical bone (tibia) – clearance half-time decades• Trabecular bone – clearance half-time years to decades

• Cumulative Blood Lead Index (CBLI) – Area under the curve of blood lead levels over time,

estimates cumulative lead dose

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Blood Lead Trends

Treatment Lead Exposed Children Trial

NEJM, 2001

• First year— small BLL drop

• Three years– No IQ impact

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Health Effects in Children

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Lead is a Systemic ToxicantHealth Effects in Children

Lead inBlood(ug/dL)

150

100807060

30

25

105

CDC Levelof Concern

1978

1985

1991

AdverseEffect

Death

AcuteEncephalopathy

Abdominal painMicrocytic anemia

Attention DeficitsLearning Disabilities

School Failure Behavior Problems

Reduced IQ

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18

19

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IQ Impairment from Blood Leads < 10 ug/dL

• Canfield & Colleagues, NEJM in April, 2003

• 172 children

• Serial Blood Lead measured every 6 months from 6 to 36 months, then at 48 & 60 months

• Stanford-Binet IQ scales at 3 and 5 years

• Impact of Blood Lead on IQ measured, after adjustment for maternal IQ and covariates

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IQ vs. Lifetime Average Blood Lead Concentration

Canfield, NEJM 2003

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Effect Size

• Linear Model, all Blood Leads: 4.6 point IQ decline for every 10 ug/dL increase in Blood Lead

• Non-linear Model, only Blood Leads below 10 ug/dL: IQ decline of 7.4 points

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Blood Lead & IQ

• Blood lead > 10 ug/dL lowers IQ by 2 to 4 points

• Doubles low IQ

• Halves high IQ

• Blood lead 1 to 10 ug/dL lowers IQ by 7 points

Verbal IQ

Cu

mu

lati

ve F

req

uen

cy D

istr

ibu

tio

n

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Lead Poisoning Causes Anemia

• Hypochromic, microcytic red blood cells

• Mimics & may occur with iron deficiency

• Rare with Blood Lead Levels < 35 ug/dL

• High Free Erythrocyte Protoporphyrin (FEP)

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Other Health or Behavioral Effects in Children & Youth

• Executive function disorders

• Complications of ADHD & school failure

• Delayed onset of puberty

• Dental carries

• Reduced linear growth

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Health Effects in Adults:Adult Workers

General Population

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Lead is a Systemic ToxicantHealth Effects in Adults

Lead inBlood(ug/dL)

150

100807060

30

AcuteExposue

Headache Confusion

Abdominal painNausea, VomitingMicrocytic anemia

ChronicExposue

Fatigue, ApathyGastrointestinal complaints

Distal motor neuropathyGout, Arthritis

Impaired concentrationRenal disease

Microcytic anemia

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Health Effects in Adult Workers

• Hematological: Microcytic anemia

• Neurological:• Irritability, headache, poor memory, tremor, depression

• Acute encephalopathy

• Peripheral neuropathy-- slowed nerve conduction, motor > sensory

• Gastrointestinal: colic, constipation, anorexia, nausea, vomiting

• Renal toxicity: • Gradual decline in renal function & interstitial fibrosis• Hypertension, hyperuricemia with/without gout

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Reproductive Effects in Adult Workers

• Males– Impotence – Reduced sperm counts & production– Malformed sperm with reduced motility

• Females – Menstrual disturbances – Sterility – Spontaneous abortions – Stillbirths

• Both -- genetic damage to germ cells

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Carcinogenesis

• 2004—National Toxicology Program– Found Lead & Lead Compounds, “Reasonably

anticipated to be human carcinogens”

• 2006—WHO, IARC Monograph – Inorganic Lead Compounds —probably

carcinogenic to humans

– Organic Lead Compounds —not classifiable as to their carcinogenicity to humans

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Health Effects in Adults From Low Level Exposure

• Hypertension & Renal Disease

• Cardiovascular Disease

• Cognition

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Lead Exposure and HypertensionAdults

• Multiple Reviews and Meta-Analyses of..

• 30 original observational studies with

• Approximately 60,000 participants

• Conclusion: Low level lead exposure is associated with hypertension

• For every 2-fold increase in blood lead (e.g. from 5 to 10 ug/dL) 0.6 to 1.25 mmHg increase in systolic blood pressure

• Findings supported by animal studies

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Lead Exposure and Cognitive Function

• Meta-Analysis conducted in 2007

• Study participants had environmental exposure or current or past occupational exposure to lead

• Supported an association between lead dose and decrements in cognitive function in all three cohorts

• Affected cognitive domains: verbal & visual memory, motor & psychomotor speed, manual dexterity, attention, executive functioning, peripheral motor strength

• Dose-response relationship in nearly all studies

EHP, 115:483, 2007

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Lead Effect Studies within the Normative Aging Study

• From cohort of 2,280 Boston resident men, selected a subset of 719 men without occupational exposure at entry

• Enrollment began 1961

• 21 to 80 years old at enrollment

• Few employed in lead occupations

• No chronic diseases or HTN at entry

• Follow up every 3 to 5 years (survey, physical exam, laboratory work)

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Lead Burden Assessment Normative Aging Study

• 1991: Blood lead & bone lead measured

• Blood Lead Distribution (n and percent): • Below 5 ug/dL (270) 38%

• 5 to 10 ug/dL (361) 50%

• 11 to 20 ug/dL (80) 11%

• > 20 ug/dL (8) 8%

• Bone Lead Burden (range and geometric mean):• Tibia: (<1-51 ug/g bone) & 20.8 ug/g bone

• Patella: (3-77 ug/g) & 29.8 ug/g bone

• Bone lead level correlated with & was the major contributor to blood lead level

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Conclusions

• Lead is a systemic toxicant with no evidence for a “safe” exposure threshold

• Integration of bone lead with blood lead measurements allows for more precise categorization of lead exposure

• Recent evidence demonstrates harm in the from low level lead burdens in children & adults