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Health Effects of Lead Exposure
Susan K. Cummins, MD, MPHSenior Science Advisor
Pediatric & Maternal Health StaffOffice of New Drugs
2
Today’s Talk
• Blood lead distribution & trends over time
• Trends in measurement and modeling of exposure
• Health effects in children and adults
3
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
4
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
5
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
7
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
9
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%
10
Exposure Scenarios
Time
Blood Lead Level
Brief Acute Exposure
Long Term Chronic Exposure
11
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%
12
Circulating Lead Increases with:
• Physiologic states that heighten bone resorption--
– Pregnancy & lactation– Prolonged bed rest (fracture in traction)– Postmenopausal osteoporosis– Hyperthyroidism– Weightlessness
13
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
14
Blood Lead Trends
Treatment Lead Exposed Children Trial
NEJM, 2001
• First year— small BLL drop
• Three years– No IQ impact
15
Health Effects in Children
16
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
17
18
19
20
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
21
IQ vs. Lifetime Average Blood Lead Concentration
Canfield, NEJM 2003
22
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
23
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
24
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)
25
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
26
Health Effects in Adults:Adult Workers
General Population
27
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
28
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
29
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
30
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
31
Health Effects in Adults From Low Level Exposure
• Hypertension & Renal Disease
• Cardiovascular Disease
• Cognition
32
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
33
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
34
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)
35
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
36
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
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