1. Health Effects of Lead Exposure
Susan K. Cummins, MD, MPH
Senior Science Advisor
Pediatric & Maternal Health Staff
Office 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 Strata0%
20%
40%
60%
80%
100%
120%
1750
1820
1930
1950
1975
Percent of Current Concentration
Year

4. Geometric mean blood lead level (ug/dL)
Geometric Mean Blood Lead Levels by Gender & Age NHANES III, 1991 to 1994
Males
Females
Geometric mean blood lead level (ug/dL)
Age (years)
Env Health Perspect, 1998

5. Geometric Mean Blood Lead Levels
Geometric Mean Blood Lead Levels in Children 1 to 5 years National Health & Nutrition Surveys 16 14
14.9 12 10
Geometric Mean Blood Lead Levels
in ug/dL whole blood 8 6 4
3.6 2
2.7
2.2
NHANES II
NHANES III
NHANES III
NHANES IV
Source: CDC

6. 13 ug/dL
3 ug/dL
2 ug/dL

7. Common Lead Sources Children Adults 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

8. 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
Time

11. Lead Uptake, Deposition & Excretion
Blood
Bone
Soft Tissue
Kidney
Urine
Humans
Inhailed
Air
Ingested Dust, Food & Water
Feces, Sweat,
Hair, Nails
Bone Lead Body Burden
Adults – 90-95%
Children – 80-95%
Source: EPA

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
First year— small BLL drop
Three years– No IQ impact
NEJM, 2001

15. Health Effects in Children

16. Lead is a Systemic Toxicant Health Effects in Children
Lead in
Blood
(ug/dL)
150
100 80 70 60 30 25 10 5
Adverse
Effect
Death
Acute
Encephalopathy
Abdominal pain
Microcytic anemia
Attention Deficits
Learning Disabilities
School Failure
Behavior Problems
Reduced IQ
CDC Level
of Concern
1978
1985
1991

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
Verbal IQ
Cumulative Frequency Distribution
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

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 Toxicant Health Effects in Adults
Lead in
Blood
(ug/dL)
150
100 80 70 60 30
Acute
Exposue
Headache
Confusion
Abdominal pain
Nausea, Vomiting
Microcytic anemia
Chronic
Exposue
Fatigue, Apathy
Gastrointestinal complaints
Distal motor neuropathy
Gout, Arthritis
Impaired concentration
Renal 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 Hypertension Adults
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