Health Effects of Lead Exposure Susan K. Cummins, MD, MPH Senior Science Advisor Pediatric & Maternal Health Staff Office of New Drugs

Today’s Talk Blood lead distribution & trends over time Trends in measurement and modeling of exposure Health effects in children and adults

Lead in Arctic Snow Strata 0% 20% 40% 60% 80% 100% 120% 1750 1820 1930 1950 1975 Percent of Current Concentration Year

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

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 1976-1980 1988-1991 1991-1994 1999-2000 NHANES II NHANES III NHANES III NHANES IV Source: CDC

13 ug/dL 3 ug/dL 2 ug/dL

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

Uptake, Distribution, Metabolism and Excretion

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%

Exposure Scenarios Time Blood Lead Level Brief Acute Exposure Long Term Chronic Exposure Time

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

Circulating Lead Increases with: Physiologic states that heighten bone resorption-- Pregnancy & lactation Prolonged bed rest (fracture in traction) Postmenopausal osteoporosis Hyperthyroidism Weightlessness

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

Blood Lead Trends Treatment Lead Exposed Children Trial First year— small BLL drop Three years– No IQ impact NEJM, 2001

Health Effects in Children

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

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

IQ vs. Lifetime Average Blood Lead Concentration Canfield, NEJM 2003

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

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

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)

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

Health Effects in Adults: Adult Workers General Population

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

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

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

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

Health Effects in Adults From Low Level Exposure Hypertension & Renal Disease Cardiovascular Disease Cognition

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

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

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)

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

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