The ‘Heavy Weight’ of LEAD in 21 st Century Developing Nations

1. The ‘Heavy Weight’ of LEAD in 21st Century Developing Nations Hoffman Moka Lantum, MD, PhD Health and Environmental Laboratories, Eastman Kodak Company Hoffman.lantum@kodak.com President, African Society for Toxicological Sciences (ASTS)

2. Lead (Latin, plumbum) • The Anglo-Saxon word "lead" means "liquid silver“ • The Latin word is "plumbum" the origin of the symbol Pb • LEAD is a bluish-white lustrous metal • Lead has been known for ages and is mentioned in Exodus. • Used in the construction of the hanging gardens of Babylon in pre-Roman times.

3. Household sources of exposure to LEAD… • Used by the Romans for plumbing (the decline of the Roman empire is attributed to lead in the water supply!) • Resurgence in usage during the industrial revolution • cable covering, plumbing*, ammunition, crystal glass, cookware and glazed ceramics, solder alloying, insecticides. • storage batteries in automobile industry • an antiknock compound in petrol (tetra ethyl lead)* • used extensively in paints*, used to contain corrosive liquids *major source for Africa and low income countries

4. Chipping paint on wall from a house in Rochester…

5. The finished house after sanding and repainting by 43 yr old male patient presenting at Strong Memorial with Lead poisoning

6. Serial blood lead levels in patient - during chelation therapy.

7. Routes of Lead Exposure • ORAL: Lead goes down iron or calcium absorption pathway in GIT (soil, paint chips, plumbing, food). • Children absorb ~50% orally dose; adults ~10%. • Children also have more hand to mouth activity. • Lead absorption is enhanced if diet is poor in iron or calcium. • Pica is one of the worst risk factors. • RESPIRATORY: Lead can be inhaled (outdoor/indoor air). • DERMAL: Tetraethyl lead can be absorbed via skin (gasoline).

8. Abdominal X-ray of a 4 year old Rochester child who ingested paint chips. Paint chips are radio-dense. (1971)

9. Evolution of LEAD poisoning… • Description of classical lead poisoning by Greek Physician Nikander inAlexipharmac:Pallor, abdominal pain, dangling paralytic hands, and ocular disturbance leading to death… • Industrial exposure associated with Reproductive function – abortion, still births, premature delivery, increased infant mortality • women not allowed to work in industries with considerable lead exposure • Environmental contamination (1920-60), particularly in urban areas, manifest as childhood lead poisoning – due to ingestion of lead-containing paint in houses. • Presented as epilepsy, coma, headaches, tremor – permanent brain and nerves damage affecting behavior – mental retardation and frequent convulsive seizures

10. Lead Poisoning Probable Cause Of Beethoven’s illnesses - Chemical Study of Hair Leads to Long-Sought Answers A four-year project to solve the mystery of what caused years of chronic illness of composer Ludwig van Beethoven has ended with an answer: lead poisoning. This toxin also may have contributed to his ultimate death. He suffered from bad digestion, chronic abdominal pain, irritability and depression. The Health Research Institute and Pfeiffer Treatment Center, 1804 Centre Point Circle, Naperville, Illinois 60563 http://www.sjsu.edu/depts/beethoven/hair/hairtestpr.html Naperville, Ill.- Oct. 17, 2000.

11. Distribution of Lead • 95% in long bones • Binds into matrix. • ~ t1/2 = 15–20 years • Released during osteolysis – menopause, gestation, fracture • 4% in soft tissue - brain, liver, kidneys. • Concentration is Schwann cells; t1/2 ~2 years • Crosses placenta, fetal toxicity • 1% blood – bound to heme in erythrocytes or free. • t1/2 ~ 35 days • Hair?

12. Concentration-dependent toxicity Environmental lead exposure: a public health problem of global dimensions. Shilu Tong, Yasmin E. von Schirnding, & Tippawan Prapamontol. Bulletin of the World Health Organization, 2000, 78 (9)

13. How High is Too High? A. 5 mg/dL – affects blood functions – immune system, anemia B. 10 mg/dL – effects on brain & nerves proven C. 15 mg/dL kidney, bone, teeth, blood pressure D. 20 mg/dL intestinal spasm, reproduction E.  40 mg/dL severe neurological disorders It is not known, but probably any level is too high

14. Normal Red blood cells (× 1500). Red Blood Cells in LEAD poisoned patient – reduced density in center and stripping.

15. Effects of LEAD on Synaptogenesis

16. Lead and Neurodevelopment • Lower IQ. • Each 0.48 µmol/l (10µg/dl) in children = 4 to 7 IQ points (US Acad. Pediatrics). • Reading difficulties that places the child at high risk for academic failure and delinquency. • Deficits in writing, drawing and construction. • Effects on behaviour are FAR WORSE. • Clumsiness that could exclude a child from fully engaging in sports and other activities. • Attention problems that can lead to academic underachievement and behavior problems in class. • Decreased impulse control leading to antisocial behavior and juvenile delinquency. • Delinquency rates are 8 times higher in the top 30% of bone lead. Needleman 1996. Needleman, Herbert L. et al, "Bone Lead Levels and Delinquent Behavior," JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Vol. 275, No. 5 (February 7, 1996), pgs.363-369. • Measurable adverse behaviour changes in 2 year olds Mendelsohn 1999. Alan L. Mendelsohn, Benard P. Dreyer, Arthur H. Fierman, Carolyn M. Rosen, Lori A. Legano, Hillary A. Kruger, Sylvia W. Lim, and Cheryl D. Courtlandt "Low-Level Lead Exposure and Behavior in Early Childhood“ Pediatrics 1998; 101: e10

17. Relationship between Lead & Classroom Behavior

18. IQ Lead effects on Population IQ status Costly to society Attention Control

19. Mechanism of neurotoxicity • Disrupts BBB • primary injury to astrocytes • secondary damage to the endothelial microvasculature. • Lead-induced brain damage preferentially in • the prefrontal cerebral cortex, hippocampus and cerebellum. • Some characteristic clinical features of lead poisoning may be attributed to this specific anatomical pattern.

20. Target on Ca++-dependent signal transduction • Molecular targets unknown • disruption of Ca++-regulated processes? • Competition: Picomolar concentrations of lead can replace micromolar concentrations of calcium in a protein kinase C (PKC) enzyme assay. • Molecular mimicry: LEAD activates PKC in intact cells and induces PKC-dependent gene expression. • Learning deficits caused by lead are associated with synaptic PKC-regulated events. Bressler J, Kim KA, Chakraborti Goldstein G. Molecular mechanisms of lead neurotoxicity. Neurochem Res 1999 Apr;24(4):595-600 • Effects on other Ca++-binding proteins – calmodulin/CAM-Kinase complexes, IP3 & ryanodine receptor function, voltage-gated channels are largely unknown. Finkelstein Y, Markowitz ME, Rosen JF Low-level lead-induced neurotoxicity in children: an update on central nervous system effects Brain Res Brain Res Rev 1998 Jul;27(2):168-76

21. Update on LEAD and Neurodegeneration • Cognitive tasks altered by elevated Bone-LL in elderly - slower responses for pattern memory. • Payton M, Riggs KM, Spiro A 3rd, Weiss ST, Hu H Relations of bone and blood lead to cognitive function: the VA Normative Aging Study. Neurotoxicol Teratol 1998 Jan-Feb;20(1):19-27 • BLL ~ 8 mg/dl significantly associated with poorer neuropsychological function • Muldoon SB, Cauley JA, Kuller LH, Morrow L, Needleman HL, Scott J, Hooper FJ Neuroepidemiology 1996;15(2):62-72 • Acute tetraethyllead intoxication in rabbits associated with hydropic degenerating neurons and classic neurofibrillary tangles characteristic of Alzheimer's pre-senile dementia in man. • Niklowitz WJ Neurofibrillary changes after acute experimental lead poisoning. Neurology 1975 Oct;25(10):927-34 • Unanswered questions • Does lead contribute to cognitive decline and Alzheimer’s disease? • Is lead a modifiable risk factor for dementia?

22. Percent > 10 µg/dL 0 1 - 9 10 - 19 20 - 29 30 - 39 40 - 49 > 50 Non-residential LEAD Exposure in USA – paint, innercity houses! Distribution of Elevated BLL ( > 10 µg/dL) Among 20,296 Children in Monroe County, October 1, 1994 - September 31, 1995

23. BLL by Age: City vs. Non-City

24. Percentage of Screened Children with Elevated Blood Lead Levels 1993-2000 by Monroe County Locality Rochester 24% Mendon 6% Brighton 4% Ogden 2% Chili 3% Parma 3% Clarkson 5% Penfield 2% Gates 4% Perinton 3% Greece 3% Pittsford 3% Hamlin 3% Webster 3% Henrietta 4% Wheatland 3% Irondequoit 4%

25. Lead Exposure in Africa • Major sources: • Gasoline – soil, air • Lead-containing paint - dust • Industrial release - air • Minor • Leaded pipes - public water system • Fertilizers - soil • Building materials – dust • Food – seafood, plant products, canned food

26. Ban on Production Marketing of Lead in gasoline implemented in 1978

27. 20 years later! – Africa Left behind EarthTrends: Featured Topic Title: Laden with Lead Author(s): Staff of World Resources Program Source: World Resources 1998-99 Date written: 1998, updated October 2001

29. Actions: • Focus on enacting • policy (*) • Limited public • Awareness() • Same for USA – United Way Day of Caring Campaign against lead poisoning in 2004 * 

30. Regional targeting!!

31. Summary: use of unleaded gasoline is still a problem • >50% of gasoline sold in Sub-Saharan Africa is unleaded • 9 countries – No unleaded gasoline – Nigeria since 2003 • 14 countries – partial action • 21 countries – action planning stage • reduce the lead content in gasoline to an average of 0.2g/L by 2003. • lead content in gasoline highest in African markets ~ 0.5 g/L • UNEP resolution to ban the use of unleaded gasoline in Sub-Saharan Africa scheduled for December 31, 2005 • Catalytic converter - low cost intermediate action

32. Impact on environment: soil and crops U R

33. Africa: Urban vs. Rural exposure • Data from children considered • Prevalence in urban areas > rural areas • Senegal: U - mean BLL = 10.7 mg/dl; R - mean BLL = 6.8 mg/dl • S. Africa: U - mean BLL = 10.0 mg/dl; R - mean BLL = 3.8 mg/dl • Nigeria: U - mean BLL = 10.6 mg/dl; R - mean BLL = 6.8 mg/dl • BLL similar to inner city of USA • High prevalence of elevated BLL > 50% in many urban city dwellings in African countries

34. Impact on environment: water and livestock

35. Relative contribution of sources • Children: BLL reflects recent environmental exposure • Adults: BLL reflects recent release from internal stores or occupational exposure • Perinatal exposure (?)

36. Post-unleaded gasoline Decreases in BLL 1980’s-1990’s

37. EarthTrends: Featured Topic Title: Laden with Lead Author(s): Staff of World Resources Program Source: World Resources 1998-99 Date written: 1998, updated October 2001 Africa vs. Other Low Income regions USA (1994) Post use of unleaded gas Mean BLL: 2.3 mg/dL Poisoned: 2.2% BLL > 10 mg/dL

38. CHILDREN’S ENVIRONMENTAL HEALTH: RISKS AND REMEDIES by Liz Creel

39. Environmental Health: A Global Access Science Source 2003, 2:5

40. Disease burden on given population • Estimated by Disability-Adjusted Life Years (DALY) • DALY combines the burden per 100,000 population due to death and disability in a single index

41. DALY for Lead in Africa vs. Other regions

43. 1 1 2 1 2 2 1 3 3 3 3 2 Environmental vs occupational/industrial toxicology • Emerging issues • Co-morbidities of environmental origin not on radar • Growing industrial sector – OECD guidelines/TSCA 8a

44. * * * * * Global: burden of disease from various risk factors • Worldwide: • 120 million people with BLL ~ 5-10 mg/dl • ~120 million people with BLL >10 mg/dl • 40% of children have BLL >5 mg/dl. • 97% of affected children live in developing regions.

45. Determinants of elevated blood lead levels in USA… • Age – Children 0–6 year () • Race – African American and Hispanic ( + Asia) • Renter vs. owner-occupied property ( overcrowding) • Income – household income below poverty line () • Value of property – poor state of repair ( - roadside) • Education – parent not completed HS () - ACTION ARRIVE with environmental injustice () – applies to developing countries

46. African Society for Toxicological Sciences (ASTS) Mission: Create awareness of existing and potential toxicological issues that affect the African continent. Promote human health and a safe environment through research and education. Focus on sharing knowledge – with government, industry, and non-profit or non-governmental organizations (NGO). www.africansocietyfortoxicologicalsciences.org