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Lead PoisoningLead Poisoning

Dr. Ben BalzerDr. Ben Balzer Technical Advisory Board memberTechnical Advisory Board member The LEAD Group Inc. (General Practice)The LEAD Group Inc. (General Practice) (Lead Education and Abatement Design Group)(Lead Education and Abatement Design Group)

6 September 2000

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Lead PoisoningLead Poisoning

Lead has no known biological function.Lead has no known biological function. There is no proven safe lower limit for lead.There is no proven safe lower limit for lead. Lead PbLead Pb++++, competes with Ca, competes with Ca++++, Fe, Fe++++

It is cheap, useful,easy to mine, thereforeIt is cheap, useful,easy to mine, therefore Lead is ubiquitous- in air, food, water, soil, Lead is ubiquitous- in air, food, water, soil,

ceilings etc.ceilings etc. Leaded petrol means that all environmental Leaded petrol means that all environmental

dusts are high in lead-contaminating ceiling dusts are high in lead-contaminating ceiling dust, topsoil, window wells etc.dust, topsoil, window wells etc.

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Uses and Sources Uses and Sources of Leadof Lead

    Paint (until 1970)Paint (until 1970)     Petrol (tetraethyl lead)Petrol (tetraethyl lead) Household dust (via settlement of air Household dust (via settlement of air

pollution)pollution) Ceiling dustCeiling dust OccupationalOccupational SolderSolder Ceramic glazesCeramic glazes     Pesticides (lead arsenate)Pesticides (lead arsenate) CigarettesCigarettes     Mines, smeltersMines, smelters

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More Uses and More Uses and Sources of Lead Sources of Lead

TV's, Computer monitorsTV's, Computer monitors     Batteries, Bullets SinkersBatteries, Bullets Sinkers AviationAviation X-ray shieldsX-ray shields Crystal-ware (high levels in decanters)Crystal-ware (high levels in decanters) ExplosivesExplosives Non-stick linings of pots (in the past)Non-stick linings of pots (in the past) Plastic colouring (wire, blinds)Plastic colouring (wire, blinds) PewterPewter

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Absorption Absorption of Leadof Lead

Lead goes down iron or calcium absorption Lead goes down iron or calcium absorption pathway in GIT.pathway in GIT.

Children absorb lead well orally (~50%) cf Children absorb lead well orally (~50%) cf adults poorly (~10%). Children also have more adults poorly (~10%). Children also have more hand to mouth activity.hand to mouth activity.

Lead absorption is enhanced if diet is poor in Lead absorption is enhanced if diet is poor in iron or calcium.iron or calcium.

Pica is one of the worst risk factors.Pica is one of the worst risk factors. Lead can be inhaled.Lead can be inhaled. Tetraethyl lead can be absorbed via skin.Tetraethyl lead can be absorbed via skin.

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Absorption of LeadAbsorption of Lead

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Contribution ofContribution ofSourcesSources

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Reduction of Lead Reduction of Lead hazards in the homehazards in the home

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Distribution of Distribution of LeadLead 95% long bones.95% long bones. Binds into matrix.Binds into matrix. Released during Released during

osteolysis.osteolysis. 4% brain,liver, 4% brain,liver,

kidneys.kidneys. 1% blood.1% blood. Crosses placenta, Crosses placenta,

foetal BBB is openfoetal BBB is open

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Release of lead Release of lead during osteolysisduring osteolysis

Pregnancy increases mobilization of lead from Pregnancy increases mobilization of lead from maternal skeletonmaternal skeleton Gulson BL, Jameson CW, Mahaffey KR, Mizon KJ, Korsch MJ, Vimpani G.. J Lab Clin Med Gulson BL, Jameson CW, Mahaffey KR, Mizon KJ, Korsch MJ, Vimpani G.. J Lab Clin Med 1997a;130:51-62 1997a;130:51-62

Mobilization of lead from the skeleton during Mobilization of lead from the skeleton during the post-natal period is larger than duringthe post-natal period is larger than during ppregnancyregnancy..Gulson BL, Mahaffey KR, Jameson CW, Mizon KJ, Korsch MJ, Cameron MA, Eisman JA. J Lab Clin Gulson BL, Mahaffey KR, Jameson CW, Mizon KJ, Korsch MJ, Cameron MA, Eisman JA. J Lab Clin Med 1998a;131:324-9Med 1998a;131:324-9

Lead is released in menopausal bone lossLead is released in menopausal bone loss Lead levels have second peak in middle age- Lead levels have second peak in middle age-

more in men than women (NHANES 3).more in men than women (NHANES 3). Lead follows calcium into and out of bone.Lead follows calcium into and out of bone.

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Lead movementLead movement

In childhood, blood lead levels reflect In childhood, blood lead levels reflect the environmental lead level ie the environmental lead level ie exogenousexogenous lead. Protection requires lead. Protection requires placing barriers between the child and placing barriers between the child and the lead.the lead.

In adults, lead levels reflect the release In adults, lead levels reflect the release of of endogenousendogenous lead from bone, as well lead from bone, as well as the intake of as the intake of exogenousexogenous lead. lead. Protection requires prevention of Protection requires prevention of exposure plus preservation of bone exposure plus preservation of bone density. density.

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Data from the US NHANES 3 study Data from the US NHANES 3 study showing the second peak of lead levels showing the second peak of lead levels in adulthood. Higher adult male levels in adulthood. Higher adult male levels reflect occupation and hobby. High risk reflect occupation and hobby. High risk occupations would be even higher. occupations would be even higher. Women get a post-menopausal peak.Women get a post-menopausal peak.

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Lead and Race. Data from the UIS Lead and Race. Data from the UIS NHANES 3 study showing NHANES 3 study showing differences with race –probably differences with race –probably reflecting differences in reflecting differences in accommodation and occupationaccommodation and occupation

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Health Health Effects of Effects of LeadLead Concentration Concentration

relatedrelated IQ/ delinquency IQ/ delinquency

related to total related to total dosage in dosage in childhoodchildhood

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Recommended Recommended Lead level Lead level <0.48 <0.48 µmol/L µmol/L (10µg/dL)(10µg/dL) < 0.48µmol/L (10µg/dL)< 0.48µmol/L (10µg/dL)

== NHMRC Goal.NHMRC Goal.>>0.48µmol/L (10µg/dL)0.48µmol/L (10µg/dL)

= elevated.= elevated.>0.72µmol/L (15µg/dL)>0.72µmol/L (15µg/dL)

=substantially elevated. =substantially elevated. Notifiable Notifiable level.level.

11.20µmol/L (25µg/dL).20µmol/L (25µg/dL)= dangerously elevated.= dangerously elevated.

>2.20µmol/L (45µg/dL)= >2.20µmol/L (45µg/dL)= SSymptomatic.ymptomatic.

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Symptoms from Symptoms from lead are rare!lead are rare!

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Lead and Lead and NeurodevelopmentNeurodevelopment

Each 0.48 µmol/L (10µg/dL)Each 0.48 µmol/L (10µg/dL) in children. in children. = 4 to 7 IQ points (US Acad. Pediatrics).= 4 to 7 IQ points (US Acad. Pediatrics). Industry/ Industry/ Australian Australian government consensusgovernment consensus

of 3-5of 3-5 IQ points. IQ points. Effects on behaviour are FAR WORSE.Effects on behaviour are FAR WORSE. Delinquency rates are 8 times higher in the Delinquency rates are 8 times higher in the

top 30% of bone lead. Needleman 1996.top 30% of bone lead. Needleman 1996.Needleman, Herbert L. et al, "Bone Lead Levels and Delinquent Behavior," JOURNAL OF THE 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.AMERICAN MEDICAL ASSOCIATION Vol. 275, No. 5 (February 7, 1996), pgs.363-369.

Measurable adverse behaviour changes in Measurable adverse behaviour changes in 2 year olds Mendelsohn 1999. 2 year olds Mendelsohn 1999. Alan L. Mendelsohn, Alan L. Mendelsohn, Benard P. Dreyer, Arthur H. Fierman, Carolyn M. Rosen, Lori A. Legano, Hillary A. Benard P. Dreyer, Arthur H. Fierman, Carolyn M. Rosen, Lori A. Legano, Hillary A. Kruger, Sylvia W. Lim, and Cheryl D. Courtlandt "Kruger, Sylvia W. Lim, and Cheryl D. Courtlandt "Low-Level Lead Exposure and Behavior in Low-Level Lead Exposure and Behavior in Early Childhood“Early Childhood“ P Pediatrics 1998; 101: e10 ediatrics 1998; 101: e10

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Lead and IQLead and IQ

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Toxicology of Toxicology of Lead 1Lead 1

Lead disrupts the main structural Lead disrupts the main structural components of the blood-brain barrier by components of the blood-brain barrier by primary injury to astrocytes with a primary injury to astrocytes with a secondary damage to the endothelial secondary damage to the endothelial microvasculature.microvasculature. Within the brain, lead- Within the brain, lead-induced damage occurs preferentially in the induced damage occurs preferentially in the prefrontal cerebral cortex, hippocampus and prefrontal cerebral cortex, hippocampus and cerebellumcerebellum. Some characteristic clinical . Some characteristic clinical features of lead poisoning may be attributed features of lead poisoning may be attributed to this specific anatomical pattern. to this specific anatomical pattern.

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Toxicology of Lead Toxicology of Lead contdcontd

Although the molecular targets for lead are Although the molecular targets for lead are unknown, a vast amount of evidence accumulated unknown, a vast amount of evidence accumulated over many years has shown that lead disrupts over many years has shown that lead disrupts processes that are regulated by calcium. processes that are regulated by calcium.

PPicomolar concentrations of lead can replace icomolar concentrations of lead can replace micromolar concentrations of calciummicromolar concentrations of calcium in a protein in a protein kinase C enzyme assay.kinase C enzyme assay. Furthermore, lead activates Furthermore, lead activates protein kinase C in intact cells and induces the protein kinase C in intact cells and induces the expression of new genes by a mechanism dependent on expression of new genes by a mechanism dependent on protein kinase C. We propose that the learning deficits protein kinase C. We propose that the learning deficits caused by lead are due to events regulated by protein caused by lead are due to events regulated by protein kinase C that most likely occur at the synapse.kinase C that most likely occur at the synapse. Bressler J, Kim KA, Chakraborti T, Goldstein GMolecular mechanisms Bressler J, Kim KA, Chakraborti T, Goldstein GMolecular mechanisms of lead neurotoxicity.of lead neurotoxicity. NNeurochem Reseurochem Res 1999 Apr;24(4):595-600 1999 Apr;24(4):595-600

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Toxicology of Toxicology of Lead 3Lead 3

The cellular, intracellular and molecular The cellular, intracellular and molecular mechanisms of lead neurotoxicity are mechanisms of lead neurotoxicity are numerous, as lead impacts many biological numerous, as lead impacts many biological activities at different levels of control: at the activities at different levels of control: at the voltage-gated channels and on the first, voltage-gated channels and on the first, second and third messenger systemssecond and third messenger systems. These . These effects could be related to lead's ability to effects could be related to lead's ability to interfere with the regulatory action of interfere with the regulatory action of calciumcalcium in cell functions. in cell functions. Finkelstein Y, Markowitz ME, Rosen JFFinkelstein Y, Markowitz ME, Rosen JF Low-level lead-Low-level lead-induced neurotoxicity in children: an update on central induced neurotoxicity in children: an update on central nervous system effectsnervous system effects Brain Res Brain Res RevBrain Res Brain Res Rev 1998 1998 Jul;27(2):168-76Jul;27(2):168-76

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Toxicology of Lead Toxicology of Lead 44

At a neuronal level, exposure to At a neuronal level, exposure to lead alters the lead alters the release of neurotransmitter from presynaptic nerve release of neurotransmitter from presynaptic nerve endings. Spontaneous release is enhanced and endings. Spontaneous release is enhanced and evoked release is inhibited.evoked release is inhibited. The former may be due The former may be due to activation of protein kinases in the nerve endings to activation of protein kinases in the nerve endings and the latter to blockade of voltage-dependent and the latter to blockade of voltage-dependent calcium channels. This disruption of neuronal activity calcium channels. This disruption of neuronal activity may, in turn, alter the developmental processes of may, in turn, alter the developmental processes of synapse formation and result in a less efficient brain synapse formation and result in a less efficient brain with cognitive deficits. with cognitive deficits. Bressler JP, Goldstein GWBressler JP, Goldstein GW Mechanisms of lead neurotoxicity.Mechanisms of lead neurotoxicity. Biochem PharmacolBiochem Pharmacol 1991 1991 Feb 15;41(4):479-84Feb 15;41(4):479-84

?Effect of lead on omega 3 and 6 fats.?Effect of lead on omega 3 and 6 fats.

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Lead and the Lead and the ElderlyElderly

Risk of dementia increases with lead Risk of dementia increases with lead burdenburden

Risk of accidental lead ingestionRisk of accidental lead ingestion

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Dementia and lead Dementia and lead 11

The relationship between performance on The relationship between performance on cognitive tasks and circulating levels of lead in cognitive tasks and circulating levels of lead in blood and accumulated levels of lead in bone blood and accumulated levels of lead in bone was examined in 141 middle-aged and elderly was examined in 141 middle-aged and elderly men Men with higher levels of blood and bone men Men with higher levels of blood and bone (tibia) lead copied spatial figures less (tibia) lead copied spatial figures less accurately; men with higher levels of bone accurately; men with higher levels of bone (tibia) lead had slower responses for pattern (tibia) lead had slower responses for pattern memory. memory. These findings suggest that low These findings suggest that low levels of lead contribute to impairments in levels of lead contribute to impairments in cognitive function among elderly men.cognitive function among elderly men.Payton M, Riggs KM, Spiro A 3rd, Weiss ST, Hu HPayton M, Riggs KM, Spiro A 3rd, Weiss ST, Hu H Relations of boneRelations of bone and blood lead to cognitive function: the VA Normative Aging Study. and blood lead to cognitive function: the VA Normative Aging Study. Neurotoxicol TeratolNeurotoxicol Teratol 1998 Jan-Feb;20(1):19-27 1998 Jan-Feb;20(1):19-27

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Dementia and Dementia and Lead 2Lead 2

/~//~/ the cross-sectional relationship between the cross-sectional relationship between blood lead levels and a variety of measures of blood lead levels and a variety of measures of neuropsychological function in a large cohort of neuropsychological function in a large cohort of elderly women elderly women /~//~/ This study This study // demonstrates demonstrates that that blood lead levels as low as 8 micrograms/dl blood lead levels as low as 8 micrograms/dl were significantly associated with poorer were significantly associated with poorer cognitive functioncognitive function as measured by certain as measured by certain neuropsychological tests. Even a slight neuropsychological tests. Even a slight decrement in cognition would have a large public decrement in cognition would have a large public health impact due to the large number of elderly health impact due to the large number of elderly at risk.at risk.

Muldoon SB, Cauley JA, Kuller LH, Morrow L, Needleman HL, Scott J, Muldoon SB, Cauley JA, Kuller LH, Morrow L, Needleman HL, Scott J, Hooper FJHooper FJ NeuroepidemiologyNeuroepidemiology 1996;15(2):62-72 1996;15(2):62-72Effects of blood lead Effects of blood lead levels on cognitive function of older women.levels on cognitive function of older women.

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Niklowitz WJ Neurofibrillary Niklowitz WJ Neurofibrillary changes after acute experimental changes after acute experimental lead poisoning.lead poisoning. NeurologyNeurology 19751975 Oct;25(10):927-34 Oct;25(10):927-34

Following acute tetraethyllead intoxication in Following acute tetraethyllead intoxication in rabbits classic neurofibrillary tangles develop.rabbits classic neurofibrillary tangles develop. As studied by electron microscopy, such As studied by electron microscopy, such tangles develop in hydropic degenerating tangles develop in hydropic degenerating neurons and consist primarily of bundles of neurons and consist primarily of bundles of 200 A diameter smooth tubules of enormous 200 A diameter smooth tubules of enormous length. In two of 16 animals a few twisted length. In two of 16 animals a few twisted tubules (periodicity of 800 A) also could be tubules (periodicity of 800 A) also could be found. The significance of these lead-induced found. The significance of these lead-induced twisted tubules, so twisted tubules, so characteristic of characteristic of Alzheimer'sAlzheimer's pre-senile dementia in man, is pre-senile dementia in man, is discussed.discussed.

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Unresolved Unresolved QuestionsQuestions

How much does lead contribute to How much does lead contribute to cognitive decline and Alzheimer’s cognitive decline and Alzheimer’s disease?disease?

Do bone preserving therapies or calcium Do bone preserving therapies or calcium supplements reduce cognitive decline?supplements reduce cognitive decline?

Is lead a modifiable risk factor for Is lead a modifiable risk factor for dementia?dementia?

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Incidence of Elevated Incidence of Elevated Blood Leads Sydney Blood Leads Sydney 1996 Mira Et Al.1996 Mira Et Al.

Childhood Risk FactorChildhood Risk FactorQuestionnaireQuestionnaire

Does your child….

Have a brother or sister, housemate or playmate with an elevated blood lead level?

No Yes

Sometimes eat non-food items such as soil or paint? No Yes

Have any of the following conditions sometimes associated with lead poisoning, eg iron deficiency anaemia, behaviour problem, learning problem or developmental delay?

No Yes

If your child is aged between 9 and 48 months, If your child is aged between 9 and 48 months, does he or she:does he or she:          Live in, or frequently visit, a house* built before Live in, or frequently visit, a house* built before 1970 with peeling or chipping paint?1970 with peeling or chipping paint?          Live in, or frequently visit, a house* built before Live in, or frequently visit, a house* built before 1970 with or ongoing renovation where old paint 1970 with or ongoing renovation where old paint (interior or exterior) has been burnt or sanded off, or (interior or exterior) has been burnt or sanded off, or where ceilings, walls or floors demolished?where ceilings, walls or floors demolished?          Live in, or frequently visit, a houseLive in, or frequently visit, a house near near a lead a lead releasing industry, eg lead mine, lead smelter, battery-releasing industry, eg lead mine, lead smelter, battery-recycling plant?recycling plant?Live with an adult whose job or hobby uses lead? (eg Live with an adult whose job or hobby uses lead? (eg lead mining or smelting, automotive repair, panel-lead mining or smelting, automotive repair, panel-beating, leadlighting, fishing sinker making, electronics, beating, leadlighting, fishing sinker making, electronics, shooting instruction, car-battery service/ repair or shooting instruction, car-battery service/ repair or manufacture).manufacture).   

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U.S. Lead Situation U.S. Lead Situation 11

1.1.        1978 Lead banned from paint1978 Lead banned from paint 2.2.        1980's- Levels higher than Australia1980's- Levels higher than Australia 3.3.        Late 1980's Removal of lead from gasolineLate 1980's Removal of lead from gasoline 4.4.        1980's Universal questionnaire screening1980's Universal questionnaire screening 5.5.        1991 Universal blood testing1991 Universal blood testing 6.6.        1990's Public housing program1990's Public housing program 7.7.        1990's Private housing program1990's Private housing program 8.8.        1990's Massive EPA environmental 1990's Massive EPA environmental

programprogram

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U.S. Lead Situation U.S. Lead Situation 22

9.9.        ~1995 Title X regulations for sale of ~1995 Title X regulations for sale of properties built before 1978.properties built before 1978.

10.10.        ~1997 Lead litigation compensation ~1997 Lead litigation compensation approaches asbestos in some states.approaches asbestos in some states.

11.11.        1998 Builders, tradesmen required to 1998 Builders, tradesmen required to issue documents warning clients of risk when issue documents warning clients of risk when they renovate properties built before 1978.they renovate properties built before 1978.

12.12.        1998 Successful reduction in community 1998 Successful reduction in community levels leads to reintroduction of questionnaire levels leads to reintroduction of questionnaire screening in some areas.screening in some areas.