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  • 1. Clinical Conditions Associated with Low Level Lead Exposure in L L lL d E i Children and Adults Dorothy Merritt, MD Spring 2009
  • 2. NOEL No Observable Effect LevelLead is unique as a toxicant in that there is agreement among these governmental agencies as to its toxicity• CDC Centers for Disease Control• ATSDR Agency f T i S b t A for Toxic Substances and Di d Disease Registry• EPA Environmental Protection Agency: “There is no toxic threshold for lead. This means there is no measurable level of lead in the body below which no harm occurs ” occurs.
  • 3. Clinical Conditions-Lead• Neurological/behavioral• Cardiovascular• Renal e a• Degenerative Cataracts, Osteoporosis, autoimmuneMajor Studies : NHANES (blood levels) NIH (bone levels) le els)• www.cdc.gov/nchs/nhanes.htm• www.ncbi.nlm.nih.gov
  • 4. Recognition of Heavy MetalExposure“Much about metals toxicity, such as the genetic factors that may render some individuals especially vulnerable to metals toxicity, remains a subject of intense investigation. investigation ”“It is possible that low level metals exposure It low-level contributes much more towards the causation of chronic disease and impaired functioning than previously thought.” h i l h h ”Howard Hu MD MPH (keynote speaker on Saturday)Harvard School of Environmental and Occupational Health (Now inMichigan)
  • 5. Low Level Environmental “ Exposure To Lead Unmasked As Silent Killer”Editorial in the American Heart Association Journalwith Latest NHANES Study On Lead And Vascualar Disease Circulation 2006;114;1347-1349 Tim S Nawrot and Jan A. Staessen S. A NHANES DATA
  • 6. Lead Toxicity in Childen• Blood-brain barrier is not complete until 6 Blood brain months of age so lead can be absorbed by CNS of fetus and young child (lead crosses placenta).• Absorption of lead is estimated to be as much as five to ten times greater in infants and young children than i adults. hild h in d l
  • 7. Lead and Children• “The developing nervous system of a child The can be affected adversely at BLLs of less than 10 µg/dL.• “For children, there may be no threshold for developmental effects.” effects• ATSDR. Case Studies in Environmental Medicine. Lead Toxicity.• www.atsdr.cdc.gov/HEC/CSEM/lead/physiologic_effe cts.html
  • 8. Evidence of PediatricToxicity Below 10 µg/dL A significant inverse relationship was observed between blood lead levels and reading and math test scores and comprehension testing. The correlation was noted at levels as low as 2.5 µg/dL. The effect of blood lead was stronger in those with levels below 5.0 µg/dL than those with levels above 5.0 µg/dL.Public Health Rep 2000;115:521-529.
  • 9. Galveston, Texas Pre Galveston Texas-Pre IKE• 20% of all Galveston children have lead levels above CDC poisoning levels- 14ug/dl• 12 block area mostly affected• Dr. Winifred J. Hamilton PhD, SM. ... "Childhood Lead Poisoning in Galveston, Texas,"
  • 10. Lead Toxicity Early Symptoms Toxicity-Early• Diffuse muscle weakness• General fatigue/lethargy• Attention deficit/ i i i i A i i i / irritability• Myalgia• Joint pain/arthritis• Loss of appetite• Unusual taste in mouth/change in taste of food
  • 11. Lead Toxicity Symptoms• Headache• Insomnia• Irritability• Diminished libido• Weight loss of 10 lbs or more without g known cause• Tremulousness
  • 12. Lead-Related Symptoms• Personality Changes• Peripheral neuropathy in e te so e p e a eu opat y extensor surfaces- most common neurological symptom in adults• Abdominal pain/cramping• Nausea/vomiting / g• Short-term memory loss• Depression
  • 13. Lead-Related Symptoms• Incoordination• Paresthesias• Constipation• Inability I bili to concentrate• Impotence
  • 14. Normative Aging NIH Study Lead in Bones• 30 year study looking at “normal aging”• Lead stored in the bones from earlier in life is released into the blood and soft tissues from increased turnover of bones associated with normal agingLead and Osteoporosis: Mobilization of lead from bone in postmenopausal women t lSibergeld,E,Schwartz,J,et al….
  • 15. Bone Storage• A study of lead-stable isotope signatures revealed that approximately 40-70 percent of blood lead in adults comes from bone lead lead.• 10 88% 10-88% of blood lead may come from bone due to increased mobilization of bone during pregnancy. approximately 80 percent of cord blood bl d may result f lt from lib liberated b t d bone.
  • 16. Populations at risk for lead toxicity from increased bone turnover• Menopausal women• Hyperthyroidism in either sex• Cisplatin chemotherapy• Patients with osteoporosis or osteopenia• Vitamin D deficiency-50% of population
  • 17. Populations at Risk For Lead Toxicity• Pregnant women with elevated BLLs may h have an i r increased chance of d h f miscarriage, spontaneous abortion or stillbirth, stillbirth and preterm labor and labor, newborns with low birth weight or neurologic problems problems.
  • 18. Populations at Risk For Lead p Toxicity• Pregnancy and lactation- young women in inner-city areas of the United States who may have had heavy exposure to lead during their childhood.• Lead mobilization during pregnancy is potentially very hazardous to the fetus. Lead passes across the placenta almost without hindrance. Blood lead levels in mother and fetus are usually identical.E i H lth P t 1996;104(S l 1)
  • 19. 44a. Distribution of workers with BLLs greater than or equal to 25µg/dL, by industry, 2003-2004 Total = 12,712 Services (3.3%) Other (1.5%) Mining (7.6%) Construction (17.1%) (17 1%) Manufacturing (70.5%) (70 5%) Section 44 of The Construction Chart Book, Fourth Edition, D b 2007
  • 20. 44c. Number of workers with BLLs greater than or equal to 25 or 40µg/dL, by detailed construction sector, 2003-2004 Blood lead levels (BLLs) Building finishing 1,051 Other specialty trade 412 Highway, street, & bridge Hi h t t b id 406 Utility 92 Foundation, structure, & building 70 25 µg/dL Residential 41 40 µg/dL Nonresidential 41 Building equipment g q p 39 Other heavy & civil engineering 14
  • 21. Adult Lead Exposure: Time for Change• We have assembled this mini-monograph on adult lead exposure to provide guidance to clinicians and public health professionals, to summarize recent thinking on lead biomarkers and their relevance to epidemiologic research and to review two key lead research, lead- related outcomes, namely, cardiovascular and cognitive.• The lead standards of the U.S. Occupational Safety and Health US Administrationare is woefully out of date given the growing evidence of the health effects of lead at levels of exposure previously thought to be safe… safe• According to a Mini Monograph published in the same journal, the authors recommend workers with BLL between 11-20 have 11 20 quarterly levels, and those under 10ug/dl have semiannual exams. Removal of high risk workers until <10. Pregnant women should avoid exposure >5ug/dl Environ Health Perspect 115:451–454 (2007) and 115: 463-471 Brian S. Schwartz and Howard Hu
  • 22. Lead Exposure and Cardiovascular Disease A Systematic Review Ana Navas-Acien, Eliseo Guallar, Ellen K. Silbergeld and Stephen J. Rothenberg doi:10.1289/ehp.9785 (available at http://dx.doi.org/) Online 22 December 2006
  • 23. Cardiovascular Disease• “ Blood lead concentrations as low as 2.07 µg/dL likely represent a public health hazard.”• In NHANES 1999 to 2000, 38% of US adults had a blood lead level above this threshold.• In areas with historical contamination of the soil by heavy metals, house dust remains a persistent source of exposure even decades after the cessation of the industrial activity.Circulation 2006;114:1347-1349
  • 24. Cardiovascular Disease• Those in the highest tertile of blood lead: ( 3.63-10.0 µg/dL ) vs (2ug)- 2.5 times risk for stroke mortality vs 1.51- 1.89 times risk for myocardial infarction mortality vs .81- 1 70 ti 1.70 times risk f cardiovascular di i k for di l disease mortality vs .55• Circulation 2006;114:1347-1349
  • 25. Lead and Hypertension• “At blood levels 4.0-31.1 µg/dL there is a positive association between both systolic and diastolic blood pressure and risks of both systolic and diastolic hypertension among women aged 40-59.” NHANES III STUDY JAMA 2003;289:1523-32• Systolic blood pressure and hypertension risks were associated with elevated tibial bone lead in a metaanalysis of papers on bone lead and hypertension Epidemiology 2008;19 496-504• There is a positive correlation of increased stress and hypertension in patients with increased bone lead levels EHP 115; 1154-1159• Cumulative lead exposure increases pulse pressure in aging populations EHP 1696-2000; 2007
  • 26. More Lead Effects• Heart rate variability as de ed as auto o c dys u ct o ea t ate va ab ty defined autonomic dysfunctionis more pronounced on high air pollution days in patients withincreased bone lead Epidemiology2008; 19; 111-120
  • 27. Blood Lead Predicts Homocysteine“ Levels• In 1140 older adults, blood lead, but NOT tibial lead, homocysteine levels increased .035 µmol/L for every 1.0 1 0 µg/L of blood lead. leadMechanisms:Ø Homocysteine metabolism is dependent on transulfuration and remethylation.Ø Enzymes necessary in the transulfuration process contain sulfhydryl groups that lead may bind to and inihibit homocysteine breakdown. Environ Health Perspect 2005;113(1):31-35.
  • 28. Methylation Pathways and LeadHeartfixer.comH tfi
  • 29. Methylation Pathways• 60% of US has MTHFR gene mutation (folate)• 50% of US has MTRR gene mutation (B12)• 25% of US has MTR gene mutation (Methionine)• 21% of US h CBS gene mutation f has t ti (transulferation)
  • 30. Methylation cycle
  • 31. The Association between Blood Lead Levels and Osteoporosis –Results from the Third National Health and Nutrition Examination Survey (NHANES III) They found a significant inverse association between lead exposure and BMD• loss Is Lead Exposure a Risk Factor for Bone Loss? (CDC) YES Journal of Women’s Health Vol 14:Number 6 2005. VIJAYALAKSHMI POTULA, Ph.D., and WENDY KAYE, Ph.D.
  • 32. Past Adult Lead Exposure Is Linked To Neurodegeneration Measured By Brain MRI The current report suggests strongly that organic lead exposure isassociated with white matter lesions, brain atrophy, and progressivecognitive decline. Could environmental exposures such as mercury,inorganic lead, pesticides, or solvents also cause progressive, long-termdamage to the brain that mimics the aging process?Neurology, 2006;66: 1462-1463 Lead Exposure Predicts Survival in p ALS Higher lead levels p g predict better survival ! EHP: 116;943-947
  • 33. Neurological Studies in Patients With Elevated Bone Lead • Chronic lead exposure is associated with brain metabolic abnormalities of glial cells (MRS) EHP 115:519-25:Jan 2007 • Chronic lead exposure in women is associated with reduction in cognitive measures EHP on line Dec 11, 2008 11 • Cumulative lead exposure and cognitive function in older men Epidemiology 2007:18: (59–66) • Cognative decline in chronic lead exposure with concurrent HFE iron polymorphisms EHP;115: 1210- 1215(2007)
  • 34. Progression to renal failure
  • 35. Lead Chelation in Renal Insufficiency• The cost of this treatment for all 32 patients in the chelation group, including chelating agents, measurements of lead, frequent hospital visits, and staff salaries, was approximately $120 000 ($3,750 per i t l $120,000 ($3 750 patient).• However, the cost of three years of hemodialysis for this number of patients would be approximately $1,950,000 ($61,000 per patient).
  • 36. Diabetes, Hypertension and Renal Failure –Normative Aging StudyTibial bone lead and blood lead levelspredicted 17.6x worsening of serumcreatinine over time in diabetichypertensives EPH: 112(11)l 1178-82 2004
  • 37. Conclusion: NOW WHAT?• Genetic Methylation defects: Take NAC And Methylated B vitamins-Metanx, Cerafolin NAC or Deplin ? Avoid Iron Overload ?• Avoid exposure-anything made or grown overseas,old houses and historical districts, districts• Test BLL yearly and prevent bone loss• EDTA EDTA-gets bt bone and bl d l d out d blood lead t• DMSA-gets blood lead out
  • 38. Lead Evaluation in a Primary Care Practice • We measure everyone with d sease/s yea y a d eve yo e ove disease/sx yearly and everyone over 50 • Average lead levels in our population are 3-5. Highest 18, lowest <1 • We do a lead H and P on most patients with disease interested in treating the lead
  • 39. Case Report 1• NORMALIZATION OF CARDIAC BLOOD FLOW ON NUCLEAR STRESS TESTING AFTER EDTA IV TREATMENTS• This report describes an asymptomatic male patient with 50% coronary LAD blockage who had reversal of ischemia on nuclear medicine stress testing after a series of IV NaEDTA treatments, Li it ™ and Alt N EDTA t t t Lipitor™ d Altace™ d i a 6 ™ during month treatment period. IV EDTA as a modality of treatment in atherosclerotic vascular disease is being evaluated by the TACT trial, a large NIH funded, multicenter prospective clinical t i l t assess chelation lti t ti li i l trial to h l ti therapy in post MI patients who are already on standard treatments including statins, ace inhibitors, B- blockers and platelet inhibitors. (1)• Unpublished- Merritt
  • 40. This 50 year old asymptomatic Hispanic male with an extensive y y p pfamily Case Report 1 C R historyfatal myocardial infarctions by age 55, requested an evaluation by his ofcardiologist. A nuclear stress test showed two major defects along theanterior wall of his heart (Figure1) and subsequent cardiaccatheterization (Figure 2) revealed a 50% lesion in his left anteriordescending artery and narrowing of the distal LAD vessel. He wasadvised t t k 20 d i d to take 20mg of LIPITOR™ 2 5 mg Alt f LIPITOR™, 2.5 Altace and an aspirin d il d i i dailyby his primary cardiologist. Seeking a more aggressive approach to hisproblem, he presented himself to our clinic for IV NaEDTA treatment.After six months and fifty IV EDTA chelation treatments he returned to treatments,his cardiologist, who was unaware of his EDTA treatments, for repeatstress testing. A repeat nuclear stress test was completely normal(Figure 3). A series of 6-hour urine collections for lead after an initial 6 hourchallenge dose of .75gm IV NaEDTA on the first dose and 3gms IVNaEDTA on the 2nd and 3rd collections performed after 15 and 50treatments showed that the total amount of lead excreted was 8.6ug,6.1ug, and .285 ug and documented a major reduction in total bodyburden of lead. His LDL-cholesterol on 20mg of Lipitor™ ranged from46-61 mg/dl during this time period. Blood pressure dropped
  • 41. Case 1 Nuclear Med Scan
  • 42. Case 1 Heart Cath
  • 43. Case 1 Nuclear Med Scan after T f Tx
  • 44. Case 1 Lead Urine Challenge• A series of 6-hour urine collections for lead a te a initial c a e ge o ead after an t a challenge dose of .75gm IV NaEDTA on the first dose and 3gms IV NaEDTA on g the 2nd and 3rd collections p performed after 15 and 50 treatments showed that the total amount of lead excreted was 8.6ug,g, 6.1ug, and .285 ug
  • 45. Check list for heavy metal symptoms used in our clinic