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Toxicity of Heavy Metals
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  1. 1. Lead Toxicity ACAM April 21, 2010 Dorothy Merritt, MD This lecture is dedicated to Clair Patterson, whose inadvertant discovery of severe lead contamination in the US while trying to date the age of the Earth, lead to the Clean Air Act of 1970 and the removal of lead from gasoline for sale in the US in 1986 despite attempts of the ETHYL Corporation to get him fired from his position at Cal Tech. His persistance paid off for the betterment of society . This lecture also recognizes Thomas Midgley, an engineer whose dabbling in chemistry resulted in lead being introduced into gasoline, CFCS (chlorofluorocarbons) being unleashed on the atmosphere. His untimely death was from being strangled in a bed of pulleys he had himself invented for turning polio victims, which he himself contracted after his construction of his device. He may deserve the 20 th century’s top “Darwin Award” for removing his DNA from the pool in a most unusual way caused by his own invention.
  2. 2. Lead –Who Is Affected The Most Blood-brain barrier is not complete until 6 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 in adults. Needleman H. Ann Rev Med 2004;55:209-222
  3. 3. Lead: Where does it come from? <ul><li>Soft vinyl lunchboxes- found to contain more than 90 times legal limit </li></ul><ul><li>Candy imported from Mexico </li></ul><ul><li>Imported children’s jewelry </li></ul><ul><li>Leaded gasoline- currently used in farm machinery, boats, racing cars </li></ul>
  4. 4. Lead: Where does it come from? <ul><li>Air - indoor dust exposure greater than soil or paint chips </li></ul><ul><li>Water - 20% of total daily exposure (“lead-free” brass fixtures 5-7% lead) </li></ul><ul><li>Imports - lead-glazed dishware, leaded crystal. Lead solder in imported canned food,foods from Mexico, China, Spices, Wine </li></ul><ul><li>Medicine - Ayurvedic and foreign medicines </li></ul><ul><li>Vinyl mini-blinds imported before 1996 </li></ul><ul><li>Cosmetics </li></ul>
  5. 5. Lead in Wine <ul><li>For 432 wines tested in the bottle, the lead in domestic wines ranged from 1 to 521 parts per billion, with an average of 41. The level in imported wines ranged from 4 to 673 parts per billion with an average of 94. </li></ul>
  6. 6. Lead in Wine <ul><li>. When the wine was poured, the level in domestic wines ranged from 3 to 720 parts per billion, with an average of 58, and imports from 13 to 1,980, with an average of 195 </li></ul><ul><li>The EPA limit for lead in drinking water is 50 parts per billion. </li></ul><ul><li>Bureau of Alcohol, Tobacco, and Firearms 1991 </li></ul>
  7. 7. Lead glaze used on plate imported from Portugal and sold at American Home Furnishings
  8. 8. Fatal Case of Lead Poisoning from Injestion of Jewelry <ul><li>A 4-year old male died of acute encephalopathy 3 days after being admitted for intractable vomiting, stomach pain, and listlessness. </li></ul><ul><li>A metal charm, seen in his stomach on radiograph and was later found to contain 99.1% lead. </li></ul><ul><li>Reebok later recalled 500,000 of these charms, which they had given away free with pairs of girl’s shoes. </li></ul><ul><li>MMWR. March 23, 2006 / 55(Dispatch);1-2 </li></ul>
  9. 9. Is There A Safe Level Of Lead? <ul><li>In Oct. 2007, the Campaign for Safe Cosmetics reported that 61% of lipsticks it tested contained lead in levels up to .65 ppm. The FDA has determined levels above </li></ul><ul><li>.1 ppm in toys are hazardous to children’s health. </li></ul><ul><li>In Nov. 2007, Sens. John Kerry, Barbara Boxer and Dianne Feinstein urged FDA to test a range of lipsticks for lead, publicly report the results, and take immediate action to reduce consumers’ exposure to lead from cosmetic products. </li></ul><ul><li>Fourteen months later, FDA has made no public statements, issued no reports, and taken no action to reduce consumers’ exposure. </li></ul>
  10. 10. Occupations at risk for lead toxicity <ul><li>Electricians, plumbers, painters, </li></ul><ul><li>ceramicists, </li></ul><ul><li>Munitions specialists, paint and ink manufacturing, etc. </li></ul><ul><li>Electrical tower and generating station maintainance . </li></ul><ul><li> </li></ul>
  11. 11. Distribution of workers with BLLs greater than or equal to 25 µg/dL, by industry, 2003-2004 Total = 12,712 Section 44 of The Construction Chart Book, Fourth Edition, December 2007 -
  12. 12. Number of workers with BLLs greater than or equal to 25 or 40 µg/dL , by detailed construction sector, 2003-2004 1,051 406 412 92 70 41 41 39 14 Section 44 of The Construction Chart Book, Fourth Edition, December 2007
  13. 13. Lead Toxicology <ul><li>Approximately 30-40% of inhaled lead is absorbed into the bloodstream. </li></ul><ul><li>Infants can absorb up to 50% of lead ingested from food, water, contaminated dust, or soil. </li></ul><ul><li>Adults absorb only 10-15% of ingested lead. </li></ul>
  14. 14. Lead Toxicology-BLL vs Bone <ul><li>Blood Lead Levels </li></ul><ul><li>Reflects last 30-60 days of exposure </li></ul><ul><li>Doesn’t show previous toxic levels that predict future toxicity </li></ul><ul><li>Approximately 40-70% comes from bone storage (isotope studies) </li></ul><ul><li>In pregnancy, 80% of the BLL can be from bone storage </li></ul><ul><li>NHANES studies use BLL in their analysis </li></ul><ul><li>Bone Lead Levels </li></ul><ul><li>Predict long term health outcomes-vascular, renal, neurological, cataracts, hypertension </li></ul><ul><li>NIH Normative Aging Studies use Bone Lead by K shell fluoroscopy in their analysis </li></ul><ul><li>Currently you must mobilize Lead from Bone with EDTA challenge to predict bone stores clinically </li></ul>
  15. 15. Deposition in Soft Tissue <ul><li>Autopsy studies show the liver to be the largest repository of soft tissue lead (33%), followed by kidney cortex and medulla, pancreas, ovary, spleen, prostate, adrenal gland, brain, fat, testis, heart, and skeletal muscle. </li></ul>
  16. 16. Routes of Excretion <ul><li>Approximately one-third of total excretion of absorbed lead occurs via bile, gastric fluid, and saliva. </li></ul><ul><li>The remainder occurs via renal excretion. </li></ul><ul><li>Lead can also be excreted in significant amounts via sweat. </li></ul>
  17. 17. NOEL N o O bservable E ffect L evel <ul><li>Lead is unique as a toxicant in that there is agreement among these governmental agencies as to its toxicity </li></ul><ul><li>CDC Centers for Disease Control </li></ul><ul><li>ATSDR Agency for Toxic Substances and Disease Registry </li></ul><ul><li>EPA Environmental Protection Agency: </li></ul><ul><li> </li></ul><ul><li>“ There is no toxic threshold for lead. This means there is no measurable level of lead in the body below which no harm occurs.” </li></ul>
  18. 18. Lead and Children <ul><li>“ The developing nervous system of a child can be affected adversely at BLLs of less than 10 µg/dL. </li></ul><ul><li>“ For children, there may be no threshold for developmental effects.” </li></ul><ul><li>ATSDR. Case Studies in Environmental Medicine. Lead Toxicity. </li></ul><ul><li> </li></ul>
  19. 20. Galveston, Texas-Pre IKE <ul><li>20% of all Galveston children have lead levels above CDC poisoning levels-14ug/dl </li></ul><ul><li>12 block area mostly affected </li></ul><ul><li>Dr. Winifred J. Hamilton PhD, SM. ... &quot; Childhood Lead Poisoning in Galveston, Texas ,&quot; </li></ul>
  20. 21. Evidence of PediatricToxicity Below 10 µg/dL <ul><li>A significant inverse relationship was observed between blood lead levels and reading and math test scores and comprehension testing. </li></ul><ul><li>The correlation was noted at levels as low as 2.5 µg/dL. </li></ul><ul><li>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. </li></ul><ul><li>Public Health Rep 2000;115:521-529. </li></ul>
  21. 22. Lead Toxicity Adult Conditions <ul><li>Neurological/behavioral </li></ul><ul><li>Cardiovascular </li></ul><ul><li>Renal </li></ul><ul><li>Degenerative </li></ul><ul><li>Cataracts, Osteoporosis, Autoimmune </li></ul><ul><li>Major Studies : NHANES (blood levels) </li></ul><ul><li>NIH (bone levels) </li></ul><ul><li> </li></ul><ul><li> </li></ul>
  22. 23. Recognition of Heavy Metal Exposure <ul><li>“ 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.” </li></ul><ul><li>“ It is possible that low-level metals exposure contributes much more towards the causation of chronic disease and impaired functioning than previously thought.” </li></ul><ul><li>Howard Hu MD MPH (keynote speaker ACAM 2009) </li></ul><ul><li>Harvard School of Environmental and Occupational Health (Now in Michigan) </li></ul>
  23. 24. CDC NHANES Blood Lead
  24. 25. Circulation 2006;114;1347-1349 Tim S. Nawrot and Jan A. Staessen NHANES DATA <ul><li>“ Low Level Environmental Exposure To Lead Unmasked As Silent Killer” </li></ul>Editorial in Circulation 2006 with Latest NHANES Study On Lead And Vascular Disease
  25. 26. Lead Toxicity-Early Symptoms <ul><li>Diffuse muscle weakness </li></ul><ul><li>General fatigue/lethargy </li></ul><ul><li>Attention deficit/ irritability </li></ul><ul><li>Myalgia </li></ul><ul><li>Joint pain/arthritis </li></ul><ul><li>Loss of appetite </li></ul><ul><li>Unusual taste in mouth/change in taste of food </li></ul>
  26. 27. Lead Toxicity Symptoms <ul><li>Headache </li></ul><ul><li>Insomnia </li></ul><ul><li>Irritability </li></ul><ul><li>Diminished libido </li></ul><ul><li>Weight loss of 10 lbs or more without known cause </li></ul><ul><li>Tremulousness </li></ul>
  27. 28. Lead-Related Symptoms <ul><li>Personality Changes </li></ul><ul><li>Peripheral neuropathy in extensor surfaces- most common neurological symptom in adults </li></ul><ul><li>Abdominal pain/cramping </li></ul><ul><li>Nausea/vomiting </li></ul><ul><li>Short-term memory loss </li></ul><ul><li>Depression </li></ul>
  28. 29. Lead-Related Symptoms <ul><li>Incoordination </li></ul><ul><li>Paresthesias </li></ul><ul><li>Constipation </li></ul><ul><li>Inability to concentrate </li></ul><ul><li>Impotence </li></ul>
  29. 30. Normative Aging NIH Study Lead in Bones <ul><li>30 year study looking at “normal aging” </li></ul><ul><li>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 aging </li></ul><ul><li>Lead and Osteoporosis: Mobilization of lead from bone in </li></ul><ul><li>postmenopausal women Sibergeld,E,Schwartz,J,et al…. </li></ul>
  30. 31. Bone Storage <ul><li>A study of lead-stable isotope signatures revealed that approximately 40-70 percent of blood lead in adults comes from bone lead. </li></ul><ul><li>10-88% of blood lead may come from bone due to increased mobilization of bone during pregnancy. approximately 80 percent of cord blood may result from liberated bone. </li></ul><ul><li>Hernandez-Avila M. Arch Environ Health 2000;55:355. </li></ul>
  31. 32. Populations at risk for lead toxicity from increased bone turnover <ul><li>Menopausal women </li></ul><ul><li>Hyperthyroidism in either sex </li></ul><ul><li>Cisplatin chemotherapy </li></ul><ul><li>Patients with osteoporosis or osteopenia </li></ul><ul><li>Vitamin D deficiency-50% of population </li></ul>
  32. 33. Populations at Risk For Lead Toxicity <ul><li>Pregnant women with elevated BLLs may have an increased chance of miscarriage, spontaneous abortion or stillbirth, and preterm labor, and newborns with low birth weight or neurologic problems. </li></ul>
  33. 34. Populations at Risk For Lead Toxicity <ul><li>Pregnancy and lactation- young women in inner-city areas of the United States who may have had heavy exposure to lead during their childhood . </li></ul><ul><li>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. </li></ul><ul><li>Environ Health Perspect 1996;104(Suppl 1) </li></ul>
  34. 35. Adult Lead Exposure: Time for Change <ul><li>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-related outcomes, namely, cardiovascular and cognitive. </li></ul><ul><li>The lead standards of the U.S. Occupational Safety and Health Administration are woefully out of date given the growing evidence of the health effects of lead at levels of exposure previously thought to be safe… </li></ul><ul><li>According to a Mini Monograph published in the same journal, the authors recommend workers with BLL between 11-20 have quarterly levels, and those under 10ug/dl have semiannual exams. Removal of high risk workers until <10. Pregnant women should avoid exposure >5ug/dl </li></ul>Environ Health Perspect 115:451–454 (2007) and 115: 463-471 Brian S. Schwartz and Howard Hu
  35. 36. 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 Online 22 December 2006
  36. 37. Lead and Cardiovascular Disease- “Silent Killer In US” <ul><li>Blood lead concentrations as low as 2.07 µg/dL likely represent a public health hazard </li></ul><ul><li>In NHANES 1999 to 2000, 38% of US adults had a blood lead level above this threshold. </li></ul><ul><li>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. </li></ul><ul><li>Circulation 2006;114:1347-1349 </li></ul>
  37. 38. Cardiovascular Disease <ul><li>Those in the highest tertile of blood lead: </li></ul><ul><li>( 3.63-10.0 µg/dL ) vs (2ug) </li></ul><ul><li>2.5 times risk for stroke mortality vs 1.51 </li></ul><ul><li>1.89 times risk for myocardial infarction mortality vs .81 </li></ul><ul><li>1.70 times risk for cardiovascular disease </li></ul><ul><li>mortality vs .55 </li></ul><ul><li>Circulation 2006;114:1347-1349 </li></ul>
  38. 39. Lead and Cardiovascular <ul><li>High Levels of Lead in Bone Associated With Increased Risk of Death from Cardiovascular Disease in Men </li></ul><ul><li>6x increased CV Death * </li></ul><ul><li>&quot;The findings with bone lead are dramatic. It is the first time we have had a biomarker of cumulative exposure to lead and the strong findings suggest that, even in an era when current exposures are low, past exposures to lead represent an important predictor of cardiovascular death, with important public health implications worldwide,“ Marc Weisskopf , assistant professor of environmental and occupational epidemiology at HSPH and lead author of the study. </li></ul><ul><li>Circulation 2000 Sept 8, online </li></ul>
  39. 40. Lead and Hypertension <ul><li>“ 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 </li></ul><ul><li>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 </li></ul><ul><li>There is a positive correlation of increased stress and hypertension in patients with increased bone lead levels EHP 115; 1154-1159 </li></ul><ul><li>Cumulative lead exposure increases pulse pressure in aging populations EHP 1696-2000; 2007 </li></ul>
  40. 41. Heart rate variability as defined as autonomic dysfunction is more pronounced on high air pollution days in patients with increased bone lead Epidemiology 2008; 19; 111-120 More Lead Effects
  41. 42. Blood Lead Predicts Homocysteine Levels <ul><li>“ </li></ul><ul><li>In 1140 older adults, blood lead, but NOT tibial lead, homocysteine levels increased .035 µmol/L for every 1.0 µg/L of blood lead. </li></ul><ul><li>Mechanisms: </li></ul><ul><li>Homocysteine metabolism is dependent on transulfuration and remethylation. </li></ul><ul><li>Enzymes necessary in the transulfuration process contain sulfhydryl groups that lead may bind to and inihibit homocysteine breakdown. </li></ul><ul><li>Environ Health Perspect 2005;113(1):31-35. </li></ul>
  42. 43. Methylation Pathways and Lead
  43. 44. Methylation Pathways <ul><li>60% of US has MTHFR gene mutation (folate) </li></ul><ul><li>50% of US has MTRR gene mutation (B12) </li></ul><ul><li>25% of US has MTR gene mutation (Methionine) </li></ul><ul><li>21% of US has CBS gene mutation (transulferation) </li></ul><ul><li>HuGe Publications (Human Genome Study) </li></ul>
  44. 45. Methylation cycle
  45. 46. 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. <ul><li>EHP 115:1018–1022 (2007). </li></ul><ul><li>James R. Campbell and Peggy Auinger </li></ul><ul><li>Department of Pediatrics, University of Rochester Medical Center, Rochester, New York, USA </li></ul>
  46. 47. Past Adult Lead Exposure Is Linked To Neurodegeneration Measured By Brain MRI <ul><li>The current report suggests strongly that organic lead exposure is associated with white matter lesions, brain atrophy, and progressive cognitive decline. Could environmental exposures such as mercury, inorganic lead, pesticides, or solvents also cause progressive, long-term damage to the brain that mimics the aging process? Neurology, 2006;66: 1462-1463 </li></ul>Lead Exposure Predicts Survival in ALS Higher lead levels predict better survival ! EHP: 116;943-947
  47. 48. <ul><li>Chronic lead exposure is associated with brain metabolic abnormalities of glial cells (MRS) </li></ul><ul><li>EHP 115:519-25:Jan 2007 </li></ul><ul><li>Chronic lead exposure in women is associated with reduction in cognitive measures </li></ul><ul><li>EHP on line Dec 11, 2008 </li></ul><ul><li>Cumulative lead exposure and cognitive function in older men </li></ul><ul><li>Epidemiology 2007:18: (59–66) </li></ul><ul><li>Cognative decline in chronic lead exposure with concurrent HFE iron polymorphisms </li></ul><ul><li>EHP;115: 1210-1215(2007) </li></ul>Neurological Studies in Patients With Elevated Bone Lead
  48. 50. Progression to renal failure
  49. 51. Lead Chelation in Renal Insufficiency <ul><li>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 patient). </li></ul><ul><li>However, the cost of three years of hemodialysis for this number of patients would be approximately $1,950,000 ($61,000 per patient) for those reaching end stage renal failure </li></ul>
  50. 52. Diabetes, Hypertension and Renal Failure –Normative Aging Study <ul><li>Tibial bone lead and blood lead levels predicted 17.6x worsening of serum creatinine over time in diabetic hypertensives </li></ul><ul><li>EPH: 112(11)l 1178-82 2004 </li></ul>
  51. 53. Epigenetics and Lead <ul><li>Prenatal lead exposure is inversely associated with genomic DNA methylation in cord blood. These data suggest that the epigenome of the developing fetus can be influenced by maternal cumulative lead burden, which may influence long-term epigenetic programming and disease susceptibility throughout the life course . </li></ul><ul><li>Pilsner JR, Hu H, Ettinger A, Sánchez BN, Wright RO, Cantonwine D, et al. 2009. Influence of Prenatal Lead Exposure on Genomic Methylation of Cord Blood DNA.Enviorn Health Perspect 117:1466-71.doi:10doi:10.1289/ehp.0800497.1289/ehp.0800497 </li></ul>
  52. 54. Conclusion: NOW WHAT? <ul><li>Genetic Methylation defects: Take NAC And Methylated B vitamins-Metanx, Cerafolin NAC or Deplin ? Avoid Iron Overload ? </li></ul><ul><li>Avoid exposure-anything made or grown overseas,old houses and historical districts, </li></ul><ul><li>Test BLL yearly and prevent bone loss </li></ul><ul><li>EDTA-gets bone and blood lead out </li></ul><ul><li>DMSA-gets blood lead out </li></ul>
  53. 55. Lead Evaluation in a Primary Care Practice <ul><li>We measure everyone with disease/sx yearly and everyone over 50 </li></ul><ul><li>Average lead levels in our population are 3-5. Highest 18, lowest <1 </li></ul><ul><li>We do a lead H and P on most patients with disease interested in treating the lead </li></ul>
  54. 56. Check list for heavy metal symptoms used in our clinic
  55. 57. 9,100 ug Pb/gm  Herbman/DMSA

Notas del editor

  • Being a child is an occupational risk for lead toxicity