Clinical Conditions Associated with L L l L d E iLow Level Lead Exposure in

Children and Adults

Dorothy Merritt, MD

Spring 2009Spring 2009

NOELNOEL No Observable Effect Level

Lead is unique as a toxicant in that there is agreement among these governmental agencies as to its toxicity

• CDC Centers for Disease Control

ATSDR A f T i S b t d Di• ATSDR Agency for Toxic Substances and 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 ”below which no harm occurs.

Clinical Conditions-Lead• Neurological/behavioral• Neurological/behavioral• Cardiovascular• Renale a• Degenerative

Cataracts, Osteoporosis, autoimmune

Major Studies : NHANES (blood levels)NIH (bone le els)NIH (bone levels)

• www.cdc.gov/nchs/nhanes.htm• www.ncbi.nlm.nih.gov

Recognition of Heavy Metal ExposureExposure“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 exposureIt is possible that low level metals exposure contributes much more towards the causation of chronic disease and impaired functioning h i l h h ”than previously thought.”

Howard Hu MD MPH (keynote speaker on Saturday)Howard Hu MD MPH (keynote speaker on Saturday)

Harvard School of Environmental and Occupational Health (Now in Michigan)

“ Low Level Environmental Low Level Environmental Exposure To Lead Unmasked

As Silent Killer”

Editorial in the American Heart Association Journal with Latest NHANES Study On Lead And Vascualarwith Latest NHANES Study On Lead And Vascualar

Disease

Circulation 2006;114;1347-1349Tim S Nawrot and Jan A StaessenTim S. Nawrot and Jan A. Staessen

NHANES DATA

Lead Toxicity in ChildenLead Toxicity in Childen

• Blood-brain barrier is not complete until 6Blood 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 hild h i d lchildren than in adults.

Lead and Children

• “The developing nervous system of a childThe developing nervous system of a child can be affected adversely at BLLs of less than 10 µg/dL.

• “For children, there may be no threshold for developmental effects ”developmental effects.

• ATSDR. Case Studies in Environmental Medicine. Lead Toxicity.

• www.atsdr.cdc.gov/HEC/CSEM/lead/physiologic_effects.html

Evidence of PediatricToxicityEvidence of PediatricToxicityBelow 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.

Galveston Texas-Pre IKEGalveston, Texas Pre IKE

• 20% of all Galveston children have lead• 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,"

Lead Toxicity-Early SymptomsLead Toxicity Early Symptoms

• Diffuse muscle weakness• Diffuse muscle weakness

• General fatigue/lethargy

A i i i / i i i i• Attention deficit/ irritability

• Myalgia

• Joint pain/arthritis

• Loss of appetiteLoss of appetite

• Unusual taste in mouth/change in taste of foodof food

Lead Toxicity SymptomsLead Toxicity Symptoms

• Headache

• Insomnia• Insomnia

• Irritability

• Diminished libido

• Weight loss of 10 lbs or more without gknown cause

• TremulousnessTremulousness

Lead-Related Symptoms

• Personality Changes

• Peripheral neuropathy in extensor e p e a eu opat y e te sosurfaces- most common neurological symptom in adults

• Abdominal pain/cramping

• Nausea/vomiting/ g

• Short-term memory loss

• DepressionDepression

Lead-Related Symptoms

• Incoordination

• ParesthesiasParesthesias

• Constipation

I bili• Inability to concentrate

• Impotence

Normative Aging NIH StudyLead 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 normalincreased turnover of bones associated with normal aging

Lead and Osteoporosis: Mobilization of lead from bone in t lpostmenopausal women

Sibergeld,E,Schwartz,J,et al….

Bone Storage

• A study of lead-stable isotope signatures revealed that approximately 40-70 percent of blood lead in adults comes from bone leadblood lead in adults comes from bone lead.

• 10-88% of blood lead may come from bone due10 88% of blood lead may come from bone due to increased mobilization of bone during pregnancy. approximately 80 percent of cord bl d lt f lib t d bblood may result from liberated bone.

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

Populations at Risk For LeadPopulations at Risk For Lead Toxicity

• Pregnant women with elevated BLLs h i r d h fmay have an increased chance of

miscarriage, spontaneous abortion or stillbirth and preterm labor andstillbirth, and preterm labor, and newborns with low birth weight or neurologic problemsneurologic problems.

Populations at Risk For Lead pToxicity

• Pregnancy and lactation- young women in inner-city areas of the United States who may have had heavy exposure to lead duringmay 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 withoutpasses 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)

44a. Distribution of workers with BLLs greater than or equal to 25 µg/dL,

by industry, 2003-2004

Total = 12,712

Services (3.3%)Mining (7.6%)

Other (1.5%)

Construction (17 1%)(17.1%)

Manufacturing (70 5%)(70.5%)

Section 44 of The Construction Chart Book, Fourth Edition, D b 2007

44c. Number of workers with BLLs greater than or equal to 25 or 40 µg/dL,

by detailed construction sector, 2003-2004

Building finishingBlood lead levels (BLLs)

1,051

Hi h t t & b id

Other specialty trade

406

412

Utility

Highway, street, & bridge 406

92

Residential

Foundation, structure, & building 25 µg/dL

40 µg/dL

70

41

Building equipment

Nonresidential 41

39

Other heavy & civil engineering

g q p

14

Adult Lead Exposure: Time for Change

• We have assembled this mini-monograph on adult lead exposure• 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-relevance to epidemiologic research, and to review two key leadrelated outcomes, namely, cardiovascular and cognitive.

• The lead standards of the U S Occupational Safety and Health• The lead standards of the U.S. Occupational Safety and Health 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…previously thought to be safe

• According to a Mini Monograph published in the same journal, the authors recommend workers with BLL between 11-20 haveauthors 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/dlavoid exposure >5ug/dlEnviron Health Perspect 115:451–454 (2007) and 115: 463-471 Brian S. Schwartz and Howard Hu

Lead Exposure and CardiovascularLead Exposure and Cardiovascular Disease

A Systematic Review

Ana Navas-Acien, Eliseo Guallar, Ellen K. Silbergeld andStephen J. Rothenberg

doi:10.1289/ehp.9785 (available at http://dx.doi.org/)Online 22 December 2006

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 persistentby heavy metals, house dust remains a persistent source of exposure even decades after the cessation of the industrial activity.

Circulation 2006;114:1347-1349

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 i k f di l di- 1.70 times risk for cardiovascular disease

mortality vs .55

• Circulation 2006;114:1347-1349

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• Cumulative lead exposure increases pulse pressure in aging populations EHP 1696-2000; 2007

• Heart rate variability as defined as autonomic dysfunction More Lead Effectsea t ate va ab ty as de ed as auto o c dys u ct ois more

pronounced on high air pollution days in patients with increased bone

More Lead Effects

increased bone lead Epidemiology

2008; 19; 111-120

Blood Lead Predicts Homocysteine LevelsLevels“

• In 1140 older adults, blood lead, but NOT tibial lead, homocysteine levels increased .035 µmol/L for every 1 0 µg/L of blood lead1.0 µg/L of blood lead.

Mechanisms:

Ø Homocysteine metabolism is dependent on transulfuration and remethylation.

Ø Enzymes necessary in the transulfuration process containØ 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.

Methylation Pathways and Lead

H tfiHeartfixer.com

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• 25% of US has MTR gene mutation (Methionine)

21% f US h CBS t ti• 21% of US has CBS gene mutation (transulferation)

Methylation cycle

The Association between Blood Lead Levels and Osteoporosis –Results from the Third National Health and

Nutrition Examination Survey (NHANES III)Nutrition Examination Survey (NHANES III)

They found a significant inverse association between lead exposure and BMD loss

•loss

Is Lead Exposure a Risk Factor for Bone Loss?(CDC)(CDC)

YES

Journal of Women’s Health Vol 14:Number 6 2005.VIJAYALAKSHMI POTULA, Ph.D., and WENDY KAYE, Ph.D.

Past Adult Lead Exposure Is Linked ToPast Adult Lead Exposure Is Linked To Neurodegeneration Measured By Brain MRI

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?damage to the brain that mimics the aging process? Neurology, 2006;66: 1462-1463

Lead Exposure Predicts Survival in pALS

Higher lead levels predict better survival ! EHP: 116;943-947g p

Neurological Studies in PatientsNeurological 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 2008on line Dec 11, 2008

• Cumulative lead exposure and cognitive function in older menmen

Epidemiology 2007:18: (59–66)

• Cognative decline in chronic lead exposure with concurrent HFE iron polymorphisms EHP;115: 1210-1215(2007)

Progression to renal failure

Lead Chelation in RenalLead 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,

i t l $120 000 ($3 750was approximately $120,000 ($3,750 per patient).

• However, the cost of three years of hemodialysis for this number of patientshemodialysis for this number of patients would be approximately $1,950,000 ($61,000 per patient).

Diabetes, Hypertension and Renal Failure –Normative

Aging StudyAging Study

Tibial bone lead and blood lead levels predicted 17.6x worsening of serum creatinine over time in diabetic hypertensives

EPH: 112(11)l 1178-82 2004

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 districtsdistricts,

• Test BLL yearly and prevent bone loss

EDTA t b d bl d l d t• EDTA-gets bone and blood lead out

• DMSA-gets blood lead out

Lead Evaluation in a Primary CareLead Evaluation in a Primary Care Practice

• We measure everyone with disease/sx yearly and everyone over d sease/s yea y a d eve yo e ove50

• Average lead levels in ourAverage lead levels in our population are 3-5. Highest 18, lowest <1lowest <1

• We do a lead H and P on most patients with disease interested inpatients with disease interested in treating the lead

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 N EDTA t t t Li it ™ d Alt ™ d i 6NaEDTA treatments, Lipitor™ and Altace™ during a 6 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,

lti t ti li i l t i l t h l timulticenter prospective clinical trial to assess chelation therapy in post MI patients who are already on standard treatments including statins, ace inhibitors, B- blockers and platelet inhibitors. (1)

• Unpublished- Merritt

This 50 year old asymptomatic Hispanic male with an extensive

C R 1y y p p

family history offatal myocardial infarctions by age 55, requested an evaluation by hiscardiologist. A nuclear stress test showed two major defects along the

Case Report 1

anterior 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 wasd i d t t k 20 f LIPITOR™ 2 5 Alt d i i d iladvised to take 20mg of LIPITOR™, 2.5 mg Altace and an aspirin daily

by 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 toAfter six months and fifty IV EDTA chelation treatments, he returned tohis 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(Figure 3). A series of 6 hour urine collections for lead after an initialchallenge 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

Case 1 Nuclear Med ScanCase 1 Nuclear Med Scan

Case 1 Heart CathCase 1 Heart Cath

Case 1 Nuclear Med Scan f Tafter Tx

Case 1 Lead UrineCase 1 Lead Urine Challenge

• A series of 6-hour urine collections for lead after an initial challenge o ead a te a t a c a e gedose of .75gm IV NaEDTA on the first dose and 3gms IV NaEDTA on gthe 2nd and 3rd collections performed after 15 and 50 ptreatments showed that the total amount of lead excreted was 8.6ug, g,6.1ug, and .285 ug

Check list for heavy metal symptoms used in our clinic