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 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 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, autoimmune
Major Studies : NHANES (blood levels)
NIH (bone levels)
le els)
• www.cdc.gov/nchs/nhanes.htm
• www.ncbi.nlm.nih.gov
4. Recognition of Heavy Metal
Exposure
“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 in
Michigan)
5. Low Level Environmental
“
Exposure To Lead Unmasked
As Silent Killer”
Editorial in the American Heart Association Journal
with 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.
10. 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,"
11. 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
12. Lead Toxicity Symptoms
• Headache
• Insomnia
• Irritability
• Diminished libido
• Weight loss of 10 lbs or more without
g
known cause
• Tremulousness
13. 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
14. Lead-Related Symptoms
• Incoordination
• Paresthesias
• Constipation
• Inability
I bili to concentrate
• Impotence
15. 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
aging
Lead and Osteoporosis: Mobilization of lead from bone in
postmenopausal women
t l
Sibergeld,E,Schwartz,J,et al….
16. 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.
17. 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
18. 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.
19. 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)
20. 44a. Distribution of workers with BLLs greater than or equal to 25
µg/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
21. 44c. Number of workers with BLLs greater than or equal to 25 or 40
µg/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
22. 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
23. 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
24. 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
25. 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
26. 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
27. 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 dysfunction
is more
pronounced on high air pollution days in patients with
increased bone
lead Epidemiology
2008; 19; 111-120
28. 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.
lead
Mechanisms:
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.
30. 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)
32. 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.
33. Past 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?
Neurology, 2006;66: 1462-1463
Lead Exposure Predicts Survival in
p
ALS
Higher lead levels p
g predict better survival ! EHP: 116;943-947
34. 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)
37. 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).
38. Diabetes, Hypertension and
Renal Failure –Normative
Aging 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
39. 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
40. 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
41. 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
42. This 50 year old asymptomatic Hispanic male with an extensive
y y p p
family Case Report 1
C R history
fatal myocardial infarctions by age 55, requested an evaluation by his
of
cardiologist. A nuclear stress test showed two major defects along the
anterior wall of his heart (Figure1) and subsequent cardiac
catheterization (Figure 2) revealed a 50% lesion in his left anterior
descending artery and narrowing of the distal LAD vessel. He was
advised 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 daily
by his primary cardiologist. Seeking a more aggressive approach to his
problem, 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 repeat
stress testing. A repeat nuclear stress test was completely normal
(Figure 3). A series of 6-hour urine collections for lead after an initial
6 hour
challenge dose of .75gm IV NaEDTA on the first dose and 3gms IV
NaEDTA on the 2nd and 3rd collections performed after 15 and 50
treatments showed that the total amount of lead excreted was 8.6ug,
6.1ug, and .285 ug and documented a major reduction in total body
burden of lead. His LDL-cholesterol on 20mg of Lipitor™ ranged from
46-61 mg/dl during this time period. Blood pressure dropped
46. 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
