Dorothy Merritt, MD
ACAM Webinair June 3, 2014

• Univ of Chicago grad student that discovered enviornmental lead contamination when trying to age the earth using
Uranium to Lead decay
• Discovery lead to Clear Air and Water Acts of the 1970s
• Ethyl Corp continuously tried to get him removed from U of
California by offering academic chair funds
• Died of an acute asthma attack at age 73
• “Recognition of
Thomas Midgley
, an engineer turned chemist who put lead in gasoline as an antiknock agent, and developed chlorofluorocarbons (CFCS) which were unleashed on the atmosphere causing depletion of the ozone layer around the earth.
• His untimely death was from being strangled in a bed of iron lung pulleys he had invented for turning polio victims. He later contracted the disease himself and became a victim of his own invention

Blood Levels
NIH-Bone Levels of lead
Lead Exposure and Cardiovascular
Disease—A Systematic Review by
A Navas-Acien et al PMID 18567711
Arsenic Exposure and Cardiovascular
Disease- A systematic review by
A Navas-Acien et al PMID 16269585

Environmental Toxicants Associated With
Cardiovascular Disease
 Lead
 Arsenic
 Mercury
 Ozone
 Aldehydes
 Carbon Monoxide
 Particulate matter
PMID 15531422

• Despite a >75% reduction in BLL since the 70’s
38% of US Adults have BLL 2ug/dl or greater
151-248% increase in death from CVA
88-189% increase in death from MI*
• Cardiovascular
• Neurological
• Renal
• Degenerative: Autoimmune, Osteoporosis,
Cataracts
* Circulation 2006

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Diffuse muscle weakness
General fatigue/lethargy
Attention deficit/ irritability
Myalgia
Joint pain/arthritis
Loss of appetite
Unusual taste in mouth/change in taste of food

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Headache
Insomnia
Irritability
Diminished libido
Weight loss of 10 lbs or more without known cause
Tremulousness

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Personality Changes
Peripheral neuropathy in extensor surfacesmost common neurological symptom in adults
Abdominal pain/cramping
Nausea/vomiting
Short-term memory loss
Depression

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Incoordination
Paresthesias
Constipation
Inability to concentrate
Impotence

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- indoor dust exposure greater than soil or paint chips
- 20% of total daily exposure (“leadfree” brass fixtures 5-7% lead)
- lead-glazed dishware, leaded crystal. Lead solder in imported canned food,foods from Mexico, China, Spices, Wine
Ayurvedic and foreign medicines

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Soft vinyl lunchboxes- found to contain more than 90 times legal limit
Candy imported from Mexico
Imported children’s jewelry
Leaded gasoline- currently used in farm machinery, boats, racing cars

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.
Bureau of Alcohol, Tobacco and Firearms, Public Affairs Branch, 1200 Pennsylvania Avenue
N.W., Washington, D.C. 20226 (202) 566-7135
CRYSTAL : leaches 2500-5500mcg/l lead in 24 hours;
PMID: 1670790
The EPA limit for lead in drinking water is 50 50mcg

A term used to denote the byproducts of sewage and wastewater treatment as a result of the Clean Water Act
Early studies indicated that biosludge can could be used to improve lawns and farmland Sold as
“Milorganite” Milwalkee Sludge “for better results naturally” or Hou-Actinte from Houston, “a naturally nutrient rich slow release organic fertilizer”
More recent studies indicate the plants growing on biosludge treated soil can uptake large quantities of heavy metals and toxic pollutants
Lead, arsenic, chromium and cadmium are estimated by the EPA to be present in detectable quantities in
100% of national sewage sludge in the US
USDA specifically forbids biosludge to be used on farms that label their produce “organic”


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Blood Lead Levels- ”Tip of the iceburg”
Reflects last 30-60 days of exposure
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Approximately 40-70% comes from bone
In pregnancy, 80% of the BLL can be from bone storage
CDC NHANES studies use BLL in their analysis
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Bone Lead Levels- “The iceburg”
Predict long term health outcomes-vascular, renal,
 neurological, cataracts, hypertension
NIH Normative Aging Studies use Bone Lead by K shell fluoroscopy in their analysis


Dorothy Merritt, MD PMID 1700910

Lead in Bone Associated With Increased Risk of
Death from Cardiovascular Disease in Men
5.63 Hazard Ratio for CV/ 2.52 All cause
8.37 Hazard Ratio adjusted for age, smoking, race
"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.
PMID: 19738141

 Menopausal women/andropausal men
 Hyperthyroidism in either sex
 Cisplatin chemotherapy
 Patients with osteoporosis or osteopenia
 Vitamin D deficiency-50% of population


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Electricians, plumbers, painters, ceramicists,
Munitions specialists, paint and ink manufacturing, etc.
Electrical tower and generating station maintenance
Distribution of workers with BLLs greater than or equal to 25 µg/dL, by industry, 2003-2004
Services (3.3%)
Mining (7.6%)
Other (1.5%)
Total = 12,712
Construction
(17.1%)
Section 44 of The
Construction Chart Book,
Fourth Edition, December
2007 -
Manufacturing
(70.5%) http://www.haz-map.com/lead.htm

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.

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Approximately one-third of total excretion of absorbed lead occurs via bile, gastric fluid, and saliva.
The remainder occurs via renal excretion.
Lead can also be excreted in significant amounts via sweat.
30 day half life in blood, 90% goes to bone

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 .
The lead standards of the U.S. Occupational Safety and
Health Administration are is woefully out of date given the growing evidence of the health effects of lead at levels of exposure previously thought to be safe…

PMID: 17306689 NIH Mini Monograph
Howard Hu MD MPH (keynote speaker ACAM 2009)
Harvard School of Environmental and Occupational Health (Now in Michigan)

 CV is the leading cause of death world wide
 Kills 2x more people than infections and parasites
 Kills 3x more people than cancer
 In US, 2400 deaths per day from CV disease - one every 37 seconds
 In US, someone has a MI every 25 sec and every minute someone dies of one.
In 2010, cost of heart disease was 316.4 BILLION $$
References: PMID: 18212285 (World Data) , 19075105 (US DATA),

TACT TRIAL CONCLUSIONS

Aspirin-Prevention in Noncardiac Patients
• 1 in 1667 were helped (cardiovascular problem prevented)
• None were helped (prevented death)
• 1 in 2000 were helped (prevented non-fatal heart attack)
• 1 in 10000 were helped (prevented non-fatal stroke )
• Harms in NNT 0.03% were harmed by developing a major bleeding event *
• 1 in 3333 were harmed (major bleeding event *
Aspirin Prevention in Known Cardiac Patients
• 98% saw no benefit
• 0.3% were helped by avoiding death
• 1.3% were helped by preventing a non-fatal heart attack
• 0.5% were helped by preventing a non-fatal stroke
• 1 in 50 were helped (cardiovascular problem prevented)
• 1 in 333 were helped (prevented death)
• 1 in 77 were helped (prevented non-fatal heart attack)
• 1 in 200 were helped (prevented non-fatal stroke)
• Harms in Percentage 0.25% were harmed by developing a major bleeding event *
Source: Antithrombotic Trialists Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009; 373(9678); 1849-60
Antithrombotic Trialists Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002 Jan 12;324(7329):71-86
.

Statins in Prevention of Heart Disease in Patients
WITHOUT Current CV Disease
Benefits in Percentage
• 98% saw no benefit
• 0% were helped by being saved from death
• 1.6% were helped by preventing a heart attack
• 0.4% were helped by preventing a stroke
• None were helped (life saved)
• 1 in 60 were helped (preventing heart attack)
• 1 in 268 were helped (preventing stroke)
Harms in Percentage
• 2% were harmed by developing diabetes * *
• 10% were harmed by muscle damage
Source: Ray KK, Seshasai SR, Erqou S, Sever P, Jukema JW, Ford I, Sattar N. Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants. Arch Intern Med. 2010 Jun 28;170(12):1024-31.
Review. PubMed PMID: 20585067.

• Statins for Heart Disease Prevention (Without Prior Heart Disease)
• Vitamins and Antioxidants for Primary Prevention of Cardiovascular Disease
• Early Invasive Management for Acute Coronary Syndromes
• Anti-Hypertensives for Cardiovascular Prevention in Mild Hypertension
• Colloids for Resuscitation in Critically Ill Patients
• Statins for Acute Coronary Syndrome
• Hormone Replacement Therapy For Cardiovascular Prevention (After Prior Heart
Attack or Stroke)
• Aspirin to Prevent a First Heart Attack or Stroke
• Clopidogrel with Aspirin for Prevention (After Prior Heart Attack or Stroke)
• Beta Blockers for Heart Attack
• ACLS Medications for Cardiac Arrest http://www.thennt.com/category/system/cardiac/?color=red&type=nnt

• Mediterranean Diet for Heart Disease Prevention (Without Known Heart Disease)
• Statins for Heart Disease Prevention (With Known Heart Disease)
• Warfarin vs. Aspirin For Atrial Fibrillation Stroke Prevention
• Warfarin for Atrial Fibrillation Stroke Prevention
• Aspirin for Cardiovascular Prevention (After Prior Heart Attack or Stroke)
• Clopidogrel for Cardiovascular Prevention (After Prior Heart Attack or Stroke)
• Clopidogrel Added to Aspirin During and After a Coronary Event or Stenting
• Hypothermia for Neuroprotection After Cardiac Arrest
• Mediterranean Diet for Post Heart-Attack Care
• Non-Invasive Positive Pressure Ventilation for Pulmonary Edema
• Defibrillation for Cardiac Arrest
• Thrombolytics for Major Heart Attack (STEMI)
• Aspirin For Major Heart Attack (STEMI) http://www.thennt.com/category/system/cardiac/?color=green&type=nnt

Top 10 CERCLA* Toxicants in US 2012
The ATSDR 2011 Substance Priority List
(No change in top 3 since 1997)
*Comprehensive Environmental Response, Compensation, and Liability Act of 1980 www.atsdr.cbc.gov/spl/index.html

Framingham Risk Assessment For Primary Care
 Age
 Hypertension
 Total Cholesterol
 Tobacco
 Diabetes
 HDL
PMID 18212285 ( D’gostino )

FRAMINGHAM AND CV RISKS
RISK FACTOR
Age
SPB-treated
Chol T
HDL
Women
49.1
125.8
215
57.6
MEN
48.5
129.7
212.5
44.9
TEN YEAR HAZARD RATIO
RISK FACTOR
Age
SPB-treated
SPB-not treated
Chol T
Diabetes
Smoking
HDL
Women
10.27
16.82
15.82
*
3.35
*
2
1.7
0.49
MEN
21.35
*
7.38 *
6.91
3.08
1.78
1.92
0.39
PMID 18212285
NHANES 3: Lead and CV risk
 1.89
times risk for myocardial infarction mortality vs. 0.81 (upper tertile vs second)
 1.70
times risk for cardiovascular disease mortality vs. 0.55(upper tertile vs second)
PMID 16982939;
NIH Normative Aging
3 rd Tertile of Lead Bone
8.37 Hazard Ratio adjusted for age, smoking, race (MEN)
PMID: 19738141

 In 2006 Circulation article, using NHANES data, 38% of US Adults were found to have lead levels (>2ug/dl) that raised their risk level of CV death by 187-250%
 In 2009, using NIH Normative aging data, the upper tertile of adults tested for bone lead body burden, had 800% more CV Death

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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 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.”

A 10-year-old worker at the gold processing site
The poisoning caused by artisanal mining from a gold rush killed at least 400 children, affected 6-
9000 adults, 1000 children need chelation, BLL
>10-700ug/dl; Soil 35Kppm vs 400ppm in US
This little girl is suffering from long term effects of lead poisoning. When she is happy she moves her tongue. When she is upset she screams. One of her eyes seems to have gone blind. Every time she wakes up from sleep, she has convulsions
Source: Doctors Without Borders

Lead pollution is a major problem in China. In 2009 a serious scandal revealed that lead smelting plants in Shaanxi and Henan provinces had poisoned thousands of children from surrounding villages (850 reported cases near the Dongling Lead and Zinc
Smelting Company in Changqing township alone).
A report released by the American
Chemical Society reveals that rice imported into the United States from China and other countries contains very high levels of lead.
Major lead poisoning cases in China since 2009
Source: asiancorrespondent.com bsalert.com – naturalnews.com

WATER DISINFECTION SYSTEM BACKFIRED
Washington, DC
1 st Half of 2001 – # of children with BLL > 10 mcg/dl = 0.5%
City-wide chemical disinfection released lead from old pipes
2 nd Half of 2001 – # of children with BLL > 10 mcg/dl = 5.0%
15 PPB lead is the “Action Level” for utilities (EPA 1991)
1 in 6 houses had > than 100 PPB
1 in 1000 houses had > than 1000 PPB
At 10 mcg/dl IQ in children drop 5-7 points
If this had occurred on a nationwide level there would be 3.5 million additional children classified as mentally retarded

http://en.wikipedia.org/wiki/Lead_contamination_in_Washington,_D.C._d
rinking_water#Congressional_review_of_the_2004_CDC_paper

BLOOD LEAD LEVELS IN THE USA: NHANES 4
Blood Lead Geometric mean and selected percentiles of blood concentrations (in μg/dL) for the U.S. population from the National Health and Nutrition Examination Survey
.

 Oxidative stress
 Nitric Oxide inactivation
 Changes in B receptor density
 Endocrine Disruption
 Renal impairment-Proximal Tubular dysfunction
 Lipid Peroxidation

BMC Nephrology 2006, 7:5 doi:10.1186/1471-2369-7-5

 Avoid Current Exposure of Lead-know where to look out for it
7E6IEG
 Keep Bones from turning over to prevent release of previous exposure – Vitamin D, Calcium, Exercise, Hormones

Environ Health Perspect. 2012 January; 120(1): a20–a21.
Published online 2012 January 1. doi: 10.1289/ehp.120-a20a
PMCID: PMC3261960
Kris S. Freeman
Lowered lead from 0.28 mg/l to .00085 mg/l in a few weeks

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Arsenic
74.9
Dorothy Merritt, MD
ACAM Webinar 6/3/14
Arsenic Exposure and Cardiovascular Disease- A systematic review
A Navas-Acien et al PMID 16269585

33
As
Arsenic
74.9
 Metalloid: Properties of a metal and a nonmetal
 Elemental Arsenic-PURE
 Inorganic Arsenic – combined with oxygen, chlorine and sulfur
 Organic Arsenic –combines with carbon and hydrogen
 #1 CERCLA toxicant in US
 Limit in drinking water: 10 ppb
Toxicological profile for arsenic 2012 http://atsdr.cdc.gov/ToxProfiles/tp2.pdf

Arsenic Poisoning Caused by Intentional
Contamination of Coffee at a Church
(Largest Mass Poisoning by Arsenic)
Abstract: An outbreak of apparent food-borne illness following a church gathering was promptly reported to the Maine Bureau of Health.
Gastrointestinal symptoms among church attendees were initially attributed to consumption of leftover sandwiches that had been served the previous day.
PMID: 20384929

Exposure to Arsenic in US Mostly By Ingestion of Food http://healthfreedoms.org/2012/09/20/u pdate-1-us-needs-arsenic-limits-in-riceconsumer-reports
US Arsenic Levels in Well Water http://www.atsdr.cdc.gov/csem/csem.asp?csem=1&po=6

33
As
Arsenic
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In 1934 farmers in the U.S. used the following insecticides
• Arsenicals, 80-90 million pounds
• Sulfur, 73 million pounds
• Kerosene, 10 million gallons
• Mineral Oil Emulsion, 40 million pounds
• Naphthalene and paradichlorobenzene, 21 million pounds
• Pyrethrum, 10 million pounds
• Nicotine sulphate, 2 million pounds
• Rotenone, 1.5 million pounds
The problem with all of these methods is that they were largely ineffective and the chemicals were potentially toxic to humans and other species. Yet, the farmers continued to use them because they didn't have anything else.
http://aenews.wsu.edu/Feb03AENews/Feb03AENews.htm

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Arsenic
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/

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Arsenic
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1) Arrythmias -especially prolonged QT and torsades de pointe
2) Increased generalized atherosclerosis of blood vessels
3) Increased IMT and carotid atherosclerosis
4) Increased AMI-2x
5) Increased PVD and Raynaud’s
PMID 16269585 A Navas-Acien Review Article

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As
Arsenic
74.9
Acute Poisoning
• Case reports of Vfib with baseline QT prolongation in an arsenic poisoned patient
• Case reports of QT-U interval and torsade de pointes
• Case report of interstitial myocarditis in arsenic poisoned patient
• Case reports of prolonged QT in AML treated with arsenic trioxide
Chronic Poisoning
• Significant association of QT prolongation in high arsenic artesian well exposure
PMID: 234034, http://www.hpspharmacies.com.au/knowledge-centre/clinical-article drugs-prolonged-qt-interval-and-torsades-de-pointes

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Arsenic
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SE Taiwan, BLACKFOOT DISEASE (PVD)
Effects and dose-response relationships of skin cancer and blackfoot disease with arsenic Tseng WP - Environ. Health Perspect. (1977) http://arteriosclerotic.org/arterioscleroticdisease-arteriosclerosis/

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Arsenic
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UNIQUE CHILEAN ARSENIC EXPOSURE
More than half of region II’s population live in Antofagasta and Mejillones (current population: 318,000) and were exposed to levels of arsenic greater than 850 lg/liter for a 13-year period (1958–1970) when local rivers highly contaminated with arsenic were used for drinking water instead of just local artesian wells.
Exposure was later sharply reduced around 1971 when installation of water treatment plants began.
This situation has not been seen before, will hopefully never reoccur, and offers an important opportunity to study the health impacts of arsenic.
The study is by far the largest to date on circulatory disease mortality, with more than 8,000 AMI deaths in the exposed population, over 10 times more than those in the largest study in Taiwan. This is also the first study to show that excess AMI deaths predominated during the high-exposure period and for about 10 years thereafter. Later, lung cancer and bladder cancer became the predominant contributors to excess deaths.
American Journal of Epidemiology ª The Author 2007. Published by the Johns Hopkins Bloomberg School of Public Health.
166, No. 12 DOI: 10.1093/aje/kwm238

33
As
Arsenic
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Arsenic Exposure and AMI risk in Chili, 1950-2000
Region 2 (exposed) vs. Region 5 (unexposed)
Source: Drinking water, volcanic activity
AMI Risk:
1.48 (men) / 1.37 (women) - 1958-1970 - High Exposure
Ten years after reduction of exposures, AMI mortality had decreased, and longer latency excess deaths from lung and bladder cancer predominated. With these three causes of death combined, increased mortality peaked in 1991–1995, with estimated excess deaths related to arsenic exposure constituting
10.9% of all deaths among men and 4.0% among women
American Journal of Johns Hopkins Bloomberg School of Public Health.Vol. 166, No. 12 DOI: 10.1093/aje/kwm238

33
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Arsenic
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EFFECTS OF ARSENIC ON HANDS
Raynaud’s

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MANO de DESIERTO - NEAR ANTOFAGASTA CHILE
About 75 km south of the town of Antofagasta, its monotony is shattered by a sight even more alien then the desert itself, and yet undoubtedly human: an 11-meter-tall hand protruding out of the sand. Mano de Desierto is a work of the Chilean sculptor Mario Irarrázabal, who is obsessed with hand art

http://www.detrick.army.mil/rab/presentations/15Jun11_04.pdf

33
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Arsenic
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Agent Orange - Vietnam Pesticide with Arsenic
Service Connected Disability -Diabetes
If you developed diabetes mellitus (type II) and were exposed to Agent Orange or other herbicides during military service in Vietnam, you do not have to prove a connection between the disease and your military service to be eligible to receive VA disability compensation. VA
presumes a service-connected relationship exists, based on the eligibility criteria below, that diabetes mellitus (Type II), or adult-onset diabetes, is associated with exposure to Agent Orange.
Eligibility
Normally, you would have to show proof of a relationship between your military service and the condition being claimed. Under presumption of service connection, however, VA presumes the relationship between exposure to meet all the following conditions:
Agent Orange and diabetes mellitus (Type II) if you
 Served in the Republic of Vietnam during the period January 9, 1962 through May 7, 1975.
(You must have physically served or visited in the Republic of Vietnam (RVN), including service in the waters offshore if the conditions of service involved duty or visitation in
Vietnam. This means the ship must have come to port in the RVN and you disembarked.)
 Been discharged under conditions other than dishonorable
 Have adult onset diabetes mellitus (Type II)
For more information on eligibility, please visit read: http://www.benefits.va.gov/compensation/claims-postservice-agent_orange.asp.

Arsenic related to increased NIDDM and concomitant macro and microvascular conditions
• 66,667 residents living in endemic areas and 639,667 in nonendemic areas- Taiwan
• Age- and gender-adjusted prevalence of microvascular disease in endemic and nonendemic areas was 20.0% and 6.0% in diabetics, and 8.6% and 1.0%, respectively, for nondiabetics
• The corresponding prevalence of macrovascular disease was 25.3% and 13.7% for diabetics, and 12.3% and 5.5% for nondiabetics.
• Conclusion: Increased diabetes in endemic regions may be related to arsenic and concomitant macro and microvascular increases
PMID 12573898 Environ Health Perspect. 2003 (Taiwan)

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Dorothy Merritt, MD
ACAM Fall 2013

Cinnabar
80
Hg
Mercury
200.6
TERLINGUA, TEXAS CEMETERY final resting place for miners who succumbed while digging for the highly toxic cinnabar ore

80
Hg
Mercury
200.6
Mercury Exposure and Cardiovascular Toxicity
 Elemental, Inorganic, Organic
 Interconvertable and can produce systemic toxicity
 Sources are fish, coal fired plants, amalgams, vaccines ,
PMID: 16973445
BIG CONCERN REGARDING FISH CONSUMPTION FOR DHA: counteracts the positive benefit due to (?) mercury/pesticides

Air-born Mercury Distribution in US-From Coal
Fired Plants and Dust Plumes From China http://www.nsf.gov/news/news_summ.jsp?cntn_id=108742

80
Hg
Mercury
200.6
7000 people in mining and milling in 4 countries: Spain, Italy,
Slovenia, Ukraine from 1900s to 1990.
In all countries, the death rate was higher than the standard for nonischemic heart disease: pulmonary hypertension / pneumocosis, myocarditis; hypertension and unclassified, nephritis and nephrosis
(between 1.25 and 2 RR)
PMID: 12107303
Children Case studies: hypertension, tachycardia, mood changes, weight loss, acrodynia mimics pheochromocytoma and
Kawasaki’s disease; Catecholamine levels high because of interference with SAMe and COMT receptor, changes platelet shape and aggregation, changes erythrocyte shape resulting in procoag action
PMC1717944 REF 101 REF 111

80
Hg
Mercury
200.6
US EPA PANEL ANALYSIS
HRV STRONG
HTN WEAK
AMI MODERATE
ATH MODERATE
OXID MOD TO STRONG
PMID: 21220222

Mercury in Patients with Idiopathic Cardiomyopathy
14 patients with IDCM biopsied endocardium and muscle and compared to ischemic, valvular or normal patients as the controls; No occupational exposure
• Hb levels 22,000 x (in endocardium but not muscle)
• Sb levels 12000x
• Au levels 11000x
• Cr levels 13000x
• Co levels 4x
• JACC 33,6,1999 1578-1600

1.
31,46,47,50
2.
29,30,34
3.
29,30,34
4.
31
5.
33
6.
33
7.
30
8.
30

1.
Oxidative Stress
2.
Inflammation
3.
Thrombosis
4.
Vascular Smooth Muscle (VMS) proliferation and migration
5.
Endothelial Dysfunction and reduced NO
6.
Dyslipidemia (O
X
HDL and Paroxonase)
7.
Immune Dysfunction
8.
Mitochondrial Dysfunction

PATHOPHYSIOLOGIC BASIS OF MERCURY
TOXICITY 35,54,55
MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS
Hg
Ubiquinone
– cytochrome B region and
NADH dehydrogenase and
Fe 2+ and Cu + ions A
3
Cub
Altered Calcium
Homeostasis
Depolarization inner mitochondrial membrane
Auto-xidation inner mitochondrial membrane
Peroxidation inner mitochondrial membrane

H
2
O
2
Depletes
Mitochondrial
GSH (> 50%)
Increased Oxidant Stress
Decreased Oxidant Defense

TBARS
Lipid
Peroxidation
> 70%
Oxidation of
Pyridine
Nucleotides
NAD(p)H

300 mg/kg in the produced phosphate fertilizers and thus in the high cadmium content in agricultural soils. Coal can contain significant amounts of cadmium, which ends up mostly in the flue dust.
48
Cd
Cadmium
112.4
Cadmium

• Cigarette Smoke: 1-2ug/cigarrette, 2 ug/pack absorbed
• Food Intake : Shellfish, offal, certain vegetables
• Ambient Air: Urban settings
Arteriosclerosis, Thrombosis, and Vascular Biology. 2009; 29: 1392-1398

Cadmium Toxicity Itai-Itai Disease
“it hurts, it hurts”
Toyama Prefecture, Japan 1912 Mining company upstream
• Severe bone brittleness and pain along with kidney failure
• High Cadmium levels
• People exposed thru river: bathing, rice irrigation, water supply

Cadmium increases the permeability of vascular endothelial monolayers in vitro—protection by zinc.

Cadmium: Mechanisms of Action on Vascular Tissues
Cadmium inhibits the proliferation of endothelial cells and causes a necrotic form of cell death.
Electron microscopic images of the aortic endothelium of ApoE KO mice exposed to Cd
Arteriosclerosis, Thrombosis, and Vascular Biology. 2009; 29: 1392-1398

Cadmium: Mechanism of Actions on Vascular Tissue
1) Atherosclerosis Risk Factors in Female Youngsters 1.6OR
(ARFY) study, (Cd) level was associated with IMT exceeding the 90 th
2) Cd-fed ApoE knockout mice yielded a significantly increased aortic plaque surface compared to controls (9.5 versus 26.0 mm2, P0.004)
3) Cd increases vascular endothelial permeability up to 6-fold by inhibition of endothelial cell proliferation
4) Cd causes induction of a casase independent but Bcl-xL-inhibitable form of cell death more than 72 hours after Cd addition. Both phenomena are preceded by Cd-induced DNA strand breaks and a cellular DNA damage response
Arteriosclerosis, Thrombosis, and Vascular Biology. 2009; 29: 1392-1398

NHANES III (1998-2004):
Hazard ratios 1.51/1.52 for blood and urine for all cause mortality
1.69/1.74 for CVD mortality
1.98/2.53 for heart disease mort.
1.73/2.09 for CAD mortality
Environ Health Perspect. 2012 July; 120(7): 1017–1022.

80
Hg
Mercury
200.6
SUMMARY- CV EFFECTS OF Pb, Hg, As,Cd
Arsenic: Ingestion mostly thru water- dose dependent manner
 Causes CV disease such as Blackfoot(gangrene) , carotid atherosclerosis, CAD,
CVA, Raynaud’s, QT prolongation
Lead: sources - inhalation, water, bone storage and turnover
 Low level lead is “silent killer” in US : MI, CVA, overall death increased
 Beta adrenergic receptors affected
Mercury: sources - inhalation and fish
 MI, nonischemic heart disease, HTN, tachycardia, pheo like sx, accelerated atherosclerosis – carotids
 calcium channel receptors affected, SAMe/COMT receptors affected
Cadmium: sources- cigarettes, inhalation of urban air , ingestion
Increased mortality from cardiovascular disease
Mechanisms of action: Free rads, DNA damage, lipid peroxidation, endothelial dysfunction, depletion of protein sulfahydryls, endocrine disruption, nitric oxide

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