ENVIRONMENTAL CARDIOLOGY

HEAVY METALSLEAD, ARSENIC, MERCURY, AND CADMIUM

Dorothy Merritt, MDACAM Webinair June 3, 2014

Dedication to Clair Patterson

• “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

• 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

NHANES-CDC Blood Levels

Normative Aging Study NIH-Bone Levels of lead

Best Sources for Lead and Arsenic

Lead Exposure and Cardiovascular Disease—A Systematic Review by A Navas-Acien et al PMID 18567711Arsenic Exposure and Cardiovascular Disease- A systematic review by A Navas-Acien et al PMID 16269585

Environmental Cardiology

Environmental Toxicants Associated With Cardiovascular Disease

Lead Arsenic Mercury Ozone Aldehydes Carbon Monoxide Particulate matter

PMID 15531422

Lead Toxicity In Primary Care

• 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

Lead Toxicity-Early Symptoms

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

Lead Toxicity Symptoms

Headache Insomnia Irritability Diminished libido Weight loss of 10 lbs or more

without known cause Tremulousness

Lead-Related Symptoms

Personality Changes Peripheral neuropathy in extensor

surfaces- most common neurological symptom in adults

Abdominal pain/cramping Nausea/vomiting Short-term memory loss Depression

Lead-Related Symptoms

Incoordination Paresthesias Constipation Inability to concentrate Impotence

Lead: Where does it come from?

Air- indoor dust exposure greater than soil or paint chips

Water- 20% of total daily exposure (“lead-free” brass fixtures 5-7% lead)

Imports- lead-glazed dishware, leaded crystal. Lead solder in imported canned food,foods from Mexico, China, Spices, Wine

Medicine- Ayurvedic and foreign medicines

Cosmetics

Lead: Where does it come from?

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

Lead in Wine

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

BIOSLUDGE RENAMED “BIOSOLIDS”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”

Blood Lead Levels- ”Tip of the iceburg”

Reflects last 30-60 days of exposure 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

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

Lead Toxicology-BLL vs. Bone

LEAD

SILENT

KILLER IN

USA - 2006

Dorothy Merritt, MD PMID 1700910

Circulation Editorial in 2006

Lead and Cardiovascular

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

Populations at risk for lead toxicity from increased bone turnover

Menopausal women/andropausal men

Hyperthyroidism in either sex

Cisplatin chemotherapy

Patients with osteoporosis or osteopenia

Vitamin D deficiency-50% of population

Occupations at risk for lead toxicity Electricians, plumbers, painters, ceramicists, Munitions specialists, paint and ink manufacturing, etc. Electrical tower and generating station maintenance

http://www.haz-map.com/lead.htm

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%)

Construction (17.1%)

Manufacturing (70.5%)

Other (1.5%)

Section 44 of The Construction Chart Book, Fourth Edition, December

2007 -

Deposition in Soft Tissue

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.

Routes of Excretion

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

Recognition of Lead Exposure andHealth Effects

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… Howard Hu MD MPH (keynote speaker ACAM 2009)

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

PMID: 17306689 NIH Mini Monograph

History and Physical for Lead : How to Document Medical Necessity

for Lead

Death From CV Disease

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*

Number Needed To Treat

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

.

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. Statinsand 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 in Prevention of Heart Disease in PatientsWITHOUT Current CV Disease

Cardiac Interventions That Don't Work* • Statins for Heart Disease Prevention (Without Prior Heart Diseas

e)• Vitamins and Antioxidants for Primary Prevention of Cardiovascu

lar 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 (A

fter 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 Arresthttp://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)

Cardiac Interventions That Work

http://www.thennt.com/category/system/cardiac/?color=green&type=nnt

Top 10 CERCLA* Toxicants in US 2012

www.atsdr.cbc.gov/spl/index.html

*Comprehensive Environmental Response, Compensation, and Liability Act of 1980

The ATSDR 2011 Substance Priority List(No change in top 3 since 1997)

Primary CV Risk FactorsFramingham Risk Assessment For Primary Care

PMID 18212285 (D’gostino)

Age

Hypertension

Total Cholesterol

Tobacco

Diabetes

HDL

RISK FACTOR Women MENAge 10.27 21.35*SPB-treated 16.82 7.38 *SPB-not treated 15.82* 6.91Chol T 3.35* 3.08Diabetes 2 1.78Smoking 1.7 1.92HDL 0.49 0.39

FRAMINGHAM AND CV RISKS RISK FACTOR Women MENAge 49.1 48.5SPB-treated 125.8 129.7Chol T 215 212.5HDL 57.6 44.9

TEN YEAR HAZARD RATIO

PMID 18212285

NIH Normative Aging

3rd Tertile of Lead Bone8.37 Hazard Ratio adjusted for age, smoking, race (MEN)

PMID: 19738141

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)

NHANES 3: Lead and CV risk

PMID 16982939;

Cardiac Risk

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

Lead and Cardiovascular

LEAD BEHAVIORAL EFFECTS

Lead Regulators in the US

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 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.”

Lead “Hot Spots” on Earth

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

Lead Poisoning Disaster in Nigeria

Source: Doctors Without Borders

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 35K ppm vs 400ppm in US

A 10-year-old worker at the gold processing site

CHINA –Kids Poisoned - Exporting

Source: asiancorrespondent.com - bsalert.com – naturalnews.com

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.

Lead pollution is a major problem in China. In 2009 a seriousscandal revealed that lead smelting plants in Shaanxi and Henanprovinces had poisoned thousands of children from surroundingvillages (850 reported cases near the Dongling Lead and ZincSmelting Company in Changqing township alone). Major lead poisoning cases in China since 2009

Lead in Animals

CONTAMINATION FROM LEAD PIPES

WATER DISINFECTION SYSTEM BACKFIRED Washington, DC

1st Half of 2001 – # of children with BLL > 10 mcg/dl = 0.5%

2nd Half of 2001 – # of children with BLL > 10 mcg/dl = 5.0%

City-wide chemical disinfection released lead from old pipes

15 PPB lead is the “Action Level” for utilities (EPA 1991)

1 in 6 houses had > than 100 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

1 in 1000 houses had > than 1000 PPB

2001-2005 Lead contamination in Washington, D.C. drinking water

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

NIH Proven Health Findings

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.

Mechanisms of Action for Toxicity

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

Bottom line Avoid Current Exposure of Lead-know where to

look out for it

Keep Bones from turning over to prevent release of previous exposure – Vitamin D, Calcium, Exercise, Hormones

7E6IEG

Environ Health Perspect. 2012 January; 120(1): a20–a21. Published online 2012 January 1. doi:  10.1289/ehp.120-a20aPMCID: PMC3261960Kris S. Freeman

Lowered lead from 0.28 mg/l to .00085 mg/l in a few weeks

Remediating Soil Leadwith Fish Bones

Arsenic and CV Disease

Dorothy Merritt, MDACAM Webinar 6/3/14

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Arsenic Exposure and Cardiovascular Disease- A systematic review A Navas-Acien et al PMID 16269585

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

Arsenic

Toxicological profile for arsenic 2012 http://atsdr.cdc.gov/ToxProfiles/tp2.pdf

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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.

Biological “Aggression”

PMID: 20384929

Exposure to Arsenic in US Mostly By Ingestion of Food

http://www.atsdr.cdc.gov/csem/csem.asp?csem=1&po=6

http://healthfreedoms.org/2012/09/20/update-1-us-needs-arsenic-limits-in-rice-consumer-reports

US Arsenic Levels in Well Water

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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Brief History of Arsenic Uses

/

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CV Effects Of Arsenic

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PMID 16269585 A Navas-Acien Review Article

1) Arrythmias -especially prolonged QT and torsades de pointe

2) Increased generalized atherosclerosis of blood vessels

3) Increased IMT and carotid atherosclerosis4) Increased AMI-2x5) Increased PVD and Raynaud’s

Arsenic and QT interval

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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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

Arsenic contaminated wells and PVD:

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/arteriosclerotic-disease-arteriosclerosis/

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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 Epidemiologyª The Author 2007. Published by the Johns Hopkins Bloomberg School of Public Health. 166, No. 12 DOI: 10.1093/aje/kwm238

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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

EFFECTS OF ARSENIC ON HANDSAs33

Arsenic74.9 Raynaud’s

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

MANO de DESIERTO - NEAR ANTOFAGASTA CHILE

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Arsenic Problem at Fort Detrick

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

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 Agent Orange and diabetes mellitus (Type II) if you meet all the following conditions: 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.

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Agent Orange - Vietnam Pesticide with ArsenicService Connected Disability -Diabetes

Arsenic related to increased NIDDM and concomitant macro and microvascular

conditions

PMID 12573898 Environ Health Perspect. 2003 (Taiwan)

• 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

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Mercury and CV Disease

Dorothy Merritt, MDACAM Fall 2013

Arsenic and Cardiovascular Disease

80

Mercury200.6

Hg

Cinnabar

TERLINGUA, TEXAS CEMETERYfinal resting place for miners who succumbed while digging for the highly toxic cinnabar ore

Mercury Exposure and Cardiovascular Toxicity

Interconvertable and can produce systemic toxicity

Sources are fish, coal fired plants, amalgams, vaccines ,

PMID: 16973445

80

Mercury200.6

Hg Elemental, Inorganic, Organic

BIG CONCERN REGARDING FISH CONSUMPTION FOR DHA: counteracts the positive benefit due to (?) mercury/pesticides

http://www.nsf.gov/news/news_summ.jsp?cntn_id=108742

Air-born Mercury Distribution in US-From Coal Fired Plants and Dust Plumes From China

Inorganic Mercury-NonIschemic CV, Pulm HTN, Myocarditis, HTN

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 non-ischemic heart disease: pulmonary hypertension / pneumocosis, myocarditis; hypertension and unclassified, nephritis and nephrosis (between 1.25 and 2 RR) PMID: 12107303Children 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

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Mercury200.6

Hg

METHYL MERCURY AND CV EFFECTS US EPA PANEL ANALYSIS

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Mercury200.6

Hg

HRV STRONGHTN WEAKAMI MODERATEATH MODERATEOXID MOD TO STRONG

PMID: 21220222

Mercury in Patients with Idiopathic Cardiomyopathy14 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

CLINICAL VASCULAR CONSEQUENCES OF MERCURY

TOXICITY

1. Hypertension31,46,47,50 2. Coronary Heart Disease29,30,34 3. Myocardial Infarction29,30,34 4. Carotid IMT and Obstruction31 5. Generalized Atherosclerosis33 6. Renal Dysfunction and Proteinuria33 7. CVA30 8. Total Mortality Increased30

SUMMARY OF VASCULAR BIOLOGIC EFFECT OF MERCURY

1. Oxidative Stress

2. Inflammation

3. Thrombosis

4. Vascular Smooth Muscle (VMS) proliferation and migration

5. Endothelial Dysfunction and reduced NO

6. Dyslipidemia (OXHDL and Paroxonase)

7. Immune Dysfunction

8. Mitochondrial Dysfunction

PATHOPHYSIOLOGIC BASIS OF MERCURY TOXICITY35,54,55

MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS

Hg

Ubiquinone – cytochrome B region andNADH dehydrogenase and

Fe2+ and Cu+ ions A3Cub

Depolarization inner mitochondrial membraneAuto-xidation inner mitochondrial membranePeroxidation inner mitochondrial membrane

Altered CalciumHomeostasis

H2O2Depletes

MitochondrialGSH (> 50%)

TBARSLipid

Peroxidation> 70%

Oxidation ofPyridine

NucleotidesNAD(p)H

Increased Oxidant StressDecreased Oxidant Defense

Arsenic and Cardiovascular Disease

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Cadmium112.4

Cd

Cadmium

Rocks mined to produce phosphate fertilizers contain varying amounts of cadmium, leading to a cadmium concentration of up to 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.

Cadmium: Sources

• 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”

• Severe bone brittleness and pain along with kidney failure• High Cadmium levels• People exposed thru river: bathing, rice irrigation, water

supply

Toyama Prefecture, Japan 1912 Mining company upstream

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

Cadmium inhibits the proliferation of endothelial cells and causes a necrotic form of cell death.

Cadmium: Mechanisms of Action on Vascular Tissues

Arteriosclerosis, Thrombosis, and Vascular Biology. 2009; 29: 1392-1398

Electron microscopic images of the aortic endothelium of ApoE KO mice exposed to Cd

Cadmium: Mechanism of Actions on Vascular Tissue

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

1) Atherosclerosis Risk Factors in Female Youngsters 1.6OR(ARFY) study, (Cd) level was associated with IMT exceeding the 90th

Arteriosclerosis, Thrombosis, and Vascular Biology. 2009; 29: 1392-1398

Cadmium and Vascular Disease

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.

Arsenic: Ingestion mostly thru water- dose dependent manner Causes CV disease such as Blackfoot(gangrene) , carotid

atherosclerosis, CAD, CVA, Raynaud’s, QT prolongationLead: sources - inhalation, water, bone storage and turnover Low level lead is “silent killer” in US : MI, CVA, overall death

increased Beta adrenergic receptors affectedMercury: sources - inhalation and fish MI, nonischemic heart disease, HTN, tachycardia, pheo like sx,

accelerated atherosclerosis – carotids calcium channel receptors affected, SAMe/COMT receptors affected

80

Mercury200.6

Hg SUMMARY- CV EFFECTS OF Pb, Hg, As,Cd

Mechanisms of action: Free rads, DNA damage, lipid peroxidation, endothelial dysfunction, depletion of protein sulfahydryls, endocrine disruption, nitric oxide

Cadmium: sources- cigarettes, inhalation of urban air , ingestion Increased mortality from cardiovascular disease

Questions????

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