Air pollution and heart disaese

AIR POLLUTION AND HEART DISEASE

Speaker : Dr Anunay Gupta

Introduction and History Air Pollution: PM, Gaseous, VOC Outdoor Pollution: Diesel/Petrol/CNG Indoor Pollution: Cigarette/CO/Angeethi Pathophysiology of Pollution and CAD (Animal studies) Pollution and CVD Evidence (Clinical studies) Pollution in India/Delhi Summary

INTRODUCTION

Lungs were considered to be the primary target affected by air pollution

Over past decade, effects on CVS have become a focus of research

Exposures to particulate matter (PM) in air at or below the current quality standards has been found to significantly increase CVD morbidity and mortality

Boris Z. Simkhovich et al Curr Opinion in Cardiology 2009

INTRODUCTION

Traditional risk factors account for majority of Ischemic cardiac events

Increasingly recognized as an important and modifiable risk factor

Global Burden of Disease Report: Particulate air pollution is estimated to cause 3.1 million deaths a year and 22% of disability adjusted Life years (DALY) due to IHD

Nicholas L. Mills MD Nat Clin Pract Cardiovasc Med 2009Lim SS et al. Lancet 2012;380:2224-60

HISTORICAL PERSPECTIVE

In 1872 , Robert Angus Smith published air pollution–related study

“Air and Rain. The Beginning of Chemical Climatology”

Pioneered studies of air pollutants as hazardous components of urban air and analyzed their presence in “acid rains.”

MAJOR EPISODES OF SEVERE AIR POLLUTION

1930: Meuse River Valley, Belgium• Main sources: zinc smelter, sulfuric acid factory, glass manufacturers• 60 deaths recorded

1948: Donora, Pennsylvania• Main sources: iron and steel factories, zinc smelting, and an acid plant • 20 deaths observed

1952: London (KILLER FOG )• Primary source: domestic coal burning• 4,500 excess deaths recorded during week- long period in December

2010 : Iceland volcano • The eruption, caused massive dislocation across Europe.

• Caused around 63,000 flights canceled in 23 European countries, stifling the lifeblood of the continent's economy.

AIR POLLUTIO

NVehicle Exhaust

Industrial emissions

Natural Fires

GASEOUSCO2CONO

OzoneSO2

VOLATILE ORGANIC COMPOUNDS

QuinonesPolycyclic aromatic

hydrocarbonsBenzenesToluenes

PARTICULATE MATTER

FineCoarse

Ultra fine

COMPOSITION OF AIR POLLUTION

AIR POLLUTION1: PARTICULATE MATTER

Mixture of particles that adversely affect health

Includes dust, dirt, soot, smoke, and liquid droplets

Broadly categorized and regulated by aerodynamic diameter (μm)

Thousands of chemicals and constituents within PM that may solely, or in combination, impart biological harm.

AIR POLLUTION1: PARTICULATE MATTER

Mobile Sources(vehicles)

VOCs, NO2, PM

Stationary Sources (power plants, factories)

NO2, SO2, PM

Area Sources(drycleaners, gas stations)

VOCs

Natural Sources (forest fires, volcanoes)

PM

AIR POLLUTION1: PARTICULATE MATTER

CONSTITUENTS

Organic / elemental carbon; Hydrocarbons, Ions- NH4, sulfate, nitrate

Metals- Fe, Al, Zn, Cu

SOURCES

Combustion sources - coal, oil, gas, wood, tree, industry

Tobacco smoke, cooking , burning candles or oil lamps and kerosene heaters

LIFETIME Days to weeks, distributed regionally (1000 or more km)

AIR POLLUTION1: PARTICULATE MATTER PM 2.5 FINE PARTICLES

Exposure : Mass of particles within a volume of air

Risk of CV disease is linear without evidence of a safe PM threshold

Daily levels may exceed 200–500 μg/m3, equivalent to passive smoking (e.g. smoky bars 500–1500 μg/m3)

Robert D. Brook Clinical Science (2008)

10 μg/m3 - Annual mean25 μg/m3 - 24-hour mean

AIR POLLUTION1: PARTICULATE MATTER LEVELS

Inhaled but deposited in the upper respiratory tract

Generated by mechanical processes , associated with human (e.g. agriculture) or natural (e.g. erosion) activities.

Constituents Dust , Endotoxin Fungi , Debris , Ground materials Metals : Si , Ca , Fe

Lifetime : hours to day , distributed over 10 – 100 kmsNicola Martinelli ET al European Journal of Internal Medicine 2013

Guidelines Values20 μg/m3 annual mean50 μg/m3 24-hour mean

AIR POLLUTION1: PARTICULATE MATTER COARSE PM 10

Diameter less than 100 nm

Measured as number of particles per m3of air because of very large numbers, but small overall mass

Constituents Primary combustion – hydrocarbons ,metals , organic carbon

Sources Traffic Related Pollution Fresh automobile and combustions emissions

Lifetime - Do not last long in the air, deposit or rapidly form fine particles by coagulation.

- Minutes to hours , distributed 100s of metres

AIR POLLUTION1: PARTICULATE MATTER ULTRAFINE PARTICLES { PM 0.1 }

ULTRAFINE PARTICLES { PM 0.1 } INCREASING IMPORTANCE !

High number of particles; a large surface area for transporting toxic materials

Capable of DIRECTLY translocating into the systemic circulation

Very acute exposure to traffic for only minutes ,conveys a particularly large CV health risk

Mills, N. L. et al Am. J. Resp. Crit. Care Med. 173,426–431

DETERMINANTS OF EXPOSURE

Pollutants vary with emission rates, weather patterns, and diurnal/seasonal cycles in solar radiation

O3 , PM2.5 and secondary VOCs, peak in afternoon Nox, CO and particle elemental carbon (combustion ) peak in rush hour Temporal behavior; governed by formation rate and the length of time it remains

in the atmosphere O3 and PM2.5 have the longest lifetime and build up over multiple days and

spread, by the prevailing winds, over large geographic regions

INDOOR AIR POLLUTION

Results from solid fuels, principally biomass and coal

Ranked as one of top 10 environmental risk factors of global burden of disease

In developing countries, organic materials such as wood, dung, or charcoal (biomass fuel) are burned and used for cooking, home heating, and lighting

The burning of solid fuels in the homes release pollutants including respirable PM, PAHs, heavy metals

AIR POLLUTION:2: GASEOUS

NITROGEN DI OXIDE SULFUR DIOXIDE

FORMS PM 2.5 and Ozone Forms PM 2.5

SOURCE combustion processes Indoor : Use of kerosene heaters

Outdoor Burning of fossil fuels (coal and oil)

EVIDENCE Associated with daily hospital emergency admissions for ACS

Sunyer et al. reported the association of daily SO2 levels with hospital admissions for CVDs in Europe

WHO. Air quality and health. WHO Factsheetsguidelines for Europe; p. 23.Sunyer J et al. Eur Heart J. 2003;24:752

OZONE LEADProperties Major Constituent of SMOG

Not to be confused with the ozone in the upper atmosphere

Naturally occurring and does not go away over time, unlike most pollutants

Source Reaction with sunlight of pollutants such as NOx from vehicle and industry and VOCs emitted by vehicles, solvents and industry.

Indoor - Old paint found in homes built before 1978Lead contaminated soil and dust tracked indoors from outsideOutdoor - Burning of leaded petrol

The highest levels occur during periods of sunny weather

Eliminated lead from gasoline and paints, significantly reduced lead in air pollution in the United States, cutting it by 98% by 2002

AIR POLLUTION:2: GASEOUS

Glenn BS et al Epidemiology. 2003;14:30–6Weiss ST et al Am J Epidemiol. 1986;123:800–8

Indoor sources - Poorly installed and maintained heating systems (angeethi ), charcoal grills, gas kitchen stoves , water heaters

Outdoor sources - Automobiles, cigarette smoke ,industrial processes, and burning of fossil fuels

Harmful effects are more profound in the myocardium than in peripheral tissues because of very high oxygen extraction

AIR POLLUTION:2: GASEOUSCARBON MONOXIDE

Consists of nicotine, tar or particulate phase with many carcinogens, and gaseous compounds including CO

Well-established risk factor for CVD

Smoke from BIDIS contains three to five times the amount of nicotine as a regular cigarette

Pryor WA, Stone K. Oxidants in cigarette smoke.. Ann N Y Acad Sci. 1993;686:12–28

AIR POLLUTION3:VOLATILE ORGANIC COMPOUNDSCIAGARATTE SMOKE

Diesel - Fuel of choice for use in mass transportation vehicles Diesel fuel and the products of its combustion represent one of the most common

toxins to which people living in both urban and rural areas of the world Majority of these particles found in the greatest concentration within immediate

vicinity of busy streets or highways. Components of diesel exhaust

Carbon monoxide and carbon dioxide

Nitrogen oxides

Sulfur oxides

HYDROCARBONS

Unburned carbon particles (soot)

Irina N. Krivoshto et al J Am Board Fam Med 2008;21:55– 62

AIR POLLUTION3:VOLATILE ORGANIC COMPOUNDSDIESEL EXHAUST

On an equal horsepower basis, diesel exhaust is 100 times more toxic

Contribute to formation of ambient particulate matter of all sizes, predominantly harmful Fine fraction and UFP

Organic compounds from diesel exhaust with known toxic and carcinogenic properties, such as polycyclic aromatic hydrocarbons (PAH adhere easily to the surface of the carbon particles and are carried deep into the lungs.

Toxic compounds in higher concentrations than gasoline engines, including nitrogen oxides, sulfur oxides, ozone, formaldehyde, benzene

Irina N. Krivoshto et al J Am Board Fam Med 2008;21:55– 62Zielinska B et al J Air Waste Manag Assoc 2004;54:1138 –50.

AIR POLLUTION3:VOLATILE ORGANIC COMPOUNDSDIESEL vs PETROL EXHAUST

Compressed natural gas, or CNG, is natural gas under pressure which remains clear, odorless, and non-corrosive.

Natural gas burns cleaner than conventional gasoline or diesel due to its lower carbon content.

Natural gas vehicles show an average reduction in ozone-forming emissions of 80 percent compared to gasoline vehicles

The emissions of primary concern include the regulated emissions of hydrocarbons, NOx, CO , CO2

http://www.afdc.energy.gov/

AIR POLLUTION3:VOLATILE ORGANIC COMPOUNDSCNG EXHAUST

SMOG Type of air pollutant

Coal

Transportation emissions The major culprits are are CO, NO and NOx, VOCs ,

sulfur dioxide, and hydrocarbons.

These molecules react with sunlight, heat, ammonia, moisture, and other compounds to form the noxious vapors, ground level ozone to form smog Photochemical smog

It is the chemical reaction of sunlight, nitrogen oxides and volatile organic compounds (VOCs) in the atmosphere Natural causes

An erupting volcano can also emit high levels of sulphur dioxide along with a large quantity of particulate matter; two key components to the creation of smog

Pathophysiology of Air Pollution and CVD

1. INDIRECT PULMONARY-DERIVED EFFECTS

Li XY et al Thorax 51 ; 1216-122Van Eeden SF et al. (2001)  Am J Respir Crit Care Med 164: 826–830Seaton A et al Lancet 345 ; 175-178

Provokes an inflammatory response in the lungs Consequent release of prothrombotic and inflammatory cytokines

into the circulation. Animal studies have demonstrated pulmonary inflammation after

inhalation of ambient PM and dilute diesel exhaust. Lead to elevated plasma cytokines such as interleukin (IL)-1β, IL-6,

and GMCSF Evidence of an acute phase response, increased CRP , plasma

fibrinogen, plasma viscosity

Fine PM or UFP could rapidly translocate into the circulation

Particle translocation seems plausible–either as naked particle or after ingestion by alveolar macrophage

Injured arteries are well known to take up blood borne nanoparticles, a fact exploited by the nanotechnology industry

2. DIRECT TRANSLOCATION INTO CIRCULATION

Nemmar A et al. (2001). Am J Respir Crit Care Med 164: 1665–1668 Kreyling WG et al. (2002) . J Toxicol Environ Health A 65: 1513–1530Oberdorster G et al. (2002)  J Toxicol Environ Health A 65:

1531–1543 

Studied the passage of radioactively labeled ultrafine particles after their intratracheal instillation.

Significant fraction of 99mTc-albumin, taken as a model of ultrafine particles, rapidly diffuses from the lungs into the systemic circulation.

Pulmonary and peripheral effects of inhaled ultrafine carbon particles in old rats that were injected with endotoxin (lipopolysaccharide, LPS) to model systemic gram-negative bacterial infection

In both strains, ultrafine particles (UFP) were found to decrease the number of blood PMNs, increase the intracellular oxidation of a fluorescent dye (DCFD) in blood PMNs, and affect plasma thrombin-anti-thrombin (TAT) complex and fibrinogen levels

3. AUTONOMIC MECHANISM

Parasympathetic nervous system withdrawal and/or sympathetic nervous system activation

PM deposited in the pulmonary tree can directly stimulate lung nerve reflexes via irritant receptors

Alter systemic autonomic balance (Change baroreceptor settings)

Robert D Brook Clinical Science 2008

4 .OXIDATIVE STRESS

MECHANISM OF DISEASE

1. ATHEROGENESIS

Repeated exposure to air pollution could induce atherosclerotic plaque expansion or rupture

Prolonged exposure to ambient PM2.5 increased aortic plaque area and burden, compared with filtered air

In a cross-sectional, population-based study, CIMT measurements in nearly 800 residents of Los Angeles, CA. For every 10 g/m3 increase in PM2.5, carotid intima–media thickness increased by 6%

Sun Q et al. JAMA 2005;294:3003–10.Hoffmann B et al. Circulation 2007;116:489–96Kunzli N et al. (2005).Environ Health Perspect 113: 201–206

2. ENHANCED THROMBOSIS

Induce a variety of prothrombotic effects including enhanced expression of TF and accumulation of fibrin and platelets on ENDOTHELIUM

Could themselves act as a focus for thrombus formation

With underlying vulnerable atherosclerotic plaques, the generation of a pro-thrombotic milieu could trigger arterial thrombosis and subsequent ACS

Long-term exposure to particulate air pollution linked to an increased risk of venous thromboembolic disease

Peters, A et al Lancet 349, 1582–1587Baccarelli A et al. 2008 Arch InternMed 168: 920–927

3. VASCULAR DYSFUNCTION

4. ARRYTHMOGENESIS

VENTRICULAR ARRHYTHMIAS In a study , 100 patients who had 223 ICD discharges . Higher levels

of NO2 , CO, black carbon, fine particles was associated with increased defibrillator therapy.

In another cohort 203 ICD patients followed for mean of 3.1 yrs with 798 confirmed ventricular arrhythmias showed a linear exposure response between PM2.5 and ozone and arrhythmias.

In a study, 211 patients suffered 140 symptomatic ventricular arrhythmias. There was an association between two-hour moving averages of PM10 and ventricular arrhythmias

Peters A et al. Epidemiology. 2000Rich DQ et al Am J Epidemiol. 2005

ATRIAL FIBRILLATION

In sub-analysis of Boston ICD study, there were 900 episodes of

paroxysmal Afib documented by the ICDs Statistically significant association between Afibs and increased O3

in the hr before arrhythmia

Weekly 30 minute Holter for 24 weeks in 32 nonsmoking adults demonstrated an increased risk of SVTs for 5-day moving averages of PM2.5, sulfate and ozone

Sarnat SE et al. Occup Environ Med. 2006Rich DQet al Am J Epidemiol. 2005

HEART RATE VARIABILITY

Putative marker of cardiac autonomic function

In controlled studies, 76 young healthy students showed decreased HRV indices associated with increases in levels of PM, sulfate, nitrate, and ozone.

Acute exposure of elderly individuals with CAD to elevated concentrations of coarse and fine particles resulted in a decrease in HRV

Chuang KJet al. Am J Respir Crit Care Med. 2007Lipsett MJ et al. Environ Health Perspect 2006Tsuji H et al. Circulation 1996

MAGNITUDE OF RELATIONSHIP

Short-term exposure studies

STUDY Source STUDY TYPE

Exposure Increment

Percent Increases in RR Cardiovascular mortality (95% CI)

NMMAPS(US)

Dominici et al2003

Time series 20ug/m3PM10

0.6 (0.3–1.0)

APHEA2(UK)

Analitis et alEpidemiology

2006

Time series 20ug/m3PM10

1.5 (0.9–2.1)

COMEAP

COMEAP2006

Meta analysis

20ug/m3 PM1010ug/m3 PM2.5

1.8 (1.4–2.4)1.4 (0.7–2.2

US, 27 cities

Franklin et alJ Expo Sci Environ Epidemiol. 2007

Case crossover

10ug/m3 PM2.5 All Cause Mortality 1.2 (0.3–2.1)

NMMAPS, National Morbidity, Mortality, and Air Pollution StudyAPHEA2, Air Pollution and Health: A European Approach 2COMEAP, Committee on the Medical Effects of Air Pollutant

IHCSIntermountain Heart Collaborative Study

Case-crossover study design

Ischemic events in 12 865 patients

PM2.5 elevated by 10 g/m3 was associated with increased risk of acute ischemic coronary events (unstable angina and myocardial infarction) equal to 4.5%

Short-term particulate exposures contributed to acute coronary events, especially among patients with underlying coronary artery disease

Circulation. 2006;114:2443-2448

Case cross-over study 691 patients with MI An association was found between exposure to traffic and the onset of a

myocardial infarction within one hour afterward (odds ratio, 2.92; 95 % CI 2.22 to 3.83; P<0.001).

The time the subjects spent in cars, on public transportation, or on motorcycles or bicycles was consistently linked with an increase in the risk

Adjusting for the level of exercise on a bicycle or for getting up in the morning changed the estimated effect of exposure to traffic only slightly (odds ratio f2.73; 95 % CI interval, 2.06 to 3.61; P<0.001).

The subject’s use of a car was the most common source of exposure to traffic There was also an association between time spent on public transportation

Long-term exposure studies

WeCohort survival analysis Cohort Survival Analysis Annual city-specific PM2.5 concentrations were measured between

1979 and 1988, and estimated for later years from publicly available data

Found an increase in overall mortality associated with each 10 g/m3 increase in PM2.5 (RR, 1.16; 95% CI, 1.07–1.26] and cardiovascular deaths (RR,1.28;95% CI, 1.13–1.44).

Improved overall mortality was associated with decreased mean PM2.5 (10 g/m3) between periods (RR, 0.73; 95% CI, 0.57–0.95)

Cohort survival analysis The extended 16-year follow-up in approx. 5,00, 000 adults

demonstrated a 12 % increase in risk for death from CV causes per 10 μg/m3 increase in long-term PM2.5 exposure.

Death from ischaemic heart disease (18 % increase) was the single largest cause of mortality

Larger risks being observed for smokers relative to nonsmokers. Mortality attributable to respiratory disease had relatively weak

associations.

Cardiovascular mortality in long term exposure studies

Associated with increments of 10 µg/m3 PM2.5 Pope and Dockery, 2006, JAWMA, 56(6)

1,00,166 people were enrolled from 1997 to 2007 and followed for an average of 11.5 years

5157 participants experienced incident events. A 5 μg/m3 increase in estimated annual mean PM2.5 was associated with a

13% increased risk of coronary events (hazard ratio 1.13, 95% confidence interval 0.98 to 1.30)

10μg/m3 increase in estimated annual mean PM10was associated with a 12%increased risk of coronary events (1.12, 1.01to1.25)

Positive associations were detected below the current annual European limit value of 25 μg/m3 for PM2.5 and below 40 μg/m3 for PM10

ARE ALL PEOPLE EQUALLY SUSCEPTIBLE ?

Susceptible populations include elderly subjects, diabetic patients ,and individuals with known coronary artery disease

Obesity and female sex have also been proposed as possible susceptibility factors

Many different polymorphisms in various genes, particularly those in oxidative and inflammatory pathways : proposed to modulate PM-related cardiovascular outcome

Brook RD, et al. Circulation 2010;121:2331–78Miller KA et al.N Engl J Med 2007;356:447–58.

AIR POLLUTION IN INDIA

Source HT 2012 OCT

AIR POLLUTION IN DELHI

AIR POLLUTION IN DELHI

Source : INDIA TODAY 2013

HT JAN 2014

PHARMACOLOGICAL THERAPY

Noticeable deficit in studies

Few epidemiological studies have suggested that use of statins or β-blocker drugs can limit the effects of PM

Done in specific populations and with limited end points investigated

Useful to consider whether current medical therapies may be useful adjunct intervention

Schwartz J et al Am. J. Respir. Crit. Care Med (2005)Pekkanen. Circulation 106(8), 933–938 (2002

ANTIOXIDANTS

Strong evidence from animal models that a range of antioxidant compounds can prevent the effects of PM both in vitro and in vivo

No evidence in man , just a reflection of the difficulty in studying oxidative stress in man

Enthusiasm for such an approach is dented by the poor outcome data from clinical trials

Cheng YW, Kang JJ. J. Toxicol. Environ. Health A 57(2)(1999)Nemmar AS et al Toxicology 263(2–3), 84–92 2009

PREVENTIVE MEASURES

Plan your activities when and where pollution levels are lower

Reduce your overall risk of heart disease or stroke

Know when and where particle and ozone pollution levels may be unhealthy

When masks are used, they should be N95 or P100 mask respirators that effectively remove very small air pollution particles

Acknowledged air pollution is a serious concern with severe public health consequences

Delhi has lost CNG gains: Need urgent action CNG pricing is a risk to CNG programme Poor emission standards Diesel price equalization with petrol or tax on diesel cars Right to safe walk and cycling on all roads

Every hour one person is either killed or injured in road accident in Delhi. Implementation of daily air quality alert with health advisory

SUMMARY

Epidemiological evidences supports the detrimental role of PM on cardiovascular morbidity and mortality

Strongest evidence is with PM (100 times more in diesel exhaust )

Increased risk is predominantly confined to susceptible individuals

Mechanism involved autonomic function , direct translocation and systemic oxidative stress with inflammation

SUMMARY

Day has come to routinely ask patients about exposure to air pollutants? (Risk factor )

All CVD patients should be educated about adverse effect of Air Pollution

Air pollution in Delhi have risen markedly making it the world’s most polluted city

Time for formation of strong policies and their implementation and adopt measures to reduce air pollution as a public health priority.

We will breathe easier when the air in community is clean and healthy

We will breathe easier when people are free from the addictive grip of cigarettes and the debilitating effects of lung disease

We will breathe easier when the air in our public spaces and workplaces are clear of second hand smoke

Until then, we are fighting for airTime to reclaim the air we breathe

VASCULAR DYSFUNCTION

The time course and numerous ways inhaled particulate matter alters cardiovascular function

MECHANISMS OF DISEASE

ANTIOXIDANTS – FUTURE PRESPECTIVE Need for better-designed antioxidant therapies that have the capacity to

specifically reach the locations under attack from the oxidative actions of PM

Antioxidants that can be readily recycled to replenish key endogenous antioxidant pools.

Other classes of pharmacological agents, for those that inhibit enzymatic sources of free radicals activated by PM (e.g., NADPH oxidase)

block the sensory receptors in the lung that could mediate the cardiovascular effects of PM via the autonomic nervous system.

Research ArticleFree radical activity and pro-inflammatory effects of particulate air pollution (PM10) in vivo and in vitro.X. Y. Li, P. S. Gilmour, K. Donaldson, W. MacNeeDepartment of Medicine, Royal Infirmary, Edinburgh, UK.AbstractBACKGROUND: Epidemiological evidence has implicated fine particulate air pollution, particularly particles less than 10 microns in diameter (PM10), in the development of exacerbations of asthma and chronic obstructive pulmonary disease (COPD) although the mechanism is unknown. The hypothesis that PM10 particles induce oxidant stress, causing inflammation and injury to airway epithelium, was tested. METHODS: The effects of intratracheal instillation of PM10 was assessed in rat lungs (three per group). Inflammatory cell influx was measured by bronchoalveolar lavage (BAL) and air space epithelial permeability was assessed as the total protein in BAL fluid in vivo. The oxidant properties of PM10 particles were determined by their ability to cause damage to plasmid DNA and by changes in reduced (GSH) and oxidised (GSSG) glutathione. The effects of PM10 particles were compared in some experiments with those of fine (CB) and ultrafine (ufCB) carbon black particles. RESULTS: Six hours after intratracheal instillation of PM10 there was an influx of neutrophils (up to 15% of total cells in BAL fluid) into the alveolar space, increased epithelial permeability, the mean (SE) total protein in the BAL fluid increasing from 0.39 (0.01) to 0.62 (0.01) mg/ml, and increased lactate dehydrogenase (LDH) concentrations in the BAL fluid. An even greater inflammatory response was seen following intratracheal instillation of ufCB but not following CB instillation. PM10 particles had free radical activity in vivo, as shown by a decrease in GSH levels in the BAL fluid from 0.36 (0.05) to 0.25 (0.01) nmol/ml following instillation. The free radical activity of PM10 was confirmed in vitro by its ability to deplete supercoiled plasmid DNA, an effect which could be reversed by mannitol, a specific hydroxyl radical scavenger. BAL fluid leucocytes from rats treated with PM10 produced greater amounts of nitric oxide (NO), measured as nitrite (control 3.07 (0.33), treated 4.45 (0.23) microM/1 x 10(6) cells), and tumour necrosis factor alpha (control 21.0 (3.1), treated 179.2 (29.4) units/l x 10(6) cells) in culture than those obtained from control animals. Since the PM10 preparation was contaminated with small amounts of filter fibres due to the extraction process, the effects of instillation of filter fibres alone was assessed. These studies showed that filter fibres did not account for the proinflammatory and injurious effects of the PM10 suspension. CONCLUSIONS: These findings provide evidence that PM10 has free radical activity and causes lung inflammation and epithelial injury. These data support the proposed hypothesis for the mechanism by which particulate air pollution causes adverse effects in patients with airways diseases.

STUDY YEAR Type of Analysis RESULTS

Harvard Six Cities (extended analysis)

2006 Cohort survival analysis

The extended 28-year follow-up in approx. 8096 people living in U.S. showed that the RR for CV death was increased significantly by 1.28 per 10 μg/m3 increase in long-term PM2.5. The decrease in PM2.5 over thestudy period resulted in a significant reduction in CV mortality (relative risk of 0.69).

American Cancer Society II (extended analysis)

2004 The extended 16-year follow-up in approx. 500 000 adults demonstrated a 12 % increase in risk for death from CV causes per 10 μg/m3 increase in long-term PM2.5 exposure. Death from ischaemic heart disease (18 %increase) was the single largest cause of mortality, with smaller absolute numbers ofpeople (although with similar relative risk elevations) dying from arrhythmias and heart failure.

ATHEROGENESIS

In a cross-sectional, population-based study, Künzli and colleagues examined CIMT measurements in nearly 800 patients

For every 10 μg/m3 increase in PM2.5, CIMT by 6%, which fell to 4% after adjustment for confounding variables

Plos One 2010

Fine particulate matter (PM2.5) Sources of PM2.5 - Both outdoor and indoor sources of fine particulates (PM with an aerodynamic

diameter less than 2.5 μm [PM2.5]).

Particles in the PM2.5 size range are commonly found in smoke and haze and are of particular health concern since they are able to travel deeply into the respiratory tract, reaching the lungs and can also affect the heart.

Human combustion of fossil fuels from different outdoor activities, such as from car, truck, bus, and off-road vehicle (e.g., construction equipment, snowmobile, locomotive) exhausts, other operations that involve the burning of fuels such as wood, heating oil, or coal, as well as natural sources such as forest and grass fires Common indoor activities, and such indoor sources of fine particles include tobacco smoke, cooking

(e.g., frying, sautéing, and broiling), burning candles or oil lamps, and operating fireplaces and fuel-burning space heaters (e.g., kerosene heaters).

Fine particles can also be emitted from the reaction of gases or droplets in the atmosphere from sources such as power generation plants.