Particulate Matter Toxicology Michael J. Wernke, R.Ph., Ph.D; Marci Balge, RN, MSN, COHN-S; Scott Phillips, MD, FACP, FACMT, FAACT.

Particulate Matter Toxicology

Michael J. Wernke, R.Ph., Ph.D; Marci Balge, RN, MSN, COHN-S; Scott Phillips, MD, FACP, FACMT, FAACT

This educational module was produced by Michael J. Wernke, R.Ph., Ph.D, Scott Phillips MD, FACP, FACMT, FAACT and Marci Balge, RN, MSN, COHN-S for The University of Texas Health Science Center at San Antonio (UTHSCSA) Environmental Medicine Education Program and South Texas Environmental Education and Research Program (STEER-San Antonio/Laredo/Harlingen,Texas)Administrative support was provided by the Association of Occupational and Environmental Clinics through funding to UTHSCSA by the Agency forToxic Substances and Disease Registry (ATSDR), U.S. Department of Health and Human Services. Use of this program must include acknowledgement of the authors, UTHSCSA and the funding support.

For information about other educational modules contact the UTHSCSA STEER office, Mail Code 7796, 7703 Floyd Curl Drive, San Antonio,Texas 78229-3900,(210)567-7407.

Case Presentation An 11-year-old boy presents with his mother

with complaints of wheezing, a productive cough with phlegm, and a runny nose

The boy has been previously diagnosed with asthma and is currently treated with an albuterol inhaler and Singulair

Case Presentation (continued) The boy has had good control of his asthma

over the past several months, but in the past few weeks he has significantly increased his inhaler use, especially after playing outdoors

Symptoms worse outdoors; feels better when in air conditioned spaces

Case Presentation (continued) Family lives in a rural area along the Texas-Mexico

border; the primary commodity grown in this area is sugarcane

Over the past few weeks workers have been setting the fields of sugarcane ablaze; onset of worsening asthma symptoms corresponded with the burning of the sugarcane

Mother questions link between the burning and her son’s asthma and additionally questions why the workers are burning the crop prior to harvest

Case Presentation (continued) Mother also reports that since the fires began

there has been a lot of smoke and haze in the air

Local media have been cautioning people with respiratory conditions to remain indoors and for others to limit their activity outdoors

Case Presentation (continued) Physical examination reveals a clear nasal

discharge, expiratory wheeze, and a product cough but is otherwise unremarkable. The boy is afebrile. Other than the respiratory complaints, the child has no other health complaints.

Case Presentation (continued) Impression: exacerbation of asthmatic symptoms

related to the burning of nearby and perhaps distant sugarcane fields

Sugarcane growers burn their fields in preparation for harvest – removes unwanted material (e.g., leaves) and increases yield

The burning also generates considerable smoke/particulate matter

Case Presentation (continued) Advise child to remain indoors in air-conditioned

environments until burning ceases Use a dust/allergy mask when outdoors; limit time

and activity outdoors until burning ceases Use asthma medications as directed and return after

air quality improves for re-evaluation

Questions To Consider What is particulate matter and how is it

defined? Can exposure to particulate matter cause or

exacerbate asthma or other respiratory conditions?

Are there other health effects associated with exposure to particulate matter?

Questions to Consider Are there certain segments of the population who are

more sensitive to the adverse health effects of particulate matter?

Are there safe levels of exposure to particulate matter – if so, what are these?

Where can one find information concerning the concentration of particulate matter in their area?

Airborne Particulate Matter A major public health issue Estimated to cause 500,000 excess deaths

annually worldwide Associated with adverse effects on the

pulmonary and cardiovascular system May cause toxicity at or below NAAQS

Airborn Particulate Matter Not a unique or single substance A mixture of organic, inorganic, and

biological materials of various size and shapes

May have bound to it other substances (e.g. metals, PAH) that cause toxicity

Composition varies by regionally, seasonally, and daily

Airborne Particulate Matter Local and distant sources can contribute to the

composition Chemical composition provides clues regarding

source (e.g. burning tires as a fuel for firing bricks along Texas-Mexico border has been shown to affect air quality of the Paso del Norte airshed in general and El Paso, Texas in particular

El Paso border; Juarez, Mexico

Airborne Particulate Matter Greatest area of interest lies in

nanotechnology and nanoparticulates Large number of people with potential

exposure Nanoparticules are small enough to directly

enter cell thereby possibly leading to toxicity

Lecture Overview Classification Existing air standards Dose considerations Deposition and clearance in lung Health effects

Particulate Matter - Regulatory Classification Regulatory classifications include total dust or

coarse, fine or ultrafine (nanoparticulate) based on MMAD

Total dust < 100 µm Coarse 2.5 - 10 µm Fine 0.1 – 2.5 µm Ultrafine < 0.1 µm

NAAQS

Particle Type Annual Mean 24-Hour Max

PM10 50 µg/m3 150 µg/m3

PM2.5 15 µg/m3 65 µg/m3

NAAQS Large database demonstrating acute and chronic

health effects at NAAQS but the reason is not clear Health effects associated with measures of mass

(µg/m3) rather than by composition or nominal size. Day-to-day fluctuations in the mass concentration of

10 µg/m3 increases mortality by abut 0.6 to 1%

ACGIH Classification Inhalable particulate (< 100 µm) Thoracic particulate (0 – 25 µm) Respirable particulate (0 – 10 µm) Occupational Guidelines (TLV) – 3 mg/m3 for

respirable particulate and 10 mg/m3 for inhalable particulate

Sampling for Particulates Area samples

Useful for identifying source and general background exposure

Depending on a number of factors, such as distance from source, time spent outdoors, weather patterns, area samples may under- or overestimate any one person’s exposure

Sampling for Particulates There are a number of continuous air

monitoring stations throughout the state of Texas, some of which are located on the Texas-Mexico border

Stations do report particulate air matter concentration (PM10 and PM2.5)

Texas Commission on Environmental Quality (www.tceq.state.tx.us)

Sampling for Particulates Personal samples

Air collected within 25 cm of the nose and mouth Provide a good measure as to that individual’s

exposure Expensive/may not be feasible in a community Need to assess representative groups

Dose Determinations Many measures of dose

Exposure dose (De)

Inhaled dose (Di)

Total deposited dose (Dd)

Regional deposited dose (Dr)

Dose deposited per regional surface area (Drsa)

Dose Determinations Various dose matrices differ in the amount of

information considered De = C x T Drsa = C x T x Vm x I x DFr/Sr

In clinical setting such calculations are not important; only likely to know average concentration and exposure duration if anything at all

Individual Factors Affecting Dose Normal individuals with airway anatomies or

breathing characteristics that are extreme in the health population distribution (outliers)

Very young, very small, or obese individuals Lung disease (e.g. COPD; Asthma)

Individual Factors Affecting Dose Physical activity Impaired clearance Proximity to source Behavioral changes, such as curtailing

physical activity outdoors, remaining in air-conditioned environments, use of air filters can lower one’s dose.

Particulate Matter Deposition Particle size determines region of respiratory

tract where a particle will be deposited. Deposition of particles on the surface of the

respiratory system brought about by a combination of lung anatomy and patterns of air flow

Particulate Matter Deposition 5 – 30 µm particles deposited in nasopharynx

by inertial impaction Abrupt directional changes and high velocity air

flow force these larger particle to impact the airway surface

Recent data indicates that very fine particles (<0.01 µm) are efficiently trapped in the upper airways by diffusion

Particulate Matter Deposition 1 – 5 µm particles deposited in the

bronchiolar region via sedimentation In this region the airways are small, changes less

abrupt, and air flow velocity low, allowing particles to settle out of the airflow and onto the airway surface

Particles ≤1 µm deposited in the alveolar region via diffusion

Particulate Matter Deposition Factors affecting deposition include:

Inactivity (periods of quiet breathing) Physical activity Breath holding Pulmonary disease (e.g. chronic bronchitis) Irritants (e.g. tobacco smoke)

Particulate Matter Clearance Lung’s main defense mechanism Rapid clearance decreases time available to

cause damage or permit systemic absorption Does not necessarily imply clearance from

body

Particulate Matter Clearance Particles removed from the respiratory system

may be transported To the stomach/GI system and absorbed To the lymphatics and enter venous circulation The pulmonary vasculature and absorbed

Coughing/nose blowing can completely removed deposited particles

Particulate Matter Clearance Nasal Clearance

Anterior portion- wiping or blowing Other portions – mucociliary transport

Insoluble particles cleared within 1 hour Soluble particles may be dissolved and absorbed

before they can be removed Olfactory regions or areas damaged by infection,

illness, or toxic injury - uncertainty

Particulate Matter Clearance Tracheobronchial Clearance

Mucociliary escalator transports particles and particle-laden macrophages to the oropharynx where they are swallowed Relatively rapid and complete within 24-48 hours

Infection and other injuries can greatly impair clearance from this area

Particulate Matter Clearance Pulmonary Clearance

Several mechanisms: Mucociliary escalator Phagocytized by macrophages and cleared via mucociliary

escalator Phagocytized by macrophages and cleared via lymphatics Substances may dissolve from surface of particle and be

removed via blood or lymphatics Direct penetration of epithelial membranes (ultrafine particles)

Particulate Matter Clearance Uptake and transport via sensory neuronal

axons Area of intense research Supported by research in laboratory animals

using dye particles, polio virus particles, and 14C-ultrafine particles

Concern entails direct entry of potentially toxic substances into the CNS

Particulate Matter Health Effects The adverse effects of particulate matter are

primarily observed in the pulmonary and cardiovascular systems, involving both morbidity and mortality. We’ll begin our discussion on with the pulmonary system and then talk about the cardiovascular system.

Particulate Matter Health Effects Asthma

Abundant evidence from epidemiological studies, including studies along the Texas-Mexico border, that particulate matter air pollution contributes to exacerbations of asthma.

Particles have been linked to worsening of symptoms, decrements in lung function, increased hospital admissions, and increased medication (e.g. inhaler) use.


Mechanism of exacerbation not fully elucidated Possibly mediated by particulate matter-induced

inflammation Direct injury Activation of cellular hose defense pathways leading

to inflammation


Support for inflammatory hypothesis Evidence that outdoor air particulates cause

inflammation in the lungs Inflammation known to play a critical role in

obstructive airway disease such as asthma


Asthmatics considered at risk for exacerbation due to ambient particulate matter because Obstructive lung disease like asthma increase airway

deposition of fine and ultrafine particles Nonspecific airways responsiveness Particle-induced inflammation may increase airway

responses to allergen exposure.

Particulate Matter Health Effects COPD

Perhaps mediated via inflammatory processes Hypothesis is that particulate matter activates

neutrophils and macrophages, causing them to release proteases and reactive oxygen species, both of which have been implicated in the lung parenchymal destruction that defines emphysema.

Particulate Matter Health Effects Other Respiratory Ailments

Long-term exposure to particulate matter has been associated with: Decrements in measures of lung function (e.g.

decreases in FEV1 and FEV1/FVC) Episodes of chronic bronchitis and chest illness in

children Chronic pulmonary symptoms, such as bronchitis, in

adults

Particulate Matter Health Effects Mortality

Several incidents, such as the Meuse Valley disaster of 1930 and the London Smog disaster of 1952 have show an association between elevated levels of particulate matter and mortality from cardiovascular and pulmonary ailments

Particulate Matter Health Effects Mortality

Studies such as the Harvard Six City Study and the American Cancer Society show that exposure to particulate matter reduced life expectancy and this effect was predominantly associated with PM2.5

Recent data suggest that short-term measures of exposure, not long-term measures, are associated with mortality

Particulate Matter Health Effects Cardiovascular Mortality and Morbidity

Mortality Changes in blood viscosity Decreased heart rate variability ST-segment depression Increased discharges of implanted defibrillators Increased blood pressure Increased circulating markers of inflammation and

thrombosis


Recent study by the ACS showed that increased levels of particles strongly associated with mortality attributable to ischemic heart disease, dysrhythmias, heart failure, and cardiac arrest.

A 10 µg/m3 elevation in fine particulate matter associated with an 8 – 18% increase in mortality risk


ACS study (continued) Risks were larger for smokers relative to non-smokers Most dramatic increase in relative risk seen in

smokers with hypertension Suggests a possible synergistic response in particulate

matter-related cardiovascular mortality between smoking and hypertension


Proposed mechanisms Sympathetic nervous system dominance Inflammatory events in the lung resulting in

circulating inflammatory and coagulation mediators and subsequent endothelial injury, thrombosis, and accelerated atherosclerosis

Direct toxic effects of particulate components on myocardium or coronary vasculature

Particulate Matter Health Effects Pregnant women and their fetuses may

represent a sensitive group Limited number of studies report an

association between exposure to high particulate air concentrations and: Low birth weight Pre-term delivery Increase risk of infant mortality

Particulate Matter Toxicology Conclusions

Abundant evidence that particulate matter causes significant cardiovascular and pulmonary morbidity and mortality and perhaps effects on fetuses

These effects have been shown to occur with air particulate levels at or near NAAQS

Removal from exposure necessary – treatment symptomatic

Questions?

Juarez, Mexico

Particulate Matter Toxicology Michael J. Wernke, R.Ph., Ph.D; Marci Balge, RN, MSN, COHN-S; Scott Phillips, MD, FACP, FACMT, FAACT.

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