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FACTORS INFLUENCING THE DOSE FOR AEROSOLS

FACTORS INFLUENCING THE DOSE FOR AEROSOLS. Yves Alarie, Ph.D Professor Emeritus U niversity of Pittsburgh,USA. A. FACTORS INFLUENCING TOTAL DOSE

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FACTORS INFLUENCING THE DOSE FOR AEROSOLS

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  1. FACTORS INFLUENCING THE DOSE FOR AEROSOLS YvesAlarie, Ph.D Professor Emeritus University of Pittsburgh,USA

  2. A. FACTORS INFLUENCING TOTAL DOSE • a) Concentration in air, C, (mg/m3) or (mg/L) or (mM/L) or fibers/cc or mppcf or any appropriate unit of mass or number of particles but not ppm. • b) Particle size, which will determine the fraction of aerosol deposited. This fraction is called α and is given in %. • c) Minute ventilation, MV, which is determined by tidal volume (VT) and number of breaths per minute (f), i.e., VT´f. • d) Duration of exposure in minutes (t). • e) Body weight (kg) or body surface area (m2) or lung surface area (m2» 70m2 in adult humans).

  3. To get a “ball park” figure, assume 50% (0.5) for α if particle size is not known. Thus, if a human is exposed at a concentration of 1mg/L for a period of 60 minutes and has a VT of 800 ml and f of 15/minute the total dose received would be:

  4. This value can then be divided by body weight, etc. for a true expression of dose. As can be seen, we now have the proper units for toxicity instead of just having an exposure concentration in mg/L or mg/m3 or ppm. Comparisons of total dose received can be made between various animal species exposed at the same concentration, on the basis of mg/kg of body weight or mg/m2 of body surface area or pulmonary surface area, or for surface area of any portion of the respiratory tract.

  5. The same formula is used to calculate the number of fibers deposited in the respiratory tract. Thus, again assuming 0.5 for α, if a human is exposed at a permissible exposure level (PEL of OSHA) of 0.2 fibers/cc of asbestos fibers, and is exposed for 8 hours, assuming again a VT of 800 ml and f of 15/min, we would have the following:

  6. B. FACTORS AND MECHANISMS AFFECTING TOTAL DEPOSITION AND REGIONAL DEPOSITION OF AEROSOLS The factors affecting deposition sites in the respiratory tract are: Size Shape Density The above 3 characteristics are taken into account simultaneously for particles > 0.5 μm by experimental determination of their aerodynamic mass equivalent diameter and for particles <0.5 μm only the size is important, as presented above.

  7. - Electrostatic attraction (depends on chemical composition) between the particle and the surface of the respiratory tract, may play a role but is difficult to investigate.- Hygroscopicity (depends on chemical composition) since a small particle can grow upon entering the 100% RH of the respiratory tract. Also we must take into account the following factor: Pattern of pulmonary ventilation including nose vs. mouth breathing, as well as volume and frequency of each breath.

  8. There are 5 major physical mechanisms by which airborne particle deposition occurs in the respiratory tract. These are depicted in the diagram below and explained below. For impaction, sedimentation and diffusion, mathematical equations have been developed a long time ago and a look at these equations is useful to understand each mechanism and are used to calculate deposition in the respiratory tract.

  9. 1. Impaction, InertiaWhen an obstacle exists in the path of the airflow, or bifurcations or tortuous paths occur such as in the nose or tracheobronchial tree, small particles will follow the air flow lines but large particles, because of greater inertia are unable to change direction and will impact.Note: Impaction is the most important mechanism of deposition for particle > 3 μm in the nasopharyngeal area and central airways of the lung.

  10. 2. Sedimentation, Settling • All particles with density greater than air experience a downward force due to gravity. • Thus, a particle accelerates downward until its velocity increases to the point where the retarding force due to its motion through air just balances its weight. If a particle is spheric and small enough so that viscous forces are the primary resistive forces, Stoke’s law applies to predict retarding forces.

  11. 3. Diffusion, BrownianMovement • Motion caused by random molecular collision, this process can be described as follows: • It is important for particles < 0.5 µm. Important to remember that particle diameter is the only factor. Diffusion will be the most important mechanism of deposition at the alveolar level.

  12. 4. Electrostatic Attraction • All aerosol particles have a + (non-metallic) or - (metallic) charge which may affect deposition. However, little is known about the effect of charge except for highly charged particles which can occur in freshly generated particles. Important for polymeric fibers, proteins (synthetic or natural) which can hold a high charge. • 5. Interception • Of importance for fibers as the inspired air comes • in close contact with a surface. Fiber deposition models are less well developed than for particles.

  13. C. DEPOSITION CALCULATIONS AND RESULTS • From the above, calculations of deposition according to aerodynamic particle size have been made for the various regions of the respiratory tract: • a) Nasal-Pharyngeal (N-P) • b) Tracheo-Bronchial (T-B) • c) Pulmonary (P) • These are presented below in Figures 2 and 3 and a quick summary is presented in Table 1.

  14. C. MAN VS. LABORATORY ANIMAL • With aerosol exposures and laboratory animals, it is important to recognize that although the same particle size may be used, deposition sites and clearance rates are likely to be different. Some general conclusions: • a) The major factor controlling net dose received seems to be minute ventilation and, therefore, the small animals will receive a higher total dose because of their higher minute ventilation to body weight ratios. However, there is variation even between animals of same species, and deposition sites will vary from deposition sites in humans despite similar particle size being used.

  15. b) The smaller the animal, the larger the probability of nasal retention. A 2 μm particle has about the same probability of being retained in the mouse nose as an 8 μm particle in man. Important for large particles. c) The larger the particles are above 3 μm the more chance of difference in regional deposition with humans. Total net dose may be the same but biological effects may be different because the deposition sites and clearance rates are different.(5) In particular, clearance rates vary widely between different species.(6) In general, clearance in rats and mice is faster than in humans, monkeys or guinea pigs.

  16. d) To have the same relation with humans between atmospheric particulate concentration and rate of deposition of particles in the lungs, fairly uniform particles around 1-3 μm (MMD) seems to be highest to use with small rodents, this would be defined as “inhalable” or “inspirable” and would also be classified as “respirable” particles for small laboratory animals. See below for the descriptions and definitions of these terms. Compare the results obtained below (Figure 4) in rats and hamsters to the results obtained in humans (Figure 3).

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