Technical report 122

Dosimetry

The dosimetry of inhaled particulate matter is determined by:

• transport of material into the respiratory tract and transfer to the surfaces/lining fluids of the different compartments;
• redistribution of the deposited matter in the lung and removal processes from the lung.

The first group of transport processes links the airborne particle concentration to the internal dose rate (DR) defined as the amount of material deposited in the lung per time. Influencing parameters are the distribution of mass concentration among the different particle size intervals covering the exposure aerosol, as well as the respiratory minute volume (RMV) and the (pulmonary) deposition fraction, fd,i of the species under consideration. The particle size is measured as aerodynamic or mobility diameter, respectively; i, is the index of the size class ranging from 1 to N , which is the total number of size classes used to characterise the size distribution. The deposition fraction quantifies the fraction of the inhaled mass of the particles in the i-th size range that is deposited in the lung.

In most of the reported inhalation studies the total dose rate is not directly measured but is calculated by adding the contributions of each of the N size classes

DR = RMV∙(c1∙fd,1 + c2∙df,2 + ….+ cN∙fd,N) ……………………………………………………. (Eq 1)

The units of the dose rate are given in μg/h, resulting from l/h for the respiratory minute volume and μg/l for the concentrations. The deposition fraction is dimensionless.

Comparison of studies carried out with different animal species and calculation of human equivalent concentrations require quantitative information on the respiratory minute volume and the deposition fraction. RMV-values are usually obtained from allometric relationships to the body weight, if not measured directly.

The particle size dependence of the regional deposition fraction is primarily controlled by physical mechanisms such as sedimentation, inertial impaction and diffusion; the first two being relevant for particles larger than 0.5 μm, the latter governing lung deposition of nanoparticles (< 0.1 μm). The anatomy of the respiratory system and the respiratory parameters together with the particle size determine in which part of the respiratory tract and to which percentage of the inhaled particles are deposited.

The deposition fraction for experimental animals is taken either directly from experimental data (Raabe et al, 1988) or they are calculated using computer models. Almost all recent inhalation studies rely on the so called multiple path particle dosimetry model (MPPD-model (CIIT Centers for Health Research, 2004) that calculates the retention of inhaled insoluble particles in rats and humans. Dose extrapolations from rats to humans are based on the deposition fractions in the pulmonary compartment calculated by the MPPD-model. New experimental data on the deposition fraction in mice and rats are generated by Kuehl et al (2012) using radio-labelled aerosols of 0.5, 1.0, 3.0 and 5.0 μm MMAD and nuclear imaging by SPECT/CIT. The MPPD modelling results for rats agree quite well with the data obtained for the micron sized aerosols but significantly underpredict the pulmonary deposition fraction of the 0.5μm aerosol: 3 % modelled versus 12.5 % measured. This could be of importance for the interpretation and extrapolation of inhalation studies carried out with aerosols having a substantial mass fraction in the submicron range.

In humans, regional particle deposition is mainly assessed by using the HRT-model (Human Respiratory Tract Model; ICRP, 1994) which is a semi-empirical model based on a large amount of experimental data carried out with humans under well controlled conditions. The deterministic MPPD model is also used for the calculation of the deposition fraction in humans. These models estimate a deposition fraction averaged over the entire lung compartment under consideration. In the past decade a large number of papers appeared where computational fluid dynamics and realistic data on airway structure were used to investigate regional particle deposition. The results brought up the issue of so called hot spots in the deposition pattern. This means that particularly in the tracheo-bronchial airways the average deposition fraction does not adequately describe local doses on the epithelial cells. It was demonstrated that the particle deposition is inhomogeneous over the surface leading to enhancements of local doses by factors up to several hundred (Phalen et al, 2010).

The second group of material transport processes involves mechanisms such as dissolution, translocation into epithelial cells and interstitial tissue, migration of particles caused by mucociliar motion, and migration after incorporation in AMs. These mechanisms determine the fate of particulate matter after deposition, particularly particle retention in the lung, the key quantity with regard to lung overload. One of the early mechanistic approaches brought up by Morrow (1988) to explain lung overload is to assume an impairment of macrophage related clearance as the particulate volumetric lung burden exceeds a certain minimum value. The critical displacement volume of particulates is 6 % of the available volume of the population of macrophage on the alveolar surface. The concentration that leads to this steady state lung burden in rats for chronic exposure can be calculated from physiological data such as for example the respiratory minute volume, the deposited aerosol fraction as calculated by the MPPD-model using the size distribution properties of the challenge aerosol, and the first order clearance constant. The NOAEL concentration calculated from the overload criteria compare reasonably well with values found in inhalation studies with different powders (Pauluhn, 2011). Human equivalent concentrations are derived by assuming the same overload threshold value for steady state volume load per macrophage and adjusting for the differences in the relevant physiological parameters i.e. clearance half-time, deposition fraction, total macrophage volume etc.. From this, the human equivalent volume concentration of respirable particles is calculated to be 0.5 μl/m³ which can be translated into mass concentration by multiplication with the particle density (measured in g/cm3). However, this result depends considerably on the values used for translation from rats to humans, e.g. the half-time of alveolar clearance in humans was set to 400 days by Pauluhn (2011) but, the most recent and probably best estimate available was derived by Gregoratto et al (2010). They estimated the alveolar half-time in humans to be 250 days. Using this estimate, the volume concentration changes to 400/250 × 0.5 ul=0.8 μl/m³

The above derivation is based on volumetric lung burden. However, the issue of the metric used for dose quantification i.e. the physical quantity to which the biological effect is related, is still under discussion. For isometric particles the mass has been the most convenient descriptor. Historically, biological effects of isometric particle have been related to the mass dose, and concentration standards are given in terms of suspended mass per volume of air. Mass can be easily determined by gravimetric and/or chemical analysis. Besides the mass, the surface area has been suggested as a parameter that sometimes correlates better with biological endpoints than mass or volume (Saager and Castranova, 2008, Rushton et al (2010)).

 

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