5 Discussion and Conclusions
5.5 Discussion of Kinetic Data Referring to the Paper of Pauluhn (2011)
Pauluhn (2011) has presented an approach how to predict NOAEL values for granu-lar poorly soluble particles following inhalation. In terms of the volume-based cumu-lative dose in lungs, target volume loads in rat studies should be in the range of approx. 1 µl/lung (no adverse effects expected) to maximum 10 µl/lung, lest a lung clearance collapse with clearance half-times > 1 year should occur.
In Figure 5.1, key information on the novel approach is given. The lung overload threshold in rats is defined as 4.2 µl particulate matter/kg b.w. Up to this value ad-verse effects due to particle load will not be observed for low soluble dusts without special surface reactivity (“inert dusts”). Using this value of 4.2 µl/kg b.w., fractional doses/day on volume basis (unit: µl/day) can be derived, varying depending on study duration, to attain the steady state (for a 4-wk study: 17.5; for a 3-mth study: 40).
The NOAEL (unit: mg/m3) can be calculated using the following equation:
NOAELpred. (mg/m3) = 1 µl x ρ (mg/µl) / 17.5 (AF) x 0.29 m3 (MV) x PMresp pred. = predicted;
AF = accumulation factor;
MV = daily respiratory volume;
PMresp = deposition fraction (%according to MPPD model)
Fig. 5.1 Basic assumptions and exemplary calculation to predict NOAEL aero-sol concentrations (Pauluhn, 2011)
Calculationof NOAELpred. for the 4-week inhalation test in this study:
NOAELpred. (mg/m3) = 1 µl x ρ (mg/µl) / 17.5 (AF) x 0.29 m3 (MV) x PMresp = 1 x 1.7 / 17.5 x 0.29 x 0.07
NOAELpred. = 4.8 mg/m3
The predicted NOAEL is approx. 5 mg/m3 and is well reflected by the experimental NOAEL detected at 3 mg/m3 for the three test items in this study.
Overall conclusion: The three TiO2 varieties of the triple used for this study did not show pronounced differences in the exhibited toxicity. Thus, the variation in proper-ties regarding crystal structure and surface modification did not alter considerably the interactions with biological structures in the respiratory tract. This was not expected with this evidence as surface modifications sometimes are reported to trigger a dra-matically increased toxic potential as compared to uncoated core particles. In this study the surface modification of rutile nanoparticles with silicone or glycerol did re-veal only small differences.
The toxicokinetic analysis in lungs (particulate and soluble TiO2) and in remote or-gans (liver and brain) showed a small solubility effect under physiological conditions.
Translocation to remote organs was negligible and values higher than the detection
of limits observed in some few animals. This confirms for the poorly soluble TiO2 par-ticles no considerable translocation to liver and no translocation at all to brain.
The NOAEL evaluation resulted in 3 mg/m3 (experimentally) for all three test items.
This value is in quite good accordance with the predicted NOAEL = 4.8 mg/m3 using Pauluhn’s (2011) general approach for poorly soluble particulates.
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Abbreviations
BAL Bronchoalveolar lavage BALF Bronchoalveolar lavage fluid GSD Geometric standard deviation HE Hematoxylin and eosin staining hr(s) Hour(s)
LALN Lung-associated lymph nodes
LUFA-ITL Landwirtschaftliche Untersuchungs- und Forschungsanstalt – Institut für Tiergesundheit und Lebensmittelqualität (= Agricultural Analytical Institute – Institute of Animal Health and Food Quality)
m Male(s)
MMAD Mass median aerodynamic diameter
OECD Organization for Economic Cooperation and Development