Irreversible pulmonary changes induced in rat lung by dust overload.

The objective of this study was to investigate whether the effects of dust overload are reversible upon cessation of subchronic exposure to test toner. Female rats were exposed 6 hr/day, 5 days/week for 3 months to a test toner at 0, 10, and 40 mg/m3. The retained quantity of test toner in the lungs at the end of exposure was 0.4 and 3.0 mg for the low and high exposure groups, respectively. Fifteen months later, the corresponding values were 0.12 and 2.65 mg in the lungs. Alveolar clearance of tracer aerosols as well as cytologic and enzymatic parameters in the bronchoalveolar fluid was investigated at the end of exposure and subsequently up to 15 months later. The alveolar clearance of 59Fe2O3, 51Cr-polystyrene, and 85Sr-polystyrene tracer aerosols was slightly retarded at the low and substantially impaired at the high exposure level. At the low exposure level, there was some recovery in the clearance behavior up to 6 months after exposure. In contrast, at the high exposure level there was no indication of a reversal of the impaired clearance. For the beta-glucuronidase activity and the number of polymorphonuclear cells, the pattern of the effects was similar to the effects on the half-time tracer particle clearance. In conclusion, the dust overload at a lung burden of 3 mg test toner in rats was persistent for at least 15 months after termination of exposure

Toxicokinetics of solid particles in chronic studies using diesel soot, carbon black, toner, titanium dioxide and quartz

During the past five years, various chronic inhalation studies with solid particles have been performed at the Fraunhofer-Institute of Toxicology and Aerosol Research (ITA) and at the Inhalation Toxicology Research Institute in Albuquerque, NM, USA (ITRI). The inhaled materials include titanium dioxide, carbon black, soot from diesel exhaust, toner for copy machines, and quartz. The objectives of this paper are presentation of retention data from three studies in a comparative manner, illustration of the relationship between lung burden and macrophage-mediated clearance, and presentation of a model by which an appropriate aerosol concentration can be selected for chronic studies

The effect of a "Nuisance" dust inhalation on lung clearance

For particles which show low solubility and/or slight biological effects a general threshold limit is applied in the occupational field, e.g. 6 mg/cubic meter (FRG) and 5 mg/cubic meter (USA). In this study the effect on lung retention and lung clearance of three typical "inert" dusts, titanium dioxide (rutil), PVC powder and iron powder was determined. Female Fischer rats (F344) were exposed nose-only 5 hours/day, 5 days/week at aerosol concentrations of 3.2, 8 and 20 mg/cubic meter up to 8 months. 1, 3 and 6 months after beginning of exposure 8 animals of each group inhaled additionally a test aerosol of Fe-59 labelled iron oxide particles and in some cases also Sr-85 labelled polystyrene particles. For lung clearance measurement the decrease of x-activity in the thoracic area of these animals was monitored for 85 days. Chronic exposure was continued during this time. Recovery of the lung clearance was investigated two months after ending of exposure. Lung retention of inhaled partic les was determined at various times during and after ending of exposure. The lung burden after 8 months of exposure has been about 7 mg for PVC, 4 mg for titanium dioxide and 0.6 mg for iron powder at the highest concentration. The PVC dust inhalation caused a severe retardation of the long-term lung clearance of labelled polystyrene particles at the medium and high concentration. For iron powder and titanium dioxide inhalation only in the high concentration group a small retardation of lung clearance was detected

Lung clearance and retention of toner, TiO2, and crystalline silica, utilizing a tracer technique during chronic inhalation exposure in syrian golden hamsters

Male and female Syrian golden hamsters were exposed 6h/day, 5 days/wk for up to 18 month to a special test toner, TiO2, and crystalline silica. The mass median aerodynamic diameters (MMAD) were about 4.0 mikro m for toner, 1.1 mikro m for TiO2, and 1.4 mikro m for silica. The target test aerosol exposure concentrations during the first 5 mo were 1.5, 6, and 24 mg/m3 (called toner low, toner medium, and toner high) for the test toner, 40 mg/m3 for TiO2, and 3 mg for SiO2. They were changed to 4, 16 and 64 mg/m3 for toner and 30 mg/m3 for TiO2 after 5 mo in order to achieve the desired lung burdens

The carcinogenic potency of carbon particles with and without PAH after repeated intratracheal administration in the rat

The role of carcinogenic PAH in soot- and carbon black-related lung tumour induction in rats was investigated after intratracheal administration of carbon blacks (CB) and two types of diesel soot (DS) either as original or as toluene extracted particles. The total particle dose per animal was 15 mg subdivided into 16-17 weekly applications. There was one vehicle control and two groups were treated with a total dose of either 30 or 15 mg pure BaP as positive control. The main tumour results were: (a) original DS induced a higher tumour rate than extracted DS; (b) the carcinogenic potency of extracted CB probably depends on the size of the primary carbon particles and on the specific surface area of the particles; (c) extracted DS covered with 11 micrograms BaP per mg carbon particles caused a lower lung tumour rate than original DS containing only 0,9 mg BaP per mg, but a variety of other PAH and N02-PAH; (d) a total dose of 15 mg pure BaP caused a lung tumour (abstract truncated

In vitro and in vivo investigations to obtain validated toxicity data of graphene nanoplatelets

The PLATOX project funded within the FP7-SIINN (Safe Implementation of Innovative Nanoscience and Nanotechnology) ERA-NET on Nanosafety, proposes a tiered approach to address the existing toxicological data gaps for graphene family nanoparticles (GFN). GFN are part of the group of carbon-based synthetic nanomaterials and are already on the market in multiple variants. GFN are currently subject of studies to accelerate their toxicological characterisation. Based on the existing toxicological database a very high toxic potential is not expected, however, the characterisation is presently incomplete and should be expanded to facilitate a proper risk assessment. The workflow of PLATOX therefore aims to link several steps (i) selection of typical candidates, representing the graphene family, (ii) performance of in vitro screening for the selected GFN, (iii) conduct of an in vivo 28-day inhalation test with two representative GFN, thereby generating toxicological in vivo data, which should be acceptable for authorities and should enable (iv) risk assessment and derivation of DNEL for the two selected GFN according to REACH procedures. The in vitro screening methodology uses lung relevant cell models and is focussed on (geno)toxicity testing and measurement of cytokine/eicosanoid release. The subsequent 28-day inhalation toxicity test will include inflammatory, (geno)toxicity and histopathological endpoints. The results will finally be evaluated and a GFN risk assessment will be done by establishing DNELs. In summary, the expected outcome of the project will be a toxicological ranking of the tested GNF species, providing an improved basis for risk assessment of these nanomaterials

Method for identification of low soluble, biopersistent dusts (GBS)

Respirable biopersistent granular dusts (GBS) show a negligible solubility in physiological lung fluid and do not exhibit a specific surface chemistry-related toxicity at volumetric non-overload conditions in lungs. The German MAK Commission proposed a TLV of 0.3 mg/m3 for GBS excluding any adverse lung effects upon chronic exposure (no volumetric lung overload). OBJECTIVES: Determination of a value of ‘low solubility’ and analysis of the inflammatory response in lungs including micro-/nanoscaled dusts. For TiO2 (rutile-micro), TiO2 (anatase-nano), Eu2O3 (micro-nano mixed), BaSO4 (micro), ZrO2 (micro) and amorphous SiO2 (nano) the solubility (day 3, 28 and 90) and inflammation (day 3 and 28) after intratracheal instillation in rats was analysed. Two doses of 0.5 (non-overload) and 1.5 μl (moderate overload) were administered. The differential cell count showed only slight inflammatory cell levels after treatment with TiO2 (rutile) and BaSO4. In contrast, the TiO2 (anatase) showed a stronger response. The rare earth Eu2O3 dust showed the strongest effect including a red-coloured lung lavage fluid. ZrO2 and amorphous SiO2 showed a strong acute response after 3 days, however, recovered mostly completely within 28 days. These data were validated by parallel subacute inhalations at same lung loads. GBS have to fulfill a ‘low solubility’ and a ‘non-significant inflammatory response’. Unlike as the microscaled most nanoscaled dusts will not meet these criteria and an individual toxicological characterization seems to be necessary for this particle class