Measurement of airborne nanoparticle surface area using a filter-based gas adsorption method for inhalation toxicology experiments

Measurement of the surface area of airborne nanoparticles as administered to an experimental subject is critical for characterizing exposures during inhalation experiments. A filter-based surface area measurement methodology is described herein that allows for such determinations. Krypton gas adsorption was used to determine total particle surface area. Track-etched polycarbonate 0.4 μm pore filters were chosen as the collection substrate for metal oxide particles due to their highly reproducible surface areas and low background weights. The subject nanomaterials included two different batches of ultrafine TiO?, TiO? nanorods, and SiO?. The instrument detection limit for surface area was 200 cm2 (0.02 m2). Ninety percent confidence interval estimates of method accuracy were 17.7-23.5% with a point estimate of 20.8%. The filter-based surface area measurement strategy is demonstrated to be a viable sampling and analysis methodology that provides much needed physical characterization information of particles as administered in an animal inhalation chamber.     

When Nanoparticles Get in the Way: Impact of Projected Area on In Vivo and In Vitro Macrophage Function

Previous reports by others establish that particle surface area is related to a change in macrophage function as measured by the ability to clear particles from the alveolar spaces. However, for nanoparticles the relation may not be strictly due to surface chemistry: The cumulative projected area of the particles may reflect the degree to which the inner or outer surface of the macrophage is shielded from other objects or molecules. We apply this alternative interpretation to in vitro measurements of macrophage uptake of 26-nm-diameter fluorescent beads and to in vivo data presented in a classic inhalation toxicology paper on nano-sized TiO₂ particles. In their paper, Oberdörster et al. (Environ. Health Perspect. 102[suppl. 5]:173–179, 1994) reported that following inhalation exposure to 20-nm or 250-nm TiO₂ particles, the half-times for alveolar clearance of polystyrene test particles were proportional to square centimeters of TiO₂ particle surface per million macrophages; macrophage toxicity from TiO₂ particle surface was assumed to be the cause of the decrease in the clearance rate of polystyrene test particles. When TiO₂ particle projected area was incorporated into the in vivo macrophage dosimetry calculations, particle projected areas ranged in value from covering only a fraction (0.1) of the macrophage surface to covering the cell surface 4 times over. The observed decrease in macrophage mediated alveolar clearance of polystyrene test particles was directly related to the potential for TiO₂ particles to mask the surface of the macrophage—a possibility that was visualized in vitro with confocal laser scanning microscopy.     

Negligible respiratory irritation and inflammation potency of pigmentary TiO2 in mice

Abstract

Titanium dioxide (TiO₂) is manufactured in millions of tons yearly, and it is used widely as pigment in various applications. Until recently, TiO₂ was considered toxicologically harmless and without adverse health effects. In this study, respiratory irritation and inflammation potencies of commercially available pigmentary TiO₂ particles (<5?µm, rutile) were studied. Single head-only exposures (30?min) of male Crl:OF1 mice at mass concentrations 6, 11, 21, and 37?mg/m³, and repeated exposures (altogether 16?h, 1?h/day, 4 days/week for 4 weeks) of female BALB/c/Sca mice at mass concentration of 16?mg/m³ to pigmentary TiO₂ were conducted. Minor sensory irritation was observed during acute and repeated exposures seen as elongation of the break after the inhalation, which is typical in sensory irritation, and caused by closure of the glottis inhibiting airflow from the lungs after inspiration. No pulmonary irritation, airflow limitation, nasal or pulmonary inflammation was observed. In conclusion, the respiratory irritation and inflammation potencies of the studied pigmentary TiO₂ particles seemed to be low and thus can serve as an ideal control exposure agent in short-term studies in mice.     

Industrial worker exposure to airborne particles during the packing of pigment and nanoscale titanium dioxide

Context: Titanium dioxide (TiO2) factory workers’ source specific exposure and dose to airborne particles was studied extensively for particles between 5?nm and 10 μm in size.

Objective: We defined TiO₂ industry workers’ quantitative inhalation exposure levels during the packing of pigment TiO₂ (pTiO₂) and nanoscale TiO₂ (nTiO₂) material from concentrations measured at work area.

Methods: Particle emissions from different work events were identified by linking work activity with the measured number size distributions and mass concentrations of particles. A lung deposit model was used to calculate regional inhalation dose rates in units of particles min^?1 and μg min^?1 without use of respirators.

Results: Workers’ average exposure varied from 225 to 700 μg m^?3 and from 1.15?×?10⁴ to 20.1?×?10⁴ cm^?4. Over 90% of the particles were smaller than 100?nm. These were mainly soot and particles formed from process chemicals. Mass concentration originated primarily from the packing of pTiO₂ and nTiO₂ agglomerates. The nTiO₂ exposure resulted in a calculated dose rate of 3.6?×?10⁶ min^?1 and 32 μg min^?1 where 70% of the particles and 85% of the mass was deposited in head airways.

Conclusions: The recommended TiO₂ exposure limits in mass by NIOSH and in particle number by IFA were not exceeded. We recommend source-specific exposure assessment in order to evaluate the workers’ risks. In nTiO₂ packing, mass concentration best describes the workers’ exposure to nTiO₂ agglomerates. Minute dose rates enable the simulation of workers’ risks in different exposure scenarios.     

Pulmonary clearance kinetics and extrapulmonary translocation of seven titanium dioxide nano- and submicron materials following intratracheal administration in rats

Abstract

We evaluated and compared the pulmonary clearance kinetics and extrapulmonary translocations of seven titanium dioxide (TiO₂) nano- and submicron particles with different characteristics, including size, shape and surface coating. Varying doses of TiO₂ nano- and submicron particles dispersed in 0.2% disodium phosphate solution were intratracheally administered to male F344 rats. The rats were euthanized under anesthesia for 3, 28 and 91 days after administration. Ti levels in pulmonary and various extrapulmonary organs were determined using inductively coupled plasma-sector field mass spectrometry (ICP-SFMS). The lungs, including bronchoalveolar lavage fluid (BALF), contained 55–89% of the administered TiO₂ dose at 3 days after administration. The pulmonary clearance rate constants, estimated using a one-compartment model, were higher after administration of 0.375–2.0?mg/kg body weight (bw) (0.016–0.020/day) than after administration of 3.0–6.0?mg/kg bw (0.0073–0.013/day) for six uncoated TiO₂. In contrast, the clearance rate constant was 0.011, 0.0046 and 0.00018/day following administration of 0.67, 2.0 and 6.0?mg/kg bw TiO₂ nanoparticle with Al(OH)₃ coating, respectively. Translocation of TiO₂ from the lungs to the thoracic lymph nodes increased in a time- and dose-dependent manner. Furthermore, the translocation of TiO₂ from the lungs to the thoracic lymph nodes after 91 days was higher when Al(OH)₃ coated TiO₂ was administered (0.93–6.4%), as compared to uncoated TiO₂ (0.016–1.8%). Slight liver translocation was observed (<0.11%), although there was no clear trend related to dose or elapsed time. No significant translocation was observed in other organs including the kidney, spleen and brain.     

Nanoparticles-containing spray can aerosol: characterization,exposure assessment,and generator design

This is the first report demonstrating that a commercially available household consumer product produces nanoparticles in a respirable range. This report describes a method developed to characterize nanoparticles that were produced under typical exposure conditions when using a consumer spray product. A well-controlled indoor environment was simulated for conducting spray applications approximating a human exposure scenario. Results indicated that, while aerosol droplets were large with a count median diameter of 22 µm during spraying, the final aerosol contained primarily solid TiO₂ particles with a diameter of 75?nm. This size reduction was due to the surface deposition of the droplets and the rapid evaporation of the aerosol propellant. In the breathing zone, the aerosol, containing primarily individual particles (>90%), had a mass concentration of 3.4?mg/m³, or 1.6?×?10⁵ particles/cm³, with a nanoparticle fraction limited to 170 µg/m³, or 1.2?×?10⁵ particles/cm³. The results were used to estimate the pulmonary dose in an average human (0.075 µg TiO₂ per m² alveolar epithelium per minute) and rat (0.03 µg TiO₂) and, consequently, this information was used to design an inhalation exposure system. The system consisted of a computer-controlled solenoid ‘‘finger’’ for generating constant concentrations of spray can aerosols inside a chamber. Test results demonstrated great similarity between the solenoid ‘‘finger’’-dispersed aerosol compared to human-generated aerosol. Future investigations will include an inhalation study to obtain information on dose–response relationships in rats and to use it to establish a No Effect Exposure Level for setting guidelines for this consumer product.     

Cytotoxicity and oxidative DNA damage by nanoparticles in human intestinal Caco-2 cells

Abstract

The use of engineered nanoparticles in the food sector is anticipated to increase dramatically, whereas their potential hazards for the gastrointestinal tract are still largely unknown. We investigated the cytotoxic and DNA-damaging effects of several types of nanoparticles and fine particles relevant as food additives (TiO₂ and SiO₂) or for food packaging (ZnO and MgO) as well as carbon black on human intestinal Caco-2 cells. All particles, except for MgO, were cytotoxic (LDH and WST-1 assay). ZnO, and to lesser extent SiO₂, induced significant DNA damage (Fpg-comet), while SiO₂ and carbon black were the most potent in causing glutathione depletion. DNA damage by TiO₂ was found to depend on sample processing conditions. Interestingly, application of different TiO₂ and ZnO particles revealed no relation between particle surface area and DNA damage. Our results indicate a potential hazard of several food-related nanoparticles which necessitate investigations on the actual exposure in humans.     

Pharyngeal aspiration of metal oxide nanoparticles showed potential of allergy aggravation effect to inhaled ovalbumin

Abstract

The inhalation of manufactured metal oxide nanoparticles may lead to pulmonary toxicity. For instance, ZnO nanoparticles are known to induce pulmonary oxidative stress and inflammation. On the other hand, the pulmonary toxicity of TiO₂ nanoparticles is less than that of ZnO nanoparticles. Although, there have been some investigations concerning the induction of pulmonary oxidative stress and inflammation caused by manufactured metal oxide nanoparticles. And, although, it has reported that some nanoparticles cause aggravation of allergic reactions, there have so far been no reports regarding allergy aggravation effects of manufactured metal oxide nanoparticles. In this study, three types of nanoparticles, TiO₂, ZnO and SiO₂, were administered to mouse lungs by pharyngeal aspiration. Subsequently, the mice inhaled ovalbumin (OVA) a total of eight times over 3 weeks. After inhalation of OVA, the concentrations of total IgE, OVA-specific IgE and OVA-specific IgG₁ in serum increased in the mice treated with ZnO. TiO₂ and SiO₂ nanoparticles did not affect the OVA-specific IgE and IgG₁ levels. These results suggest that ZnO nanoparticles have the potential to aggravate allergic reactions. The results also suggest that Zn²⁺ release from ZnO nanoparticles is involved in the aggravation potential of allergies. However, pharyngeal aspiration of ZnCl₂ solution was not able to aggravate allergic reactions. Continuous Zn²⁺ release from ZnO nanoparticles to the lung is necessary for the aggravation of allergic reactions.     

Development of a Short-Term Inhalation Test in the Rat Using Nano-Titanium Dioxide as a Model Substance

Evidence suggests that short-term inhalation studies may provide comparable prediction of respiratory tract toxicity to 90-day studies, presenting the opportunity to save time and resources in screening inhalation toxicity of test substances. The aim of this study was to develop a short-term inhalation test that could be employed to provide early evidence on respiratory tract effects which might occur from long-term exposure to aerosols of nano-materials. Male Wistar rats were exposed to aerosols of 0 (control), 2, 10 and 50 mg/m³ nano-titanium dioxide (TiO₂) by inhalation for 6 h/day for 5 days. Necropsies were performed either immediately after the last exposure or after 3 and 16 days post exposure (study days 5, 8 and 21, respectively). Treatment with nano-TiO₂ resulted in morphological changes in the lung, with 50 mg/m³ nano-TiO₂ producing an increase in lung weight. Lung inflammation was associated with dose-dependent increases in bronchoalveolar lavage fluid (BALF) total cell and neutrophil counts, total protein content, enzyme activities and levels of a number of cell mediators. No indications of systemic effects could be found by measurement of appropriate clinical pathology parameters. Cell replication (determined by incorporation of 5-bromo-2′-deoxyuridine) was increased at all nano-TiO₂ dose levels in large/medium bronchi and terminal bronchioles. The effects on the parameters measured were most prominent either on study day 5 or 8, with some endpoints returning to control levels by day 21. Overall, the pulmonary effects of nano-TiO₂ observed in this short-term study were comparable to those previously reported in subchronic inhalation studies.     

The effect of zinc oxide and titanium dioxide nanoparticles in the Comet assay with UVA photoactivation of human sperm and lymphocytes

A method to investigate the dependence of the physicochemical properties of nanoparticles (e.g., size, surface area and crystal phase) on their oxidant generating capacity is proposed and demonstrated for TiO₂ nanoparticles. Gas phase synthesis methods that allow for strict control of size and crystal phase were used to prepare TiO₂ nanoparticles. The reactive oxygen species (ROS) generating capacity of these particles was then measured. The size dependent ROS activity was established using TiO₂ nanoparticles of nine different sizes (4–195 nm) but the same crystal phase. For a fixed total surface area, an S-shaped curve for ROS generation per unit surface area was observed as a function of particle size. The highest ROS activity per unit area was observed for 30 nm particles, and observed to be constant above 30 nm. There was a decrease in activity per unit area as size decreased from 30–10 nm; and again constant for particles smaller than 10 nm. The correlation between crystal phase and oxidant capacity was established using TiO₂ nanoparticles of 11 different crystal phase combinations but similar size. The ability of different crystal phases of TiO₂ nanoparticles to generate ROS was highest for amorphous, followed by anatase, and then anatase/rutile mixtures, and lowest for rutile samples. Based on evaluation of the entire dataset, important dose metrics for ROS generation are established. The implications of these ROS studies on biological and toxicological studies using nanomaterials are discussed.     

Comparing fate and effects of three particles of different surface properties: Nano-TiO2, pigmentary TiO2 and quartz

The fate of nano-TiO₂ particles in the body was investigated after inhalation exposure or intravenous (i.v.) injection, and compared with pigmentary TiO₂ and quartz. For this purpose, a 5-day inhalation study (6 h/day, head/nose exposure) was carried out in male Wistar rats using nano-TiO₂ (100 mg/m³), pigmentary TiO₂ (250 mg/m³) and quartz dust DQ 12 (100 mg/m³). Deposition in the lung and tissue distribution was evaluated, and histological examination of the respiratory tract was performed upon termination of exposure, and 2 weeks after the last exposure. Broncho-alveolar lavage (BAL) was carried out 3 and 14 days after the last exposure. Rats were also injected with a single intravenous dose of a suspension of TiO₂ in serum (5 mg/kg body weight), and tissue content of TiO₂ was determined 1, 14 and 28 days later.     

A role for surface reactivity in TiO2 and quartz-related nanoparticle pulmonary toxicity

A variety of pulmonary hazard studies in rats have demonstrated that exposures to ultrafine or nanoparticles (generally defined as particles in the size range < 100 nm) produce more intensive inflammatory responses when compared with bulk-sized particle-types of similar chemical composition. However, this common perception of greater nanoparticle toxicity is based on a limited number of studies, conducted primarily with titanium dioxide and carbon black particle-types. Apart from variables such as particle size and surface area, it is conceivable that several additional physicochemical particle characteristics could play more significant roles in facilitating the development of nanoparticle-related toxicity; particularly when considering particle surface-cell interactions. These include but are not limited to: (i) Surface reactivity of particle-types; (ii) surface coatings; (iii) aggregation/disaggregation potential; and (iv) the method of nanoparticle synthesis. We present results of pulmonary bioassay hazard/safety studies with quartz particles of varying sizes/surface areas. These demonstrated that intratracheal instillation exposures to fine-sized, Min-U-Sil quartz particles (0.5 µm [particle size] – 5 m²/g [surface area]) produced (persistent) enhanced pulmonary toxicity (inflammation, cytotoxicity, cell proliferation and/or histopathology) in rats when compared to nanoscale quartz particles (50 nm–31 m²/g), but not when compared to smaller nanoscale quartz sizes (e.g., 12 nm–91 m²/g). The toxicity results correlated with red blood cell hemolytic potency as a measure of particle surface reactivity. In a second pulmonary bioassay study in rats, pulmonary hazard effects were measured following exposures to three different ultrafine (nano) TiO₂ particle-types, each with similar particle size distributions. The various TiO₂ particles differed in their crystal structures and surface reactivity endpoints as measured by the Vitamin C yellowing assay. Moreover, the surface activity characteristics correlated with potency of hazard biomarkers as described above, in these dose/response, time-course studies. It is concluded that particle surface reactivity, rather than particle size/surface area endpoints correlated best with lung inflammatory potency following exposures to particles.     

A Venturi Disperser as a Dry Powder Generator for Inhalation Studies

Abstract

This paper describes the design and operation of a dry power disperser based on the Venturi principle. The flow in the Venturi tube creates suction near the constricted area to feed powders into the device, and the shear flow downstream of the Venturi tube disperses particles into aerosol form. Powders are fed into the Venturi disperser by a screw feeder. The Venturi tube is simple in design and easy to operate. We have adopted the Venturi/screw feeder as an aerosol generator that can be operated in the flow rate range of between 60 and 200 I/min, as a function of the compressed air pressure and the geometry of the Venturi tube. At low flow rates, this generation system can be adapted for nose-only inhalation exposure to dry powders, and in fact was used to generate quartz and TiO₂ for 7-month inhalation studies. Our results indicated that the Venturi tube was useful in providing stable aerosol generation of sticky powders.     

Acute and subchronic oral toxicity studies in rats with nanoscale and pigment grade titanium dioxide particles

Data generated using standardized testing protocols for toxicity studies generally provide reproducible and reliable results for establishing safe levels and formulating risk assessments. The findings of three OECD guideline-type oral toxicity studies of different duration in rats are summarized in this publication; each study evaluated different titanium dioxide (TiO₂) particles of varying sizes and surface coatings. Moreover, each study finding demonstrated an absence of any TiO₂ -related hazards. To briefly summarize the findings: 1) In a subchronic 90-day study (OECD TG 408), groups of young adult male and female rats were dosed with rutile-type, surface-coated pigment-grade TiO₂ test particles (d₅₀ = 145 nm − 21% nanoparticles by particle number criteria) by oral gavage for 90 days. The no-adverse-effect level (NOAEL) for both male and female rats in this study was 1000 mg/kg bw/day, the highest dose tested. The NOAEL was determined based on a lack of TiO₂ particle-related adverse effects on any in-life, clinical pathology, or anatomic/microscopic pathology parameters; 2) In a 28-day repeated-dose oral toxicity study (OECD TG 407), groups of young adult male rats were administered daily doses of two rutile-type, uncoated, pigment-grade TiO₂ test particles (d₅₀ = 173 nm by number) by daily oral gavage at a dose of 24,000 mg/kg bw/day. There were no adverse effects measured during or following the end of the exposure period; and the NOAEL was determined to be 24,000 mg/kg bw/day; 3) In an acute oral toxicity study (OECD TG 425), female rats were administered a single oral exposure of surface-treated rutile/anatase nanoscale TiO₂ particles (d₅₀ = 73 nm by number) with doses up to 5000 mg/kg and evaluated over a 14-day post-exposure period. Under the conditions of this study, the oral LD₅₀ for the test substance was >5000 mg/kg bw. In summary, the results from these three toxicity studies – each with different TiO₂ particulate-types, demonstrated an absence of adverse toxicological effects. Apart from reporting the findings of these three studies, this publication also focuses on additional critical issues associated with particle and nanotoxicology studies. First, describing the detailed methodology requirements and rigor upon which the standardized OECD 408 guideline subchronic oral toxicity studies are conducted. Moreover, an attempt is made to reconcile the complex issue of particle size distribution as it relates to measurements of nanoscale and pigment-grade TiO₂ particles. Clearly this has been a confusing issue and often misrepresented in the media and the scientific literature. It is clear that the particle-size distribution for pigment-grade TiO₂, contains a small (“tail”) component of nanoscale particles (i.e., 21% by particle number and <1% by weight in the test material used in the 90-day study). However, this robust particle characterization finding should not be confused with mislabeling the test materials as exclusively in the nanoscale range. Moreover, based upon the findings presented herein, there appears to be no significant oral toxicity impact contributed by the nanoscale component of the TiO₂ Test Material sample in the 90-day study. Finally, it seems reasonable to conclude that the study findings should be considered for read-across purposes to food-grade TiO₂ particles (e.g., E171), as the physicochemical characteristics are quite similar.     

Polar Molecular Surface as a Dominating Determinant for Oral Absorption and Brain Penetration of Drugs

Purpose. To study oral absorption and brain penetration as a function of polar molecular surface area. Methods. Measured brain penetration data of 45 drug molecules were investigated. The dynamic polar surface areas were calculated and correlated with the brain penetration data. Also the static polar surface areas of 776 orally administered CNS drugs that have reached at least Phase II efficacy studies were calculated. The same was done for a series of 1590 orally administered non-CNS drugs that have reached at least Phase II efficacy studies. Results. A linear relationship between brain penetration and dynamic polar surface area (Ų) was found (n = 45, R = 0.917, F_1,43 = 229). Brain penetration decreases with increasing polar surface area. A clear difference between the distribution of the polar surface area of the 776 CNS and 1590 non-CNS drugs was found. It was deduced that orally active drugs that are transported passively by the transcellular route should not exceed a polar surface area of about 120 Ų. They can be tailored to brain penetration by decreasing the polar surface to <60–70 Ų. This conclusion is supported by the inverse linear relationship between experimental brain penetration data and the dynamic polar surface area of 45 drug molecules. Conclusions. The polar molecular surface area is a dominating determinant for oral absorption and brain penetration of drugs that are transported by the transcellular route. This property should be considered in the early phase of drug screening.     

Potential impact of inorganic nanoparticles on macronutrient digestion: titanium dioxide nanoparticles slightly reduce lipid digestion under simulated gastrointestinal conditions

Titanium dioxide (TiO₂) particles are used in some food products to alter their optical properties, such as whiteness or brightness. These additives typically contain a population of TiO₂ nanoparticles (d?2 particles on the gastrointestinal fate of oil-in-water emulsions using a simulated gastrointestinal tract (GIT) that includes mouth, stomach, and small intestine phases. Theoretical predictions suggested that TiO₂ nanoparticles might inhibit lipid digestion through two physicochemical mechanisms: (i) a fraction of the lipase adsorbs to TiO₂ particle surfaces, thereby reducing the amount available to hydrolyze lipid droplets; (ii) some TiO₂ particles adsorb to the surfaces of lipid droplets, thereby reducing the lipid surface area exposed to lipase. The importance of these mechanisms was tested by passing protein-coated lipid droplets (2%, w/w) through the simulated GIT in the absence and presence of TiO₂ (0.5%, w/w) nanoparticles (18?nm) and fine particles (167?nm). Changes in particle characteristics (size, organization, and charge) and lipid digestion were then measured. Both TiO₂ nanoparticles and fine particles had little impact on the aggregation state and charge of the lipid droplets in the different GIT regions, as well as on the rate and extent of lipid digestion. This suggests that the theoretically predicted impact of particle size on lipid digestion was not seen in practice.     

Influence of particle surface area on the toxicity of insoluble manganese dioxide dusts

The objective of this study was to examine the influence of specific surface area on the biological activity of insoluble manganese dioxide (MnO₂) particles. The biological responses to various MnO₂ dusts with different specific surface area (0.16, 0.5, 17 and 62 m²/g) were compared in vitro and in vivo. A mouse peritoneal macrophage model was used to evaluate the in vitro cytotoxic potential of the particles via lactate dehydrogenase (LDH) release. In vivo, the lung inflammatory response was assessed by analysis of bronchoalveolar lavage after intratracheal instillation in mice (LDH activity, protein concentration and cellular recruitment). In both systems, the results show that the amplitude of the response is dependent on the total surface area which is in contact with the biological system, indicating that surface chemistry phenomena are involved in the biological reactivity. Freshly ground particles with a specific surface area of 5 m²/g were also examined in vitro. These particles exhibited an enhanced cytotoxic activity, which was almost equivalent to that of 62 m²/g particles, indicating that undefined reactive sites produced at the particle surface by mechanical cleavage may also contribute to the toxicity of insoluble particles. We conclude that, when conducting studies to elucidate the effect of particles on the lung, it is important for insoluble particles such as manganese dioxide to consider the administered dose in terms of surface area (e.g. m²/kg) rather than in gravimetric terms (e.g. mg/kg). Received: 24 March 1997 / Accepted: 21 May 1997     

Lung Dosimetry and Risk Assessment of Nanoparticles: Evaluating and Extending Current Models in Rats and Humans

Risk assessment of occupational exposure to nanomaterials is needed. Human data are limited, but quantitative data are available from rodent studies. To use these data in risk assessment, a scientifically reasonable approach for extrapolating the rodent data to humans is required. One approach is allometric adjustment for species differences in the relationship between airborne exposure and internal dose. Another approach is lung dosimetry modeling, which provides a biologically-based, mechanistic method to extrapolate doses from animals to humans. However, current mass-based lung dosimetry models may not fully account for differences in the clearance and translocation of nanoparticles. In this article, key steps in quantitative risk assessment are illustrated, using dose-response data in rats chronically exposed to either fine or ultrafine titanium dioxide (TiO₂), carbon black (CB), or diesel exhaust particulate (DEP). The rat-based estimates of the working lifetime airborne concentrations associated with 0.1% excess risk of lung cancer are approximately 0.07 to 0.3 mg/m³ for ultrafine TiO₂, CB, or DEP, and 0.7 to 1.3 mg/m³ for fine TiO₂. Comparison of observed versus model-predicted lung burdens in rats shows that the dosimetry models predict reasonably well the retained mass lung burdens of fine or ultrafine poorly soluble particles in rats exposed by chronic inhalation. Additional model validation is needed for nanoparticles of varying characteristics, as well as extension of these models to include particle translocation to organs beyond the lungs. Such analyses would provide improved prediction of nanoparticle dose for risk assessment.     

Inflammatory response of mice to manufactured titanium dioxide nanoparticles: Comparison of size effects through different exposure routes

TiO₂ is a widely used manufactured nanomaterial and the opportunity for human exposure makes it necessary to study its health implications. Using murine models for inflammation, size effects of inflammatory response in instillation and acute inhalation exposures of TiO₂ nanoparticles with manufacturers’ average particles sizes of 5 and 21 nm were investigated. The properties of the primary nanoparticles, nanoparticle agglomerates aerosol and instillation solution for both sized nanoparticles were evaluated. Mice were acutely exposed in a whole-body exposure chamber or through nasal instillation and toxicity was assessed by enumeration of total and differential cells, determination of total protein, LDH activity and inflammatory cytokines in BAL fluid. Lungs were also evaluated for histopathological changes. Results show the larger TiO₂ nanoparticles were found to be moderately, but significantly, more toxic. The nanoparticles had different agglomeration states which may be a factor as important as the surface and physical characteristics of the primary nanoparticles in determining toxicity.     

Seawater activated TiO2 photocatalyst for degradation of organic compounds

The world's oceans are polluted by a continuous inflow of plastic. Plastic fragments finally into microplastic, which can be taken up, for example by plankton, and subsequently by the entire ocean food web. An approach to reduce plastic pollution constitutes the accelerated microplastic degradation in marine environments. TiO₂ (anatase) is commonly used as an oxidative photocatalyst and well known to catalyze the degradation of organic compounds upon UV irradiation.In this study, a selective activation of TiO₂ (anatase) particles encapsulated by Ca- or Sr-polyphosphate is presented. The TiO₂ polyphosphate core-shell particles are envisaged as additives in plastic products. The highly concentrated cations from seawater, viz. Na⁺ and Mg²⁺, displace the Ca²⁺ or Sr²⁺ cations from the polyphosphate shell. As a result, the polyphosphate coating dissolves and thus the photocatalytically active TiO₂ core is released. The stability of the TiO₂ polyphosphate particles in potable water and the seawater activated disintegration of methylene blue, methyl methacrylate, terephtalic acid, and poly(vinyl alcohol) was shown. It has been demonstrated, that the sweetwater stable polyphosphate coating degrades in the presence of seawater, which could be monitored by the activation of the TiO₂ (anatase) photocatalyst.