Tissue distribution of gold and silver after subacute intravenous injection of co-administered gold and silver nanoparticles of similar sizes.

Gold (AuNPs, 12.8 nm) and silver nanoparticles (AgNPs, 10 nm), mixed or separate, were injected into the caudal vein of male Sprague-Dawley rats for 4 weeks. The rats were allowed to recover for further 4 weeks to examine the differences in AuNP/AgNP tissue distribution and clearance. The size distribution of injected AuNPs and AgNPs were not statistically different. The dose groups (five males per group for the administration and three males for the recovery) consisted of seven divisions, i.e., control, AgNPs (with a low dose of 10 µg/kg/day, and, a high dose of 100 µg/kg/day), AuNPs (with a low dose of 10 µg/kg/day, and, a high dose of 100 µg/kg/day), as well as mixed AgNPs/AuNPs (with a low dose of 10/10 µg/kg/day, and a high dose of 100/100 µg/kg/day). The AgNPs accumulated in a dose-dependent manner in the liver, spleen, kidneys, lung, brain, testis or blood. Au concentration increased also in a dose-dependent manner in the liver, kidneys, spleen and lungs, but not in the brain, testis and blood. Ag concentration in the tissues increased dose-dependently after 4 weeks of AgNP/AuNP mixed administration, but to a much lower extent than those observed when they were administered separately. Ag concentration in the tissues after 4 weeks of AgNP/AuNP mixed administration cleared dose-dependently after 4 weeks of recovery. Au concentration in the tissues increased dose-dependently after 4 weeks of AgNp/AuNP mixed administration, while Au concentration in the tissues did not clear as seen in Ag after 4 weeks recovery. Au concentration showed biopersistency or accumulation in the liver, kidneys, spleen and brain of the 4 weeks of recovery. In conclusion, AgNPs and AuNPs showed different toxicokinetic properties and the mixed administration of AgNPs with AuNPs resulted in mutual reduction of their tissue distribution which appeared to be due to competitive inhibition. Furthermore, this subacute intravenous injection study has suggested that these nanoparticles were distributed to the organs in particulate instead of ionic forms.

Physicochemical analysis and repeated-dose 90-days oral toxicity study of nanocalcium carbonate in Sprague-Dawley rats.

In our previous studies of nanocalcium carbonate, in which we performed physicochemical analysis, genotoxicity, acute single-dose and repeated-dose 14-day oral toxicity testings in Sprague-Dawley (SD) rats, nanocalcium carbonate did not show a difference in toxicity compared to vehicle control. Here, we provide the first report of a repeated-dose 90-day oral toxicity test of nanocalcium carbonate in Sprague-Dawley rats, with physicochemical comparison of micro and nanocalcium carbonate. We find that the two particles differ in size, hydrodynamic size, and specific surface area, with no differences in components, crystalline structure and radical production. In terms of ionization ability, nanocalcium carbonate was slightly more ionized within 1% than microcalcium carbonate at pH 5 and pH 7. In the repeated-dose 90-day oral toxicity test of nanocalcium carbonate, there was no significant toxicity, and similar blood concentrations of Ca(2+) compared to the vehicle control group. Based on our results, although nanocalcium carbonate has different physicochemical properties, nanocalcium carbonate does not differ from microcalcium carbonate in terms of toxicity. Based on the results, we suggest that the no-observed-adverse-effect level (NOAEL) of nanocalcium carbonate is 1000 mg kg(-1) day(-1) in SD rats according to the maximum dose (OECD guideline 408). However, the NOAEL might be higher than 1000 mg kg(-1) day(-1) because there were no adverse effects revealed by consistent pathological findings or biochemical parameter changes. To justify a safe concentration of nanocalcium carbonate, which is a low toxicity chemical, more data is required on dose levels above 1000 mg kg(-1). Our findings may be useful for creating safety guidelines for the use nanocalcium carbonate.

Biopersistence of silver nanoparticles in tissues from Sprague-Dawley rats.

Silver nanoparticles are known to be distributed in many tissues after oral or inhalation exposure. Thus, understanding the tissue clearance of such distributed nanoparticles is very important to understand the behavior of silver nanoparticles in vivo. For risk assessment purposes, easy clearance indicates a lower overall cumulative toxicity. Accordingly, to investigate the clearance of tissue silver concentrations following oral silver nanoparticle exposure, Sprague-Dawley rats were assigned to 3 groups: control, low dose (100 mg/kg body weight), and high dose (500 mg/kg body weight), and exposed to two different sizes of silver nanoparticles (average diameter 10 and 25 nm) over 28 days. Thereafter, the rats were allowed to recover for 4 months. Regardless of the silver nanoparticle size, the silver content in most tissues gradually decreased during the 4-month recovery period, indicating tissue clearance of the accumulated silver. The exceptions were the silver concentrations in the brain and testes, which did not clear well, even after the 4-month recovery period, indicating an obstruction in transporting the accumulated silver out of these tissues. Therefore, the results showed that the size of the silver nanoparticles did not affect their tissue distribution. Furthermore, biological barriers, such as the blood-brain barrier and blood-testis barrier, seemed to play an important role in the silver clearance from these tissues.

Gene expression profiling of kidneys from Sprague-Dawley rats following 12-week inhalation exposure to silver nanoparticles.

The specific properties of silver nanoparticles (AgNPs), such as antimicrobial activity and electrical conductivity, allow them to be used in many fields. However, their expanding application is also raising health, environmental and safety concerns. Previous in vivo AgNP toxicity studies have indicated a gender-different accumulation of silver in the kidneys, with 2-3 times more silver in female kidneys compared to male kidneys. However, no other studies have further addressed this gender difference. Accordingly, the current study investigated the gender-dependent effect of AgNPs on the kidney gene level based on toxicogenomic studies of kidneys obtained from rats exposed to AgNPs via inhalation for 12 weeks. When compared with the fresh air control, the silver nanoparticle-exposed kidneys included 104 genes with a more than 1.3-fold expression increase. For the male rat kidneys exposed to a low or high dose of silver nanoparticles, 96 genes exhibited expression changes, where six genes changed with both the low and high dose; four increased and two decreased. Meanwhile, for the female rat kidneys exposed to a low or high dose of silver nanoparticles, 66 genes exhibited expression changes, where 11 genes changed with both the low and high dose; nine increased and two decreased. Gender-dependent gene expression changes of more than 2-fold were linked to 163 genes, with 79 genes in the male kidneys and 84 genes in the female kidneys, plus gender-dependent gene expression changes of more than 5-fold were linked to 21 genes. However, no genes involved in apoptosis or the cell cycle were activated by the 12-week silver nanoparticle inhalation exposure. Overall, the male rat kidneys showed a higher expression of genes involved in xenobiotic metabolism, while the female rat kidneys showed a higher expression of genes involved in extracellular signaling.

Genotoxicity, acute oral and dermal toxicity, eye and dermal irritation and corrosion and skin sensitisation evaluation of silver nanoparticles.

To clarify the health risks related to silver nanoparticles (Ag-NPs), we evaluated the genotoxicity, acute oral and dermal toxicity, eye irritation, dermal irritation and corrosion and skin sensitisation of commercially manufactured Ag-NPs according to the OECD test guidelines and GLP. The Ag-NPs were not found to induce genotoxicity in a bacterial reverse mutation test and chromosomal aberration test, although some cytotoxicity was observed. In acute oral and dermal toxicity tests using rats, none of the rats showed any abnormal signs or mortality at a dose level of ∼ 2000 mg/kg. Similarly, acute eye and dermal irritation and corrosion tests using rabbits revealed no significant clinical signs or mortality and no acute irritation or corrosion reaction for the eyes and skin. In a skin sensitisation test using guinea pigs, one animal (1/20) showed discrete or patchy erythema, thus Ag-NPs can be classified as a weak skin sensitiser.