Masashi Gamo

Tissue distribution and clearance of intravenously administered titanium dioxide (TiO2) nanoparticles.

Abstract The organ-tissue distribution and clearance of Degussa P25 TiO2 nanoparticles were determined after intravenous administration to rats (0.95 mg/kg bodyweight) using an inductively coupled plasma sector field mass spectrometer. The detection limits of Ti analysis, 0.54 and 1.4 ng/mL for blood and urine and 0.35–2.0 ng/g tissue for several organ tissues, enabled determination of tissue distribution and clearance for organs in which Ti content could not be previously determined due to low concentrations. Blood concentrations of TiO2 were 420 and 19 ng/mL at 5 and 15 min after administration, which were equivalent of only 2.8% and 0.13% of the administration dose, respectively. At 6 h, 94%, 2.0%, 0.17%, 0.023%, 0.014% and 0.026% of administered TiO2 was found in the liver, spleen, lung, kidney, heart and blood, respectively. Liver and spleen TiO2 burden was significantly higher in the administration than control group (p < 0.01) and did not decrease up to 30 days after administration, while TiO2 burden in the lung, kidney, heart and blood decreased over time. A two-step decay model was more suitable than a one-step decay model for the decay curves of pulmonary TiO2 burden but did not improve fitting to the decay curves of kidney TiO2 burden. No translocation to the brain was confirmed at a lower detection limit than was applied in previous studies. Ti content in faeces and urine in the TiO2 administration group did not differ from that in the control group.

Ranking the risks of 12 major environmental pollutants that occur in Japan.

The risks posed by 12 major environmental pollutants in Japan were evaluated and ranked on the same scale. These were arsenic, benzene, cadmium, chlordane, chlorpyrifos, DDTs, dioxins, formaldehyde, methylmercury, radon, toluene, and xylenes. Approximately half of these substances are carcinogenic while the other half are non-carcinogenic. We applied a risk estimation framework that can evaluate both cancer and non-cancer risks on the same scale. The framework consists of two parts: the calculation of the probability of adverse health effects, and the evaluation of the severity of the effects. In order to calculate the probability of adverse health effects, individual variabilities in exposure level, metabolizing rate, and sensitivity were taken into account. Loss of life expectancy (LLE; days) was used as a measure of severity of the adverse health effects and of the resulting risk level. The risk level of the substances in terms of LLE ranged from approximately 0.01 to 10 days. The risks from radon and formaldehyde were found to be the highest, while those from DDT and chlordane were the lowest. Our findings also suggested that the risk levels posed by non-carcinogenic substances were comparable to those posed by carcinogenic substances.

A review of reproductive and developmental toxicity of silver nanoparticles in laboratory animals

We summarized significant effects reported in the literature on the reproductive and developmental toxicity of silver nanoparticles (AgNPs) in laboratory animals. AgNPs showed testicular/sperm toxicity in males and ovarian and embryonic toxicity in females. Maternal injection of AgNPs delayed physical development and impaired cognitive behavior in offspring. Ag was accumulated in the testes after administration of AgNPs. AgNPs were identified in the visceral yolk sac after administration during early gestation in mice. Radiolabeled AgNPs were detected in placenta, breast milk, and pre- and postnatal offspring after injection during late gestation in rats. Ag in the ionic form, and possibly also particles, was suggested to be bioavailable. Although this review provides initial information on the potential reproductive and developmental toxicity of AgNPs, data is still very limited. Further studies using state-of-the-art methodologies and the relevant routes and doses for human exposure are required.

A review of toxicity studies on graphene-based nanomaterials in laboratory animals

Abstract We summarized the findings of toxicity studies on graphene‐based nanomaterials (GNMs) in laboratory mammals. The inhalation of graphene (GP) and graphene oxide (GO) induced only minimal pulmonary toxicity. Bolus airway exposure to GP and GO caused acute and subacute pulmonary inflammation. Large‐sized GO (L‐GO) was more toxic than small‐sized GO (S‐GO). Intratracheally administered GP passed through the air‐blood barrier into the blood and intravenous GO distributed mainly in the lungs, liver, and spleen. S‐GO and L‐GO mainly accumulated in the liver and lungs, respectively. Limited information showed the potential behavioral, reproductive, and developmental toxicity and genotoxicity of GNMs. There are indications that oxidative stress and inflammation may be involved in the toxicity of GNMs. The surface reactivity, size, and dispersion status of GNMs play an important role in the induction of toxicity and biodistribution of GNMs. Although this review paper provides initial information on the potential toxicity of GNMs, data are still very limited, especially when taking into account the many different types of GNMs and their potential modifications. To fill the data gap, further studies should be performed using laboratory mammals exposed using the route and dose anticipated for human exposure scenarios. HighlightsToxicity studies of graphene‐based nanomaterials (GNMs) in mammals were reviewed.Various effects were reported after various routes of exposure to GNMs.Physico‐chemical properties of GNMs are determinants of the toxicity.Oxidative stress and inflammation may be involved in the toxicity of GNMs.Studies using the relevant route and doses of human exposure are warranted.

Risk Assessment of the Carbon Nanotube Group.

This study assessed the health risks via inhalation and derived the occupational exposure limit (OEL) for the carbon nanotube (CNT) group rather than individual CNT material. We devised two methods: the integration of the intratracheal instillation (IT) data with the inhalation (IH) data, and the “biaxial approach.” A four‐week IH test and IT test were performed in rats exposed to representative materials to obtain the no observed adverse effect level, based on which the OEL was derived. We used the biaxial approach to conduct a relative toxicity assessment of six types of CNTs. An OEL of 0.03 mg/m3 was selected as the criterion for the CNT group. We proposed that the OEL be limited to 15 years. We adopted adaptive management, in which the values are reviewed whenever new data are obtained. The toxicity level was found to be correlated with the Brunauer‐Emmett‐Teller (BET)‐specific surface area (BET‐SSA) of CNT, suggesting the BET‐SSA to have potential for use in toxicity estimation. We used the published exposure data and measurement results of dustiness tests to compute the risk in relation to particle size at the workplace and showed that controlling micron‐sized respirable particles was of utmost importance. Our genotoxicity studies indicated that CNT did not directly interact with genetic materials. They supported the concept that, even if CNT is genotoxic, it is secondary genotoxicity mediated via a pathway of genotoxic damage resulting from oxidative DNA attack by free radicals generated during CNT‐elicited inflammation. Secondary genotoxicity appears to involve a threshold.

Dustiness testing of engineered nanomaterials

We investigated the dustiness (the propensity of a material to generate airborne dust during its handling) of various nanomaterials, including carbon nanotubes and metal oxides, by the vortex shaker method. The number concentrations and size distributions (~10->10 000 nm) of aerosol particles released during agitation were measured. It was found that the modal diameter was greater than 100 nm for all tested nanomaterials, and for most of them some sub-100 nm particles were observed. The dustiness differed by two (or three) orders of magnitude among the test nanomaterials.

Developmental toxicity of engineered nanomaterials in rodents

We summarized significant effects reported in the literature on the developmental toxicity of engineered nanomaterials (ENMs) in rodents. The developmental toxicity of ENMs included not only structural abnormalities, but also death, growth retardation, and behavioral and functional abnormalities. Most studies were performed on mice using an injection route of exposure. Teratogenic effects were indicated when multi-walled carbon nanotubes (MWCNTs), single-walled carbon nanotubes (SWCNTs), and TiO2-nanoparticles were administered to mice during early gestation. Reactive oxygen species levels were increased in placentas and malformed fetuses and their placentas after prenatal exposure to MWCNTs and SWCNTs, respectively. The pre- and postnatal mortalities and growth retardation in offspring increased after prenatal exposure to ENMs. Histopathological and functional abnormalities were also induced in placentas after prenatal exposure to ENMs. Maternal exposure to ENMs induced behavioral alterations, histopathological and biochemical changes in the central nervous system, increased susceptibility to allergy, transplacental genotoxicity, and vascular, immunological, and reproductive effects in offspring. The size- and developmental stage-dependent placental transfer of ENMs was noted after maternal exposure. Silver accumulated in the visceral yolk sac after being injected with Ag-NPs during early gestation. Although currently available data has provided initial information on the potential developmental toxicity of ENMs, that on the developmental toxicity of ENMs is still very limited. Further studies using well-characterized ENMs, state-of the-art study protocols, and appropriate routes of exposure are required in order to clarify these developmental effects and provide information suitable for risk assessments of ENMs.

Quantitative identification of sources of dioxin‐like polychlorinated biphenyls in sediments by a factor analysis model and a chemical mass balance model combined with monte carlo techniques

The major sources of dioxin-like polychlorinated biphenyls (PCBs) in two sediment cores from Tokyo Bay and Lake Shinji (both in Japan) were identified and their source contributions estimated using two receptor models. The first was a nonnegative constrained factor analysis (FA) model, and the second was a nonnegative constrained chemical mass balance model combined with Monte Carlo techniques (CMB-MC) to take into account the variability and uncertainty in both PCB congener profiles of sources and environmental samples. According to the FA model, variations in the concentrations of dioxin-like PCBs in each sediment core were accounted for almost entirely by two factors, which were considered to correspond to Kanechlors (KCs; Japanese PCB products) and incineration. The CMB-MC model investigated the trends of the burdens from four types of KCs and incineration to the concentrations of dioxin-like PCBs in each sediment core. The results for both sediment cores obtained by both models indicated that the burden from KCs increased gradually beginning in the 1950s, peaked around 1970, and declined thereafter, whereas the burden from incineration increased gradually from the 1950s to the early 1990s. The estimated contribution from incineration to the toxic equivalent concentration of dioxin-like PCBs was comparable to that from KCs.

Dose-dependent clearance kinetics of intratracheally administered titanium dioxide nanoparticles in rat lung

AEROSIL(®) P25 titanium dioxide (TiO2) nanoparticles dispersed in 0.2% disodium phosphate solution were intratracheally administered to male F344 rats at doses of 0 (control), 0.375, 0.75, 1.5, 3.0, and 6.0 mg/kg. The rats were sacrificed under anesthesia at 1 day, 3 days, 7 days, 4 weeks, 13 weeks, and 26 weeks after administration. Ti levels in various pulmonary and extrapulmonary organs were determined using sensitive inductively coupled plasma sector field mass spectrometry. One day after administration, the lungs contained 62-83% of TiO2 administered dose. Twenty-six weeks after administration, the lungs retained 6.6-8.9% of the TiO2 administered at the 0.375, 0.75, and 1.5 mg/kg doses, and 13% and 31% of the TiO2 administered at the 3.0 and 6.0 mg/kg doses, respectively. The pulmonary clearance rate constants from compartment 1, k1, were estimated using a 2-compartment model and were found to be higher for the 0.375 and 0.75 mg/kg doses of TiO2 (0.030/day for both) than for TiO2 doses of 1.5-6.0 mg/kg (0.014-0.022/day). The translocation rate constants from compartment 1 to 2, k12, were estimated to be 0.015 and 0.018/day for the 0.375 and 0.75 mg/kg doses, and 0.0025-0.0092/day for doses of 1.5-6.0mg/kg. The pulmonary clearance rate constants from compartment 2, k2, were estimated to be 0.0086 and 0.0093/day for doses of 0.375 and 0.75 mg/kg, and 0-0.00082/day for 1.5-6.0 mg/kg doses. Translocation of TiO2 from the lungs to the thoracic lymph nodes increased in a time- and dose-dependent manner, accounting for 0.10-3.4% of the administered dose at 26 weeks. The measured thoracic lymph node burdens were a much better fit to the thoracic lymph node burdens estimated assuming translocation from compartment 1 to the thoracic lymph nodes, rather than those estimated assuming translocation from compartment 2 to the thoracic lymph nodes. The translocation rate constants from the lungs to the thoracic lymph nodes, kLung→Lym, were 0.000037-0.00081/day, and these also increased with increasing doses of TiO2. Although a small amount of TiO2 had translocated to the liver by 3 days after the administration (0.0023-0.012% of the highest dose administered, 6.0 mg/kg), translocation to the other extrapulmonary organs was not detected.

Fullerene C60: Inhalation Hazard Assessment and Derivation of a Period-Limited Acceptable Exposure Level

Fullerene C(60) has great potential for use in many industry and medical nanotechnology applications. Although the use of nanomaterials has been increasing in the recent years, limited information about its potential hazardous effects is available. Therefore, safety of nanomaterials is a world concern. Before health effects arise in workers and the general population, development and use under appropriate management are desirable. Therefore, we aimed to determine an acceptable exposure level for humans by reviewing the limited animal toxicity data available. Here, we present an initial hazard assessment, including a review of the available toxicity information of the effects of C(60) on the lungs. We then estimated the no-observed-adverse-effect level (NOAEL) of C(60) on rat lung toxicity by using lung retention of C(60) in inhalation exposure and intratracheal instillation tests. The NOAEL of C(60) on rat lung toxicity was estimated to be 3.1 mg/m(3). Because this is the NOAEL for subchronic toxicity, a period-limited acceptable exposure level (AEL(PL)) for humans was proposed, which assumed 15 years of exposure and modification within the next 10 years since more knowledge will be gained in the future. The AEL(PL) of C(60) particles with a geometric mean of 96 nm and a geometric standard deviation (GSD) of 2.0 was estimated to be 0.39 mg/m(3) for healthy workers and 1.4 × 10(-2) mg/m(3) for the general human population. The AEL(PL) of C(60) particles with different sizes was estimated to be for healthy workers and for the general human population.