Kinetics and dissolution of intratracheally administered nickel oxide nanomaterials in rats.

BACKGROUND: The toxicokinetics of nanomaterials are an important factor in toxicity, which may be affected by slow clearance and/or distribution in the body. METHODS: Four types of nickel oxide (NiO) nanoparticles were single-administered intratracheally to male F344 rats at three doses of 0.67-6.0 mg/kg body weight. The rats were sacrificed under anesthesia and the lung, thoracic lymph nodes, bronchoalveolar lavage fluid, liver, and other organs were sampled for Ni burden measurement 3, 28, and 91 days post-administration; Ni excretion was measured 6 and 24 h after administration. Solubility of NiO nanoparticles was determined using artificial lysosomal fluid, artificial interstitial fluid, hydrogen peroxide solution, pure water, and saline. In addition, macrophage migration to trachea and phagosome-lysosome-fusion rate constants were estimated using pulmonary clearance and dissolution rate constants. RESULTS: The wire-like NiO nanoparticles were 100% dissolved by 24 h when mixed with artificial lysosomal fluid (dissolution rate coefficient: 0.18/h); spherical NiO nanoparticles were 12% and 35% dissolved after 216 h when mixed with artificial lysosomal fluid (1.4 × 10-3 and 4.9 × 10-3/h). The largest irregular-shaped NiO nanoparticles hardly dissolved in any solution, including artificial lysosomal fluid (7.8 × 10-5/h). Pulmonary clearance rate constants, estimated using a one-compartment model, were much higher for the NiO nanoparticles with a wire-shape (0.069-0.078/day) than for the spherical and irregular-shaped NiO nanoparticles (0-0.012/day). Pulmonary clearance rate constants of the largest irregular-shaped NiO nanoparticles showed an inverse correlation with dose. Translocation of NiO from the lungs to the thoracic lymph nodes increased in a time- and dose-dependent manner for three spherical and irregular-shaped NiO nanoparticles, but not for the wire-like NiO nanoparticles. Thirty-five percent of the wire-like NiO nanoparticles were excreted in the first 24 h after administration; excretion was 0.33-3.6% in that time frame for the spherical and irregular-shaped NiO nanoparticles. CONCLUSION: These findings suggest that nanomaterial solubility differences can result in variations in their pulmonary clearance. Nanoparticles with moderate lysosomal solubility may induce persistent pulmonary inflammation.

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

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.

Comparison of the local pulmonary distribution of nanoparticles administered intratracheally to rats via gavage needle or microsprayer delivery devices.

Intratracheal administration methods are used to conduct toxicological assessments of inhaled nanoparticles (NPs), and gavage needles or microsprayers are common intratracheal delivery devices. The NP suspension is delivered in a liquid state via gavage needle and as a liquid aerosol via microsprayer. The differences in local pulmonary NP distribution (called the microdistribution) arising from the different states of the NP suspension cause differential pulmonary responses; however, this has yet to be investigated. Herein, using microbeam X-ray fluorescence microscopy, we quantitatively evaluated the TiO2 pulmonary microdistribution (per mesh: 100 µm × 100 µm) in lung sections from rats administered an intratracheal dose of TiO2 NPs (6 mg kg-1 ) via gavage needle or microsprayer. The results revealed that: (i) using a microsprayer appears to reduce the variations in TiO2 content (ng mesh-1 ) among rats (e.g., coefficients of variation, n = 3, microsprayer vs gavage needle: 13% vs 30%, for the entire lungs); (ii) TiO2 appears to be deposited less in the right middle lobes than in the rest of the lung lobes, irrespective of the chosen intratracheal delivery device; and (iii) similar TiO2 contents (ng mesh-1 ) and frequencies are deposited in the lung lobes of rats administered TiO2 NPs via gavage needle or microsprayer. This suggests that the physical state of the administered NP suspension does not markedly alter TiO2 pulmonary microdistribution. The results of this investigation are important for the standardization of intratracheal administration methods. Copyright © 2016 John Wiley & Sons, Ltd.

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.

A review of toxicity studies of single-walled carbon nanotubes in laboratory animals.

We summarized the findings of in vivo toxicity studies of single-walled carbon nanotubes (SWCNTs) in laboratory animals. The large majority addressed the pulmonary toxicity of SWCNTs in rodents. Inhalation, pharyngeal aspiration, and intratracheal instillation studies revealed that SWCNTs caused acute and chronic inflammation, granuloma formation, collagen deposition, fibrosis, and genotoxic effects in the lungs. Pulmonary toxicity of well-dispersed SWCNTs was more potent than less dispersed ones. Airway exposure to SWCNTs also induced cardiovascular diseases in mice. Oxidative stress was caused by the administration of SWCNTs. Injected SWCNTs were distributed throughout most of the organs including the brain, mainly retained in the lungs, liver, and spleen, and eliminated through the kidney and bile duct. Orally administered SWCNTs are suggested to be absorbed from the gastrointestinal tract to the blood circulation in mice and rats. Although no definitive study on the carcinogenicity of SWCNTs is available at present, evidence of carcinogenicity has not been reported in toxicity studies cited in this review. Overall, the available data provides initial information on SWCNT toxicity. To further clarify their toxicity and risk assessment, studies should be conducted using well-characterized SWCNTs, standard protocols, and the relevant route and doses of human exposure.

Quantitative evaluation of local pulmonary distribution of TiO2 in rats following single or multiple intratracheal administrations of TiO2 nanoparticles using X-ray fluorescence microscopy.

Uneven pulmonary nanoparticle (NP) distribution has been described when using single-dose intratracheal administration tests. Multiple-dose intratracheal administrations with small quantities of NPs are expected to improve the unevenness of each dose. The differences in local pulmonary NP distribution (called microdistribution) between single- and multiple-dose administrations may cause differential pulmonary responses; however, this has not been evaluated. Here, we quantitatively evaluated the pulmonary microdistribution (per mesh: 100 µm × 100 µm) of TiO2 in lung sections from rats following one, two, three, or four doses of TiO2 NPs at a same total dosage of 10 mg kg(-1) using X-ray fluorescence microscopy. The results indicate that: (i) multiple-dose administrations show lower variations in TiO2 content (ng mesh(-1) ) for sections of each lobe; (ii) TiO2 appears to be deposited more in the right caudal and accessory lobes located downstream of the administration direction of NP suspensions, and less so in the right middle lobes, irrespective of the number of doses; (iii) there are not prominent differences in the pattern of pulmonary TiO2 microdistribution between rats following single and multiple doses of TiO2 NPs. Additionally, the estimation of pulmonary TiO2 deposition for multiple-dose administrations imply that every dose of TiO2 would be randomly deposited only in part of the fixed 30-50% of lung areas. The evidence suggests that multiple-dose administrations do not offer remarkable advantages over single-dose administration on the pulmonary NP microdistribution, although multiple-dose administrations may reduce variations in the TiO2 content for each lung lobe. Copyright © 2016 John Wiley & Sons, Ltd.

Quantitative evaluation of the pulmonary microdistribution of TiO2 nanoparticles using X-ray fluorescence microscopy after intratracheal administration with a microsprayer in rats.

The unevenness of pulmonary nanoparticle (NP) distribution, which hinders the establishment of an absolute dose-response relationship, has been described as one of the limitations of intratracheal administration techniques for toxicological assessment of inhaled NPs. Quantification of the NP microdistribution would facilitate the establishment of a concentration-response relationship in localized regions of the lung; however, such quantitative methods have not been reported. Here, we established a quantitative method for evaluating pulmonary TiO2 NP microdistribution in rats using X-ray fluorescence microscopy. Ti intensity in lung sections from rats intratracheally administered 10 mg kg(-1) TiO2 NPs with a microsprayer was measured using X-ray fluorescence with a 100 µm beam size. Ti reference samples were prepared by dropping different concentrations of Ti solutions on glass slide or lung sections of untreated rat. Ti intensity increased linearly with Ti content in the reference samples on both substrates. The detection limit of TiO2 was estimated to be 6.3 ng mm(-2) . The reproducibility was confirmed for measurements done in the short- (2 weeks) and long-term (6 months). The quantitative results of TiO2 NP microdistribution suggested that more TiO2 NPs were distributed in the right caudal and accessory lobes, which are located downstream of the administration direction of the NP suspension, and the lower portion of each lobe. The detection rates of TiO2 NPs were 16.6-25.0%, 5.19-15.6%, 28.6-39.2%, 21.4-38.7% and 10.6-23.2% for lung sections from the right cranial, middle, caudal, accessory and left lobes, respectively.

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/m(3) 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.

Inter-laboratory comparison of pulmonary lesions induced by intratracheal instillation of NiO nanoparticle in rats: Histopathological examination results.

OBJECTIVE: In this study, in order to investigate the usefulness of intratracheal instillation in assessing the pulmonary toxicity of nanomaterials, intratracheal instillation of nickel oxide-nanoparticles (NiO-NP) was performed. METHODS: In this study, rats were administered test materials by intratracheal instillation at five different research institutions in order to assess the validity of using intratracheal instillation for hazard identification of nanomaterials. Eight-week-old male SD rats were administered NiO-NP dispersed in deionized water by a single intratracheal instillation at doses of 0 (vehicle control), 0.2, 0.67, and 2 mg/kg BW. Three days after instillation, histopathological examination of the lungs was performed. RESULTS: NiO-NP was distributed in the vicinity of hilus of the lung and in the alveoli around the bronchioles. Histopathological changes such as degeneration/necrosis of macrophages, inflammation, and proliferation of type II pneumocyte in the lung were observed, and their severity corresponded with increasing dose. The histopathological observations of pulmonary toxicity were almost similar at each institution. CONCLUSION: The similarity of the histopathological changes observed by five independent groups indicates that intratracheal instillation can be a useful screening method to detect the pulmonary toxicity of nanomaterials.

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.

Effect of methyl p-hydroxybenzoate on the culture of mammalian cell.

Several chemicals, such as methyl p-hydroxybenzoate (MHB), have been widely used as preservatives in the water baths of CO2 incubators used for mammalian cell culture, and they are not considered to produce any biological effects. However, no detailed analyses of the effects of these compounds on cultured cells have been reported. In this study, we thus examined whether MHB in the incubator water bath affects cell viability or genome-wide gene expression in mouse embryonic stem cells under control conditions [using only dimethyl sulfoxide (DMSO) in the culture medium] and under chemical-treated conditions using benzene and chloroform; conditions that simulate a cell-based toxicity assay. We found that (i) MHB significantly altered cell growth rate, and (ii) MHB affected gene expression levels related to pathways that modulate cell growth and basic molecular processes, not only under control conditions but also the chemical-treated conditions. Furthermore, Gene Ontology term analyses revealed that the effects of MHB cannot be accounted for by subtracting the gene expression pattern in the control conditions from that in the chemical-treated conditions. Thus, we suggest that the use of MHB or other preservatives in a CO2 incubator water bath is reconsidered in terms of potential confounding effects on cultured cells.

Identification of RNA biomarkers for chemical safety screening in mouse embryonic stem cells using RNA deep sequencing analysis.

Although it is not yet possible to replace in vivo animal testing completely, the need for a more efficient method for toxicity testing, such as an in vitro cell-based assay, has been widely acknowledged. Previous studies have focused on mRNAs as biomarkers; however, recent studies have revealed that non-coding RNAs (ncRNAs) are also efficient novel biomarkers for toxicity testing. Here, we used deep sequencing analysis (RNA-seq) to identify novel RNA biomarkers, including ncRNAs, that exhibited a substantial response to general chemical toxicity from nine chemicals, and to benzene toxicity specifically. The nine chemicals are listed in the Japan Pollutant Release and Transfer Register as class I designated chemical substances. We used undifferentiated mouse embryonic stem cells (mESCs) as a simplified cell-based toxicity assay. RNA-seq revealed that many mRNAs and ncRNAs responded substantially to the chemical compounds in mESCs. This finding indicates that ncRNAs can be used as novel RNA biomarkers for chemical safety screening.

Assessment of exposure to and risk posed by toluene in Japanese residents: combining exposure from indoor and outdoor sources.

Toluene is a chemical substance whose release to the atmosphere is the largest among the pollutant release and transfer registers (PRTR) chemicals and is regarded as one of the major indoor air pollutants. We have developed a method of estimating the distribution of personal exposures of Japanese residents, combining exposure from indoor and outdoor sources. Personal exposure was divided into contributions of indoor and outdoor sources. Ambient toluene concentration was estimated for a 5 x 5 km square grid spatial resolution using the National Institute of Advanced Industrial Science and Technology-atmospheric dispersion model for exposure and risk assessment (AIST-ADMER) using PRTR emission data. The contribution of indoor sources was assumed to be the difference between indoor and outdoor concentrations, which was regarded to have a lognormal distribution. The health risk from toluene exposure in Japanese residents is expressed as the number of people whose personal exposure exceeded the reference values, which were set on the basis of a review of epidemiological studies. Finally, a risk-reduction strategy is suggested according to the proposed principle of risk management.

Estimating health risk from exposure to 1,4-dioxane in Japan.

Exposure to 1,4-dioxane from the atmosphere around high-emission plants and from consumer products used in daily life that contain the substance may have adverse health effects; however, its emission into the atmosphere is not regulated. In this study, the health risk posed by 1,4-dioxane is assessed to investigate whether measures should be undertaken to reduce exposure to 1,4-dioxane. The notion of the margin of exposure (MOE), given by the ratio of no observed adverse effect level (NOAEL) to actual or projected exposure level, is used to assess risk. In exposure assessment, two types of exposure channel are considered: (a) the use of consumer products that contain 1,4-dioxane and (b) the inhalation of air around high-emission plants. To estimate exposure via channel (a), we measured the concentration of 1,4-dioxane in consumer products and estimated the interindividual variability of exposure by Monte Carlo simulation that reflects the measured data. To estimate exposure via channel (b), we employed a local-level atmospheric dispersion model to estimate the concentration of 1,4-dioxane immediately around high-emission plants. For hazard assessment, we derived the inhalatory and oral NOAELs for liver adenomas and carcinomas and the uncertainty factor. The results suggest that measures are not needed to reduce exposure to 1,4-dioxane from consumer products. As for inhalation exposure around high-emission plants, some residents may be exposed to health risks if certain conservative analytical conditions are assumed. Even in this case, we conclude that it is not necessary for Plant A to stop the use of 1,4-dioxane immediately and that medium- to long-term emission reduction measures should be sufficient.

Genome-wide gene expression analysis of mouse embryonic stem cells exposed to p-dichlorobenzene.

Because of the limitations of whole animal testing approaches for toxicological assessment, new cell-based assay systems have been widely studied. In this study, we focused on two biological products for toxicological assessment: mouse embryonic stem cells (mESCs) and long noncoding RNAs (lncRNAs). mESCs possess the abilities of self-renewal and differentiation into multiple cell types. LlncRNAs are an important class of pervasive non-protein-coding transcripts involved in the molecular mechanisms associated with responses to chemicals. We exposed mESCs to p-dichlorobenzene (p-DCB) for 1 or 28 days (daily dose), extracted total RNA, and performed deep sequencing analyses. The genome-wide gene expression analysis indicated that mechanisms modulating proteins occurred following acute and chronic exposures, and mechanisms modulating genomic DNA occurred following chronic exposure. Moreover, our results indicate that three novel lncRNAs (Snora41, Gm19947, and Scarna3a) in mESCs respond to p-DCB exposure. We propose that these lncRNAs have the potential to be surrogate indicators of p-DCB responses in mESCs.

Categorization of nano-structured titanium dioxide according to physicochemical characteristics and pulmonary toxicity.

A potentially useful means of predicting the pulmonary risk posed by new forms of nano-structured titanium dioxide (nano-TiO2) is to use the associations between the physicochemical properties and pulmonary toxicity of characterized forms of TiO2. In the present study, we conducted intratracheal administration studies in rats to clarify the associations between the physicochemical characteristics of seven characterized forms of TiO2 and their acute or subacute pulmonary inflammatory toxicity. Examination of the associations between the physicochemical characteristics of the TiO2 and the pulmonary inflammatory responses they induced revealed (1) that differences in the crystallinity or shape of the TiO2 particles were not associated with the acute pulmonary inflammatory response; (2) that particle size was associated with the acute pulmonary inflammatory response; and (3) that TiO2 particles coated with Al(OH)3 induced a greater pulmonary inflammatory response than did non-coated particles. We separated the seven TiO2 into two groups: a group containing the six TiO2 with no surface coating and a group containing the one TiO2 with a surface coating. Intratracheal administration to rats of TiO2 from the first group (i.e., non-coated TiO2) induced only acute pulmonary inflammatory responses, and within this group, the acute pulmonary inflammatory response was equivalent when the particle size was the same, regardless of crystallinity or shape. In contrast, intratracheal administration to rats of the TiO2 from the second group (i.e., the coated TiO2) induced a more severe, subacute pulmonary inflammatory response compared with that produced by the non-coated TiO2. Since alteration of the pulmonary inflammatory response by surface treatment may depend on the coating material used, the pulmonary toxicities of coated TiO2 need to be further evaluated. Overall, the present results demonstrate that physicochemical properties may be useful for predicting the pulmonary risk posed by new nano-TiO2 materials.

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.

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

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.

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.

Environmental risk evaluation of chemicals: achievements of the project and seeds for future--development of metrics for evaluating risks.

Achievements of the research project entitled "Establishment of a scientific framework for the management of toxicity of chemicals based on environmental risk-benefit analysis" supported by the JST were introduced and reviewed, focusing on the development of the methodology for estimating risks; human health risks and ecological risks. The usefulness of loss of life expectancy as a metric for evaluating cancer and noncancer risks was demonstrated. To evaluate ecological risks, three metrics, 1/T, logT and T, developed based on the mean extinction time (T) of species were proposed. Then, their implication and feasibility were examined in terms of what ecological system should be conserved and how easily people can understand the implications of metrics. Protocols for estimating human health risks and ecological risks are illustrated.