Toxicity of graphene-family nanoparticles: a general review of the origins and mechanisms
Toxicity of GFNs in organs
Toxicity in internal organs
GO can result in acute inflammation response and chronic injury by interfering with the normal physiological functions of important organs [32, 81]. Oral gavage experiments did not show detectable absorption of GO through the gastrointestinal tract [95]. Interesting, a low dose of GO caused serious damage to the gastrointestinal tract after maternal mice drank a GO suspension rather than a high-dose of GO because a low dose of GO without agglomeration can easily attach to the gastrointestinal surface and cause destruction through its abundant sharp edges [53]. GFNs caused inflammation and remained in the lung on day 90 after a single intratracheal instillation, and even translocated to lung lymph nodes by a nose-only inhalation [96, 97]. A high dose of GO that forms aggregations can block pulmonary blood vessels and result in dyspnea [50, 98], and platelet thrombi were observed at high concentrations of 1 and 2 mg/kg body weight via intravenous injection [89]. GO reportedly disrupted the alveolar-capillary barrier, allowing inflammatory cells to infiltrate into the lungs and stimulate the release of pro-inflammatory cytokines [99]. Fibrosis and inflammation could be verified by the increased levels of the protein markers collagen1, Gr1, CD68 and CD11b in the lungs. The use of Tween 80 to disperse FLG or a pluronic surfactant to disperse graphene was suggested to reduce the likelihood of lung fibrosis formation in cells or mice, whereas lung fibrosis was observed when graphene was suspended with bovine serum albumin (BSA) [100]. In addition, radioactive isotopes can be delivered into the lungs, accompanied by a depth distribution of 125I-NGO in the lungs, and the isotopes might deposit there and result in mutations and cancers [30]. However, recent publications claimed no obvious pathological changes in mice exposed to low dosages of GO and functionalized graphene by intravenous injection, including aminated GO (GO-NH2), poly(acrylamide)-functionalized GO (GO-PAM), poly(acrylic acid)-functionalized GO (GO-PAA) and GO-PEG; only GO-PEG and GO-PAA induced less toxicity than pristine GO in vivo [31, 79, 89]. So the functional groups of GFNs and the working concentration or aggregate state largely influence the toxicity of GFNs. Recently, the ways to modify the functional group of GFNs, decrease the working concentration or change the aggregate condition are usually used to decrease the toxicity of GFNs.
Toxicity in the central nervous system
Graphene has largely benefited neurosurgery with the application of drug/gene delivery for brain tumour treatment, intracranial and spinal biocompatible devices, biosensing and bioimaging techniques. Studies regarding the potentialities or risks of graphene in the brain have emerged. In the chicken embryo model, pristine graphene flakes decreased the ribonucleic acid level and the rate of deoxyribonucleic acid synthesis, leading to harmful effects on brain tissue development and the atypical ultrastructure was observed in the brain [101]. The recent researches of GFNs in the central nervous system are mostly involved in the application rather than the toxicity. The data of the toxic study on GFNs is underway.
Toxicity in reproduction and development system
Pristine graphene reduced the vascularization of the heart and the density of branched vessels after injection into fertilized chicken eggs followed by incubation for 19 d [101]. GO and rGO damage zebrafish embryos by influencing the embryo hatching rate and body length in a concentration-dependent manner. Although no obvious malformation or mortality was observed in exposed zebrafish embryos [102], GO adhered to and was wrapped in the chorion of the zebrafish embryos, causing remarkable hypoxia and hatching delay. GO aggregates were retained in many organelles, such as the eyes, heart, yolk sac, and tail of the embryos, and apoptosis and reactive oxygen species (ROS) generation were observed in these regions [103].
The GFNs exert different toxicological effects on male or female reproductive system. Data showed that GO exerted very low or nearly no toxic effects on male reproduction even at a high dose via intra-abdominal injection [66]. Additionally, rGO did not change the serum estrogen levels of non-pregnant female mice. The condition is different in the female mouse: mouse dams could give birth to healthy offspring after rGO injection before mating or during early gestation, and only a few abnormal foetuses were present among the rGO-injected dam litters. However, the pregnant mice had abortions at all dose, and most pregnant mice died when the high dose of rGO was injected during late gestation [44]. Notably, the development of offspring in the high dosage group was delayed during the lactation period. The high dose of GO decreased the maternal mice’s water consumption by oral exposure, which reduced milk production and thus postponed the growth of offspring [53]. Though the findings indicate that GFNs are potentially harmful to development, but data on reproductive and developmental toxicity are still deficient. Studies of the influence of GFNs on male and female reproduction and development are still required to elucidate the underlying toxicity mechanism.
Influence of haemocompatibility
GO release into the blood is ineluctable. The haemocompatibility of GO was found to be dependent on the functional coating and the exposure conditions. GO with submicron size resulted in the greatest haemolytic activity, while aggregated graphene induced the lowest haemolytic reaction. Pristine graphene and GO demonstrated haemolytic effect up to 75 μg/mL [104]. GO-polyethylenimine (GO-PEI) exhibited notable toxicity by binding to HSA, even at 1.6 μg/mL [105]. Carboxylated graphene oxide (GO-COOH) showed significant cytotoxicity toward T lymphocytes at concentrations above 50 μg/mL and had good biocompatibility below 25 μg/mL, whereas GO-chitosan nearly inhibited haemolytic activity [106]. Until now, the corresponding risk of haemocompatibility has remained largely unknown.
In conclusion, the lung injury induced by GFNs has been studied in several studies, the results of which have demonstrated inflammatory cell infiltration, pulmonary edema and granuloma formation in the lungs. However, only a few specific studies have evaluated in other organs, such as the liver, spleen, and kidney, and the injury symptoms, damage index and level of damage to these internal organs were not fully investigated. Moreover, studies on the neurotoxicity of GFNs are quite rare; no data has revealed which nerves or brain areas experience damage, nor have the related behavioural manifestations been studied. The developmental toxicity of GFNs may induce structural abnormalities, growth retardation, behavioural and functional abnormalities, and even death. A study on the reproductive and developmental toxicity of GFNs will be extremely significant and gain extensive attention in the future. Almost all the GFNs toxicity studies were short-period experiments, and no studies have investigated long-term chronic toxic injury. However, based on studies of other nanomaterials toxicity, long-term GFNs exposure may be an important factor harming health [107–109]. Therefore, the long-term study of GFNs is necessary.
Toxicity of GFNs in cell models
The cytotoxicity of GFNs in vitro has been verified in various cells to change the cell viability and morphology, destroy the membrane integrity, and induce DNA damage [110–112]. GO or rGO decrease cell adhesion; induce cell apoptosis; and enter lysosomes, mitochondria, cell nuclei, and endoplasm [113]. GQDs entered cells and induced DNA damage by the increased expression of p53, Rad 51, and OGG1 proteins in NIH-3 T3 cells [87]. However, GQDs did not pose significant toxicity to human breast cancer cell lines (at a dose of 50 μg/mL) or human neural stem cells (at a dose of 250 μg/mL) [114, 115]. GO derivatives dramatically decreased the expression of differential genes that are responsible for the structure and function of the cell membrane, such as regulation of the actin cytoskeleton, focal adhesion and endocytosis [89]. In rat pheochromocytoma cells (PC12 cells), graphene and rGO caused cytotoxic effects and mitochondrial injury, such as the release of lactate dehydrogenase (LDH), an increase in the activation of caspase-3, and the generation of ROS [82, 116].
Graphene can increase cell viability [117] or cause cell death [118] depending on the cell line, type of graphene material and the doseage. GO cytotoxicity was observed in human fibroblasts and lung epithelial cells at concentrations above 20 μg/mL after 24 h, but minimal toxicity was found in A549 cells at concentrations higher than 50 μg/mL [119]. The biological responses induced by GO such as ROS, malondialdehyde (MDA), and LDH increased, whereas superoxide dismutase (SOD) decreased dose-dependently in HeLa cells [120]. However, GO-molecular beacon (GO-MB) showed low cytotoxicity even at 20 μg/mL in HeLa cells [121]. GO decreased the viability of A549 cells, while the same concentration and time of exposure increased the cell viability of CaCo2 colorectal carcinoma cells [122]. Another study reported that GO dramatically enhanced the differentiation of SH-SY5Y, accompanied by increasing neurite length and the expression of neuronal marker MAP2 at low concentrations but that GO suppressed the viability of SH-SY5Y cells at high doses (≥80 mg/mL) [123]. Functionalized coatings on GO, such as GO-PEG [124] and GO-chitosan [125], can profoundly attenuate the particles’ cytotoxicity by inhibiting the interactions between cells.
The toxicity of GFNs in vitro is summarized in Table 2. Data on the cytotoxicity of graphene nanomaterials are contrasting, and varying characteristics influence the results. The mechanisms and influencing factors of toxicity need to be elucidated in detail.
Origins of GFNs toxicity
Reportedly, the characteristics of graphene, including its concentration, lateral dimension, surface structure, functional groups, purity and protein corona, strongly influence its toxicity in biological systems [2, 7, 104, 126–129].
Concentration
Numerous results have shown that graphene materials cause dose-dependent toxicity in animals and cells, such as liver and kidney injury, lung granuloma formation, decreased cell viability and cell apoptosis [130–134]. In vivo studies, GO did not exhibit obvious toxicity in mice exposed to a low dose (0.1 mg) and middle dose (0.25 mg) but induced chronic toxicity at a high dose (0.4 mg). The high content of GO mainly deposited in the lungs, liver, spleen, and kidneys and was difficult to be cleaned by the kidneys via a single tail vein injection [135]. Intriguingly, increasing the dose resulted in a dramatic decrease in the hepatic uptake but an increase in the pulmonary uptake of s-GO by intravenous injection [31], because the high dose of GO potentially surpassed the uptake saturation or depleted the mass of plasma opsonins, which consequently suppressed the hepatic uptake. Moreover, an in vitro study reported that 20 μg/mL GO nanosheets exhibited no cytotoxicity in A549 within 2 h of incubation, but a higher concentration (85 μg/mL) decreased the cell viability to 50 % within 24 h [136, 137]. Lü et al. also demonstrated that GO had no obvious cytotoxicity at low concentrations for 96 h in a human neuroblastoma SH-SY5Y cell line, but the viability of cells sharply decreased to 20 % after treatment with 100 mg/mL GO for 96 h of incubation [123]. The results in HeLa cells, NIH-3 T3 cells, and breast cancer cells (SKBR3, MCF7) treated with graphene nanoribbons also showed a dose- (10–400 mg/ml) and time-dependent (12–48 h) decrease in cell viability [138]. Increasing concentrations of GO entered the lysosomes, mitochondria, endoplasm, and cell nucleus [119]. Several data indicated that rGO caused apoptosis-mediated cell death at a lower dose and early time point but that necrosis was prevalent with the increase in time/dose [110, 135].
9 件のコメント:
>酸化グラフェン
厚労省幹部は「磁石に反応する物質で……」「金属片かモデルナ製、……」「大きいもので数ミリ」
ファイザー製のワクチンを接種後、打った部位に磁石をつけると反応するとネットなどで報告されていたが、
これがその原因だったのか？
これが、大量に打ち込まれて、体内の各臓器に影響を与えるわけだ。
発見者はノーベル物理学賞を授与されているから、役に立つ夢の物質のようだ
ワクチン打ったら超伝導人間になったでござる（嘘）
これが次の金儲けと実験のネタっすかね？ｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗ
ばーちゃるりありてぃｗあいおーてぃーｗえーあいｗうちゅうりょこうｗことごとくズッコケちゃって大したもの生み出せてませんもんねｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗ
スターウォーズｗだの攻殻機動隊ｗだのマトリックスｗだのそーどあーとおんらいんｗだのビデオやゲーム麻薬オーバードーズのすぎの知能が低いヲタク諸君はまたコロッと感染して踊り狂い続けるんでせうかねｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗｗ
あれ？
まだ米ZEROとは
集中するのかとオモタw
治験中なので、プラセボも入っている。
ロットによって薄い、濃いもあって、
酸化グラフェン沢山いれたら、ばれちゃったﾃﾍﾍﾟﾛ が今でしょうか
アルミニウム塩
も
この度の
酸化グラフェン
も
磁石に付かない
そうで
でも
コバルト磁石で
磁石ひっつき虫に！！
以下の記事にはないけど
金属混入は日本だけとか
本当かなスペイン製薬会社
海外で磁石が接種部位に
ひっつき虫って動画も
案外ハッタリでは無いのか
磁性金属片入った方々
今後MRIもマズいのでは
新型コロナ: モデルナワクチンの異物、一部は金属の可能性も 厚労省: 日本経済新聞 https://www.nikkei.com/article/DGXZQOUA25EKV0V20C21A8000000
(抜粋)
"モデルナ「安全性や有効性の問題は確認されていない」
【ニューヨーク=野村優子】米バイオ製薬モデルナは25日、日本に供給された同社製の新型コロナウイルスワクチンの一部で異物混入が確認されたことについて「スペインの委託先工場の製造ラインで発生したと考えている。現時点で安全性や有効性の問題は確認されていない」と説明した。
同社広報が、日本経済新聞の問い合わせに応じた。「日本で流通しているワクチンのうち1つの製造ロットに、粒子状物質が混入しているとの報告が複数寄せられていることを確認した。品質の保証を優先させるため、隣接する2つの製造ロットの接種も保留した」と述べた。
今後については「現在問題を調査中であり、提携する武田薬品工業や規制当局と透明性を持って迅速に対応する」という。
モデルナはスペインの製薬会社ラボラトリオス・ファルマセウティコス・ロビに、ワクチンの充填や仕上げなどの工程を委託している。"
>混入が見つかったロット番号は3004667（約57万回接種分）、可能性があるのは3004734（約52万回接種分）と3004956（約54万回接種分）。「接種済証」で確認できる。
混入が見つかったワクチンの接種者が2人亡くなった。７PMのTVニュースで流れる。
ぱんちゃん璃奈「私は金属アレルギーです」 異物混入ワクチンと同ロット接種 呼吸困難で救急搬送明かす
https://www.sponichi.co.jp/entertainment/news/2021/08/28/kiji/20210828s00041000630000c.html
接種後に30代2人死亡 異物混入疑い、因果関係は不明 朝日新聞デジタル 8月28日
https://www.asahi.com/articles/ASP8X61P0P8XULBJ00C.html
厚生労働省は28日、東京や埼玉などで異物の混入が見つかった米モデルナ製の新型コロナウイルスワクチンと同じ工程で製造され、接種が見合わせられたワクチンを接種した後、2人が死亡していたと発表した。異物が入っていたのか、死亡と接種に因果関係があるのか、厚労省はいずれも不明とし、専門家による分析を進めるとしている。
亡くなったのは38歳と30歳の基礎疾患やアレルギー歴のない男性で、いずれも2回目の接種後。38歳の男性は15日の接種後、16日に発熱し、18日に死亡。医療機関から21日に報告があり、解剖して詳しく調べる。30歳の男性は22日にうち、23日に発熱、25日に亡くなった。都道府県から報告を受け、情報を収集している。
2人が2回目に接種したワクチンのロット番号は「3004734」。これまで異物混入は確認されていない。2人は厚労省が26日に接種見合わせを発表する前に接種していた。見合わせ対象となった3ロット計163万回分のうち、50万回以上が接種済みだと河野太郎行政改革相が明らかにしている。
ワクチンの副反応による安全性を評価する厚労省の専門家部会の森尾友宏部会長は「これらの死亡例が偶然に生じた可能性もあり、現時点では、ワクチン接種との関係は不明」としている。モデルナ製では、接種1226万1354回のうち、接種後の死亡報告例は8日までに11件（100万回あたり0・9件）ある。報告には医師が死因をワクチン接種と関連が低いと判断しているケースも入っており、現時点ですべて因果関係が「評価できない」ものと判断されている。
厚労省は、異物の混入問題を受け、「（接種を見合わせている）同一ロットで複数の死亡例があり、透明性向上のため」として発表したと説明した。
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