著者
Harumi Okuyama Naoki Ohara Kenjiro Tatematsu Shinya Fuma Tomoyuki Nonogaki Kazuyo Yamada Yuko Ichikawa Daisuke Miyazawa Yuko Yasui Seijiro Honma
出版者
日本毒性学会
雑誌
The Journal of Toxicological Sciences (ISSN:03881350)
巻号頁・発行日
vol.35, no.5, pp.743-747, 2010-10-01 (Released:2010-10-01)
参考文献数
25
被引用文献数
4 or 5

Canola and some other types of oil unusually shorten the survival of stroke-prone spontaneously hypertensive rats (SHRSP), compared with soybean oil, perilla oil and animal fats. Since differential effects of canola and soybean oil on steroid hormone metabolism were suggested by a preliminary DNA microarray analysis as a reason for this, the steroid hormone levels in the serum and tissues of SHRSP fed different oils were investigated. The testosterone levels in the serum and the testes were found to be significantly lower in the canola oil group than in the soybean oil group, while no significant differences were detected in the corticosterone and estradiol levels in tissues. In a second experiment, it was found that hydrogenated soybean oil, with a survival-shortening activity comparable to that of canola oil, also decreased the testosterone level in testes to a similar degree. The testosterone-lowering activity of canola and hydrogenated soybean oil observed in SHRSP was considered in relation to other factors possibly affecting the physiology of SHRSP.
著者
Jeffrey C. Raber Sytze Elzinga Charles Kaplan
出版者
日本毒性学会
雑誌
The Journal of Toxicological Sciences (ISSN:03881350)
巻号頁・発行日
vol.40, no.6, pp.797-803, 2015-12-01 (Released:2015-11-10)
参考文献数
9
被引用文献数
6 or 0

Cannabis concentrates are gaining rapid popularity in the California medical cannabis market. These extracts are increasingly being consumed via a new inhalation method called ‘dabbing’. The act of consuming one dose is colloquially referred to as “doing a dab”. This paper investigates cannabinoid transfer efficiency, chemical composition and contamination of concentrated cannabis extracts used for dabbing. The studied concentrates represent material available in the California medical cannabis market. Fifty seven (57) concentrate samples were screened for cannabinoid content and the presence of residual solvents or pesticides. Considerable residual solvent and pesticide contamination were found in these concentrates. Over 80% of the concentrate samples were contaminated in some form. THC max concentrations ranged from 23.7% to 75.9% with the exception of one outlier containing 2.7% THC and 47.7% CBD. Up to 40% of the theoretically available THC could be captured in the vapor stream of a dab during inhalation experiments. Dabbing offers immediate physiological relief to patients in need but may also be more prone to abuse by recreational users seeking a more rapid and intense physiological effect.
著者
Sanghwa Kim Seong-Ho Hong Choon-Keun Bong Myung-Haing Cho
出版者
日本毒性学会
雑誌
The Journal of Toxicological Sciences (ISSN:03881350)
巻号頁・発行日
vol.40, no.5, pp.535-550, 2015-10-01 (Released:2015-09-10)
参考文献数
100
被引用文献数
5 or 0

Air freshener could be one of the multiple sources that release volatile organic compounds (VOCs) into the indoor environment. The use of these products may be associated with an increase in the measured level of terpene, such as xylene and other volatile air freshener components, including aldehydes, and esters. Air freshener is usually used indoors, and thus some compounds emitted from air freshener may have potentially harmful health impacts, including sensory irritation, respiratory symptoms, and dysfunction of the lungs. The constituents of air fresheners can react with ozone to produce secondary pollutants such as formaldehyde, secondary organic aerosol (SOA), oxidative product, and ultrafine particles. These pollutants then adversely affect human health, in many ways such as damage to the central nervous system, alteration of hormone levels, etc. In particular, the ultrafine particles may induce severe adverse effects on diverse organs, including the pulmonary and cardiovascular systems. Although the indoor use of air freshener is increasing, deleterious effects do not manifest for many years, making it difficult to identify air freshener-associated symptoms. In addition, risk assessment recognizes the association between air fresheners and adverse health effects, but the distinct causal relationship remains unclear. In this review, the emitted components of air freshener, including benzene, phthalate, and limonene, were described. Moreover, we focused on the health effects of these chemicals and secondary pollutants formed by the reaction with ozone. In conclusion, scientific guidelines on emission and exposure as well as risk characterization of air freshener need to be established.
著者
Kosuke Kawamoto Itaru Sato Midori Yoshida Shuji Tsuda
出版者
日本毒性学会
雑誌
The Journal of Toxicological Sciences (ISSN:03881350)
巻号頁・発行日
vol.35, no.6, pp.929-933, 2010-12-01 (Released:2010-12-01)
参考文献数
16

Several appliance manufacturers have recently released new type air purifiers that can disinfect bacteria, fungi and viruses by diffusing reactive oxygen species (ROS) into the air. In this study, mice were exposed to the outlet air from each of 3 air purifiers from different manufacturers (A, B, C), and the lung was examined for DNA damage, lipid peroxidation and histopathology to confirm the safety of these air purifiers. Neither abnormal behavior during exposure nor gross abnormality at necropsy was observed. No histopathological changes were also observed in the lung. However, significant increase of DNA damage was detected by the comet assay in the lung immediately after the direct exposure for 48 hr to models A and B, and for 16 hr to model B. As for model B, DNA migration was also increased by 2 hr exposure in a 1 m3 plastic chamber but not by 48 hr exposure in a room (12.6 m3). Model C did not cause DNA damage. Lipid peroxidation and 8-hydroxy deoxyguanosine (8-OH-dG) was not increased under the conditions DNA damage was detected by the comet assay. The present results revealed that some models of air purifiers that diffuse ROS potentially cause DNA damage in the lung although the mechanism was left unsolved.
著者
Akifumi Eguchi Hidenobu Miyaso Chisato Mori
出版者
日本毒性学会
雑誌
The Journal of Toxicological Sciences (ISSN:03881350)
巻号頁・発行日
vol.41, no.5, pp.667-675, 2016-10-01 (Released:2016-09-24)
参考文献数
52

The toxicity of decabromodiphenyl ether (BDE-209) has been reported in several studies. However, there is not much known about the toxicological biomarkers that characterize BDE-209 exposure. In this study, we subcutaneously exposed mice to 0.025 mg/kg/day BDE-209 on postnatal days 1‑5 and sacrificed the animals at 12 weeks of age (day 84). Flow injection analysis and hydrophilic interaction chromatography-triple quadrupole mass spectrometry were used to determine the serum metabolomes of these mice in order to characterize the effects of BDE-209 exposure. Data analysis showed a good separation between control and exposed mice (R2 = 0.953, Q2 = 0.728, and ANOVA of the cross‑validated residuals (CV‑ANOVA): P‑value = 0.0317) and 54 metabolites were identified as altered in the exposed animals. These were selected using variable importance (VIP) and loadings scaled by a correlation coefficient criteria and orthogonal partial least squares discriminant analysis (OPLS‑DA). BDE‑209‑exposed mice showed lower levels of long-chain acylcarnitines and citrate cycle-related metabolites, and higher levels of some amino acids, long-chain phospholipids, and short-chain acylcarnitines. The disruption of fatty acid, carbohydrate, and amino acid metabolism observed in the serum metabolome might be related to the previously observed impaired spermatogenesis in mice with early postnatal exposure to a low dose of BDE-209.
著者
Nozomi Asaoka Hiroyuki Kawai Naoya Nishitani Haruko Kinoshita Norihiro Shibui Kazuki Nagayasu Hisashi Shirakawa Shuji Kaneko
出版者
日本毒性学会
雑誌
The Journal of Toxicological Sciences (ISSN:03881350)
巻号頁・発行日
vol.41, no.6, pp.813-816, 2016-12-01 (Released:2016-11-16)
参考文献数
16

N-[[1-(5-fluoropentyl)-1H-indazol-3-yl]carbonyl]-3-methyl-D-valine methyl ester (5F-ADB) is one of the most potent synthetic cannabinoids and elicits severe psychotic symptoms in humans, sometimes causing death. To investigate the neuronal mechanisms underlying its toxicity, we examined the effects of 5F-ADB on midbrain dopaminergic and serotonergic systems, which modulate various basic brain functions such as those in reward-related behavior. 5F-ADB-induced changes in spontaneous firing activity of dopaminergic and serotonergic neurons were recorded by ex vivo electrophysiological techniques. In dopaminergic neurons, 5F-ADB (1 μM) significantly increased the spontaneous firing rate, while 5F-ADB failed to activate dopaminergic neurons in the presence of the CB1 antagonist AM251 (1 μM). However, the same concentration of 5F-ADB did not affect serotonergic-neuron activity. These results suggest that 5F-ADB activates local CB1 receptors and potentiates midbrain dopaminergic systems with no direct effects on midbrain serotonergic systems.
著者
Asuka Kaizaki Sachiko Tanaka Satoshi Numazawa
出版者
日本毒性学会
雑誌
The Journal of Toxicological Sciences (ISSN:03881350)
巻号頁・発行日
vol.39, no.1, pp.1-6, 2014-02-01 (Released:2014-01-10)
参考文献数
23
被引用文献数
19 or 0

1-phenyl-2-(1-pyrrolidinyl)-1-pentanone (α-PVP) is a new designer drug of the cathinone type. People who have taken drugs containing α-PVP or other synthetic cathinone reportedly lose consciousness, develop difficulty breathing, and at worst case, die. However, the mechanism underlying α-PVP-induced neurotoxicity is unknown. The objective of the present study was to investigate the effect of α-PVP on the central nervous system (CNS) and compare its neurotoxicity with that of methamphetamine (METH) in mice. Balb/c male mice (8 weeks old) were orally administered α-PVP (25 mg/kg) or METH (5 mg/kg). α-PVP induced a significant increase in locomotor activity, which occurred earlier than locomotor activity induced by METH. This increase was inhibited by the D1 receptor antagonist SCH23990 (50 µg/kg, i.p.) and the D2 receptor antagonist sulpiride (50 mg/kg, i.m.). The extracellular concentration of dopamine (DA) in the striatum, determined by in vivo microdialysis increased immediately after α-PVP administration. These results suggest that α-PVP stimulates DA release, causing an increase in locomotor activity, and that this stimulatory effect of α-PVP on CNS is mediated, at least in part, by the D1 and D2 receptors.
著者
Satoshi Hori Kosaku Kinoshita
出版者
日本毒性学会
雑誌
The Journal of Toxicological Sciences (ISSN:03881350)
巻号頁・発行日
vol.41, no.6, pp.765-773, 2016-12-01 (Released:2016-11-16)
参考文献数
12

OBJECTIVE: The purpose of this study was to identify the clinical aspects leading to overdose of multiple psychotropic drugs, in order to determine areas which need attention in the proper treatment of overdose patients. METHODS: Patients who were treated for overdose of psychotropic drugs at our emergency and critical center over two years were targeted. The clinical data was gathered from the medical records and database of all patients, including age, gender, vital signs, and laboratory data, drugs, and medical complications during hospital stay. In addition primary patient care at the emergency department was examined. RESULTS: Among the 277 patients treated during this study period, 255 (74.0%) used two or more types of psychotropic drugs. Risk factors associated with endotracheal intubation and aspiration pneumonitis included the use of antipsychotics and/or barbiturates as types of overdose drugs. The mean number of days in the ICU was 3.4 days. Seventy-four patients (26.7%) stayed 4 days or more in the ICU of which 16 patients (5.8%) still had suicidal thoughts. A significantly higher incidence of extended ICU stay or endotracheal intubation and aspiration pneumonitis was observed in the group who overdosed on more than 50 or 60 tablets of psychotropic drugs, respectively. CONCLUSIONS: Patients who ingested an overdose of more than 60 tablets of psychotropic drugs should be considered a high-risk group requiring intensive care with extended ICU stay. In case of including antipsychotics and/or barbiturates, the patient should be observed carefully due to a higher risk of medical complications.
著者
Jonggun Kim Yooheon Park Kyong Sup Yoon J. Marshall Clark Yeonhwa Park
出版者
日本毒性学会
雑誌
The Journal of Toxicological Sciences (ISSN:03881350)
巻号頁・発行日
vol.38, no.5, pp.655-660, 2013-10-01 (Released:2013-09-11)
参考文献数
46
被引用文献数
4 or 0

Recently, scientific evidence supports a connection between environmental chemical exposures, which includes insecticides, and development of type 2 diabetes. However, there is limited information about the link between influences of neonicotinoid insecticides and incidence of type 2 diabetes. Thus, the purpose of the study was to determine effects of imidacloprid, a neonicotinoid insecticide, on glucose metabolism. Three different cell models were used; adipocytes (3T3-L1), hepatocytes (HepG2), and myotubes (C2C12). These cells were treated with imidacloprid (0, 10, and 20 μM) for 4-6 days followed by treatment with insulin for 15 min to determine responses. Insulin stimulated glucose uptake was reduced by imidacloprid in all three cell culture models. Treatment with imidacloprid reduced phosphorylation of protein kinase B (AKT), one of the major regulators of insulin signaling, without changing overall AKT expression. Subsequently, imidacloprid reduced phosphorylation of ribosomal S6 kinase (S6K), which is a downstream target of AKT and also a feed-back inhibitor of insulin signaling. These results suggest that imidacloprid could induce insulin resistance by affecting the insulin signaling cascade, particularly up-stream of AKT, in adipocytes, liver, and muscle.
著者
Kent R. Walters Jr. S. Indu Rupassara R.J. Cody Markelz Andrew D.B. Leakey William M. Muir Barry R. Pittendrigh
出版者
日本毒性学会
雑誌
The Journal of Toxicological Sciences (ISSN:03881350)
巻号頁・発行日
vol.37, no.4, pp.773-790, 2012-08-01 (Released:2012-08-01)
参考文献数
55
被引用文献数
1 or 1

Methamphetamine (MA) appears to produce neurotoxic effects, in part, through disruptions of energy metabolism. A recent study of the whole-body proteome of Drosophila melanogaster showed many changes in energy metabolism-related proteins, leading us to hypothesize that MA toxicity may cause whole-body disruptions of energy metabolism. To test this, we monitored the response of energy reserves and other metabolites to MA-exposure with and without the addition of dietary glucose. We also monitored changes in feeding behavior, locomotor activity and respiration rates associated with MA-exposure to investigate how MA affects energy balance. We observed that glycogen and triglyceride levels decreased dramatically within 48 hr of MA-exposure, indicating a strongly negative caloric balance. Behavioral assays revealed that MA-treated flies decreased food consumption by 60-80% and exhibited a 2-fold increase in locomotion. Caloric expenditure decreased with MA-exposure, apparently due to a compensatory decrease in resting metabolism, showing that anorexia was the primary driver of the negative caloric balance. Additionally, we observed that glucose supplementation of MA-containing diet increased glycogen reserves by 44% at 48 hr, leading to a commensurate increase in survivorship. We conclude that dietary sugar supplementation enhances survivorship by partially compensating for decreased caloric intake resulting from MA-induced anorexia. The observation that MA produces similar behavioral changes in Drosophila and humans, i.e. increased locomotor activity and anorexia, further supports the use of Drosophila as a model organism for the study of the effects of MA.
著者
Guojun Yin Liping Cao Jinliang Du Rui Jia Takio Kitazawa Akira Kubota Hiroki Teraoka
出版者
日本毒性学会
雑誌
The Journal of Toxicological Sciences (ISSN:03881350)
巻号頁・発行日
vol.42, no.4, pp.455-459, 2017-08-01 (Released:2017-07-13)
参考文献数
16

Fish hepatobiliary syndrome, characterized by hepatomegaly and fatty liver, has been frequently reported in many cultured fish species and has caused a dramatic economic loss in China. Glucocorticoids are thought to be important non-nutritional factors for hepatomegaly and fatty liver development. In the present study, a dexamethasone-induced zebrafish model of fatty liver and hepatomegaly was established, and the role of glucocorticoid receptor (GR) in the development of hepatomegaly and fatty liver was investigated using developing zebrafish. Exposure of larval zebrafish at 5 days post fertilization (dpf) to dexamethasone for 24 hr caused significant increases of liver size and number of fish with hepatic steatosis at 6 dpf. The increase of liver size caused by dexamethasone was significantly reversed by treatment with RU486, a GR antagonist, and by gene knock-down with a morpholino against the GR. The dexamethasone-induced hepatic steatosis was also inhibited by treatment with RU486. Overall, the results highlight larval zebrafish as a useful model for stress-induced liver failure.
著者
関田 清司 井上 達
出版者
日本毒性学会
雑誌
The Journal of Toxicological Sciences (ISSN:03881350)
巻号頁・発行日
vol.24, no.5, pp.app.147-app.158, 1999-12-20

今日,コカインや覚せい剤などの薬物乱用問題は世界的な取り組の対象となっている。わが国においても,一時,減少傾向にあった覚せい剤の乱用者数が,特にこの数年,増加傾向と低年齢化を示しており危機に直面している。こうした,乱用される薬物は,生体に摂取されることにより,その薬理作用による高揚感や多幸感などの精神的「満足感」を引き起こす。脱し難い薬物依存の形成機序はともかくとして,薬物乱用はこの自覚効果の再体験への欲求にもとづく行動と考えられている。ところで近年,コカインや覚せい剤などのように麻薬及び向精神薬取締法などの法規の取締対象物として所持や使用が厳しく規制を受ける「違法な薬物」とは別に,これらの法的規制外で、多幸感や気分の高揚が得られるなどとの標傍のもとに,いわゆる「合法ドラッグ」と称する「商品」が流通している実態がある。現在取締対象となっている「乱用薬物」も、多くは今日の「合法ドラッグ」に似た位置づけにあったものと考えられるので、本稿では,代表的な「乱用薬物」であるコカインや覚せい剤などが乱用される機構を整理し,それらが法規制の対象になるに至った経緯などについて通覧することにより,今日の「合法ドラッグ」の性質やその危険性を明らかにすることを目的としている。
著者
Takashi Ashino Kanae Hakukawa Yuka Itoh Satoshi Numazawa
出版者
日本毒性学会
雑誌
The Journal of Toxicological Sciences (ISSN:03881350)
巻号頁・発行日
vol.39, no.6, pp.815-820, 2014-12-01 (Released:2014-11-06)
参考文献数
23

Synthetic cannabinoids developed by chemical modification are believed to bind to cannabinoid receptors and cause neurological effects similar to cannabis; however, their effects on drug metabolizing enzymes are unknown. This study aimed to elucidate the effect of synthetic cannabinoids on cytochrome P450 1A activity. Naphthoylindole, a basic structure of the major synthetic cannabinoids, strongly inhibited CYP1A activity in a competitive manner; the apparent Ki value was 0.40 μM. The N-Alkylated derivatives of naphthoylindole, MAM-2201 and JWH-019, also inhibited CYP1A activity in a concentration-dependent manner; however, their inhibitory effects were weaker than naphthoylindole. An adamantylamidoindole derivative, STS-135, showed inhibition of CYP1A activity in a concentrationdependent manner, but the adamantoylindole derivatives, AB-001 and AM-1248, did not. A tetramethylcyclopropanoylindole derivative, UR-144, showed a weak inhibition of CYP1A activity at high concentrations. These results suggest that synthetic cannabinoids and their basic molecules are capable of inhibiting CYP1A enzymatic activity.
著者
中野 茂樹 桑田 雅彦 長谷川 浩之 入村 兼司 丸伝 章 森田 健一
出版者
日本毒性学会
雑誌
The Journal of Toxicological Sciences (ISSN:03881350)
巻号頁・発行日
vol.14, pp.13-59, 1989-10-31
被引用文献数
3 or 0

ラットにP-4を2, 10, 50および150mg/kg/dayの投与量で13週間経口投与し, その亜急性毒性ならびに回復性を検討し, 以下の知見を得た. 1. 一般状態の観察では, 50mg/kg/day以上の雌雄各群で投薬後一過性の流涎と主に雌で尿による下腹部の汚染が観察された. その他に重篤な中毒症状はみられず, P-4投与によると思われる死亡例もなかった. 2. 体重は, 雄の50mg/kg/day以上, 雌の150mg/kg/dayの群で増加抑制がみられたが, 摂餌量に著しい変動はなかった. 摂水量は雌雄とも50mg/kg/day以上群で, 投薬初期より明らかな増加を示した. 3. 尿検査では, 50mg/kg/day以上の雌雄各群で尿量の増加, 浸透圧の低下, 蛋白およびウロビリノーゲンの陰性化, さらに電解質排泄量の軽度増加がみられた. 4. 血液学的検査では,150mg/kg/day群の雌雄に赤血球数の増加およびAPTTの短縮, さらに雄ではヘモグロビン量およびヘマトクリット値の増加, 白血球数の減少と雌ではフィブリノーゲン量の増加がいずれも軽度にみられた. 5. 血液生化学的検査では, 雄の50mg/kg/day以上および雌の150mg/kg/dayの群に中性脂肪の減少とγ-GTPおよびAlP活性, および尿素窒素の増加がみられた. さらに雄では総および遊離コレステロール, およびリン脂質が減少し, 雌では総コレステロールの増加およびコリンエステラーゼ活性の減少がみられた. 6. 病理学的検査では, 50mg/kg/day以上の雌雄各群に胸腺および脾臓の肉眼的萎縮がみられたが, 病理組織学的異常は認められなかった. 雄の50mg/kg/day以上および雌の150mg/kg/day群では肝臓重量または重量比が増加し, 病理組織学的検査で肝細胞の肥大および脂肪変性が観察された. 電子顕微鏡検査では, 同群でさらに肝細胞に著明な滑面小胞体の増殖を認めた. 腎臓では, 雄の10mg/kg/day以上, 雌の50mg/kg/day以上の群の近位尿細管上皮細胞内に好酸性の核内封入物を認めたが, その細胞質に腎障害像は全くみられなかった. 7. 回復試験では, P-4投与によるいずれの変化も回復ないし回復傾向を示し, 可逆性の変化であることが示唆された. 8. 無影響量は雄で2mg/kg/day, 雌で10mg/kg/day, 確実中毒量は雄で50mg/kg/day, 雌で150mg/kg/dayと推察された.
著者
Ken-ichi Wakabayashi Yoshimasa Kurata Tomoo Harada Yasushi Tamaki Naohiro Nishiyama Toshio Kasamatsu
出版者
日本毒性学会
雑誌
The Journal of Toxicological Sciences (ISSN:03881350)
巻号頁・発行日
vol.37, no.4, pp.691-698, 2012-08-01 (Released:2012-08-01)
参考文献数
23
被引用文献数
10 or 0

Glycidol fatty acid esters (GEs) have been identified as contaminants in refined edible oils. Although the possible release of glycidol (G) from GEs is a concern, little is known about the conversion of GEs to G in the human body. This study addressed the toxicokinetics of glycidol linoleate (GL) and G in male Crl:CD(SD) rats and cynomolgus monkeys. Equimolar amounts of GL (341 mg/kg) or G (75 mg/kg) were administered by gavage to each animal. G was found in both species after the G and GL administration, while plasma GL concentrations were below the lower limit of quantification (5 ng/ml) in both species. In rats, the administration of GL or G produced similar concentration-time profiles for G. In monkeys, the Cmax and AUC values after GL administration were significantly lower than those after G administration. The oral bioavailability of G in monkeys (34.3%) was remarkably lower than that in rats (68.8%) at 75 mg/kg G administration. In addition, plasma G concentrations after oral administration at three lower doses of GL or G were measured in both species. In monkeys, G was detected only at the highest dose of G. In contrast, the rats exhibited similar plasma G concentration-time profiles after GL or G administration with significantly higher G levels than those in monkeys. In conclusion, these results indicate that there are remarkable species differences in the toxicokinetics of GEs and G between rodents and primates, findings that should be considered when assessing the human risk of GEs.
著者
中川 静紀 政本 浩二 住吉 博道 原田 浩
出版者
日本毒性学会
雑誌
The Journal of Toxicological Sciences (ISSN:03881350)
巻号頁・発行日
vol.9, no.1, pp.57-60, 1984-02-25 (Released:2008-02-21)
参考文献数
5
被引用文献数
12 or 0

The acute toxicity test of garlic extract was studied in Wistar rats and ddY mice. The LD<50> values of garlic extract by P.O., I.P. and S.C. administration were estimated over 30 ml/kg respectively in male and female of both rodents. In 30 ml/kg of I.P. group, five of ten in male rats and one of ten in female rats were died within a day after administration, however no specific signs due to garlic extract were observed in survivals for 7 days.
著者
Shuji Tsuda
出版者
日本毒性学会
雑誌
The Journal of Toxicological Sciences (ISSN:03881350)
巻号頁・発行日
vol.41, no.Special, pp.SP27-SP36, 2016-12-20 (Released:2016-12-20)
参考文献数
57

Perfluoroalkyl substances (PFASs) are persistent environmental contaminants. Perfluorooctane sulfonate (PFOS) and Perfluorooctanoic acid (PFOA) are representatives of PFASs. Recently, the U.S. Environmental Protection Agency (US EPA) set the health advisory level as 70 parts per trillion for lifetime exposure to PFOS and PFOA from drinking water, based on the EPA’s 2016 Health Effects Support Documents. Then, a monograph on PFOA was made available online by the International Agency for Research on Cancer, where the agency classified PFOA as “possibly carcinogenic to humans” (Group 2B). The distinction between PFOS and PFOA, however, may not be easily understood from the above documents. This paper discussed differential toxicity between PFOS and PFOA focusing on neurotoxicity, developmental toxicity and carcinogenicity, mainly based on these documents. The conclusions are as follows: Further mechanistic studies may be necessary for ultrasonic-induced PFOS-specific neurotoxicity. To support the hypothesis for PFOS-specific neonatal death that PFOS interacts directly with components of natural lung surfactant, in vivo studies to relate the physicochemical effects to lung collapse may be required. PFOA-induced DNA damage secondary to oxidative stress may develop to mutagenicity under the condition where PFOA-induced apoptosis is not sufficient to remove the damaged cells. A study to find whether PFOA induces apoptosis in normal human cells may contribute to assessment of human carcinogenicity. Studies for new targets such as hepatocyte nuclear factor 4α (HNF4α) may help clarify the underlying mechanism for PFOA-induced carcinogenicity.
著者
Ikuo Horii
出版者
日本毒性学会
雑誌
The Journal of Toxicological Sciences (ISSN:03881350)
巻号頁・発行日
vol.41, no.Special, pp.SP49-SP67, 2016-12-31 (Released:2017-03-01)
参考文献数
65

Pharmaceutical (drug) safety assessment covers a diverse science-field in the drug discovery and development including the post-approval and post-marketing phases in order to evaluate safety and risk management. The principle in toxicological science is to be placed on both of pure and applied sciences that are derived from past/present scientific knowledge and coming new science and technology. In general, adverse drug reactions are presented as “biological responses to foreign substances.” This is the basic concept of thinking about the manifestation of adverse drug reactions. Whether or not toxic expressions are extensions of the pharmacological effect, adverse drug reactions as seen from molecular targets are captured in the category of “on-target” or “off-target”, and are normally expressed as a biological defense reaction. Accordingly, reactions induced by pharmaceuticals can be broadly said to be defensive reactions. Recent molecular biological conception is in line with the new, remarkable scientific and technological developments in the medical and pharmaceutical areas, and the viewpoints in the field of toxicology have shown that they are approaching toward the same direction as well. This paper refers to the basic concept of pharmaceutical toxicology, the differences for safety assessment in each stage of drug discovery and development, regulatory submission, and the concept of scientific considerations for risk assessment and management from the viewpoint of “how can multidisciplinary toxicology contribute to innovative drug discovery and development?” And also realistic translational research from preclinical to clinical application is required to have a significant risk management in post market by utilizing whole scientific data derived from basic and applied scientific research works. In addition, the significance for employing the systems toxicology based on AOP (Adverse Outcome Pathway) analysis is introduced, and coming challenges on precision medicine are to be addressed for the new aspect of efficacy and safety evaluation.
著者
Xin Cao Yuji Nakamura Takeshi Wada Hiroko Izumi-Nakaseko Kentaro Ando Atsushi Sugiyama
出版者
日本毒性学会
雑誌
The Journal of Toxicological Sciences (ISSN:03881350)
巻号頁・発行日
vol.41, no.3, pp.439-447, 2016-06-01 (Released:2016-05-17)
参考文献数
21

Since amantadine-induced long QT syndrome has been clinically reported, we investigated its electropharmacological effects to estimate the extent of proarrhythmic risk by using the halothane-anesthetized beagle dogs (n = 4). Amantadine in doses of 0.1, 1 and 10 mg/kg was infused over 10 min with a pause of 20 min under the monitoring of multiple cardiovascular variables. J-Tpeak and Tpeak-Tend were separately measured on the lead II electrocardiogram to precisely analyze the net balance between inward and outward current modifications by amantadine. The low dose increased the ventricular contractile force, but suppressed the intraventricular conduction. The middle dose prolonged the QT interval besides enhancing the changes induced by the low dose. The high dose increased the mean blood pressure, left ventricular end-diastolic pressure and total peripheral resistance, and accelerated the atrioventricular nodal conduction, but decreased the cardiac output besides enhancing the changes induced by the middle dose. A reverse use-dependence was confirmed in the repolarization delay. Amantadine hardly affected the J-Tpeak, but prolonged the Tpeak-Tend. Amantadine can be considered to stimulate Ca2+ channel but inhibit Na+ and K+ channels in the in situ heart. J-Tpeak and Tpeak-Tend analysis suggests that amantadine may possess modest risk for arrhythmia.
著者
Biswadev BISHAYI Subhashree ROYCHOWDHURY Soumya GHOSH Mahuya SENGUPTA
出版者
日本毒性学会
雑誌
The Journal of Toxicological Sciences (ISSN:03881350)
巻号頁・発行日
vol.27, no.3, pp.139-146, 2002 (Released:2003-01-31)
参考文献数
25
被引用文献数
30 or 0

Effect of Tinospora cordifolia extract on modulation of hepatoprotective and immunostimulatory functions in carbon tetrachloride (CCl4) intoxicated mature rats is reported here. Administration of CCl4 (0.7 ml/kg body weight for 7 days) produces damage in the liver as evident by estimation of enzymes such as serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transminase (SGPT) and alkaline phosphatase (ALP) as well as serum bilirubin level. CCl4 administration also causes immunosuppressive effects as indicated by phagocytic capacity, chemotactic migration and cell adhesiveness of rat peritoneal macrophages. However, treatment with T. cordifolia extract (100 mg/kg body weight for 15 days) in CCl4 intoxicated rats was found to protect the liver, as indicated by enzyme level in serum. A significant reduction in serum levels of SGOT, SGPT, ALP, bilirubin were observed following T. cordifolia treatment during CCl4 intoxication. Treatment with T. cordifolia extract also deleted the immunosuppressive effect of CCl4, since a significant increment in the functional capacities of rat peritoneal macrophages (PMφ) was observed following T. cordifolia treatment. The results of our experiment suggest that treatment by T. cordifolia extract may be the critical remedy for the adverse effect of CCl4 in liver function as well as immune functions.