マレーシア、 クランバレーにおける内分泌撹乱化学物質(EDCs)の人への曝露と環境中動態

京都大学新制・論文博士博士(工学)乙第13495号論工博第4202号新制||工||1786(附属図書館)(主査)教授 米田 稔, 教授 高野 裕久, 教授 松井 康人学位規則第4条第2項該当Doctor of Philosophy (Engineering)Kyoto UniversityDGA

Endocrine-Disrupting Chemicals Role in Drug Abuser: A Review Study

Endocrine-disrupting Chemicals (EDCs) are exogenous chemicals that influence many aspects of natural hormone actions. Bisphenol is used in the industry, for increasing the thickness and durability of materials in certain plastics and resins. Paraben is used as preservatives in many pharmaceuticals, cosmetics, and some food products. EDCs can increase estrogen levels inside the body, and estrogen itself can increase the monoamine effect (dopamine, serotonin), neuronal excitability, neuropeptide transmitter mechanism, and drug metabolism. In drug abusers, this effect can develop greater craving behavior, addiction, and relapse

Pharmaceuticals, hormones, plasticizers, and pesticides in drinking water

Humans are exposed to endocrine disrupting compounds (EDCs) in tap water via drinking water. Currently, most of the analytical methods used to assess a long list of EDCs in drinking water have been made available only for a single group of EDCs and their metabolites, in contrast with other environmental matrices (e.g., surface water, sediments, and biota) for which more robust methods have been developed that allow detection of multiple groups. This study reveals an analytical method of one-step solid phase extraction, incorporated together with liquid chromatography-tandem mass spectrometry for the quantification of multiclass EDCs (i.e., pharmaceuticals, hormones, plasticizers, and pesticides) in drinking water. Fifteen multiclass EDCs significantly varied in amount between field samples (p < 0.05), with a maximum concentration of 17.63 ng/L observed. Daily exposure via drinking water is unlikely to pose a health risk (risk quotient < 1). This method serves as an analytical protocol for tracing multiclass EDC contamination in tap water as part of a multibarrier approach to ensure safe drinking water for good health and well-being. It represents a simpler one-step alternative tool for drinking water analysis, thereby avoiding the time-consuming and expensive multiextraction steps that are generally needed for analyzing multiclass EDCs

Liquid Chromatographic Tandem Mass Spectrometric (LC-MS/MS) Determination of Perfluorooctane Sulfonate (PFOS) and Perfluorooctanoic Acid (PFOA) in the Yolk of Poultry Eggs in Malaysia

Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are widely used in products, and are known for their water and grease repellent properties. The persistence nature and potential toxicity of these substances have raised substantial concerns about health effects. Regarding humans, food consumption has reportedly been a significant source of exposure for both compounds. Hence, this study was performed to develop and validate an analytical method for PFOS and PFOA in egg yolks using liquid chromatographic tandem mass spectrometry (LC-MS/MS) followed by the determination of concentration of both compounds in the yolk of poultry eggs in Malaysia. A total of 47 poultry egg yolk samples were extracted by a simple protein precipitation technique using acetonitrile. The analytical method was developed using LC-MS/MS and validated based on the Food and Drug Administration (FDA)&rsquo;s Bioanalytical Method Validation guidelines. The results revealed that PFOS was quantitatively detected in six samples, with the concentration range between 0.5 and 1.01 ng g&minus;1. Among these, five samples were from home-produced chicken eggs, and one sample was from a quail egg. The levels of PFOA in all samples were below the quantifiable limit (&lt;0.1 ng g&minus;1). This indicated that the contamination of PFCs in poultry eggs were mostly attributed to the nature of free foraging animals, which had direct contact with the contaminants in soil and feed. In conclusion, a fast and robust analytical method for analyzing PFOS and PFOA in egg yolk samples using LC-MS/MS was successfully developed and validated. The presence of these emerging contaminants in this study signified widespread pollution in the environment

In vitro and in vivo evaluation of a novel testosterone transdermal delivery system (TTDS) using palm oil base

Objective (s): Transdermal preparations for testosterone are becoming popular because of their unique advantages such as avoidance of first-pass effect, convenience, improved bioavailability, and reduction of systemic side effects. A novel testosterone transdermal delivery system (TDDS) was developed using a palm oil base called HAMINTM (a commercial product) and tested using in vitro and in vivo skin permeability test methods. Materials and Methods: The physical characteristics of the formulation such as particle size and viscosity were determined by using Franz diffusion cell and Brookfield viscometer, respectively. In vivo skin permeability test was performed on healthy rabbits through the skin. Testosterone in serum was analyzed using the validated Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) technique. Results:  In vitro study showed that the cumulative amount of testosterone diffused was between 40 to 1400 ngcm-² over a period of five hr after application of TDDS through the artificial Strat-M™ membrane. In the in vivo rabbit skin permeability test, the results indicated that testosterone was well absorbed with a mean Cmax and Tmax of 60.94 ngml-1 and 2.29 hr after application of TDDS while no increase was observed in placebo treatment. Particle size analysis ranged from 79.4 nm to 630.0 nm for placebo and 97 to 774.0 nm for TDDS. Conclusion: The formulation was successfully prepared using HAMINTM, which has demonstrated great potential for topical delivery of testosterone

Trace Level Detection of Bisphenol A Analogues and Parabens by LC-MS/MS in Human Plasma from Malaysians

In this study, a novel LC-MS/MS method was designed using a simple extraction procedure that was scientifically developed to capture the most relevant bisphenol A (BPA) analogues (BPB, BPF, BPS, and BPAF) and parabens (propylparaben, ethylparaben, butylparaben, and methylparaben) in human plasma. The LC-MS/MS method was validated using US FDA guidelines, and all validation requirements were satisfactory. This is the method that allows for the detection of plasma bisphenols and parabens in one run and is also the fastest BPA analogue and paraben detection technique for human plasma. The method was used to analyze samples from 150 healthy volunteers from Malaysia who enrolled in the study. No BPB was detected in any of the volunteers; however, 99.3% were positive for BPF. Only 24% and 10.7% of volunteers were positive for BPAF and BPS, respectively. A high percentage of volunteers were negative for propylparaben, ethylparaben, butylparaben, and methylparaben (56%, 68%, 86.7%, and 83.3%, respectively). These results suggest that persons in Malaysia are exposed to different BPA analogues and parabens, from both the daily use of products (cosmetic and plastic products) and the environment. © 2020 Idha Arfianti Wiraagni et al

Validation of a simple extraction procedure for bisphenol A identification from human plasma

The general population is exposed to bisphenol A (BPA) orally, parenterally, transdermally, and environmentally as a result of the use of BPA in food packaging, plastics, and personal care products. The majority of the population nowadays (91–99%) has detectable levels of BPA inside their body. In this study, we successfully performed an inexpensive, rapid, and simple protein precipitation procedure for extraction of BPA from human plasma, followed by analysis by LC-MS/MS. This method was specifically developed for handling large numbers of samples with minimum cost and volume of sample. The developed method was accurate, precise, and reproducible for quantification of BPA from human plasma samples in the concentration range of 10–2000 ng/mL. The method was performed on samples from 150 healthy volunteers who were enrolled in the study. The mean of observed BPA level was 2.22 ± 9.91 ng/mL. Higher BPA levels were observed for females compare to that of males (p-value = 0.002), the BPA levels were higher in participants 33 years of age and older compared to those less than 33 years of age (p-value = 0.000), then the BPA levels higher in subjects with tap water as source of drinking (p-value = 0.005). This method may be valuable for general risk assessment of BPA for a large and varied population because of its efficiency and economical aspects. © 2019 Wiraagni et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Active pharmaceutical ingredients in Malaysian drinking water: consumption, exposure, and human health risk

Active pharmaceutical ingredients (APIs) are typical endocrine disruptors found in common pharmaceuticals and personal care products, which are frequently detected in aquatic environments, especially surface water treated for drinking. However, current treatment technologies are inefficient for removing emerging endocrine disruptors, leading to the potential contamination of tap water. This study employed an optimized analytical method comprising solid-phase extraction and liquid chromatography-tandem mass spectrometry (SPE-LC-MS/MS) to detect APIs in tap water in Putrajaya, Malaysia. Several therapeutic classes of pharmaceuticals and personal care products, including anti-inflammatory drugs (dexamethasone and diclofenac), antibiotics (sulfamethoxazole and triclosan), antiepileptics (primidone), antibacterial agents (ciprofloxacin), beta-blockers (propranolol), psychoactive stimulants (caffeine), and antiparasitic drugs (diazinon), were detected in the range of < 0.03 to 21.39 ng/L, whereas chloramphenicol (an antibiotic) was below the detection limit (< 0.23 ng/L). A comparison with global data revealed the spatial variability of emerging tap water pollutants. Diclofenac accounted for the highest concentration (21.39 ng/L), followed by triclosan and ciprofloxacin (9.74 ng/L and 8.69 ng/L, respectively). Caffeine was observed in all field samples with the highest distribution at 35.32%. Caffeine and triclosan exhibited significantly different distributions in household tap water (p < 0.05). Humans are exposed to these APIs by drinking the tap water; however, the estimated risk was negligible (risk quotient < 1). APIs are useful water quality monitoring indicators for water resource conservation and water supply safety related to emerging organic contaminants; thus, API detection is important for safeguarding the environment and human health

Occurrence of endocrine disrupting compounds in mariculture sediment of Pulau Kukup, Johor, Malaysia

Endocrine-disrupting compounds (EDCs) such as hormones, pesticides, phenolic compounds, and pharmaceuticals compounds can cause adverse effects on humans, animals, and other living organisms. One of the largest mariculture areas situated in Pulau Kukup, Johor, Malaysia, is actively involved in exporting marine fish to other countries worldwide. This paper aims to provide baseline data on the level of EDC pollutants found in mariculture sediments in Malaysia since no reports have investigated this issue. Calculated samples recovered are between 50.39 and 129.10% at 100 ng/g spiking level. The highest concentration in the sediment samples was bisphenol A (0.072–0.389 ng/g dry weight) followed by diethylstilbestrol (<0.208–0.331 ng/g dry weight) and propranolol (<0.250–0.275 ng/g dry weight). Even though the concentrations of the targeted compounds obtained were low, their effects could become more evident longer term, which raises not only environmental health concerns but the potential risk to humans

Quantitative LC/MS/MS analysis of acetaminophen–cysteine adducts (APAP–CYS) and its application in acetaminophen overdose patients

A more sensitive approach by liquid chromatography–tandem mass spectrometry (LC/MS/MS) method using the AB Sciex QTRAP 5500 was developed and validated for the detection and quantification of acetaminophen–cysteine adducts (APAP–CYS) in human plasma. Chromatographic separation was achieved using a Protecol P C18 column (2.1 mm i.d. × 100 mm, 3 microns). The mobile phase consists of A: 2 mM ammonium formate in water (0.2% formic acid) and B: 2 mM ammonium formate in acetonitrile (0.2% formic acid). The analysis was performed using positive and negative ion electrospray ionization (ESI) in multiple reaction monitoring mode (MRM) with a total run time of 7 min per assay. The MS/MS ion transitions monitored were m/z 271 → 140 for APAP–CYS (positive mode) and m/z 154 → 111 for acetaminophen-D4 (negative mode). The newly developed method showed good linearity in the range of 1.0 to 100 ng mL−1. Inter and intra batch precision and accuracy of the method ranged from 0.28 to 5.30% and 87.0 to 113% respectively. LOD was 0.5 ng mL−1 and LLOQ was 1.0 ng mL−1. Analytes were extracted from plasma samples by simple protein precipitation using acetonitrile. The method was successfully applied in a preliminary clinical study to determine APAP–CYS concentration from 46 acetaminophen overdose patients treated at outpatient clinic in the University Malaya Medical Centre