Shoichi Kunikane

National Institute of Public Health, Saitama, Saitama, Japan

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Publications (28)68.4 Total impact

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    ABSTRACT: The present study was performed to determine the occurrence of 64 pharmaceuticals and metabolites in source water and finished water at 6 drinking water purification plants and 2 industrial water purification plants across Japan. The analytical methods employed were sample concentration using solid-phase extraction cartridges and instrumental analysis by liquid chromatography with tandem mass spectrometry (LC-MS/MS), liquid chromatography with mass spectrometry (LC/MS), or trimethylsilyl derivatization followed by gas chromatography with mass spectrometry (GC/MS). Thirty-seven of the 64 target substances were detected in the source water samples. The maximum concentrations in the source water were mostly below 50 ng/L except for 13 substances. In particular, residual concentrations of iopamidol (contrast agent) exceeded 1000 ng/L at most facilities. Most of the residual pharmaceuticals and metabolites in the source water samples were removed in the course of conventional and/or advanced drinking water treatments, except for 7 pharmaceuticals and 1 metabolite, i.e., amantadine, carbamazepine, diclofenac, epinastine, fenofibrate, ibuprofen, iopamidol, and oseltamivir acid. The removal ratios of the advanced water treatment processes including ozonation and granular activated carbon filtration were typically much higher than those of the conventional treatment processes. The margins of exposure estimated by the ratio of daily minimum therapeutic dose to daily intake via drinking water were substantial, and therefore the pharmacological and physiological impacts of ingesting those residual substances via drinking water would be negligible. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Water Research 06/2015; 76. DOI:10.1016/j.watres.2015.02.059 · 5.53 Impact Factor
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    ABSTRACT: Currently, most developing countries have not set up municipal solid waste management systems with a view of recovering energy from waste or reducing greenhouse gas emissions. In this article, we have studied the possible effects of introducing three energy recovery processes either as a single or combination approach, refuse derived fuel production, incineration and waste power generation, and methane gas recovery from landfill and power generation in Ulaanbaatar, Mongolia, as a case study. We concluded that incineration process is the most suitable as first introduction of energy recovery. To operate it efficiently, 3Rs strategies need to be promoted. And then, RDF production which is made of waste papers and plastics in high level of sorting may be considered as the second step of energy recovery. However, safety control and marketability of RDF will be required at that moment.
    Journal of Environmental Sciences 12/2014; 28. DOI:10.1016/j.jes.2014.08.018 · 2.00 Impact Factor
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    ABSTRACT: The impact of climate change on the seasonality of water resources in the Upper Ca River Watershed in mainland Southeast Asia was assessed using downscaled global climate models coupled with the SWAT model. The results indicated that temperature and evapotranspiration will increase in all months of future years. The area could warm as much as 3.4(°)C in the 2090s, with an increase of annual evapotranspiration of up to 23% in the same period. We found an increase in the seasonality of precipitation (both an increase in the wet season and a decrease in the dry season). The greatest monthly increase of up to 29% and the greatest monthly decrease of up to 30% are expected in the 2090s. As a result, decreases in dry season discharge and increases in wet season discharge are expected, with a span of ±25% for the highest monthly changes in the 2090s. This is expected to exacerbate the problem of seasonally uneven distribution of water resources: a large volume of water in the wet season and a scarcity of water in the dry season, a pattern that indicates the possibility of more frequent floods in the wet season and droughts in the dry season.
    08/2014; 2014:279135. DOI:10.1155/2014/279135

  • Journal of Water and Environment Technology 01/2014; 12(3):275-283. DOI:10.2965/jwet.2014.275
  • Pham Quy Giang · Kosuke Toshiki · Shoichi Kunikane · Masahiro Sakata ·
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    ABSTRACT: The present study investigates the hypothesis that arsenic concentrations correlate with tubewell depth, and examines the effectiveness of spline interpolation, specifically completely regularized spline (CRS) and spline with tension (SWT) in estimating the magnitude of arsenic contamination in groundwater in Thanh Tri, a densely populated district located in the southern part of Hanoi City, Vietnam. Groundwater sampling conducted in 72 tubewells drilled into shallow aquifers yielded an average arsenic concentration of 82 mu g/L with a maximum of 395 mu g/L, far higher than the World Health Organization (WHO) guideline value of 10 mu g/L. The average concentration in the lower Pleistocene aquifer was 86 mu g/L, slightly higher compared with the average of 78 mu g/L in the upper Holocene aquifer. Interestingly, regression analysis revealed that in the Holocene aquifer, depth of wells influenced arsenic concentrations significantly. Such an influence, however, was insignificant in the lower Pleistocene aquifer. Both the CRS and SWT spatial interpolation models resulted in plausible predictions for the arsenic concentration data. The problem of arsenic contamination in the study area should be considered seriously, as 99% of the area was estimated to be affected by arsenic levels exceeding the WHO guideline value.
    Aqua 09/2013; 62(6):385. DOI:10.2166/aqua.2013.102 · 0.84 Impact Factor
  • K. Kosaka · M. Asami · S. Kunikane ·

    Reference Module in Earth Systems and Environmental Sciences, 01/2013; , ISBN: 9780124095489
  • Shoichi Kunikane · Kosuke Toshiki · Phung Hoang Van · Nguyen Thi Thu Trang ·
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    ABSTRACT: Using government records, data from hazardous waste treatment companies, and on-site surveys, we evaluated the effectiveness of the current industrial solid waste management system in Ho Chi Minh City (HCMC), which was established according to the revised Law on Environmental Protection of 2005 and related regulations. In addition, we examined the relationship between the management system and environmental compliance by companies. Attention was paid to the classification of industrial solid waste, its amount finally disposed, and the cost of its disposal in HCMC. The results showed: one, the incoherence of the revised law and regulations in solid waste management caused serious pressure on landfills, and two, the implementation of the regulations has been neglected at all aspects of the current management system due to low levels of companies' registration and reporting, as well as low levels of compliance among companies in industrial zones. A solution for dealing with the current problems is proposed.
    International Journal of Environment and Pollution 01/2012; 49(3/4):210 - 225. DOI:10.1504/IJEP.2012.050896 · 0.43 Impact Factor
  • Shigezo Shukuya · Kosuke Toshiki · Shoichi Kunikane ·

    01/2012; 41(9):563-568. DOI:10.5956/jriet.41.563
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    ABSTRACT: The thyroid hormone agonist/antagonist activities of halogenated derivatives of bisphenol A (BPA) were assessed using a yeast two-hybrid assay incorporating the human thyroid hormone α (TRα), both with and without possible metabolic activation by rat liver S9 preparation. In the absence of the rat liver S9 preparation, 3,3',5,5'-tetrabromobisphenol A (TBBPA), 3,3',5,5'-tetrachlorobisphenol A (TCBPA), and 3,3',5-trichlorobisphenol A (3,3',5-triClBPA) exhibited agonist activity, whereas 3-chlorobisphenol A (3-ClBPA), 3,5-dichlorobisphenol A (3,5-diClBPA), 3,3'-dichlorobisphenol A (3,3'-diClBPA), and BPA did not. The activities of TBBPA and TCBPA increased markedly (7.6-fold and 3.1-fold, respectively) after their metabolic activation with the rat liver S9 preparation. TBBPA, TCBPA, and 3,3',5-triClBPA inhibited the binding of triiodothyronine (T3) to TRα at 2×10(-5) M without rat liver S9 treatment and 4×10(-6) M with rat liver S9 treatment, demonstrating their T3 antagonist activity. These results revealed that metabolic activation by rat liver S9 significantly increased the agonist/antagonist potential of some halogenated BPAs.
    Chemosphere 05/2011; 84(10):1527-30. DOI:10.1016/j.chemosphere.2011.04.045 · 3.34 Impact Factor
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    Koji Kosaka · Hiroyuki Koshino · Nobue Yoshida · Shoichi Kunikane ·
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    ABSTRACT: The behaviour of pyrene and its decomposition by-products in chlorination and their aryl hydrocarbon receptor (AhR) ligand activities were investigated. In the study on pyrene behaviour in chlorination, the pyrene and chlorine concentrations and the pH range were 0.82-21 mu gl(-1), 2.0-2.1mgl(-1) and 3.2-10, respectively. In the pH range of 3.2-5.1, pyrene was decomposed faster in the order of pH 3.2, 3.7 and 5.1. However, when the pH ranged from 5.1 to 10, pyrene was decomposed faster in a pH range of approximately 7.8-8.8. When the effects of the initial pyrene concentration were investigated, a lower pyrene concentration was decomposed faster. Pyrene decomposition in chlorination was inhibited by the presence of 30mM ethanol, but was enhanced by the presence of 3.0 and 6.0mgCl(-1) humic acid. Pyrene decomposition by-products in chlorination were also characterized (pyrene, 92 mu gl(-1); chlorine, 7.9mgl(-1); pH, 7.1). 1-Chloropyrene, 1,6- and 1,8-dichloropyrenes, and pyrene-4,5-dione were identified as pyrene decomposition by-products. 1-Chloropyrene and pyrene-4,5-dione in chlorination were found to be major by-products at pH 3.2, but minor by-products at pH 7.1 (pyrene, 56-67 mu gl(-1); chlorine, 3.9-4.0mgl(-1)). The yeast assay revealed that pyrene-4,5-dione was an AhR agonist.
    Aqua 02/2010; 59(1). DOI:10.2166/aqua.2010.083 · 0.84 Impact Factor
  • Koji Kosaka · Mari Asami · Yusuke Konno · Masami Oya · Shoichi Kunikane ·
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    ABSTRACT: In Japan, N-nitrosodimethylamine (NDMA) formation associated with ozonation at a relatively high concentration has been reported only at a small number of water treatment plants (WTPs) in the western part of Japan for which the source water is the Yodo River. In the present study, the formation of relatively high concentrations of NDMA was found upon ozonation of water samples taken from sewage treatment plants (STPs) located upstream of the water intake points of the WTPs in the Yodo River basin. NDMA concentrations before and after ozonation were 16-290 and 14-280 ng/L, respectively. At least some of the STPs investigated receive industrial effluents. At one STP in this area, an extremely high concentration of NDMA (10,000ng/L) was found in one influent water sample after ozonation. To identify potential NDMA precursors upon ozonation in the influent at this STP, the concentrated extracts of the influent were fractionated by high-performance liquid chromatography (HPLC). Ultraperformance liquid chromatography coupled with tandem mass spectrometry (UPLC/MS/MS) identified 4,4'-hexamethylenebis(1,1-dimethylsemicarbazide) (HDMS) and 1,1,1',1'-tetramethyl-4,4'-(methylene-di-p-phenylene)disemicarbazide (TMDS) as precursors of NDMA on ozonation of the influent. Both HDMS and TMDS are used as antiyellowing agents in polyurethane fibers and as light stabilizers in polyamide resins. Their contributions to NDMA production on ozonation of water samples at STPs were up to 17%. The remaining unidentified NDMA precursors may be hydrophilic compounds that were not trapped by the cartridges used for extraction of the water samples. HDMS and TMDS were frequently present in surface waters and STP effluents in the Yodo River basin and were also detected in surface waters from several other areas in Japan.
    Environmental Science and Technology 08/2009; 43(14):5236-41. DOI:10.1021/es900227g · 5.33 Impact Factor
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    ABSTRACT: Genotyping of F-specific RNA phages is currently one of the most promising approaches to differentiate between human and animal fecal contamination in aquatic environments. In this study, a total of 18 river water and sediment samples were collected from the Tonegawa River basin, Japan, in order to describe the genogroup distribution of F-specific RNA and DNA phages using genogroup-specific real-time PCR assays. F-specific phages were detected in nine (100%) river water and six (67%) sediment samples. Eighty-five phage plaques were isolated from these samples and subjected to real-time PCR assays specific for the phages. F-specific RNA phages of human genogroups (II and III) were detected in 32 (38%) plaques, whereas those of animal genogroups (I and IV) were detected in 17 (20%) plaques. No correlation was observed between the genogroup distribution of F-specific RNA phages and the occurrence of human adenovirus genomes, suggesting that genotyping of the phages alone is inadequate for the evaluation of the occurrence of viruses in aquatic environments. SYBR Green-based real-time PCR assay revealed the presence of F-specific DNA phages in four (5%) plaques, which were further classified into two genogroups (fd- and f1-like phages) by sequence analysis. Thirty-two (38%) plaques were not classified as the F-specific phage genogroups, indicating the limited applicability of these real-time PCR assays to a wide range of aquatic environmental samples worldwide.
    Water Research 07/2009; 43(15):3759-64. DOI:10.1016/j.watres.2009.05.043 · 5.53 Impact Factor
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    Ai Jia · Yang Xiao · Jianying Hu · Mari Asami · Shoichi Kunikane ·
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    ABSTRACT: A sensitive method was developed for the trace determination of six tetracyclines and ten of their degradation products in influent, effluent, and river waters using liquid chromatography-electrospray tandem mass spectrometry detection, combined with Oasis hydrophilic-lipophilic balance (HLB) cartridge extraction and Oasis mixed-mode strong anion exchange (MAX) cartridge cleanup. Tetracyclines and their products were separated by liquid chromatography in 9.5min, and the instrument detection limits were generally between 0.03 and 0.1microg/L except for minocycline (0.5microg/L). The chromatograms were improved through the MAX cleanup and no apparent matrix effect was found. The recoveries of all the target compounds except for 4-epianhydrochlortetracycline and anhydrochlortetracycline (34-52%) were 75-120% for influent, 61-103% for effluent, and 64-113% for river waters. The method detection limits (MDLs) of the analytes varied in the range of 0.8-17.5ng/L in all studied matrices. The method was applied for the determination of tetracyclines and their products in a sewage treatment plant (STP) and surface waters in Beijing, China. Oxytetracycline (3.8-72.5ng/L), tetracycline (1.9-16.5ng/L), and five products including 4-epitetracycline, 4-epioxytetracycline, isochlortetracycline, anhydrotetracycline, and 4-epianhydrochlortetracycline (5.7-25.3ng/L) were detected in wastewater, while only oxytetracycline and tetracycline (2.2 and 2.1ng/L) were detected in surface water samples.
    Journal of Chromatography A 05/2009; 1216(22):4655-62. DOI:10.1016/j.chroma.2009.03.073 · 4.17 Impact Factor
  • Mari Asami · Koji Kosaka · Shoichi Kunikane ·
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    ABSTRACT: A survey was conducted to reveal the concentrations of bromate, chlorite, chlorate and perchlorate as impurities in sodium hypochlorite solutions and those of chlorate and perchlorate in raw and processed waters including a metropolitan area. High concentrations of bromate (max. 414 mg l(-1)) and chlorate (max. 260,000 mg l(-1)) were found in purchased sodium hypochlorite solutions for drinking water disinfection that had been stored for a long time, more than two years at a maximum. In the survey of chlorate and perchlorate in raw and processed waters in the Tone River Basin, the highest concentration of chlorate in raw water was 78 mu g l(-1) and that of perchlorate was 40 mu g l(-1). Chlorate and perchlorate concentrations in 32 purchased sodium hypochlorite solutions and six on-site-generated hypochlorite solutions were also analysed. In the purchased sodium hypochlorite solutions, perchlorate concentrations ranged from 0.170 to 33.0 mg l(-1). In hypochlorite solutions whose measured FAC (free available chlorine) concentration was lower than the manufacturer-specified FAC concentrations, the chlorate and perchlorate concentrations were higher than those in relatively fresh sodium hypochlorite solutions. In on-site-generated hypochlorite solutions, the maximum concentrations of chlorate and perchlorate were 1,700 mg l(-1) (140 mg g(-1) of measured FAC) and 0.660 mg l(-1) (0.053 mg g(-1) of measured FAC), respectively.
    Aqua 03/2009; 58(2). DOI:10.2166/aqua.2009.014 · 0.84 Impact Factor
  • Masami Oya · Koji Kosaka · Mari Asami · Shoichi Kunikane ·
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    ABSTRACT: Formation of N-nitrosodimethylamine (NDMA) by ozonation of commercially available dyes and related compounds was investigated. Ozonation was conducted using a semi-batch type reactor, and ozone concentration in gas phase and the ozone gas flow were 10 mg L(-1) and 1.0 L min(-1), respectively. NDMA was formed by 15 min of ozonation of seven out of eight selected target compounds (0.05 mM) at pH 7. All the target compounds with N,N-dimethylamino functions were NDMA precursors in ozonation. The lowest and highest NDMA concentrations after ozonation of the target compounds were 13 ng L(-1) for N,N-dimethylformamide (DMF) and 1600 ng L(-1) for N,N-dimethyl-p-phenylenediamine (DMPD), respectively. NDMA concentrations after 15 min of ozonation of 0.05 mM methylene blue (MB) and DMPD increased with an increase in pH in its range of 6-8. The effects of coexisting compounds on NDMA concentrations after 15 min of ozonation of 0.05 mM MB and DMPD were examined at pH 7. NDMA concentrations after ozonation of MB and DMPD increased by the presence of 0.05 mM (0.7 mg L(-1) as N) nitrite (NO(2)(-)); 5000 ng L(-1) for MB and 4000 ng L(-1) for DMPD. NDMA concentration after MB ozonation decreased by the presence of 5mM tertiary butyl alcohol (TBA), a hydroxyl radical (HO.) scavenger, but that after DMPD ozonation was increased by the presence of TBA. NDMA concentrations after ozonation of MB and DMPD were not affected by the presence of 0.16 mM (5.3 mg L(-1)) hydrogen peroxide (H(2)O(2)). When 0.05 mM MB and DMPD were added to the Yodo and Tone river water samples, NDMA concentrations after 15 min of their ozonation at pH 7 increased compared with those in the case of addition to ultrapure water samples.
    Chemosphere 11/2008; 73(11):1724-30. DOI:10.1016/j.chemosphere.2008.09.026 · 3.34 Impact Factor
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    Hong Chang · Shimin Wu · Jianying Hu · Mari Asami · Shoichi Kunikane ·
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    ABSTRACT: A sensitive ultra-performance liquid chromatography-electrospray tandem mass spectrometry method, combined with solid-phase extraction and silica cartridge cleanup, was established for nine androgens (androstenedione, 19-nor-4-androstene-3,17-diol, androsterone, epiandrosterone, testosterone, methyltestosterone, trenbolone, nandrolone, stanozolol) and nine progestogens (progesterone, 17alpha-hydroxyprogesterone, 21alpha-hydroxyprogesterone, 6alpha-methyl-hydroxyprogesterone, 17alpha,20beta-dihydroxy-4-pregnene-3-one, megestrol acetate, norethindrone, norgestrel, medroxyprogesterone acetate) in environmental waters. For the various water matrices considered, the overall method recoveries were from 78 to 100%, and no apparent signal suppression was found. The method detection limits for the eighteen analytes in the influent, effluent and surface water samples were 0.20-50, 0.04-20 and 0.01-12 ng/L, respectively. This method was used to analyze the residual androgens and progestogens in the wastewater and surface water samples from Japan, and ten analytes (0.03 (medroxyprogesterone acetate)-1441 ng/L (androsterone)) were detected in the wastewater samples, and four analytes (0.06 (progesterone)-0.46 ng/L (androstenedione)) were detected in the surface water samples.
    Journal of Chromatography A 07/2008; 1195(1-2):44-51. DOI:10.1016/j.chroma.2008.04.055 · 4.17 Impact Factor
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    Hong Chang · Jianying Hu · Mari Asami · Shoichi Kunikane ·
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    ABSTRACT: A sensitive liquid chromatography-electrospray tandem mass spectrometry method combined with solid-phase extraction and silica cartridge cleanup was established for 16 sulfonamides and trimethoprim in various water matrices. Signal suppression of all target analytes in sewage treatment plant influent, effluent and river water was improved by this method developed in this study. The method detection limits for 17 analytes were 20-200 pg/L for influent, 16-120 pg/L for effluent and 8.0-60 pg/L for river water with overall mean recoveries of 62-102% in all studied matrices. This method was used to analyze residual sulfonamides and trimethoprim in wastewater and river samples from Japan, and 8 analytes (0.08 (sulfadimethoxine)-161 ng/L (sulfapyridine) in wastewater and 10 (0.03 (sulfamethizol)-8.9 ng/L (sulfaquinoxaline) in river samples were detected.
    Journal of Chromatography A 06/2008; 1190(1-2):390-3. DOI:10.1016/j.chroma.2008.03.057 · 4.17 Impact Factor
  • D Simazaki · J Fujiwara · S Manabe · M Matsuda · M Asami · S Kunikane ·
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    ABSTRACT: Removal property of nine pharmaceuticals (clofibric acid, diclofenac, fenoprofen, gemfibrozil, ibuprofen, indomethacin, ketoprofen, naproxen and propyphenazone) by chlorination, coagulation-sedimentation and powdered activated carbon treatment was examined by laboratory-scale experiments under the conditions close to actual drinking water treatment processes. Indomethacin and propyphenazone were completely degraded by chlorination within 30 minutes, but others remained around 30% (naproxen and diclofenac) or more than 80% of the initial concentration after 24 hours. A couple of unidentified peaks in a chromatogram of the chlorinated samples suggested the formation of unknown chlorination by-products. Competitive adsorption was observed when the mixed solution of the target pharmaceuticals was subjected to batch adsorption test with powdered activated carbon. Clofibric acid and ibuprofen, which were relatively less hydrophobic among the nine compounds, persisted around 60% of the initial concentration after 3 hours of contact time. Removal performance in actual drinking water treatment would become lower due to existence of other competitive substances in raw water (e.g. natural organic matter). Coagulation-sedimentation using polyaluminium chloride hardly removed most of the pharmaceuticals even under its optimal dose for turbidity removal. It is suggested that the most part of pharmaceuticals in raw water might persist in the course of conventional drinking water treatments.
    Water Science & Technology 02/2008; 58(5):1129-35. DOI:10.2166/wst.2008.472 · 1.11 Impact Factor
  • Koji Kosaka · Mari Asami · Yukiko Matsuoka · Masahiro Kamoshita · Shoichi Kunikane ·
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    ABSTRACT: The occurrence of perchlorate in the Tone River Basin was investigated using an ion chromatograph (IC) coupled with a tandem mass spectrometer (MS/MS). Perchlorate was found at high concentrations in the upper Tone River and its tributary, Usui River, and the maximum concentrations were 340 and 2300 microg/L, respectively. The possible sources of perchlorate in two areas were attributable to industrial effluents. In case of the upper Tone River, perchlorate concentration in an effluent was 1100 microg/L and its concentrations in a tributary (or waterway) directly downstream of the outlet of the effluent ranged from 44 to 1500 microg/L. In case of the Usui River, perchlorate concentration in another effluent was 15,000 microg/L and its concentrations downstream of the outlet of the effluent were 1100-3900 microg/L. Due to the discharge of perchlorate in the upper Tone River Basin, perchlorate concentrations in the river waters of the middle and lower Tone River Basin were generally 10-20 microg/L. Perchlorate concentrations in 30 tap water samples were investigated. Water sources of three tap water samples were other than the Tone River Basin and their perchlorate concentrations were 0.16-0.87 microg/L. On the other hand, water sources of the remaining 27 samples were the upper, middle and lower Tone River Basin and their perchlorate concentrations were 0.06-37 microg/L. Perchlorate concentrations were more than 1 microg/L in 19 tap water samples and more than 10 microg/L in 13 samples. It was shown that tap waters in the Tone River Basin were widely contaminated with perchlorate. To our knowledge, this study was the first to report on perchlorate contamination of environmental and drinking waters in Japan.
    Water Research 09/2007; 41(15):3474-82. DOI:10.1016/j.watres.2007.05.011 · 5.53 Impact Factor
  • I Kasuga · D Shimazaki · S Kunikane ·
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    ABSTRACT: The influence of backwashing on the biofilm community developed on biological activated carbon (BAC) used in a drinking water treatment plant was investigated by means of bacterial cell enumeration and terminal-restriction fragment length polymorphism (T-RFLP) fingerprinting analysis of bacterial and eukaryotic ribosomal RNA genes (rDNA). After backwashing, the attached bacterial abundance in the top layer of the BAC bed decreased to 64% of that before backwashing. The community level changes caused by backwashing were examined through the T-RFLP profiles. In the bacterial 16S rDNA analysis, the relative abundances of some terminal-restriction fragments (T-RFs) including the Planctomycetes-derived fragment increased; however, the relative abundances of some T-RFs including the Betaproteobacteria-derived fragments decreased. In the eukaryotic 18S rDNA analysis, the relative abundances of some T-RFs including the protozoan Cercozoa-derived fragments increased; however, the relative abundances of some T-RFs including the metazoan Chaetonotus- and Paratripyla-derived fragments decreased. The T-RFLP analysis suggests that backwashing can cause changes in the relative compositions of microorganisms in a BAC biofilm in the top layer of the bed.
    Water Science & Technology 02/2007; 55(8-9):173-80. DOI:10.2166/wst.2007.256 · 1.11 Impact Factor