12 research outputs found
Identification and Fate of Bioactive Transformation Products of Pharmaceuticals and Industrial Antioxidants
Thesis (Ph.D.)--University of Washington, 2021Human society discharges complex chemical mixtures into the aquatic environment that cause various adverse effects to aquatic organisms and humans. Upon discharge, organic chemicals typically form multiple transformation products (TPs) during abiotic and biotic environmental transformations. While many TPs are likely benign and unable to interact with biological pathways, some TPs can contribute significantly to the environmental risks of complex mixtures. There is a pressing need to identify stable and/or toxic TPs, to study their environmental fate and transport, and to evaluate the potential for TP toxicity in comprehensive risk assessments of environmental contaminants. In this thesis, we focused on the environmental transformations of two classes of organic contaminants: steroid hormone pharmaceuticals and industrial antiozonants used in tire rubbers. Specifically, project analytes include the photoproducts of trenbolone (TBOH) and altrenogest (ALT), compounds that occur in agricultural environments, and two synthetic progestins, dienogest (DIE) and drospirenone (DRO), that are contaminants of municipal wastewaters. These analytes represented novel steroid hormone pharmaceuticals that are potent and used widely but are less well characterized in the scientific literature. In addition, we focused on understanding the fate and transformation of 6PPD (N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine) and its structural analogues, which are globally ubiquitous antioxidants used in tire rubber and other consumer products. Our group recently identified 6PPD as a pre-toxicant responsible for the massive coho salmon (Oncorhynchus kisutch) mortality observed in the Pacific Northwest. For the above analytes, laboratory experiments were used to simulate environmentally relevant abiotic (e.g., photolysis, ozonation) and biotic transformation processes to (i) quantitatively analyze known TPs with liquid chromatography-tandem mass spectrometry (LC-MS/MS), (ii) determine the rate and extent of contaminant transformations, (iii) identify unknown TPs with high-resolution mass spectrometry (HRMS) based suspect screening and non-target analysis, and (iv) evaluate TPs bioactivity and environmental occurrence.
Chapter 2 discussed a novel and sensitive analytical method for the detection and quantification of metastable TBOH and ALT photoproducts in agricultural receiving waters. The developed method employed solid phase extraction and LC-MS/MS analysis. Because commercial analytical standards are not available, reference standards for photoproducts were generated from TBOH or ALT with a solar simulator. With cold and pH neutral conditions, rapid sample processing, minimal extract storage, and reduction of cationic artifacts, we achieved efficient detection of the metastable photoproducts with method detection limits at the low ng/L ranges. The analytical method was then employed to evaluate the sorption of the steroid photoproducts in batch soil-water systems. We showed that the photoproducts exhibited reduced sorption affinity (logKoc of 1.92-2.57) relative to the more hydrophobic parent structures (logKoc of 2.46-2.76). Therefore, traditional runoff management practices in agroecosystems would be expected to exhibit reduced treatment effectiveness when the photoproducts were considered.
Chapter 3 evaluated the biotransformation of ALT and its primary photo-cycloaddition product (ALT-CAP) in agricultural receiving waters and identified the TPs with HRMS. We showed that ALT-CAP (half-life, 1.6 days) demonstrated ~2-fold faster biotransformation than ALT (half-life, 3.5 days). However, the absolute abundance (based on electrospray ionization (ESI) HRMS peak areas) of the major ALT-CAP TPs, including dehydrogenation TPs, hydroxylation TPs, and isomerization TPs, was often an order of magnitude higher than that of ALT TPs. This indicated that biotransformation of ALT seemed to produce less abundant and less stable TPs, while ALT-CAP biotransformation tended to produce larger, and more stable TPs with higher potential for retained steroid structures. Therefore, the exposure risks of ALT are prone to underestimation if the formation and subsequent biotransformation products of ALT-CAP are not considered as part of the environmental fate of these compounds.
In Chapter 4, we investigated the biotransformation of DIE and DRO with representative activated sludge batch incubations and identified relevant TPs using HRMS. We showed that DIE exhibited slow biotransformation (16-30 hr half-life), and proceeded through a quantitative aromatic dehydrogenation (molar yields ~55%) to form an aromatic TP ~30% estrogenic as 17β-estradiol. DRO experienced more rapid biotransformation (<0.5 hr half-life), and 1,2-dehydrogenation formed the major product (molar yields ~40%) as an anti-mineralocorticoid drug candidate named spirorenone. Lactone ring hydrolysis was another important biotransformation pathway for DRO (molar yields ~20%) and generated a pharmacologically inactive TP. Other minor pathways for DIE and DRO included hydroxylation, methoxylation, and 3-keto and C4(5) double bond hydrogenation; distinct bioactivities are plausible for such TPs, including anti-gestagenic activity, anti-gonadotropic activity, and pregnancy inhibition effects. These results demonstrated that biotransformation of DIE and DRO formed bioactive TPs in large quantities during wastewater treatment, which should be considered in future risk assessments of synthetic progestins.
Chapter 5 focused on the identification and environmental fate of tire rubber-derived chemicals acutely toxic to coho salmon. Firstly, this chapter described the contribution of Nina Zhao to a large collaborative research project, led by Dr. Zhenyu Tian (postdoc scientist of our group), to identify the causal toxicant(s) for the coho salmon mortality from aqueous leachates of tire tread wear particles (TWPs). After initial purification of the TWP leachate by Dr. Tian, Zhao and Tian developed orthogonal HPLC fractionation steps that effectively separated the pure toxicant from ~600 chemicals in the purified TWP leachate. Thereafter, the coho toxicant was identified to be a highly toxic quinone TP of 6PPD formed during ozonation (i.e., 6PPD-quinone). This chapter then expanded this reaction pathway to analogue substituted-PPD antioxidants. Furthermore, this chapter explored the ozonation TPs of 6PPD beyond 6PPD-quinone with HRMS screening. Twenty-one potential TPs were identified, with five confirmed through reference standards and eleven with likely or probable structures proposed based on MS/MS spectra and literature information. The major 6PPD TPs were then retrospectively screened in archived sample extracts of TWP, TWP leachate, roadway runoff, and creek stormwater. We revealed widespread presence of 6PPD TPs in these sample matrices (ΣTPs: TWP methanolic extracts, 110 ± 7 µg/g; TWP leachate (0.25 g TWP/L water), 11 ± 2.7 µg/L; roadway runoff, 40 ± 15 µg/L; creek stormwater, 59 ± 20 µg/L).
Overall, the results presented in this thesis confirmed our overall hypothesis that environmental transformations produced TPs that could contribute to residual biological activity in the aquatic environments. These TPs are discharged in large quantities and should be evaluated in future environmental risk assessments of the synthetic steroids and rubber antioxidants. More generally, holistic assessments of the environmental transformation processes are needed for future risk assessment of high potency environmental chemicals, in order to accurately assess the fate and exposure risks of these contaminants of emerging concerns
Ex vivo study of molecular changes of stained teeth following hydrogen peroxide and peroxymonosulfate treatments
Abstract White teeth can give confidence and tend to be associated with a healthier lifestyle in modern society. Therefore, tooth-bleaching strategies have been developed, including the use of hydrogen peroxide. Recently, peroxymonosulfate has been introduced as an alternative bleaching method to hydrogen peroxide. Although both chemicals are oxidizing agents, their effects on the molecular composition of the stained teeth are yet unknown. In this study, the molecular profiles of teeth bleached with hydrogen peroxide and peroxymonosulfate were compared using Liquid Chromatography-Tandem Mass Spectrometry. Statistical analyses were used to assess the samples. In addition, reference spectral libraries and in silico tools were used to perform metabolite annotation. Overall, principal component analysis showed a strong separation between control and hydrogen peroxide and peroxymonosulfate samples (p < 0.001). The analysis of molecular changes revealed amino acids and dipeptides in stained teeth samples after hydrogen peroxide and peroxymonosulfate treatments. Noteworthy, the two bleaching methods led to distinct molecular profiles. For example, diterpenoids were more prevalent after peroxymonosulfate treatment, while a greater abundance of alkaloids was detected after hydrogen peroxide treatment. Whereas non-bleached samples (controls) showed mainly lipids. Therefore, this study shows how two different tooth-whitening peroxides could affect the molecular profiles of human teeth
Enabling pan-repository reanalysis for big data science of public metabolomics data
Public untargeted metabolomics data is a growing resource for metabolite and phenotype discovery; however, accessing and utilizing these data across repositories pose significant challenges. Therefore, we\u27ve developed pan-repository universal identifiers and harmonized cross-repository metadata. This novel ecosystem facilitates discovery by integrating diverse data sources from public repositories including MetaboLights, Metabolomics Workbench, and GNPS/MassIVE. Our approach simplifies data handling and unlocks previously inaccessible reanalysis workflows, fostering unmatched research opportunities
Measuring low energy atmospheric neutrino spectra with the JUNO detector
Atmospheric neutrinos are one of the most relevant natural neutrino sources that can be exploited to infer properties about Cosmic Rays and neutrino oscillations. The Jiangmen Underground Neutrino Observatory (JUNO) experiment, a 20 kton liquid scintillator detector with excellent energy resolution is currently under construction in China. JUNO will be able to detect several atmospheric neutrinos per day given the large volume. A study on the JUNO detection and reconstruction capabilities of atmospheric and fluxes is presented in this paper. In this study, a sample of atmospheric neutrinos Monte Carlo events has been generated, starting from theoretical models, and then processed by the detector simulation. The excellent timing resolution of the 3" PMT light detection system of JUNO detector and the much higher light yield for scintillation over Cherenkov allow to measure the time structure of the scintillation light with very high precision. Since and interactions produce a slightly different light pattern, the different time evolution of light allows to discriminate the flavor of primary neutrinos. A probabilistic unfolding method has been used, in order to infer the primary neutrino energy spectrum from the detector experimental observables. The simulated spectrum has been reconstructed between 100 MeV and 10 GeV, showing a great potential of the detector in the atmospheric low energy region
JUNO Physics and Detector
The Jiangmen Underground Neutrino Observatory (JUNO) is a 20 kton LS detector at 700-m underground. An excellent energy resolution and a large fiducial volume offer exciting opportunities for addressing many important topics in neutrino and astro-particle physics. With 6 years of data, the neutrino mass ordering can be determined at 3-4 sigma and three oscillation parameters can be measured to a precision of 0.6% or better by detecting reactor antineutrinos. With 10 years of data, DSNB could be observed at 3-sigma; a lower limit of the proton lifetime of 8.34e33 years (90% C.L.) can be set by searching for p->nu_bar K^+; detection of solar neutrinos would shed new light on the solar metallicity problem and examine the vacuum-matter transition region. A core-collapse supernova at 10 kpc would lead to ~5000 IBD and ~2000 (300) all-flavor neutrino-proton (electron) scattering events. Geo-neutrinos can be detected with a rate of ~400 events/year. We also summarize the final design of the JUNO detector and the key R&D achievements. All 20-inch PMTs have been tested. The average photon detection efficiency is 28.9% for the 15,000 MCP PMTs and 28.1% for the 5,000 dynode PMTs, higher than the JUNO requirement of 27%. Together with the >20 m attenuation length of LS, we expect a yield of 1345 p.e. per MeV and an effective energy resolution of 3.02%/\sqrt{E (MeV)}$ in simulations. The underwater electronics is designed to have a loss rate <0.5% in 6 years. With degassing membranes and a micro-bubble system, the radon concentration in the 35-kton water pool could be lowered to <10 mBq/m^3. Acrylic panels of radiopurity <0.5 ppt U/Th are produced. The 20-kton LS will be purified onsite. Singles in the fiducial volume can be controlled to ~10 Hz. The JUNO experiment also features a double calorimeter system with 25,600 3-inch PMTs, a LS testing facility OSIRIS, and a near detector TAO
JUNO sensitivity to low energy atmospheric neutrino spectra
Atmospheric neutrinos are one of the most relevant natural neutrino sources that can be exploited to infer properties about cosmic rays and neutrino oscillations. The Jiangmen Underground Neutrino Observatory (JUNO) experiment, a 20 kton liquid scintillator detector with excellent energy resolution is currently under construction in China. JUNO will be able to detect several atmospheric neutrinos per day given the large volume. A study on the JUNO detection and reconstruction capabilities of atmospheric and fluxes is presented in this paper. In this study, a sample of atmospheric neutrino Monte Carlo events has been generated, starting from theoretical models, and then processed by the detector simulation. The excellent timing resolution of the 3'' PMT light detection system of JUNO detector and the much higher light yield for scintillation over Cherenkov allow to measure the time structure of the scintillation light with very high precision. Since and interactions produce a slightly different light pattern, the different time evolution of light allows to discriminate the flavor of primary neutrinos. A probabilistic unfolding method has been used, in order to infer the primary neutrino energy spectrum from the detector experimental observables. The simulated spectrum has been reconstructed between 100 MeV and 10 GeV, showing a great potential of the detector in the atmospheric low energy region
TAO Conceptual Design Report: A Precision Measurement of the Reactor Antineutrino Spectrum with Sub-percent Energy Resolution
The Taishan Antineutrino Observatory (TAO, also known as JUNO-TAO) is a satellite experiment of the Jiangmen Underground Neutrino Observatory (JUNO). A ton-level liquid scintillator detector will be placed at about 30 m from a core of the Taishan Nuclear Power Plant. The reactor antineutrino spectrum will be measured with sub-percent energy resolution, to provide a reference spectrum for future reactor neutrino experiments, and to provide a benchmark measurement to test nuclear databases. A spherical acrylic vessel containing 2.8 ton gadolinium-doped liquid scintillator will be viewed by 10 m^2 Silicon Photomultipliers (SiPMs) of >50% photon detection efficiency with almost full coverage. The photoelectron yield is about 4500 per MeV, an order higher than any existing large-scale liquid scintillator detectors. The detector operates at -50 degree C to lower the dark noise of SiPMs to an acceptable level. The detector will measure about 2000 reactor antineutrinos per day, and is designed to be well shielded from cosmogenic backgrounds and ambient radioactivities to have about 10% background-to-signal ratio. The experiment is expected to start operation in 2022
TAO Conceptual Design Report: A Precision Measurement of the Reactor Antineutrino Spectrum with Sub-percent Energy Resolution
The Taishan Antineutrino Observatory (TAO, also known as JUNO-TAO) is a
satellite experiment of the Jiangmen Underground Neutrino Observatory (JUNO). A
ton-level liquid scintillator detector will be placed at about 30 m from a core
of the Taishan Nuclear Power Plant. The reactor antineutrino spectrum will be
measured with sub-percent energy resolution, to provide a reference spectrum
for future reactor neutrino experiments, and to provide a benchmark measurement
to test nuclear databases. A spherical acrylic vessel containing 2.8 ton
gadolinium-doped liquid scintillator will be viewed by 10 m^2 Silicon
Photomultipliers (SiPMs) of >50% photon detection efficiency with almost full
coverage. The photoelectron yield is about 4500 per MeV, an order higher than
any existing large-scale liquid scintillator detectors. The detector operates
at -50 degree C to lower the dark noise of SiPMs to an acceptable level. The
detector will measure about 2000 reactor antineutrinos per day, and is designed
to be well shielded from cosmogenic backgrounds and ambient radioactivities to
have about 10% background-to-signal ratio. The experiment is expected to start
operation in 2022
Feasibility and physics potential of detecting B solar neutrinos at JUNO
The Jiangmen Underground Neutrino Observatory (JUNO) features a 20 kt multi-purpose underground liquid scintillator sphere as its main detector. Some of JUNO's features make it an excellent location for B solar neutrino measurements, such as its low-energy threshold, high energy resolution compared with water Cherenkov detectors, and much larger target mass compared with previous liquid scintillator detectors. In this paper, we present a comprehensive assessment of JUNO's potential for detecting B solar neutrinos via the neutrino-electron elastic scattering process. A reduced 2 MeV threshold for the recoil electron energy is found to be achievable, assuming that the intrinsic radioactive background U and Th in the liquid scintillator can be controlled to 10 g/g. With ten years of data acquisition, approximately 60,000 signal and 30,000 background events are expected. This large sample will enable an examination of the distortion of the recoil electron spectrum that is dominated by the neutrino flavor transformation in the dense solar matter, which will shed new light on the inconsistency between the measured electron spectra and the predictions of the standard three-flavor neutrino oscillation framework. If eV , JUNO can provide evidence of neutrino oscillation in the Earth at approximately the 3 (2 ) level by measuring the non-zero signal rate variation with respect to the solar zenith angle. Moreover, JUNO can simultaneously measure using B solar neutrinos to a precision of 20% or better, depending on the central value, and to sub-percent precision using reactor antineutrinos. A comparison of these two measurements from the same detector will help understand the current mild inconsistency between the value of reported by solar neutrino experiments and the KamLAND experiment