KR20210078881A - Multi-elemental analysis of urine by inductively coupled plasma/mass spectrometry - Google Patents
Multi-elemental analysis of urine by inductively coupled plasma/mass spectrometryDownload PDFInfo
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Abstract
Translated fromKoreanDescription
Translated fromKorean본 발명은 유도결합 플라즈마 질량분석법을 이용한 소변 내 금속류 동시분석법에 관한 것으로, 분석시료의 전처리 조건의 최적화, 분석 조건을 확립하여 3 ml 이하의 소량의 소변 시료로부터 바나튬, 크롬, 망간, 코발트, 니켈, 구리, 아연, 비소, 티타늄, 셀레늄, 베릴륨, 스트론튬, 몰리브덴, 카드뮴, 인듐, 주석, 안티몬, 세슘, 바륨, 텅스텐, 백금, 탈륨, 납, 및 우라늄 등과 같은 금속류를 동시에 분석하는 방법에 관한 것이다.The present invention relates to a simultaneous analysis of metals in urine using inductively coupled plasma mass spectrometry, and by optimizing the pretreatment conditions of the analyte sample and establishing the analysis conditions, vanatium, chromium, manganese, cobalt, A method for simultaneously analyzing metals such as nickel, copper, zinc, arsenic, titanium, selenium, beryllium, strontium, molybdenum, cadmium, indium, tin, antimony, cesium, barium, tungsten, platinum, thallium, lead, and uranium will be.
생체시료는 인체의 건강상태, 영양상태, 환경오염, 약물중독 및 병리학의 기초연구 등에 많이 이용되고 있고, 이러한 생체시료의 미량원소분석은 생리활성이 있는 원소 또는 중금속과 관련한 연구 등에서 필수적이라 할 수 있다.Biological samples are widely used in basic research on human health, nutritional status, environmental pollution, drug addiction, and pathology, etc., and the analysis of trace elements in these biological samples is essential in research related to elements with physiological activity or heavy metals. have.
따라서, 유해한 미량원소, 특히 환경오염 문제에서 큰 비중을 차지하는 중금속의 생체 내 축적여부 및 생물의 중금속에 대한 노출정도의 측정 등을 목적으로 생체시료를 사용하여 신속 정확하게 분석할 수 있는 방법에 관한 연구가 요구되고 있다.Therefore, a study on a method that can be quickly and accurately analyzed using biological samples for the purpose of measuring the accumulation of harmful trace elements, particularly heavy metals, which account for a large proportion in the environmental pollution problem, and the degree of exposure to heavy metals of organisms is being requested
생체 내 축적된 유해 원소 및 필수 영양원소의 검사에 사용되는 생체시료로서는 전통적으로 혈액 또는 뇨(尿)를 사용하고 있다.Traditionally, blood or urine is used as a biological sample used for the examination of harmful elements and essential nutrients accumulated in the living body.
한편, 생체시료 중에 존재하는 미량 원소 분석방법으로는 원자흡수분광법(AAS), 중성자방사화분석법, 원자방출분광법(ICP-AES) 및 유도결합 플라즈마 질량분석법(ICP-MS) 등이 있다.On the other hand, methods for analyzing trace elements present in biological samples include atomic absorption spectroscopy (AAS), neutron emission spectroscopy, atomic emission spectroscopy (ICP-AES), and inductively coupled plasma mass spectrometry (ICP-MS).
원자흡수분광법은 통상적으로 가열판을 이용하여 시료를 산 분해하여 용해한 후에 실시하게 되는 바, 가열판을 이용한시료 분해시간이 길고(2 ∼ 3 시간 이상 소요됨), 이러한 전처리 과정에서 외부 오염 및 휘발성 원소의 손실이 발생할 수 있으며, 특히 원자흡수분광법이 단일 원소 정량에 널리 사용되는 분석법으로 미량의 중금속 검출에는 효과적이라 할 수 있지만 여러 원소를 동시에 분석할 수 없다는 단점이 있다. 그리고, 중성자방사화분석법은 시료의 처리나 오염, 파괴없이 직접 분석할 수 있으며 특히 동시 다원소 고감도 분석법으로 잘 알려져 있으나, 국가 거대 시설인 원자로를 사용해야 하므로 이용에 많은 제약이 따르며 분석대상 원소 중 반감기가 오랜 원소가 포함되어 있으면 분석기간이 오래 걸리는 어려움이 있고, 인체에 치명적인 납(Pb)과 필수 영양소인 인(P)을 분석하지 못하는 단점이 있다. 또한, 원자방출분광법은 여러 원소를 동시에 분석할 수 있는 가장 일반적인 방법으로 고온의 유도결합 플라즈마(Inductively Coupled Plasma)나 직류 플라즈마(Direct Current Plasma)에 시료를 주입하였을 때 방출되는 빛을 분석하는 방법으로 원소와의 간섭이 적어 검출한계가 ppb 수준이며 농도에 대한 신호의 직선성도 좋은 장점이 있으나, 원자방출분광법은 검출한계가 ppb 수준으로 아직 부족한 수준이다. 이에 반하여, 유도결합 플라즈마 질량분석법(ICP-MS)은 원자방출분광법(ICP-AES)과 마찬가지로 다원소 동시분석, 분석의 자동화, 넓은 농도범위 분석, 적은 간섭효과와 빠른 시간 안에 분석이 가능하다는 장점을 가지고 있다. 또한, 유도결합 플라즈마 질량분석법(ICP-MS)은 원자방출분광법(ICP-AES)에 비해 10 ∼ 100배 정도까지 검출한계가 낮으며 대부분의 원소들에 대해 수십 ppt(Part-per-trillion)까지 얻을 수 있고, 원자방출분광법(ICP-AES) 보다 스펙트럼이 매우 간단하여 정성 및 정량분석이 가능하다는 또 다른 장점을 가지고 있다.Atomic absorption spectroscopy is usually carried out after acid decomposition and dissolution of a sample using a heating plate, and the decomposition time of the sample using a heating plate is long (it takes 2 to 3 hours or more), and external contamination and loss of volatile elements in this pretreatment process In particular, atomic absorption spectroscopy is a widely used analysis method for single element quantification, and it can be said to be effective for detecting trace amounts of heavy metals, but has a disadvantage in that it cannot analyze multiple elements at the same time. In addition, the neutron radiation analysis method can analyze directly without sample treatment, contamination, or destruction, and is particularly well known as a simultaneous multi-element high-sensitivity analysis method. If it contains a long element, there is a difficulty in taking a long analysis period, and there are disadvantages in that it is not possible to analyze lead (Pb), which is fatal to the human body, and phosphorus (P), an essential nutrient. In addition, atomic emission spectroscopy is the most common method that can analyze several elements at the same time. It is a method of analyzing the light emitted when a sample is injected into high-temperature inductively coupled plasma or direct current plasma. There is little interference with elements, so the detection limit is at the ppb level, and the linearity of the signal with respect to the concentration is good. However, the atomic emission spectroscopy method is still insufficient with the detection limit at the ppb level. In contrast, inductively coupled plasma mass spectrometry (ICP-MS), like atomic emission spectroscopy (ICP-AES), has advantages of simultaneous multi-element analysis, automation of analysis, wide concentration range analysis, low interference effect and quick analysis. has a In addition, inductively coupled plasma mass spectrometry (ICP-MS) has a detection limit of 10 to 100 times lower than that of atomic emission spectroscopy (ICP-AES), and for most elements up to several tens of ppt (Part-per-trillion). It has another advantage that qualitative and quantitative analysis is possible because the spectrum is much simpler than that of atomic emission spectroscopy (ICP-AES).
이상에서 설명한 바와 같이, 최근 분석기술의 발달로 여러 가지 분석법에 의한 생체시료의 동시 다원소 분석법이 시도 되고 있으나, 여전히 시료의 전처리 과정을 거치거나 다량의 시료 사용 등의 문제가 제기되고 있으며, 혈액과 뇨 같은 생체시료에 존재하는 다량의 공존원소(Ca, Cl, P, Na, K,C,S)와 매질에 존재하는 산소, 질소 및 플라즈마 생성에 사용되는 아르곤이온에 의해 동중간섭(Isobaric interference) 및 매질 차이에서 오는 간섭이 크게 나타나는 한계가 있었다.As described above, with the recent development of analysis technology, simultaneous multi-element analysis of biological samples by various analysis methods has been attempted, but problems such as pre-treatment of samples or the use of large amounts of samples are still being raised. Isobaric interference by a large amount of coexisting elements (Ca, Cl, P, Na, K, C, S) present in biological samples such as urine and oxygen, nitrogen, and argon ions used for plasma generation in the medium. ) and the interference from the medium difference was limited.
이러한 배경 하에서, 본 발명의 발명자들은 시료의 전처리 조건, 유도결합 플라즈마 질량분석법(ICP-MS) 수행 조건 등을 최적화 하여 소량의 소변 시료로부터 카드뮴, 수은 등과 같은 금속류를 동시에 빠르고 정확하게 분석할 수 있다는 것을 알게 되어 본 발명을 완성하였다.Under this background, the inventors of the present invention have found that metals such as cadmium and mercury can be simultaneously and accurately analyzed from a small amount of urine sample by optimizing the sample pretreatment conditions and inductively coupled plasma mass spectrometry (ICP-MS) performance conditions. As a result, the present invention was completed.
본 발명의 목적은 유도결합 플라즈마 질량분석법을 이용한 소변 내 금속류 동시분석법을 제공하는 데에 있다.It is an object of the present invention to provide a simultaneous analysis of metals in urine using inductively coupled plasma mass spectrometry.
상기 목적을 달성하기 위하여, 본 발명은 (a) 채취한 소변에 희석액과 질산용액을 넣어 혼합한 분석시료, 중금속이 포함된 표준용액, 희석액과 질산용액을 넣어 혼합한 공시료를 각각 준비하는 단계; (b) 상기 분석시료, 표준용액, 및 공시료를 유도결합플라즈마-질량분석기를 이용하여 분석하는 단계; (c) 농도별 표준물질에 대한 검정곡선을 작성하고 하기 수학식 1로부터 산출된 분석시료의 농도를 산출하는 단계; 및 (d) 상기 분석시료의 농도를 하기 수학식 2로 표시되는 크레아틴 농도를 보정하여 최종농도를 산출하는 단계를 포함하는, 유도결합 플라즈마 질량분석법을 이용한 소변 내 금속류 동시분석법을 제공한다.In order to achieve the above object, the present invention (a) preparing a sample mixed with a diluted solution and a nitric acid solution in the urine, a standard solution containing heavy metals, and a blank sample mixed with a diluted solution and a nitric acid solution, respectively ; (b) analyzing the analysis sample, the standard solution, and the blank sample using an inductively coupled plasma-mass spectrometer; (c) creating a calibration curve for the standard material by concentration and calculating the concentration of the analyte sample calculated from Equation 1 below; and (d) calculating the final concentration by correcting the concentration of the analyte sample by correcting the creatine concentration expressed by
[수학식 1][Equation 1]
분석농도(㎍/L)= [(시료 기기 검출농도(㎍/L) - 공시료 기기 검출농도(㎍/L)) × 희석 배율(Dilution Factor)Assay concentration (㎍/L) = [(sample device detection concentration (㎍/L) - blank sample device detection concentration (㎍/L)) × dilution factor (Dilution Factor)
[수학식 2][Equation 2]
최종농도(㎍/g)= 분석농도(㎍/L)÷크레아틴(㎍/L)Final concentration (μg/g) = Assay concentration (μg/L) ÷ Creatine (μg/L)
본 발명에 따른 소변 내 금속류 동시분석법은 생체 시료 내 20여 종 이상의 금속을 동시 정량분석이 가능하며, 선택성, 직선성, 감도, 검출범위, 검출한계, 정확도, 및 정밀도도 우수하여 체내 미량 금속을 신속하고 정확하게 분석할 수 있다.Simultaneous analysis of metals in urine according to the present invention enables simultaneous quantitative analysis of more than 20 types of metals in a biological sample, and has excellent selectivity, linearity, sensitivity, detection range, detection limit, accuracy, and precision to detect trace metals in the body. It can be analyzed quickly and accurately.
또한, 본 발명에 따른 분석법은 인체에 축척된 오염물질의 오염원과 오염경로를 파악할 수 있으며, 종래의 분석법인 흑연로 원자흡광광도법(GF-AAS, graphite furnace atomic absorption spectrometry) 보다 검출한계가 낮고, 동시에 여러 항목을 측정할 수 있어 분석시간이 빠르다는 장점을 갖는 바, 국내 생체 모니터링 분석방법으로 활용될 수 있다.In addition, the analysis method according to the present invention can identify the source of contamination and the path of contamination of contaminants accumulated in the human body, and the detection limit is lower than that of the conventional analysis method, graphite furnace atomic absorption spectrometry (GF-AAS), Since it can measure several items at the same time, it has the advantage of fast analysis time, so it can be used as a domestic bio-monitoring analysis method.
도 1은 본 발명에 따른 ICP-AES 분석법에 따라 분석하여 얻은 소변 중 중금속 다항목 검정곡선 결과이다.
도 2는 카드뮴에 대한 상관계수 및 급내상관계수에 대한 결과 그래프이다.
도 3은 수은에 대한 상관계수 및 급내상관계수에 대한 결과 그래프이다.1 is a result of a heavy metal multi-item calibration curve in urine obtained by analysis according to the ICP-AES analysis method according to the present invention.
Figure 2 is a graph of the results for the correlation coefficient and the internal correlation coefficient for cadmium.
3 is a graph showing the results of the correlation coefficient for mercury and the intraclass correlation coefficient.
이하에서는 본 발명을 구체적으로 설명한다.Hereinafter, the present invention will be described in detail.
본 발명자들은 시료의 전처리 조건의 최적화, 유도결합 플라즈마 질량분석기기의 수행 조건을 최적화를 통해, 생체시료에 존재하는 다량의 공존원소(Ca, Cl, P, Na, K,C,S), 매질에 존재하는 산소, 질소 및 플라즈마 생성에 사용되는 아르곤이온에 의해 동중간섭(Isobaric interference), 및 매질 차이에서 오는 간섭원을 제어함으로써 소량의 소변 시료로부터 카드뮴, 수은 등과 같은 금속류를 동시에 빠르고 정확하게 분석할 수 있다는 것을 알게 되어 본 발명을 완성하였다.The present inventors optimize the pretreatment conditions of the sample and optimize the performance conditions of the inductively coupled plasma mass spectrometer, so that a large amount of coexisting elements (Ca, Cl, P, Na, K, C, S) present in the biological sample, the medium By controlling isobaric interference by oxygen, nitrogen, and argon ions used to generate plasma, and interference sources from differences in media, it is possible to analyze metals such as cadmium and mercury from a small amount of urine sample at the same time quickly and accurately. It was found that it was possible to complete the present invention.
본 발명은 (a) 채취한 소변에 희석액과 질산용액을 넣어 혼합한 분석시료, 중금속이 포함된 표준용액, 희석액과 질산용액을 넣어 혼합한 공시료를 각각 준비하는 단계; (b) 상기 분석시료, 표준용액, 및 공시료를 유도결합플라즈마-질량분석기를 이용하여 분석하는 단계; (c) 농도별 표준물질에 대한 검정곡선을 작성하고 하기 수학식 1로부터 산출된 분석시료의 농도를 산출하는 단계; 및 (d) 상기 분석시료의 농도를 하기 수학식 2로 표시되는 크레아틴 농도를 보정하여 최종농도를 산출하는 단계를 포함하는, 유도결합 플라즈마 질량분석법을 이용한 소변 내 금속류 동시분석법을 제공한다.The present invention comprises the steps of: (a) preparing an analytical sample mixed with a diluted solution and a nitric acid solution in the collected urine, a standard solution containing heavy metals, and a blank sample mixed with a diluted solution and a nitric acid solution; (b) analyzing the analysis sample, the standard solution, and the blank sample using an inductively coupled plasma-mass spectrometer; (c) creating a calibration curve for the standard material by concentration and calculating the concentration of the analyte sample calculated from Equation 1 below; and (d) calculating the final concentration by correcting the concentration of the analyte sample by correcting the creatine concentration expressed by
[수학식 1][Equation 1]
분석농도(㎍/L)= [(시료 기기 검출농도(㎍/L) - 공시료 기기 검출농도(㎍/L)) × 희석 배율(Dilution Factor)Assay concentration (㎍/L) = [(sample device detection concentration (㎍/L) - blank sample device detection concentration (㎍/L)) × dilution factor (Dilution Factor)
[수학식 2][Equation 2]
최종농도(㎍/g)= 분석농도(㎍/L)÷크레아틴(㎍/L)Final concentration (μg/g) = Assay concentration (μg/L) ÷ Creatine (μg/L)
상기 (a) 단계에서 희석액은 질산, 로듐(Rh), 이리듐(Ir), 및 물을 포함하는 용액이다.The diluent in step (a) is a solution containing nitric acid, rhodium (Rh), iridium (Ir), and water.
상기 표준용액에는 바나튬(V), 크롬(Cr), 망간(Mn), 코발트(Co), 니켈(Ni), 구리(Cu), 아연(Zn), 비소(As), 티타늄(Ti), 셀레늄(Se), 베릴륨(Be), 스트론튬(Sr), 몰리브덴(Mo), 카드뮴(Cd), 인듐(In), 주석(Sn), 안티몬(Sb), 세슘(Cs), 바륨(Ba), 텅스텐(W), 백금(Pt), 탈륨(Tl), 납(Pb), 및 우라늄(U)으로 이루어진 군으로부터 선택된 1종 이상을 포함한다.The standard solution includes vanatium (V), chromium (Cr), manganese (Mn), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As), titanium (Ti), Selenium (Se), beryllium (Be), strontium (Sr), molybdenum (Mo), cadmium (Cd), indium (In), tin (Sn), antimony (Sb), cesium (Cs), barium (Ba), and at least one selected from the group consisting of tungsten (W), platinum (Pt), thallium (Tl), lead (Pb), and uranium (U).
상기 내부표준물질은 로듐(Rh), 이리늄(Ir), 텔루륨(Te), 및 금(Au)로 이루어진 군으로부터 선택된 1종 이상이다.The internal standard material is at least one selected from the group consisting of rhodium (Rh), irinium (Ir), tellurium (Te), and gold (Au).
상기 (b) 단계에서 유도결합플라즈마-질량분석기 분석 시 RF 증폭기(power)는 1200 내지 1600 W 범위 내에서 수행할 수 있다.Inductively coupled plasma-mass spectrometer analysis in step (b) above, the RF amplifier (power) may be performed within the range of 1200 to 1600 W.
상기 (b) 단계에서 유도결합플라즈마-질량분석기의 분석 시간은 5 내지 15 분 동안 수행할 수 있다.Inductively coupled plasma-mass spectrometer analysis in step (b) may be performed for 5 to 15 minutes.
상기 (b) 단계에서 주입되는 플라즈마 가스(plasma gas), 보조 가스(auxiliary gas), 분무 가스(nebulizer gas)는 아르곤 가스를 사용할 수 있다.Argon gas may be used as the plasma gas, auxiliary gas, and nebulizer gas injected in step (b).
상기 플라즈마 가스는 14 내지 16 L/min의 속도로 주입되는 것이 바람직하고, 상기 보조 가스는 1.1 내지 1.3 L/min의 속도로 주입되는 것이 바람직하고, 상기 분무 가스는 0.8 ~ 1.2 L/min 속도로 주입하는 것이 바람직하다.The plasma gas is preferably injected at a rate of 14 to 16 L/min, the auxiliary gas is preferably injected at a rate of 1.1 to 1.3 L/min, and the atomizing gas is injected at a rate of 0.8 to 1.2 L/min. Injection is preferred.
상기 표준물질은 바나튬(V), 크롬(Cr), 망간(Mn), 코발트(Co), 니켈(Ni), 구리(Cu), 아연(Zn), 비소(As), 티타늄(Ti), 셀레늄(Se), 베릴륨(Be), 스트론튬(Sr), 몰리브덴(Mo), 카드뮴(Cd), 인듐(In), 주석(Sn), 안티몬(Sb), 세슘(Cs), 바륨(Ba), 텅스텐(W), 백금(Pt), 탈륨(Tl), 납(Pb), 및 우라늄(U)으로 이루어진 군으로부터 선택된 1종 이상이다.The standard material is vanadium (V), chromium (Cr), manganese (Mn), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As), titanium (Ti), Selenium (Se), beryllium (Be), strontium (Sr), molybdenum (Mo), cadmium (Cd), indium (In), tin (Sn), antimony (Sb), cesium (Cs), barium (Ba), It is at least one selected from the group consisting of tungsten (W), platinum (Pt), thallium (Tl), lead (Pb), and uranium (U).
본 발명에 따른 분석방법은 종래의 분석법인 흑연로 원자흡광광도법(graphite furnace atomic absorption spectrometry, GF-AAS) 보다 검출한계가 낮고, 동시에 여러 항목을 측정할 수 있어 분석시간이 빠르다는 장점을 갖는 바, 국내 생체 모니터링 분석방법으로 활용될 수 있다.The analysis method according to the present invention has a lower detection limit than the graphite furnace atomic absorption spectrometry (GF-AAS), which is a conventional analysis method, and has the advantage of fast analysis time because it can measure several items at the same time. , it can be used as a domestic bio-monitoring analysis method.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for explaining the present invention in more detail, and it is to those of ordinary skill in the art to which the present invention pertains that the scope of the present invention is not limited by these examples according to the gist of the present invention. it will be self-evident
<참고예> 시료의 준비<Reference example> Sample preparation
인체 유래물 시료의 채취, 전달, 및 분석에 대하여 중앙대학교 생명윤리위원회의 연구 윤리 승인을 받은 후(IRB no. 1041078-201709-BR-179-01) 건강한 성인과 소아를 대상으로 20 내지 50 mL의 소변 시료를 채취하였다. 기타 모든 시약은 특급 혹은 분석용을 구입하여 사용하였다.After obtaining research ethics approval from the Bioethics Committee of Chung-Ang University (IRB no. 1041078-201709-BR-179-01) for the collection, delivery, and analysis of human-derived samples, 20 to 50 mL for healthy adults and children of urine samples were collected. All other reagents were purchased from express or analytical use.
이하 흑연로 원자흡광광도법(GFA-AS), 골드 아말감법(DMA)의 분석방법의 검출한계, 처리속도 등의 문제점을 개선하기 위하여 ICP/MS 분석법을 이용해 시료의 전처리 방법 및 기기조건, 정확도, 재현성, 검출한계, 정량한계 등을 확인하였다. ICP/MS 분석방법으로 실제 생체시료에 대한 적용성을 검토하였으며, ICP-MS 분석방법과 GFAAS 분석방법과의 측정값 편차 정도를 파악하기 위하여 동일 시료에 대한 비교 분석을 수행하였다.Hereinafter, in order to improve the problems such as the detection limit and processing speed of the graphite furnace atomic absorption spectroscopy (GFA-AS) and gold amalgam method (DMA), the ICP/MS analysis method is used to improve the sample pre-treatment method, equipment conditions, accuracy, Reproducibility, detection limit, quantitation limit, etc. were confirmed. Applicability to actual biological samples was reviewed with the ICP/MS analysis method, and comparative analysis was performed on the same sample to determine the degree of deviation between the ICP-MS analysis method and the GFAAS analysis method.
<실시예 1> ICP-MS를 통한 분석<Example 1> Analysis through ICP-MS
채취한 소변을 교반기에서 녹인 후, 마이크로 피펫을 이용하여 상층액 0.3 mL을 취하여 희석액 2.4 mL와 1% HNO3 0.3 mL에 넣은 뒤 혼합기를 사용하여 잘 섞어 분석 시료를 준비하였다. 아울러, 소변 내 중금속 다항목 분석을 위해 사용한 시약은 분석용 특급시약을 구입하여 사용하였다. 다원소 스톡 용액(Stock Solution)은 Multi-Element Calibration Standard 3으로 10 mg/L(PerkinElmer, USA) 제품을 사용하였고, 수은 스톡 용액(Stock Solution)은 Mercury standard solution Hg 10 mg/L(PerkinElmer, USA) 제품을 사용하였다. 또한 표 3에 나타낸 바와 같이 각 개별원소의 표준물질 1,000 mg/L(SPEX CertiPrep, USA)을 구매하여 표준용액을 제조하였다. 시료의 분해를 위해 사용한 시약 질산 용액(HNO3, purity 70%, Dong Woo Fine Chem. Co. Ltd., Korea)는 반도체급을 사용하였다. 내부 정도관리 등을 확인하기 위한 인증표준물질(CRM, Certified Reference Materials)로는 미국국립표준기술연구소(NIST, National Institute of Standards and Technology)의 Toxic Elements in Frozen Human Urine(NIST 2668)을 구입하여 사용하였다. 또한 상업적 표준물질인 ClinChek® Level 1 and 2(Catalog no 8847, 8848 Recipe® Chemicals + Instruments GmbH, Munich, Germany)를 사용하였다.After dissolving the collected urine on a stirrer, take 0.3 mL of the supernatant using a micropipette, put it in 2.4 mL of dilution and0.3 mL of 1% HNO 3 , and mix well using a mixer to prepare an analysis sample. In addition, reagents used for multi-item analysis of heavy metals in urine were purchased and used for analysis. For the multi-element stock solution, 10 mg/L (PerkinElmer, USA) was used as Multi-Element Calibration Standard 3, and the mercury stock solution was Mercury
유도결합플라즈마-질량분석기(ICP-MS) 기기는 NexION 2000B(Perkin Elmer, Massachusetts, US)를 사용하였다. 동중원소 방해요소를 제어하기 위한 시스템으로 DRC 모드가 적용되었다. 하기 표 2는 ICP-MS 수행 조건을 나타낸 것이고, 표 4는 내부표준물질을 나타낸 것이다. 도 1은 본 발명에 따른 ICP-AES 분석법에 따라 분석하여 얻은 소변 중 중금속 다항목 검정곡선 결과이다.An inductively coupled plasma-mass spectrometer (ICP-MS) instrument was used as a NexION 2000B (Perkin Elmer, Massachusetts, US). The DRC mode was applied as a system for controlling isobaric elements. Table 2 below shows the conditions for performing ICP-MS, and Table 4 shows internal standards. 1 is a result of a heavy metal multi-item calibration curve in urine obtained by analysis according to the ICP-AES analysis method according to the present invention.
(mL)Volume
(mL)
(mg/L)Concentration
(mg/L)
(mL)Volume
(mL)
(mg/L)Concentration
(mg/L)
<비교예 1> 흑연로 원자흡광광도법(GF-AAS)을 통한 분석<Comparative Example 1> Analysis through graphite furnace atomic absorption spectroscopy (GF-AAS)
상기 실시예 1과 동일한 시료로 수행하되, 카드뮴을 흑연로 원자흡광광도법(GFAAS)으로 분석 수행하였다.The same sample as in Example 1 was used, but cadmium was analyzed by graphite furnace atomic absorption spectroscopy (GFAAS).
<비교예 2> 골드아말감 수은전용분석법(DMA)을 통한 분석<Comparative Example 2> Analysis through gold amalgam mercury-only analysis (DMA)
상기 실시예 1과 동일한 시료로 수행하되, 수은을 골드아말감 수은전용분석법(DMA)으로 분석 수행하였다.It was performed with the same sample as in Example 1, but mercury was analyzed by gold amalgam mercury-only analysis (DMA).
<실험예> 직선성(Linearity), 정확도 및 정밀도 확인<Experimental example> Check linearity, accuracy and precision
일내(intra-day) 및 일간(inter-day) 정확도와 정밀도는 세 가지 다른 농도의 샘플을 이용하였다. 일내 및 일간 정확도는 5 회씩 분석하도록 하며 정밀도 및 회수율을 평가하였다. 또한 NIST의 SRM 2668 Level 1, Level 2(2 개), Clinchek Level 1, Level 2(2 개) 등의 샘플을 분석하고 이를 통한 정확도를 평가하였다. 정밀도 실험은 3 가지의 농도를 반복 측정하였으며, 일내와 일간 각각 5 회의 측정을 수행하고 상대표준편차(RSD, relative standard deviation)를 산출하였다. 또한 방법검출한계는 검정곡선 중 제일 낮은 농도의 매질시료로 7 회 반복 측정하여 구하였다. 정확도와 정밀도의 기준은 산출된 결과의 ±15 % 범위로 하였다.Three different concentrations of samples were used for intra-day and inter-day accuracy and precision. The intraday and daily accuracy were analyzed 5 times, and the precision and recovery rate were evaluated. In addition, NIST's SRM 2668 Level 1, Level 2 (2 pieces), Clinchek Level 1, Level 2 (2 pieces) samples were analyzed and the accuracy was evaluated. In the precision experiment, three concentrations were repeatedly measured, and measurements were performed 5 times each day and within a day, and the relative standard deviation (RSD) was calculated. In addition, the detection limit of the method was determined by repeating 7 measurements with the medium sample with the lowest concentration among the calibration curves. The standard of accuracy and precision was within the range of ±15% of the calculated result.
채취한 소변 시료 66 개에 대하여 본 발명에 따른 ICP-MS 분석법과 기존 분석방법(GF-AAS, DMA)을 이용하여 소변 내 중금속을 동시에 다분석 하였다. 즉, 동일한 시료를 대상으로 신규 개발 방법과 기존 방법에서 도출된 결과를 비교하였으며, 상관계수 및 급내상관계수(ICC, intra class correlation)를 산출하여 기존 분석법과 신규 분석법 간 분석결과의 상관성과 일치도를 산출하였다.For 66 collected urine samples, heavy metals in urine were analyzed simultaneously using the ICP-MS analysis method according to the present invention and the existing analysis methods (GF-AAS, DMA). That is, the results derived from the newly developed method and the existing method were compared for the same sample, and the correlation and intra class correlation (ICC) were calculated to determine the correlation and consistency of the analysis results between the existing method and the new method. calculated.
그 밖에 두 분석결과에서 도출된 값들의 상관성을 검증하기 위하여 Pearson’s 상관계수를 산출하였으며, 두 군간 차이를 비교하기 위하여 Paired t-test를 수행하였다. 통계분석에는 SPSS 프로그램(version 23, IBM Corp., NY, US)을 이용하였다.In addition, Pearson's correlation coefficient was calculated to verify the correlation between the values derived from the two analysis results, and a paired t-test was performed to compare the difference between the two groups. For statistical analysis, SPSS program (version 23, IBM Corp., NY, US) was used.
(1) 직선성(Linearity) 확인(1) Check Linearity
소변 중 금속류 동시분석법 대상 원소는 25 종을 포함하였으며 이는 베릴륨(Be, beryllium), 티타늄(Ti, titanium), 바나듐(V, vanadium), 크롬(Cr, chromium), 망간(Mn, manganese), 코발트(Co, cobalt), 니켈(Ni, nickel), 구리(Cu, copper), 아연(Zn, zinc), 총비소(tAs, total arsenic), 셀레늄(Se, selenium), 스트론듐(Sr, strontium), 몰리브덴(Mo, molybdenum), 카드뮴(Cd, cadmium), 인듐(Indium), 주석(Sn, tin), 안티몬(Sb, antimony), 세슘(Cs, cesium), 바륨(Ba, barium), 텅스텐(W, tungsten), 백금(Pt, platinum), 수은(Hg, mercury), 탈륨(Tl, thallium), 납(Pb, lead), 우라늄(U, uranium)을 포함한다. 본 ICP-MS의 가스모드는 분석물질별로 표준, 암모니아, 헬륨 모드를 적용하였으며, 검정곡선 작성 시 각 물질의 직선성(R2)은 최소 0.999로 산출되었다(표 5). 이로서 직선성을 확인할 수 있었다.Elements subject to the simultaneous analysis of metals in urine were included in 25 species, which were beryllium (Be, beryllium), titanium (Ti, titanium), vanadium (V, vanadium), chromium (Cr, chromium), manganese (Mn, manganese), and cobalt. (Co, cobalt), nickel (Ni, nickel), copper (Cu, copper), zinc (Zn, zinc), total arsenic (tAs, total arsenic), selenium (Se, selenium), strontium (Sr, strontium) ), molybdenum (Mo, molybdenum), cadmium (Cd, cadmium), indium, tin (Sn, tin), antimony (Sb, antimony), cesium (Cs, cesium), barium (Ba, barium), tungsten (W, tungsten), platinum (Pt, platinum), mercury (Hg, mercury), thallium (Tl, thallium), lead (Pb, lead), uranium (U, uranium). For the gas mode of this ICP-MS, standard, ammonia, and helium modes were applied for each analyte, and the linearity (R2 ) of each material was calculated to be at least 0.999 when the calibration curve was drawn up (Table 5). This confirmed the linearity.
[표 5][Table 5]
(2) 일내 및 일간 정확도 확인(2) Check intra-day and daily accuracy
채취한 소변 시료를 이용하여 일내 정확도 및 일간 정확도를 평가하였다. 평가 결과, 일내 실험의 경우 17 개 항목(V, Cr, Mn, Co, Ni, Cu, Zn, tAs, Se, Sr, Mo, Cd, In, Sn, Sb, Cs, Ba)에서, 일간 시험의 경우 20 개 항목(Ti, V, Cr, Mn, Co, Ni, Cu, Zn, tAs, Se, Sr, Mo, Cd, In, Sn, Sb, Cs, Ba, W, Pt)에서 각각 정확도 및 정밀도가 15% 이하로서, 설정한 기준(≤ ±15%)에 부합하였다(표 6).The intraday accuracy and the daily accuracy were evaluated using the collected urine samples. As a result of the evaluation, in the case of intraday experiments, in 17 items (V, Cr, Mn, Co, Ni, Cu, Zn, tAs, Se, Sr, Mo, Cd, In, Sn, Sb, Cs, Ba), Accuracy and precision in each of 20 cases (Ti, V, Cr, Mn, Co, Ni, Cu, Zn, tAs, Se, Sr, Mo, Cd, In, Sn, Sb, Cs, Ba, W, Pt) was 15% or less, which met the set criteria (≤±15%) (Table 6).
[표 6][Table 6]
아울러, NIST의 인증표준물질과 상업적 표준물질인 ClinChek®을 이용한 분석은 두 개의 농도 범위에서 수행하였으며(Level 1 and 2), NIST를 확보한 19 개 물질 중 15 개 물질(Be, V, Cr, Ni, Cu, tAs, Mo, Cd, Sn, Sb, Cs, Pt, Tl, Pb, U)에서도 ±15% 이내의 정확도를 나타내었다(표 7).In addition, analysis using NIST's certified standard material and commercial standard ClinChek® was performed in two concentration ranges (Level 1 and 2), and 15 substances (Be, V, Cr, Ni, Cu, tAs, Mo, Cd, Sn, Sb, Cs, Pt, Tl, Pb, U) showed an accuracy within ±15% (Table 7).
[표 7][Table 7]
따라서, 본 발명에 따른 ICP-MS 분석법은 소변 내 중금속을 동시에 다분석 할 수 있음을 확인할 수 있다.Therefore, it can be confirmed that the ICP-MS analysis method according to the present invention can simultaneously multi-analyze heavy metals in urine.
(3) 상관계수(Pearson’s correlation coefficient) 및 급내상관계수(ICC) 확인(3) Confirmation of Pearson's correlation coefficient and intraclass correlation coefficient (ICC)
앞서 언급한 바와 같이, 상관계수 및 급내상관계수(ICC, intra class correlation)를 산출하여 기존 분석법과 신규 분석법 간 분석결과의 상관성과 일치도를 산출하여 도 2 및 도 3에 나타내었다.As mentioned above, correlation coefficients and intra-class correlation coefficients (ICC) were calculated to calculate the correlation and consistency of the analysis results between the existing analysis method and the new analysis method, and are shown in FIGS. 2 and 3 .
도 2는 카드뮴에 대한 상관계수 및 급내상관계수 결과로서, 카드뮴의 경우 GF-AAS 방법과 ICP-MS 방법에서 측정된 분석농도 값의 상관계수(Pearson’s correlation coefficient)가 0.928이었고(p-value<0.001), 급내상관계수(ICC)가 0.952로 계산되었는바(p-value<0.001), 두 군간 차이를 확인할 수는 없었다(p-value=0.220 by Paired t-test).2 shows the correlation coefficient and intraclass correlation coefficient results for cadmium. In the case of cadmium, the correlation coefficient between the analysis concentration values measured by the GF-AAS method and the ICP-MS method was 0.928 (p-value <0.001). ), the intraclass correlation coefficient (ICC) was calculated to be 0.952 (p-value<0.001), and the difference between the two groups could not be confirmed (p-value=0.220 by Paired t-test).
도 3은 수은에 대한 상관계수 및 급내상관계수 결과로서, 수은은 기존에 적용되고 있는 골드 아말감법과 본 연구에서 개발한 ICP-MS 방법을 비교하였으며, 0.844 (p-value<0.001)의 상관계수와 0.911의 급내상관계수(p-value<0.001), 두 군간 차이가 없음을 확인할 수 있었다(p-value=0.054 by Paired t-test).3 is a result of correlation coefficient and intraclass correlation coefficient for mercury, comparing the previously applied gold amalgam method with the ICP-MS method developed in this study, and a correlation coefficient of 0.844 (p-value <0.001) and The intraclass correlation coefficient of 0.911 (p-value<0.001), it was confirmed that there was no difference between the two groups (p-value=0.054 by Paired t-test).
상기 언급한 바와 같이, 본 발명에 따른 분석법은 동시에 많은 항목을 분석할 수 있기 때문에 GFA-AS 분석방법에 비해 분석시간을 크게 단축할 수 있으며, 검출한계도 GFA-AS 분석방법보다 낮은 장점이 있다. 따라서 ICP/MS 분석방법은 분석대상 물질이 극미량으로 존재하는 혈액 및 뇨와 같은 생체시료를 다량으로 분석해야 하는 미량금속 생체노출 조사사업의 분석방법으로 사용 가능하다고 판단된다.As mentioned above, since the analysis method according to the present invention can analyze many items at the same time, the analysis time can be greatly reduced compared to the GFA-AS analysis method, and the detection limit is also lower than the GFA-AS analysis method. . Therefore, it is judged that the ICP/MS analysis method can be used as an analysis method for the trace metal bioexposure investigation project, which requires analyzing a large amount of biological samples such as blood and urine in which the analyte is present in very small amounts.
Claims (7)
Translated fromKorean(b) 상기 분석시료, 표준용액, 및 공시료를 유도결합플라즈마-질량분석기를 이용하여 분석하는 단계;
(c) 농도별 표준물질에 대한 검정곡선을 작성하고 하기 수학식 1로부터 산출된 분석시료의 농도를 산출하는 단계; 및
(d) 상기 분석시료의 농도를 하기 수학식 2로 표시되는 크레아틴 농도를 보정하여 최종농도를 산출하는 단계;
를 포함하는, 유도결합 플라즈마 질량분석법을 이용한 소변 내 금속류 동시분석법:
[수학식 1]
분석농도(㎍/L)= [(시료 기기 검출농도(㎍/L) - 공시료 기기 검출농도(㎍/L)) × 희석 배율(Dilution Factor)
[수학식 2]
최종농도(㎍/g)= 분석농도(㎍/L)÷크레아틴(㎍/L)
(a) preparing an analytical sample mixed with a diluted solution and a nitric acid solution in the collected urine, a standard solution containing heavy metals, and a blank sample mixed with a diluted solution and a nitric acid solution;
(b) analyzing the analysis sample, the standard solution, and the blank sample using an inductively coupled plasma-mass spectrometer;
(c) creating a calibration curve for the standard material by concentration and calculating the concentration of the analyte sample calculated from Equation 1 below; and
(d) calculating the final concentration by correcting the concentration of the analysis sample by creatine concentration expressed by Equation 2 below;
Simultaneous analysis of metals in urine using inductively coupled plasma mass spectrometry, including:
[Equation 1]
Assay concentration (㎍/L) = [(sample device detection concentration (㎍/L) - blank sample device detection concentration (㎍/L)) × dilution factor (Dilution Factor)
[Equation 2]
Final concentration (μg/g) = Assay concentration (μg/L) ÷ Creatine (μg/L)
상기 희석액은 질산, 로듐(Rh), 이리듐(Ir), 및 물을 포함하는 용액인 것을 특징으로 하는, 유도결합 플라즈마 질량분석법을 이용한 소변 내 금속류 동시분석법.
The method of claim 1,
The diluent is nitric acid, rhodium (Rh), iridium (Ir), characterized in that the solution containing water, the simultaneous analysis of metals in urine using inductively coupled plasma mass spectrometry.
상기 표준물질은 바나튬(V), 크롬(Cr), 망간(Mn), 코발트(Co), 니켈(Ni), 구리(Cu), 아연(Zn), 비소(As), 티타늄(Ti), 셀레늄(Se), 베릴륨(Be), 스트론튬(Sr), 몰리브덴(Mo), 카드뮴(Cd), 인듐(In), 주석(Sn), 안티몬(Sb), 세슘(Cs), 바륨(Ba), 텅스텐(W), 백금(Pt), 탈륨(Tl), 납(Pb), 및 우라늄(U)으로 이루어진 군으로부터 선택된 1종 이상을 포함하는 것을 특징으로 하는, 유도결합 플라즈마 질량분석법을 이용한 소변 내 금속류 동시분석법.
The method of claim 1,
The standard material is vanadium (V), chromium (Cr), manganese (Mn), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As), titanium (Ti), Selenium (Se), beryllium (Be), strontium (Sr), molybdenum (Mo), cadmium (Cd), indium (In), tin (Sn), antimony (Sb), cesium (Cs), barium (Ba), Tungsten (W), platinum (Pt), thallium (Tl), lead (Pb), characterized in that it contains at least one selected from the group consisting of uranium (U), in the urine using inductively coupled plasma mass spectrometry Simultaneous analysis of metals.
상기 (b) 단계에서 유도결합플라즈마-질량분석기 분석 시 RF 증폭기(power)는 1400 내지 1600 W 범위 내에서 수행하는 것을 특징으로 하는, 유도결합 플라즈마 질량분석법을 이용한 소변 내 금속류 동시분석법.
The method of claim 1,
Inductively coupled plasma in the step (b) - Simultaneous analysis of metals in urine using inductively coupled plasma mass spectrometry, characterized in that the RF amplifier (power) is performed within the range of 1400 to 1600 W during mass spectrometry analysis.
상기 (b) 단계에서 유도결합플라즈마-질량분석기의 분석 시간은 5 내지 15 분 동안 수행하는 것을 특징으로 하는, 유도결합 플라즈마 질량분석법을 이용한 소변 내 금속류 동시분석법.
The method of claim 1,
In the step (b), inductively coupled plasma-mass spectrometry analysis time is performed for 5 to 15 minutes, the simultaneous analysis of metals in urine using inductively coupled plasma mass spectrometry.
상기 (b) 단계에서 주입하는 가스로서 플라즈마 가스는 14 내지 16 L/min의 속도, 보조 가스는 1.1 내지 1.3 L/min의 속도, 분무 가스는 0.8 ~ 1.2 L/min 속도로 주입되는 것을 특징으로 하는, 유도결합 플라즈마 질량분석법을 이용한 소변 내 금속류 동시분석법.
The method of claim 1,
As the gas injected in step (b), plasma gas is injected at a rate of 14 to 16 L/min, auxiliary gas is injected at a rate of 1.1 to 1.3 L/min, and atomization gas is injected at a rate of 0.8 to 1.2 L/min. Simultaneous analysis of metals in urine using inductively coupled plasma mass spectrometry.
상기 (b) 단계에서 주입하는 가스는 아르곤(Ar)인 것을 특징으로 하는, 유도결합 플라즈마 질량분석법을 이용한 소변 내 금속류 동시분석법.7. The method of claim 6,
Simultaneous analysis of metals in urine using inductively coupled plasma mass spectrometry, characterized in that the gas injected in step (b) is argon (Ar).
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| PC1203 | Withdrawal of no request for examination | St.27 status event code:N-1-6-B10-B12-nap-PC1203 | |
| PN2301 | Change of applicant | St.27 status event code:A-3-3-R10-R11-asn-PN2301 St.27 status event code:A-3-3-R10-R13-asn-PN2301 | |
| R18-X000 | Changes to party contact information recorded | St.27 status event code:A-3-3-R10-R18-oth-X000 |