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Consumer chemicals and kidney function markers: observational studies in the general populations : 생활화학물질 노출과 신장 기능 지표: 일반인구집단에서의 관찰 연구

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dc.contributor.advisor최경호-
dc.contributor.author강하병-
dc.date.accessioned2020-10-13T03:21:43Z-
dc.date.available2020-10-13T03:21:43Z-
dc.date.issued2020-
dc.identifier.other000000163147-
dc.identifier.urihttps://hdl.handle.net/10371/169869-
dc.identifier.urihttp://dcollection.snu.ac.kr/common/orgView/000000163147ko_KR
dc.description학위논문 (박사) -- 서울대학교 대학원 : 보건대학원 환경보건학과, 2020. 8. 최경호.-
dc.description.abstractChronic kidney disease (CKD) is a growing public health concern worldwide. Recently, environmental exposure to chemicals has been suggested as a risk factor to kidney disease. For several chemicals used in consumer products, e.g., phthalates and bisphenol A, epidemiological and experimental evidences on association with kidney disease have been accumulating. However, attempt to expand this research topic to other various chemicals in consumer products such as environmental phenols and organophosphate esters (OPEs) is minuscule yet. In this context, the present study explored possible associations of various chemicals in consumer products with kidney disease in a series of epidemiological observations.
The aim of the first study was to identify chemical determinants of the urinary albumin-to-creatinine ratio (ACR), which is a kidney disease marker, among multiple chemicals including phthalate metabolites, bisphenols, and benzophenones. For this purpose, Korean women (20–45 years old, n = 441) were recruited, and questionnaire survey and urine and blood sample collection were conducted. Firstly, using the variables measured for the participants, the creatinine-adjusted urinary concentration of each urinary chemical was associated with ACR in a linear regression model (single-pollutant model). Then, compounds with a significant association with ACR in the single-pollutant model were added in a multi-pollutant model and evaluated for their association with ACR. Several compounds measured in the urine showed a significant association with ACR in the single-pollutant model. In the multi-pollutant model, however, only monobutyl phthalate (MBP), monoisobutyl phthalate (MiBP), monobenzyl phthalate (MBzP), and benzophenone-1 (BP-1) showed significant positive associations. The association of MBP and BP-1, which are metabolites of dibutyl phthalate (DBP) and benzophenone-3 (BP-3), respectively, remained significant in a couple of the sensitivity analyses with a different adjustment of urine dilution and in a subpopulation with normal ACR. In summary, among dozens of urinary chemicals, MBP and BP-1 consistently showed a strong association with urinary ACR.
The second study was designed to verify the potential chemical determinants of kidney disease which was identified in the first study using the US general adult population by employing data from the US National Health and Nutrition Examination Survey (NHANES) 2005-2016. Among the 9008 adults, the associations of the urinary chemicals with chronic kidney disease (CKD) and related parameters, i.e., estimated glomerular filtration rate (eGFR) and ACR were assessed. To account for urine dilution, in addition to conventional creatinine adjustment, covariate-adjusted creatinine standardization, which controls for potential confounding by kidney function, was employed. Multi-pollutant models were also constructed to verify the associations observed in the models on individual chemicals. Several chemicals were positively associated with eGFR when the conventional creatinine adjustment was applied, while most of the chemicals were negatively associated with eGFR with the covariate-adjusted standardization method, implying significance of adjustment method for urine dilution. Regardless of the adjustment methods, MBP was positively associated with ACR, and MBzP was also associated with ACR with a marginal significance, which is in line with the observations in the first study. In the multi-pollutant model, MBP, MBzP, and BPA showed significant association with eGFR, and among these three chemicals, MBP were significantly associated with CKD outcome defined by eGFR and ACR ranges. In summary, among the US general population, MBP, MBzP, and BPA were associated with CKD related parameters, and the association with CKD outcome was most evident for MBP.
In the third study, association of OPE exposure with chronic kidney disease was evaluated employing US general adult population (NHANES 2013–2014). Among 1578 adults, the associations of the urinary OPE metabolites with CKD and related parameters were assessed. As in the second study, both the conventional creatinine adjustment and covariate-adjusted creatinine standardization were applied. Multi-pollutant models were also considered. The urinary bis(2-chloroethyl) phosphate (BCEP) level was negatively associated with eGFR only with the covariate-adjusted standardization method, but not with the conventional creatinine adjustment. In addition, both bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) and di-n-butyl phosphate (DNBP) were positively associated with the ACR, regardless of methods of urine dilution adjustment. These three compounds were also associated with CKD. Following adjusting urine dilution with the covariate-adjusted standardization method, the association became more evident. Moreover, similar results were observed in the secondary analysis with the multi-pollutant models. In summary, among the US general population, several OPEs were identified as potential chemical determinants of CKD.
In the fourth study, effect modification by vitamin D was evaluated on the association between chemical exposure and CKD observed in the second and the third studies. For this purpose, population with relevant measurements were selected from NHANES 2009-2014 (n = 3207) and NHANES 2013-2014 (n = 1069). Effect modification by serum vitamin D level was tested as assessing association between the chemical concentrations and CKD parameters in stratification by vitamin D status (deficiency, insufficiency, and sufficiency). Association between OPE metabolites (i.e., BDCIPP, BCEP, and DNBP) and eGFR was decreased as serum vitamin D level was increased. Also, association of MEP and DNBP with ACR was also decreased with the increase of serum vitamin D. In a secondary analysis in stratification with sun-exposure time and dietary vitamin D intake, the associations of BDCIPP and BCEP with eGFR were lower in groups where high vitamin D is expected (high sun-exposure time and high vitamin D intake) than in a reference group (low sun-exposure time and low vitamin D intake). On the other hand, effect modification was not obvious for other associations. In summary, vitamin D status was suggested as an effect modifier on the association between exposure to several OPEs and eGFR.
Through a sequence of the studies, chemical risk factors for kidney disease were identified. The multi-pollutant approach could identify major chemical determinants of kidney disease, i.e., MBP, MBzP, BP-1, and BPA, among the various chemicals used in consumer products. Several OPEs were also associated with CKD. Some of these associations could be modified by vitamin D status. The finding in this study will provide basic knowledge for chemical management, and the methodologies applied in this study will help conduct future studies.
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dc.description.abstract만성신장질환(CKD)는 전세계적으로 급증하고 있는 질환으로 최근 환경오염물질의 노출과의 연관성이 보고되고 있다. 프탈레이트 가소제나 비스페놀 A(BPA)와 같은 생활제품에 사용되는 물질들이 신장질환과 연관될 수 있다는 증거들이 역학연구와 실험연구를 통해 보고되고 있다. 하지만 이러한 연구들은 일부 물질들에만 국한되어 있고, 함께 생활제품을 통해 노출될 수 있는 기타 환경성페놀류나 유기인계 에스터화합물(OPEs)에 대한 연구는 전무한 상황이다. 이 연구에서는 생활제품 사용을 통해 함께 노출될 수 있는 여러 화학물질과 신장질환 간의 연관성을 일련의 인구집단 연구를 통해 확인하였다.
첫번째 연구는 신장질환의 지표인 뇨중 알부민-크레아티닌 비율(ACR)과 연관성을 가지는 화학물질을 확인하기 위하여 20-45세의 한국 여성 441명을 모집하였다. 이들 여성들에게서 소변과 혈액 시료를 수집하고 설문조사를 수행하였다. 연구 참여자들에게서 측정된 변수들을 이용하여 크레아티닌으로 보정된 소변 중 화학물질과 ACR 간의 연관성을 선형회귀모형으로 확인하였다(단일물질 모형). 또한 단일물질 모형에서 유의한 연관성이 나타난 물질들을 하나의 선형회귀모형에 독립변수로 포함시켜 다중물질 모형을 구성하였다. 단일물질 모형에서 여러 화학물질이 ACR과의 유의한 연관성을 보였다. 그러나 유의한 연관성을 보인 물질들을 포함한 다중물질 모형에서는 모노뷰틸 프탈레이트(MBP)와 모노이소뷰틸 프탈레이트(MiBP), 모노벤질 프탈레이트(MBzP), 벤조페논-1(BP-1)가 ACR과의 유의한 연관성을 보였다. 디뷰틸 프탈레이트(DBP)와 벤조페논-3(BP-3)의 대사체인 MBP와 BP-1은 신장이 건강한 참여자들로 제한한 분석과 비중 보정을 사용한 분석에서도 비슷하게 나타나 MBP와 BP-1이 뇨중 ACR의 증가의 중요한 위험인자로 제안된다.
두번째 연구에서는 미국 국민건강영양조사(NHANES) 2005-2016년 자료를 활용하여 첫번째 연구에서 확인된 화학물질과 신장질환 지표 간의 연관성을 미국 일반인구 집단에서 재확인하였다. 총 9008명의 성인을 대상으로 소변 중 화학물질과 CKD 및 관련 지표들 간의 연관성을 확인하였다. 신기능 변화로 인한 편향(bias)을 제거하기 위하여 일반적인 크레아티닌 보정법과 함께 신기능이 반영된 개선된 크레아티닌 보정법을 적용하여 소변 묽기를 보정하였다. 또한 다중물질 모형에서도 연관성을 확인하였다. 통계분석 결과, 일반적인 크레아티닌 보정법을 적용하였을 때에 일부 화학물질이 eGFR과 양의 연관성을 보인 반면에, 개선된 방법을 적용하였을 때에는 대부분의 물질이 eGFR과 음의 연관성을 보여 크레아티닌 보정 방법이 중요함을 확인하였다. 크레아티닌 보정 방법과 무관하게MBP가 ACR과 양의 연관성을 보였고 MBzP는 ACR과 약하게 양의 연관성을 보여서 첫번째 연구에서 관찰한 결과를 재현하였다. 다중물질 모형에서 MBP, MBzP, BPA가 eGFR과 양의 연관성을 보였고, 이 물질들 중에서 MBP가 CKD와의 연관성이 가장 크게 나타나 CKD의 중요한 위험인자임이 재확인되었다.
세번째 연구에서는 OPEs의 노출과 CKD 간의 연관성을 미국일반인구 집단(NHANES 2013-2014)을 이용하여 확인하였다. 총 1578명의 성인을 대상으로 소변 중 OPE 대사체와 CKD 및 관련 지표들 간의 연관성을 확인하였다. 두번째 연구와 동일하게 일반적인 크레아티닌 보정법과 개선된 크레아티닌 보정법을 적용하였다. 통계모형 분석 결과, 새로운 크레아티닌 보정이 적용된 뇨중 bis(2-chloroethyl) phosphate(BCEP)의 농도는 추정사구체여과율(eGFR)과 음의 연관성을 보였고 뇨중 bis(1,3-dichloro-2-propyl) phosphate(BDCIPP)과 di-n-butyl phosphate(DNBP)는 소변 묽기 보정방법에 무관하게 ACR과 양의 연관성을 보였다. CKD와의 연관성을 로지스틱회귀분석으로 확인하였을 때 위의 세 가지 물질은 모두 유의한 연관성을 보였다. 이러한 연관성은 새로운 크레아티닌 보정 방법을 적용하였을 때 더 크게 나타났다. 다중물질 모형을 구성하였을 때에도 세가지 물질에 대해 나타난 연관성이 재현되었다.
네번째 연구에서는 세번째 연구에서 관찰된 화학물질 노출과 신장질환 간의 연관성에 비타민D가 영향을 줄 수 있는지 확인하는 분석을 수행하였다. NHANES 2009-2015(n=3207)와 2013-2014(n = 1069) 인구를 대상으로 혈청 중 비타민 D 수준이 소변 중 화학물질과 CKD간의 연관성에서 효과변경인자로 작용할 수 있는 지 확인하였다. 혈청 중 비타민D가 증가할 수록 OPE 대사체(BDCIPP, BCEP, DNBP)와 eGFR 간의 연관성은 줄어들었다. 또한 MEP 또는 DNBP와 ACR 간의 연관성도 비타민 D가 증가할수록 감소하였다. 햇빛 노출 시간과 비타민D 섭취량을 이용하여 층화한 분석에서도 BDCIPP 또는 BCEP와 eGFR 간의 연관성이 대조 집단(낮은 햇빛 노출 시간 및 낮은 비타민D 섭취량)에 비해 비타민 D가 높을 것으로 기대되는 집단(높은 햇빛 노출 시간 및 높은 비타민 D 섭취량)에서 낮게 관찰되었지만 다른 연관성들에 대해서는 효과변경이 명확하지 않았다.
이 연구에서는 일련의 인구집단 관찰을 통하여, 신장질환의 위험인자로 작용할 수 있는 화학물질들을 확인하였다. 다중노출 모형을 이용하여 생활제품 사용을 통해 노출될 수 있는 여러 화학물질 중 MBP, MBzP, BP-1, BPA가 신장질환과의 연관성에서 중요할 수 있음을 제시하였고, 일부 OPE 물질들이 CKD와 연관될 수 있음을 확인하였다. 이러한 화학물질 노출과 CKD와의 연관성에서 비타민D 수준이 효과변경인자로 작용할 수 있음을 확인하였다. 이 연구에서 확인한 결과들은 화학물질 관리에 도움이 되는 기초자료로 활용될 수 있으며, 연구에서 사용한 방법론들은 향후 관련 연구에서 적용될 수 있을 것이다.
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dc.description.tableofcontentsChapter 1. General introduction: linking chemical exposure and kidney health 13
1.1 Chronic kidney disease and chemical exposure 13
1.2 Chemical exposure and kidney disease: Findings from previous epidemiology studies 19
1.3 Chemical exposure and kidney disease: Findings from experimental studies 28
1.4 Study design and objectives 32
Chapter 2. Association of phthalate and environmental phenol metabolites with albuminuria: a Korean women population 34
2.1 Introduction 34
2.2 Materials and methods 37
2.3 Results 49
2.4 Discussion 62
2.5 Summary and implications 66
Chapter 3. Association of phthalate metabolites and environmental phenols with CKD: NHANES 2005-2016 67
3.1 Introduction 67
3.2 Materials and methods 69
3.3 Results 75
3.4 Discussion 90
3.5 Summary and implications 93
Chapter 4. Association of metabolites of organophosphate esters (OPEs) with CKD: NHANES 2013-2014 94
4.1 Introduction 94
4.2 Materials and methods 97
4.3 Results 104
4.4 Discussion 119
4.5 Summary and implications 123
Chapter 5. Vitamin D status on the association between chemical exposure and chronic kidney disease 124
5.1 Introduction 124
4.2 Materials and methods 128
5.3 Results 132
5.4 Discussion 149
5.5 Summary and implications 152
Chapter 6. Conclusion 153
6.1 Urinary metabolites of several low-molecular-weight phthalates were identified as risk factors for CKD 153
6.2 DEHP exposure was not a major risk factor for CKD in our study population 154
6.3 Exposure to benzophenone-3 may be linked to CKD, but further studies on its biomarker are needed 154
6.4 Bisphenol A was associated with eGFR not with ACR 155
6.5 Several OPEs were associated with CKD, which was attenuated by vitamin D status 155
6.6 A novel urine dilution adjustment demonstrated significance of considering influence of GFR on urinary creatinine excretion 156
6.7 Concluding remarks 156
References 157
국문 초록(Abstract in Korean) 174
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dc.language.isoeng-
dc.publisher서울대학교 대학원-
dc.subjectchronic kidney disease (CKD)-
dc.subjectrenal function-
dc.subjectcreatinine-
dc.subjectalbuminuria-
dc.subjectglomerular filtration rate (GFR)-
dc.subjectphthalates-
dc.subjectenvironmental phenols-
dc.subjectorganophosphate esters (OPEs)-
dc.subjectvitamin D-
dc.subject만성신장질환-
dc.subject신기능-
dc.subject크레아티닌-
dc.subject알부민뇨-
dc.subject사구체여과율-
dc.subject프탈레이트-
dc.subject환경성페놀류-
dc.subject유기인계 에스터화합물-
dc.subject비타민 D-
dc.subject.ddc363.7-
dc.titleConsumer chemicals and kidney function markers: observational studies in the general populations-
dc.title.alternative생활화학물질 노출과 신장 기능 지표: 일반인구집단에서의 관찰 연구-
dc.typeThesis-
dc.typeDissertation-
dc.contributor.department보건대학원 환경보건학과-
dc.description.degreeDoctor-
dc.date.awarded2020-08-
dc.identifier.uciI804:11032-000000163147-
dc.identifier.holdings000000000043▲000000000048▲000000163147▲-
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