加氯消毒是台灣地區飲用水主要的消毒方式。加氯消毒的過程會產生許多消毒副產物，例如三鹵甲烷、含鹵乙酸。消毒副產物造成可能的健康危害已經被大量研究及討論。許多毒理研究、動物實驗與流行病學研究均指出，暴露於消毒副產物和癌症、生殖異常可能有相關性，但結果仍不一致。本研究的目的，為探討母親在懷孕的第一孕程和第三孕程中，暴露到飲用水中的總三鹵甲烷，與生殖異常的相關性。探討之生殖異常包括總缺陷、心臟缺陷、神經系統缺陷、唇顎裂、死產、足月低出生體重和子宮內成長遲滯。
研究族群為國健局出生通報資料庫中，2001-2009年於台灣出生之單胞胎新生兒及死產。共有1,126,714個活產和10,337個死產納入第一孕程的分析，1,148,308個活產納入第三孕程的分析。本研究使用2001-2005、2007-2009年環保署定期監測之配水系統中總三鹵甲烷濃度作為暴露資料，計算出不同區域每年每月平均總三鹵甲烷濃度，並以複迴歸模式推估缺乏監測資料之月平均總三鹵甲烷濃度。利用羅吉斯迴歸模式估計勝算比(Odds ratio, OR)及其95%信賴區間，探討母親於第一孕程和第三孕程暴露之平均總三鹵甲烷濃度與生殖異常的關係。暴露濃度以兩種方式分組。
研究結果顯示，即使我們改進先前的暴露評估，以及改善台灣總三鹵甲烷濃度過低所造成的研究限制，仍發現只有死產在兩種分組方式之高暴露濃度組，以及將濃度視為連續變項時，有達到正相關之統計上顯著差異(OR=1.077, 95%CI=1.01-1.49; OR=1.148, 95%CI=1.056-1.248; and OR=1.003, 95%CI=1.001-1.006)。其他生殖異常在不同暴露濃度組間皆未達到正相關之統計上顯著差異。在總三鹵甲烷與足月低出生體重和死產之間，發現些微劑量效應之關係。
依研究結果我們可暫時推論，在平均總三鹵甲烷濃度為9.86±10.05 µg/L的狀況下，不需要擔心總三鹵甲烷對生殖異常的影響。因此從本研究結果來看，美國環保署制定的總三鹵甲烷預期管制目標40 µg/L，應可充分保障民眾的健康。但仍需進一步研究以確認在多少濃度範圍內可能有影響，以利未來訂定更嚴格的法規。也需進一步探討是否其他毒性更強的消毒副產物才是主要造成生殖異常的原因。

Water chlorination has been the major disinfection process of drinking water in Taiwan. Disinfection by-products could be produced during the disinfection process, such as trihalomethanes (THMs) and haloacetic acids (HAAs). Concerns about the potential health effects from exposures to the disinfection by-products have been raised. Many toxicological and epidemiological studies have been conducted to investigate the possible associations between the maternal exposure to disinfection by-products and the adverse health effects such as cancers and adverse birth outcomes, but the results were inconsistent. The objective of this study was to examine the effects of maternal exposure to total THMs (TTHMs) in drinking water during the first and the third trimesters on the risks of adverse birth outcomes in Taiwan. The adverse birth outcomes investigated in this study included all congenital malformations, congenital heart disease, nervous system defects, orofacial cleft, stillbirth, term low birth weight, and small for gestational age.
We used the birth registration data to conduct a registry-based study between 2001 and 2009 in Taiwan. There were 1,126,714 live births and 10,337 stillbirths, and 1,148,308 live births included in the analysis of the first and the third trimesters, respectively. We obtained the TTHMs data routinely collected in distribution systems by Taiwan EPA from 2001 to 2005 and 2007 to 2009 as our exposure data, and used multiple regression models to estimated unavailable monthly average TTHMs concentrations. Adjusted ORs (95% CIs) were calculated by logistic regression, for the association between TTHMs exposure of the mothers averaged over the first and the third trimesters, and various adverse birth outcomes under two ways of classifying TTHMs exposure groups. Although we improved the previous exposure assessments and overcame the study limitation of low-level TTHMs in Taiwan, we still found no statistically significant positive associations between the TTHMs and the adverse birth outcomes, except stillbirth in the two classifying ways of the high exposure group of TTHMs, as well as treating complete exposure data as continuous (OR=1.077, 95%CI=1.01-1.49; OR=1.148, 95%CI=1.056-1.248; and OR=1.003, 95%CI=1.001-1.006, respectively). Weak evidence of a dose-response trend was found between TTHM exposure groups and TLBW and stillbirth.
We temporarily concluded that with low levels of average TTHMs concentrations (9.86 ± 10.05 µg/L) in Taiwan, we do not need to worry about the effects of TTHMs on adverse birth outcomes. If we strictly revise the MCL of TTHMs to 40µg/L in the future, the health of the people will be sufficiently protected. Further studies with individual water use and other exposure routes were needed to find the range above which TTHMs concentration would have an effect on adverse birth outcomes in order to set up stricter regulation to control the TTHMs to be within the safe range. Further studies of examining the relationship between other more toxic DBPs and adverse birth outcomes are also required.

Contents
Chapter 1 Introduction....................................1
　1.1 Background..........................................1
　1.2 Objective...........................................2
Chapter 2 Literature review...............................4
　2.1 THMs in drinking water..............................4
　　2.1.1 Formation, categories, and characteristics of DBPs ................................................4
　　2.1.2 Exposure routes and pathways of THMs............5
　　2.1.3 Regulations of THMs.............................7
　2.2 Studies of THMs and adverse health outcomes.........8
　　2.2.1 Toxicological studies and possible mechanisms of
THMs and adverse birth outcomes.................8
　　2.2.2 Epidemiological studies of THMs and adverse birth
outcomes.......................................11
　　2.2.3 Gene-environment interaction...................17
　　2.2.4 Exposure period................................18
Chapter 3 Materials and methods..........................20
　3.1 Study population...................................20
　3.2 Exposure data ......................................21
　　3.2.1 Introduction of exposure data..................21
　　3.2.2 Study region...................................22
　　3.2.3 TTHM exposure..................................23
　3.3 Adverse birth outcomes.............................28
　3.4 Statistical methods................................29
Chapter 4 Results........................................30
　4.1 Distribution of TTHMs concentrations in Taiwan.....30
　4.2 Complete TTHMs exposure data.......................33
　　4.2.1 Tests to determine equation curves for estimating
TTHMs exposure data............................34
　　4.2.2 Combination of observed and estimated TTHMs data ...............................................36
　4.3 Characteristics of the study population............40
　　4.3.1 The study population included in the analysis of
the first trimester............................40
　　4.3.2 The study population included in the analysis of
the third trimester............................45
　4.4 Prevalence rates of various adverse birth outcomes.49
　　4.4.1 Prevalence rates of various adverse birth
outcomes by TTHMs exposure groups..............49
　　4.4.2 Congenital malformations and stillbirth........49
　　4.4.3 Prevalence rates of various adverse birth
outcomes by potential risk factors.............52
　　4.4.4 Prevalence rates of various adverse birth
outcomes by years..............................68
　4.5 Logistic Regression models on the occurrence of
congenital malformations...........................74
Chapter 5 Discussions....................................78
　5.1 Effects of TTHMs exposure on birth outcomes........78
　5.2 TTHMs exposure data................................82
　5.3 Registration and outcomes data.....................84
　5.4 Low levels of TTHMs in Taiwan......................87
　5.5 Limitations of study...............................90
Chapter 6 Conclusions and Suggestions....................91
References...............................................94
Appendixes..............................................109

List of Tables
Table 2.1 Summary of epidemiological studies on THMs and adverse birth outcomes in countries with low levels of THMs...................................................13
Table 4.1 Distribution of TTHMs concentrations (μg/L) in Taiwan, 2001-2009......................................31
Table 4.2 Results of F-test of two models performed separately for each of the seven regions...............36
Table 4.3 The characteristics of the total study population and four TTHMs exposure groups included in the analysis of the first trimester....................................43
Table 4.4 The characteristics of the total study population and three counties/cities included in the analysis of the first trimester........................................44
Table 4.5 The characteristics of the total study population and four TTHMs exposure groups included in the analysis of the third trimester ....................................47
Table 4.6 The characteristics of the total study population and three counties/cities included in the analysis of the third trimester........................................48
Table 4.7 Prevalence rates of various adverse birth outcomes by TTHMs exposure groups......................51
Table 4.8 The prevalence rates of congenital malformations among live births and stillbirths......................51
Table 4.9 Prevalence rates of congenital heart disease by potential risk factors.................................54
Table 4.10 Prevalence rates of nervous system defects by potential risk factors.................................56
Table 4.11 Prevalence rates of orofacial cleft by potential risk factors...........................................58
Table 4.12 Prevalence rates of all congenital malformations by potential risk factors..............................60
Table 4.13 Prevalence rates of stillbirth by potential risk factors................................................62
Table 4.14 Prevalence rates of TLBW by potential risk factors................................................64
Table 4.15 Prevalence rates of SGA by potential risk factors................................................66
Table 4.16 Prevalence rates of congenital heart disease by years..................................................70
Table 4.17 Prevalence rates of nervous system defects by years..................................................70
Table 4.18 Prevalence rates of orofacial cleft by years..71
Table 4.19 Prevalence rates of all congenital malformations by years.................................................71
Table 4.20 Prevalence rates of stillbirth by years.......72
Table 4.21 Prevalence rates of TLBW by years.............72
Table 4.22 Prevalence rates of SGA by years..............73
Table 4.23 The number of cases and adjusted ORs (95% CIs) for the association between maternal exposure to TTHMs averaged over the first trimester and various congenital malformations under two ways of classifying TTHMs exposure groups...................................................76
Table 4.24 The number of cases and adjusted ORs (95% CIs) for the association between maternal exposure to TTHMs averaged over the first trimester and stillbirth, and exposure to TTHMs averaged over the third trimester and TLBW and SGA under two ways of classifying TTHMs exposure groups...................................................77


List of Figures
Figure 4.1 Yearly average TTHMs concentrations (μg/L) by five areas in Taiwan, 2001-2005 and 2007-2009............32
Figure 4.2 Yearly average TTHMs concentrations (μg/L) by three counties/cities in Taiwan, 2001-2005 and 2007-2009..33
Figure 4.3 The complete monthly average TTHMs concentrations (μg/L) in Taipei City, 2001-2005 and 2007-2008.....................................................37
Figure 4.4 The complete monthly average TTHMs concentrations (μg/L) in Kaohsiung City, 2001-2005 and 2007-2008................................................37
Figure 4.5 The complete monthly average TTHMs concentrations (μg/L) in Kinmen County, 2005, 2007 and 2008.....................................................38
Figure 4.6 The complete monthly average TTHMs concentrations (μg/L) in north area, 2001-2005 and 2007-2008.....................................................38
Figure 4.7 The complete monthly average TTHMs concentrations (μg/L) in south area, 2001-2005 and 2007-2008.....................................................39
Figure 4.8 The complete monthly average TTHMs concentrations (μg/L) in east area, 2001-2005 and 2007-2008.....................................................39
Figure 4.9 The complete monthly average TTHMs concentrations (μg/L) in offshore islands, 2001-2005 and 2007-2008................................................40
Appendix A. Distribution of HAAs concentrations (μg/L) in Taiwan, 2006-2009.......................................109
Appendix B. Average concentrations (μg/L) of individual HAAs from 2006 to 2009 by five areas in Taiwan..........109
Appendix C. Average concentrations (μg/L) of HAA5, HAA6, and HAA9 from 2006-2009 by five areas in Taiwan.........110
Appendix D. Yearly average HAA9 concentrations (μg/L) by five areas in Taiwan, 2007-2009.........................110
Appendix E. Eurocat subgroups of congenitalmalformations.111

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