高氯酸鹽、硝酸鹽及硫氰酸鹽為近年來受關注之甲狀腺干擾物質，常應用於工業、軍事和農業上，可透過生產、使用及廢棄等過程而釋放至環境介質，因其具高水溶性且化學穩定之特性，使得廣泛存在於環境水體、土壤及空氣當中，進而污染飲用水及食物。人體可以透過攝入、吸入及皮膚接觸方式暴露高氯酸鹽、硝酸鹽及硫氰酸鹽，以飲食攝入為主要暴露途徑。過去已有許多研究均指出，碘為製造甲狀腺荷爾蒙之主要元素，但高氯酸鹽、硝酸鹽及硫氰酸鹽進入人體後，會競爭性抑制甲狀腺細胞對碘離子之吸收，導致甲狀腺荷爾蒙分泌不足，進而影響人體代謝功能及生長發育。其中，懷孕婦女及胎兒為主要之敏感族群，懷孕初期胎兒之大腦及中樞神經發育皆需仰賴母體之甲狀腺荷爾蒙，若懷孕婦女甲狀腺荷爾蒙分泌不足，則可能影響胎兒之生長發育。台灣於2018年雖已分析甲狀腺干擾物質之暴露對甲狀腺功能之影響，但其樣本數較少，故需進再進一步調查，除了生物偵測之方法以外，過去已針對群體暴露進行高氯酸鹽之模式預測，但對於個體仍缺乏預測性，因此本研究的目的為評估懷孕婦女暴露於高氯酸鹽、硝酸鹽及硫氰酸鹽對其甲狀腺功能之影響，並應用以生理學為基礎之藥物動力學模式（Physiologically-based pharmacokinetic model, PBPK model）探討個體之飲食暴露與尿液中生物指標之相關性。
　　本研究自成大醫院婦產科門診招募205位懷孕婦女，並排除其他甲狀腺干擾物質相關之職業暴露以及服用荷爾蒙藥物治療者，簽署人體試驗同意書後，進行問卷調查、尿液及血液樣本採集，尿液樣本進行高氯酸鹽、硝酸鹽、硫氰酸鹽及尿碘濃度之量測，血液樣本進行甲狀腺荷爾蒙及相關抗體之檢測，以探討高氯酸鹽、硝酸鹽及硫氰酸鹽之暴露對甲狀腺功能之影響，並利用Berkeley Madonna建立PBPK模式以預測尿液中生物指標濃度。205位受試者之平均年齡為35歲，各孕期之平均懷孕週數為10、25及34週，其每孕期（第一孕期：0-16週、第二孕期：17-29週、第三孕期：30週-分娩）之尿液濃度檢測結果，高氯酸鹽濃度：6.92 vs. 9.61 vs. 9.76 μg/L、硫氰酸鹽濃度：1116 vs. 1554 vs. 1465 μg/L，硝酸鹽濃度：63.5 vs. 62.1 vs. 66.3 mg/L，尿碘數濃度：87.5 vs. 93.2 vs. 87.8 μg/L，依據世界衛生組織（World Health Organization, WHO）訂定尿碘建議值150 μg/L，結果顯示本研究之懷孕婦女對碘營養攝取仍為不足。經creatinine校正後高氯酸鹽、硫酸酸鹽、硝酸鹽及碘離子濃度之ICC介於0.01-0.25。飲食調查結果顯示，以日暴露劑量進行分組，高暴露組其對蔬菜及水果類食品之攝食量顯著高於低暴露組（P<0.05）。高氯酸鹽、硝酸鹽及硫氰酸鹽與尿碘濃度四者間互相呈顯著正相關，高氯酸鹽與游離三碘甲狀腺荷爾蒙（Free Triiodothyronine, FT3）呈顯著負相關，與促甲狀腺刺激素（Thyroid-stimulating hormone, TSH）呈顯著正相關；硫氰酸鹽與四碘甲狀腺荷爾蒙（Thyroxine, T4）和游離四碘甲狀腺荷爾蒙（Free Thyroxine, FT4）呈顯著負相關，與TSH呈顯著正相關；硝酸鹽及高氯酸鹽毒性當量濃度（Perchlorate Equivalence Concentration, PEC）與FT4呈顯著正相關。以複迴歸分析並校正干擾因子後（年齡、BMI、懷孕週數等），結果顯示於不分孕期下，尿液中高氯酸鹽、硫氰酸鹽及其日暴露劑量、PEC與硝酸鹽之日暴露劑量與尿碘濃度呈顯著正相關（β=79.5, P<0.01；β=72.6, P<0.05；β=77.7, P<0.01；β=69.1, P<0.05；β=63.8, P<0.05；β=58.9, P<0.05），尿液中高氯酸鹽濃度及其日暴露劑量與血液中TSH呈顯著正相關（β=0.057, P<0.05；β=0.060, P<0.05），尿液中硫氰酸鹽濃度及其日暴露劑量均與T4（β= -0.218, P<0.05；β= -0.210, P<0.05）和FT4呈顯著負相關（β= -0.014, P<0.05；β= -0.013, P<0.05），且尿液中硫氰酸鹽與TSH呈顯著正相關（β= 0.057, P<0.05）。使用混合線性模型分析於重複量測下高氯酸鹽、硝酸鹽及硫氰酸鹽之暴露對甲狀腺功能之影響，結果顯示尿液中高氯酸鹽、硫氰酸鹽、硝酸鹽及其日暴露劑量和PEC與尿碘濃度皆呈顯著正相關（P<0.01）；尿液中硫氰酸鹽濃度及其日暴露劑量與T3和T4呈顯著負相關（P<0.05），與TSH呈顯著正相關（P<0.05）；於懷孕前中期硫氰酸鹽、硝酸鹽和PEC與T4亦呈顯著負相關（P<0.05）。進一步探討高氯酸鹽、硝酸鹽及硫氰酸鹽之共同暴露影響甲狀腺荷爾蒙平衡之貢獻，結果顯示尿液中硝酸鹽濃度及其日暴露劑量對FT3之貢獻權重為最高（66.7 vs. 69.2%），尿液中高氯酸鹽則對FT4貢獻權重為最高（53%）。計算其飲食攝入劑量以PBPK模式預測個體之多點尿液中生物指標之濃度與實測值具有高度相關（r = 0.83），單點尿液則僅有中度相關（r = 0.51），尤其是第三孕期時具有較高之預測效率。
　　綜合上述結果，若懷孕婦女於碘攝取不足之情況下，同時暴露於高氯酸鹽、硝酸鹽及硫氰酸鹽將會抑制甲狀腺細胞對碘離子之吸收，而加劇影響甲狀腺荷爾蒙之調控平衡。完善之PBPK模式可以成功預測個體單點及多點尿液中高氯酸鹽之濃度，且具有中至高度之預測效力。本篇為首篇應用PBPK模式應用於探討懷孕婦女高氯酸鹽暴露與尿液中生物指標之相關性研究，未來可以將模式運用於風險評估，以進一步探討高氯酸鹽進入甲狀腺器官對碘離子吸收之抑制情形。

The objectives of present study are to investigate the association between perchlorate, nitrate and thiocyanate exposure and thyroid function in pregnant women, and use the PBPK model to link urinary biomarker concentrations with dietary exposure of perchlorate. 205 pregnant women were recruited from obstetrics and gynecology clinics in NCKU in southern Taiwan. The mean maternal age is 35 years, and the gestation weeks of three trimesters are 10, 25 and 34 weeks, respectively. Urinary perchlorate, nitrate, thiocyanate and iodide concentrations in three trimesters were 6.92 vs. 9.61 vs. 9.76 μg/L, 63.5 vs. 62.1 vs. 66.3 mg/L, 1116 vs. 1554 vs. 1465 μg/L, 87.5 vs. 93.2 vs. 87.8 μg/L, respectively. The results of dietary surveys showed that the high exposure group of perchlorate, thiocyanate and nitrate had significantly higher intake of vegetables and fruits than the low exposure group (P<0.05). After adjusting for the confounding fators, urinary levels and daily intakes of perchlorate, nitrate, thiocyanate and PEC were significantly positively associated with UIC (all P<0.05). Perchlorate and thiocyanate were significantly positively associated with TSH. Thiocyanate was significantly negatively associated with T4 and FT4. We used the linear mixed model to assess the effect of perchlorate, nitrate and thiocyanate exposure on thyroid function under repeated measurements. Thiocyanate was significantly negatively associated with T3 and T4, and positively associated with TSH. Weighted quantile sum (WQS) regression results also show that nitrate and perchlorate have the highest weights in reducing serum FT3 and FT4, respectively. PBPK model was used to predict that the concentration of biomarkers in the urine of individuals and the results showed highly correlated with the measured data (r =0.83). In conclusion, exposure to environment perchlorate, nitrate and thiocyanate may reduce the iodide absorption and disrupt thyroid hormones balance during pregnancy. The well-established PBPK model can successfully predict the concentration of biological indicators in individual or multiple urine in our participants.

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