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標題: 三聚氰胺與三聚氰酸混合對大鼠亞慢性腎毒性作用及回復試驗之研究
The Subchronic Feeding Study of Melamine and Cyanuric Acid Mixture-Induced Nephrotoxicity and Recovery in Rats
作者: Ching-Ann Wu
關鍵字: 三聚氰胺;三聚氰酸;melamine;cyanuric acid
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三聚氰胺具高含氮量特性,自2004年起動物飼料及人類奶粉被添加入三聚氰胺,以假性增加蛋白質含量,卻引致動物高致死率之急性腎衰竭,以及人類孩童因尿路結石之阻塞性腎病。目前已有許多文獻闡述各種動物口服投予三聚氰胺和三聚氰酸 (melamine–cyanuric acid, MCA)混合之短期毒性試驗及致病機制探討。而在本研究中,則是進行對大鼠中長期3個月亞慢性毒理試驗,並以傳統組織病理學佐以泌尿道損傷相關生物指標蛋白及氧化酵素表現量,作為腎毒性傷害敏感性之判斷依據,以推定「無顯著毒害作用劑量」(no-observed-adverse-effect level, NOAEL),進而推算人體每日可攝取量 (acceptable daily intake, ADI)。
六週齡大鼠(SD品系),每組20隻,雌雄各半。依據28天前試驗結果,以1:1 MCA混拌飼料餵食藥物劑量濃度選擇,分別雄鼠為低劑量 (100 ppm, M100)、中劑量 (150 ppm, M150)及高劑量 (200 ppm, M200)和雌鼠為低劑量 (100 ppm, F100)、中劑量 (200 ppm, F200) 及高劑量 (300 ppm, F300)連續13週,及雌、雄高劑量組 (FR300, MR200)停藥4週之回復試驗。結果在雌性大鼠F200、F300組,BUN和creatinine具顯著性上升,但於雄性大鼠M200組皆不見具臨床意義之增加。SOD、catalase的氧化傷害和腎組織總蛋白評估中發現catalase在雌性大鼠劑量200 ppm以上時即具顯著下降,而SOD、腎組織總蛋白至F300組時,兩者皆大幅度的降低,巨噬細胞於慢性炎症反應分泌之細胞激素IL-1β表現量的評估中,雌性大鼠於F200組以上即具顯著性增加,但於雄性大鼠皆無改變,顯示雌性大鼠給予劑量300 ppm時,腎組織經歷嚴重的炎症反應及氧化壓力,此外,在被認為極具敏感性及診斷意義的泌尿道相關生物指標蛋白KIM-1和NGAL的表現量,可見於雌、雄大鼠投予劑量大於或等於200 ppm的組別均表現出顯著性差異,低於200 ppm均無變化,但組織病理學檢查下,顯示雄性大鼠於M150組仍可見腎小管內MCA結晶沉積,且造成腎小管局部擴張、腎間質單核細胞浸潤、腎小管壞死、再生的特徵性的病變,需至M100組雄性大鼠才未出現因誘導而產生的特徵性組織傷害。
綜合以上,在偵測及判斷腎毒性傷害,著重應用新的泌尿道相關生物指標蛋白時,於毒性試驗的毒理評估,組織病理學變化的判讀仍具有重要的影響力,應視為首要的參考依據。因此以組織病理學檢查為最終依據,MCA之NOAEL值為100 ppm,經換算後雌雄鼠每日每公斤體重攝取量分別為9.7及7.2 mg/kg bw/day,依100倍安全係數推算人類每日ADI 為0.07 mg/kg bw/day,遠低於WHO (0.2 mg/kg) 與ESFA (0.5 mg/kg),針對單獨攝取三聚氰胺之每日可攝取量。本實驗結果可作為日後訂定三聚氰胺和三聚氰酸混合毒性之安全性閥值參考依據。

Melamine has been used to adulterate animal food and infant formula in order to give false elevated results in the protein content of food. It's a well-known issue that simultaneous ingestion of melamine and cyanuric acid (MCA) could induce acute renal failure and high mortality in animals or obstructive nephropathy in infants. Many investigators have been devoted to the studies of MCA combined toxicity and the mechanisms of MCA-induced renal injury. In our study, we conducted the subchronic toxicity test of nephrotoxicity of melamine and cyanuric acid combination via repeated feeding for 13 weeks, and the possible recovery effect in rats. The data were evaluated by histopathologic examination, the gold standard for assessing a compound's effect on an animal system of nephrotoxicity, the urinary biomarkers and oxidative enzymes. The objective of our study was to evaluate the acceptable daily intake (ADI) in human by assessing the no-observed-adverse-effect level (NOAEL) in subchronic nephrotoxicity study of MCA combination via repeated feeding in rats.
Sprague-Dawley rats (10 males and 10 females per dose group) were fed ad libitum for 13 weeks with 0 (control), 100, 150, 200 ppm in both sex and 300 ppm (female only). Furthermore, the recovery groups for 4 weeks were designed as 0, 200 ppm in male and 0, 300 ppm in female. The results of BUN and creatinine showed significantly increase in the F200, F300 groups of females, but not in M200 group of male rats. In the F200, F300 groups of female rats, the oxidative stress markers, SOD and catalase, showed significant decrease and inflammatory cytokine, IL-1s, were significantly increased. The data confirmed that renal tissue is overwhelmed by the oxidative stress and severe inflammatory response. The urinary biomarkers, KIM-1 and NGAL, which is considered to be more sensitive and diagnostic markers of nephrotoxicity caused by MCA, showed significant increased in both M200 and F200 group of male and female rats, but not in the lowest 100 ppm group. Otherwise, histopathologic examination showed the results that MCA crystals still could cause the MCA lesions such as deposition of MCA crystal, mononuclear cell infiltration in interstitial area, tubular dilation, regeneration and necrosis in kidney, above 150 ppm dosage group, implied that the safety risk in this dosage.
Based on the results, the histopathological examination of renal lesions should be the primary consideration of renal damage in nephrotoxical evaluation. The NOEAL of 100 ppm MCA was set in rats in the 13-week repeated subchronic study. There is equivalent dosage of MCA to be about 7.2 mg/kg bw/day in both sexes. According to this result, the acceptable daily intake (ADI) in human is recommended to be 0.07 mg/kg bw/day of MCA.
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