全氟碳化物在嚙齒動物的毒理動力學研究

Toxicokineticstudies of perfluorinated chemicals in rodents

劉千玉(Chien-Yu Liu)

指導教授 ： 吳焜裕

國立臺灣大學/公共衛生學院/職業醫學與工業衛生研究所/碩士(2012年)

https://doi.org/10.6342/NTU.2012.02791

摘要

全氟碳化物是一種人工合成的物質，因為本身物理和化學性質皆很穩定，過去被廣泛運用於商業中，而科學家在全球各地的環境、動物甚至人類身上都廣泛的偵測到全氟碳化物，因全氟碳化物隨著結構上碳數的增加會使半衰期延長，且不易從生物體中被代謝，引起大家的關注，許多動物及人類的研究發現全氟碳化物會造成生物體肝臟、腎臟及生殖器官的危害甚至有致癌性。全氟碳化物種類相當多，但實際上有研究半衰期的種類屈指可數，如果在體內停留時間越久，慢性危害就更令人擔憂，而多種全氟碳化物同時存在生物體內，彼此間的半衰期及代謝速率等會如何交互影響都值得進一步探討，因此本研究主要探討全氟碳化物的共同暴露在SD大鼠體內所造成的交互作用。
在動物實驗方面將SD大鼠(N=3)分為控制組、低暴露組和高暴露組，利用胃灌食在低暴露組餵與0.002 mg/kg PFBA、PFHxA以及 0.05 mg/kg PFOA、PFNA、PFOS、PFDA和PFDoDA；高暴露組餵與0.0125 mg/kg PFBA、PFHxA以及 1 mg/kg PFOA、PFNA、PFOS、PFDA和PFDoDA，並在不同時間點收集大鼠的血液和尿液，利用新發展的線上固相萃取結合液相層析串聯質譜儀方法分析全氟碳化物，並利用藥物動力學的模式分析數據。
實驗結果發現PFBA在高暴露組於暴露後的2個小時血液中可測到325 ng/mL，而24小時後只偵測到濃度約42 ng/mL左右，在暴露後四小時尿液中的濃度可達573 ng/mL之後便偵測不到。在高暴露組於暴露後2小時在血液中測到微量濃度約3-4 ng/mLPFHxA，在暴露後四小時尿液中可高達1954 ng/mL，之後便無法偵測不到。PFOA、PFNA高暴露組在暴露2小時候，血液中濃度可高達7000左右ng/mL，但PFNA在尿液中濃度最高約100 ng/mL左右而PFOA可高達1100 ng/mL，PFNA從尿液中代謝少，而血液中濃度在81天時仍維持400-1000 ng/mL。PFOS、PFDA在高暴露組於暴露後兩小時濃度達2000-3000 ng/mL，但在尿液中只能偵測到~50 ng/mL左右的濃度，血液中濃度在81天時仍維持400-1000 ng/mL的濃度。PFDoDA在高暴露組暴露2小時候濃度約1000 ng/mL左右，尿液中無法測量，在暴露後81天血液中仍有300 ng/mL左右濃度。可見碳鏈的長短會影響全氟碳化物在生物體的半衰期長短以及是否從尿液中代謝。
從實驗結果發現大鼠同時暴露多種全氟碳化物會造成PFOA和PFNA的半衰期延長。在SD大鼠病理切片證實，同時暴露多種全氟碳化物會使得高暴露組(1 mg/kg)SD大鼠肝臟出現脂肪小泡，且使睪丸的精子生成減少，而整理文獻後發現多種全氟碳化物同時暴露會造成毒性加成反應，雖然各別的全氟碳化物效應影響必須在進一步的執行實驗佐證，但仍表示在環境中同時暴露多種低濃度的全氟碳化物會有毒性累積的危害。

關鍵字

全氟碳化物 ； 半衰期 ； 藥物動力學

並列摘要

Perfluorinated chemicals (PFCs) include a group of man-made organic compounds, which are very stable and widely used in commercial and industrial applications. Recently, exposures to PFCs are concerned about their widely present in the animals and humans. They may cause potential adverse health effects to human such as hepatoxicity, nephrotoxicity, reproductive toxicity, and endocrines interference. At present, kinetic data is only available for single compound among a few of PFC. However, human have been exposed to a mixtures of PFCs in daily life. Therefore, the objective of this study is to explore the kinetics of PFCs mixtures in rodents to evaluate the potential interactions due to co-exposures to PFCs mixtures.
The male SD rats were classified into control, low exposure, and high exposure groups. Low exposure group were treated with a mixtures of 0.002 mg/kg PFBA、PFHxA and 0.05 mg/kg PFOA、PFNA、PFOS、PFDA and PFDoDA , and the high exposure group were treated with a mixtures of 0.0125 mg/kg PFBA、PFHxA and 1 mg/kg PFOA、PFNA、PFOS、PFDA and PFDoDA by the oral gavage. Subsequently urine and serum samples were collected and analyzed for these PFCs with a newly-developed on-line solid-phase extraction liquid chromatography tande, mass spectrometry (LC-MS/MS) method. These data were analyzed to construct their pharcokinetic models.
After data analysis, results show that PFBA can be eliminated during 24 hours from urine, and PFHxA is most rapidLy eliminated so that it was not detectable in serum or urine at 4 hours after treatment. At 2 hours after treatment, the PFOA and PFNA concentration in serum reached the maximum at 7000 ng/mL. PFNA was not well metabolized and excreted from urine and maintained the steady level in serum even at 81 days after treatment. PFOS、PFDA、PFDoDA couLd be determined at 1000-2000 ng/mL in serum at 2 hours after treatment, however, they couldn't be detected at urine ,so they retained 500~1000 ng/mL in the serum.
These results suggest that the longer is the carbon chain of the PFCs; the longer is their half life; however, the half-lives of PFOA and PFNA may increase for co-exposure PFCs .The study showed that co-exposure PFCs at dose of 1 mg/kg would induce reproductive toxicity and liver toxicity, and we comprised the reference to find the addition reaction of toxicity.

並列關鍵字

Perfluorinated chemicals ； Half-Lives ； Pharmacokinetics

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