臨床毒物學

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1 從食安風暴談起 - 毒物科醫師的看法洪東榮中國醫藥大學附設醫院毒物科中國醫藥大學臨床醫學研究所藥物安全研究所

3 有害人體健康嗎? 會中毒嗎?

5 中毒的定義任何含有毒素的物質, 不管固體液體氣體的型態, 經由口服食入呼吸道吸入注射或皮膚接觸, 而進入人體, 破壞人體器官, 損害健康甚至造成死亡

7 Paracelsus ( 現代毒物學之父 ): 所有物質都是毒物, 沒有例外, 劑量是毒物與否的唯一決定性因素藥物 or 毒物致毒物任何物質在生物體會產生不良反應的, 稱之 Philippus Theophrastus Bombastus Von HOHENHEIM PARACELSUS ( )

9 部分代表性毒化物的半數致死劑量 ( 動物 ) 毒化物半數致死劑量 LD 50, mg/kg 酒精 10,000 氯化鈉 ( 食鹽 ) 4,000 Ferrous sulfate 1,500 Morphine sulfate 900 Phenobarbital 150 巴拉刈農藥 50 氰化鉀 5 番木鱉鹼 2 尼古丁 1 d-tubocurarine 0.5 河豚毒素 0.10 戴奧辛肉毒桿菌毒素

11 慢性暴露容許標準? 某種傷害 = 危害 1+ 危害 2+ 危害 3+ 危害 4+ 危害亞氯酸鹽未觀察到不良反應之劑量 (NOAEL)=2.9 mg/kg BW/day ( 動物實驗 ) 每日容許攝取量 (TDI, Tolerable Daily Intake) 為 30 g/ kg BW/day ---WHO

12 致癌性毒化物評估致癌性風險評估, 顧名思義就是針對具有致癌性的毒化物進行評估, 例如多氯聯苯 (polychlorinated biphenyls) 戴奧辛 (dioxin) 無機砷 (inorganic arsenic) 及甲基汞 (methylmercury) 等在人體或動物會造成癌症的物質被認為具有非閾值效應, 亦即並沒有安全暴露的水平任何暴露都具有一些風險, 當暴露增加, 致癌反應的機率也增加 ( 參見圖 3-3) NOAEL 毒性反應

13 致癌風險之推估 - 總致癌性風險總致癌風險為所有暴露途徑致癌風險之總和 ( 常用基準值 =10-6, 百萬分之一 ) n Riskt Riski i 1 Risk t = 單一暴露途徑致癌風險 Risk i = 第 i 個毒物個別致癌風險

14 國際癌症研究中心 (IARC) 將致癌物質分為四類分類證據例子 1. 人類致癌物充份 ( 人類 ) 石綿砷鈹鎘鎳黃麴毒素鉻氯乙烯單體苯環氧乙烷甲醛戴奧辛檳榔酒精多氯聯苯香菸苯并蒎 benzo(a)pyrene 2A. 對人類可能為致癌物 2B. 對人類懷疑為致癌物有限 ( 人類 ) 充份 ( 動物 ) 充份 ( 動物 ) 無 ( 人類 ) 無機鉛四氯丹瘧疾氯仿 DDT 多溴聯苯 3. 致癌證據不足不足 ( 動物 ) 氟化氫阿特靈 4. 無任何證據無

15 Cigarette as example 香菸看似無害. 燃燒時會放出約 4,000 chemical--a dangerous cocktail more than 70 cancer-causing chemicals hundreds of other poisons. nicotine, a highly addictive drug additives designed to make cigarettes taste nicer and keep smokers hooked

16 Cancer-causing chemicals in tobacco smoke Tar - a mixture of dangerous chemicals Arsenic - used in wood preservatives Benzene - an industrial solvent, refined from crude oil Cadmium - used in batteries Formaldehyde - used in mortuaries and paint manufacturing Polonium a highly radioactive element Chromium - used to manufacture dye, paints and alloys 1,3-Butadiene - used in rubber manufacturing Polycyclic aromatic hydrocarbons - a group of dangerous DNAdamaging chemicals Nitrosamines - another group of DNA-damaging chemicals Acrolein - formerly used as a chemical weapon Other chemicals

Alcoholic beverages Cancer of the oral cavity and pharynx Cancer of the larynx Cancer of the oesophagus Cancer of the liver Breast cancer Cancer of the stomach Cancers of the colon and/or rectum

17 Alcoholic beverages Cancer of the oral cavity and pharynx Cancer of the larynx Cancer of the oesophagus Cancer of the liver Breast cancer Cancer of the stomach Cancers of the colon and/or rectum Cancer of the pancreas Cancer of the lung Cancer of the urinary bladder Cancer of the endometrium Cancer of the ovary Cancer of the uterine cervix Cancer of the prostate Cancer of the kidney Cancer of the lymphatic and haematopoietic system Cancer at other sites

18 Aflatoxin 黃麴毒素 Environ Health Perspect June; 118(6):

Aristolochic acid-associated urothelial cancer in Taiwan Aristolochic acid, a potent human carcinogen produced by Aristolochia plants, is associated with urothelial carcinoma of the upper urinary

22 Aristolochic acid-associated urothelial cancer in Taiwan Aristolochic acid, a potent human carcinogen produced by Aristolochia plants, is associated with urothelial carcinoma of the upper urinary tract (UUC). Following metabolic activation, aristolochic acid reacts with DNA to form aristolactam (AL)-DNA adducts. These lesions concentrate in the renal cortex, where they serve as a sensitive and specific biomarker of exposure, and are found also in the urothelium,where they give rise to a uniquemutational signature in the TP53 tumor-suppressor gene. Using AL-DNA adducts and TP53 mutation spectra as biomarkers,we conducted a molecular epidemiologic study of UUC in Taiwan, where the incidence of UUC is the highest reported anywhere in the world and where Aristolochia herbal remedies have been used extensively for many years. Our study involves 151 UUC patients, with 25 patients with renal cell carcinomas serving as a control group. The TP53mutational signature in patients with UUC, dominated by otherwise rare A:T to T:A transversions, is identical to that observed in UUC associated with Balkan endemic nephropathy, an environmental disease. Prominent TP53 mutational hotspots include the adenine bases of 5 AG (acceptor) splice sites located almost exclusively on the nontranscribed strand. A:T to T:Amutations also were detected at activating positions in the FGFR3 and HRAS oncogenes. AL-DNA adducts were present in the renal cortex of 83% of patients with A:T to T:A mutations in TP53, FGFR3, or HRAS. We conclude that exposure to aristolochic acid contributes significantly to the incidence of UUC in Taiwan, a finding with significant implications for global public health.

23 癌病對個人及社會的衝擊!

24 可控制的致癌危險因子食物 35% 香菸 30% 酒精 5% 某種傷害 = 危害 1+ 危害 2+ 危害 3+ 危害 4+ 危害職業 4% 陽光 3% 病毒 5% 其他 12%

26 A regular diet including apiaceous vegetables ( 傘形科蔬菜 )such as carrots, parsnips( 美國食用芹菜 ), celery and parsley, may reduce the carcinogenic effects of aflatoxin (Food and Chemical Toxicology 44 (2006) ) 茴香香菜 (Parsley) 芫荽

27 Cruciferous Vegetables Arugula ( 芝麻 ) Bok choy Broccoli Brussels sprouts Cabbage Cauliflower Collard greens Horseradish( 辣根 ) Kale Radishes Rutabaga( 大頭菜 ) Turnips( 蘿蔔 ) Watercress( 豆瓣 ) Wasabi

28 Cruciferous Vegetables and Cancer Prevention Cruciferous vegetables rich in nutrients, including several carotenoids (beta-carotene, lutein, zeaxanthin); vitamins C, E, and K; folate; and minerals, and chemicals known as glucosinolates( 芥子油苷 ). They also are a good fiber source. Glucosinolates break down into several biologically active compounds that are being studied for possible anticancer effects. Some of these compounds have shown anticancer effects in cells and animals, but the results of studies with humans have been less clear.

29 Glucosinolates in cruciferous vegetables Glucosinolates are broken down to form biologically active compounds such as indoles, nitriles, thiocyanates, and isothiocyanates during food preparation, chewing, and digestion.(hayes et al. European Journal of Nutrition 2008;47 Suppl 2:73-88) protect cells from DNA damage. inactivate carcinogens. have anti-inflammatory effects. induce cell death (apoptosis). inhibit tumor blood vessel formation (angiogenesis) and tumor cell migration (needed for metastasis).

31 薑黃素抑制發炎反應

32 The dose makes the poison. Paracelcus ( , 現代毒物學之父 ): Everything is a poison, there is nothing which is not. Only the dose differentiates a poison from a remedy. Errors of omission. The major causes of cancer (other than smoking) do not involve exposures to exogenous chemicals that cause cancer in high-dose tests; rather, the major causes are dietary imbalances( 飲食均衡 ), hormonal factors( 荷爾蒙 ), infection( 感染 ) and inflammation( 發炎 ), and genetic factors( 遺傳 ). Insufficiency of many vitamins and minerals, which is preventable by supplementation, causes DNA damage by a mechanism similar to radiation. Ames, B.N. and Gold, L.S. Cancer Prevention and the Environmental Chemical Distraction In: Politicizing Science: the Alchemy of Policymaking. Michael Gough ed., Hoover Institute Press, Stanford, California. pp

33 Figure 1 Lifecycle GHG emissions (CO2-Ceq) for 22 different food types.the data are based on an analysis of 555 food production systems: a, per kilocalorie; b, per United States Department of Agriculture (USDA)-defined serving; c, per gram of protein. The mean and s.e.m. are shown for each case. Extended Data Tables 1 3 list data sources, items included in each of the 22 food types and show the mean, s.e.m. and number of data points for each bar, respectively. NA, not applicable.

36 謝謝各位的用心聆聽歡迎批評指教

Toxicology is a Multidisciplinary Field of Study Pharmacology Pathology Physiology Chemistry Public Health Biology Immunology Toxicology Environmental

Toxicology is a Multidisciplinary Field of Study Pharmacology Pathology Physiology Chemistry Public Health Biology Immunology Toxicology Environmental - Pollutant is a substance present in greater than natural concentration as a result of human activity, and which has a net detrimental effect upon its environment or upon something of value in that environment.

臨 床 毒 物 學

臨床毒物學