狂牛病的警訊 周晉澄 Chin-Cheng Chou, DVM, Ph.D. 國立台灣大學獸醫學系教授 Institute of Veterinary Medicine National Taiwan University Taipei, Taiwan chouchin@ntu.edu.tw 02-23630495; 02-33661292

畜產業生產人類食用的優質動物性蛋白，獸醫則確認各種動物的健康及動物性產品的安全與衛生 專業目的 畜產業生產人類食用的優質動物性蛋白，獸醫則確認各種動物的健康及動物性產品的安全與衛生

各類型經濟動物養殖場: 豬、牛、 羊、鹿、兔、雞、鴨、鵝、魚、 蝦、甲魚、牛蛙等; 野生動物園; 寵物畜養場; 動物醫院; 屠宰場、化製廠等 獸醫畜產環境 各類型經濟動物養殖場: 豬、牛、 羊、鹿、兔、雞、鴨、鵝、魚、 蝦、甲魚、牛蛙等; 野生動物園; 寵物畜養場; 動物醫院; 屠宰場、化製廠等

獸醫畜產環境公害 旨揭該環境引起人們不愉快之感受，即構成公害的條件。這些感受可能經由空氣、水、廢棄物等途徑引起，不悅的感受不一定必須以引起疾病之有無作為判斷的依據。獸醫畜產環境的維護在於公共衛生的認知，尤其是獸醫公共衛生的充分發揮。

獸醫公共衛生 Veterinary Public Health Veterinary Public Health (VPH) was defined by the WHO consultation on "future trends in veterinary public health" held in Teramo, Italy in 1999 as "the sum of all contributions to the physical, mental and social well-being of humans through an understanding and application of veterinary science". -- 即以獸醫科技來促進人類的身心健康福祉！

牛海綿狀腦病 (BSE) -- 養牛業與化製業的噩夢 Known as Human Mad Cow Disease (人類狂牛病) or new variant Creutzfeldt-Jakob disease(vCJD; 新型庫賈氏病) Long incubation period of 5 to 20 years (May be more than 50 years – The Lancet, 367: 2068-74, 2006) 217 vCJD patients (1996-2009. 10) 11 countries: UK 170, France 25, Spain 5, Ireland 4, USA 3, Netherlands 3, Portugal 2, Italy 2, 1 each in Canada, Japan and Saudi Arabia

Bovine Spongiform Encephalopathy (BSE) Infectious, progressive neurodegenerative, fatal brain disease in cattle – first identified in 1986 in UK Suspect pathogen: Accumulation of protein infectious particle PrPSC (normal cellular prion protein普利昂蛋白PrPC converted into PrPSC) in nervous tissue Incubation period of 20 months to more than 10 years before showing ataxia, attitude and behavior changes, uncoordinated movements, trouble standing and walking, weight loss clinical symptoms, and may process from 2 weeks to 6 months and dies eventually

Pathogenesis of BSE Oral exposure – trapping of BSE agent in lymphoid tissue of gut After oral challenge, detect BSE first in distal ileum associated with Peyer’s patches in 6 months Transport the agent (abnormal prion protein) to Central Nervous System (CNS) – (along nerve tracks?) Accumulation of abnormal prion protein in brain, spinal cord, and nervous tissue Detectable only 3-6 months prior to clinical signs

The Global Spread of BSE Japan 2001 2000 1989 1986 2002 1997 Canada USA 2003 1997 2000 2001 2001 1990 1991 2001 2001 This slide demonstrates that BSE has become a truly global phenomenon which is no longer isolated to Europe. All of the countries shown on this map have experienced some period of trade disruption for beef. 1994 2001 2000 Israel 2002

World Animal Health Situation 25 BSE countries between 1989 and 2009 Austria, Belgium, Canada, Czech Republic, Denmark, Finland, France, Germany, Greece, Ireland, Israel, Italy, Japan, Liechtenstein, Luxembourg, Netherlands, Poland, Portugal, Slovakia, Slovenia, Spain, Sweden, Switzerland, UK, USA

狂牛病的警訊 18世紀就有羊的搔癢症了，為何沒有人類的病例傳出呢? 變性蛋白質病原經一次的跨物種傳播後可能獲得改變宿主範圍的能力， 因此當羊的搔癢症病原感染牛後，可能改變病原特性，而可以感染另一物種人類了!

The incidence of BSE and vCJD

Risk Goods Cattle feed with meat and bone meal (MBM) containing infectious prion protein Significant accumulation of prion at cattle body- Specific Risk Materials (SRM): Brain, trigeminal ganglia, spinal cord, dorsal root ganglion, eyes of cattle age > 30 months, and distal ileum of the small intestine and tonsil from all ages (OIE)

Specified Risk Materials 9 CFR §310.22 January 12, 2004 Spinal Cord Vertebral Column Dorsal Root Ganglia Brain Skull Eyes Trigeminal ganglia One of the more important aspects of the new USDA BSE mitigation rules is the identification of BSE Specified Risk Materials (SRM’s). In cattle greater than 30 months of age, several primary and secondary nervous tissues have been identified (Brain, TRG, DRG, Spinal Cord and Eyes). Because the entry of the agent (the prion) is believed to be through some lymphoreticular tissues (normal entry points for digested nutrients) , the tonsils and the distal ileum of the small intestine have been identified as BSE risk materials in cattle of all ages. Tonsils Tonsils Distal Ileum (Small Intestine) Distal Ileum (Small Intestine) > 30 Months of Age < 30 Months of Age

SRM List Reg (EC) 999/2001- Annex XI (update 04/22/2008) Bovines: Animals > 12 months: Skull (excluding mandible), Brain, Eyes, Spinal cord. Animals > 30 months: Vertebral column (excluding the vertebrae of the tail, spinous and transverse processess of the cervical, thoracic and lumbar vertebrae and the median sacral crest and the wings of sacrum), Dorsal root ganglia Animals of all ages: Tonsils, Intestines (from the duodenum to rectum), Mesentery Ovines and Caprines: Animals > 12 months (or which have a permanent incisor): Skull, Brain, Eyes, Tonsils, Spinal cord Spleen and Ileum

BSE transmission Oral transmission Meat-and-bone meal (MBM) Environmental residues Sewage sludge, Soil, Wastewater from slaughterhouse Maternal transmission Iatrogenic transmission Medical applications: Serum, blood, implant, vaccine Tallow-based calf milk-replacer Horizontal transmission (Lupi, 2006) From skin and mucous membranes by ectoparasites (Wilesmith et al., 1991) (Gale, 2001; Rigou et al., 2006; Gungmundur et al., 2006; Brown et. al., 1991; Yamamoto et. al., 2006) (Cohen et al., 2003; Castilla et al., 2005) (USDA, 2001; Chou et al., 2005 ; Bradbury, 1999) 可試著做動畫 Waste water from slaughterhouse (Rigou et al., 2006; Gungmundur et al., 2006) 本張投影片可以做圖畫來描述會更生動 (Paisley LG and Pedersen JH, 2003)

Dose-Response Assessment Infection Dose: 100% infection: > 2.0 co ID50 (Joshua et. al., 2003) The most accessible age: 1.31 years (Cummmins et al., 2001) Infectivity of SRM: Brain 5000 co ID50 Spinal cord 2000 co ID50 Trigeminal ganglia 200 co ID50 Dorsal root ganglion 300 co ID50 (Brain 64.1%, Spinal cord 25.6%, Trigeminal ganglia 2.6%, Dorsal root ganglia 3.8%, Ileum 3.3%, Eyes 0.04%)

Uncertainty Dose-response Summary of attack rate and IP (incubation periods, months) according to dose of BSE-affected brain. Dose-response (J. Gen. Virol. 2007; 88:1363-1373) Dose Attack rate* IP Rangea Mean SEM Phase 1 3 × 100 g 100 g 10 g 1 g 10/10 7/9 7/10 33–45 31–60 41–72 45–72 37 44 53 58 1.2 2.8 4.9 3.2 Phase 2 100 mg 10 mg 1 mg 3/4b 7/15 1/15 58–73 53–98 56 68 65 72 4.4 6.6

Infectivity of the beef, bone, blood, and milk? OIE: no infectivity, free trade 老鼠肌肉發現普利昂蛋白，打破動物肌肉不會含有狂牛症病原的迷思 (Prusiner, 2002) 2008年，日本在牛的舌頭和骨骼肌的周邊神經組織中檢驗出了狂牛症病原！(如舌下、迷走、胸腺、腎上腺、內臟、交感、臂叢、坐骨神經等) (陳順勝) Infectivity in skeletal muscle of BASE-infected cattle (Silvia Suardi1, 2009) 骨呢? -- 骨髓, 骨附屬物等有明顯感染力

Exposure Assessment 7500 co ID50 reduced to 34 co ID50 (Morley, 2003) Rendering Processes: -50 mm, 133oC, 20 mins, 3 bar (OIE) - No infectivity or Decrease infectivity? Decrease 200-1000 folds (Schreuder, 1998), Decrease 50-100 folds (Taylor, 1995) 7500 co ID50 reduced to 34 co ID50 (Morley, 2003) to 1.7co ID50 (Paisley, 2005) Incineration: Fly ash and Bottom ash 8.7*10-101.7co ID50 (Paisley, 2005)

Risk Control Feed ban SRM removal Death, Disable, Diseased, Downer Testing Active surveillance and monitoring

反芻飼料的禁用　 牛海綿狀腦病之主要傳播途徑為餵飼肉骨粉予牛群所致，雖於因應措施中已禁止肉骨粉之輸入，台灣農委會(美國亦同)於1997年8月依照國際動物衛生法典規定，公告禁止國內反芻動物肉骨粉餵飼反芻動物，又於2001年12月(美國則至2008年4月）公告禁止動物性飼料（魚源除外）餵飼反芻動物

Percentages of breaches in ruminant feed and raw materials (EU15) 2001 2002 2003 2004 2005 Ruminant Feed 2.89 0.12 0.18 0.16 0.05 Raw Materials 1.73 0.63 0.54 0.47 0.33 (%) EU, 2006.

屠宰牛隻年齡為30月齡以內 99.87%的牛海綿狀腦病病例是30月齡以上的牛隻，限制屠宰牛隻的年齡為30月齡以下，可有效排除大部分可能病例 美日EV規定，輸出日本牛隻屠體綜合成熟度調查的結果評分為A40要求為20月齡以下

牛籍回溯系統 2005年7月美國開始執行牛籍管理制度(非強迫性) ： 假使輸入的牛隻ㄧ旦發現有病原存在，能回溯追蹤到原來的飼養場、族群及屠宰場等。 如果不限制來源證明，是有回溯盲點。加拿大與日本則都納入管理。整體上在制度面與資料的透明公開管理，孰勝孰非？ 美日EV規定，屠牛必須做牛海綿狀腦病篩檢及屠宰場、飼養場和製造者亦必須符合規定，牛隻(包含個體和族群)必須能追溯到屠畜生前之出生與製造記錄 美韓EV規定中要求必須保留屠宰記錄2年 台灣並沒有類似要求 台灣只要求牛隻必須在美國屠宰

EU 27 BSE monitoring of 2007 Active monitoring: Passive monitoring: - 1,445,280 risk bovine animals (Fallen, Emergency slaughter, Clinical signs at AM). - 8,262,517 healthy slaughtered animals - 1,466 animals culled in connection to BSE case Passive monitoring: - 1860 official BSE suspects. Results of 174 BSE positives:91% from Active and 9% from passive monitoring.

BSE普測還是高風險檢測? 美國在2004-2006年8月採樣了約79萬個牛隻樣本(每二百五十頭採樣一頭)，包含健康與高風險族群，共篩檢出兩個病例。之後至今則降低約十倍(每二千五百頭採樣一頭)，主要為高風險族群。在一億頭飼養牛隻的美國至今共發現三個病例。 日本上市者都要接受測試的，每年大約檢測125萬頭。四百四十萬飼養牛隻頭數的日本有36個病例(2009年亦有)。 加拿大自2004年後每年採樣高風險族群至少3萬頭牛隻檢測(約500頭採樣一隻，但實際每年採樣測試約5萬個樣本)。在一千五百萬飼養牛隻頭數的加拿大有18個病例發現(2009年仍有)。 加拿大飼養方式與美國類似，美加邊境牛隻來往頻繁，很多加拿大牛隻肥育期是在美國境內牧場完成並屠宰，所以很難分彼我。就這種管理、測試比例及技術等，美國真的僅此三例?

GBR Classfication (): EFSA assessment; *:SSC reassessment GBR level Countries GBR I: high unlikely Uruguay, Botswana (II), Namibia (II), Nicaragua (II), Swaziland (II), Singapore, Brazil (II), New Caledonia, Costa Rica (II), El Salvador (II), Panama (I), Iceland, Vanuatu, Australia(I), Norway (II), Argentina (I), Chile (III), Paraguay (I), New Zealand (I) GBR II: unlikely but not excluded Colombia, India, Mauritius, Pakistan, Kenya, Nigeria, Canada (III), Sweden (II), USA (III), Austria* (III 2005/05), Finland*(III 2005/05) GBR III: likely but not confirmed or confirmed at a lower level Switzerland, Lithuania, Albania, Czech, Japan, Hungary, Poland, Slovak Republic, Cyprus, Estonia, Belarus, Former Yugoslavian Republic of Macedonia, Romania, Slovenia, Bulgaria, Croatia, Latvia, San Marino, Turkey, Belgium, Denmark, France, Germany, Ireland, Italy, Luxembourg, Netherlands, Spain, Israel, Malta, Andorra, Greece GBR IV: confirmed at a high level Portugal, United Kingdom (): EFSA assessment; *:SSC reassessment

BSE Status of OIE Members Negligible BSE risk 10 countries Argentina, Australia, Chile, Finland, Iceland, New Zealand, Norway, Paraguay, Singapore, Sweden and Uruguay. Controlled BSE risk 32 countries Austria, Belgium, Brazil, Canada, Chinese Taipei, Colombia, Cyprus, Czech Republic, Denmark, Estonia, France, Germany, Greece, Hungary, Ireland, Italy, Japan, Latvia, Lichtenstein, Lithuania, Luxembourg, Malta, Mexico, Netherlands, Poland, Portugal, Slovak Republic, Slovenia, Spain, Switzerland, United Kingdom, United States of America Undetermined BSE risk (Adopted by the International Committee of the OIE on 11 June 2009)

Why is Taiwan a controlled risk area? I come from USA. I come from Taiwan. I come from UK.

Importation Permission of Beef Product into Taiwan Country Bone-in beef Boneless beef Offal BAPHIQ certificated beef industries USA Y ◎ Canada Australia New Zealand Panama Nicaragua Honduras Paraguay Costa Rica <BAPHIQ, 2007.10.15>

BSE Exposure Assessment Scheme Import Live Cattle Import MBM Import serum and vaccine Import breeder Abandon Abandon Slaughter Maternal transmission Waste water treatment Rendering MBM Surgical Implant and experimental usage Tow, Tallow Fertilizer TSE sensitive animals Environmental Residue Sporadic prion disease BSE outbreak

人類為了一己之私，強迫牛隻改變食性，終於架禍於自己 科學的知識是相當薄弱的，通常是出事後才能找出原因或才能證明的。如果動物化製原料沒有分種別而專一處理且再餵食經濟動物或寵物，難保類似狂牛病的案例不會再發生。再者，同類相食的情況涉及到道德與倫理的問題。 台灣對化製業的管理要好好的思考，不要造成另一公共衛生的浩劫。

是全牛還是30個月齡以下? 美台協議書英文版並未談及30個月以下的牛肉與產品的事, 只有定義高風險物質時才用到30個月齡以上的限制要求, 即協議書是可以開放不分年齡所有的帶或不帶骨牛肉.

密室協商是什米碗糕? 美國給肉商的輸出產品說明(Export Requirements for Taiwan (Dec 2, 2009)提到"As a temporary market transition measure, U.S. exporters will ship only U.S. deboned and bone-in beef products from cattle less than 30 months of age.", 可知這是一個暫時性的措施, 也因此可知為何180天後要檢討開放情形. 不過美國USDA AMS目前公告Export Verification (EV) Program Specified Product Requirements for Beef - Taiwan仍然是2007年的不帶骨牛肉版. 這些所有資料都不一致, 雙方政府秘室協商後在中英文公告上有相當多套不同的要求, 兩者在變通處置上果然默契是有一套!

Importation and Risk (Miller, 1993; OIE, 1997; Morley, 1993; Yu, et al., 1997)

Risk Communication Figure: Components of risk analysis Hazard Identification Risk Assessment Risk Management Risk Communication Figure: Components of risk analysis Steps of risk assessment (RA) Release assessment Exposure assessment Consequence assessment Risk estimation OIE, 2004 風險評估：（1）釋出評估（release assessment）；（2）暴露評估（exposure assessment）；（3）結果評估（consequence assessment）；（4）風險估算（risk estimation）

世界動物衛生組織的規範 WTO委由世界動物衛生組織訂定各會員國協商時的基本標準, 這是一個參考性的規範準則, 不是絕對的. 比如說歐盟訂出的高風險物質就比世界動物衛生組織標準嚴格, 日本與美國的協議就完全不適用該標準, 我們是模範生要完全遵守該規範? 同樣的, 因為中國的關係, 我們在世界動物衛生組織的會籍名稱也同意改了兩次, 模範生必備的條件看來難道就是只有忍辱負重嗎? 為什麼台灣公民的我們不能自主!

結論 牛海綿狀腦病的疫情已有效控制住但仍未完全滅絕，人類狂牛病病例仍有繼續發現，要有耐心的觀察與等待，不屈服威脅與接受利誘 牛隻與牛肉及其產品的輸出入，除要依循疫區規範認真確實嚴加執行外，充份的風險溝通是必須的，阻絕於境外是優先的選項 雖然經由肉製品輸入而傳入台灣的風險非常的低，但因應可能的人類病例，除了重新思考輸入國之牛源與牛籍管理要求外，要啟動特殊疾病國家保險制度

期許與勉勵 畜產工業強權耗用畜牧業糧食、產生糞尿污染、砍伐森林與使用長程冷凍運輸，產生了大量的溫室氣體，是地球殺手。大家該少吃外來牛肉，少用動物皮草油脂與化妝品，除了讓自己免遭狂牛病天譴外，更可以為子孫救地球。

動物用藥殘留標準 第一條本標準依食品衛生管理法第十條規定訂定之。 第二條本標準所稱殘留容許量係「指標性殘留物質 (marker residue) 」之含量 ，包括該藥物原體及與該藥物殘留量具明顯關係之代謝產物。 第三條食品中之動物用藥殘留量應符合下列規定，本表中未列之藥品品目，不得檢出。若表中藥品品目非屬行政院農業委員會核准使用之動物用藥，僅適用進口肉品。

Deboned and bone-in beef derived from (1) cattle born and raised in the United States, (2) cattle raised in the United States for at least 100 days prior to slaughter, or (3) cattle legally imported into the United States from a country deemed eligible by Taiwan to export deboned beef to Taiwan. (Presently, Australia and New Zealand can export to directly to Taiwan with no restrictions.) Beef or beef products of cattle from Canada fed less than 100 days prior to slaughter in the United States is limited at this time to deboned beef derived from animals less than 30 months of age. Eligible deboned and bone-in beef must be produced under an approved AMS program for beef to Taiwan. For more information on AMS official listings and dates, see C. and D. of the Documentation Requirements below. If FSIS inspection personnel become aware of concerns that an AMS approved EV establishment is not properly executing its EV program, export certification should not be issued for the product in question and AMS should be notified at ARCBranch@usda.gov. Inspection personnel should include their immediate supervisor on messages to AMS. The following information should be included in the message: Establishment name, address, and establishment number Product type, product code, and quantity of product Date of production, lot number, and shift Date and nature of observation Name of country product is intended for export Export certificate number (if applicable) Any other information to verify claim Name of inspection official As a temporary market transition measure, U.S. exporters will ship only U.S. deboned and bone-in beef products from cattle less than 30 months of age. AMS has set up a voluntary Quality System Assessment (QSA) Program to verify that beef from participating plants will be from cattle less than 30 months of age. Exporting establishments may choose to participate in the AMS Quality System Assessment (QSA) Program that verifies that the beef being certified is from cattle less than 30 months of age. At this time, Taiwan will not accept at ports of entry shipments of beef without the QSA program statement in the Remarks section of the FSIS 9060-5 as described in the Documentation section, and Taiwan quarantine authorities will return shipments without the statement to the owner/agent of the product. A list of QSA-approved establishments and their approval dates can be obtained from the AMS website. Eligible deboned beef must be derived from animals slaughtered on after the QSA program approval date of the slaughter establishment. Certain beef and beef products derived from certain categories of cattle imported from Canada are ineligible. See B. Ineligible Products. More information about the status of other beef products will be provided as it becomes available.