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健康風險評估議題與法規分析

江舟峰 教授兼教務長

風險分析中心、環境醫學研究所

中國醫藥大學

2008年10月

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江舟峰簡介Ph.D., Environ. Engr., Excellent Res. Award, Iowa State Univ., 1988.Post Doctor, Univ. of Arkansas -Respirometer, 1989.PM, General Physics Environ. Services, 1988-1991.Prof. Engr. (PE), State of Maryland, 1992.環境工程技師 (CEE)，1993.經濟部標準局，專利代理人，1994。朝陽科技大學，環境工程與管理系所，副教授，1997。教學優良教師，2001。主任，2002。台中市，環境影響評估委員會委員，1997-2000。國科會 ，ATAT 計畫主持人，1998-迄今。環保署，建築物污水處理設施委員會委員，1998-迄今。經濟部，RAIC 計畫主持人，2001-2003。內政部營建署，綠建築評審委員，2002-迄今。國科會，載體嵌合計畫主持人，2003-迄今。法務部，仲裁人，2004-迄今。永續會，中部科學園區健康風險評估模式計畫共同主持人，2005-迄今。中國醫藥大學，環境 醫學研究所，教授，2003。風險管理系，主任，2004-2007，風險分析中心主任，教務長 2007-

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China Medical University

China MedicalUniversityChina MedicalChina MedicalUniversityUniversity

TaiwanTaiwanTaiwan

Located in central partLocated in central partof Taiwan (Taichung)of Taiwan (Taichung)

Founded in 1958Founded in 1958

Comprises 4 colleges:Comprises 4 colleges:College of MedicineCollege of MedicineCollege of Chinese MedicineCollege of Chinese MedicineCollege of PharmacyCollege of PharmacyCollege of Public HealthCollege of Public Health---- Department of RiskDepartment of Risk

Management (2002)Management (2002)----Center for Risk analysisCenter for Risk analysis

(2007)(2007)

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Outline

Basics and definitionsThe “Red Book” conceptionIRIS review process (NCEA visit)Cancer risk from showering (TNSC)Modification for encapsulation (TNSC)Medical risk analysis (TNSC)Risk perception and communication (NPSF, TDOE)

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出處：中時94.07.01

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中國時報A2中國民國九十六年八月二十日/星期一

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Risk analysis

Risk assessmentRisk managementRisk communication (between stakeholders and risk assessor/manager)Product or system oriented

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International institutesUSEPA/NCEA, IRIS, FDA, DOH/NIH, CPSC, DOL/OSHA, NOAAHarvard Center for Risk Analysis (HCRA)Society for Risk Analysis (SRA)John Hopkins, Institute for Risk Science and Public PolicyEU World Congress on Risk Society AnalysisKey journals: EI, J. SRA, SETAC

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公司營運管理公開發行公司建立內部控制制度處理準則

保險業務臺灣地區與大陸地區保險業務往來許可辦法

勞安衛檢查勞工安全衛生組織管理及自動檢查辦法

申請污水經處理後注入地下水體許可證勞工安全衛生組織管理及自動檢查辦法

健康風險評估指引衛生署國民健康局

廢 (污) 水不得注入於地下水體或排放於土壤。水污染防制法

空氣污染防制費專供空氣污染防制空氣污染防制法

土壤及地下水污染整治計畫土壤及地下水污染整治法

住宅社區開發、工業區開發、高爾夫球場、文教及醫療建設開發、石油及石油產品儲存槽設置

環境影響評估法-審議規範

第22條，政府決策環境基本法 (2002)

適用行為法源

Taiwan’s regulations

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Needs for health risk

Superfund siteEIA/HIA (stack emission)Food and water (chemicals and microbes)Consumer products (toys, mobile phone)Environmental riskLife behavior (computer syndrome)

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What is risk and underlined assumptions?

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What is risk?

The potential for realization of unwanted, adverse consequencesto human life, health, property, or the environment.

-- SRA on-line glossary

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Question 1: Why take risk?

Voluntary vs. involuntaryRisk vs. benefit

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Question 2: What is adverse consequence?

Endpoint (causal target outcome)Multiple endpointsCritical endpointMeasurable? Detectable?Culture and economic?

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Question 3: Accidental or consequential? Individual vs. population?

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Question 4: How to quantify?Estimation of risk is usually based on the expected value of the conditional probability of the event occurring times the consequence of the event given that it has occurred.

-- SRA on-line glossary

Expectation Risk = f1 (damage) × f2 (occurrence) Cancer Risk = f1 (potency) × f2 (exposure time) Hazard Index = (Exposed Dose)/(Reference Dose)Uncertainty analysis

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Question 5: How to regulate?

Default values (lifetime, weight)Regulatory toxicology (dose response assessment and UF in IRIS)Decision making process (from scientific assessment to risk management)

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The “Red Book” Review Conclusion

(NRC, 1983)

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Major questions

Separate analytic functions from regulatory functions?Designate a single organization?Develope uniform risk assessment guidelines?

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Major conclusionsBasic problems: sparseness and uncertainty of the scientific knowledge of the health hazards, no ready solution.Separation of the administrative responsibility for risk assessment from risk management would lead to improvement.administrative relocation (single organization) will not improve the knowledge base, and cannot eliminate controversy.

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Define 4 steps of risk assessment

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Recommendation A

The analytic functions of developing risk assessment (scientific findings and policy judgments) should be separated from the regulatory functions of making policy decision (political, economic, and technical considerations).

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Recommendation B

Uniform inference guidelinesshould be developed for the use of federal regulatory agencies in the risk assessment process.

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Recommendation C

A Board on Risk Assessment Methods (in congress) should be established to perform various functions among federal agents (EPA, FDA, OSHA, CPSC) for continual improvement.

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IRIS Review Process

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Integrated risk information system (IRIS)

The NCEA is charged for the scientific reviewUS$ 30,000 ~ 40,000 and 8 ~ 10 months for each chemical review.544 chemicals listed as of Dec 2006.In 1990, USEPA first use of BMD for noncancerchemicals (carbon disulfide).Since 1995, over US$ 5 millions spent with an annual budget of US$ 100 K.2005 Cancer Guideline requires the use of BMDS for all cancer assessment.Future changes: list for different endpoints, for acute effects, and using CatReg for mixed endpoints.

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IRIS review process (hazardous pollutants)

OMB = Office of Management and Budget

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Cancer Risk from Inhalation and Dermal Absorption of VOCs during Showering

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TTHM及VOC飲用水標準

Total Trihalomethanes (TTHMs) USEPA TTHMs = 0.10 mg/L, 0.008 mg/L after 12/31/03我國 TTHMs = 0.10 mg/L, 0.008 mg/L after 07/01/95USEPA 及我國另規範6種 VOCs 標準

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THM’s Human Study (Gorden et al, 2006)

Showering

Air/water = 20%

Breath/water =2% Blood/water = 0.015%

Bathing

Twice of showering exposure

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Cancer risk of inhaling VOCs during showering (Chiang, 2007)

0.05.0

10.015.020.025.030.035.040.045.050.0

Benzene TCE chloroform CT C 1,2-DCA 1,1-DCE

六種VOCs

EL

CR

(10-6

)

雙年齡層

單年齡層

*平均值±標準差。** 引用94年國人兩性平均餘命77年[17]。*** 引用USEPA, Standard Default Exposure Factors, 1991, BW=70 kg、

ET=30 min、EF=350 day/year、AT=70 yaer [8].

70×365***77×365**77×365 **77×365**終身平均日數(AT, day)

58584612暴露期間 (ED, year)

350***350***350***350***暴露頻率 (EF,

day/year)

30***12.8±6.5*13.4±6.6*11.6±6.3*淋浴時間 (ET, min)

-34.3±5.2*34.8±5.1*33.1±5.2*淋浴水溫 (Temp,0C)

70***58.7±11.6*62.2±10.7 *51.2±10.0*體重 (BW, kg)

美國環保署

慣用值

7-64歲(n=95)

19-64歲(n=65)

7-18歲(n=30)

年齡層參數

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Cancer risk from inhalation and dermal absorption of VOCs during showering

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Modification for Encapsulation

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土壤及地下水污染整治法

319公頃第五級濃度土壤重金屬調查591座站齡超過10年的加油站193處大型貯槽15處非法棄置場調查工作609個污染控制場址5個污染整治場址1164個解除列管場址

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生物有效性修正之各項法源

USEPA同意使用，在biosolids處置上最為明確 (Part 503)，且涵蓋各種非人體攝入之動植物暴露路徑。有害廢棄物方面不明確海洋大氣總署 (NOAA) 採用經驗統計方法篩檢底泥品質，但並未明確提及生物有效性，但USEPA則利用固液分離理論(acid volatile sulfides) 評估底泥的毒性，美國工兵署(Army corps of Engineers) 也使用試驗方法測試挖掘底泥的毒性，較明確考量生物有效性。受污場址可依據 Risk Assessment Guidance for Superfund, Appendix A: Adjustments for Absorption efficiency，但並未規定計算或試驗方式。美國Solubility/Bioavailability Research Consortium (SBRC)針對受污場址建議知指引，已為USEPA Region 8採用，As及Pb已有案例。我國目前沒有規定。

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何謂生物有效性?

介質(如土壤)中目標污染物(如砷)經由特定路俓，進入血液的劑量與總暴露量的百分比。

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體外試驗

模擬經由食入途徑，胃腸消化、吸收作用，分別計算胃或腸階段中萃取出污染物的總量與暴露量百分比

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GI Bioabailability

絕對生物有效性 相對生物有效性

100%(kg)W(mg/kg)C

V(L)(mg/L)C

100%MMABF(%)

ST

Y

T

Y

×××

=

×=

100%

MM

MM

100%ABFABFRBF(%)

SRMT

Y

XT

Y

SRM

X

×

⎥⎦

⎤⎢⎣

⎡

⎥⎦

⎤⎢⎣

⎡

=

×=

MY=胃或腸階段所萃取出的總量(mg)MT=污染物在介質中的總量(mg)CY=胃或腸階段所萃取出的濃度(mg/L)V=反應槽有效容積(L)CT =污染物在介質中的全濃度(mg/kg)WS=樣品總量(kg)

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RBFs from literature

以二階段之模擬為主

受礦物型態影響，砷RBF為5-50%(變異大)

經由燃燒製程所產生物質(包封度較高)，如slag及calcine 其RBF較一般的土壤低

但均未報告砷酸鈉(SRM)的ABF，故難以評估此一變異是否受到不同試驗萃取效率的影響

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Gastric phase Intestinal phase Intestinal absorption

As R

BF

(%)

NIST 2710 (Hamel 1998)

AHD-I (Ruby 1996)

ARS-I (Ruby 1996)

ARS-II (Ruby 1996)

iron slag (Rodriguez 1999)

soil I (Davls 1992)

Jersey City (Hamel 1998)

iron slag (Ruby 1996)

calcine (Rodriguez 1999)

calcine (Ruby 1996)

不同物質中砷RBF之比較圖

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The RBF test setup at CMU

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研究方法--

試驗程序

反應 1 小時後，以注射針收集 15 mL 胃液

反應槽設計 1. 使用 500 mL 血清瓶 2. 恆溫 37±0.5 ℃ 3. 使用磁力攪拌( 350~2000 rpm ) 4. 隨時監測 pH 值、溫度、ORP

Phase II：Intestinal Phase Digestion

再加入猪的膽汁 1.75 gm 及 胰酵素 0.175 gm

備製飽和 NaHCO3溶液並將胃液pH 值調至 5.5 做為小腸液

Phase I：Gastric Phase

備製 500 mL 胃液( 0.15 M NaCl & 1 % porcine pepsin )

加入樣品( 500~2000 mL/gm )

以濃 HCl 溶液調整 pH 至 1.8

離心(3500 rpm，15 min) 以 0.45µm 濾紙過濾

ICP-AES 分析砷

萃取液前處理及分析

反應 1 小時後，以注射針收集 15 mL 小腸液

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Results of QC criteria

36±10%26~55%, SD=3~10%RBFI (n=6)

ND.=non-detected (Method Detection Limit=0.0397 mL/gm)

40±10%28~58%, SD=5~10%RBFG (n=6)介質標準管制

100±2%97~100%, SD=1~2%ABFI (n=6)

100±6%95~102%, SD=1~6%ABFG (n=6)SRM標準管制

濃度

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ELCR for arsenic with different RBFs

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0 1 2 3 4 5 6 7 8 9 10 11 12 13

Exc

ess L

ifetim

e C

ance

r R

isk×1

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CT as As (mg/gm)

RBF=90% RBF=70%

RBF=50% RBF=30%

RBF=10%

Hamel et al. (1998)NIST 2710 soil

本研究

NIST 2710 soil

Hamel et al. (1998)Jersey City composite soil

Davls et al. (1998) soil I

Ruby et al.(1996)ARS-II

Ruby et al.(1996)AHD-I

Ruby et al.(1999) slag

Ruby et al.(1999)calcine

Ruby et al.(1996) ARS-I

單位致癌風險係數為1.5 (mg/kg-d)-1，當攝入率(IR)為0.1 gm/day ， 平 均 體 重 (BW) 為 70 kg ， 估 算 ELCR 為1.3~26.7×10-4，較一般可接受範圍(10-6~10-4)高

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Medical Risk Analysis

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Preventable AE (PAE, 可預防的負面事件)

The adverse event that is attributable; or the error that causes injuryPAE should be determined from medical recordsBut most conceived from events being surfaced out (medical mistakes)

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The Harvard study (Brennan et al., 1991)

To estimate the incidence of adverse events (injury) and negligence (preventable)Two-stage sampling (?)to create 30,121 records from 2,671,863 non-psychiatric patients of 51 nonfederal hospitals in NY in 1984Screened by trained nurses and medical-records analystsIf positive, reviewed by two physicians independently on a confidence scale of 0 to 6

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Estimated PEA casesAE 4% of admitted, where 6.6% led to death, where 50% preventable (1997)USA fatal PAE = (11%)(4%)(6.6%)(50%)

(302 millions)= (145 per million)(302

millions) = 44,000 (8th)Motor vehicle accidents = 43,578Breast cancer = 42,297AIDS = 16,516

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200

300

400

500

76 77 78 79 80 81 82 83 84 85 86 87 88 89 90

Year

Cas

e pe

r Y

ear

Taiwan fatal PAE (2000)

=(11%)(4%)(6.6%)(50%)(22.9 millions)

=3,300 per year

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2000 IOM’s national agendaBreaking the cycle of inaction;By creating external environmentfor sufficient pressure;Specifically by organizationalsystematic (4-tiered) approaches;To achieve at least 50% reduction in PAE

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Risk Perception and Communication

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Risk perception

Source: Roberts, Counting on Science at EPA, Science, 1990.

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1997 NPSF study -ObjectiveRef: Public opinion of patient safety issues research findings (NPSF/AMA, 1997)In 7 categories (25 questions):

safety in general (一般認知): A1~A3safety precautions (預防措施): B1~B3health care professionals (醫護人員): C1~C2patient safety (安全制度): D1~D4awareness of medical mistakes (過失察覺): E1~E3experience with medical mistakes (過失經驗): F1~F6preventing medical mistakes (過失預防): G1~G4

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Methods

Sampling: random household nationwide, American adults (age 18+, 1513 responders, ±2.5% error)Survey time: July 30 to August 21, 1997Interview: telephone aided by computerized questionnaire, callback procedureData handling: Score for safety, matched by population for age, race, and genderSignificance test: t-test at 95 % CI for subgroups(past experience, education, risk averse behavior, health insurance, income)

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Safety in general (A1~A3)A1: Health care environment safe?

5 %13 %7 %

10 %

16 %

21 %

15 %

12 %4.2Nuclear power

1 %4 %6 %

15 %

21 %

32 %

13 %

8 %4.4Food handling

1 %4 %4 %

8 %16 %

31 %

24 %

13 %

4.9Health care

3 %2 %3 %

7 %11 %

31 %

29 %

14 %5.2The workplace

1 %7 %2 %

5 %9 %30 %

26 %

20%5.2Airline travel

Don’t Know

1UNSAF

E

234567SAFE

Mean Score

Environment

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Health care professionals (C1~C2) C2: Subgroup analysis of satisfaction.

2%17%81%They gave you enough information about all possible treatments to make aninformed decision about your care

1%18%81%They spent enough time with you

4%9%87%They made an accurate diagnosis

1%10%89%Those involved in your care were attentive to your needs

3%6%91%The treatment was carried out just as it was explained to you

4%6%91%You were given sufficient instructions on how to take prescribed medication

1%7%92%You know how to care for yourself once you left the health care setting

*2%98%The health care setting was clean

Don’t Know

NoYes Statement

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2007 教育部計畫—目的

編撰及推廣大專院校通式教材

提升環境風險暴露辨識與認知素養

降低風險認知偏差

促進健康的行為

有利公共政策的推行

培訓環境領航員

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風險認知問卷調查

目的

專家與學生(民眾)的風險認知現況與差異教材編撰之參考:找出需加強教育之處教育介入的成效評估:學生前測與後測比較

回收現況

13所大專院校:北(5)、中(3)、南(4)、東(1)合計13所環境相關科系，18所非環境相關科系合計:~1350份問卷(回收率89%)

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參考文獻:Slovic, Science, 1987.

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Closing remarks

Risk analysis has been developed toward problem solving for regulation as needed in private and public sectors.Various applications from product (food) to system (EIA) oriented.Areas most needed: superfund site, EIA/HIA, FDA, OHSA, consumer products, risk perception and communication, cost benefit analysis.Limitations to be overcome: governing equation, toxicological extrapolation, exposure data, multiple chemicals, mixed endpoints, regulatory process.Organizational framework and procedure should be established in Taiwan for decision making based on risk assessment and risk management.

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References

Chiang CF (2006) Three-month study report at NCEA at RTP, prepared for Taiwan National Science Council, Feb 2007.

Chiang CF et al (2006) Problems and perspectives of applying In-vitro bioavailability test to health risk assessment, Taiwan Journal Public Health, 2006:25,1, 1-9.

Chiang CF et al (2006) Health risk assessment and uncertainty analysis during showering for the residents of central Taiwan, final report, Taiwan National Science Council.

Chiang CF et al. (2007) Health risk assessment and risk characterization during showering for the residents of central Taiwan (Accepted), Mid-Taiwan Journal of Medicine.

USEPA (1992) Guidelines for exposure assessment, EPA/600/Z-92/001, Risk Assessment Forum, USEPA, Washington D.C.

USEPA (1995) The use of the benchmark dose approach in health risk assessment, EPA/630/R-94/007, Office of Research and Development, Washington, DC.

USEPA (1998) Guidelines for ecological risk assessment, EPA/630/R-95/002F, Risk Assessment Forum, USEPA, Washington, DC.

USEPA (1997) Exposure factors handbook, National Center for Environmental Assessment, USEPA, Washington, DC.

USEPA (2000) Benchmark dose technical guidance document, External Review Draft, EPA/630/R-00/001, Risk Assessment Forum, USEPA, Washington, DC.

USEPA (2001) The factor finder CD-ROM user’s guide, EPA/600/R-01/029, National Center for Environmental Assessment, USEPA, Washington, DC.

USEPA (2004) Example exposure scenario, National Center for Environmental Assessment, USEPA, Washington, DC.

USEAP (2005) Guideline for carcinogen risk assessment, EPA/630/P-03/001F, Risk Assessment Forum, USEPA, Washington, DC.

USEPA (2006) Preliminary methodology for assessment of health effects from acute inhalation exposures, Interagency review draft, EPA 600/R-05/112, USEPA, Washington, DC.

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謝 誌

國家科學委員會大專生專題計畫(94-96)國家科學委員會短期出國進修

美國National Center for Environmental Assessment(95)中國醫藥大學精英教師計畫(95)

教育部環保小組通識教育教柴材編撰計畫(96)中國醫藥大學教學卓越計畫(95-96)

中國醫藥大學附設醫院/大里仁愛醫院(95-96)美國Univ of North Carolina, School of Public Health(95)美國Tulane University, School of Public Health (96)

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報 告 完 畢敬 請 指 教