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第四第四､､五五､､六節六節

健康風險評估概說

謝顯堂教授

中國醫藥大學健康分析中心

11.13.2008

勞研所勞研所健康風險評估講習班健康風險評估講習班

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風險分析是國際間公認的最佳環境安全管理方式

風險分析：

1. 風險評估

2. 風險溝通

3. 風險管理

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風險管理的一貫程序

風險評估

風險溝通

風險管理

風險減免

制定目標

達成目標

1 2 3 4 5 6

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風險評估是環境安全管理的第一步

以科學方法，推算出健康考量之《可接受劑量》

針對環境中有問題的檢出物，算出《可容許多少？》

不是《有沒有》的問題，而是《有多少》的問題

例：猪肉中瘦肉精

國際間有24國有瘦肉精容許量美國：50 μg/kg台灣：不得檢出

所以是

沒有《安全問題》只有《法規問題》

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國人極須培養劑量觀念

「什麼都可以吃，

只要不過量，

就安全。」

風險評估就是要算出「不過量」是多少？

“ The dose makes the poison“劑量決定毒性

• “All things are poison and nothing is without poison、only the dose permits something not to be poisonous.”

‧萬物皆有毒﹐但每一物都有「可接受劑量」

Paracelsus1493-1541

Father of Toxicology

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風險管理

風險減免

無須啟動風險評估機制

危害辨識

劑量反應分析

暴露評估

風險特性描述

可接受之風險 不可接受之風險

健康風險評估

健康風險評估架構

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課程大綱課程大綱

1. 健康風險評估概論2. 風險溝通3. 危害辨識4. 劑量反應分析5. 暴露評估6. 風險特徵描述7. 風險管理

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Definitions

Risk = the probability of occurrence of a harm風險（風險度） = 傷害發生的機率 (0 ~ 1)

Risk assessment = to estimate the probability of the occurrence of a harm (risk = 0 ~ 1 )風險評估 = 估算傷害發生的機率

Health risk assessment = to scientifically estimate the probability of a harm to occur due to exposure to a harmful agent 健康風險評估 = 使用既有數據估算在某暴露狀況下發生某傷害的機率

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Human receptor受體人

Exposure (contact) 暴露

Chemical agents化學品

Response反應

Desirable responses有益反應

Undesirable responses有害反應

Dose

Toxic effects毒害

Therapeutic effects療效

Risk

Dose – response relationship

•Carcinogens致癌物

•Non-carcinogens非致癌物

(0-6 – 1)(mg/kg-day)

HEALTH RISK ASSESSMENT OF CHEMICALS化學物之健康風險評估

(0 – 1)

風險

劑量

Environmental Impact and Regulatory Pathway

Source

Agent

Environmental fate

Exposure

Toxicokinetics

Toxicodynamics

Toxic endpoint

Dose-response relationship

Risk assessment

Assessment report Risk management

Alternatives to risk reduction

Legal process

Regulatory standards

Enforcement(Natural, man-made)

(Chemicals, heat, radiation)

(Ambient media, exposure media)

(Inhalation, ingestion, skin contact)

(Potential dose, internal dose, effective dose)

(Signal transduction)

(Reversible effects, non-reversible effects)

(Toxicity parameters)

(Determination of acceptable dose)

RISK ASSESSMENT DOCUMENTS

Features of a risk assessment document:

a. Assessment is for a single agent or a group of functionally closely related agents.

b. The content of the document includes:

1) Description of the agent2) Hazard identification3) Dose-response analysis4) Exposure assessment5) Risk characterization6) Executive summary7) Bibliographic citations

These documents can be best prepared, evaluated, and critiqued by environmental toxicologists with course work and training in risk assessment.

第五節第五節

1. 1. 危害辨識危害辨識

2.2.劑量反應分析劑量反應分析

謝顯堂謝顯堂

中國醫藥大學健康分析中心

11.13.2008

勞研所健康風險評估講習班勞研所健康風險評估講習班

1. 1. 危害辨識危害辨識 (Hazard identification)(Hazard identification)

是一種定性分析是一種定性分析

任何生物化學的、生理的、解剖的、病理的及/或行為的改變而引起的功能性損傷，很可能影響整個有

機體的表現或降低該有機體對另一個刺激物的反應

能力。

不良健康效應不良健康效應 (Adverse effect)(Adverse effect)

(USEPA Environmental Criteria and Assessment Office, 1983)

1. 體重減輕是否為不良效應？

a) Reduced feed intake and body weight gain from inhalation exposure

b) Change in feed intake and body weight from oral exposure

2. 可逆性效應可視為不良效應嗎？

a) Lacrimation from acute exposure to organophosphate

b) Vomiting in dogs within 3 hours of gavage dosing

c) Tremors from acute exposure to pyrithroid

不良性不良性 (ADVERSITY) (ADVERSITY) 的定義及考量的定義及考量

重金屬對人體產生之重要影響重金屬對人體產生之重要影響 (toxic endpoint) (toxic endpoint)

肺癌、支氣管癌、鼻中膈缺損、腎功能異常鉻6+胰臟受損、高密度膽固醇較少、貧血、金屬燻煙熱鋅

四肢與身體的反應遲鈍a、接觸性皮膚炎硒腎臟受損、鉛腦症、認知行為異常、貧血鉛

肺癌、鼻癌、胃腸癌、金屬燻煙熱鎳

四肢與身體的反應遲鈍錳

肝臟及腎臟的損害、貧血銅

心臟與肺部損害、皮膚炎鈷

肺癌、前列腺癌、腎癌、痛痛病、貧血鎘

肺癌、皮膚癌、膀胱癌、肝癌、腎臟癌、攝護腺癌烏腳病、生殖泌尿方面(血尿、蛋白尿、無尿症) 、貧血砷

人類毒性

戴奧辛戴奧辛

Chemical structures of polychlorinated dibenzo-para-dioxins (PCDDs) and polychlorinated dibenzofurans(PCDFs)

Chemical structure of 2,3,7,8-tetrachlorodibenzodioxin (TCDD)

C3H6N6

三聚氰胺(Melamine)

它是一種白色化工原料，無味、略溶於水，可溶於酒精、甲醇，常用於製造美耐皿餐具、建材、塗料等，不可用為食品或食品添加物

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步驟一 : 危害辨識 (三聚氰胺為例)

傷害Toxic endpoints

經腸胃道吸收後，可能於腎臟中結合沈積，形成腎結石，嚴重者會造成腎臟功能受損；這種現象較易發生在腎臟尚未發育完全的嬰幼兒

危害因子Hazard or risk factor

三聚氰胺 (melamine)掺雜物三聚氰胺酸(cyanuric acid)

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毒性數據 (USFDA 2007)

• The toxicity of melamine to mammals is low. • The most sensitive LD50) is 3161 mg/kg in rats.• The most recent reported NOAEL are:

63 mg/kg bw/day (13 weeks, oral with feed, in rats) 240 mg/kg bw/day (28 days, oral with feed, in rats) 417 mg/kg bw/day (14 days, oral with feed, in rats)1600 mg/kg bw/day (13 weeks, oral with feed, in mice)

• Tthe most sensitive calculated NOAELs for oral reproductive and developmental toxicity in rats are:

400 mg/kg bw/day (maternal)1060 mg/kg bw/day (fetal)

•The most commonly observed effects in animal oral experiments are: reduced food consumptionbody weight loss bladder stones crystalluria, epithelial hyperplasia of urinary bladder, and lowered survival rate

1. 一般定義

• 鑑定危害因子可能引起的傷害種類

• 決定某一物質是否會致癌

危害辨識的一般定義危害辨識的一般定義

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Health Risk Assessment of Toxic Substances毒物風險評估- Internationally unified protocols : 國際通用程式

1. Threshold protocol for non-carcinogens 有閾值

2. Non-threshold protocol for genotoxic carcinogens

- more stringent 無閾值 – 較嚴謹

危害辨識的非致癌性鑑定危害辨識的非致癌性鑑定

毒性物質毒性等級分類標準毒性物質毒性等級分類標準

資料來源：健康風險評估指引

/kg

/kg

/kg

/kg

/kg

g

危害辨識的致癌性鑑定危害辨識的致癌性鑑定

國際癌症中心對癌症之分類方法國際癌症中心對癌症之分類方法(IARC, 2002)(IARC, 2002)

資料來源：健康風險評估指引

危害辨識的致癌性鑑定危害辨識的致癌性鑑定((續續))

表表3.23.2、、美國環保署對癌症之分類方法美國環保署對癌症之分類方法

證據顯示非致癌物 (Evidence of noncarcinogenicity)E

無法分類 (Not classifiable)D

也許是人類致癌物 (Possible human carcinogen)C

人類可能致癌物 (Probable human carcinogen)B1：表示人體研究資料不足B2：表示動物試驗資料充分，但人體研究資料不足或

缺乏

B

人類致癌物 (Human carcinogen)A

描述(Description)

分類(Group)

2. 2. 劑劑量反應分析量反應分析(Dose(Dose--response assessment)response assessment)

是兩類數據間的定是兩類數據間的定量量分析分析

DoseDose = = 因因ResponseResponse = = 果果

營養素和毒素之劑量反應關係營養素和毒素之劑量反應關係

Dose (劑量, mg/Kg-day)

Res

pons

e (反

應, %

)

Exposure (contact)

Chemical agents

Toxic response毒性反應

Dose Risk

Toxicity parameters:毒性參數

•Carcinogens

•Non-carcinogens (10-6 – 100%)(mg/kg-day)

TOXICOLOGICAL APPROACH – toxicity assay毒理學作法

Animal model動物模式

•Acute toxicity assay 急性毒性測試

•Subacute or subchronic assay亞急性毒性測試

•Chronic assay慢性急性毒性測試

•Potential dose 表面劑量•Applied dose•Internal dose 內在劑量•Biologically effective dose

•NOAEL 無反應劑量•LOAEL 最低反應劑量•ED50 (50%有效劑量), ED10 (10%有效劑量)

•SF (Slope factor) or Potency斜率度、致癌強度

Dose – response relationship

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NOAEL (no-observable effect level) = 10 mg/kg-d 無反應劑量

LOAEL (lowest observable effect level) = 20 mg/kg-d 最低反應劑量

TD50 (50% toxic dose) = 30 mg/kg-d 50%有效劑量

A chronic toxicity assay (life-time exposure) in mice as an example:

Daily dose used: 0, 5, 10, 20, 40, 80, 100 mg/kg-day

0

10

20

30

40

50

60

70

80

90

100

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100

Dose (mg/kg-d)

Har

m (

% =

risk

)

TD50NOEL

LOEL

Illustration: a toxicity assay in mice範例

Mice

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UF: 10 for interUF: 10 for inter--species difference; 10 for intraspecies difference; 10 for intra--species species variation; 10 for other considerations such as severity of effecvariation; 10 for other considerations such as severity of effect, t, high susceptibility, high uncertainty, etc. high susceptibility, high uncertainty, etc.

0

10

20

30

40

50

60

70

80

90

100

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100

Dose (mg/kg-d)

Har

m (

% =

risk

)

TD50NOAEL

LOEL

1. Threshold protocol for non-carcinogens 有閾值

Mice

Reference dose (RfD) = NOAEL / UF where UF = 10 × 10 × (1 ~ 10) = 100 ~ 1000

RfD = 10 mg/kg-day / (100 ~ 1000) = 0.1 ~ 0.01 mg/kg-day

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計算 RfD 或 ADI

RfD (Reference Dose, 每日容許參考劑量) = TDI (Tolerable Daily Intake, 每日容許攝取量)

定義: 每人每日攝入三聚氰胺劑量如低於此值，則終生無受毒害之虞。

RfD (成人) = NOAEL / UF = 63 mg/kg bw/day / 100

= 0.63 mg/kg bw/day (歐盟: 0.5 mg/kg bw/day)

RfD (嬰孩) = NOAEL / UF = 63 mg/kg bw/day / 1000

= 0.063 mg/kg bw/day (歐盟: 0.05 mg/kg bw/day)

Body weight: 60 kg (成人) 7 kg (嬰孩 < 2 yrs)

每人每日容許攝取量:

成人: 0.63 × 60 = 37.8 mg/day

嬰孩: 0.063 × 7 = 0.441 mg/day

每天餵食嬰兒240公克奶粉:

可忍受三聚氰胺含量: 0.441/240000 = 1.84/1000000 = 1.84 ppm

液相層析串聯質譜儀（ＬＣ／ＭＳ／ＭＳ）之儀器偵測極限 = 0.5 ppm (>不得檢出)

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Risk = (Slope Factor, SF) × (Lifetime daily dose)

Lifetime daily dose) = Risk / SF

0

10

20

30

40

50

60

70

80

90

100

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100

Dose (mg/kg-d)

Har

m (

% =

risk

)

TD50NOAEL

LOEL

2. Non-threshold protocol for carcinogens 無閾值

Mice

Assuming no threshold: NOAEL = 0 mg/kg-day

A linear dose-response curve with a slope of SF is used for risk assessment

SF

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0

10

20

30

40

50

0 5 10 15 20 25 30

Dose (mg/kg-day)

Har

m (%

= ris

k)

LOEL

SF

MiceRisk = SF (slope factor) × Dose = Potency × Dose

Potency : global; Dose: locally specific

Potency (mice) = SF = 0.0125 (mg/kg-d)-1

Potency (man) = Potency (mice) × (BWH / BWM)1/4

Potency (man) = 0.0125 × 6.95 = 0.0869 (mg/kg-d)-1

Cancer risk for man = (0.0869) × (Dose)

10-6 = de minimus risk = acceptable risk

Acceptable risk = 10-6 = (0.0869) × (Acceptable dose)

Acceptable dose = 1.15 × 10-5 mg/kg-d

Comparison: RfD = NOAEL / UF = 10 / 1000 = 1.0 × 10-2 mg/kg-d

斜率度、致癌強度

2. Non-threshold protocol for carcinogens 無閾值（續）

Res

pons

e

ED10LED10

10%

0%Projec

ted Linear

Dose

Extrapolation Range Observed Range

Confi

denc

e Lim

it on D

ose

Centr

al Es

timate

Human Exposure of interest

Dose-response analysis – Benchmark approach劑量反應關係的基標分析

ThresholdModel

Non-thresholdModel

Dose (mg/kg/day)

Res

pons

e (%

)

Threshold

有閾值評估程序（非致癌物）有閾值評估程序（非致癌物）

無閾值評估程序（致癌物）無閾值評估程序（致癌物）R

espo

nse

(%)

Dose (mg/kg/day)

Clin

ical

sig

nsLi

ver i

njur

y

Kidn

ey in

jury

Dea

th

Canc

er

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步驟三：暴露評估 - 推算終生平均每日劑量LADD

a. Average daily dose (ADD)平均每日劑量 (mg/Kg-d)

ADDint = [ C x IR x ED x AR] / [BW x AT] (unit: mg/kg-d)

Where (暴露參數):AT = time period over which the dose is averaged (day)BW = average body weight of the human receptorC = concentration (mg/kg) of chemical in the exposure mediumIR = intake rate of the exposure medium (e.g. 2 L water/person-d)ED = duration of actual exposure (hr or day)AR = absorption rate (%)

b. Lifetime (LT) average daily dose (LADD) 終生平均每日劑量

LADDint = [ C x IR x ED x AR] / [BW x LT] (unit: mg/kg-d)

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以嬰兒暴露三聚氰胺為例

暴露參數:

AT = 2 years (730 days)BW = 7.9 kgC = 2.5 ppm (mg/kg diet)IR = 240 g powdered milk equivalent per dayED = 1 dayAR = 100%

Daily intake of melamine: 2.5 ×240/7.9 = 0.076 mg/kg-bw/day

RfD (嬰孩) = 0.063 mg/kg bw/day (歐盟: 0.05 mg/kg bw/day)

國民營養現況60.5kg體重焚化爐實地多介質風險評估計畫0.05g/day土壤攝取率焚化爐實地多介質風險評估計畫0.53m3/hr空氣吸入速率焚化爐實地多介質風險評估計畫2.5L/day水之攝取率

國民營養現況58g/day魚之攝取率國民營養現況42g/day雞肉之攝取率國民營養現況31g/day雞蛋之攝取率國民營養現況107g/day猪肉之攝取率國民營養現況57g/day乳品類之攝取率國民營養現況6g/day牛肉之攝取率國民營養現況190g/day水果之攝取率台灣農業年報423g/day非根部蔬菜之攝取率台灣農業年報32g/day根部蔬菜之攝取率資料來源平均值單位參數

表5.1 國人每人每天各類食物攝食參數

EXPOUSRE ASSESSMENT – BASIC EQUATION

DFFx BWt

Intakex onConentratiExposure =

DFF: Duration Frequency Factor

DFF = ED x AT x LT

ED: Exposure Duration: # hrs/24 hrAT: Averaging Time: # days/7day (weekly)LT: Lifetime: # year/70 years

EXPOUSRE ASSESSMENT – Example 1

mg/kg/day 0.5 0.5x day / BWt kg 1

feed kg 0.1x feed kg 1

EP mg 10 ADDabsorb ==

In a study, one group of mice was fed diets containing 10 ppmof Chemical “X” for 2 years. Assuming that mice eat 10% of their BWt per day, and the AF is 50%, what is the ADD absorp?

EXPOUSRE ASSESSMENT – Example 2

g/kg/day 0.4 0.8x kg 10

daywaterliter1x

waterliter 1TCAg5

(child) ADDabsorb µ=

µ

=

g/kg/day 0.1 0.8x kg 70

daywaterliter2x

waterliter 1TCAg5

(adult) ADDabsorb µ=

µ

=

What is the AADDabsorb of a child and an adult drinking water that contains 5 ppb of 1,1,2-Trichloroethane (TCA)?

Assume: 10 kg child drinks 1 liter of water per day 70 kg adult drinks 2 liters of water per dayabsorption factor = 80%

EXPOUSRE ASSESSMENT – Air Unit Conversion

33 mg/m 24.5MWt mg/m

VolM WtM ppm 1 ==

FROM “VOLUME PER VOLUME” TO “WT PER VOLOLUME”

A work site has 30 μg/m3 xylene in the air. Assuming that an average worker weighs 63 kg, is at the work site 8 hrs per day, 5 days per week, and for 40 years in a lifetime of 70 years. What are the occupational AADDabsorb and LADDabsorb? Assume that the breathing rate is 0.7 m3/hr at work, and the AF is 50%.

EXPOUSRE ASSESSMENT – Example 3

g/kg/day 0.95 0.5x days 7days 5x

kg 63dayhrs 8x

hrm 0.7

x g/m 30 AADD

3

3absorb µ=µ=

g/kg/day 0.54 yrs70 yrs40x AADD LADDabsorb µ==

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步驟四：風險特徵描述

For non-carcinogenic effects: (非致癌反應)

a. Margin of Safety (MOS) 安全邊際 = NOAEL (動物) / Exposure (人)

MOS is expected to be ≧ 100

Comparison :

RfD = NOAEL / 100

100 = NOAEL / RfD (MOS at RfD)

b. Hazard Quotient (HQ) 危害商數 = ADD / RfD (%)

HQi = ADDi / RfD (%)

where i = different exposure pathways

Hazard Index (HI) 危害指數 = Σ HQi

HI is expected to be < 1 equivalent to ADDtotal = Σ ADDi < RfD

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步驟四：風險特徵描述（續）

For carcinogenic effects: (致癌反應)

Risk = LADDint × PotencyH (human slope factor)

Acceptable Risk = Acceptable LADDint × PotencyH

Acceptable LADDint = Acceptable Risk / PotencyH

Acceptable Risk = 10-3 ~ 10-6

LADD = [ C x IR x ED x AR] / [BW x LT]

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步驟四：風險特徵描述（續）

Acceptable concentration (Cacc) in the environmental media

ADDint = [ C x IR x ED x AR ] / [BW x AT]

C = ADDint x [BW x AT] / (IR × ED × AR)

RfC = (RfD or Accepted LADD) × (BW × AT) / (IR × ED × AR)

Contribution factor (CF): For multiple routes of exposure ( i )

Route specific permissible C ( i ) = RfC × CF

Example :

Total exposure to the chemical of interest via drinking water is 20% (CF)

Permissible C (drinking water) = RfC x 20% = RfC × 0.2

frequ

ency

his

togr

am

Uncertainty Analysis

Potential dose

cum

ulat

ive

prob

abilit

y

Model Output

Environmental Fate& Exposure

Model

(p + 1) dimensionalresponse surface

reaction half-life

soil moisture

X1

X2

Stochastic Inputs

prob

abilit

ypr

obab

ility

Kow

Xp

prob

abilit

y

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Monte Carlo Simulation（蒙地卡羅模擬）

Frequency Compar ison

.000

.015

.029

.044

.058

0.000E+0 5.625E-10 1.125E-9 1.688E-9 2.250E-9

Risk

Overlay Char t

52

第四節第四節結束結束