104年度導入健康風險評估科技精進我國食品安全雄才大略計畫食...

104年度導入健康風險評估科技精進我國食品安全雄才大略計畫食品風險評估人才訓練課程

October 7, 2015

劑量反應評估-

基準劑量軟體教學與演練

食品風險評估人才訓練課程:食品安全風險評估之實務演練

Dose-response assessment:Benchmark dose modeling

and practicesShu-Han You, Ph.D.

Postdoctoral Fellow National Institute of Environmental Health Sciences

National Health Research Institutes, Taiwan

2


Learning Objects of the Course

Provide participants with training on

1. General Benchmark Dose (BMD) methods and its application to dose-response assessment

2. U.S. EPA BMD guidance

3. Use of U.S. EPA’s BMD software

This course is not intended to be a primer on basic concepts of toxicology,

nor a detailed examination of the statistical underpinnings of dose-response models.

3


Outline

4

1. Review of Key Terminology

2. Dose-Response Assessment in Risk Analysis

3. How to Implement and Creating a Dataset in BMD analysis?


Outline

5




食品風險評估人才訓練課程:食品安全風險評估之實務演練 6

Review of Key Terminology 劑量反應關係

Dose-Response RelationshipThe relationship between a quantifiedexposure (dose) and the proportion ofsubjects in incidence and /or in degree ofchange (response).

基準反應Benchmark Response (BMR)

A predetermined change in the responseof an adverse effect relative to thebackground response of this effect.

沒有可觀察到的不良影響值

No Observed Adverse Effect Level (NOAEL)

The highest exposure level at which there areno biologically significant increases in theseverity of adverse effects between the exposedpopulation and its appropriate control group.

基準劑量Benchmark Dose (BMD)

A dose of a substance that when ingestedproduces a predetermined change in theresponse of an adverse effect relative tothe background response of this effect.


Outline

7





Dose-Response Assessment in Risk Analysis

8

Research

Risk management

Risk assessment

1. Hazard identification

2. Dose-response assessment3. Exposure assessment4. Risk characterization


Dose-Response Curve

9

To establish a cause-effect relationship between exposure to a toxic substance (dose administered) and an observed effect (response)

in order to determine a safe exposure level

Dose

Re

spo

nse


Threshold dose (ThD)閾值劑量

10

Dose

Re

spo

nse

閾值劑量為低於檢測無不利效應觀察值

(ThD below which no adverse effects are detected)

NOAEL

ThD approximated by a NOAEL (No Observed Adverse Effect Level，沒有可觀察到的不良影響值)


Non-Threshold 非閾值劑量

11

Dose

Re

spo

nse

Non-Thresholdex: genotoxic carcinogens …

Threshold


Benchmark Dose (BMD) Approach (1)

NOAEL approach used only single points, shape of dose-response is ignored.

BMD is calculated from the curve fitted to the dose-response data, so all information is used.

BMD is not replacement for NOAEL.

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Benchmark Dose (BMD) Approach (2)1. A mathematical

model is applied to the experimental data to produce a dose-response curve.

2. BMR is defined as 10% (or 5%, or 1%).

13Dose

% R

esp

on

se

BMRBMD

Animal model: Mouse, rat, etc

Mathematical model


Outline

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Scenario 1 (Problem formulation)(Chen H, et al. 2015. Environmental Toxicology and Pharmacology)

Polychlorinated biphenyls(PCB)Developing country: China

Recycled electronic waste ↑

Source from http://www.ecy.wa.gov/programs/swfa/pbt/pcb.html

If the current toxicological threshold will really shield people

from harm of PCBs toxicity (Thyroid disruption)?


Groups Number Measurement：Thyroid follicular epithelium/colloid ratio (%)

0 10 0.67

0.1 10 0.64

1 10 0.99

5 10 1.2

10 10 1.72

Table 1. Data in PCBs-treated ovariectomized SD rats for using BMD approach. (Chen et al., 2015)

1) Manually enter these data (Table 1)2) Run the Logistic, Loglogistic, and Weibull (Dichotomous) models 3) Output your results and check the answer Threshold


Creating a dataset

Running an specific model

Opening output and

plot files

How to implement and creating a dataset in BMDS?



Opening output and

plot files after analysis

Creating a dataset

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Open new dataset

CLICK

1

2

3


Enter Data Manually

Enter Data Manually

Groups Number Measurement: Thyroid follicular epithelium/colloid

ratio (%)

0 10 0.67

0.1 10 0.64

1 10 0.99

5 10 1.2

10 10 1.72

00.1

15

10

10101010

10

0.670.640.99

1.2

1.72


Renaming column headers

CLICK RIGHT MOUSE BUTTON→RENAME (ex: dose, N, etc.)

0.115

10

1010

10

0.670.640.99

1.2

1.72Groups Number Measurement:

Thyroid follicular epithelium/colloid ratio (%)

0 10 0.67

0.1 10 0.64

1 10 0.99

5 10 1.2

10 10 1.72



Opening output and


Creating a dataset




Select a Model Type



Select a Model Name


Biological interpretation

Policy decision

Otherwise

• Saturabel processes demonstrating Miichaelis-Mentenkinetics (Hill model)

• Two-stage clonal expansion model

• U.S. EPA’s IRIS program uses the multistage model for cancer data

• Whether various models mathematically describe the data

Selection of an Appropriate Dichotomous Model



Proceed to option screen


Option Screen - Step 1: Selecting Colum assignments

Groups Number Thyroid follicular epithelium/colloid ratio (%)

0 10 0.67

0.1 10 0.64

1 10 0.99

5 10 1.2

10 10 1.72


To prevent biologically implausible results(U.S. EPA Recommendations)

Background do not set to zero unless biologically justifiable

Multistage β restrict to be positive

Power and slope restrict to be 1 or greater

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Option Screen - Step 2: Selecting parameter assignments

Logistic model Weibull model Multistage model


Option Screen - Step 3: Selecting Other assignments

Default

An extra risk of 10% is recommended as a standard by the IRIS (not default)




Creating a dataset

Opening output and



Opening output and plot files

2. Fit statistics

3. BMD & BMDL Estimates

1. Parameter estimates



2. Fit statistics



Does the Model Fit the Data?

Global Goodness-of-fit p-value (p > 0.1)(p數值越小表示擬合越不好)

(Global fit)



2. Fit statistics



(Local fit)

Scaled residuals (Absolute value < 2.0)

Does the Model Fit the Data?



2. Fit statistics




Groups Number Thyroid follicular epithelium/colloid ratio (%)

0 10 0.67

0.1 10 0.64

1 10 0.99

5 10 1.2

10 10 1.72

Table 1. Data in PCBs-treated ovariectomized SD rats for using BMD approach. (Chen et al., 2015)

ModelGoodness-of-fit

BMD BMDLp-value AIC

Logistic

Loglogistic

Weibull

Run BMD and Output your results


Model Goodness-of-fit BMD BMDL

p-value AIC

Logistic 0.9952 36.7 9.35337 4.3235

Loglogistic 0.9969 36.7 9.06215 2.23557

Weibull 0.9968 36.7 9.08583 2.54285

1. More than one model p>0.1 & lowest AIC will result in an acceptable fit to the data.

2. Consider using the lowest BMDL, if BMDL estimates from acceptable models are not sufficiently close, indicating model dependence.

• 通常BMD數值應不能大於BMDL 3倍

>3-fold

>3-fold

Check the Answer

/

/


Thank you

for your listening

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104年度導入健康風險評估科技 精進我國食品安全雄才大略計畫 食...

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104年度導入健康風險評估科技精進我國食品安全雄才大略計畫食...