Communicating uncertainty - Illustrated by the new …€¦ ·  · 2013-07-183 “All substances are poisons; there is none which is not a poison. The right dose differentiates a

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Communicating uncertainty - Illustrated by the new

approach for risk assessment (Margin of Exposure)

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TECHNICAL TRAINING ON RISK ANALYSIS FOR

SAARC COUNTRIES

FAO RAP, Bangkok, Thailand Quality Council of India Delhi, India, June 17-21, 2013

John LUM Scientific Officer

Centre for Food Safety Hong Kong

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Content

Dose Response Assessment

Health-based Guidance Values

Margin of Exposure (MOE)

Example of Risk Assessment using MOE –

Acrylamide

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“All substances are poisons; there is none

which is not a poison. The right dose

differentiates a poison and a remedy”. Paracelsus, 1538

Aspirin taken for a headache:

- one lick of a pill won’t have desired effect

- two pills should relieve pain

- the entire packet could poison

Dose-response Assessment (1)

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Dose-response Assessment (2)

The determination of the relationship between

magnitude of exposure (dose) to an agent

and the severity and/or frequency of the

adverse health effects (response)

By toxicological tests / experimental data

To derive health-based guidance values

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A typical dose-response curve

0

20

40

60

80

100

Dose

Response

0.10.01 1 10 100 1000

NOAEL

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NOAEL (No-observed-adverse-effect level)

Greatest concentration or amount of a substance, found

by experiment or observation, that causes no adverse

alteration of morphology, functional capacity, growth,

development or lifespan of the target organism

distinguishable from those observed in normal (control)

organisms of the same species and strain under the same

defined conditions of exposure

Dose-response Assessment (3)

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Uncertainties of NOAEL

From animal to human

Interspecies difference

Difference among individuals in human

population

Genetics, genders, diseases status

Dose-response Assessment (4)

Adapted from Andrew G Renwick, Pest Manag Sci 58: 1073-1082

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Acceptable Daily Intake (ADI) NOAEL

Estimate of the amount of a substance in food

and/or drinking water, expressed on a body

weight basis that can be ingested daily over a

lifetime WITHOUT appreciable health risk

Health-based Guidance Values (1)

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Use of dose-response curve to derive ADI

0

20

40

60

80

100

Dose

Response

0.10.01 1 10 100 1000

ADI

Average human

Sensitive human

10 10

UF

NOAEL

Test species

Toxic effect

For animal

to average human

For average human

to sensitive human

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In general, toxic effect is assumed to have a

threshold

A quantitative expression of exposure Deterministic values

Exposure of substances below the health-based

guidance value without appreciable health risk

Health-based Guidance Values (2)

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Additives, pesticide/veterinary drug residues

Intentionally added

Acceptable Daily Intake (ADI)

Contaminants

Tolerable Intakes

Permissible levels of intake of contaminants

unavoidably associated with the consumption of

otherwise wholesome and nutritious food

Provisional Maximum Tolerable Daily Intake (PMTDI)

or Provisional Tolerable Weekly Intake (PTWI)

Health-based Guidance Values (3)

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Genotoxic carcinogens

Any level can potentially cause adverse effect No

threshold for toxic effect health-based guidance

values CAN NOT be set

Alternative approach for risk assessment Margin of

Exposure (MOE) approach:

A qualitative description for a possible prioritisation

of risks

Base on the benchmark dose derived from dose

response modelling

E.g. acrylamide

Health-based Guidance Values for

Genotoxic Carcinogen?

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Margin of exposure (MOE) (1)

Benchmark dose (BMD)

Dose corresponding to a specified change in effect

over background, e.g. tumour formation

Modelling based on sufficient experimental data

Mathematical model is selected, based on the data

that are being analysed and the characteristics of the

response

Databases with larger numbers of dose groups and a

greater experimental complexity will be better suited

for more complex models

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Margin of exposure (MOE) (2)

BMDL (Benchmark dose lower confidence limit)

The lower confidence limit (lower bound 95% confidence limit) of a point on the dose-response curve that characterises adverse effect, to account for uncertainty in the data

BMDL5 or BMDL10 - BMDL give rise to 5% or 10% of effect level

The BMDL can NOT be regarded as a safety reference value

when dietary exposure below the BMDL, it does not mean that there is no health risk

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BMD & BMDL

Adopted from Anne Constable and Susan Barlow - Application of the Margin of Exposure Approach to Compounds in Food which

are both Genotoxic and Carcinogenic, ILSI

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Margin of exposure (MOE) (4)

= BMDL10 / Estimated Dietary Exposure

Provide an indication of the level of health concern without actually quantifying the risk

The higher the MOE the lower the health concern

Use for priority setting for risk management actions

Genotoxic carcinogens:

a MOE of 10,000 (based on a BMDL10 from animal study)

low public health concern

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Example of RA using MOE -

Acrylamide

A food processing contaminant

First reported by the Swedish researchers in 2002

High levels were formed in food during frying or

baking

An industrial chemical that has been used

since the mid 1950s in the production of

polyacrylamide

Also a component of tobacco smoke

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Formation of acrylamide in food

Form where foods are cooked or processing in high

temperature (usually > 120oC), mainly via Maillard

reactions

* Glucose, fructose, decomposition products of sucrose and other sugars as well as

other suitable intermediates (e.g. aldehydes)

Other formation mechanisms, e.g pyrolysis of the wheat

protein gluten

may be of minor importance

Only trace amounts can be formed by boiling

CH2 NH2 C

NH2

COOH O

asparagine

HC H2C

O

CH NH2 C

acrylamide

Sugar *

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Toxicity

Toxic to the nervous system of both animals and

human

Reproductive and developmental effects in

animals

Genotoxic

A multi-site carcinogen in rodents

Group 2A agent (IARC)

Probably carcinogenic to humans

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BMDL for acrylamide

JECFA (2010)

BMDL10

A 10% extra risk of tumours in animals

For Harderian gland tumours in male mice:

0.18 mg/kg bw/day

For mammary tumours in female rats:

0.31 mg/kg bw/day

Epidemiological studies do not provide any consistent evidence that occupational exposure or dietary exposure to acrylamide is associated with cancer in humans

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RA study on acrylamide in food in

Hong Kong

Study conducted in 2010

Determine the acrylamide levels in local food

Estimate the dietary exposure of the local population

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Dietary exposure estimation

MOE > 10,000 low concern

Suggest that there is health concern among

the local population because of the relatively

low MOE values

* MOEs were calculated based on the BMDL10 for Harderian

gland tumours in male mice (0.18 mg/kg bw/day)

Dietary exposure (g/kg bw /day) [MOE]

Average High consumer

2010 study 0.13 [1385*] 0.69 [261*] (P97.5)

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Limitations

Limited sample size

Only focuses on foods which may have higher risk

(in terms of the acrylamide level);

Uncertainties in the exposure estimation

Large variations between brands of the same

product and between batches of the same brand,

thus making direct comparison difficult

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Advice to Public and Trade

Public

Do not over-heat food but ensure the food is cooked

thoroughly

Maintain a balanced diet i.e. eat more fruits and vegetables

and to moderate the consumption of fried and fatty foods

Trade

To seek ways to reduce the level of acrylamide in food, while

not compromising the safety and nutrition value of the

products

Make reference to the guidelines on reduction in acrylamide

level to be published by CFS

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MOE of various chemicals

10,000 1

310

Acrylamide 65,000

1,3-Dichloro-2-propanol

25,000

Polycyclic aromatic hydrocarbons

19,000

Ethyl carbamate

133,000

Malachite green

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Conclusion

RA based on Health-based Guidance Values

Deterministic

RA based on MOE

A relative indication of the level of health concern without actually quantifying the risk

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Conclusion (2)

The MOE approach is both a prioritisation tool and a risk assessment tool, which gives a relative indication of the level of health concern without actually quantifying the risk

In general, small MOEs indicate high concern, and large MOEs low concern

The MOE should always be

accompanied by a narrative to explain the background and the uncertainties in the reference point and exposure estimates

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Conclusion (3)

Uncertainty

communication between risk assessors and risk managers

communication between risk managers and consumers

Risk Assessors moderate their certainty

Risk Managers hoping for the most certain statements

Consumers perceiving the risk as a function of non scientific

criteria i.e. "outrage factors"

Risk Assessment * Science based

Risk Management * Policy based

Risk Communication * Interactive exchange of information

and opinions concerning risks

Risk Analysis

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Conclusion (4)

Need for more formalisation in order to help risk managers in dealing with unknowns and uncertainties

Systematic expression of types of uncertainty

Transparency of the level of agreement among experts

Characterization of the level of confidence of experts

Need for improved communication to consumer

Simple language

Clear graphic representation

Assess risk perception

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Conclusion (5)

Better communication tools on the concept of the MOE approach and resulting levels of concern need to be developed

needs cooperation between risk assessors, risk managers and risk communicators

consumer perceptions about these tools have not yet been addressed adequately

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Reference

Guidance for Risk Management Options in Light of Different Risk Assessment

Outcomes – Report of the Sixth Session of the Codex Committee on

Contaminants in Foods

http://www.codexalimentarius.nl/sites/default/files/page_attachtment/REP12_CFe.pdf

Application of the Margin of Exposure (MOE) Approach to Substances in Food

that are Genotoxic and Carcinogenic – Food and Chemical Toxicology. Vol 48,

Suppl. 1, Jan 2010

Application of the Margin of Exposure Approach to Compounds in Food which

are both Genotoxic and Carcinogenic – ILSI Europe Report Series

http://www.ilsi.org.ar/administrador/panel/newsletter/news27/moe_ws_report.pdf

Risk assessment Studies reports of the Centre for Food Safety

http://www.cfs.gov.hk/english/programme/programme_rafs/programme_rafs.html

Thank you!