food chemical safety – an industry perspective

Food Chemical Safety – An industry perspective

Brett Jeffery

1st March 2011

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Food Chemical Safety

•Definitions

•Chemical Hazards

•Risk Assessment

•Hazard identification

•Dose response

•Exposure assessment

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Definitions

HazardInherent property of an agent or situation having the potential to cause adverse effects when an organism, system or (sub) population is exposed to that agent.

ExposureConcentration or amount of a particular agent that reaches a target organism, system or (sub) population in a specific frequency for a defined duration.

RiskThe probability of an adverse effect in an organism, system or (sub) population caused under specified circumstances by exposure to an agent.

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Risk Assessment

Four steps:

•Hazard identification

•Hazard characterisation (dose response relationship)

•Exposure assessment

•Risk characterisation (compared with exposure level)

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Risk characterisation•Simply put:

•‘an estimate of the probability that an adverse health effect will occurrence following exposure to a chemical at a particular exposure level’

Risk management•Decision-making process - involving considerations of

political, social, economic, and technical factors

•Include risk assessment

•Should be kept separate from risk assessment

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Chemical Hazards

Naturally occurring

•e.g. mycotoxins, shellfish toxins, plant toxins.

Man made

•e.g.dioxins, heavy metals, pesticide residues.

Process related

•e.g. acrylamide, furans, 3-MCPD.

•bisphenol A

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Hazards in Pet care products

Core ingredients:•- garlic, lutein.

Micronutrients:• - vitamin D

Functional ingredients:•.alginate

Contaminants•Melamine/cyanuric acid

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How do you find out about chemical contamination?

•Supplier

•Consumer complaints

•Regulators

•Inbound testing

•Trade associations

•External analytical laboratory

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How do you know if a chemical is toxic?

•Published literature

•Veterinary expertise

•Toxicological databases

•Global Quality and Food Safety Team

•Waltham Center for Pet Nutrition

•Anecdotal reports

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Databases available at:

http://jecfa.ilsi.org/http://www.who.int/ipcs/food/jecfa/en/www.inchem.orghttp://toxnet.nlm.nih.gov/

Other sources of informationEuropean Food Standards Agency - www.efsa.euUS Food and Drug Administration - www.fda.gov

– Contaminant levelsWHO Joint meeting on Pesticides Residues (JMPR) -http://www.who.int/ipcs/publications/jmpr/en/

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Paracelsus (1493-1541)

German

"All things are poison and nothing is without poison, only the dose permits something not to be poisonous."

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Why are chemicals toxic?

•Dose dependent

– acute or chronic

•Detoxification mechanisms

•Mechanism of action

– Receptor mediated– Physical obstruction– Oxidative stress Log10 Dose

Response

LD50

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Why do a toxicological risk assessment?

•To determine whether there is sufficient data to provide reassurance that there is little likelihood of adverse health effects occurring under given exposure conditions.

•Does not estimate magnitude of risk I.e no of people effected.

•Setting intake or exposure levels

• Identify compounds that are mutagens, genotoxic carcinogens,

e.g. benzene. These are non-threshold compounds.

•Requires overall toxicological profile of a chemical.

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Toxicological risk assessment

Four stages•Hazard identification: what are the substances of

concern and what are the adverse effects?

•Dose (concentration) - response (effect) relationship: Is the a threshold below which no effect is observed?

•Exposure assessment: Intake data, distribution of intake in population, different routes of exposure.

•Risk characterisation: Comparison of a toxicologically derived exposure limit with an exposure estimate.

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Hazard identificationWhat are the substances of concern and what are the adverse effects?

•Physico-chemical properties

e.g. irritant -styrene, corrosive - H2SO4

•Acute toxicity - after a single exposure.

•Chronic toxicity - repeated exposure over a longer time period.

•Reproductive and developmental toxicity

•Epidemiology - retrospective case control studies.

•Reversible vs.. Irreversible.

e.g. skin irritation, anaesthesiakidney damage due to Cd, cancer

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Toxicity studies

•Derive exposure level e.g. Tolerable Daily Intake (TDI)

In vivo studies

Different species - rat, mouse

Different strains - Sprague dawley (rat) /C57BL (mouse)

Route of administration

i.e. oral, intra-venous, intra-peritoneal, sub-cutaneous.Consider vehicle in which compound is administered e.g

solvent

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In vivo toxicity studies

•Use high doses then extrapolate to human exposure

•Typically use inbred strains of animals

•Identify most sensitive toxicological end point

•Account for uncertainties

•For most chemicals the data set will be incomplete

•Require knowledge of:

•Toxicokinetics - Absorption, Distribution, Metabolism and Excretion (ADME)

•Toxicodynamics - Target organ response

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Acute toxicity and LD50 values

•LD50: The dose of a toxic compound that causes death in 50% of a group of experimental animals to which it is administered. It can be used to assess the acute toxicity of a compound, but is being superseded by more refined methods.

•Provides no information on the dose response relationship i.e the LD50 value cannot be used to derive a NOAEL.

•LD50 provides a crude assessment of acute toxicity over a specified time period.

•Allow identification of a starting dose in acute oral toxicity studies.

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Class LD50 for the rat (mg/kg body weight) Oral Dermal

Solids Liquids Solids LiquidsIa Extremely hazardous 5 or less 20 or less 10 or less 40 or lessIb Highly hazardous 5-50 20-200 10-100 40-400II Moderately hazardous 50-500 200-2000 100-1000 400-4000III Slightly hazardous Over 500 Over 2000 Over 1000 Over 4000

The terms solids and liquids refer to the physical state of the active ingredient being classified.

E.g.,pesticide toxicities have been classified according to oral and dermal LD50 values.

Basis of WHO pesticide classification according to LD50 values

Acute toxicity and LD50 values

LD50 mg/kg Toxicity class Number ofchemicals

Chemicals (%)

25 1 Very toxic 0 0> 25 – 200 2 Toxic 35 3.1> 200- 2000 3 Harmful 235 21.1> 2000 4 Unclassified 845 75.8

EU Chemical classification (pre-REACH)

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Derivation of a Exposure Limit for threshold

compounds

•Exposure limits can be derived for compounds where the data indicates that there is a dose or concentration below which adverse effects will not occur

•WHO/FAO Joint Expert Committee on Food Additives (JECFA) European Food Standards Authority

•National authorities e.g. US FDA, UK Food Standards Agency.

•Undertaken by Experts

• Independent Advisory Committees

•Scientific process separate from policy decisions

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Types of Exposure Limit

•Acceptable Daily Intake (ADI): An estimate of the amount of a substance in food or

drinking water, expressed on a body-weight basis, that can be ingested daily over a

lifetime without appreciable risk (standard human = 60 kg). The ADI is listed in units of

mg per kg of body weight.

Tolerable Daily Intake (TDI): An estimate of the amount of contaminant, expressed on a

body weight basis (e.g. mg/kg bodyweight), that can be ingested daily over a lifetime

without appreciable health risk.

An ADI is typically derived for food additives, pesticides and veterinary medicines.

A TDI is derived for chemical contaminants.

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Types of Exposure Limit (continued)

Acute reference dose (ARfD): Estimate of the amount of a substance in food or drink,

expressed on a body weight basis, that can be ingested in a period of 24 hours or less

without appreciable health risk.

PTMI (Provisional Tolerable Monthly Intake):An endpoint used for a food contaminant

with cumulative properties that has a very long half-life in the human body. Its value

represents permissible human monthly exposure to a contaminant unavoidably

associated with otherwise wholesome and nutritious foods.

PTWI (Provisional Tolerable Weekly Intake):An endpoint used for food contaminants such as heavy metals with cumulative properties. Its value represents permissible human weekly exposure to those contaminants unavoidably associated with the consumption of otherwise wholesome and nutritious foods.

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Dose response curve

Log10 Dose

Response

LD50

•The LD50 is the mid-point of the dose response curve and the point at which the 95% confidence intervals are narrowest.

•As a result the LD50 value is the most useful for comparison of toxicity between chemicals

NOAEL

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Derivation of a Exposure LimitFrom in vivo studies identify ‘pivotal study’

Select No Observed Adverse Effect Level (NOAEL)

Consider interspecies toxicodynamics - apply x2.5 uncertainty factor

Consider interspecies toxicokinetics - apply x4.0 uncertainty factor

Interspecies variability uncertainty factor is x10 (2.5x4)

Consider human variability in toxicodynamics - apply x3.2 uncertainty factor

Consider human variability in toxicokinetics - apply x3.2 uncertainty factor

Uncertainty factor for variation in human population is x10 (3.2 x 3.2)

Other considerations - nature of toxicity , knowledge gaps in toxicological profile

Use a default overall uncertainty factor of x100

The ADI or TDI is obtained by dividing the critical NOAEL by the overall uncertainty factor

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Derivation of a Exposure Limit (companion animals)

From in vivo studies identify ‘pivotal study’

Select No Observed Adverse Effect Level (NOAEL)

Consider animal variability in toxicodynamics - apply x3.2 uncertainty factor

Consider animal variability in toxicokinetics - apply x3.2 uncertainty factor

Uncertainty factor for variation in human population is x10 (3.2 x 3.2)

Other considerations - nature of toxicity , knowledge gaps in toxicological profile

Apply addition factor of x 10 if limited data available

Use a default overall uncertainty factor of x100

The ADI or TDI is obtained by dividing the critical NOAEL by the overall uncertainty factor

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Derivation of a Exposure Limit - other considerations

•Is all the toxicity data available?

•Addition uncertainty factor if Lowest Observed Adverse Effect Level is identified (in absence of a NOAEL).

•Is it possible to use data derived uncertainty factors compared to default values?

•Is the test species more or less sensitive?

Other approaches•Margin of Exposure (MoE) e.g acrylamide

• Approach compares estimate of exposure to the critical NOAEL

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Derivation of an Exposure Limit - Examples

• Ochratoxin A

Last considered by JECFA in 2007 which set a PTWI of 100ng/kg bw

•Cyanogenic glycosides

Last considered by UK CoT in March 2006.

Based on limited data the UK CoT concluded that ‘The range for the lethal dose

in humans was 0.5 to 3.5 mg/kg bw/day,applying a 100 fold uncertainty factor to

the lowest lethal dose, to allow for extrapolation from LOAEL to NOAEL and for

inter-individual differences would result in a TDI of 5 mg/kg bw/day.’

• Dioxin (TCDD)Last considered by JECFA in 2001 who set a PTMI 70 pg/kg bw

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Exceedance over the Exposure Limit

•If exposure is above the level derived from the NOAEL/LOAEL

•Indicates potential health concern

•Raw material / finished product may be illegal or out of spec.

•Food safety risk assessment

•Part of Business risk assessment

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What to do in the absence of a specific relevant LD50 value?

•Indicative that very little toxicity data is available.

•History of safe use

•Generally Regarded as Safe (GRAS) status

•Novel food?

• Regulatory requirements•Insufficient toxicity data - cannot derive exposure limit

•Ingredient prohibited from use

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Risk assessment of non-threshold compounds

•Compounds which interact with DNA i.e. mutagens and

genotoxic carcinogens.

•Assume any exposure is associated with increased risk.

•Exposure to a compound believed to be genotoxic

carcinogen should be as low as reasonably practicable

(ALARP).

•Alternative approach : Margin of Exposure

•Managed by routine monitoring and exposure

assessments.

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Risk assessment of non-threshold

compounds

•Examples

•Lead

•Benzene

•Vinyl chloride

International Agency for Research of Cancer

(IARC)

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Exposure assessment

For companion animals

•What species? - dog, cat….

•Diet fed in solus according to nutritional guidelines

– Based on energy requirements•Consider different groups

• Adults• Infants– Gestating/lactating animals

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Food chemical safety

Exposure assessment

•Assume max. measured contaminant level in raw material

•No loss on processing

•Consider % incorporation into final product

•Quantity of final product consumed

– Frequency of intake

– Pack size

Short term or long term consumption

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Summary

•Every chemical is toxic at sufficient dose

•May occur as a contaminant or naturally occurring chemical

•4 steps in risk assessment» Hazard identification» Dose response relationship» Exposure assessment» Risk characterisation

•Requires toxicity data

•Uncertainty factors

Thank you

food chemical safety – an industry perspective

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