Transcript Mars Template

Food Chemical Safety – An industry perspective
Brett Jeffery
1st March 2011
Food Chemical Safety
• Definitions
• Chemical Hazards
• Risk Assessment
• Hazard identification
• Dose response
• Exposure assessment
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Food Chemical Safety
Definitions
Hazard
Inherent 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.
Exposure
Concentration or amount of a particular agent that reaches a target organism, system
or (sub) population in a specific frequency for a defined duration.
Risk
The 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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Food Chemical Safety
Risk Assessment
Four steps:
• Hazard identification
• Hazard characterisation (dose response relationship)
• Exposure assessment
• Risk characterisation (compared with exposure level)
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Food Chemical Safety
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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Food Chemical Safety
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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Food Chemical Safety
Hazards in Pet care products
Core ingredients:
• - garlic, lutein.
Micronutrients:
• - vitamin D
Functional ingredients:
• .alginate
Contaminants
• Melamine/cyanuric acid
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Food Chemical Safety
How do you find out about chemical contamination?
• Supplier
• Consumer complaints
• Regulators
• Inbound testing
• Trade associations
• External analytical laboratory
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Food Chemical Safety
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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Food Chemical Safety
Databases available at:
http://jecfa.ilsi.org/
http://www.who.int/ipcs/food/jecfa/en/
www.inchem.org
http://toxnet.nlm.nih.gov/
Other sources of information
European Food Standards Agency - www.efsa.eu
US Food and Drug Administration - www.fda.gov
– Contaminant levels
WHO Joint meeting on Pesticides Residues (JMPR) http://www.who.int/ipcs/publications/jmpr/en/
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Food Chemical Safety
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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Food Chemical Safety
Why are chemicals toxic?
• Dose dependent
– acute or chronic
LD50
• Detoxification mechanisms
Response
• Mechanism of action
– Receptor mediated
– Physical obstruction
– Oxidative stress
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Log10 Dose
Food Chemical Safety
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 nonthreshold compounds.
• Requires overall toxicological profile of a chemical.
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Food Chemical Safety
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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Food Chemical Safety
Hazard identification
What 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, anaesthesia
kidney damage due to Cd, cancer
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Food Chemical Safety
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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Food Chemical Safety
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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Food Chemical Safety
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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Food Chemical Safety
Acute toxicity and LD50 values
Class
Ia
Ib
II
III
Extremely hazardous
Highly hazardous
Moderately hazardous
Slightly hazardous
LD 50 for the rat (mg/kg body weight)
Oral
Dermal
Solids
Liquids
Solids
Liquids
5 or less
20 or less
10 or less
40 or less
5-50
20-200
10-100
40-400
50-500
200-2000
100-1000
400-4000
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
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LD50 mg/kg
Toxicity class
 25
> 25 – 200
> 200- 2000
> 2000
1 Very toxic
2 Toxic
3 Harmful
4 Unclassified
Number of
chemicals
0
35
235
845
Chemicals (%)
0
3.1
21.1
75.8
EU Chemical classification (preREACH)
Food Chemical Safety
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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Food Chemical Safety
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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Food Chemical Safety
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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Food Chemical Safety
Dose response curve
•The LD50 is the mid-point of the dose response curve and the
point at which the 95% confidence intervals are narrowest.
LD50
Response
NOAEL
Log10 Dose
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•As a result the LD50 value is the most useful for comparison of
toxicity between chemicals
Food Chemical Safety
Derivation of a Exposure Limit
From 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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Food Chemical Safety
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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Food Chemical Safety
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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Food Chemical Safety
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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Food Chemical Safety
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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Food Chemical Safety
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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Food Chemical Safety
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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Food Chemical Safety
Risk assessment of non-threshold compounds
• Examples
• Lead
• Benzene
• Vinyl chloride
International Agency for Research of Cancer (IARC)
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Food Chemical Safety
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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Food Chemical Safety
Summary
• Every chemical is toxic at sufficient dose
• May occur as a contaminant or naturally occurring chemical
• 4 steps in risk assessment
»
»
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Hazard identification
Dose response relationship
Exposure assessment
Risk characterisation
• Requires toxicity data
• Uncertainty factors
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Thank you