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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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Food Chemical Safety
DefinitionsHazardInherent property of an agent or situation having the potential to cause adverse effectswhen 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 causedunder specified circumstances by exposure to an agent.
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Food Chemical Safety
Risk AssessmentFour 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 HazardsNaturally 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 productsCore ingredients:
- garlic, lutein.
Micronutrients: - vitamin D
Functional ingredients: .alginate
Contaminants Melamine/cyanuric acid
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Food Chemical Safety
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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Food Chemical Safety
Paracelsus (1493-1541)German
"All things are poison and nothing iswithout poison, only the dose permitssomething not to be poisonous."
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Food Chemical Safety
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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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 non-
threshold compounds. Requires overall toxicological profile of a chemical.
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Food Chemical Safety
Toxicological risk assessmentFour 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 isobserved?
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 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, 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 studiesDifferent species - rat, mouse
Different strains - Sprague dawley (rat) /C57BL (mouse)
Route of administrationi.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
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 usedto 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
Class LD50 for the rat (mg/kg body weight)
Oral Dermal
Solids Liquids Solids Liquids
Ia Extremely hazardous 5 or less 20 or less 10 or less 40 or less
Ib Highly hazardous 5-50 20-200 10-100 40-400
II Moderately hazardous 50-500 200-2000 100-1000 400-4000
III 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 LD50values.
Basis of WHO pesticide classification according to LD50values
Acute toxicity and LD50 values
LD50 mg/kg Toxicity class Number of
chemicals
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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Food Chemical Safety
Types of Exposure LimitAcceptable 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
Dose response curve
Log10 Dose
Response
LD50
The LD50 is the mid-point of the dose response curve and thepoint at which the 95% confidence intervals are narrowest.As a result the LD50 value is the most useful for comparison oftoxicity between chemicals
NOAEL
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Food Chemical Safety
Derivation of a Exposure LimitFrom in vivostudies 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 uncertaintyfactor
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Food Chemical Safety
Derivation of a Exposure Limit (companion animals)From in vivostudies 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 Examples
Lead
Benzene
Vinyl chloride
International Agency for Research of Cancer (IARC)
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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
Hazard identification
Dose response relationship
Exposure assessment
Risk characterisation
Requires toxicity data
Uncertainty factors
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Thank you