Mars Template - Teal Accent

1
Food Chemical Safety An industry perspective
Brett Jeffery
1st March 2011
2
Food Chemical Safety

• Definitions
• Chemical Hazards
• Risk Assessment
• Hazard identification
• Dose response
• Exposure assessment

3
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.

4
Food Chemical Safety

• Risk Assessment
• Four steps
• Hazard identification
• Hazard characterisation (dose response
  relationship)
• Exposure assessment
• Risk characterisation (compared with exposure
  level)

5
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

6
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

7
Food Chemical Safety

• Hazards in Pet care products
• Core ingredients
• - garlic, lutein.
• Micronutrients
• - vitamin D
• Functional ingredients
• .alginate
• Contaminants
• Melamine/cyanuric acid

8
Food Chemical Safety

• How do you find out about chemical contamination?
• Supplier
• Consumer complaints
• Regulators
• Inbound testing
• Trade associations
• External analytical laboratory

9
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

10
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/

11
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."

12
Food Chemical Safety

• Why are chemicals toxic?
• Dose dependent
• acute or chronic
• Detoxification mechanisms
• Mechanism of action
• Receptor mediated
• Physical obstruction
• Oxidative stress

13
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.

14
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.

15
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

16
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

17
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

18
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.

19
Food Chemical Safety
Acute toxicity and LD50 values
E.g.,pesticide toxicities have been classified
according to oral and dermal LD50 values. Basis
of WHO pesticide classification according to LD50
values
EU Chemical classification (pre-REACH)
20
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

21
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.

22
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.

23
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.
• As a result the LD50 value is the most useful for
  comparison of toxicity between chemicals

LD50
Response
NOAEL
Log10 Dose
24
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

25
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

26
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

27
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

28
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

29
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

30
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.

31
Food Chemical Safety

• Risk assessment of non-threshold compounds
• Examples
• Lead
• Benzene
• Vinyl chloride
• International Agency for Research of Cancer
  (IARC)

32
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

33
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

34
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

35
Thank you