Food Chemical Safety – An industry perspective Brett Jeffery 1 st 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: Other sources of information European Food Standards Agency - US Food and Drug Administration - –Contaminant levels WHO Joint meeting on Pesticides Residues (JMPR) -

11 Food Chemical Safety Paracelsus ( ) 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 Log 10 Dose Response LD 50

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 - H 2 SO 4 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 LD 50 values LD 50 : 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 LD 50 value cannot be used to derive a NOAEL. LD 50 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 E.g.,pesticide toxicities have been classified according to oral and dermal LD 50 values. Basis of WHO pesticide classification according to LD 50 values Acute toxicity and LD 50 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 Log 10 Dose Response LD 50 The LD 50 is the mid-point of the dose response curve and the point at which the 95% confidence intervals are narrowest. As a result the LD 50 value is the most useful for comparison of toxicity between chemicals NOAEL

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 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 LD 50 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

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