What are hazards in food system? Physical – Fish bones, nail, hair, etc… Chemical – Environmental pollutants Heavy metal Polymers – Pesticides – Antibiotic residues – Food additives (legal or illegal)

Biological – Bacteria – Fungi – viruses – Parasites – Prion

Natural toxins – Bacterial toxins – Mycotoxins – Animal toxins Puffer fish, cigatoxins, PSP, – Plant toxins

Toxicity is determined by the dosage Anything and everything is toxic

Risk assessment Define risk, danger, and hazard Types of hazards Toxicity of the hazards – Toxic dosage – Concentrations of the hazards – Contact and absorption pathway Food, water, air, and skin. – Balance of absorption and detoxication Age, gender, body size, health status

Decide which hazard Toxicological studies of the hazard Concentrations of the hazard in food or environment Maximally possible absorption concentration – The worst case scenario

Evaluation of toxicity of substances Epidemiological studies of human or other populations exposed to the toxic compound Animal test (in vivo) Test lower organisms (in vivo) Test cell cultures (in vitro) Computer calculations (in silico)

Epidemiological studies Incidental via environment, occupation, or diet – Accidentally uptaken from environment, occupation, or diet Intentional, for example, with a drug or food additive – Intentionally added into food system – Human volunteers – Phase I and Phase II

Cohort studies – Drug vs. placebo Case control Cross-sectional Ecological studies – Compare different geographic areas

Absolute excess risk – A=the number of the cases of an illness in an exposed population – B=the number of nonaffected individuals in the control population – C=the number of the exposed nonaffected individuals – D=the number of the individuals who have fallen ill without any exposure to the toxicant

Animal tests Quantitative-structure activity relationship QSAR Nonobserved adverse effect level (NOAEL) Lowest adverse effect level (LAEL) Safety factor – Inter-species – Intra-species Body area and dosage

Animals from wild populations or open colonies Animals from closed colonies (pure line)

Organism-independent factors influencing compound toxicity Species Genetic Genertic Age Dietary conditions Health conditions

Cell culture Computer

Acute Sub-chronic Chronic – Acceptable daily intake (ADI) – Tolerable daily intake (TDI) – Reference daily intake (RDI)

Toxicological safety and risk analysis Toxicological safety – There is not a single chemical compound in the world has been conclusively proved to be absolutely harmless. – Therapeutic index (TI) – TI=TDx/EDx – TD: toxic dosage; ED effective dosage – Higher TI has a higher therapeutic effect and lower toxic effect (high toxic dosage and low effective dosage)

GRAS: generally regarded as safe The substance has been used for a long period of time without obvious toxic effect, such as salt (NaCl), sugar, vinegar (acetic acid), lactic acid, ect….

Risk assessment Risk management Risk communication

Risk assessment Risk = hazard x exposure 1.Hazard identification 2.Dose-response 1.TI 3.Exposure assessment 1.The worst case scenario 2.Air, food, water, contact, 4.Risk characterization

Hazard identification Human epidemiology – Real cases Animal toxicity tests – Dose-response – Replacement, reduction and refinement – If any intro test exist, the animal test should be replaced – The number of animal should be reduced – The method should be refined

In vivo, in vitro and other studies – Toxicokinetics – Absorption – Distribution (including inside the human body and environment) – metabolism

Dose-response Extrapolation from high doses in animal tests to much lower doses of a potential human exposure On-hit model Linearized multistage model Multihit model Probability unit model

Physiologically based pharmacokinetic model – Absorption – Distribution – Metabolism – Accumulation – Elimination

Assessment of exposure – The worst case scenario – Food, water, air, contact – Average intake amount Risk characterization – NOAEL and LOAEL – 70 year

individual difference (the same species) Interspecies difference Lower than chronic doses are being used in the animal studies Use LOAEL instead of NOAEL ADI=NOAEL/safety factor

Evaluation of toxicity of substances Epidemiological studies Animal tests with higher organisms (in vivo) Tests with lower organisms Tests with cell culture Computer calculations

Epidemiological studies Well documented accidents with chemicals Occupational exposure of workers Volunteers – New drug – Phase I, II, and III Cohort studies Case-control studies of an incident Cross-sectional ecological

Animal test For safety reason, human is considered as 10 times more sensitive than animials. Body area M 2 =k x w/100 Animal number – Small number of animals with high dose

The difference between human and the tested rats Animal source – Wild population – Closed colonies – Stemming from colonies by C-section

Intraspecies and intrapopulaitionvariabilities of the character and strength of toxic response Dependence on species Genetic variabilities Generic variabilities (sex or gender difference) Dependence on age Dietary condition

– Stimulation of a limited number of colonic bacteria strains is an alternative mechanism, which natural compounds may use to facilitate the defense of an organism against food-borne toxicants. E. g. inulins Health condition – Pathological conditions of the liver – Simultaneous contact with several xenobiotics

Cell culture test Computer calculations Acute toxicity tests Subacute/subchronic tests Chronic tests