Introduction to Toxicology Koen Van Deun, Jennifer Sasaki, Walter Janssens, Mark Martens Beltox Seminar, Part 2 1

Introduction to Toxicology Definition of toxicology Hazard versus Risk (assessment) Subspecialties in toxicology Areas where toxicology is used Role of the toxicologist Considerations for toxicity testing Principles in toxicology Discussion & conclusion 2

Definition of toxicology Toxicology: Used to be the study of the adverse effects of substances / xenobiotics on living organisms Modern toxicology goes beyond that: Also applies to ‘endogeneous’ molecules Assimilates knowledge from biology, chemistry, physiology, biochemistry, genetics,... Applies Hazard and risk Assessment Alternative methods are promoted. Casarett and Doull’s Toxicology: The Basic Science of Poisons, Curtis D. Klaassen, 6 th Ed.,

Hazard = toxicity = danger – Potential to cause an adverse effect – Is intrinsic to the agent (chemical) – Cannot be controlled Risk – Likelihood that an adverse effect will occur – Is determined by the circumstances (dose, protection, sensitivity, …) – Control possible (prevention) Hazard vs Risk (1) 4

Hazard vs Risk (2) Same hazard/danger High risk Low risk 5 «The danger is acceptable if the risk is sufficiently low »

Subspecialties in toxicology Safety pharmacology Acute dose toxicology Repeated dose toxicology (subacute, subchronic, chronic) Genetic toxicology & Carcinogenicity Local tolerance Reproductive toxicology In vitro toxicology Mechanistic toxicology Toxicological epidemiology Ecotoxicology 6

Areas where Toxicology is used (1) Drugs and/or medical devices Chemicals Pesticides – Insecticides – Herbicides – Fungicides Food: – Additives / Contaminants – Food packaging materials – Genetically modified organisms Consumer goods – Household products – Cosmetics and personal care products 7

Areas where Toxicology is used (2) Frequency of calls according to product type 1.Pharmaceuticals 2.Household products 3.Food & contaminants 4.Plant protection products 5.Cosmetics 6.Plants, fungi 7.Animals 8.Others, e.g.: tabacco, alcohol, drugs Annual report 2009 Not precised 0.31% Others 8.90% Plants/Fungi 1.74% Animals 1.67% Food % Cosmetics 1.98% Plant protection products 3.88% Household products 28.15% Pharmaceuticals 49.25%

9 Number of calls Years Areas where Toxicology is used (3) Frequency of calls per year

10 Child 1-4 y: 33% Child 5-9 y: 5% Child y: 3% Child...? y: 6% Child <1-4 y: 4% Adult: 49% Areas where Toxicology is used (4) Frequency of calls according to age

Role of the Toxicologist in Society (1) Study/investigate/determine the toxicological profile of the agent of interest Risk assessment – Risk benefit analysis Risk communication and education of the public 11

Role of the Toxicologist in Society (2) Toxicologists utilize tools from many other fields including: Pharmacology – Pharmacokinetics/”ADME” Medicine Veterinary medicine Histopathology Hematology Clinical chemistry “-omics” technologies – Genomics/Proteonomics Biostatistics Mathematical modelling 12

Role of the Toxicologist in Society (3) Researchers/Academicians/ Investigators – Fundamental research in toxicology methods – Development and/or validation of testing methods – Training of the next generation of experts – Scientific advice and expertise to regulators and industry 13

Role of the Toxicologist in Society (4) Regulators – Evaluation and/or approval of toxicology dossiers for regulated products – Prepare/discuss/revise/approve/implement guidelines for toxicity testing and evaluation – National & international authorities Be: FOD Volksgezondheid / SPF Santé Public EU: EMEA / EFSA / ECHA US: FDA / EPA 14

Industry – Design and conduct of toxicology strategies & studies – Product safety documentation (dossiers, material & safety data sheets, classification & labeling...) Medicine – Emergency medicine – Poison management – Forensic medicine Role of the Toxicologist in Society (5) 15

Considerations for Toxicity Testing Ethical limits to toxicity testing 3Rs (Reduction, Refinement, Replacement) Use of in vitro or alternative systems should be implemented whenever possible Risk benefit considerations Pharmaceutical for a non-life threatening versus life threatening indication? Cosmetics or “lifestyle” product? Regulatory requirements Compliance with regulatory guidelines Compliance with GLP (Good Laboratory Practice) 16

Some Principles of Toxicology (1) Route and site of exposure e.g.: Local effects vs systemic effects Duration and frequency of exposure E.g. ethanol – Acute E.g.: redness, CNS effects (loss of reflexes...) – Chronic E.g.: Development of tumors 20 years after exposure to a carcinogen, (liver cirrhosis and formation of scar tissue) 17

Some Principles of Toxicology (2) Dose-effect/dose-response and threshold – Establish the dose-effect relationship: Is there an increasing toxic effect/response with increasing exposure to the toxic agent? Toxicology studies typically employ three dose levels with one control group Threshold – is there a “safe” dose at or below which there is no effect? – Safety margin Does the substance exert its intended beneficial effect at exposure levels that cause no or minimal toxicity? 18

Some Principles of Toxicology (3) “population” dose response Dose (g) Toxicity % Response 19

Some Principles of Toxicology (4) cummulative dose response ED 50 = Effective dose in 50% of the individuals TD 50 = Toxic dose in 50% of the individuals Dose (g) % response Effect: cummu- lative Toxicity: cummu- lative 20

Some Principles of Toxicology (5) Differences in the toxic response – Species and sex differences – Physiological and metabolic differences – Age differences The young or old may be more susceptible – Diseased/compromised populations – Selective toxicity eg: Anti-infective drugs and pesticides: greatest toxicity for target infection or pest 21

Some Principles of Toxicology (6) Metabolism & Excretion – Biochemical modification (via enzymes) of substances in the body is intended to increase excretion (and terminate biological activity) – Occurs in liver, kidney, lung, gastrointestinal track, and other organs – Can be an important determinant of the duration and intensity of the toxicological effect of a substance Liver Adapted from © 2008 Society of Toxicology, Liver is a primary site of metabolism 22

Some Principles of Toxicology (7) Metabolism in liver and other organs Less toxic metabolic product excreted (eg: alcohol to water + acetic acid) LiverLungKidney Urine Organism exposed to toxic substance Bile, Feces Expired air 23

Metabolism by liver and other organs Bioactivation to more toxic metabolic product (eg: paracetemol to N-acetyl-p-benzo-quinone imine (NAPQI) Ensuing toxic effects (eg: liver toxicity of paracetamol at high doses) Organism exposed to substance Some Principles of Toxicology (8) 24

Thank You! 25 Discussion & Conclusion