Beltox Seminar Part 2 Introduction to Toxicology Koen

Beltox Seminar, Part 2 Introduction to Toxicology Koen Van Deun, Jennifer Sasaki, Walter Janssens, Mark Martens 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. , 2008 3

Hazard vs Risk (1) • 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) 4

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

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. . . www. poisoncentre. be Annual report 2009 Others 8. 90% Not precised 0. 31% Plants/Fungi 1. 74% Animals 1. 67% Food. . . 4. 13% Cosmetics 1. 98% Plant protection products 3. 88% Pharmaceuticals 49. 25% Household products 28. 15% 8

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

Areas where Toxicology is used (4) Frequency of calls according to age Child 1 -4 y: 33% Child <1 -4 y: 4% Child 5 -9 y: 5% Child 10 -14 y: 3% Child. . . ? y: 6% Adult: 49% 10

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

Role of the Toxicologist in Society (5) • 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 15

Considerations for Toxicity Testing • Ethical limits to toxicity testing • 3 Rs (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 % Response Toxicity Dose (g) 19

Some Principles of Toxicology (4) cummulative dose response % response Effect: cummulative Toxicity: cummulative Dose (g) ED 50 = Effective dose in 50% of the individuals TD 50 = Toxic dose in 50% of the individuals 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 is a primary site of metabolism Adapted from © 2008 Society of Toxicology, http: //www. toxicology. org/ai/eo/intro_toxslides. asp 22

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

Some Principles of Toxicology (8) Organism exposed to substance 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) 24

Discussion & Conclusion Thank You! 25