Introduction to Toxicology Koen Van Deun, Jennifer Sasaki, Walter Janssens, Mark Martens Beltox...
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Transcript of Introduction to Toxicology Koen Van Deun, Jennifer Sasaki, Walter Janssens, Mark Martens Beltox...
![Page 1: Introduction to Toxicology Koen Van Deun, Jennifer Sasaki, Walter Janssens, Mark Martens Beltox Seminar, Part 2 1.](https://reader035.fdocuments.in/reader035/viewer/2022062300/56649e1c5503460f94b0a79b/html5/thumbnails/1.jpg)
Introduction to Toxicology
Koen Van Deun, Jennifer Sasaki,Walter Janssens, Mark Martens
Beltox Seminar, Part 2
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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
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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
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• 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)
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Hazard vs Risk (2)
Same hazard/danger
High riskLow risk5
«The danger is acceptable if the risk is sufficiently low »
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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
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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
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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...
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www.poisoncentre.be Annual report 2009
Not precised 0.31%
Others 8.90%
Plants/Fungi 1.74%
Animals1.67%
Food...4.13%
Cosmetics1.98%
Plant protection products3.88%
Household products 28.15%
Pharmaceuticals 49.25%
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Number of calls
Years
Areas where Toxicology is used (3)
Frequency of calls per year
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Child 1-4 y: 33%
Child 5-9 y: 5%
Child 10-14 y: 3%
Child ...? y: 6%
Child <1-4 y: 4%
Adult: 49%
Areas where Toxicology is used (4)
Frequency of calls according to age
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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
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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
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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
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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 PublicEU: EMEA / EFSA / ECHA US: FDA / EPA
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• 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)
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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)
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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)
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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?
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Some Principles of Toxicology (3)
“population” dose response
0
5
10
15
20
25
30
35
40
0 10 20 30 40 50 60 70 80 90 100 110 120 130
% respons
Dosis (g)
Effect
Toxiciteit
Dose (g)
Toxicity
% Response
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Some Principles of Toxicology (4)
cummulative dose response
ED50 = Effective dose in 50% of the individuals
TD50 = Toxic dose in 50% of the individuals
Dose (g)
% response
Effect: cummu-lative
Toxicity: cummu-lative
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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
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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, http://www.toxicology.org/ai/eo/intro_toxslides.asp
Liver is a primary site
of metabolism
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Some Principles of Toxicology (7)
Metabolism in liver and other organsMetabolism in liver and other organs
Less toxicLess toxic metabolic product excreted metabolic product excreted
(eg: alcohol to water + acetic acid)(eg: alcohol to water + acetic acid)
LiverLiver LungLungKidneyKidney
UrineUrine
Organism exposed to toxic substanceOrganism exposed to toxic substance
Bile, FecesBile, Feces Expired airExpired air23
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Metabolism by liver and other organsMetabolism by liver and other organs
Bioactivation to Bioactivation to more toxicmore toxic metabolic product metabolic product
(eg: paracetemol to N-acetyl-p-benzo-quinone imine (NAPQI)(eg: paracetemol to N-acetyl-p-benzo-quinone imine (NAPQI)
Ensuing toxic effectsEnsuing toxic effects
(eg: liver toxicity of paracetamol at high doses)(eg: liver toxicity of paracetamol at high doses)
Organism exposed to substanceOrganism exposed to substance
Some Principles of Toxicology (8)
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Thank You!
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Discussion & Conclusion