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

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 »

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

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

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