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Summary TT Toxicology incl. lectures with answers

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All substance for the toxicology exam with the information from the Blackboard modules and the lectures with answers

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  • September 29, 2021
  • 22
  • 2020/2021
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Principles of Toxicology

Toxin: poisonous substance produced by plants, animals or bacteria

Toxicant: the specific poisonous chemical

Xenobiotic: man-made substance not normally found in the body

Contamination: presence of a biological, chemical, physical or radiological substance normally absent in
the environment

Pollution: any addition to air, water, soil or food that threatens the health and survival capibilities of
humans or other living beings (causes harm)

Target: the particular macromolecule, cell, organ or biological process that the toxicant disrupts

Mode of action: common set of physiological and behavioral signs that characterize a type of adverse
biological response

Mechanism of action: the way the toxicant is able to disrupt the target process, i.e. the specific
biochemical process underlying the mode of action

Hill criteria (ethical standards):

- Strength of association: dependent – independent variables
- Consistency: replication of results by different studies
- Biological gradient: strength of dose-response relationship
- Temporal sequence: cause before effect
- Biological or theoretical plausibility: mechanism of action
- Coherence with established knowledge: no competing hypothesis

Hazard: intrinsic characteristic of the compound

Risk: probability of the hazard being expressed

Basic principles of hazard-risk:

- Exposure: single or chronic, external or internal
- Kinetics: what does to body do to the chemical
- Dynamics: what the chemical does to the body (effect); interaction with the target molecule and
alteration of the biological environment
- Dose-effect relations: what dose will result in an (adverse) effect

Exposure concepts:

- Routes of exposure: ingestion, absorption, injection, inhalation
o Can be age dependent
- Frequencies of exposure
- Duration of exposure

Efficacy: the power to produce an effect

,Idiosyncratic reaction: abnormal reaction to chemical based on genetic susceptibility of individual

Dose response relations

The dose gets placed on the X axis (logarithmic scale), whereas the response is plotted on the Y axis.

NOAEL (No Observed Adverse Effect Level): the highest dose level at which no effect is observed

LOAEL (Lowest Observed Adverse Effect Level): the lowest dose at which an adverse effect is observed

Hill equation: maximal response / ( 1 + 10^(logED50 – dose) * Hill slope )

- ED50: dose at which 50% of the test population exhibits a response
o LD50: dose that is lethal for 50% of the test population
 The lower the LD50 or ED50, the more potent the toxicant
 Therapeutic index: the safety margin between the ED50 and the LD50
 LD50 / ED50  a higher therapeutic index means a higher margin of
safety
- Hill slope: slope at ED50

In quantal dose-response relationships at any given dose an individual in the population is classified as
a responder or a non-responder. This graph will have a sigmoid shape. In individual/graded dose-
response relationships the response of an individual organism to varying doses of a chemical is
described, the measured effect is continuous. These graphs are U-shaped (hormesis).

Toxic mechanisms

Mechanisms of toxicity take place in four fixed steps:

1. Delivery: distribution of the toxicant in the body, excretion via feces or urine, and the route of
exposure determine the extent to which a toxicant reaches a target molecule to react with.
Covalent binding to a protein does not play a role in this. It’s regulated through ADME:
- A: Absorption
o Toxicants can be absorbed through ingestion, inhalation and dermal exposure.
 Oral ingestion: a slow rise with a slow fall (low Cmax and high Tmax)
 Interveinous administration: a quick rise with a relatively slow fall (higher Cmax
and lower Tmax)
 Inhalation: very quick rise with a relatively slow fall (very high Cmax and low
Tmax)
o The two kinetic parameters of concern are the rate of absorption and the extent of
absorption.
 Cmax: the maximum absorbed concentration of the toxicant
 Tmax: the time when Cmax has been reached
o You want to decrease the extent of absorption (bioavailability)
- D: Distribution
o The volume of distribution = amount of toxicant in the body / concentration toxicant
in the blood
o You want to reduce the chemical rate of distribution

, o Kc (equilibrium constant) is dependent on:
 Permeability of barriers
 pH of compartments
 Binding capacity
- M: Metabolism (biotransformation)
o First-pass metabolism is a phenomenon whereby the concentration of a drug,
specifically when administered orally, is greatly reduced before it reaches the systemic
circulation
o There are two types of metabolism:
 Phase 0: binding to a xenosensor; transcription and translation of modifying
enzymes
 Detoxification (phase 1: oxidation, reduction or hydrolysis of the parent
toxicant)
 Mostly in ER of liver cell
 Cytochrome P450
o Most common phase I xenobiotic enzyme
o Broad substrate pecificty
o Mainly in liver microsomes
o Heme containing proteins: Fe3+
o Levels regulated by xenosensors
 Bioactivation (phase 2: conjugation of the toxicant to another molecule)
 Metabolic conversion of lipophilic xenobiotic compounds to more water
soluble compounds that can easily be excreted via urine or feces
 Hanges toxic potentcy and reduces half-life and accumulation of
xenobiotic in organism
o You want to promote chemical detoxification and elimination
- E: Excretion
o Clearance = (Cu * Vu)/Cp
 Cu: concentration toxicant in the urine
 Vu: volume of the urine
 Cp: concentration of the toxicant in the plasma
o First order kinetics: a constant proportion of toxicant is eliminated per unit time
o Zero order kinetics: a constant amount of toxicant is eliminated per unit time
 The kidney is the primary excretory organ, followed by the gastrointestinal
tract and the lungs (also sweat, tears and milk)
 Solubility in water, lipophilicity and volatility affect excretion
o You want to prevent toxicodynamic interaction responsible for toxic effect
2. Interaction: with a target molecule or a biological environment. A target molecule must be in
the right steric configuration to allow interaction with a toxicant. Also of importance is whether
the target molecule is accessible and of critical function.
All biomolecules constitute potential targets for toxicants, but the most prevalent targets are
nucleic acids, proteins and membrane lipids.

There are several kinds of chemical reactions:

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