Portfolio of drug toxicology and translational technology
Name: Anouk Morsink
Date: 6 May 2024
Sources which were used to write this summary are the lectures from Anika Nagelkerke, Pe-
ter Olinga, Mathieu Vinken, and Nynke Kramer (2024)
1
,Content
Chapter 1 basic principles of toxicology 16-4-2024. Keywords: drug safety and
efficacy, parameters of interest, organ-specific toxicity ............................................... 3
Chapter 2 toxicity testing in laboratory models 17-04-2024. Keywords: cell culture
models, translation technologies, biomaterials, induced-pluripotent stem cells,
organoids, precision-cut tissue slices, organ-on-a-chip, bioprinting ............................ 6
Chapter 3 adverse outcome pathways 17-04-2024. Keywords: Molecular initiating
event, key event, key event relationship, adverse outcome and risk assessment ...... 9
Chapter 4 biomarkers 19-4-2024. Keywords: biomarkers for toxicity, read-outs,
biomarker specificty, extracellular vesicles ............................................................... 12
Chapter 5 omics approaches 23-04-2024. Keywords: toxicogenomics,
transcriptomics, proteomics, metabolomics, phosphoproteomics, prinicipal
component analysis, pathway analysis, high-throughput screening ......................... 15
Chapter 6 QIVIVE 24-04-2024.Key words: QIVIVE, risk assessment, toxicokinetics,
toxicodynamics, PBK modelling ................................................................................ 18
Chapter 7 toxicokinetic modelling 24-04-2024. Keywords:toxicity prediction,
populations at risk, SimCYP, and digital twin concept............................................... 21
Hand-out of the slides ............................................................................................... 24
2
, Chapter 1 basic principles of toxicology 16-4-2024
In this lecture the mechanism behind organ and tissue specific toxicity, factors that
influence toxicity (drug, host and interaction) and the need of prediction of drug toxicity
was discussed. Also it was discussed if we can predict toxicity events. Keywords: drug
safety and efficacy, parameters of interest and organ-specific toxicity.
Toxicology (acute or chronic) means the amount of which a compound can be harmful
to a organism. Acute happens directly after administration (minutes, hours, days), by
high dose. Chronic happens after multiple dosages (sublethal or low dose), on long
term-> subtle changes, the drug accumulates and cause toxicity. Toxicity can be de-
sired (efficacy) and undesired (safety), desired (remedy) is during chemotherapy (cy-
totoxicity) and undesired (poison) is during other treatment.
Drug safety and efficacy: It is important to keep in mind by model system that it de-
pends on the compound, and the host. The parameters which determine the drug
safety and efficacy: in person can be a combination of the following: dose, age, gender,
comedication, diseases (comorbidities), ADME, diet, excretion, administration route,
form and innate chemical activity, life stage; embryo, foetus, adult, infant, species and
circadian rhythms (time of day). Also the physico-chemical properties (redox, com-
plexation, ionization, solubility, hydrogen bonding) has influence on drug. Drug formu-
lations get more complex. Different formulation can alter a drug’s toxicity profile (ap-
ple pie example) it can influence the pharmacokinetics, biodistribution (distribution to
different organs) and the efficacy of drugs.
Different cells, tissues, organs and organ systems together make up the entire organ-
ism. Homeostasis: the body maintenance the internal steady state, changes are de-
tected by the receptor and via the brain impulses are sent to the effector which regu-
lates a response and thereby the imbalance is corrected (homeostasis is not keeping
a static conditions, but keeping conditions within tightly regulated physiological toler-
ance limits). When cells are damaged the cells can be regenerated and repaired when
this is not possible the cell will die. The effect on the drug on the cell is dependent on
the type of cell, dose, duration, host (e.g. age) and environmental factors.
Specificity of toxicity: some drugs have specific effects in certain organs and tissues.
Causes: characteristics of organ and tissue, the uptake, metabolism, concentration, a
mechanism which is specific for tissue and organ, and the route of administration. Tox-
icity which occur due to organ and tissue specificity mechanism are e.g. hepatotox-
icity (major issue), nephrotoxicity and neurotoxicity, the toxicity of a specific compound
can be due to characteristics tissue, dose, duration, ad-
ministration, distribution, host, environmental factors.
Embryotoxicity is organ and tissue specific and stage-
specific mechanism, stem cells are relative easy to re-
pair. Genotoxicity: is not limited to specific tissue type,
it is the most dangerous for humans since all cells are
attacked. Sometimes in specific cases (cancer therapy)
exploited. Species-specific mechanisms: of meta-
bolic enzymes, drug transporters e.g. visceral gout is a
disease of birds in which the birds die due to urates (due
Figure 1 scheme metabolism
to diclofenac) in the organs,
3
Name: Anouk Morsink
Date: 6 May 2024
Sources which were used to write this summary are the lectures from Anika Nagelkerke, Pe-
ter Olinga, Mathieu Vinken, and Nynke Kramer (2024)
1
,Content
Chapter 1 basic principles of toxicology 16-4-2024. Keywords: drug safety and
efficacy, parameters of interest, organ-specific toxicity ............................................... 3
Chapter 2 toxicity testing in laboratory models 17-04-2024. Keywords: cell culture
models, translation technologies, biomaterials, induced-pluripotent stem cells,
organoids, precision-cut tissue slices, organ-on-a-chip, bioprinting ............................ 6
Chapter 3 adverse outcome pathways 17-04-2024. Keywords: Molecular initiating
event, key event, key event relationship, adverse outcome and risk assessment ...... 9
Chapter 4 biomarkers 19-4-2024. Keywords: biomarkers for toxicity, read-outs,
biomarker specificty, extracellular vesicles ............................................................... 12
Chapter 5 omics approaches 23-04-2024. Keywords: toxicogenomics,
transcriptomics, proteomics, metabolomics, phosphoproteomics, prinicipal
component analysis, pathway analysis, high-throughput screening ......................... 15
Chapter 6 QIVIVE 24-04-2024.Key words: QIVIVE, risk assessment, toxicokinetics,
toxicodynamics, PBK modelling ................................................................................ 18
Chapter 7 toxicokinetic modelling 24-04-2024. Keywords:toxicity prediction,
populations at risk, SimCYP, and digital twin concept............................................... 21
Hand-out of the slides ............................................................................................... 24
2
, Chapter 1 basic principles of toxicology 16-4-2024
In this lecture the mechanism behind organ and tissue specific toxicity, factors that
influence toxicity (drug, host and interaction) and the need of prediction of drug toxicity
was discussed. Also it was discussed if we can predict toxicity events. Keywords: drug
safety and efficacy, parameters of interest and organ-specific toxicity.
Toxicology (acute or chronic) means the amount of which a compound can be harmful
to a organism. Acute happens directly after administration (minutes, hours, days), by
high dose. Chronic happens after multiple dosages (sublethal or low dose), on long
term-> subtle changes, the drug accumulates and cause toxicity. Toxicity can be de-
sired (efficacy) and undesired (safety), desired (remedy) is during chemotherapy (cy-
totoxicity) and undesired (poison) is during other treatment.
Drug safety and efficacy: It is important to keep in mind by model system that it de-
pends on the compound, and the host. The parameters which determine the drug
safety and efficacy: in person can be a combination of the following: dose, age, gender,
comedication, diseases (comorbidities), ADME, diet, excretion, administration route,
form and innate chemical activity, life stage; embryo, foetus, adult, infant, species and
circadian rhythms (time of day). Also the physico-chemical properties (redox, com-
plexation, ionization, solubility, hydrogen bonding) has influence on drug. Drug formu-
lations get more complex. Different formulation can alter a drug’s toxicity profile (ap-
ple pie example) it can influence the pharmacokinetics, biodistribution (distribution to
different organs) and the efficacy of drugs.
Different cells, tissues, organs and organ systems together make up the entire organ-
ism. Homeostasis: the body maintenance the internal steady state, changes are de-
tected by the receptor and via the brain impulses are sent to the effector which regu-
lates a response and thereby the imbalance is corrected (homeostasis is not keeping
a static conditions, but keeping conditions within tightly regulated physiological toler-
ance limits). When cells are damaged the cells can be regenerated and repaired when
this is not possible the cell will die. The effect on the drug on the cell is dependent on
the type of cell, dose, duration, host (e.g. age) and environmental factors.
Specificity of toxicity: some drugs have specific effects in certain organs and tissues.
Causes: characteristics of organ and tissue, the uptake, metabolism, concentration, a
mechanism which is specific for tissue and organ, and the route of administration. Tox-
icity which occur due to organ and tissue specificity mechanism are e.g. hepatotox-
icity (major issue), nephrotoxicity and neurotoxicity, the toxicity of a specific compound
can be due to characteristics tissue, dose, duration, ad-
ministration, distribution, host, environmental factors.
Embryotoxicity is organ and tissue specific and stage-
specific mechanism, stem cells are relative easy to re-
pair. Genotoxicity: is not limited to specific tissue type,
it is the most dangerous for humans since all cells are
attacked. Sometimes in specific cases (cancer therapy)
exploited. Species-specific mechanisms: of meta-
bolic enzymes, drug transporters e.g. visceral gout is a
disease of birds in which the birds die due to urates (due
Figure 1 scheme metabolism
to diclofenac) in the organs,
3
