TOXICOLOGY 2026 – SUMMARY
INTRODUCTION/OVERVIEW
➢ Paracelsus: “It’s the dose that makes the poison”, thus toxicity is dose-dependent
[non-toxic compounds can be toxic at high doses, while highly toxic compounds may be harmless at low doses]
Pharmacology: chemical with ‘positive’ effect on organism
Toxicology: how does a chemical lead to ‘negative’ effects in a organism (multidisciplinary)
(1) mechanistic: cellular, biochemical/molecular mechanism [translating animal studies, individual sensitivity]
(2) descriptive: In vitro and in Vivo toxicity testing [determining hazard of substance]
(3) regulatory; based on toxicological data [determine safe values]
(4) risk assessment; determine societal impact [cause-effect]
Bradford-Hill-criteria
= determine if observed association between exposure (blootstelling) and outcome (effect) is causal ipv. Chance
- Strength of association (in)dependent variables - Temporal sequence for cause before effect
- replication for consistency - Mechanism of action for biological plausibility
- biological gradient for dose-response relationship, - Coherence with established knowledge
“WHY” en “HOW” are chemicals toxic by evaluating:
1. HAZARD (‘how’): intrinsic characteristic of a compound
2. RISK (‘when’): probability of the hazard being expressed
--> “Exposure (blootstelling)’ needed to determine risk of hazard & hazard needed for risk
--> hazard * exposure = risk
HAZARD IDENTIFICATION
= variation in dynamics and kinetics per species and individual due to differences in characteristics [age, gender]
I. Exposure: single vs. chronic | external vs. internal
(1) magnitude = concentration
(2) frequency= disappear or build up of effect through accumulation
(3) duration= half-time
(4) routes of exposure and characteristics of exposed population
II. Kinetics: ‘what’ does body do to compound
➔ ADME: Absorption (exposure), Distribution (location), Metabolism (biotransformation), Elimination (secretion)
(1) How does substance enter body --> passing physical barriers
(2) Time-dependent activity --> storage vs. circulation
(3) Conversion to toxic conjugates or metabolites
(4) Lungs, Skin, kidneys, liver and IG-tract through breathing, sweat, urine, bile and feces
III. Dynamics: ‘what’ does compound do to body [possibility of effect]
= binds and damages proteins, DNA, lipids or reacts with oxygen through free radical formation under oxidative stress
= interaction with cellular targets: local vs. systemic, (ir)reversible, direct vs. delayed, tolerance, allergies
IV. Dose-effect relations: ‘what’ dose results in (adverse) effect
ADVERSE OUTCOME PATHWAY
= describing the effect as different routes/intermediate steps, like a chain of involved mechanisms/structures [mode of action]
• MIE: molecular initiating event [direct effect of compound]
• KE(R): key event (relationship) [molecular, organelle, cellular, tissue, organ]
• AO: adverse outcome [level of individual or population]
TOXICOLOGIC TESTING
(1) animal studies/in vivo, (2) ADME studies, (3) behavioural, (4) mutagenicity, (5) neurotoxicity, (6) omics with data
➢ Animals and humans differ in physical characteristics
= presence/absence of cellular components, bodyweight (BW), volume-surface area (SA)
• Pharmacokinetics modelling: enables for translation between different organisms due to parameters
• Tolerable Daily intake (TDI): determines risk by extrapolating animal>human>sensitive sub-population
= LO(A)EL / SAFETY FACTOR
, DOSE-RESPONSE CURVE
= quantification of hazard through increasing dose exposure --> for comparison and determining safe doses/effect intensity
= not generally applicable due to not-acute toxic effects and underlying differences in sensitivity per individual
Y-as: response (effect) → different per graph
X-as: dose (concentration/exposure)
(1) Graded: continues scale and magnitude determines effect
(2) Quantal: population divided into groups, left= sensitive and right= resistant
Threshold: below specific concentration no adverse effect, depended on sensitivity
No threshold: 1 particle leads to effect [carcinogens and mutagens that cause mutations]
Difficiency: high effect at low at high does, but dip at medium concentration
Non-monotonic: >2 amplitudes due to feedback-loops and receptor selectivity
Hormesis: positive effect at low concentrations [under x-as]
~Initiation phase~
→ No observed (adverse) effect level: highest concentration without adverse effect [NO(A)EL]
→ Lowest observed (adverse) effect level: lowest measured concentration that displays significant effect [LO(A)EL]
• Potency: required concentration to induce specific, defined adverse effect, higher potency = lower EC50 and LD50
• Efficacy: capacity to induce specific effect, magnitude
• EC50: median effective concentration, 50% shows specific response
1. control for coincidence
2. threshold determines NO(A)EL, start of upward trend
3. determine LO(A)EL from experimental data
RISK ASSESMENT
Hazard identification= determine whether or not a substance is toxic (yes/no) and to what extent
Hazard characterization= determine dose/concentration at which compound caused adverse effect
Exposure assessment=exposure in the intended organism and environment
EFFECTS IN MIXTURES
• additivity: total effect of 2 chemicals with same effect is sum of both
• Synergism: total effect of 2 chemicals is higher than the sum of individual substances [higher potency]
• Potentiation: only effect in combination, not individually
• Antagonism: total effect of 2 substances with comparable effects lower than the sum of individual substances
- Full agonist: complete binding to receptor and maximum effect
- Partial agonist: same potency but lower efficacy
- Competitive antagonist: binds at the same site but produces no effect
- Non-competitive antagonist: binds at different binding site and leads to lower efficacy
INTRODUCTION/OVERVIEW
➢ Paracelsus: “It’s the dose that makes the poison”, thus toxicity is dose-dependent
[non-toxic compounds can be toxic at high doses, while highly toxic compounds may be harmless at low doses]
Pharmacology: chemical with ‘positive’ effect on organism
Toxicology: how does a chemical lead to ‘negative’ effects in a organism (multidisciplinary)
(1) mechanistic: cellular, biochemical/molecular mechanism [translating animal studies, individual sensitivity]
(2) descriptive: In vitro and in Vivo toxicity testing [determining hazard of substance]
(3) regulatory; based on toxicological data [determine safe values]
(4) risk assessment; determine societal impact [cause-effect]
Bradford-Hill-criteria
= determine if observed association between exposure (blootstelling) and outcome (effect) is causal ipv. Chance
- Strength of association (in)dependent variables - Temporal sequence for cause before effect
- replication for consistency - Mechanism of action for biological plausibility
- biological gradient for dose-response relationship, - Coherence with established knowledge
“WHY” en “HOW” are chemicals toxic by evaluating:
1. HAZARD (‘how’): intrinsic characteristic of a compound
2. RISK (‘when’): probability of the hazard being expressed
--> “Exposure (blootstelling)’ needed to determine risk of hazard & hazard needed for risk
--> hazard * exposure = risk
HAZARD IDENTIFICATION
= variation in dynamics and kinetics per species and individual due to differences in characteristics [age, gender]
I. Exposure: single vs. chronic | external vs. internal
(1) magnitude = concentration
(2) frequency= disappear or build up of effect through accumulation
(3) duration= half-time
(4) routes of exposure and characteristics of exposed population
II. Kinetics: ‘what’ does body do to compound
➔ ADME: Absorption (exposure), Distribution (location), Metabolism (biotransformation), Elimination (secretion)
(1) How does substance enter body --> passing physical barriers
(2) Time-dependent activity --> storage vs. circulation
(3) Conversion to toxic conjugates or metabolites
(4) Lungs, Skin, kidneys, liver and IG-tract through breathing, sweat, urine, bile and feces
III. Dynamics: ‘what’ does compound do to body [possibility of effect]
= binds and damages proteins, DNA, lipids or reacts with oxygen through free radical formation under oxidative stress
= interaction with cellular targets: local vs. systemic, (ir)reversible, direct vs. delayed, tolerance, allergies
IV. Dose-effect relations: ‘what’ dose results in (adverse) effect
ADVERSE OUTCOME PATHWAY
= describing the effect as different routes/intermediate steps, like a chain of involved mechanisms/structures [mode of action]
• MIE: molecular initiating event [direct effect of compound]
• KE(R): key event (relationship) [molecular, organelle, cellular, tissue, organ]
• AO: adverse outcome [level of individual or population]
TOXICOLOGIC TESTING
(1) animal studies/in vivo, (2) ADME studies, (3) behavioural, (4) mutagenicity, (5) neurotoxicity, (6) omics with data
➢ Animals and humans differ in physical characteristics
= presence/absence of cellular components, bodyweight (BW), volume-surface area (SA)
• Pharmacokinetics modelling: enables for translation between different organisms due to parameters
• Tolerable Daily intake (TDI): determines risk by extrapolating animal>human>sensitive sub-population
= LO(A)EL / SAFETY FACTOR
, DOSE-RESPONSE CURVE
= quantification of hazard through increasing dose exposure --> for comparison and determining safe doses/effect intensity
= not generally applicable due to not-acute toxic effects and underlying differences in sensitivity per individual
Y-as: response (effect) → different per graph
X-as: dose (concentration/exposure)
(1) Graded: continues scale and magnitude determines effect
(2) Quantal: population divided into groups, left= sensitive and right= resistant
Threshold: below specific concentration no adverse effect, depended on sensitivity
No threshold: 1 particle leads to effect [carcinogens and mutagens that cause mutations]
Difficiency: high effect at low at high does, but dip at medium concentration
Non-monotonic: >2 amplitudes due to feedback-loops and receptor selectivity
Hormesis: positive effect at low concentrations [under x-as]
~Initiation phase~
→ No observed (adverse) effect level: highest concentration without adverse effect [NO(A)EL]
→ Lowest observed (adverse) effect level: lowest measured concentration that displays significant effect [LO(A)EL]
• Potency: required concentration to induce specific, defined adverse effect, higher potency = lower EC50 and LD50
• Efficacy: capacity to induce specific effect, magnitude
• EC50: median effective concentration, 50% shows specific response
1. control for coincidence
2. threshold determines NO(A)EL, start of upward trend
3. determine LO(A)EL from experimental data
RISK ASSESMENT
Hazard identification= determine whether or not a substance is toxic (yes/no) and to what extent
Hazard characterization= determine dose/concentration at which compound caused adverse effect
Exposure assessment=exposure in the intended organism and environment
EFFECTS IN MIXTURES
• additivity: total effect of 2 chemicals with same effect is sum of both
• Synergism: total effect of 2 chemicals is higher than the sum of individual substances [higher potency]
• Potentiation: only effect in combination, not individually
• Antagonism: total effect of 2 substances with comparable effects lower than the sum of individual substances
- Full agonist: complete binding to receptor and maximum effect
- Partial agonist: same potency but lower efficacy
- Competitive antagonist: binds at the same site but produces no effect
- Non-competitive antagonist: binds at different binding site and leads to lower efficacy
