All the lectures of the course Toxicology and Development, including notes. This course is part of the minor Biomedical Topics in Health Care, given at the VU university.
Lectures Toxicology
and Development
Course of the minor Biomedical Topics in Health Care (VU)
Content
Introduction lecture .......................................................................................................................................................... 1
Introduction in toxicology ................................................................................................................................................. 2
What compounds are poisonous? ................................................................................................................................ 2
How are humans and the environment exposed?........................................................................................................ 7
How are compounds poisonous?................................................................................................................................ 15
How can we test if a compound is poisonous? ........................................................................................................... 18
What are the risks? How can we prevent risks? ......................................................................................................... 23
AOP framework ............................................................................................................................................................... 36
Physiologically-based kinetic models for human and environmental risk assessment .................................................. 44
Teratogens and birth defects .......................................................................................................................................... 54
Developmental toxicity ................................................................................................................................................... 64
Human biomonitoring and the exposome ...................................................................................................................... 69
Introduction metabolomics ............................................................................................................................................ 78
Chromatography and mass spectrometry (analysis methods for metabolomics).......................................................... 86
Processing and interpretation of metabolomics data .................................................................................................... 93
Application of environmental metabolomics in toxicology and environmental chemistry ........................................... 99
Exposure assessment epidemiology ............................................................................................................................. 107
Human health risk assessment ..................................................................................................................................... 111
,Introduction lecture
Department environment & health
Chemistry = analysis of the concentrations of contaminants in the environment (indoor and outdoor), measurement
of endogenous substances and contaminates in organisms
Toxicology = analysis of the effects of contaminants in the environment, determining safe concentrations,
understanding mechanisms of actions
Course content
Developmental toxicology: studies the impact of substances in daily life products on human health. Special focus is
given on effects on early development. We will start with assessing human exposure using analytical chemistry;
furthermore toxic modes of action of commonly found substances will be linked to diseases. At the end social
impacts and appropriate health care measures are discussed. During the course students will work on their own
project.
Course objectives
- Have basic knowledge about analytical chemistry. You will know how human material can be sampled. How
samples need to be prepared and what analytical methods could be applied to identify potential toxic
compounds
- Be able to understand the basic concepts of toxicology, e.g. dose-response relationships; absorption,
distribution, metabolization and excretion of chemicals
- Got deeper insights into toxicological epidemiological studies
- Be able to describe toxic mechanisms and adverse outcome pathways relevant for human development
- Got a basic understanding of toxicological bio-assays
- Have knowledge about chemical legislation and risk assessment in Europe
- Know how to design and perform a scientific study
- Have integrated your own results and literature data and presented your findings
- The course is designed to combine theoretical knowledge from lectures with working groups
- The student project resembles a scientific research project investigating all relevant aspects of a human
toxicological study
Content
Studying toxicological effects on the development is a multidisciplinary research field. First we have to identify the
compounds we are exposed to (analytical chemistry). Then we have to apply epidemiological studies to identify
correlation between developmental diseases and those compounds (epidemiology). To proof causality we apply
bioassays in the laboratory (toxicology). This course will
introduce you to the basic principles covering the three
different research fields.
Course structure
- Lectures: are pre-recorded videos. To get access you
have to fulfil the prerequisite. The lectures are
grouped with related topics into modules. Every topic
has a short assignment. Assignments need to be
submitted per student not per group.
- The discussion meetings are organized via zoom. Every
topic/assignment has its own discussion meeting. Post
questions about a topic or assignment before the
meeting in the corresponding discussion forum. We
will discuss all questions at the meeting. After the
meeting every student has to answer its own question
in the forum.
- There is no practicum. Instead there will be a general
assignment. The general assignment is an e-book
project. The chapter of the book will be written by you
1
, in teams of 5. You will be graded as group. Every week there will be also a discussion group for the general
assignment.
- Grading: general assignment (30%) and written exam (70%).
- Exam: the exam consists of multiple-choice questions, as well as open questions.
Introduction in toxicology
Toxicology: multidisciplinary
- Biology/chemistry/biochemistry
- Physiology
- Genetics
- Mathematics/statistics
- Medicine
- Pharmacology
Definitions in toxicology
- Compound: a chemical substance that is composed of a particular set of molecules or ions (e.g. potassium
ferricyanide)
- Toxicant or xenobiotic is a type of poison that is made by humans or introduced into the environment by
human activity
- Toxin: poison produced naturally by an organism
- Contaminant or pollutant: biological, chemical, physical or radiological substance (normally absent in the
environment) which can adversely affect living organisms
What compounds are poisonous?
Paracelsus (1493-1541)
- Philippus Aurelus Theophrastus Bombastus von Hohenheim
- Alchemist and physician in Salzburg
- Founder of modern toxicology
- Chemicals may have specific effect
- ‘Everything is poisonous, nothing is not poisonous; only the dose/concentration makes something
poisonous’ → dose-response curve
Dose-response curve
- Higher dose/concentration means more effect/response
Two types (different type of response)
- Dichotomous response/quantal data = % surviving animals (only whole animals die/live)
- Continuous response (any data point possible) = % enzyme activity
- Higher dose → decrease of activity/surviving animals
Dose-response curves are characterized by:
- Location (ED50, potency) → how potent is a toxic compound?
- Lowest EC50 = most potent → more effect with lower dose/concentration
- Maximum response (effectiveness) → what can a compound do?
- Not all compounds are able to kill a whole set of animals (no maximum achieved)
- Steepness of the curve → steep vs. flat
- Steeper: quicker effect with increase in dose/concentration
Forward use
- From dose to response
- Predict what might happen when you know the dose
- The percentage of affected individuals for example
3
,Backward use
- From response to dose
- What dose/concentration is responsible for 50% effect? (ED50)
- Other characteristics might also be determined: NOAEL and LOAEL
Toxicity values derived from dose-effect relationships
- LD50: lethal dose 50% → concentration where 50% of the treated animals are dead
- ED50: effect dose 50% → concentration where 50% of the treated animals are affected (malformed & dead)
- NOAEL: no observed adverse effect level (dose) → highest concentration with no effects compared to the
control group
- LOAEL: lowest observed adverse effect level (dose) → lowest concentration with effects compared to the
control group
In aquatic studies (e.g. fish):
- LC50: median lethal concentration in water (µmol/L, % alcohol)
- EC50: concentration with 50% effect
- LOEC: lowest observed adverse effect concentration
- NOEC: no observed effect concentration
In studies with rodents (as models for humans):
- LD50: median lethal dose (mg per kg body weight)
- ED50: dose with 50% effect (mg per kg body weight)
- LOAEL: lowest observed adverse effect level (dose)
- NOAEL: no observed adverse effect level (dose)
Acute oral toxicity of selected chemicals expressed as µg per kg body weight
→ grey = made by nature; red = made by man (xenobiotics); green = food additive
4
,Teratogenicity values
- Teratogenic index (TI) = LC50/EC50
- Developmental malformations = teratogenicity
- Relative teratogenic index = LC1/EC5
- The higher the TI, the more specific teratogenic effects of the chemical can be expected compared to overall
embryotoxicity, as measured by mortality of organisms
→ TI = gap between the two curves
Bench mark dose
- A benchmark dose (BMD) is a dose or concentration that produces a predetermined change in the response
rate of an adverse effect. This predetermined change in response is called the benchmark response (BMR).
- Normally, the default BMR is 5% or 10% change in
the response rate of an adverse effect relative to the
response of control group
- It should be noted that each fitted (and accepted)
model results in a confidence interval for the
estimated BMD. The BMD we get from statistical
model is a range, rather than a fixed number. Usually
we use benchmark dose (lower confidence limit)
(BMDL) to calculate human health guidance value
since it is more conservative. The BMDL can be
regarded as a dose at which the effect is smaller than
the BMR (with defined confidence).
Advantages and limitations
5
, Different dose-response models
Non-essential compounds, e.g. cadmium and pesticides
- Logarithmic dose-response curves are generally sigmoidal and monophasic and can be fit to a classical Hill
equation
Essential compounds, e.g. sodium, copper, vitamins
→ toxic on the left and right side
Single hit model
- Assumes that every molecule that were exposed to already does induce a response → no threshold (no safe
concentrations)
6
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