Toxicology and Development
summary
,What are toxicants, and how are we exposed? 3
Absorption, Distribution, Metabolism and Excretion 7
How can we test if compounds are poisonous? 12
Introduction to Metabolomics 18
Chromatography and Mass Spectrometry 21
Teratogens and Birth Defects 23
Data Processing, Interpretation, Big Data Analysis 29
Application of Metabolomics in Toxicology and Environmental Chemistry 31
Hazard and Risk 34
Developmental Toxicology 38
Solvent Toxicity 43
Human Biomonitoring and the Exposome 46
PFASs: Per uoroalkyl Substances 51
Flame Retardants, Indoor Pollution and Fast Screening Methods 54
Epigenetics and the Developmental Origins of Health and Disease (DOHaD)
56
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, What are toxicants, and how are we exposed?
BASICS ON TOXICOLOGY
- Toxicology: the study of the adverse e ects of chemicals on living organisms
- Started with Socrates who was sentenced to die by drinking hemlock
- Concerns: How can we test if a compound is poisonous? How are humans and the
environment exposed? How are compounds poisonous? What are the risks and how can
we prevent them?
- A toxicologist is trained to examine the nature of these e ects and assess the probability
of their occurrence
- Toxicology testing is conducted to determine the degree by which a substance damages
organisms
- Di erent areas of toxicology:
- Mechanistic toxicology: identi es the cellular, biochemical and molecular mechanisms by
which chemicals exert their toxic e ects
- Descriptive toxicology: focused on toxicity testing to provide information on safety
evaluation and regulatory requirements
- Regulatory toxicology: the responsibility to decide whether a drug or another chemical is
of su ciently low risk to be marketed for a stated purpose
- Types of toxic e ects:
- Death — arsenic, cyanide
- Organ damage — lead, ozone
- Mutagenesis — PAHs
- A chemical or physical agent capable of inducing changes in DNA called mutations
- Carcinogenesis — benzine, asbestos
- Any substance, radionuclide, or radiation that promotes carcinogenesis, i.e. the
formation of cancer
- Teratogenesis — thalidomide
- Substances that produce physical or functional defects in the human embryo/fetus
- Neurotoxicity — pesticides
- Toxic e ects are classi ed into 2 types:
- Systemic toxicity: refers to toxic e ects caused as a result of absorption and distribution
of a substance that a ects the whole body rather than a speci c (local) area, i.e. to an area
distant from its entry point
- Most chemicals that produce systemic toxicity do not cause a similar degree of
toxicity in all organs, but usually cause major toxicity to 1 or 2 organs, which are
referred to as the target organs of toxicity for that chemical
- Some chemicals may be more toxic to the liver, while others to the brain
- Organ-speci c toxicity:
- Reproductive toxicity: damage to the male or female reproductive organs
- E ects: impotence, infertility, interrupted pregnancy, infant death, altered sex
ratio, chromosome abnormalities, birth defects, childhood cancer
- Hepatotoxicity: toxicity to the liver, bile duct and gall bladder
- Due to the extensive blood supply and role in metabolism, the liver is highly
susceptible to xenobiotics
- E ects: steatosis (=lipid accumulation in hepatocytes), hepatitis (=in ammation
of liver), cancer, cirrhosis (=chronic brosis, ~ alcohol)
- Nephrotoxicity: toxicity to the kidney and urethra
- The kidney is susceptible to toxicants due to the high volume of blood ow, and
because it lters large amounts of toxicants which can concentrate in the kidney
tubules
- E ects: decreased ability to excrete waste, inability to maintain body uid and
electrolyte balance, decreased synthesis of hormones
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, - Neurotoxicity: damage to the cells of the CNS (brain and spine) and PNS
- Most common target organ of toxicity
- E ects: neuronopathy (=damaged directly by substances), axonopathy (=indirect
damage to the axon), myelopathy (=damage to the myelin sheath or neuroglia),
damage to the synaptic signaling
- Neuronopathy — aluminum (degenerative changes in cortex), arsenic
(axonal degeneration in PNS), methanol (degeneration in ganglion cells)
- Axonopathy — acrylamide (axonal degradation)
- Immunotoxicity: toxicity of the immune system
- Can take several forms: hypersensitivity (allergy), immunode ciency, uncontrolled
proliferation (leukemia)
- E ects: contact dermatitis, systemic lupus erythematosus (exposure to
hydrazine), immunosuppression (cocaine), leukemia (benzene)
- Respiratory toxicity: relating to any e ect on the upper respiratory system (nose,
pharynx, larynx, trachea) and lower respiratory system (bronchi, lung alveoli)
- E ects: pulmonary irritation, asthma/bronchitis, reactive airway disease,
emphysema, brotic lung disease, pneumoconiosis, lung cancer
- 99% of the world’s population is now breathing polluted air, killing ~7 million
people each year across the world
- Blood and cardiac toxicity: xenobiotics acting directly on cells in the circulating
blood, bone marrow and heart
- E ects: hypoxia (carbon monoxide binding hemoglobin), decrease in circulating
leukocytes, leukemia, arteriosclerosis, death of cells around the heart
DOSE RESPONSE
- Paracelsus principle:
- “All substances are poisons: there is non which is not a poison. The proper dose separates
a poison from a remedy”
- Paracelsus principle is important activity of toxicologists: the establishment of dose-e ect
relationships
- Usually, a graph with performance of tested organisms (growth/survival) plotted as a
function of concentration of a toxicant in water, soil or air
- There are di erent types of concentration-response relationships:
- Response of the endpoint decreases with increasing concentration
- % survival = dichotomous/quantal response
- % enzyme activity = graded (continuous) response
- Response of the endpoint increases with increasing exposure concentration
- % mortality = dichotomous/quantal response
- % enzyme inhibition = graded (continuous) response
- Toxicity measures derived from concentration-response relationships:
- LD50: median lethal dose
- LC50: median lethal concentration in soil, water, air or food
- EC/ED50: concentration/dose causing 50% e ect
- EC/ED10: concentration/dose causing 10% e ect
- NOEC (no observed e ect concentration): the highest test concentration that does not
cause a signi cant adverse e ect, compared to the corresponding control
- LOEC (lowest observed e ect concentration): the lowest test concentration that causes a
signi cant adverse e ect, compared to the corresponding control
- NEL: no e ect level
- Note that the units can di er
- LD50, ED50 = dose in mg/kg body weight, often oral or topical dosing
- LC50, EC50, EC10, NOEC, LOEC = concentration in medium
- Air: mg/m3
- Water: mg/L
- Soil, sediment or food: mg/kg
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summary
,What are toxicants, and how are we exposed? 3
Absorption, Distribution, Metabolism and Excretion 7
How can we test if compounds are poisonous? 12
Introduction to Metabolomics 18
Chromatography and Mass Spectrometry 21
Teratogens and Birth Defects 23
Data Processing, Interpretation, Big Data Analysis 29
Application of Metabolomics in Toxicology and Environmental Chemistry 31
Hazard and Risk 34
Developmental Toxicology 38
Solvent Toxicity 43
Human Biomonitoring and the Exposome 46
PFASs: Per uoroalkyl Substances 51
Flame Retardants, Indoor Pollution and Fast Screening Methods 54
Epigenetics and the Developmental Origins of Health and Disease (DOHaD)
56
fl
, What are toxicants, and how are we exposed?
BASICS ON TOXICOLOGY
- Toxicology: the study of the adverse e ects of chemicals on living organisms
- Started with Socrates who was sentenced to die by drinking hemlock
- Concerns: How can we test if a compound is poisonous? How are humans and the
environment exposed? How are compounds poisonous? What are the risks and how can
we prevent them?
- A toxicologist is trained to examine the nature of these e ects and assess the probability
of their occurrence
- Toxicology testing is conducted to determine the degree by which a substance damages
organisms
- Di erent areas of toxicology:
- Mechanistic toxicology: identi es the cellular, biochemical and molecular mechanisms by
which chemicals exert their toxic e ects
- Descriptive toxicology: focused on toxicity testing to provide information on safety
evaluation and regulatory requirements
- Regulatory toxicology: the responsibility to decide whether a drug or another chemical is
of su ciently low risk to be marketed for a stated purpose
- Types of toxic e ects:
- Death — arsenic, cyanide
- Organ damage — lead, ozone
- Mutagenesis — PAHs
- A chemical or physical agent capable of inducing changes in DNA called mutations
- Carcinogenesis — benzine, asbestos
- Any substance, radionuclide, or radiation that promotes carcinogenesis, i.e. the
formation of cancer
- Teratogenesis — thalidomide
- Substances that produce physical or functional defects in the human embryo/fetus
- Neurotoxicity — pesticides
- Toxic e ects are classi ed into 2 types:
- Systemic toxicity: refers to toxic e ects caused as a result of absorption and distribution
of a substance that a ects the whole body rather than a speci c (local) area, i.e. to an area
distant from its entry point
- Most chemicals that produce systemic toxicity do not cause a similar degree of
toxicity in all organs, but usually cause major toxicity to 1 or 2 organs, which are
referred to as the target organs of toxicity for that chemical
- Some chemicals may be more toxic to the liver, while others to the brain
- Organ-speci c toxicity:
- Reproductive toxicity: damage to the male or female reproductive organs
- E ects: impotence, infertility, interrupted pregnancy, infant death, altered sex
ratio, chromosome abnormalities, birth defects, childhood cancer
- Hepatotoxicity: toxicity to the liver, bile duct and gall bladder
- Due to the extensive blood supply and role in metabolism, the liver is highly
susceptible to xenobiotics
- E ects: steatosis (=lipid accumulation in hepatocytes), hepatitis (=in ammation
of liver), cancer, cirrhosis (=chronic brosis, ~ alcohol)
- Nephrotoxicity: toxicity to the kidney and urethra
- The kidney is susceptible to toxicants due to the high volume of blood ow, and
because it lters large amounts of toxicants which can concentrate in the kidney
tubules
- E ects: decreased ability to excrete waste, inability to maintain body uid and
electrolyte balance, decreased synthesis of hormones
ffff ffi ff fi fi ff ff fi fi fffffi ff ff fi fl fl fl
, - Neurotoxicity: damage to the cells of the CNS (brain and spine) and PNS
- Most common target organ of toxicity
- E ects: neuronopathy (=damaged directly by substances), axonopathy (=indirect
damage to the axon), myelopathy (=damage to the myelin sheath or neuroglia),
damage to the synaptic signaling
- Neuronopathy — aluminum (degenerative changes in cortex), arsenic
(axonal degeneration in PNS), methanol (degeneration in ganglion cells)
- Axonopathy — acrylamide (axonal degradation)
- Immunotoxicity: toxicity of the immune system
- Can take several forms: hypersensitivity (allergy), immunode ciency, uncontrolled
proliferation (leukemia)
- E ects: contact dermatitis, systemic lupus erythematosus (exposure to
hydrazine), immunosuppression (cocaine), leukemia (benzene)
- Respiratory toxicity: relating to any e ect on the upper respiratory system (nose,
pharynx, larynx, trachea) and lower respiratory system (bronchi, lung alveoli)
- E ects: pulmonary irritation, asthma/bronchitis, reactive airway disease,
emphysema, brotic lung disease, pneumoconiosis, lung cancer
- 99% of the world’s population is now breathing polluted air, killing ~7 million
people each year across the world
- Blood and cardiac toxicity: xenobiotics acting directly on cells in the circulating
blood, bone marrow and heart
- E ects: hypoxia (carbon monoxide binding hemoglobin), decrease in circulating
leukocytes, leukemia, arteriosclerosis, death of cells around the heart
DOSE RESPONSE
- Paracelsus principle:
- “All substances are poisons: there is non which is not a poison. The proper dose separates
a poison from a remedy”
- Paracelsus principle is important activity of toxicologists: the establishment of dose-e ect
relationships
- Usually, a graph with performance of tested organisms (growth/survival) plotted as a
function of concentration of a toxicant in water, soil or air
- There are di erent types of concentration-response relationships:
- Response of the endpoint decreases with increasing concentration
- % survival = dichotomous/quantal response
- % enzyme activity = graded (continuous) response
- Response of the endpoint increases with increasing exposure concentration
- % mortality = dichotomous/quantal response
- % enzyme inhibition = graded (continuous) response
- Toxicity measures derived from concentration-response relationships:
- LD50: median lethal dose
- LC50: median lethal concentration in soil, water, air or food
- EC/ED50: concentration/dose causing 50% e ect
- EC/ED10: concentration/dose causing 10% e ect
- NOEC (no observed e ect concentration): the highest test concentration that does not
cause a signi cant adverse e ect, compared to the corresponding control
- LOEC (lowest observed e ect concentration): the lowest test concentration that causes a
signi cant adverse e ect, compared to the corresponding control
- NEL: no e ect level
- Note that the units can di er
- LD50, ED50 = dose in mg/kg body weight, often oral or topical dosing
- LC50, EC50, EC10, NOEC, LOEC = concentration in medium
- Air: mg/m3
- Water: mg/L
- Soil, sediment or food: mg/kg
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