NOTES Toxicology and Development
LECTURE 1. Toxicology part 1 – What are toxicants and how are we exposed?
- Terminology:
o Toxicology: The study of adverse effects (outcomes) of chemicals on living
organisms.
o Toxicologist: Someone who is trained to examine the nature of those adverse
effects and they assess the probability of their occurrence.
o Toxicology testing: Is a test that is conducted to determine the degree by
which a substance damages organisms.
- Areas of toxicology:
o Mechanistic toxicology: Identifies the cellular, biochemical and molecular
mechanisms by which chemicals give their toxic effects.
o Descriptive toxicology: Focused on toxicity testing to provide information on
safety evaluation and regulatory requirements.
o Regulatory toxicology: The responsibility to decide if a drug or another
chemical is of sufficiently low risk to be marketed for a stated purpose –
RIVM/ EMA.
- Types of toxic effects:
o Death – main one; when something is really toxic. Caused by substances like
arsenic and cyanide.
o Organ damage – caused by substances like lead, ozone, and alcohol for
instance.
o Mutagenesis – Substances can result in DNA damage leading to mutations;
like PAHs, which are polycyclic aromatic hydrocarbons, made when certain
substances are burned. They cause DNA adduct formation and oxidative
stress.
o Carcinogenesis – Formation of cancer. Certain substances can promote
carcinogenesis, like asbestos for instance.
o Teratogenesis – Substances that produce physical or functional defects in the
human embryo/foetus.
▪ Teratogen: anything capable of disrupting embryonic or foetal
development and producing malformations such as birth defects.
▪ Key substance that promotes teratogenesis is thalidomide.
• Thalidomide scandal: thalidomide was given as a morning
sickness medication to pregnant women in the 1950s-1960s.
Thalidomide lead to children with a range of severe
deformities, as well as thousands of miscarriages. The birth
defects of thalidomide led to the development of greater drug
regulation and monitoring in many countries.
o Neurotoxicity – pesticides.
X There are two types of effects:
1. Systemic toxicity:
- Systemic toxicity all have something to do with ADME of a substance. It refers to the
toxic effects caused as a result of absorption and distribution of a substance that
, affects the whole body rather than a specific (local) area, i.e. to an area distant from
its entry point.
o Most chemicals that produce systemic toxicity do not cause a similar degree
or type of toxicity in all organs, but usually cause major toxicity to one or two
organs. Some might be more toxic to the liver, while others are more toxic to
the nervous system.
▪ These organs are referred to as the target organs of toxicity for that
chemical.
2. Organ specific toxicity:
o Reproductive toxicity: Damage to the male and female reproductive organs.
▪ Effects: can range from impotence, and Infertility to infant death,
birth defects, and childhood cancer.
o Hepatoxicity: Liver toxicity; gall bladder and bile duct also affected. The liver
is a prime site for toxicity due to the extensive role of the liver in drug
metabolism and it has a lot of blood vessels going to it (blood supply is high),
resulting in the liver being highly susceptible to xenobiotics.
▪ Effects: steatosis, hepatitis, cancer, and cirrhosis.
o Nephrotoxicity: Kidney toxicity; again lots of toxicity because of the high
blood supply and because the kidneys filter a lot of water and toxicants.
▪ Effects: decreased ability to excrete waste, inability to maintain body
fluid and electrolyte balance, and decreased synthesis of hormones.
o Neurotoxicity: Brain and nervous system toxicity, one of the most commonly
targeted organs. The nervous system is very susceptible to damage.
▪ Effects: Determined by what the substance impacts, so if it impacts
the peripheral or central nervous system and which types of neurons.
Like neuronopathies are caused by direct damage, axonopathies are
caused by indirect damage to the axons, and myelopathies are caused
by damage to the myelin sheets.
o Immunotoxicity: Can be hypersensitivity (allergies), immunodeficiencies, and
uncontrolled proliferation (leukaemia).
o Respiratory toxicity: upper respiratory system + lower respiratory system.
▪ Effects: pulmonary irritation, asthma, emphysema, lung cancer, etc.
• 99% of the world’s population is now breathing polluted air;
this polluted air kills approx. 7 million people each year across
the world.
o Blood and cardiac toxicity: Xenobiotics cause a lot of effects in the blood (or
cells in the blood) that act directly on the heart or bone marrow.
▪ Effects: Hypoxia, Leukemia, arteriosclerosis, decrease in circulating
leukocytes, and death of heart cells (cardiomyocytes).
X How can we test if a compound is toxic/ poisonous? – First year toxicology notes.
Toxicology is the sciences of poisons – Paracelsus is the father of medicine. He acted as a
doctor. Paracelsus claimed that the compound (Toxicon) as starting point was toxic and not
the mixture. He claimed that “all substances are poisons: there is none which is not a
poison. The proper dose separates a poison from a remedy”
- His points of departure:
1. Experimenting is essential to know if something is toxic.
,2. He distinguished between poisonous and therapeutic properties – they cannot always be
distinguished.
3. Compounds (Toxicons) may have specific effects.
- Concentration-response relationships:
o Response of the endpoint decreases with increasing exposure concentration:
▪ % of survival or % enzyme activity.
o Response of the endpoint increases with increasing exposure concentration:
▪ % mortality and % enzyme inhibition.
- Measurements and characteristics of dose-response curve:
Measurements – Toxicological endpoints:
o LD50: median lethal dose.
▪ 50% mortality rate; a very low number is most toxic because you only
need a small amount of compound to reach 50% mortality.
o LC50: median lethal concentration in soil, air, or food.
o EC/ED50: Concentration causing 50% effect – Median effect concentration.
o EC/ED10: Concentration causing 10% effect.
o NOEC: No Observed Effect Concentration; The highest test concentration that
does not give a significant response or cause a significant adverse effect.
o LOEC: Lowest Observed Effect Concentration; The lowest test concentration
that does give a significant response or cause a significant adverse effect.
o NEL: No effect Level.
, Characteristics:
1. Potency: The power or concertation to influence something (ED 50, X-axis).
2. Effectiveness (maximum response on the Y-axis; Emax): the degree to which the
concentration produces a response.
3. Steepness: the steeper the curve, the smaller the window between therapeutic
and poisonous.
The units of the measurement will differ, they depend on what you are looking at.
- LD or ED are doses in mg/kg body weight.
- LC, EC, NOEC, LOEC are concentrations in mg/m3, mg/L, or mg/kg.
o All endpoints are measures of toxicity, they enable a comparison of toxic
potency of chemicals – the lower the endpoint value, the more toxic the
chemical.
- LC50, EC50, and EC10 are determined by fitting dose-response models; here you
predict the measurements.
- LOEC and NOEC are determined by statistical test; actual data you might get. Here
you use actual values to determine actual concentrations.
- Logarithmic dose-response curves are generally sigmoidal and monophasic.
- Forward vs backward use:
o Forward use: Predict the effect caused by a specific toxicant concentration;
To predict the effect size – Dose (X-axis) to response (Y-axis).
▪ What is the risk of a given exposure?
