Introduction Flashcards
The word toxicology is derived from what Greek words?
Toxicology is derived from the Greek words
toxicon (= poison) and logos (= scientific
study): “Study of poisons”
Define the term toxicology.
Definition has changed over time. The most current definition: “Study of adverse effects of xenobiotics on living systems”
* Changing definition highlights the evolving nature of the discipline
Define the term toxin. Give an example.
Toxin: A poison produced by a living
organism, e.g., botulinum neurotoxin: produced by a bacteria of the genus clostridium.
Define the term toxicant. Give an example.
Toxicant: A man-made (i.e., not produced within living organisms) poisonous substance, e.g., organophosphates, which are pesticides.
Define the term xenobiotic.
Xenobiotic: Any substance foreign to an organism (or any compound not found within the normal metabolic pathways of a biologic system)
What are the universal symbols of poisonous substances?
- Skull and crossbones
- Symbol may appear with different colors,
borders and supplemental information
What key subjects have contributed greatly to toxicology?
chemistry, biochemistry, physiology, and pathology
Define mechanistic toxicology.
Study of cellular, biochemical & molecular mechanisms of action
Identify and understand the cellular, biochemical, and molecular mechanisms by which chemicals exert toxic effects on living organisms
Define descriptive toxicology.
Toxicity testing for safety & regulatory purposes
Define regulatory toxicology.
Assessment of chemicals risk from available data
decides on the basis of data provided by descriptive and mechanistic toxicology, whether a drug or other chemical poses a sufficiently low risk to be marketed for a
stated purpose or subsequent human or environmental exposure resulting from its use. It is involved in the establishment of standards for the amount of chemicals permitted in ambient air, industrial atmospheres, and drinking water.
Define forensic toxicology.
Medical-legal aspects of poisoning (CSI toxicology)
is a hybrid of analytic chemistry and fundamental toxicological principles.
It is concerned primarily with the medicolegal aspects of the harmful effects of chemicals on
humans and animals.
Define clinical toxicology.
Diagnosing diseases caused by or associated with toxic substances and their diagnosis and treatment.
Define environmental toxicology. How does it differ from ecotoxicology?
Effects of chemicals in the environment on nonhuman subjects such as fish, birds, terrestrial animals, etc.
Ecotoxicology is a specialized area within environmental toxicology that focuses more specifically on the impacts of toxic substances on population dynamics in an ecosystem
What knowledge did early humans have on toxicology?
– Early humans knew what to eat without harm
– Early humans recognized poisonous plants and animals and used their extracts for hunting and warfare
What knowledge did early toxicologists have of toxins?
Early toxicologists:
– Herbalists, witches, philosophers, alchemists
Who are present day toxicologists?
– Multidisciplinary scientists, medical and
veterinary practitioners
What is Ebers Papyrus?
- Oldest documentation of medicine
- Discovered in 1873
- Contains >800 magical formulae and remedies
- Has information on toxic plants and metals Egyptian document now @ University of Leipzig Library
Who is the father of toxicology?
1500 AD: Paracelsus (Theophrastus Phillipus Auroleus Bombastus von Hohenheim-Paracelsus)
* ‘Father of toxicology’
– Advocated focus on “toxicon” (the primary toxic agent)
* Pioneered the dose-response relationship
“What is there that is not a poison? All things are poison and nothing is without poison. It is only the dose that makes a thing not a poison”
What concepts were advanced by paracelsus?
Paracelsus believed that experiments needed to be conducted to determine the therapeutic and toxic affects of a given chemical in order to understand the effects of sad chemical.
- Need for experimentation in examining responses to chemicals
- Need to distinguish between therapeutic and toxic properties of chemicals based on
dose - Specificity of therapeutic and toxic effects of chemicals
Who was Orfila?
Marsh test = measure arsenic in humans.
Who was Francois Magendie?
- French physician and experimental physiologist
- Pioneered mechanistic toxicology
– Determined mechanisms of action of strychnine, emetine, and arrow poisons
1960s are described as?
The era of public awareness of toxicology.
Many birth defet cases associated with use of lithomid for morning sickness.
DDT wiping out bird populations
Documented in silent spring by Rachel Carson in 1962. Led to nationwide ban of DDT and grassroots movement –> EPA created.
What movement happened in the early 1960s that led to many modern environmental protection laws we have today?
What chemicals were being used? Did they pose a harm to human and environmental health? Explain.
– Early humans knew what to eat without harm
– Early humans recognized poisonous plants and animals and used their extracts for hunting and warfare
Dr. Sappal Notes:
The 1960s can be described as the era of Public Awareness of Toxicology. At this time there were many cases of birth defects that were associated with the use of Thalidomide for the treatment of morning sickness. Additionally, the massive use of insecticides such as DDT was wiping out bird populations across the United States. These environmental problems caused by the use of pesticides were documented in the book Silent Spring written by Rachael Carson in 1962. This book led to a nationwide ban on DDT and the grassroots environmental movement that it
inspired led to the creation of the United States Environmental Protection Agency
How would you describe the field of toxicology prior to the 20th century?
Pre 20th century: observational toxicology
– Mostly focused on domestic animals used for food,
fiber, transportation and power
* Emphasised knowledge of plants toxicoses and their
antidotes
How would you describe the field of toxicology in the mid 20th century?
- Mid 20th century: change of focus
– Experimental toxicology, increased population of companion animals, large scale food animal production, reduced use of animal power
by the mid-20th century there was a major shift of focus with the increased population of companion animals and large-scale production of food animals. Much of the toxicology at this time was experimental in nature and it has now evolved into the
current mechanistic toxicology
Why is Aspirin considered a poison?
Taking 30 tablets = severe signs of toxicity: vomiting, hyperthermia, confusion
105 tablets = lethal
Generally, 2 tablets of Aspirin are recommended to relieve pain however taking 30 tablets will result in severe signs of toxicity including vomiting, hyperthermia, and confusion, while taking
100 tablets will be lethal. It is important to know that when assessing whether a substance will cause toxicity, the risk is an important factor to consider
Describe the spectrum of toxicity.
What is the definition of LD50?
Spectrum of toxicity varies.
What is the function of LD50?
x <1 mg/kg = ?
x > 15 g/kg = ?
LD50 has been used to classify chemicals into groups.
x <1 mg/kg = extremely toxic
x > 15 g/kg = harmless
What are the cons of LD50?
Some survivors may have suffered permanent damage and may need to be euthanized.
Toxicant and receptor must be ________ to elicit a response.
compatible
What processes affect target dose and toxic effect?
Concentration of toxicant at the target site is the main factor that determines the strength of the effect. Two main processes that determine the type and strength of toxic response: Toxicokinetics, Toxicodynamics.
TK: det. conc, of toxicant at target site and degree of strenght of effect.
TD: type of target site and nature of inte4raction with toicant dete the type of resonse. Target site might be a recpeotr in CNS which is either inhibited or stimulated by todicant resulting in depression or excitation of CNS.
Exposure to potentially toxic substance does not mean toxicity will occur. Explain.
It is important to understand that exposure to a potentially toxic substance does not mean toxicity will occur, For toxicity to occur the toxic substance or its metabolite must first access an appropriate receptor site at sufficient conc. and for sufficient time For this to occur the rate of uptake and distribution to the target site must exceed the rate of elimination from the target site
The toxic effect occurs over a wide range of ________ organization, generally, the effects that are seen at the ecosystem levels ultimately originate from the interaction between a _____ substance and one or several ________. This interaction may alter cell ________ which in turn may alter the function of the ______ the cell is part of. Impaired organ ________ impacts organisms as a whole and effect at the individual level can affect the ________ at large and ultimately the _______.
biological, toxic, biomolecules, function, organ, function, populations, ecosystem
What does the blue line in the figure represent? How about the red line? What do each to these represent? How is the response obtained?
Generally within a population, the majority of individuals respond _______ to a given toxicant, however, a wide variant of response may be seen with some individuals being very _____ and
others being _____ to the toxicant. These occur due to _____ idiosyncrasies within a
population where some individuals may have low levels of ______ that are important in the metabolism of a toxicant, whereas others may have higher levels of the same ____.
- Frequency distribution = blue line or
Cumulative frequency = red line.
Cumulative frequency is the running total of frequencies where each frequency from a frequency distribution is added to the sum of its predecessors. The frequency distribution is bell-shaped and is termed normal distribution whereas cumulative frequency is sigmoid. - The response is obtained by specifying an endpoint of the toxicant effect and determining the number of animals that achieve that endpoint as a function of the toxicant dose.
similarly, sensitive, resistant, genetic, enzymes, enzyme
The graded dose-response curve in contrast relates the dose of a toxicant to the _______ of the response. The rate of response is initially _____ but becomes progressively ______ as the dose increases,
eventually, a ______ effect is achieved and a further ______ in the dose does ____ produce a response.
In this plot, the conc. that involves _____ the maximal response is known as EC50
intensity, fast, slower, maximal, increase, not, half
- The graded dose-response curve can be plotted on a semi-log scale if?
- The dose that elicits a _____-maximal response is the EC50.
- What are Graded D-R curves used for?
- If AB and C are different drugs for treating 1 disease such as high Blood Pressure, then which drug is more potent?
- the dose range used in the test is very wide.
- half
- Therapeutic dose, potency & efficacy, safety, mechanism of action.
- drug B is more potent than drugs A and C. Moreover drugs A and C behave differently at low and high conc. but have the same EC50
Graded D-R curves are used for?
Which drug is more potent?
B b/c have lower EC50.
Which drug is more potent?
Which drug is more effective?
red line
black line = more effective
This figure explains efficacy and potency, and these terms are more relevant and much more widely used in Pharmacology than in toxicology
e.g.: the drug depicted by the red line is more potent than the one shown by the black line and the drug depicted by black is more efficacious than depicted by the red line
An additional characteristic of graded dose response is that for most substances toxicity is associated with a threshold dose consistent with Paracelsus dogma.
Here a response is not seen until a ________ dose is attained giving the appearance of a hockey stick.
While most substances exhibit a threshold dose, a linear no-threshold model is used for estimating the effects of _________ __________. Here the assumption is that the effect is directly proportional to the ______ at _____ levels of exposure, that is ________ is always considered harmful with no safety threshold and the sum of several small exposures is considered to have the same effect as 1 large exposure.
An additional characteristic of graded dose response is that for most substances toxicity is associated with a threshold dose consistent with Paracelsus dogma.
Here a response is not seen until a threshold dose is attained giving the appearance of a hockey
stick.
While most substances exhibit a threshold dose, a linear no-threshold model is used for estimating the effects of ionizing radiation.
Here the assumption is that the effect is directly proportional to the doses at all levels of exposure, that is radiation is always considered harmful with no safety threshold and the sum of several small exposures is considered to have the same effect as 1 large exposure.
Trace nutrients such as _________ and ___________ trace metals have a unique dose-response curve that is ___-shaped in nature. This arises from the fact that both _____ and ______ concentrations of essential nutrients are associated with adverse effects.
What is the relationship between deficiency, toxicity, and homeostasis in the example pictured below?
Trace nutrients such as vitamins and essential trace metals have a unique dose-response curve that is u-shaped in nature.
This arises from the fact that both low and high concentrations of essential nutrients are associated with adverse effects.
Here, the adverse effects associated with deficiency are high at very low doses and as the dose increases these adverse effects of deficiency decrease until they completely disappear. However with further increase in the dose, other adverse effects start to appear, this time associated with toxicity. Therefore, for these substances the conc. need to be maintained within the homeostatic range at
which there is neither sign of deficiency nor toxicity
What is the Hermetic dose response associated with?
Explain what is happening in the figure below.
The hermetic dose response is associated with some non-nutritional toxic substances and may also impart beneficial or stimulatory effects at low doses but, at higher doses, they produce adverse effects.
For example, chronic alcohol consumption causes liver cancer, and cirrhosis whereas low to
moderate consumption of alcohol reduces the incidence of coronary heart disease and stroke.
These dose-response curves appear as u-shaped or inverted U depending on the endpoint.
For e.g. in Panel A where the benefit is plotted on the y-axis and the amount of stressor/toxicant on the x-axis, it is an inverted U.
Here the degree of benefit increases with toxicant conc. to a maximum then starts to decrease with an increase in conc. of toxicant until the adverse effects occur.
In Panel B on the other hand, an adverse effect that is the number of tumors is plotted on the y- axis and the toxicant conc. on the x-axis, here the no of tumors initially decreases with an increase in conc. but at higher conc. of the toxicant, the incidence of tumors increases.
The proponents of hormetic response argue that it is a widespread generalized phenomenon but should be used as a default assumption for risk assessment instead of the current threshold and
linear models that are used in risk assessment.
Non-monotonic Dose Responses (NMDR) are defined as?
Dose-response relationships in which the
direction of the response changes with
increasing or decreasing dose.
U shaped or inverted U shaped depending on end point.
E.g. stimulationof growth at low dosea and inhib at high doses = inverted u
decrease in tumor incidence at low dose and increase at higher doses = u shaped.
