Introduction Flashcards
TOX
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.
Toxin: A poison produced by a living
organism, e.g., botulinum neurotoxin
Define the term toxicant.
Toxicant: A man-made (i.e., not produced
within living organisms) poisonous
substance, e.g., organophosphates
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
Define descriptive toxicology.
Toxicity testing for safety & regulatory purposes
Define regulatory toxicology.
Assessment of chemicals risk from available data
Define forensic toxicology.
Medical-legal aspects of poisoning (CSI toxicology)
Define clinical toxicology.
Diagnosis and treatment of toxicoses
Define environmental toxicology.
Effects of chemicals in the environment on nonhuman subjects such as fish, birds, terrestrial animals, etc.
What knowledge did early humans have of toxic things in the environment?
– 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
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?
- 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.
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
How would you describe the field of toxicology today?
mechanistic toxicology with comparative
approach driven by concerns for human health. Many vet toxicologists work for pharmaceutical companies.
Toxicology today is what type of science?
basic and applie
Why is the field of toxicology so important?
- Toxicology continues to grow in response to
regulatory needs or perceived risk
– Increasing number of new chemicals and
increasing levels of chemical contaminants - Public mistrust of chemicals, hopes and awareness
depend largely on the expertise of toxicologists
– But…public perception of risk may not match
reality
What substances are considered poisonous? Who came to this conclusion?
All substances are poisons; there is none
which is not poison. The dose
differentiates a poison from a remedy
(Paracelsus 1493-1541 AD)
Why is Aspirin considered a poison?
Taking 30 tablets = severe signs of toxicity: vomiting, hypothermia, confusion
105 tablets = lethal
Describe the spectrum of toxicity.
Spectrum of toxicity varies.
What is the function of LD50?
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.
What is the dose-response relationship?
- A fundamental concept in toxicology
- It is a correlative relationship that brings
together the characteristics of exposure and
the spectrum of effects
What are the fundamentals of the D-R relationship?
- Response is due to the chemical administered or the toxicant to which the animal is exposed
- The chemical interacts with a molecular or receptor site to produce a response
- The degree of response is correlated with
the concentration of the toxicant at the
receptor site(s) - The concentration of the toxicant at the
receptor site(s) is related to the dose of the
toxicant received - There exist methods of measuring and
expressing toxic effects
Toxicant and receptor must be compatible to elicit a response.
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.
What are exposure-related facotrs?
Exposure-related: e.g., dose, route and site,
duration and frequency of exposure, concentration
at site of action, prior exposure
The higher the exposrue dose and conc at site of action the greater the response observed.
Toxicant related factors
Toxicant-related: e.g., physical and chemical
properties, formulation
Deter. ease of absorption and diuration og the effect. Lipid solubility is the main determinant of rate of absorption.
Animal-related factors influencing toxic response.
Animal-related: e.g., species, strain, age, size,
sex, metabolism, nutritional status, health status
Environmental factors influencing toxic response?
Environment: e.g., temperature, humidity, winds, drought, time of the year
Myco and plan poisonings are correlted with env and climate changes. Fungi that secrete Mycotoxins req high humidity and temp to grow. Blue green algae toxicity is facilitated by wind whereas nitrate accumulating plants grow well during drought.
Toxic effects occur over a wide range of biological organization.
effects At ecosystem level ultimately originate from interaction between toxic substance and one or more molecules. Thisinteraiton may alter dcel function, organ cell is apart of. Impaired organ function impacts organism at whole and effect at individual level can effect pop at large and ultimately ecosystem.
Effect at all levels of bio org are significant because each level finds its explanation of mech below and significance in levels above. Key features of toxicant effects at various levels: lower org = shorter time, response time increases are higher levels of bio org.
NT mediate effects occur within seconds at molecular level but within ecosystem or pop it would take years.
Describe Quantal D-R
Quantal D–R: distribution of responses to
different doses in a population of organisms
– All–or–nothing: individuals are either
responders or non-responders. E.g. LD 50 trial: animals classified as dead or alive because in this test the endpoint you are looking for is death.
D-R relationships are illustrated graphically
as D-R curves
Describe Graded D-R:
Graded D–R: response of a biological
system to varying doses of a chemical
– Continuous and gradual: from minimum
detectable to a maximal response. E.g,
D-R relationships are illustrated graphically
as D-R curves
freq distribution = blue ; bell shaped and is termed normal distribution.
cum freq = red; each freq from distribution is added to sum of predeccors; sigmoidal.
Reuslt is obtained by determining an endpoint and countin the numebr of animals that reached.
Rate of response initiall fast but becomes progressively slower as dose increases. EVentualy max effect achived and further increase in dose does not produce a response.
If dose range is very wide, can plot on semi-log scale.
Graded D-R curves are used for?
Which drug is more potent?
B b/c have lower EC50.
Define potency
Potency = amount required to elicit effect of a given
magnitude (typically calculated as 1/EC50)
Define efficacy
Efficacy = maximal response [effectiveness]
Which drug is more potent?
red line
black line = more effective
Most substances, toxicity is associated with a trhedhols dose consistent with paraselsus dogma.
Linear = estimates effects of ionixing radiation. effect directly proprtional to doses at all levels of exposure. Radiation is alwasy harmful at all levels of exposure. Sum of several Short duration has same effect as one long duration. No safety threshold. Keep in mind: threhold dose falls between NOEL and LOEL.
Unique dose response curve that is U shaped in nature. Arises fro the fact tht both low and high conc. of a central nutients assocaited with adverse effects. Ad effects asociated with deficney are high at very low doses and as these doses increase thse ad effects of defiivency decrease until disappear. with further increasing dose, othr ad effectw appear and are associated with oxicity. For these substances, conc need to be maintained within hoemostatic range at which there is neitehr sign of defieicney nor toicity.
Characteized by: this type fo dose respons eis assoc with non=nutritional toic substances that may impart some benefiical or stimulatory effects at low doses. high doses = adverse effect.
high Alcohol = liver damage, cancer, serosis.
low alcohol = reduces heart failure and stroke
A: degree of ebenfit increases and starts to decrease with increase in conc of toxicant until adverse effects occurs
B: # of tumors initally decrase with incraseing con. higher con of toxicant –> tumors increase.
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.
Review questions = help with exam
Do we need to know tox terminology PDF?
