Introduction and Principles of Toxicology Flashcards
What is toxicology?
study of adverse effects of xenobiotics on living systems
toxicon = poison
logos = scientific study
STUDY OF POISONS
What is the difference between toxins and toxicants?
TOXIN = poison produced by living organisms (botulinum neurotoxin)
TOXICANT = man-made poisonous substance (organophosphates)
What are xenobiotics?
any substances foreign to an organism, or any compound no found within the normal metabolic pathways of a biologic system
What is the universal symbol of poisonous substances?
skull and crossbones
Toxicology is multidisciplinary. What 4 fields greatly contribute?
- chemistry
- physiology
- biochemistry
- pathology
What is mechanistic toxicology? Descriptive toxicology? Regulatory toxicology?
MECHANISTIC: study of cellular, biochemical, and molecular mechanisms of action
DESCRIPTIVE: toxicity testing for safety and regulatory purposes
REGULATORY: assessment of chemical risk from available data
What is forensic toxicology? Clinical toxicology? Environmental toxicology?
FORENSIC: medical-legal aspects of poisoning (CSI)
CLINICAL: diagnosis and treatment of toxicoses
ENVIRONMENTAL: effects of chemicals and pollutants in the environment on nonhuman subjects
Why is toxicology considered as old as humanity? Who where the early toxicologists?
early humans knew what to eat without harm and were able to recognize poisonous plants and animals and used their extracts for hunting and warfare
herbalists, witches, philosophers, alchemists
What is the oldest documentation of medicine?
Ebers Papyrus from 1500 BC, which contains >800 magical formulae and remedies with information on toxic plants and metals
Who is considered the father of toxicology? Why?
Paracelsus
advocated focus on “toxicon” and pioneered the dose-response relationship
all things are poisonous, it is only the dose that makes a thing not a poison
What 3 concepts were advanced by Paracelsus?
- need for experimentation in examining response 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? What did he discover?
pioneered quantitative toxicology to relate chemical content and toxicity and introduced experimental and forensic toxicology
used autopsy material and chemical analysis for legal proof of arsenic poisoning - Marsh Test (cause and effect)
What did Francois Magendie do?
pioneered mechanistic toxicology to determine the mechanisms of action of strychnine, emetine, and arrow poisons
What was the 1960s considered with regard to toxicology? What important agency was discovered?
era of public awareness - birth defects, pesticides wiping out bird populations (Rachel Carson and Silent Spring)
launch of the Environmental Movement lead to the development of the US Environmental Protection Agency
How has toxicology developed from the pre-20th century to the mid-20th century? Today?
PRE-20TH CENTURY - observational; mostly focused on domestic animals used for food, fiber, transportation, and power (plant toxicoses and their antidotes)
MID-20TH CENTURY - experimental; increased population of companion animals, large-scale food animal production, and reduced use of animal power
TODAY - mechanistic; comparative approach driven by concerns for human health
What makes something poisonous?
the dose
all substances are poisons, the dose differentiates a poison from remedy
What is LD50? What are 3 important limitations?
dose lethal to 50% of exposed animals
- does not reflect full spectrum of toxicity (low acute toxicity may be carcinogenic or teratogenic)
- tells us nothing about the nature or severity of effects in survivors
- specific to exposure conditions (species, age, sex, size, route and duration of exposure, environment and physiological conditions)
Some of the most toxic agents are ______.
natural
When are substances generally recognized as safe (GRAS)?
relatively harmless at > 15 g/kg
What is the dose-response (D-R) relationship?
correlative relationship that brings together the characteristics of exposure and the spectrum of effects
What does the toxicant-receptor interaction depend on?
configuration and accessibility (must be compatible)
What are the 5 fundamentals to the dose-response (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
- degree of response is correlated with the concentration of the toxicant at the receptor site
- 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
What is included in toxicokinetics?
Absorption
Distribution
Metabolism
Excretion
external exposure —> internal dose —> target dose
What is toxicodynamics?
interaction of toxicant with target site
target dose —> toxic effect
What condition must be met for toxicity to occur?
uptake (K1) must exceed elimination (K2) leading to accumulation of the toxicant
K1 > K2
when a xenobiotic or its metabolite reaches appropriate sites in the body at adequate concentrations and at an adequate length of time
What are some exposure, toxicant, animal, and environment-related factors that influence toxic response?
EXPOSURE - dose, route, site, duration and frequency of exposure, concentration at the site of action, prior exposure
TOXICANT - physical and chemical properties, formulation
ANIMAL - species, strain, age, size, sex, metabolism, nutritional status, health
ENVIRONMENT - temperature, humidity, wind, drought, time of year
How does response time, difficulty linking toxicant, and importance change up the levels of biologic organization?
- increases
- increases
- increases
How do the lower and higher levels of biological organization give information about toxicants?
LOWER = explains mechanisms
HIGHER = provides significance
Are effects at all levels of biological organization significant?
YES
How are dose-response relationships illustrated graphically? What are the 2 main types?
D-R curves
- QUANTAL - distribution of responses to different doses in a population of organisms in an all-or-nothing way (responders or not responders)
- GRADED - response of a biological system to varying doses of a chemical in a continuous and gradual way from minimum detectable to a maximal response
What do quantal dose-response curves look like? How are they applied?
sigmoidal
prediction of the proportion of a population that respond in a specified manner to doses of the toxicant - relating dose to frequency of response
Within a population how will a majority of respond to a given toxicant dose?
the majority will respond similarly
What do graded dose-response curves look like? How are they applied?
a curve that plateaus
relates dose to the intensity of response
What is EC50?
value on a graded dose-response curve that is half the maximal concentration
What are the 4 major uses of graded dose-response curves?
- therapeutic dose
- potency and efficacy
- safety
- mechanisms of action
What is potency? Efficacy?
POTENCY = amount required to elicit an effect of a given magnitude (typically calculated as 1/EC50)
EFFICACY = maximal response (effectiveness)
What is the NOEL and LOEL in graded dose-response curves? Threshold dose?
NOEL = no observed effect level
LOEL = lowest observed effect level
THRESHOLD = beginning of a response
Label the graded dose-response curve.
1 = NOEL
2 = threshold (response)
3 = LOEL
blue line = linear = something that is always a toxicant, not matter the dose (ionizing radiation)
What does the dose-response curve for trace elements, like vitamins and metals, look like?
U-shaped with responses at deficiency levels and toxic levels - within the U and below the adverse effect threshold is at homeostasis
What is hormesis? What does the graph look like? What are 3 common toxicants that fall into this category?
low-dose stimulation, high-dose inhibition
- beneficial at low doses, dangerous at high doses
regular or inverted curve beginning at 0
alcohol, dioxin, cancer drugs
Inverted hormesis dose-response curve:
What are non-monotonic dose responses (NMDR)?
dose-response relationship in which the direction changes with increasing or decreasing dose
