Exam 3: Lecture 9, Intro to Toxicology Flashcards
Important concept of Toxicology?
Dose makes the poison
Toxicology definition?
study of adverse effects of chemical, biological or physical agents on living organisms and the environment
Tox substances:
Toxins = naturally occurring
Toxicants = synthetic chemicals with different intended purposes
Hazard is
ability of substance to cause damage, inherent propery
Risk is…
chance/probability of toxicity from exposure
risk assessment - estimate potential effect on human health
LD50
Lethal dose, at which half subjects die
the Higher it is, the less toxic something is
Idosyncratic reactions are…
abnormal reactivity of an individual to a chemical based on its genetic, or other individual sensitivity factors with relatively low incidence
can occur in any organ system, skin/liver/hematopoeitic/immune system must affected
Reversible Toxicity
largely depends on ability of an injured tissue to adapt, repair and regenerate
Live and GI have high ability to regenerate
Irreversible Toxicitiy
CNS has much more limited ability to divide and replace damage neurons
cancers and birth defects cause by chemical exposures
Local Toxicity
occur when contact is 1st made by toxicant and the biological system
produced by ingestion of toxic substances or inhalation of irritant materials
Systemic Toxicity
require absorption and distribution of toxicant from its entry point to a distance site where the deleterious effects are produced
most substances produce systemic effects except highly reactive
Most chemicals usually elicit major toxicity in…
only 1 or 2 organs and not all organs
not always site of highest conc
target organs of toxicity
Additive effect
combined responses of two chemicals is equal to cub of responses to each chemical given alone
Synergistic effect
combined responses of two chemicals are much greater than the sum of the responses to each chemical given alone
Potentiation
one substance does not produce any toxicity on a particular tissue or system but when added to another chemical makes that chemical more toxic
Antagonism
Two chemicals administered together interfere with each others actions or one interferes with the action of the other
Receptor antagonism
two chemicals bind to same receptor produce less of an effect when given together relative to the addition of their separate effects
Chemical antagonism or inactivation
direct chemical interaction between 2 compounds that produce a less toxic effect
Dispositional antagonism
disposition is altered such that the conc and or duration of chemical at target organ is reduced
Functional antagonism
2 chemicals counter balance each other by producing opposing effects on the same physiological function
Tolerance
repeated exposure to a chemical can reduce its pharmacological and/or toxicologic response
Dispositional tolerance
amount of chemical reaching site of action decreases over time
Chemical or cellular tolerance
lower availability of receptors and/or mediators
Species Differences
different doses can cause different effects in different species
Factors affecting toxicity?
Genetics Age Gender Diet Lifestyle Disease state Medication
Desirable drugs
Optimal safety
optimal PK/ADME
Optimal Formulation
Optimal Potency/Selectivity
Two principal concepts underlie animal toxicity testing which are not true
effects produced by compounds in lab animals are applicable to humans
exposure of experimental animal to high doses of chemical is a necessary and valid method of discovering possible hazards in humans
When extrapolating high to low doses across species it is important to…
consider molecular, biochemical and cellular mechanisms responsible for toxicological responses
S4
Toxicity Testing
S9
Anticancer pharmaceuticals
Acute toxicity Testing
aim to approximate the LD50
Subacute (Repeated-Dose) Toxicity Testing
performed after 3/4 repeated admin
aid to establish doses for sub chronic studies
Subchronic Toxicity Testing
Establish a no observed adverse effect level (NOAEL)
90 days (13 weeks) is the most common test duration
Chronic Toxicity testing
usually 6 month - 2 yr in rodent
over 1 yr in non rodents
Developmental and Reproductive Toxicity Testing
study adverse effects on developing organism occurring anytime during life span
study of occurrence of adverse effects on male/female repro system
Mutagenicity
Ames Test
Carcinogenicity testing
Mice: 18 month - 2 yr
rodents 2 - 2.5 yrs
most expensive, to evaluate carcinogenic potential of chemicals
Neurotoxicity Assessment
Hard to ases
Immunotoxicity Assessment
xenobiotic exposure can alter immune system
Eye and Skin Irritation and corrosion
eye injury assessed between 3-21 days after app of chemical to rabbits eye
skin testing done by applying patches containing test chemical to shaved section of skin for period of time
