-Descriptive toxicologists are concerned directly with toxicity testing to provide information for safety evaluation and regulatory requirements.
-Mechanistic toxicologists are involved with identifying and understanding the mechanisms by which chemicals exert toxic effects on living organisms.
- Regulatory toxicologists are responsible for deciding, on the basis of data provided by descriptive and mechanistic toxicologists, whether a drug or chemical poses a sufficiently low risk to be marketed for a stated purpose.
Definitions of chemical exposure.
-acute exposure is defined as exposure to a chemical for less than 24 hours.
-subacute exposure - one month or less.
-subchronic exposure - 1 to 3 months.
-chronic exposure - for more than 3 months.
A CHEMICAL ALLERGY is an immunologically mediated adverse reaction to a chemical resulting from previous exposure to that chemical.
A CHEMICAL IDIOSYNCRASY refers to a genetically determined abnormal reactivity to a chemical.
ADDITIVE EFFECTS occur when the combined effect of two chemicals is equal to the sum of the effects of each agent given alone(example 3 plus 4 =7).
SYNERGISTIC EFFECTS occur when the combined effects of two chemicals are greater than the sum of the effects of each agent given alone(example 2 plus 2 = 300).
POTENTIATION occurs when one substance does not have a toxic effect but when added to another chemical makes that chemical much more toxic (example 0 plus2 =10).
ANTAGONISM occurs when two chemicals administered together interfere with each other's actions or one interferes with the action of the other.
There are 4 types of ANTAGONISM:
a) - functional - when two chemicals counterbalance each other by producing opposite effects;
b) - chemical - when two compounds react and produce a less toxic product;
c) - dispositional - when the absorption, biotransformation, distribution or excretion of a chemical is altered so that the concentration and/or duration of the chemical at the target organ is diminished.
d) - receptor - when two chemicals that bind to the same receptor produce less of an effect when given together than the addition of their separate effects (example 4 plus 6=8), or when one chemical antagonizes the effect of the second chemical (example: 0 plus 4 =1)
LD50 = lethal dose in 50% of test species
ED50 = effective dose in 50% of test species
LC50 = lethal concentration in 50% of test species (fish studies use this one)
Therapeutic Index = LD/ED
Margin of Safety= LD/ED
Weak Acids are absorbed in the acidic stomach and excreted in alkaline urine.
Weak bases are absorbed in an alkaline environment and excreted in acidic urine
Unionized (or uncharged) chemicals cross membranes
ionized (or charged) chemicals bind to proteins
Volume of distribution in L/Kg relates to distribution of chemical
- 0.04 or less in plasma water;
- 0.6 or less total body water;
- greater than 0.6 in lipids;
- >than 1 in tissue structure.
Most weak acids bind to plasma albumin
Most weak bases bind to alpha 1-acid glycoprotein
Question: Since placenta is thickest in first trimester of pregnancy and thinnest in last trimester (in humans) would you expect more chemicals to pass, more easily in last trimester or first trimester?
Answer: chemicals can cross the placenta during each of the three trimesters.
Representative pH's of fluids:
Semen has a pH of 7.4; blood 7.4; saliva and milk 6.5
Question:Will weak acids or bases more likely be excreted in milk?
Hint: milk is acidic - look back at urine pH (acidic or alkaline) excretion characteristics of weak acids and weak bases.
LIPOPROTEINS
- VLDL (Very Low Density Lipoprotein) carries primarily triglycerides from liver to___
- chylomicrons carry lipids from intestine to liver
- LDL (Low Density Lipoprotein) carries cholesterol from liver to ____
- HDL (High Density Lipoprotein) carries cholesterol from ____to liver
How can LDL be considered "bad" while HDL is considered "good" when they are both carriers for cholesterol?.
Phase 1 makes chemical more water soluble;
phase 2 conjugates to allow more ease of excretion via kidneys
Remember - cytochrome P450 system enzymes are numero uno in phase I reactions:
found in liver endoplasmic reticulum (microsomes) and in virtually all tissues.
Also, microsomal and mitochondrial P450 enzymes play key role in the biosynthesis or catabolism of steroid hormones, bile acids, fat-soluble vitamins, fatty acids and eicosanoids (prostaglandins)
agonist has affinity and produces efficacy
affinity means can bind to a receptor;
efficacy is a measurable response or effect
antagonist has affinity but produces no efficacy
agonist = stimulant;
antagonist=blocker
In classical pharmacology, toxicology - one must use a triplet - agonist, antagonist, and agonist to determine receptor activity
