Chapter 3 - Factors Influencing Toxicity Flashcards
Main factors that affect toxicity
- Factors in the toxicant that influence how it interacts with receptors or the cell membrane
- Factors in the host animal that change its ability to activate, detoxify or adapt to the toxicant
- Factors in the environment that affect either the toxicant or the host animal
Factors in the toxicant that affect toxicity
- Composition of the sample
- impurities
- modification of the basic active molecule
- instability of hte toxicant under conditions of use
- Solubility, polarity and ionization
- chemicals with high lipid solubility are more readily absorbed through the cell membrane
- nonpolar compounds of low molecular weight are more readily absorbed than large complex molecules
- compounds containing groups ionized at physiologic pH are more water soluble (and less likely to absorb across membranes)
- Binding of toxicant to physiologic proteins can restrict the availability of active drug by limiting its passage across membranes.
- Formulation and vehicle effects
- Direct chemical interactions
- can result in formation of insoluble precipitates (reduce toxicity or efficacy)
- can change composition and apparent toxicity.
Factors in the host animal that affect toxicity
- Biotransformation and bioactivation
- Morphologic characteristics can account for species differences pertaining to toxicity
- Metabolic characteristics account for most of the known genetic and species differences associated with a toxic reaction
- Distribution and excretion
- Sex and hormone differences
- Age, maturity and metabolic activity
- Pathologic conditions
What is the MFO, main organ, major site of activity and key component
- MFO is the mixed function oxidases, a complex system of enzymes to metabolize foreign compounds.
- The smooth endoplasmic reticulum is a major site of MFO activity.
- Liver
- Key component: cytochrome P-450.
How can the mechanisms of biotransformation (factors in the host animal) affect toxicity ?
Foreign compounds are metabolized by the mixed function oxidases (MFO’s).
- Phase I metabolism (bioactivation): MFO acts on nonpolar lipophilic compounds and adds functional groups that are polar and less lipophilic.
- can be enhanced by enzime induction
- can be inhibited (e.g. by piperonyl butoxide, used to increase pyrethrin toxicity in insects)
- Phase II metabolism (conjugation): series of conjugation reactions involving xenobiotics modified in phase I with endogenous agents.
- produces a compound less lipophilic and more water soluble
- excreted in urine and are less toxic than parent
Examples of MFO enzyme inducers
Barbiturates, halogenated hydrocarbons, and endogenous steroids.
Phase I metabolism reactions
oxidation (e.g. hydroxylation, sulfoxide formation)
reduction
hydrolysis
Common conjugating agents involved in Phase II metabolism
- glucuronic acid,
- amino acids,
- acetates,
- sulfates
- glutathione
Effect of liver disease on biotransformation and metabolism
Liver reduce may reduce the activity of MFO’s
Examples of diseases that reduce hepatic biotransformation
Greatest to least effect:
- cirrhosis
- liver toxicosis
- carcinoma
- cholestasis
Effect of biotransformation in guinea pigs compared with other animals
Guinea pigs have compromised N-demethylation activity compared with other animals
How sex differences affect biotransformation?
Males have higher MFO activity related to endogenous steriods such as testosterone.
Effect of body temperature on biotransformation of a toxicant
Decreased body temperature may decrease activity of microsomal enzymes.
Circumstances (in the host animal) that alter biotransformation and affect toxicity
- Liver disease
- Location of toxicant in tissues with little MFO activity
- Age
- Nutrient deficiencies
- Different species, breeds or strains
- Sex differences
- Route of exposure
- Decrease body temperature
- Diurnal variations in cytochrome P-450 and reduced glutathione (GSH)
How can morphologic characteristics account for species differences in toxicity ?
- Ruminants store large volumes of ingesta, prologing absorption of toxicant
- Microbial action in the rumen can reduce toxicity (metabolizing the poison)
- Ruminal metabolism can enhance toxicity by activating the toxic agent (e.g. nitrate converted to nitrite)
- Inability to vomit (e.g. horse, rat, rabbit) can increase the adverse effects of poisons that are emetic in nature
- Poor developed blood-brain barrier permits the passage of certain chemicals (e.g. ivermectin in collies)
What is lethal synthesis (in bioactivation of compounds)
Bioactivation of compounds (i.e. phase I metabolism) to more toxic forms.
Why are dogs more susceptible to flouroacetate than rats?
Dogs rapidly metabolize the rodenticide fluoroacetate to fluorocitrate, and its toxicity is 6 to 8 times greater for dogs than rats.
(example of lethal synthesis - bioactivation of compounds to more toxic forms)
Why are mice and sheep more resistant to aflatoxin compared to other species ?
Mice and sheep form only limited amounts of bioactivated aflatoxin.
(example of lethal synthesis - bioactivation of compounds to more toxic forms)
Examples of differences in phase II biotransformation (conjugation) :
- glucuronide
- sulfate conjugation
- mercapturic acids
- acetylation of aromatic amino compounds
- glucuronide formation is reduced in the cat and the Gunn rat (highly susceptible to poisoning by phenols)
- sulfate conjugation is defective in swine
- mercapturic acids are poorly formed in guinea pigs
- acetylation of aromatic amino compounds is deficient in dogs.
An example of high lipid solubility that may cause accumulation in specific organs (e.g. DDT)
DDT insecticide in nervous tissue
When are sex differences in susceptibility to chemicals minimal
How does pregnancy and lactation affect metabolism of poisons?
Pregnancy and lactation cause marked hormone and metabolic changes:
- Liver, adrenals, ovaries, uterus increase in size and in protein during pregnancy (which increases biotransformation)
- development of the placenta enhances the metabolism of some xenobiotics
- lactation may enhance the excretion of some lipophilic toxicants (e.g. DDT, PCBs)
- Lactation increases the size and weight of the gastrointestinal tract allowing for some dilution of orally ingested toxicants.
How does age (animal factors) affect toxicity
Age affects absortion or passage across biologic membranes:
- The gastrointestinal mucosa and blood-brain barrier in young animals are less well developed than in older animals
- Active transport systems may be less effective in neonates
Young animals have less active xenobiotic-metabolizing enymes (disappears by adolescence)
How does general metabolic activity in the host animal affect toxicity ?
General metabolic activity is usually greater in smaller or younger animals (higher rates of biotransformation).
