Chapter 3 - Factors Influencing Toxicity

Question 1

Main factors that affect toxicity

Answer 1

• 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

Question 2

Factors in the toxicant that affect toxicity

Answer 2

• 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.

Question 3

Factors in the host animal that affect toxicity

Answer 3

• 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

Question 4

What is the MFO, main organ, major site of activity and key component

Answer 4

• 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.

Question 5

How can the mechanisms of biotransformation (factors in the host animal) affect toxicity ?

Answer 5

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

Question 6

Examples of MFO enzyme inducers

Answer 6

Barbiturates, halogenated hydrocarbons, and endogenous steroids.

Question 7

Phase I metabolism reactions

Answer 7

oxidation (e.g. hydroxylation, sulfoxide formation)

reduction

hydrolysis

Question 8

Common conjugating agents involved in Phase II metabolism

Answer 8

• glucuronic acid,
• amino acids,
• acetates,
• sulfates
• glutathione

Question 9

Effect of liver disease on biotransformation and metabolism

Answer 9

Liver reduce may reduce the activity of MFO’s

Question 10

Examples of diseases that reduce hepatic biotransformation

Answer 10

Greatest to least effect:

• cirrhosis
• liver toxicosis
• carcinoma
• cholestasis

Question 11

Effect of biotransformation in guinea pigs compared with other animals

Answer 11

Guinea pigs have compromised N-demethylation activity compared with other animals

Question 12

How sex differences affect biotransformation?

Answer 12

Males have higher MFO activity related to endogenous steriods such as testosterone.

Question 13

Effect of body temperature on biotransformation of a toxicant

Answer 13

Decreased body temperature may decrease activity of microsomal enzymes.

Question 14

Circumstances (in the host animal) that alter biotransformation and affect toxicity

Answer 14

1. Liver disease
2. Location of toxicant in tissues with little MFO activity
3. Age
4. Nutrient deficiencies
5. Different species, breeds or strains
6. Sex differences
7. Route of exposure
8. Decrease body temperature
9. Diurnal variations in cytochrome P-450 and reduced glutathione (GSH)

Question 15

How can morphologic characteristics account for species differences in toxicity ?

Answer 15

• 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)

Question 16

What is lethal synthesis (in bioactivation of compounds)

Answer 16

Bioactivation of compounds (i.e. phase I metabolism) to more toxic forms.

Question 17

Why are dogs more susceptible to flouroacetate than rats?

Answer 17

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)

Question 18

Why are mice and sheep more resistant to aflatoxin compared to other species ?

Answer 18

Mice and sheep form only limited amounts of bioactivated aflatoxin.

(example of lethal synthesis - bioactivation of compounds to more toxic forms)

Question 19

Examples of differences in phase II biotransformation (conjugation) :

• glucuronide
• sulfate conjugation
• mercapturic acids
• acetylation of aromatic amino compounds

Answer 19

• 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.

Question 20

An example of high lipid solubility that may cause accumulation in specific organs (e.g. DDT)

Answer 20

DDT insecticide in nervous tissue

Question 21

When are sex differences in susceptibility to chemicals minimal

Question 22

How does pregnancy and lactation affect metabolism of poisons?

Answer 22

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.

Question 23

How does age (animal factors) affect toxicity

Answer 23

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)

Question 24

How does general metabolic activity in the host animal affect toxicity ?

Answer 24

General metabolic activity is usually greater in smaller or younger animals (higher rates of biotransformation).

Question 25

What is true metabolic body weight (mbw) ?

Answer 25

True metabolic body weight (mbw) is defined by animal surface area and is related to actual body weight (bw) by the ecuation:

mbw = bw^2/3

Question 26

Factors in the environment that affect toxicity

Answer 26

• Volume and concentration of the toxicant
• Route and site of administration
• Environmental temperature
• Atmospheric pressure
• Nutritional and dietary factors

Question 27

How do volume and concentration of the toxicant (environmental factors) affect toxicity

Answer 27

Volume and concentration affect exposure (dosage) and the rate of exposure (e.g. bolus may produce poisoning with much lower dosage than diluted in entire day’s food supply and voluntary consumed)

Question 28

How does environmental temperature (environmental factors) affect toxicity

Answer 28

• Low environmental temperature enhance biotransformation (increase of metabolic activity to keep animal warm)
• temperature may influence the amount and pattern of food intake
• high environmental temperature increase water intake, increasing exposure to water-borne toxicants.
• high environmental temperatures increase susceptibility to poisons that alter metabolism or thermal regulation. (e.g. dermal toxicosis of insecticides greater in hot weather - blood in skin to cooling)

Question 29

How does atmospheric pressure (environmental factors) affect toxicity

Answer 29

• Changes in response to toxicants are generally associated with changes in environmental oxygen tension.
• Hyperbaric oxygen exposure has been used to treat poisoning by carbon monoxide, barbiturates and cyanide.

Question 30

How does calcium and zinc influence the absortion of lead?

Answer 30

They compete for the same divalent cation transport system.

Question 31

How do nutritional and dietary factors (environmental factors) affect toxicity

Answer 31

1. Inactivation of chemicals by dietary components
2. Palatability may increase voluntary intake
3. Nutrient deficiencies and excesses:
   
   1. fasting: (reduced blood glucose): decrease the activity of drug metabolizing enzymes.
   2. protein malnutrition impairs enzyme synthesis, MFO activity and glutathione concentration
   3. vitamin deficiency (vit C and E) result in increased damaged from free radical formation.