Comparative Toxicology

• Aniline may be metabolized into either para- or ortho-hydroxyl compounds:

The preferred route of hydroxylation varies significantly, and correlates with toxicity. Thus species which produce more o-aminophenol (e.g. cats and dogs), which is more toxic, are more sensitive to aniline than those which produce more p-aminophenol (e.g. rats and hamsters). Species differences in aniline hydroxylation are compared in Table 5.9, p 139 of Timbrell 4th.

• Malathion is an example where people have taken advantage of species differences in metabolism. Malathion is a relatively low toxicity compound which is metabolized quite differently by mammals and insects:

Malaoxon is a potent cholinesterase inhibitor, and thus acts as a neurotoxin for insects, while the diacid is excreted after conjugtion by mammals with little harm.

• Amphetamine metabolism is another compound where there are significant differences in terms of metabolic product, as shown in the figure below:

• Additional examples include species differences in hexobarbital metabolism as seen in Table 5.10, p 140 of Timbrell 4th., and hepatic reductase activities in various species as seen in Table 5.11, p 142 of Timbrell 4th.

Variations in Absorption, Distribution, and Excretion of compounds.

• Skin penetration vs. Toxicity of Organophosphorous Compounds. (overhead - Table 5.2, p 135)
• Salivary and Gastric pH. (overhead - Table 5.3, p 135)
• Binding of Plasma Proteins. (overhead - Table 5.4, p 136)
• Biliary Excretion. (overhead - Table 5.7, p 137)
• Urinary Volume and pH. (overhead - Table 5.5, p 136)
  • Note scaling as possible explanation.
• Urinary Excretion. (overhead - Table 5.6, p 137)
  • Note scaling as possible explanation.

Strain/genetic variations in toxicity

An important example of strain/genetic variation in toxicity is seen in the differences between so-called fast and slow acetylators as shown in Figure 5.23 (p 153) and tables 5.14 (p 152) & 5.16 (p 155) of Timbrell 4th.

Physiological Factors & Toxicology

Stress

Stress can have a variety of effects on health and on toxin metabolism. For example, cold stress and excess noise both increase the hydroxylation of aromatic compounds.

Diet

Diet can have a diverse impact on xenobiotic metabolism. Variations in enzyme expression can have particular impacts:

• Particular foods and/or food balance can induce enzyme production (due to food or food additives - repeated doses needed).
• Foods and/or food additives can cause enzyme inhibition (single dose can be effective).

Both enzyme induction and inhibition can in turn have diverse and unexpected results:

• Can see reduced toxicity due to increased processing (higher enzyme activity).
• Can see increased toxicity due to increased processing (higher enzyme activity).
• Can see increased toxicity due to decreased conjugation of altered toxin.

Enzyme induction can often result in remarkably specific changes as a result of the new spectrum of enzyme activities.

As a result prediction of the effects of inducers requires a good deal of prior knowledge regarding the xenobiotic's metabolism as well as the enzyme induced.

Inhibitors on the other hand can display considerable specificity for tissues and effects (e.g. neurotoxicity due to neuron receptor inhibition).

Nutritional status can also effect toxin action. For example, the lack of a nutrient can have both positive and negative effects.

• For example, consider low protein:
  • As measured in vitro microsomal enzyme activities are decreased >2-fold when going from a 20% protein diet to a 5% protein diet. (Barbiturate sleeping times are in agreement with these in vitro results, supporting the 2-fold effect.)
  • Carbon tetrachloride is less toxic (due to its lowered metabolism).
  • Paracetamol is increased in toxicity (due to a reduction of conjugation).
  • Aflatoxin has a decrease in carcinogenicity (because there is less formation of the active epoxide).
  • Serum protein concentrations decrease, which can affect toxin binding, and thus thresholds for some toxins.

Last modified 23 March 2010

© RA Paselk 2001