Phase Two Reactions, cont.

Methylation involves the transfer of an "activated" methyl group, most commonly from S-Adenosyl methionine (methyl H₄ folate and methyl Vitamin B₁₂ are other possibilities). The organism can then use this system to methylate amine, hydroxyl, or sulfhydral compounds. Bacteria can also methylate heavy metals, most notoriously mercury to give dimethyl mercury.

Example: Methylation of dihydroxy benzoic acid by catechol O-methyl transferase.

Methylation of histamine:

Methylation of mercaptoethanol:

Comparative Toxicology

We are interested in comparative aspects of toxicology at a variety of levels and for various reasons. We find that variations in toxic response occur across phylogenetic lines, within species (genetic variation), with sex and hormonal variation, with age/development, and with environment.

Reasons for interest include:

• Selective toxicity - development of specific toxins as pharmaceuticals, pesticides, herbicides etc.
• Experimental models - modeling human and other species of interest via the responses of laboratory species/varieties.
• Environmental xenobiotic cycles.
• Comparative toxicology as a discipline.

Let's look at some examples of in vivo toxicity differences first, just to provide some perspective before looking at factors affecting disposition and metabolism.

1. DDT: Insects and marine organisms are extremely susceptible (LD₅₀ = 1.6 mg/kg as a larvicide [Handbook of Biological Data]) while mammals and birds are quite resistant (LD₅₀ = 40-500 mg/kg and 800-4000 mg/kg, respectively). DDT does cause thinning of eggshell in falcons and ducks, but not in gallinaceous birds (fowl).
2. CCl₄: Generally a highly hepatotoxic compound. However, chickens are practically immune.
3. DNP (dinitrophenol): Causes cataracts in humans, ducks and chickens, but not other experimental animals! (Thus normal laboratory testing would not discover its side effect of blindness in humans when used as a dieting drug!)
4. Thalidomide: Causes severe birth defects in humans (a potent teratogen), but not in experimental animals such as the laboratory rat or mouse. Thus it was tested and used as a pharmaceutical for a while in Europe with disastrous effect!
5. In general we can order the toxicity of common pesticides to humans and mammals as: herbicides = fungicides< molluscides < acaracides < nematocides < insecticides< rodenticides.

Let's look at some specific examples of variations in toxicity.

Species variations in toxicity

• "Dioxin" (TCDD = 2,3,7,8-tetrachlorodibenzo-p-dioxin):

Dioxin has been touted as the most deadly chemical known. This may be true for male guinea pigs, but not across the board, as can be seen in the comparison of oral toxicity data in the table below:

Data from article in Scientific American, February 1986. Organism LD50(micrograms/kg) Guinea pig (male) 0.6 Guinea pig (female) 2.1 Rabbit 115 Monkey (female) <70 Rat (male) 22 Rat (female) 45-500 Mouse (male) <150 Dog (male) 30-300 Dog (female) >100 Frog 1,000 Hamster 1,157

• Variations in the rates of Phase I oxidation reactions can have significant impact (NOTE - quantity not quality).
  • Ethylene glycol is a low toxicity compound which can be processed into oxalic acid, which is toxic, or broken down to carbon dioxide:

The rate of of production of oxalic acid for some experimental species is: cat > rat > rabbit, which is reflected in the increasing toxicity of ethylene glycol, as seen in Figure 5.6 on p 124 of Timbrell 3rd. (Oxalate's toxicity results from its complexing of magnesium and calcium ions, making them unavailable. A large loss of sheep in the 1970's(?), originally thought to be due to a nerve gas release, turned out to be due to oxalate poisoning by a foraged plant.)

Last modified 11 March 2010

© RA Paselk 2001