Extrapolation from Animals to Humans

Differences in the toxicity of specific substances between humans and laboratory animals cause considerable uncertainty in the application of animal data to humans. The differences can sometimes be isolated to differences in absorption, distribution, biotransformation, and excretion. For example, 2-naphthalamine is converted to the carcinogen 2-naphthyl hydroxylamine by dogs and humans. This is excreted by the kidneys and causes bladder cancer. However rats, rabbits, and guinea pigs do not excrete this metabolite and do not get bladder cancer from the original compound. Ethylene glycol is metabolized by two pathways with the separate end products oxalic acid or CO2. Cats metabolize more of the ethylene glycol to oxalic acid, whereas rabbits produce more CO2. Consequently, ethylene glycol is more toxic to cats than to rabbits. The LD50 for dioxin (TCDD) is 5 mg/kg in hamsters but only 0.001 mg/kg in guinea pigs. This large range in toxicity between species has produced considerable controversy over the setting of dioxin standards for humans.

Because of this uncertainty, the use of animal toxicity data for humans is often attacked as not being "scientifically valid.'' However, there are degrees of scientific validity, and there is certainly correlation between the toxicities to two different mammalian species. We must ask ourselves whether it would be prudent to expose large populations of humans to substances that harm rats if we don't have specific information that it would be safe to do so.

The U.S. EPA suggests selecting data from tests on animals that respond most like humans. If this type of data is not available, all acceptable data should be used, with emphasis placed on the most sensitive species, strain, and sex.

Animal data are scaled to human dosages by the ratio of either body mass or body surface area. Body surface area is preferred by the U.S. EPA. It is more conservative, producing risks that are higher by a factor of 5 when extrapolating from rat data, and 12 times higher when using mouse data. Furthermore, safety factors are usually applied to extrapolate from animals to humans to provide additional conservatism.

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