Evaluation of the toxicity of drug residues in food: the case for 'relay' toxicity studies.
The tissue residues of veterinary drugs given to food-producing animals are an ill-defined mosaic of parent drug and metabolites. Consumers are only ever exposed to this mixture in the presence of a vast excess of the excipient, food. Given the modifying effects of food on the absorption and disposition of co-administered xenobiotics, it follows that the toxicity of these residues can only be properly evaluated in the presence of a large excess of food. Adoption of a relay toxicity strategy addresses these two points. The proposed relay toxicity testing approach is as follows. The target species receives a recommended dosage regimen of the drug, but a dose level three- to five-fold higher than normal and the animals are then killed several days earlier than the projected withdrawal period. The tissues from these animals, containing the residue mixture at artificially high concentrations, are then administered to laboratory animals for conventional toxicological evaluation. In this approach the residues do not require individual identification and their potential toxicity is evaluated in the presence of the inescapable excipient, food. Determination of an 'exposure' level without observerable toxicity provides, in principle, the means of relating human safety to a No-Observed Effect Level in laboratory animals in the traditional manner.
Galer
D M
DM
Pfizer Central Research, Groton, CT 06340, USA.
Monro
A M
AM
D000818:Animals; D001682:Biological Availability; D004350:Drug Residues / Q000633:toxicity*; D005502:Food; D005506:Food Contamination / Q000032:analysis*; D006358:Hot Temperature; D006801:Humans; D051379:Mice; D019055:No-Observed-Adverse-Effect Level; D051381:Rats