A Practical Approach, Second Edition=Ronald D. Ho.pdf

NONCLINICAL JUVENILE TOXICITY TESTING 289Table 8.4Flexible cannula intubation error rates in juvenile Crl:CD ® (SD)IGS BR ratsAge atIntubationNumberofAnimalsNumber ofDosesAdministeredConfirmedIntubationErrors aSuspectedIntubationErrors bIntubationError Rate,%PND 4-31 256 7,168 4 0 0.056PND 7-13 3681 25,767 0 5 0.019PND 7-34 256 7,936 0 0 0.000PND 14 or 21 376 376 0 0 0.000PND 14-41 1800 50,400 0 0 0.000PND 19-21 212 636 2 0 0.314PND 21-34 520 14,560 0 0 0.000PND 22-41 285 5,700 0 0 0.000All ages combined 7386 112,543 6 5 0.010aIntubation errors were confirmed at necropsy by observation of a perforated esophagus.bSuspected intubation errors resulted in animal death, with reddened esophagus and/or foamy contentsin trachea and/or lungs noted at necropsy.Source: Data were collected at WIL Research Laboratories, LLC (9/22/00 – 6/10/04).litter are exposed simultaneously to the test article during early postnatal life of the pups untilweaning. Therefore, specialized whole-body inhalation chambers must be used for the animalsduring exposure (refer to Figure 8.9). If the pups are exposed without the dam, the temperature ofthe inhalation chamber must be maintained appropriately since neonatal rats are inefficient atregulating core body temperature, although this is not recommended early in lactation. The inhalationroute of administration for juvenile rodents must be whole-body until the animal reachessufficient size to make head- or nose-only inhalation possible. The whole-body route of exposureintroduces the possibility that the juvenile and/or the maternal animal (if concurrently exposed)may also be exposed orally (during grooming) and dermally. Finally, neonatal animals in thesemodified inhalation chambers may be exposed to lower than desired concentrations of the testarticle as a result of filtration when nursing. 77 In contrast, exposure by the inhalation route presentsfewer technical difficulties when using larger species because they may be exposed via head- ornose-only methodology, with some acclimatization.Less common routes of administration, such as intravenous, present technical challenges thatare related to animal size. It is technically more feasible to administer a test article intravenouslyto a puppy or a piglet than to a rodent pup. There are more sites into which the dose may beadministered in a larger animal (e.g., jugular, saphenous, marginal ear, or femoral vein) than in arodent. If intravenous administration is required and the animal of choice is the rodent, theinvestigator may have to compromise by using older animals at the onset of dose administration.Continuous infusion would not be possible in rodent juvenile studies that initiate prior to weaning.Moreover, the logistical challenges involved in continuous infusion in any species may be dauntinggiven the potential need to provide new catheters at multiple intervals throughout the study tocompensate for growth of the animal.The dermal route is another option for administration of the test article to the juvenile, althoughInternational Life Sciences Institute (ILSI) does not recommend this route for juvenile rodentsbecause of architectural differences between rodent and human skin. 77 The use of this route shouldbe limited to the postweaning period to prevent unintended oral administration to the dam duringgrooming and/or maternal rejection of the offspring because of changes in olfactory cues causedby application of the material. Moreover, if siblings are gang-housed after weaning, a period ofseparation may be required for those studies requiring dermal applications. Finally, to preventingestion of the test article, Elizabethan collars (see Chapter 7, Figure 7.5A) may be required, andthe size of these collars should be monitored closely and appropriately adjusted to accommodatethe growth of the animal during the dose administration period.© 2006 by Taylor & Francis Group, LLC