DEVELOPMENT OF AN INHALATION SYSTEM FOR THE SIMULTANEOUS EXPOSURE OF RAT DAMS AND PUPS DURING DEVELOPMENTAL NEUROTOXICITY STUDIES

Abstract

Due to mass flux constraints, the exposure of pups along with dams to particles cannot be easily done in traditional whole-body inhalation systems. Typical inhalation developmental neurotoxicity studies rely on maternal separation during exposure, resulting in pup stress that may alter behavioral development, thereby confounding study results. We developed an individual-rat, whole-body inhalation exposure cylinder that allows for the simultaneous exposure of rat dams and their pups to vapors, aerosols, and particles. We evaluated pup growth and development following gestational and lactational 6-h/ day exposures to HEPA-filtered air using the novel exposure cylinder, in which dams and pups were maintained together, versus rat pups for which only the dams were exposed or control animals that remained in the domiciliary cage with the dams. Rat pups that were separated from their dams during neonatal exposure to HEPA-filtered air demonstrated significant delays in several developmental landmarks such as surface righting, negative geotaxis, and eye opening, as well as decreased terminal body and brain weights. Increased spontaneous motor activity was observed on postnatal day (PND) 13, 17, and 60 in pups that were separated from their dams. Malnutrition is the likely cause for the observed hyperactivity and delayed development. We then compared maternal blood levels of tertiary amyl methyl ether (TAME) and its metabolite tertiary amyl alcohol (TAA) in the 2 exposure systems following exposure to 500 ppm TAME for 6 h. Dams exposed in the novel exposure cylinder had higher blood levels of TAME compared with those exposed in stainless steel caging. We also compared levels of particulate manganese phosphate within the novel exposure cylinder to determine if levels achieved within the exposure cylinder were similar to levels generated within a 1-m3 chamber. The novel exposure cylinder is an ideal system for exposure of dams and pups to particles, due to the high horizontal flow rates, which result in an adequate mass flux flowing past the breathing zone of the animals with retained normal growth and development.