Dosing via gavage or diet for reproduction studies: a pilot study using two fat-soluble compounds-hexachlorobenzene and aroclor 1254.
The choice of a dosing route for in vivo toxicological tests is often dictated by practical constraints. Reproduction studies are particularly challenging in this regard since the determination of no-effect levels and allowable daily intakes from reproduction data encompasses exposure of the dam to the test xenobiotic prior to pregnancy, during gestation and during lactation. The fetus/infant can be exposed to the xenobiotic as well as the dam's metabolic products of the test xenobiotic during gestation and lactation. We initiated a series of two-litter, pilot reproduction studies with Sprague-Dawley and Fischer 344 rats to specifically ascertain the amount of xenobiotic and its metabolites ingested by the nursing neonate on lactation days 4, 7, 12, 17 and 21, when its dam received the xenobiotic via its diet or by gavage. The xenobiotics studied in this initial series of experiments were hexachlorobenzene (HCB) and Aroclor(R) 1254 (polychlorinated biphenyls; PCBs). The dams were dosed for 28 days, mated to untreated males and then remated approximately 2 weeks after weaning their first litter to a second untreated male. Dietary levels of 10 ppm HCB or 10 ppm PCBs, and gavage doses of 0.9 mg HCB or 0.8 mg PCBs/kg body weight/day were chosen and resulted in similar doses of HCB and PCBs per unit of the body weight of the dam during the premating period. There were no apparent toxicological effects regarding the dam nor were any of the reproduction parameters (feed consumption, dam weight, litter size, pup weight, external anomalies and day 4 viability index) significantly different from control values. Following impregnation, the body weight of the dam increased appreciably during gestation, but its feed consumption increased only slightly. During lactation, the dam's feed consumption increased markedly while its body weight increased slightly. Consequently, when dams received the xenobiotic in their diet they consumed slightly less xenobiotic per unit of body weight during gestation when compared to the gavaged dams, whereas the situation was dramatically reversed during lactation. While the greater consumption of xenobiotic by the dietary-dosed dams during lactation did result in more HCB (P</=0.0001 for both litters) and PCBs/metabolites (litter one: P=0.05; litter two: P</=0.0001) in the suckling neonate's stomach contents in both generations, there was no evidence of any differences between the two litters when each sampling date was assessed separately, except for the day 4-HCB results when the litter one pups had more HCB in their stomachs (P=0.018). For the PCBs, the F344 neonates were found to have more PCBs in their stomachs (litter one P=0.0015; litter two P=0.002) than the Sprague-Dawley neonates. In addition, the amount of HCB, PCBs and fat in the neonates' stomachs decreased during lactation, as the pups age increased (P</=0.035). These preliminary results suggest that analogous amounts of HCB and PCBs given via diet or gavage may not result in similar lactational exposure by the suckling neonate.
Arnold
D L
DL
Toxicology Research Division, Canada. doug_arnold@hc-sc.gc.ca
Bryce
F R
FR
Clegg
D J
DJ
Cherry
W
W
Tanner
J R
JR
Hayward
S
S
D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism; D020111:Chlorodiphenyl (54% Chlorine) / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics / Q000633:toxicity; D004032:Diet; D004333:Drug Administration Routes; D005223:Fats; D005260:Female; D005766:Gastrointestinal Contents / Q000737:chemistry; D006581:Hexachlorobenzene / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics / Q000633:toxicity; D007441:Intubation, Gastrointestinal / Q000379:methods*; D007774:Lactation / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008892:Milk / Q000737:chemistry; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects; D012995:Solubility; D018675:Toxicity Tests / Q000379:methods*
D005223:Fats; D020111:Chlorodiphenyl (54% Chlorine); D006581:Hexachlorobenzene