Postnatal day

An additional study reported age-dependent effects. Lakshmana and Raju (1994) found that oral treatment of rat pups with endosulfan from postnatal days 2-10 resulted in changes in the concentration of noradrenalin, dopamine, and serotonin in various brain areas that differed either in magnitude or direction from changes seen in pups treated from postnatal days 2-23. While the results from this study do not necessarily indicate that neonates are more sensitive to the toxic effects of endosulfan, they do show that the duration of exposure in neonates is an important parameter to consider. 

No effects on female fertility were noted in rats treated by gavage with trichloroethylene in com oil at 1,000 mg/kg/day for 2 weeks before mating through gestation and postnatal days 0-31 (Manson et al. 1984). Maternal body weight gain was about 9% lower than controls at 1,000 mg/kg/day. 

In Sprague-Dawley rat dams exposed to 20, 50, or 75 ppm of hydrogen sulfide for 7 hours/day from gestation day 1 through postnatal day 21, blood glucose levels were increased about 50% at all exposure concentrations (Hayden et al. 1990a). 

Imprinted genes are shown in bold pl5, postnatal day 15 p5, postnatal day 5. (Adapted from Efstratiadis 1998.)... 

Impairment has also been reported at low blood lead levels in other types of behavior/leaming studies in rats. In a test of spatial discrimination, rats were exposed to lead acetate at 745 mg lead/kg/day in the diet indirectly via administration to their dams through gestation and lactation and then directly until testing (at 100 and 200 days of age) (Winneke et al. 1977). The lead-exposed rats were slower to leam the discrimination than were controls. Their PbB levels at postnatal day 16 averaged 26.6 pg/dL and the levels at 190 days averaged 28.5 pg/dL. 

Decreased numbers of dendritic spines and malformed spines in brain parietal cortex were observed at postnatal day 30 in rat pups whose mothers were administered 256-480 mg lead/kg/day as lead acetate in drinking water during gestation and lactation (Murray et al. 1978). PbB levels were not reported. 

Strain genetically deficient in copper (Menkes disease) given subcutaneous injections of 50 pg copper chloride (CuCI2) on postnatal days 7 and 10. Before therapy, liver copper concentration was 3.1 mg/kg FW (vs. 30.1 mg/kg FW in normal mice)... 

Rat 2000 pg/kg in diet (as Pacific blue marlin) gestation through postnatal day 16 Adverse behavioral changes in offspring 6... 

Eriksson and co-workers have reported that neonatal exposure to low doses of the pyrethroids bioallethrin and deltamethrin by oral administration from postnatal days 10 to 16 induced an increase in muscarinic cholinergic receptor (MAChR) density in cerebral cortex at the age of 17 days. That resulted in a decrease in the cortical MAChR density, an increase in motor activity, and a lack of habituation at the adult age of 4 months in mice [48-50]. 

To confirm their results and check for methodological problems, some studies have been carried out. As there was a probability that hypothermic conditions during temporary removal from dam may have affected the results, Pauluhn and Schmuck administered S-bioallethrin and deltamethrin to neonatal mice from postnatal day 10 to 16 under a hypo-, normo-, or hyperthermic environment, and measured the MAChR density at the age of 17 days [51]. Increase in MAChR in Cortex at PND 17 in animals treated with S-bioallethrin was observed. Meanwhile, no changes were observed in animals treated with deltamethrin. In addition, an enormous influence of environmental temperature on the density of MAChR receptors in the crude synaptosomal fraction of the cerebral cortex was ascertained. Tsuji et al. exposed mouse dams with their litters to D-allethrin by inhalation for 6 h from postnatal day 10 to 16. The inhalation administration method is the most relevant route of exposure for humans, including babies and infants, after indoor use of D-allethrin. The neonatal exposure to D-allethrin by inhalation did not induce effects either on the brain MAChR density or motor activity at 17 days and 4 months of age, or on performance in the leaming/memory test at 11 months of age [52]. Other unpublished studies with D-allethrin, S -bioallethrin, or deltamethrin were examined to confirm the results of Eriksson et al. and showed inconsistent results [53]. The reasons for discrepancy among these findings are unknown. 

The effects of developmental exposure of pyrethroids on the dopaminergic system, which is considered to be related to behavior, were examined in several studies, but inconsistent results were obtained. Administration of deltamethrin between gestation day 6 and 15 induced increase of DOPAC (dopamine metabolite) levels in adult rats [54]. Exposure of fenvalerate on gestation day 18 and during postnatal days 2-5 produced no effect on monoamine levels on postnatal day 21 [55]. Gestational and lactational exposure to fenvalerate decreased and increased 3H-spiroperidol binding in striatum after development, respectively, whereas only lactational exposure of cypermethrin induced increase in 3H-spiroperidol binding [56]. 

If adult odor preferences are in fact influenced by early olfactory experience, then chemosensory processing must be functional early in rodent development. Indeed, the chemosensory systems develop very early in rodents (Alberts 1976 Astic and Saucier 1981), and chemosensory processing appears to be functional both prena-tally (Pedersen and Blass 1982 Stickrod, Kimble and Smotherman 1982) and peri-natally, as evidenced by behavioral responses to odors (Devor and Schneider 1974 Gregory and Bishop 1975 Leon and Moltz 1971 Porter and Etscorn 1974). For example, Syrian hamster pups display behavioral preferences for different types of artificial odorants as early as postnatal day 4 (Devor and Schneider 1974). These data suggest that young rodents are able to both process and respond to odors present in their early environment. 

These components would normally be evaluated in a rodent species (preferably rats) and, in addition, embryo-fetal development would be evaluated in a second species, typically the rabbit. The most probable option in the ICH guideline is the case where three rodent studies would be conducted that separately addressed each of the components listed above. These study designs are described below. The day of insemination or detection of evidence of mating is considered Day 0 of gestation and the day of birth is considered postpartum and postnatal Day 0. Figure 8.1 presents line charts for the ICH Stage-Study Designs. 

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