Postnatal toxicity

Reproduction studies (fertility and general reproductive performance, embryo-toxicity and peri/postnatal toxicity) ... 

The US-EPA has concluded that in many cases, concerns regarding pre- and postnatal toxicity can be addressed by calculating an RfD by using pre- or postnatal developmental endpoints and applying the UFs (interspecies (Section 5.3), intraspecies (Section 5.4), LOAEL-to-NOAEL (Section 5.7), subchronic-to-chronic (Section 5.6), and database-deficiency (Section 5.9)) to account for deficiencies in the toxicity data when there are gaps considered essential for setting a reference value, including lack of data on children (US-EPA 2002). 

The overlap of areas covered by the FQPA factor and those addressed by the traditional UFs was recognized, and it was concluded that the current UFs, if appropriately applied using the approaches recommended in the review (i.e., US-EPA 2002), will be adequate in most cases to cover concerns and uncertainties regarding the potential for pre- and postnatal toxicity and the completeness of the toxicology database. In other words, an additional UF is not needed in the RfC/RfD methodology because the currently available factors are considered sufficient to account for uncertainties in the database from which the reference values are derived (and it does not exclude the possibility that these UFs may be decreased or increased from the default value of 10). 

Hellwig J, Liberacki AB Evaluation of the pre-, peri-, and postnatal toxicity of mono-ethanolamine in rats following repeated oral administration during organogenesis. Fundam Appl Toxicol 40 158-162, 1997... 

Figure 21.4 Abbreviated protocol for a teratology test and for a perinatal/postnatal toxicity test in rats.

Nau H, Bass R, Neubert D. 1986. Transfer of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) via placenta and milk, and postnatal toxicity in the mouse. Arch Toxicol 59 36-40. 

As already described earlier, NHP also experience significant loss at term and shortly thereafter [45], Hence in a pre-/postnatal toxicity study overall reproductive failure (prenatal loss, stillbirth, neonatal and infant death) can amount to 40% or even 50% losses in single experimental groups. For developmental toxicity studies naive animals are frequently requested. Female animals with proven fertility and breeding experience might improve this... 

These study protocols combine the design of a fertility study and of a peri- and postnatal toxicity study. The study element of an embryo-fetal toxicity study can be included. In both cases, provided clearly negative results at sufficiently high doses or exposure are achieved, no further reproduction studies in rodents are required. Such a combination of all the study designs mentioned would provide all examinations required in a most probable option using considerably fewer animals. But an embryo-fetal toxicity study in a second species is expected. 

When behavior studies are conducted in the pups of a pre- and postnatal toxicity study, it has to be taken into consideration that the effects may be induced primarily by the intake of the drug via the mother s milk. Up to now, its significance as a toxic or reproductive developmental toxic effect is unclear. 

Peri- and postnatal toxicity studies commence before mating or in early pregnancy and observe the effects during pregnancy, at delivery and during the entire lactation period until weaning. 

In all reproduction toxicity studies at least three doses (minimally toxic, intermediate, non-toxic) should be given, preferrably by the proposed clinical route of application. Fertility and peri- and postnatal toxicity studies require tests in only one species (usually rats or mice), the teratology segment must be tested in two species (e.g. rodents and rabbits). Pharmacokinetic data and differences in the placentation may suggest other modes of application and/or other test species, e.g. primates. Of course the minimum animal numbers for the standard tests do not apply to studies in primates. 

Peri- and postnatal toxicity studies are recommended as a continuation of a part of the fertility or teratology studies, thus the treatment periods vary. At least 12 (-20) pregnant mice or rats per group are examined during pregnancy, delivery and during the lactation... 

No adverse effects were observed in offspring of mice fed a flavonoid mixture obtained from the leaf of hawthorn at a dose of 100 mg/kg daily for 1 month (Manolov and Daleva 1969). No teratogenic effects were observed in pregnant rats and rabbits orally administered 1.6 g/kg of a hydroethanolic extract of hawthorn leaf and flower. The same study showed no postnatal toxicity in rats or their offspring (ESCOP 2003). 

In summary, the aggregate data from animal studies demonstrate that developmental toxicity is a sensitive endpoint for all PFCs. Mice may be more sensitive to the adverse developmental effects than rats due to pharmacokinetic considerations, and brief in utero exposure alone is sufficient to induce postnatal toxicity into adulthood. Although additional data on the effects of FTOH in mice are needed, comparison of the postnatal effects of PFCAs versus FTOH in rats suggests that FTOH may be slightly less toxic than the PFCAs. However, the conflicting data from epidemiological studies and the results from PPAR-ot-KO smdies raise the issue of the applicability of the findings from rodent studies to humans. 

Developmental Toxicity—The occurrence of adverse effects on the developing organism that may result from exposure to a chemical prior to conception (either parent), during prenatal development, or postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point in the life span of the organism. 

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. 

Tetrachlorodibenzo-p-dioxin elicited no apparent prenatal or postnatal effects when doses of up to 800 /xg/kg/day were given orally for 10 days of gestation. Treatment with 250-2000 /xg/kg/day of 2,7-di-chlorodibenzo-p-dioxin (99% purity) had no significant effect on prenatal and postnatal measures of toxicity but caused a low incidence of cardiac lesions. 2,3-Dichlorodibenzo-p-dioxin and 2-chlorodibenzo-p-dioxin up to 2000 /xg/kg/day had no adverse effect on survival, average weight, and skeleton of term fetuses. 

In rodents, a greater proportion of nervous system development takes place postnatally than in humans. Accordingly, rodent studies of developmental neurobehavioral toxicity that extend exposure into the early postnatal period are probably more analogous to human prenatal exposure than are rodent studies that use only prenatal exposure. 

Grant LD, Kimmel CA, West GL, et al. 1980. Chronic low-level lead toxicity in the rat II. Effects on postnatal physical and behavioral development. Toxicol Appl Pharmacol 56 42-58. 

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