Embryo-fetal lethality

Monooctyltin/ dioctyltin (contd) Rat DOT stabilizer mix (DOT(IOMA) MOT(IOMA) 80 20) Gestation days 6-15 at 0, 1,5, and 25 mg/kg body weight Marginal maternal toxicity marginal but significant embryo-fetal lethal effect LOAEL = 25 NOAEL = 5 Sobering AG (1991)... 

A case in point would be a study in which the doses were such that an increase in minor anomalies or skeletal variants was found at the lower doses and a high incidence of in utero death at the top dose (Doses A, B, and C in Fig. 1). It is possible that there are malformations occurring at a dose intermediate between those with anomalies and that resulting in embryo-fetal lethality (B and C). This is another instance where additional work should be done to ascertain whether this is indeed the case. In the author s experience, this pattern of findings can occur with various teratogens, particularly cardiovascular teratogens, and cardiovascular malformations should be suspected if they have not been found at the initial examination. 

Maternal toxicity effects description Fetal effect observed malformations and other effects Fetal effects description Number of malformed or affected fetuses Percentage malformed or affected fetuses Qualitative results - teratogenicity Qualitative results - embryo-fetal lethality Qualitative results - growth retardation Qualitative results - maternal toxicity Qualitative results - embryo-fetal toxicity Peer review evaluation of results -teratogeni ci ty... 

Peer review evaluation of results -embryo-fetal lethality Peer review evaluation of results -growth retardation Peer review evaluation of results -maternal toxicity... 

Data from a study that includes a littering phase can be used to assist in the interpretation of data from embryo-fetal developmental toxicity (EFD) studies reduced viability in a littering study can provide supporting evidence of the occurrence of lethal malformations in an EFD study. Another possibility if an effect on viability has been found is that a lethal metabolic condition has ensued. 

Embryo-fetal toxicity is determined from the number of dead fetuses and resorption sites relative to the number of implantation sites. In addition to the possibility of lethal malformations, such toxicity can be due to maternal toxicity, stress, or direct toxicity... 

It is known that more fetal wastage than generally believed and many spontaneous abortions arise as a result of the presence of dominant lethal mutations in the developing embryo, many of which appear to be due to major chromosomal damage. In addition, impairment of male fertility may also be a consequence of exposure to mutagens. 

Intra-amniotic administration of acrolein in rats induced a significant number of fetal malformations, whereas intravenous administration was embryo lethal. Pregnant rabbits given 4.0 and 6.0mg/kg/day on days 7 through 19 of gestation had high incidences of mater-... 

The results led Upshall to conclude that CS is neither teratogenic nor lethal to embryos. No significant increases in numbers of abnormal fetuses or in resorptions were noted. No dose-related effects were observed, except in one experiment in which rats had marginally lower fetal weights. A high incidence of abnormalities occurred in two control groups of rats. 

Several studies have also demonstrated that sulfur mustard causes dominant lethal mutations. Rozmiarek et al. (1973) reported a dominant lethal mutation rate of 9.4% ( 1.9%) in rats after adult males had been exposed to 0.1 mg HD/m for 12 weeks. Sasser et al. (1990) reported that a dominant lethal effect occurred after male Sprague-Dawley rats were dosed orally with 0.5 mg HD/kg/day 5 days/week for 10 weeks. The observed effects included increases in early fetal absorptions, preimplantation losses, and decreases in total live embryo implants. A significant increase in the percentage of abnormal sperm was also reported. Dominant lethal mutations, as well as chromosome rearrangements, have also been observed in Drosophila melanogaster exposed to sulfur mustard (Auerbach and Robson, 1946). 

Whole-rat embryo culture Fetal development/malformations/lethality Hazard identification of embryotoxicants... 

In pregnant rats orally administered annatto (28% bixin) on days 6 to 15 of pregnancy at doses of 0 to 500 mg/kg, no increase in embryo lethality and no reduction of fetal body weight were observed among annatto-exposed rats, and annatto did not induce any increase in the incidence of externally visible, visceral, or skeletal anomalies in the exposed offspring. The maternal and fetal no-observed-adverse-effect level (NOAEL) for orally consumed annatto was over 500 mg/kg daily (Paumgartten et al. 2002). 

In a subsequent study, oral doses of synephrine of up to 100 mg/kg body weight (at least 20 times the normal equivalent human dose) given to pregnant rats for 20 days did not produce developmental toxicity. No adverse effects were observed with respect to fetal weight, embryo-lethality, or incidence of gross, visceral or skeletal abnormalities. In this study, administration was either as a natural constituent in a bitter orange extract standardized to 6% synephrine, or as relatively pure 90% synephrine extract (Hansen et al. 2011). 

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