Fetal effects

No fetal effects were noted in a dose range-finding developmental study in which pregnant Sprague-Dawley rats were exposed to 150 ppm hydrogen sulfide on gestation days 6-20, despite body weight loss in the dams (Saillenfait et al. 1989). 

No adverse maternal or fetal effects (Infurna et al. 1988) Increased salivation initial reduction in feed consumption (Infurna et al. 1988)... 

Intelligence quotient (IQ) loss effect on lifetime earnings Fetal effects from maternal exposure... 

Clark, R.L., Robertson, R.T., Minsker, D.H., Cohen, S.M., Tocco, D.J., Allen, H.L., James, M.L. and Bokelman, D.L. (1984). Association between adverse maternal and embryo-fetal effects in norfloxacin-treated and food-deprived rabbits. Fund. Appl. Toxicol. 7 272-286. 

Particularly alarming are fetal effects of alcohol and drugs on food-related odor responses in humans. Apart from the severe fetal alcohol syndrome, alcohol can affect the chemosensory behavior of a fetus. Alcohol administered to pregnant female rats impaired odor aversions and preferences in their offspring. A... 

Astroff AB and Young AD. The relationship between maternal and fetal effects following maternal organophosphate exposure during gestation in the rat. Toxicol Ind Health 14(6) 869-89, 1998... 

Administered by inhalation to pregnant rats on days 1-19 of gestation for 7 hours/day, 7000 ppm caused an increased incidence in resorptions, reduced fetal weights, significant maternal toxicity in the form of narcosis, reduced feed consumption, and reduced weight gain. At 3 500 ppm some maternal toxicity was observed, but there were no fetal effects. 

In rat developmental studies, fetal effects including delayed ossification and decreased locomotor activity occurred at doses that also caused maternal toxicity. Cadmium sulfate injected into the lingual vein of female hamsters on day 8 of pregnancy caused a high incidence of resorption and malformed offspring. Acute necrosis of rat testes followed large doses orally or parenterally, but testicular effects have not been reported thus far in humans." ... 

Samimi BS, Harris SB, DePeyster A Fetal effects of inhalation exposure to cyclohexanone vapor in pregnant rats. Toxicol Ind Health 5 1035-1043, 1989... 

Diethyl phthalate administered in the diet to rats during major organogenesis increased the incidence of fetal lumbar ribs only at 3200mg/kg/day, a maternally toxic dose. In another report, there also was an increased incidence of supernumerary ribs, but no other embryo/fetal effects, in the offspring of rats fed 5% DEP on gestational days 6-15 maternal toxicity was evident as reduced body weight gain. ... 

No evidence of teratogenesis or adverse fetal effects was apparent in the offspring of rats exposed at concentrations of 40 ppm for 6 hours/day from day 6 to day 15 of pregnancy." In a two-generation reproduction study in rats, a decrease in the fertility index of the Fq and Fi generations occurred. 

When PNCB was administered to pregnant rabbits or rats, fetal effects were observed only at doses that produced severe maternal toxicity. A progressive decrease in fertility... 

Results from a number of animal studies indicate that exposure to levels of toluene that begin to produce maternal toxicity can cause fetal effects, including reduced fetal survival and retardation of growth and skeletal development toxicity. Rat studies also suggest that exposure in utero can impair behavioral development. Exposure to 2000 ppm 6 hours/day, for 80 days before mating and through lactation, produced no significant maternal toxicity but caused retardation of both fetal and postnatal development in rats. ... 

Skowronski et al. (1985) administered Alcide (a liquid sterilizer consisting of sodium chlorite and lactic acid that form chlorine dioxide) to mice and rats in gavage doses of 1 and 0.1 mL, respectively, on gestation days 6-15. No signs of maternal toxicity were observed, and there were no statistically significant adverse fetal effects. 

One way to circumvent such (unjustified) labeling is to try to prove a causal relationship between the maternal effects and those in offspring, thus trying to show that the latter ones are unspecific secondary consequences of the former ones. So for the sound interpretation of study results it is important to find a good balance between maternal and fetal effects. For example, if a 10% reduction in maternal net weight gain is accompanied by a comparable reduction in fetal weight, then this puts the fetal effects in the correct perspective and would not lead the experimenter to conclude that the compound is a (specific) developmental toxicant. On the other hand if in the same situation the number of fetal anomalies (in particular malformations) is increased, then this could most unlikely be explained as a consequence of maternal toxicity. 

Most descriptions of both maternal and fetal effects are based on group mean or incidence values. However, the effects on individual animals and their litters, and sometimes of individual fetuses... 

When maternal toxicity and developmental toxicity occur together in the same animals, it is ofren difficult to determine whether the observed fetal effects are secondary to maternal toxicity or due to selective developmental toxicity. The FDA Redbook states the following In situations where developmental effects are observed only at doses where there is a substantial amount of maternal toxicity, then the possible relationship between maternal toxicity and the developmental effects should be evaluated in order to make a proper assessment regarding the toxicity of a test substance. No guidance is given on how this should be done. A more useful consensus document on this subject has recently been published (9), which is discussed in detail in Chapter 24. 

As discussed by Hood and Miller (7), and in the lecture by Hood at the Maternal Toxicology Symposiums in 2009 (summarized in Beyer et al. (8)), it can be argued that it is Khera s interpretation, rather than the developmental toxicity study results themselves, that may be of concern. Khera s literature review indicated a possible association between maternal toxicity and embryo-fetal effects, but it did not establish a causal relationship between these two observations. Additional criticisms of Khera s hypothesis include the fact that his literature review was retrospective, there was a potential selection bias arising from the general tendency not to publish negative data, and the failure to adequately address maternal toxicity endpoints in the published literature of the time. In fact, Khera himself stated that in 40% of the studies he evaluated in support of his hypothesis the maternal toxicity data were insufficient or nonexistent (9). 

Developmental toxicity can be induced by different maternally mediated mechanisms, several examples relate to induction of disturbed embryonic oxygenation. However, such adverse fetal effects should be characterized as developmental toxicity even if it is mediated via maternal pharmacological mechanisms. The observed effects may, or may not, be relevant in the human exposure situation. If a company claims that the observed developmental toxicity is not relevant in the human, the regulatory authorities will expect the company to provide appropriate and convincing evidence to that effect (e.g., mechanistic studies together with kinetic data). 

Chahoud I, Ligensa A, Dietzel L et al (1999) Correlation between maternal toxicity and embryo/fetal effects. Reprod Toxicol 13 75-81... 

Clark RL, Robertson RT, Peter CP et al (1986) Association between adverse maternal and embryo-fetal effects in norfloxacin-treated and food-deprived rabbits. Fundam Appl Toxicol 7 272-286... 

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