Developmental Toxicity of Sarin in Rats and Rabbits

Abstract

Sarin (Agent GB, isopropyl methylphosphonofluoridate) is an organophosphate cholinesterase inhibitor. Sarin (Type I or Type II) was administered by gavage to CD rats on d 6-15 of gestation at dose levels of 0, 100, 240, or 380 micrograms/kg/d and to New Zealand White (NZW) rabbits on d 6-19 of gestation at dose levels of 0, 5, 10, or 15 micrograms/kg/d. Females were weighed on gestational days (GD) 0, 6-16 for rats and 6-20 for rabbits, and immediately prior to termination (GD 20 for rats and GD 29 for rabbits). All animals were monitored daily for clinical signs of toxicity throughout dosing and until sacrifice. At necropsy, gravid uteri were weighed and examined for the number and status of implants (live, resorbed, or dead). Individual fetal body weight, malformations, and variations (external, visceral, and skeletal) were recorded. Rat and rabbit dams in the high-dose groups exhibited significant signs of maternal toxicity and increased maternal mortality. Examination of gravid uteri revealed no statistical differences among treatment groups in the incidence of resorptions or of dead or malformed fetuses, or in average body weight of live fetuses per litter. These results show no evidence or developmental toxicity in the CD rat or NZW rabbit following exposure to either Type I or Type II sarin during embryonic differentiation and major organogenesis, even at a dose that produced maternal toxicity.

Transplacental Disposition and Teratogenic Effects of Chlorpyrifos in Rats

“…15 mg/kg/d. The study supports the finding of several authors (Lachner and Abdel-Rehman, 1984;Clemens et al, 1990;Leborde et al, 1996 andFarag et al, 2000). These studies suggest that doses which are not maternally toxic (symptoms appeared but no death occurred) were unable to produce fetotoxicity or teratogenicity.…”

Sarin (GB, O-isopropyl methylphosphonofluoridate) neurotoxicity: critical review

“…LaBorde et al (1996) found no evidence of developmental toxicity in the fetuses of pregnant rats treated on days 6–15 of gestation and pregnant rabbits treated on days 6–18 or exposed orally to both Type I and Type II sarin (Type I and II differ based on the stabilizer included [tributylamine and diisopropylcarbodiimide, respectively]) at various doses after gestation day 6 during “the period of important embryonic differentiation and major organogenesis.” In fact, no significant alterations in normal fetal development, such as structural malformations or changes in fetal weight, were observed despite the observable maternal toxicity. Similarly, studies testing exposure to sarin vapor at various doses and for various durations in SD rats did not produce either developmental or reproductive toxicity (Denk 1975; Opresko et al 2001).…”

“…A recent study found no evidence of developmental toxicity in the CD rat or NZW rabbit following exposure to either Type I or Type II sarin during embryonic differentiation and major organogenesis, even at doses that produced maternal toxicity (LaBorde et al 1996). …”

“…In 1982, the Surgeon General of the U.S. Army issued a warning against the possible teratogenic effects of sarin after the teratogenicity of another OP compound structurally similar to sarin was confirmed (LaBorde et al 1996). LaBorde et al (1996) found no evidence of developmental toxicity in the fetuses of pregnant rats treated on days 6–15 of gestation and pregnant rabbits treated on days 6–18 or exposed orally to both Type I and Type II sarin (Type I and II differ based on the stabilizer included [tributylamine and diisopropylcarbodiimide, respectively]) at various doses after gestation day 6 during “the period of important embryonic differentiation and major organogenesis.” In fact, no significant alterations in normal fetal development, such as structural malformations or changes in fetal weight, were observed despite the observable maternal toxicity.…”

Acute Effects of Organophosphorous Compounds on the Ovine Fetus

“…However, there is minimal information, and considerable controversy, regarding the acute, sub-acute and chronic effects of organophosphorous anticholinesterases on the fetus. Studies in rats and rabbits found no evidence of fetal toxicity with either soman or sarin at doses that produced significant toxicity to the mother (Bates et al, 1990;LaBorde et al, 1996).…”