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bisphenol a and reproductive health research
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Bisphenol A Reproductive and Devleopmental Toxicity Research

Bisphenol A has been extensively studied for reproductive and developmental toxicity in experimental animals and is not considered a reproductive or developmental toxin.

Toxic levels of BPA exposure result in weight loss in laboratory animals, with other effects related to the weight loss as a consequence. A study by Richard Morrissey and colleagues at the U.S. National Institute of Environmental Health Sciences looked for the effects on normal development of laboratory rats and mice exposed to BPA during pregnancy. The study concluded that even doses of BPA high enough to be toxic to the pregnant animals did not alter fetal development of the pups.

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In a study conducted by GE Plastics (Wazeter 1976, Table 1.), BPA was given to weanling rats in their diets at concentrations of 1000, 3000 or 9000 ppm for 17 weeks before mating. The offspring (F1) were then initiated on a 90-day feeding study with the same concentrations. Body weights were slightly decreased in F0 animals at the 3000 ppm dose and moderately decreased at the 9000 ppm dose. In the F1 generation, body weights were decreased for female rats at all doses and for males at 3000 and 9000 ppm. Food consumption was normal in the F0 animals, but decreased in the F1 females at all doses and in males at the 9000 ppm dose. No compound-related gross lesions or symptoms of exposure were reported in any group. No microscopic lesions that were treatment-related were reported in tissues from the 9000 ppm animals. No differences considered to be treatment-related were observed for any of the reproductive parameters measured.

In a follow-up study by GE Plastics of similar design with BPA in rats, no significant effects of exposure were observed (Goldenthal 1978, Table 2.). Slightly lowered male mean body weights at the 1000 ppm dose was the only effect reported. All other parameters measured were considered similar to the controls.

Hardin et al. (1981, Table 3.) Injected BPA intraperitoneally into pregnant rats on days 1-15 of gestation at a dose of 125 mg/kg/day. This dose produced a dramatically reduced pregnancy ratio (4/12), which caused the authors to add a lower dose of 85 mg/kg/day, but only with 4 animals in that group. Both doses had a significantly reduced number of live fetuses per litter and fetal toxicity was observed as significant dose-related reductions of fetal body weight and crown-rump length. Microscopic examination of maternal tissues showed histiocytosis in the 125 mg/kg/day group. The small numbers of animals and litters made the findings of this study questionable.

A series of studies for the NTP examined the teratogenic potential of BPA in rats and mice (Reel et al. 1984, Reel et al. 1987, George at al. 1985, George et al. 1985a, Morrissey et al. 1987, and Morrissey et al. 1989).

In the first study (Reel et al. 1984, Tables 4a and 4b), a continuous breeding design using implanted silastic tubing containing doses of 25, 50 or 100 mg of BPA was conducted in mice for 126 days. No effects of BPA were reported on fertility or reproduction in male or female CD-1 mice (NTP, 1984).

In a follow-up study, Reel et al. 1985 (Tables 5a-5d) used a similar design to expose male and female mice to 0.25, 0.50 or 1.0% BPA in daily diet for 126 days. Exposure of the F0 generation to 0.5 or 1.0% BPA produced a significant reduction in the number of litters per pair, live pups per litter, and live pup weight. In the 1.0% group, a significant decrease in the proportion of pups born alive also occurred. The toxicity reported could be due to maternal effects, since there was a significant body weight reduction in the 1.0% group (pups gained weight in a similar manner and rate as controls for the F1 offspring during the second exposure phase). Continuous exposure to the F1 mice produced death in 37.5% of the 1.0% dose, 13.9% of the 0.5% dose, 3.8% of the 0.25% dose and 6.3% of the controls. At necropsy, F0 and F1 male and female mice at 1.0% BPA had significantly increased liver and kidney weights and histopathological lesions in both tissues. Treated F0 and F1 males also had significantly reduced seminal vessel weights and reduced sperm motility. The authors concluded that BPA was a reproductive toxicant that caused a reduction in the number of live pups born in the F0 generation, reduced sperm motility and weight of some male reproductive organs in both the F0 and F1 generation, and reduced postnatal survival of the F1 generation (NTP, 1985). These effects were accompanied by significant hepatic and renal toxicity in the parental F0 and F1 animals. Some or all of the adverse reproductive effects may have been secondary to the parental toxicity of BPA.

In 1985, George et al. (Tables 6a and 6b;) reported that pregnant female rats given 160, 320 or 640 mg/kg/day of BPA during gestation days 6-15 had significantly reduced body weights and body weight gains during the study. BPA treatment during organogenesis produced fetal toxicity only at doses causing maternal toxicity and did not significantly alter fetal morphological development at any dose.

Similar findings were reported for mice given 500, 750, 1000 or 1250 mg/kg/day of BPA daily by gastric intubation during gestational days 6-15 (George et al. 1985a, Tables 7a and 7b). Mortality occurred at the highest dose (18% mortality), as did significant effects on the developing fetus (increased resorptions per litter, increased nonlive implants per litter, reduced average fetal body weight per litter). BPA did not affect any other reproductive parameter at the highest dose and did not significantly alter malformation incidences at any dose. Thus, BPA administration did not produce fetal abnormalities at any dose and produced fetal toxicity only at doses producing maternal toxicity. The results of these studies have also been summarized in publications by Morrissey et al. (1987, 1989).

In summary, BPA has been extensively studied for reproductive and developmental toxicity in experimental animals. In no study has BPA been shown to produce fetal morphological abnormalities. It has not been shown to produce maternal toxicity. Effects observed in the presence of maternal toxicity include fetal toxicity (decreases in fetal body weight, number of live pups per litter, percent of pups born alive and postpartum dam weights) and decreased sperm motility, and weight of testis, epididymis and seminal vesicles. Because all effects were seen in the presence of maternal toxicity, BPA should not be considered a selective reproductive or developmental toxicant.

For risk assessment purposes, the lowest no effect level (NOEL) when considering all studies for either maternal or fetal effects is 50 mg/kg/day (1000 ppm) (Wazeter, 1976 and Goldenthal, 1978).

In more recent years, extensive studies have been conducted to determine if
BPA could cause reproductive or developmental effects at very low-doses by
an endocrine mediated mechanism. Included in these studies is a
comprehensive three-generation reproductive toxicity study in rats, which
confirmed that BPA does not cause reproductive or developmental effects at
any realistic dose. For additional details on this study, please click here

For a broader discussion of BPA and low-dose endocrine effects research,
please click here
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Reproductive And
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