Adverse health effects of bisphenol A: Chahoud's response. (Correspondence).

Heinze stated in his letter that according to two long-term studies, bisphenol A (BPA) does not induce any effect on reproduction in offspring at the low dose level. Several other studies have reported adverse effects of BPA; I briefly discuss two examples below.

Markey et al. (2001) investigated the effect of fetal exposure to BPA [25 and 250 [micro]g/kg body weight (bw)] on the development of the mammary gland in CD-1 mice.

   They concluded their results as follows:
   The altered relationship in DNA synthesis
   between the epithelium and stroma and the
   increase in terminal ducts and terminal end buds
   are striking, because these changes are associated
   with carcinogenesis in both rodents and humans.

Kawai et al. (2003) carried out a study to evaluate the effect of fetal exposure to BPA (2 and 20 ng/kg bw) on male offspring. They observed that in utero exposure at these dose levels resulted in significantly reduced relative testis weight and concluded that low doses of BPA interfered with the normal development of reproductive organs.

I would like to take the opportunity to discuss the problem of the interpretation of so-called negative studies.

Ashby et al. (1999) aimed to disprove studies published by vom Saal and colleagues (Nagel et al. 1997; vom Saal et al. 1997, 1998). Ashby et al. were not able to confirm the results described by vom Saal and colleagues; however, their study (2 and 20 [micro]g BPMkg bw) shows significantly elevated testis and epididymal weights, even after adjustment for body weight. Ashby et al. considered this clear effect "an equivocal finding."

Tyl et al. (2002) conducted a three-generation reproductive toxicity study on dietary BPA in CD Sprague-Dawley rats. The [F.sub.2] generation showed no statistically significant difference in body weight compared to the control. However, at doses of 1 [micro]g, 300 [micro]g, and 5,000 [micro]g BPA/kg bw, the absolute and relative paired ovary weights exhibited a significant decrease in the [F.sub.2] generation compared to control. Tyl et al. considered these effects not biologically significant.

Investigators are in the position to interpret the adversity of their own data, and readers also have the freedom to build their own opinion regarding the adversity of the effects. In conclusion, I would like to emphasize the need for mechanistic experimental studies as well as follow-up studies in humans regarding low-dose effects.

The author declares he has no conflict of interest.

REFERENCES

Ashby J, Tinwell H, Hasemann J. 1999. Lack of effects for low dose levels of bisphenol A and diethylstilbestrol on the prostate gland of CF-1 mice exposed in utero. Regul Toxicol Pharmacol 30:156-166.

Kawai K, Nozaki T, Nishikata H, Aou S, Takii M, Kubo C. 2003. Aggressive behavior and serum testosterone concentration during the maturation process of male mice: the effects of fetal exposure to bisphenol A. Environ Health Perspect 111:175-178.

Markey CM, Luque EH, Munoz de Toro M, Sonnenschein C, Soto AM. 2001. In utero exposure to bisphenol A alters the development and tissue organization of the mouse mammary gland. Biol Reprod 65:1215-1223.

Nagel SC, vom Saal FS, Thayer KA, Dhar MG, Boechler M, Welshons WV. 1997. Relative binding affinity-serum modified access (RBA-SMA) assay predicts the relative in vivo bioactivity of the xenoestrogens bisphenol A and octylphenol. Environ Health Perspect 105:70-76.

Tyl RW, Myers CB, Marr MC, Thomas BF, Keimowitz AR, Brine DR, et al. 2002. Three-generation reproductive toxicity study of dietary bisphenol A in CD Sprague-Dawley rats. Toxicol Sci 68:121-146.

vom Saal FS, Cooke PS, Buchanan DL, Palanza P, Thayer KA, Nagel SC, et al. 1997. A physiologically based approach to the study of bisphenol A and other estrogenic chemicals on the size of reproductive organs, daily sperm production, and behavior. Toxicol Ind Health 14(1-2):239-260.

vom Saal FS, Timms BG, Montano MM, Palanza P, Thayer KA, Nagel SC, et al. 1998. Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses. Proc Natl Acad Sci USA 94(5):2056-2061.

Ibrahim Chahoud

Institute of Clinical Pharmacology

and Toxicology

Free University Berlin

Berlin, Germany

E-mail: [e-mail]