Bisphenol A: A Scientific Evaluation

Michael A. Kamrin, PhD

Disclosures
In This Article

What Is the Toxicity of BPA?

To determine the toxicologic implications of the above exposure values, an assessment of the doses required to produce human toxicity is mandatory. The first step in this assessment is to examine how BPA is metabolized by humans as compared with animals, so that the human relevance of the results of toxicology tests in animals can be evaluated. A number of studies of the metabolism of BPA have been performed in rodents, mainly rats.[1,6] The results of these investigations show that BPA is rapidly absorbed from the gastrointestinal tract after ingestion and is then converted to a number of metabolites, mainly BPA glucuronide, in the liver. After 2-3 days, excretion of BPA and its metabolites, mainly in the feces, is mostly complete. A very small fraction, less than 1%, is retained in the tissues. BPA can be transferred to rodent offspring through the placenta and in maternal milk, but quantities found are only a very small fraction of the amount administered to the mother.[2] There is no evidence of accumulation of BPA in the fetus.

Until recently, the results from rat metabolism studies were assumed to be directly applicable to humans. However, a recent study performed by Völkel and coworkers[7] with human volunteers indicates that humans metabolize orally administered BPA much more completely and more rapidly than rats. The results showed that BPA glucuronide is very rapidly formed and excreted in urine, and that this process is essentially complete within 24 hours. Practically none of the BPA is retained in the bodies of humans. These differences in metabolism need to be considered when extrapolating the results of toxicology studies from rodents to humans. For example, the more rapid excretion in humans leaves less time for interactions of BPA and its metabolites with tissues. For another, the very complete conversion to the BPA glucuronide means that effects in rodents due to the parent compound (BPA) are unlikely to be found in humans. The significance of such differences is explored more fully subsequently.

BPA has been in use commercially for over 50 years, and workers producing this compound and its products (eg, epoxy resins) have been exposed to time-weighted average air levels to about 10 mg/m3 over decades. From this experience, it has been found that high exposures to BPA are irritating to the eye and respiratory tract, and may cause skin lesions and photosensitization of the skin. No studies reporting systemic effects were identified, and no epidemiologic studies of workers who have been exposed occupationally were found.

Thus, understanding of the toxic effects of BPA is based mainly on studies of rats and mice. Although there is general agreement about the ability of BPA to cause adverse effects in these animals when administered at high doses, its ability to cause effects at low doses has been a matter of contention.[8] This conflict has mainly centered on the possibility of adverse reproductive and developmental effects from low-dose BPA exposure, and has focused on whether or not BPA acts as a hormone disruptor or modulator at such doses.

However, before carefully examining the results of the low-dose research, it is useful to review what has been learned from the high-dose studies. In lifetime feeding studies on rats and mice conducted by the US National Toxicology Program (NTP),[9] the only sign of toxicity at high doses was reduced body weight, and this occurred only at doses greater than 50 mg/kg bw/day. Other research, including multigeneration feeding studies,[10,11] reinforce the conclusion that reduced body weight is essentially the only consistent and reproducible effect produced when high doses are administered. One study[12] showed that extremely high doses, 1250 mg/kg bw/day, led to fetal toxicity, but this finding is of limited relevance because the effects only occurred in association with significant toxicity in the mother. Even at such high doses, no fetal malformations were found.

As part of the NTP studies mentioned above,[9] a careful evaluation of possible carcinogenic effects of BPA was performed. The results indicate that BPA does not have carcinogenic potential even at very high doses. Supporting these findings are studies of the genotoxicity of BPA. Although there were some indications of genotoxicity at high doses in a limited number of studies, the weight of evidence from all of the standard assays indicates that BPA is not mutagenic. The combination of negative cancer bioassay results and negative mutagenicity assays strongly indicates that BPA is not carcinogenic in animals,[13] and provides no support for the hypothesis that this substance is carcinogenic in humans.

In recent years, however, attention has focused on the possibility that low, environmentally relevant doses of BPA can cause effects on human development and reproduction. This attention was based on general concerns about the endocrine effects of environmental contaminants and the experimental evidence that BPA binds to the estrogen receptor, although very weakly.[14] As a result, research on possible endocrine effects of BPA was initiated and resulted in reports that BPA causes (1) increases in weight and size of the prostate gland in male offspring of treated mice, (2) decreases in sperm efficiency in young mice, and (3) earlier puberty in female offspring of exposed mouse mothers.[8]

However, attempts to replicate these findings in other laboratories and as part of larger, more comprehensive investigations have been unsuccessful. No effects on prostate size or weight, on sperm quality, or on sexual development were seen in studies designed to replicate the experiments described previously.[8] In addition, no low-dose effects of any kind were found in a large-scale, 3-generation feeding study.[11] This is consistent with the lack of low-dose effects seen in another recent, large, 2-generation animal study.[10]

In light of the conflicting results, independent scientific panels have been convened to evaluate whether or not the weight of the evidence shows that BPA can cause effects on reproduction and development at low doses. One group, empanelled by the NTP in 2001, carefully examined each of the studies and came to the conclusion that "the Subpanel is not persuaded that a low dose effect of BPA has been conclusively established as a general or reproducible finding.[8]" The European Commission Scientific Committee on Toxicity, Ecotoxicity and the Environment (CSTEE) examined the same evidence and came to the conclusion that "a number of high quality studies on the reproductive and developmental effects of BPA are already available and do not support low dose effects.[15]"

Recent decisions by government agencies reinforce the conclusion that there is no consistent evidence supporting any low-dose effects. For example, the European Commission Scientific Committee on Food reached this conclusion with respect to its tolerable daily-intake value for BPA.[2]

An additional low-dose study was published recently after the evaluations described in the previous paragraphs had been completed, a study that has been heavily publicized. In this experiment conducted by Hunt and coworkers,[16] BPA was fed to female mice and the oocytes that they produced were examined. The results suggested that low doses of BPA caused abnormalities in these oocytes, which led to the hypothesis that BPA may cause effects on reproduction and development. Although attempts to replicate this particular study have not yet been reported, the lack of reproducibility of previous positive studies of BPA's reproductive and developmental toxicity potential greatly lessens the confidence that can be placed in the results of this one experiment. This confidence is further weakened by the lack of effect on reproduction and development seen in comprehensive, large-scale studies performed in recent years.[10,11] In sum, the weight of evidence as to the lack of low-dose effects expressed by a number of expert panels is unlikely to be changed by this one study.

It should also be noted that the panel reports described above did not incorporate the recent study cited earlier,[7] showing that the metabolism of BPA is much more rapid and complete in humans than in rodents. This evidence suggests that results of toxicologic studies on rodents are not directly applicable to humans because BPA and its metabolites spend less time in the bodies of humans as compared with rodents, and less of BPA and its metabolites remain in humans after exposure. Further, studies, such as those by Matthews and coworkers,[17] have shown that the glucuronide metabolite, which is formed rapidly and almost exclusively in humans, does not bind to the estrogen receptor. This suggests that BPA is even less likely to be an endocrine modulator than was concluded on the basis of the results of the rodent-metabolism studies. In addition, as pointed out by the European Commission Scientific Committee on Food,[2] published data indicate that the pregnant mouse is extremely sensitive to estrogens, as compared with humans. Thus, the metabolic and physiologic differences between rodents and humans, coupled with the toxicologic differences between BPA and BPA glucuronide, indicate that endocrine effects in humans, if they occur, are likely to require much higher exposures than those required to cause comparable effects in rodents.

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