Research findings cast doubt on endocrine `cornerstone'

The debate on the effects of endocrine modulators has taken a new twist with the completion of a new study which casts doubt on some of the key assumptions behind the calls for further regulation of these chemicals. Researchers sponsored by chemicals producers in the US and Europe failed to replicate the results of experiments which suggested that a widely-used compound, bisphenol A (BPA), could have oestrogen-like effects at doses far below those generally accepted to cause adverse effects.

It's a fundamental tenet of toxicology that compounds are only harmful above a certain dose, known as the no observed adverse effect limit (NOAEL). Below another value, the no observed effect limit (NOEL), they have no effects at all. However, this assumption was challenged by Susan Nagel and Fred vom Saal of the University of Missouri in 1995, based on a series of tests they had performed on mice using BPA.

Although this compound - a raw material in the manufacture of polycarbonate and epoxy resins - has been known as a mild oestrogen mimic since the 1930s, the NOAEL and NOEL had been established at high levels. However, vom Saal and Nagel found that the male offspring of pregnant mice fed much smaller amounts of BPA suffered adverse effects - their reproductive organs were smaller than those from untreated mice, and their sperm counts were lower. Vom Saal theorised that there was an `inverted-U' relationship between the dose of BPA and the response - very small amounts could have disproportionate effects.

Epoxy resin and polycarbonate are both used in food packaging, and small amounts of BPA are known to migrate into food. These amounts were previously thought to be harmless, but vom Saal's research set alarm bells ringing - the dosages which he claimed caused adverse effects approached the amounts that humans might ingest. The results were seized upon by environmentalists and the food safety lobby as a major part of their argument against endocrine modulators.

This was where the current research came in. Sponsored by the BPA Groups of the European Chemical Industry Council, Cefic, and the US Society of Plastics Manufacturers, SPI, the research was carried out by a contract laboratory, MPI Research. The experiment was an attempt to replicate vom Saal's results with a larger number of animals and under more stringent conditions, and also to further investigate the `inverted U' effect by using a wider range of doses.

According to Jim Lamb, a member of the National Academy of Sciences' BPA panel, the MPI experiment was constructed to be as similar as possible to vom Saal work. MPI researchers were trained in vom Saal techniques for removing and handling tissues.

The MPI experiments used 28 mice per dose group where vom Saar had used seven; tested 548 male offspring compared with 25 in the previous work. Moreover, more tests were performed on the male offspring.

The MPI researchers could find no sign of any of the effects that vom Saal had reported. Compared with controls, there were no effects on the health of the pregnant mice; and no difference in the number or health of their offspring; in the male offspring's reproductive organs or sperm counts for any dosage of BPA. All the results were consistent with the previously established NOELs and NOAELs for these compounds.

`I would be inclined to view [the MPI experiment] as more powerful, sensitive and reliable than vom Saal's work,' commented Lamb. The MPI team used more animals, making the results more statistically significant, he noted.