# A non-estrogenic alternative to Bisphenol A at last?

*Published:* 2017-01-23
*Author:* Sarah Vogel

*[Sarah Vogel, Ph.D.](https://www.edf.org/people/sarah-vogel),* is Vice-President for Health.

Last week a new study was published showing promising results for a non-estrogenic alternative to polymers based on bisphenol A (BPA) used to line the inside of food cans. The [paper,](http://pubs.acs.org/doi/abs/10.1021/acs.est.6b04704) in *Environmental Science & Technology (ES&T),* evaluated the estrogenicity of an alternative to BPA— tetramethyl bisphenol F (TMBPF) — and its final polymer product developed by [Valspar](http://www.valsparpackaging.com), a major paint and resin company. The authors found that, unlike BPA and some of its analogs that have been used as substitutes, TMBPF exhibited no signs of estrogenicity.

This was an unusual paper on a number of fronts—how the material was selected, how it was evaluated and by whom. In this post I’m going to explore who was involved, what testing was done and what this might mean for the BPA alternatives market.

But first a bit of context because you may be asking, aren’t there already non-BPA-based polymer alternatives for use in food cans? What about those cans that say “BPA-free”? The reality is that despite serious, decades-long concerns about the estrogenicity of BPA, the chemical continues to be widely used to make linings of food cans due to the considerable versatility of the material, which has made it challenging for alternatives to penetrate the market. There are a few alternatives available but none have offered a total replacement of BPA-based coatings used in nearly all food cans today.

The new research described in the *ES&T* paper was funded by Valspar, which immediately raises concerns about conflicts of interest, given the considerable financial stakes it has in finding an effective and safer replacement to BPA. But here is where it gets interesting in terms of who was involved in this project and how conflicts of interests were managed.

**Who did the research?**

To assess the estrogenicity of TMBPF, Valspar worked with leading researchers who have been publicly outspoken about the adverse health effects of BPA and other endocrine-disrupting chemicals. Dr. Ana Soto, the lead author, runs a laboratory at Tufts University which has been researching BPA and other endocrine-disrupting compounds for decades. And co-author Dr. Maricel Maffini, who also worked at Tufts in Dr. Soto’s lab, has an extensive publication record on the adverse effects of BPA. One could argue that they have an interest in finding a safer alternative to BPA-based resins.

What we know from the disclosure of competing financial interests included in the paper is that Valspar provided Dr. Soto’s laboratory with “unrestricted funds” to conduct tests of the estrogenicity of TMBPF and the final polymer. Valspar also contracted with Dr. Maffini to serve as technical consultant on the project. In addition, a Valspar employee and a former Valspar employee were also co-authors.

(For full disclosure on our part, Dr. Maffini is also a consultant with EDF. We would not financially benefit from the successful marketing of this material.)

**Why TMBPF?**

The selection of TMBPF for evaluation arose from a reframing of the design problem. Rather than searching for a novel or alternative polymer material, the problem was turned on its head: can the same polymer be used – but employ a safer bisphenol building block? More specifically, how could the highly effective 4,4’-Methylenediphenol polymer chain used in food can linings be made without using an estrogenic bisphenol, like BPA?

The authors note that they selected TMBPF because predictive modeling suggested it was unlikely to bind to the estrogen receptor. They also note that TMBPF was preferred because it could be employed in a two-step process that created an intermediate and hence avoided TMBPF being directly used in the final polymerization process; this would reduce the likelihood of unbounded monomer remaining in the final product—a problem with the BPA-based polymers.

**What testing did they do?**

The first step was to evaluate the migration of TMBPF from the polymer coating in order to assess the likelihood of exposure in food. No migration of TMBPF was detected above the level of detection of 0.2ppb well below [reported levels of BPA migrants from epoxy can linings](http://onlinelibrary.wiley.com/doi/10.2903/j.efsa.2015.3978/epdf).

The authors then selected a series of *in vitro* and *in vivo* tests that assessed TMBPF’s and the final polymer’s estrogenicity. The *in vitro* tests included the following:

- **E-SCREEN:** This uses a human breast cancer estrogen-sensitive cell line called MCF-7. Both TMBPF and migrants from the final polymer were evaluated, along with positive controls (BPA and estradiol) and negative controls. Neither TMBPF nor the migrated material resulted in an increase in proliferation of the cells—which would indicate estrogen receptor activation.
- **Real-time quantitative PCR:** This test evaluated gene expression of four genes known to be regulated by estrogen receptors. TMBPF was evaluated and compared with a positive control (estradiol) and negative control. TMBPF did not activate expression of any of the genes.

Moving up in biological complexity, the researchers conducted two *in vivo* whole-animal studies:

- **Uterotrophic assay:** This test, which followed the Environmental Protection Agency’s (EPA) Endocrine Disruptor Screening Program (EDSP) protocol, evaluated the effect of TMBPF exposure on the development of the uterus in immature female rodents.
- **Pubertal assay:** This test also followed the EPA’s EDSP guidelines to assess development of puberty and thyroid effects. The researchers also evaluated effects on the development of the reproductive organs including the mammary gland.

The paper reports no significant effects of TMBPF on any of these endpoints. (The uterotrophic assay included a positive control while the pubertal assay did not.) Valspar also made reports of tests available [on-line](https://valspar.ent.box.com/s/olwkx8ahnu0a2dna1jvwvonbxih67lk8).

**What additional disclosures would be helpful?**

It would be useful to have a more complete description of the criteria used to select the different tests for estrogenicity and how these decisions were made and by whom. A discussion of the terms of the contract would make more transparent the level of independence given to the Tufts Laboratory. We strongly encourage additional disclosure of these details.

That said, the rigor of the assessment went well above anything required by current law. And that deserves praise. While the effectiveness of the final polymer derived from the use of TMBPF (i.e. shelf-life, performance, etc.) as well as additional safety assessments were beyond the scope of this paper, we are cautiously optimistic that Valspar has identified a non-estrogenic replacement for BPA-based polymers food cans.

That is encouraging news.