Bisphenol-A

G. Ballon, C. Doinguez, B. Sheth and J. Stahn

Introduction

• Bisphenol-A (BPA)• Bisphenol-a is a polycarbonate

compound with two phenol functional groups. It is majorly used in the production of plastic ware.

• Mimics the estrogen hormone by attaching to the estrogen receptor.

• BPA is exposed by leaching from plastic containers.

• Environmental concerns

• FDA Controversy

• Safety Precautions

Bisphenol-A molecule:

Estrogen Molecule:

Mechanisms and Implications of BPA toxicity in Humans

Bisphenol-A mimics the Estrogen Hormone Binds ER with moderate affinity Many downstream effects

1. Estrogen Receptor α (NR3A1) is activated by estrogen and analog (BPA) (Couse)

A. Nuclear Receptor located in cytosol

i. Activates transcription factor• Dimerization and nuclear localization• Binds DNA at Hormone Response Elements

ii. Inactivated by phosphorlation

B. Membrane associated receptor

i. Complexes with Tyrosine and G-coupled protien kinases• MAPK• GSK

…Mechanisms and Implications of BPA toxicity in Humans

2. Estrogen Receptor is highly concentrated in:i. Endometrialii. Breast cancer cellsiii. Hypothalamusiv. Ovarian stroma cellsv. Adipose tissue

3. Acute Hyperestrgenemiai. Increased risk of thrombosis from over-activation of endogenous

vasodilators (Couse)

4. Obesity Implicationsi. Increased estrogen receptor activityii. Increased receptors for fat deposition (Couse)

5. Psychosocial Behaviori. Disrupted estrogen-testosterone Balance (Wise)

….Mechanisms and Implications of BPA toxicity in Humans

6. Breast Cancer i. Can support estrogen-receptor (+) cancers (Santen)

ii. BPA affects chemotherapeutics for anti-estrogen (Santen,Toolson)

• Can affects Tamoxifen dosage regimine

What is theAppropriate dose?

BPA is an agonist

Exposure Rate/Routes

Leaches into food and liquids from containers. Rate of leaching increases with

increasing temperature Rate of leaching increases if

liquids are acidic or erosive cleaner is used.

Leaches into waterways Leaves behind EDC’s (Endocrine

Disrupting Chemicals)

Source: Baby bottles Lining of canned food Dental sealants Plastic laboratory equipment PVC pipes (water pipes) Refrigerator shelves And various household items

Environmental concerns

Waterways BPA is entering waterways such

as streams, lakes across the world By being carried through

sewage into rivers. Recycled waste water often

becomes drinking water. GOT BPA?

Study: Pharmaceutical sales are on the rise

and so are EDC’s (Endocrine Disrupting Chemicals) in the environment and water. (Khetan)

Figure: Fate of pharmaceuticals in the environment.

FDA ControversyBPA approved by the FDA

FDA supports that BPA has an impact on humans when administered over the “safe” dose, while the EFSA panel supports that it does not cause an impact on humans.

Levels of BPA are considered safe when the amount a person is exposed to does not harm him/her.

Studies have shown that low doses of BPA throughout their lifespan have an impact on their health.

Low doses of BPA are enough to cause effects In efforts to disprove the FDA and the

“safe“ dose of BPA a study conducted by Fredrick S. vom Saala and others proved that low doses of BPA have profound effects on humans.

Studies have been funded by the government in efforts to find a safe intake of BPA.

There is still controversy between those that say it does not have an effect in humans because we have a faster way of eliminating the toxin compared to rodents.

Long term effects of BPA exposure

In rodents it has shown to induce oxidative stress.

In rodents BPA has shown to have an effect on the brain and their behaviors.

In women, BPA blood levels have shown a relationship with ovarian disease and recurrent miscarriages.

BPA has shown to block the beneficial effects of estradiol on neuronal synapse formation.

Long term effects of BPA exposure

However, chemistry industries who have conducted studies have found in 100% of their cases that BPA leaves the body rapidly. But because we are exposed to it daily it is common.

There are currently studies being done with women, to prove that there are long term effects for constant low amounts of BPA.

Removal of Bisphenol-A

BPA is considered an EDC (Endocrine disrupting chemical) in water reclamation.

To remove Bisphenol-A a couple of ideas have been proposed: Removal by a membrane

bioreactor Removal by a micro alga

BPA is hydrophobic and will associate with organic material. Accumulation of these and other estrogenic compounds could lead to long term toxicological effects. (Robinson)

Studies: Membrane Bioreactor (Chen)

A membrane bioreactor (MBR) and conventional activated sludge reactor (CASR) were used to absorb BPA. Initially BPA was removed but decreased over time suggesting that a microorganism was needed.

Micro alga Stephanodiscus hantzschii (Li)

A diatom that showed to accumulate and biodegrade BPA in low concentrations. At higher concentrations of BPA Stephandosicus hantzschii growth and ability to biodegrade was inhibited.

Other Studies

960 men and women’s urine levels were measured for several different environmental chemicals and their effect on oxidative stress by the use of biomarkers. (Hong) The study went a step further to

associate the measured levels of BPA and it’s affect on the increased sensitivity of insulin. Insulin resistance increases the

chance of developing Type II diabetes.

Results showed that BPA was related to increased blood sugar levels.

Neonatal mice were injected with levels of Bisphenol-A for 5 consecutive days with doses of 10, 100 and 1000 (mg/kg/day). Control mice received corn oil. (Newbold) Uterine Leimyomas were more

common in BPA treated mice and none were found in control.

This study suggested that exposure to BPA at critical periods of development can result in adverse effects of growth.

The two lower doses are projected to be what we are exposed to.

Conclusion

From researching the effects of BPA’s toxicity in animals and human we assume that there is negative consequences. Although, some research tries to imply that there is no direct correlation with pathologies and BPA contamination, there is over-whelming evidence that it causes the disruption of dynamic processes, most notably, endocrine disruption (Saala).

FDA is full of it!

Removal of Bisphenol-A should be researched more to provide clean water, food and environment.

Focus on removal of BPA by microorganisms.

In the meantime use precaution with use of BPA products.

Safety Measures

Has been banned in Canada Baby bottles have banned the

ingredient Bisphenol-A

Use glass bottles Do not heat in microwave Do not use erosive cleaners Do not reuse water bottles RECYCLE!!

References Ahmada Firoz, Ansari A. Rizwan, Bhatiab Kanchan, Islam Fakhrul, Kaur Manpreet,

Rahman Shakilur, Raisuddin Sheikh, 2008. Iron deficiency augments bisphenol A-induced oxidative stress in rats. Toxicology 256: 7-12.

Couse JF, Lindzey J, Grandien K, Gustafsson JA, Karach KS. Tissue distrubution and quantitative analysis of estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta) messenger ribonucleic acid in the wild-type and ERalpha-knockout mouse. Endocrinology 138; 4613-4621, 1997.

Dana D. Wise, Angela Felker and Stephen M. Stahl. Tailoring treatment of depression for women acreoss the reproductie lifecycle: the importance of pregnancy, vasomotor symptoms, and other estrogen-related events in psychompharmacology. Psychopharmacology Education Updates (PsychEdUp) 5.1 (Jan 2009)

Gioiosa Laura,Palanza Paola, Frederick S. vom Saal Frederick S. vom , Parmigiani Stefano, 2008. Effects of developmental exposure to bisphenol A on brain and behavior in mice. Environmental Research 180: 150-157.

Hong, Yun-Chul. 2009. Community Level Exposure to Chemicals and Oxidative Stress in Adult Population. Toxicology Letters. Vol 158, Issue 2, pp:139-144.

References Saala vom S. Frederick, Welshons V. Wade, 2004. Large effects from small

exposures. The importance of positive controls in low-dose research on bisphenol A. Environmental Research 100: 50-76.

Khetan, Sushil K., Collins and Terrance J. Human Pharmaceuticals in the Aquatic Environment: A Challenge to Green Chemistry. Chemistry Reviews. 2007. Vol 107, Issue 6, pp: 2319-2364. DOI: 10.1021/cr020441w

Li, Rui., Chen, Gui-Zhu., Fung Yee Tam, Nora., Luan, Tian-Gang., Paul, K.S., Cheung, S.G. and Lui, Yu. 2009. Toxicity of Bisphenol-A and its bioaccumilation and removal by a marine micro alga Stephanodiscus hantzschii. Ecotoxicology and Envirnomental Safety. Vol 72, Issue 2, pp:321-328.

Newbold, RR., Jefferson, W.R., Banks, E.P. 2007. Longterm adverse effects on Neonatel Exposure to Bisphenol-A on Murine Female Reproductive Tract. Reproductive Toxicology. Vol 24, pp:253-258.

McDonald, R.G., Hudson, A.L., Dunn, S.M., You, H., Baker, G.B., Whittal, R.M., Martin, J.W., Jha, A., Edmondson, D.E. and Holt, A. 2008. Bioactive Contaminants Leach from Disposable Laboratory Plasticware. Science. Vol 7, p:917.

References Santen, Richard J.; Fan, Ping; Zhang, Zhenguo; Bao, Yongde; Song, Robert X.-D.;

Yue, Wei. Estrogen signals via an extra-nuclear pathway involving IGF-1R and EGFR in tamoxifen-sensitive and -resistant breast cancer cells. Steroids, Jul2009, Vol. 74 Issue 7, p586-594, 9p; DOI: 10.1016/j.steroids.2008.11.020

Robinson, Brian J., Hui, Joseph H.I., Soo, Evelynn, C. and Hellou, Jocelyne. Estorgenic Compounds In Seawater And Sediment From Halifax Harbour, Nova Scotia, Canda. 2009. Environmental Toxicology and Chemistry. Vol 28, No.1,p18-25.

Snyder, R. W., Maness, S. C., Gaido, K. W., Welsch, F., Sumner, S. C., and Fennell, T. R. (2000) Metabolism and disposition of bisphenol A in female rats. Toxicol. Appl. Pharmacol. 168, 225−234.

http://www.sriconsulting.com/CEH/Public/Reports/619.5000/ http://www.environmentalhealthnews.org/newscience/2007/2007-

0802newboldetal.html http://www.thefatherlife.com http://www.steadyhealth.com/articles/

FDA_Urged_to_Ban_BPA_Found_In_Plastics_Due_to_Its_Links_To_Heart__Diabetes_and_Liver_Problems_a748.html

http://www.indoorquality.org/pollutants/bisphenolA.cfm