Sunday, December 3, 2017

Plasticized - Put Up or Shut Up: How Toxic is Our Daily Load of Bisphenol A and What are the Main Routes of Exposure?

"BPA free" labels may help to sell products. With more and more of the replacements being identified as just as, sometimes more hazardous than the original, they are, however, by no means as safe as the average consumer is made to believe by the industry.
I have been keepin' you up-to-date on the latest research on bisphenol A and often not less toxic alternatives in the Facebook news (if you didn't do that already, like facebook.com/SuppVersity to see them in your newsfeed). The publication of a new review by scientists from the West Pomeranian University of Technology in Szczecin in Poland reminded me that it may be worth addressing this ubiquitous hormonal disrupter in a detailed article again.

As Tomza-Marciniak et al. point out as early as in the first sentence of the abstract to their review (which had been published ahead of print in June and was now officially published in the Journal of Applied Toxicology), "bisphenol A (BPA) is characterized by a pronounced influence on human hormonal regulation" (Tomza-Marciniak 2017).
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The aim of the scientists' latest work "was to collect and summarize data on the influence of BPA exposure on reproductive health" (Tomza-Marciniak 2017). An undertaking that yielded quite disconcerting results, namely:
  • strong proof confirming that BPA is an ovarian, uterine and prostate toxicant at a level below the lowest observed adverse effect level (50 mg/kg body weight) as well as a level below the proposed safe level (4 μg kg−1 bodyweight);
  • reliable evidence in relation to the negative effect of BPA on sperm quality and motility;
  • limited evidence pertaining to the case of the potential of BPA to affect polycystic ovary syndrome occurrence
What makes this review particularly useful are the illustrations of the proven and suspected (side) effects on sex hormones, fertility, etc. - figures like Figure 1 and Figure 2.
Figure 1: Effect of BPA on female reproductive processes. BPA, bisphenol A (Tomza-Marciniak 2017).
Figures that leave little doubt that fish and frogs which live in "plastic intoxicated" environments are by no means the only victims of environmental BPA exposure.
Figure 2: Effect of BPA on male reproductive processes. BPA, bisphenol A (Tomza-Marciniak 2017).
In fact, convincing evidence exists that BPA could be one of the factors that are promoting the increase in the number of couples who are willing, but unable to conceive. Epidemiological studies, for example, found statistically highly significant correlations between sexual function and the concentration of BPA in almost 500 male subjects. More specifically, Li et al. observed significant (P < 0.001) decreases of libido, erection problems and a lower ejaculation intensity with increased levels of urinary BPA in 2010 and a 3.4-fold increased risk of having a critically low sperm count, a 3.3-fold increase of low sperm vitality, a 4.1-fold increased risk of low sperm counts and a 2.3-fold increased risk of low sperm motility. Moreover, the Polish scientists report that...
"[n]egative effects of BPA on the reproductive abilities of men were obtained in a cross-sectional study by Liu et al. (2015) on 592 men from China stated that a high exposure to BPA is related to a significantly increased concentration of prolactin (P < 0.001) and sex steroid binding globulin (P < 0.001) and to a reduced androstenedione level (P < 0.001) in blood and free androgen index (P = 0.021) and in this way may contribute to male infertility" (Tomza-Marciniak 2017). 
Next to a potential direct toxic effect on the testes and/or sperm, its ill effects on hormonal health are thus probably the cornerstone of BPAs anti-fertility + anti-virility effects - with corresponding side effects having been observed in females.
Migration levels of bisphenol A from 12 polycarbonate baby bottles according to the days of use (Brede 2003).
How to limit your BPA exposure: As previously highlighted, our exposure to BPA starts at the very moment we're conceived and thus significantly before we're born (Ikezuki 2002). It is thus of particular importance for mothers-to-be to avoid all of the sources of BPA - sources which include foods from cans with epoxy resin linings, drinking water, air and even dust.

Ever since the 1990s, we've known that BPA leaches from plastic bottles - including, baby bottles. In that, the leaching has been found to be present even in brand new bottles (Vandenberg 2007).

As Brede et al. (2003) found out the leaching of BPA into whatever you store in these plastic containers will significantly increase whence they've been in a dishwashing machine, in/exposed to boiling water or brushed to scrub them clean. Using plastic containers to heat food (in the microwave or elsewhere) should be a no-go, the use of PVC stretch films to wrap foods has been associated with food contaminations ranging from 43 to 483 mg/kg - with fatty products, like olive oil, being even more susceptible to the effect than acidic ones.

And the former are only the most obvious routes of exposure. Sign. amounts of BPA have also been found in various other consumer goods from paper towels made from recycled paper (0.55-24.1 mg/kg), food containers made from both recycled paper (0.19-26 mg/kg | lower levels in virgin paper). Then, there's the better-known exposure from metallic food cans which are protected from rusting and corrosion by the application of epoxy resins as inner coatings that is quantified at 4-23 microgram of BPA per can and 1.7-fold to 55.4-fold increases of the original concentration of BPA when the cans were heated (100°C).

Few of us will be aware, though, that we don't even have to eat something to be exposed to the hazardous plastics. As Tomza-Marciniak et al. point out "[s]
everal resin-based monomers are used in dentistry as preventative sealants, adhesives, and restorative materials" - for example, since the 1960’s, BPA diglycidyl methacrylate has been used as a component of many dental restorative materials. And while 60-80% of these monomers are typically polymerized in situ small quantities of unreacted monomers have been shown to leach from polymerized dental materials.

What's even more alarming, though, is that German studies indicate that our drinking water is increasingly polluted with BPA. With twenty percent of the samples, Kuch & Ballschmiter collected in 2001 containing detectable levels of BPA (LOD: 11 ng/L) and nine locations presenting with levels over 100 ng/L, that alone wouldn't be a problem. The observation does, however, add to the evidence of the ubiquitousness of BPA in our environment. In fact, significantly higher concentrations have been found in the waters of 30 US rivers that have been tested for their BPA content and showed levels ranging from 0.14 micrograms per liter to a maximum measure of 12 micrograms per liter. Even breathing can be a problem today: In a survey of 120 homes for the presence of endocrine disrupting chemicals, Rudel et al. found BPA present in 86% of house dust samples at concentrations ranging from 0.2-17.6 micrograms/gram of dust. So what? Stop breathing? The problem is that you may still absorb BPA from the various cosmetics that are either packaged in BPA-containing bottles or contain it as a stabilizer and/or antioxidant (Demierre 2012).

To avoid BPA exposure altogether does thus seem impossible, what is possible, however, is to not use re-usable plastic containers or throw-away plastic films - specifically not for heating or storing fatty or acidic foods; as well as to be skeptical about the alleged superiority of "BPA-free" products that may not contain BPA but alternatives like BPS of which we already know that they are at least as problematic as the original (Hill 2017).
Interestingly enough, other studies, like Goldstone et al. (2015) "did not show any evidence that BPA decreased semen quality" in men. With Mendiola et al. (2010) reporting no significant associations between any of the semen parameters and urinary BPA concentration, in a cross-sectional study, examining a group of 375 men confirming the fertility-related observations of Goldstone et al. but highlighting that there is a ...
"significant inverse association between urinary BPA concentration and free androgen index (β = −0.01, 95% CI: –0.09, −0.004) and the free androgen index/luteinizing hormone ratio (β = −0.11, 95% CI: 0.18, −0.03) as well as a significant positive association between BPA and sex hormone-binding globulin (β = 0.07, 95% CI: 0.007, 0.13)" (Tomza-Marciniak 2017)
Moreover, it seems that evaluations of BPA exposure using urine or blood should also consider using semen. It appears that although the content of different xenobiotics including BPA in semen can reflect the content in blood, the results of statistical analyses are not always similar.
Figure 3: Hyperprolactinemia (=elevated levels of prolactin) are only the most significant hormonal side effect of BPA exposure in men Liu et al. observed in their 2015 paper in Environmental Toxicology and Pharmacology.
For instance, Vitku et al. (2016) have found that BPA levels in blood plasma were positively correlated (P < 0.001) with BPA levels in semen, yet only seminal BPA, not plasma BPA, was negatively associated with different parameters of semen, such as sperm concentration (r = −0.198; P = 0.009), sperm count (r = −0.178; P = 0.018) and morphology (r = −0.160; P = 0.044).

We know very little about the real-world effects of BPA on women

In the understandable absence of obviously unethical controlled long-term studies on women (including pregnant women), we will once again have to focus on epidemiological data, here. Said studies have shown quite consistently that ...
  • BPA disturbs hormonal regulation and contributes to infertility in women - with infertile women being reported to have 2x higher BPA levels than fertile controls 
  • there is a significant association between BPA levels in the blood and the risk of infertility (+730%! La Rocca 2014) in otherwise healthy women - especially in metropolitan areas
  • elevated BPA levels are associated with endometriosis (although not in all studies) and polycystic ovary syndrome aka PCOS (in almost all studies).
I guess you will now think: "Well, all that is not news!" - and in fact, you're right. What is "news" or at least worth revisiting is the increasingly convincing evidence that ...

...the officially proposed safe level (4 μg/kg bodyweight | EFSA 2015) of exposure may enough to trigger hormonal and non-hormonal side effects!

What's making things worse is that BPA, which will directly bind to human estrogen and androgen receptors is by far not the only hormonal disruptor we are exposed to on a daily basis (Wetherill,  2007; Viñas 2012). Against that background, it is only a semi-relevant argument that ...
"a large number of experimental studies are performed at high doses, levels not occurring in daily life, or are carried in in vitro conditions, causing a possible inadequacy to a real risk of human BPA exposure" (Tomza-Marciniak 2017).

In fact, both men and women are subjected (practically from the moment of conception) to “cocktail” of compounds, such as BPA, which have a relatively high toxicity threshold only when assessed in isolation, but unknown and difficult to quantify effects on reproductive health when they are administered together. It is thus, as Tomza-Marciniak et al. point out imperative that future studies assess the "effects of a combined activity of a few toxicants that chronically act on humans" (Tomza-Marciniak 2017). As of now, all we have are a bunch of animal studies using combinations such as additive (negative) health effects of nonylphenol and bisphenol A in swordfish (Kwak 2001), or cell line studies that show how BPA and titanium-dioxide, commonly found in food and cosmetics exert synergistic effects (Zheng 2012), too. If you want to learn more about this issue in general, you may want to read the review by Carpenter et al. (2003 | free FT).
In view of the fact that the said allegedly "safe level of BPA" is probably everything but safe (esp. w/ the co-exposure to other xenoestrogenic plasticizers), I suspect that the website of the Polycarbonate/BPA Global Group which represents the leading global manufacturers of bisphenol A (BPA) and polycarbonate plastic is not going to soothe you.
What's the verdict, then? Even though there's an (urgent) need for studies investigating the joint effect of exposure to multiple toxicants, there's "strong evidence that BPA is a toxicant (ovarian, uterine and prostate) at a level below the lowest observed adverse effect level (50 mg/kg bw) as well as a level below the proposed safe level (4 μg/kg bw)" (Tomza-Marciniak 2017).

The answer to the question of whether we achieve these concentrations, or not, depends on whom you're asking. While the European Union claims that the BPA exposure of its average citizen ranges from 0.48 ot 1.6 µg/kg body weight/day, New Zealanders are supposedly exposed to much higher doses of 4.8 µg/kg body weight/day - an amount that is slightly above the "proposed safe level", of which you've already heard that many scientists believe that it is not safe, anyways; and beyond good and evil for babies, for whom scientists estimate the exposure per kg body weight at whopping 24.14 µg/kg body weight/day for new-borns and 15 µg/kg for three months olds!

Speaking of safety. Little doubt exists about the experimentally and epidemiological confirmed toxic effects on the prostate gland, sperm (quality and motility) and fertility. However, "[l]imited evidence" is available of the ability of BPA to cause PCOS, while "no clear consistent results" from either epidemiological or animal model studies exist with respect to: (1) the evaluation of associations between BPA and implantation failure in women; (2) evaluation of associations between BPA and sexual dysfunction in men; and (3) impact of BPA on birth rate, birth weight and length of gestation in human beings | Comment on Facebook!
References:
  • Brede, C., et al. "Increased migration levels of bisphenol A from polycarbonate baby bottles after dishwashing, boiling and brushing." Food Additives & Contaminants 20.7 (2003): 684-689.
  • Carpenter, David O., Kathleen Arcaro, and David C. Spink. "Understanding the human health effects of chemical mixtures." Environmental Health Perspectives 110.Suppl 1 (2002): 25.
  • Demierre, Anne-Laure, et al. "Dermal penetration of bisphenol A in human skin contributes marginally to total exposure." Toxicology letters 213.3 (2012): 305-308.
  • Ikezuki, Yumiko, et al. "Determination of bisphenol A concentrations in human biological fluids reveals significant early prenatal exposure." Human reproduction 17.11 (2002): 2839-2841.
  • Kuch, Holger M., and Karlheinz Ballschmiter. "Determination of endocrine-disrupting phenolic compounds and estrogens in surface and drinking water by HRGC−(NCI)− MS in the picogram per liter range." Environmental science & technology 35.15 (2001): 3201-3206.
  • La Rocca, Cinzia, et al. "Exposure to endocrine disrupters and nuclear receptor gene expression in infertile and fertile women from different Italian areas." International journal of environmental research and public health 11.10 (2014): 10146-10164.
  • Kwak, Hyeong‐Il, et al. "Effects of nonylphenol, bisphenol A, and their mixture on the viviparous swordtail fish (Xiphophorus helleri)." Environmental toxicology and chemistry 20.4 (2001): 787-795.
  • Li, De‐Kun, et al. "Relationship Between Urine Bisphenol‐A Level and Declining Male Sexual Function." Journal of andrology 31.5 (2010): 500-506.
  • Liu, Xiaoqin, et al. "Exposure to bisphenol-A and reproductive hormones among male adults." Environmental toxicology and pharmacology 39.2 (2015): 934-941.
  • Tomza‐Marciniak, Agnieszka, et al. "Effect of bisphenol A on reproductive processes: A review of in vitro, in vivo and epidemiological studies." Journal of Applied Toxicology (2017).
  • Vandenberg, Laura N., et al. "Human exposure to bisphenol A (BPA)." Reproductive toxicology 24.2 (2007): 139-177.
  • Viñas, René, Yow-Jiun Jeng, and Cheryl S. Watson. "Non-genomic effects of xenoestrogen mixtures." International journal of environmental research and public health 9.8 (2012): 2694-2714.
  • Wetherill, Yelena B., et al. "In vitro molecular mechanisms of bisphenol A action." Reproductive toxicology 24.2 (2007): 178-198.
  • Zheng, Dan, et al. "Effects of the interaction of TiO 2 nanoparticles with bisphenol A on their physicochemical properties and in vitro toxicity." Journal of hazardous materials 199 (2012): 426-432.