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One Study Shows BPA Safety

Discussion in 'Research' started by joshualevy, Dec 2, 2013.

  1. joshualevy

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    Bisphenol A (BPA) is a chemical that is used to soften plastics. It has been used in many flexible plastics (such as water bottles, baby bottles, pacifiers, and the plastic inner liners on some food cans).

    Over the last few years, I've seen repeated questions about BPA triggering type-1 diabetes. These worries were not fueled by direct evidence, but rather by indirect evidence. Some researchers consider BPA to be an endocrine disruptor and since insulin is part of the endocrine system, it might be possible that BPA was triggering type-1, or making it more likely to be triggered.

    Also, until now, there were no intervention studies that looked specifically at BPA's effect on type-1 diabetes. There had been some general safety testing, but nothing specifically targeting type-1 diabetes.

    Recently, however Bodin and team reported on their intervention safety study. This one study found that BPA does not effect type-1 diabetes diagnosis in humans in the amounts that people are exposed to. Although, by itself, this is not proof of safety, it is very reassuring.

    The Study

    The basic format was this: NOD mice were divided into four groups of 20. One group got no BPA, another got the equivalent of 20 times the amount that humans consume (more on this later), the third group got 200 times, and the forth group got 2000 times as much as people do. Each group was studied both for overall type-1 diabetes rate and the timing of type-1 onset, and also for a variety of internal immune changes.

    Obviously, this was a mouse study, and mice are not people. However, when it comes to safety studies, they are the best we have. No one is going to test a chemical on people to see if it is safe. ("Parent, we'd like to give your children a chemical to see if it causes them to get type-1 diabetes, please sign here!") That's unethical. So we are stuck with animals; and NOD mice are the best animal model for type-1 diabetes that we have. [d1] Obviously, I pay little attention to cure results in animals, but for safety results, for intervention studies, there really is no choice.

    I discuss the dose levels more below, but for now, the important thing to remember is that the only two dose levels that matter in the real world, are the zero dose, and the 20x normal level. Obviously, if a chemical shows no bad effects, even when 20x the normal dose is consumed, then it's pretty safe.

    Results

    When measuring rates of type-1, the zero group, the 20x group and the 200x group all had the same overall levels of type-1 diabetes [d2]. The 2000x group was slightly higher.

    Also, in terms of when the NOD mice got type-1 diabetes, the zero, 20x, and 200x groups all were diagnosed at about the same time [d2], while the 2000x group was a little earlier.

    For the various immunological markers, the results were all over the place. Some markers showed a dose-response change, while other showed no change, and others had peaks in the middle of the dosing range. There might be some work here for immunologists, but I think a more likely results is going to be "if you take a massive overdose of BPA, strange things happen". The same is true of aspirin, salt, water, insulin, meat, water, indeed just about every substance there is. [d3]

    Discussion

    How much BPA are real people exposed to?
    When I described the tested doses, I described them in comparison to the normal human consumption. However, there is some controversy about exactly what is the normal human consumption. The European equivalent to the EPA has estimated this at 1.5 ug/kg, and that's the number I used. However, this is an estimated exposure, not a measured exposure, and not everyone agrees with it. Some researchers think this estimate is too low to explain the levels commonly seen in blood tests.

    So, the most important thing to remember is this: my opinion on this test is based on the European EPA's estimate of human exposure being accurate (or at least within 10x of the right number). If future research shows that the actual human exposure is wildly different, then this research will need to be reevaluated, based on the real dose. But in the meantime, this study shows safety even well above the currently estimated dose.

    Is More Research Warranted?
    I am fond of saying that one clinical trial never answers a question, because even if the results are very clear, it is still just one study, and more are needed to be truly persuasive. And I think that is true for this research. So in the perfect world, another group would do a similar study, and that second study would confirm these results, and that would be the end of it.

    But we live in a world with limited resources, and a huge number of artificial chemicals. So, if someone has money to study chemicals that might cause type-1 diabetes, should they say "well, these other guys suggest that BPA does not cause type-1 (at the exposures that people actually get) so I'll spend that money to do a confirmation study" [d4] Or should they say "With one study showing BPA safety, I'll investigate some other chemical".

    There is an "opportunity cost" here. There are 100s or 1000s or even 10000s of chemicals out there. We now have one animal study showing that this one does not affect type-1 diabetes in doses even 100s of times bigger than people actually get. If we get funding for another study, why not put it into a chemical that has zero animals studies done on it?

    For BPA specifically, there is an even more pressing question: how much BPA are real people exposed to? Maybe a better place to put funding is to determine the real human exposure level, rather than run another test on a dose which might be way off?

    What are the ethics of using mega-overdoses in safety testing?
    To give you some idea of the scale of this research, consider that a normal dose of aspirin is 1 pill. Now, if someone did a safety study and told you that aspirin was unsafe, because they had given the equivalent of 2000 pills to a mouse and the mouse had problems, your reaction might be to ask them why they gave the animal such a huge amount [d5]. You probably would not be worried about the safety of Aspirin, nor should you be, especially if they told you Aspirin was safe at 20 and even 200 pill doses. Yet, that is exactly what these researchers did, and many reporters are trumpeting the danger, based on the mega-overdose they gave.

    For me, a huge question in this research is, why did the researchers choose such a silly dosing level? I mean 20 times actual dose is high, but reasonable because it gives a big safety margin. But 200 times and especially 2000 times average exposure seem so high as to be a joke.

    What troubles me about this experiment's design is the following: Everyone (including researchers) should know that headline writers ignore dose levels. So a researcher can manipulate a headline writer (and often the reporter, as well), by including a dose level so high that something bad is bound to happen. Then the headlines will scream that there is a danger, even if the researcher knows the danger only exists with exposure levels so high they never happen.

    In future, does type-1 diabetes drop in countries that ban BPA?
    If using BPA increases the type-1 diabetes rate, then removing BPA would decrease the type-1 rate.

    Another type of research which might be interesting here, would be to see if type-1 diabetes cases start to drop, or the average age goes up, in countries were BPA has been banned. Data from those countries could be examined for 10 to 20 years after the ban. This type of study (a population-based study) is not as well controlled as an intervention-based study, but it is done in people, so (if type-1 numbers continued to go up or stayed the same), it would provide some support that BPA is not involved. Comparing different countries' consumption of BPA over different years might provided a range of interesting data. Conversely, if the numbers go down, that would suggest that maybe BPA was involved, especially if they went down the same number of years after BPA stopped being used in each country.

    Summary of BPA Safety

    The one intervention study we have, where BPA was directly tested in animals for type-1 diabetes, found no increase in type-1 diabetes, nor any earlier diagnosis of type-1 diabetes, even when given in doses hundreds of times higher than estimated human exposures. This was just one study, and there is some controversy about how much BPA people consume. Of course, it is always possible that BPA might be dangerous in other ways; this discussion is focused on type-1 diabetes.



    Wikipedia link: http://en.wikipedia.org/wiki/Bisphenol_A
    Huge summery of BPA research as of 2008: http://ntp.niehs.nih.gov/ntp/ohat/bisphenol/bisphenol.pdf
    Other US Information: http://www.niehs.nih.gov/health/topics/agents/sya-bpa/


    Extra Discussion

    [d1] This is a general problem with all safety research: we want to know safety in people, but are forced to test safety in animals.
    [d1b] The difference in outcome was not statistically significant, in both these cases. With only 20 NOD mice, the numbers were usually not exactly the same, nor would they be expected to be exactly the same. However, the differences were never statistically significant, which is what matters in these kinds of tests.


    [d1c] Even water would be toxic at 2000x a normal amount. If a normal amount of water is 1 gallon a day, then 2000 gallons a day could easily cause death.

    [d4] For safety testing in general, people who don't like the results, often want to rerun the test in a different animal. (No matter which side they are on.) But in this case, there are very few animals that get autoimmune-based diabetes (ie. a diabetes similar to human type-1), so there are not a lot of choices, and NOD mice are generally considered the closest.

    [d5] For another comparison, the FDA wants us to eat about 2 grams of salt per day. The actual average is 3 grams per day. Would you do safety studies based on 6 kilograms per day? Would that study have any connection to reality at all? 6 kilograms is over 13 pounds.


    Joshua Levy -- http://cureresearch4type1diabetes.blogspot.com
    publicjoshualevy at gmail dot com
    All the views expressed here are those of Joshua Levy, and nothing here is official JDRF, JDCA, or Tidepool news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.


     
  2. sgh

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    I find this study alarming, not reassuring

    I'm having trouble with the "multiquote" function so will do my best to address a few points here:

    BPA is an endocrine disruptor.

    This is not really what they found; they found that, "transmaternal BPA exposure, in utero and through lactation, accelerated the spontaneous diabetes development in NOD mice. This acceleration appeared to be related to early life modulatory effects on the immune system, resulting in adverse effects later in life." (http://www.ncbi.nlm.nih.gov/pubmed/24189131) I don't find that reassuring at all.

    Except that is essentially what we are doing when we use chemicals like BPA in products without testing them first-- we test them in the general population. And we don't get to sign any consent forms either. Fetuses are exposed to hundreds of untested chemicals in the womb, and we have no idea what the effects of these individually and in combination are in humans. We are all part of an unethical experiment. The FDA approves drugs before they are released in the market, but there is not a similar process for chemicals. Many are trade secrets and we don't even know what they are. I find that alarming.

    That is not a correct assumption and not how toxicology works. It is especially inaccurate with endocrine disruptors-- high dose effects do not necessarily predict low dose effects. For more on endocrine disruptors, see http://endocrinedisruption.org/.

    Most effects seen in this study showed a clear linear dose-response effect. Also, endocrine disruptors can show non-linear changes as well, so you may indeed have peaks in the middle of the dosing range.

    Yes, thank you for including this point. Human exposures are higher than implied in the rest of the summary here; the 20x and 2000x and so on are not really accurate assumptions of human exposure levels. Based on these exposure levels, we shouldn't see any BPA in human blood, and we do, so we are getting exposed more than we think.

    I don't think this shows "safety" of any kind; it shows clear changes, along with another study they did as well: http://www.ncbi.nlm.nih.gov/pubmed/23496298
    "long-term BPA exposure at a dose three times higher than the tolerable daily intake of 50 ?g/kg, appeared to accelerate spontaneous insulitis and diabetes development in NOD mice." Yes, it is at higher doses, but now we need to look at lower doses, and at human exposures. Both studies showed effects of BPA on NOD mice. We cannot assume that just because these effects were statistically significant only at the higher levels in mice that they would be absent at lower levels in humans.

    I'll ask them. They are probably using higher levels to make sure they get results so they can get published and then get grants to fund more research that will look into mechanisms, and lower doses, and humans, and so forth.

    As I see it, there are a lot of chemicals out there that now have been shown to have effects (at various doses and in various animals) that MIGHT be significant for type 1 diabetes development (including BPA). And yet essentially NONE of these chemicals have been measured in human studies of type 1 development. I've been urging the researchers to do that, but there are various roadblocks (like, storing the samples in plastic, which contaminates them), money, the lack of animal studies on this topic, lack of enough blood, etc etc etc. The NIEHS is working on this also. The more of this type of study, the more likely that researchers will measure for BPA and other chemicals in human studies of type 1. I don't think we will get a complete picture of how type 1 develops if we don't include measurements of chemicals. What if it is a combination of things, like different chemicals, at different exposure times, in different doses, or in conjunction with other factors like vitamin D deficiency or gut permeability? What if BPA plays a role in there somehow? We need to know that. Studies like this are a tiny first step, and more studies, with more chemicals, need to be done. I don't think this study shows that BPA is safe at all; it shows that there were effects, yes at high doses, but that is not a reason to conclude that BPA is safe at low doses. (In addition to the fact that BPA is linked to tens or hundreds of other diseases as well; it is not safe).

    I'm a little behind, but I've summarized a bunch of research on chemicals and diabetes here: www.diabetesandenvironment.org, if you are interested in what studies are out there. Almost all are on type 2, but I think many of them have implications for type 1 as well. If you ask me, a chemical that can mess with beta cells, or the immune system, or cause insulin resistance, (BPA can do all of these) has no place in our bodies, and should be a suspect in the effort to find out what is causing type 1 diabetes.

    Thanks

    Sarah Howard
     
  3. sgh

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    Response from the author

    Here's what the first author on the study responded, when I asked why they use high doses:

    "The reason for including such a high exposure dose is because of finding in the literature from other groups. As you mentioned we wanted to use a dose
    that we more or less knew from earlier studies could affect the immune system and then also use lower doses to see if they have negative/pathological effects.

    The high dose in our first study (long term exposure of BPA) gives an estrogen-effect and also affects the immune system, so it can not be
    classified as safe based on the fact that the mice do not show high blood glucose levels, when they in real life actually suffer from diabetes
    type 2 symptoms that are "hidden" in this mouse model.

    The transmaternal study starts with lower doses and the highest dose is 10 times lower that in the first study. The numbers seems higher due to the
    amount of water a pregnant mouse drinks (3-4 times more) compared to a non pregnant mouse in the first study. Here one should remember that in real
    life there is most likely a higher exposure to the newborn baby through newborn formula/baby food than through mothers consumption of food/canned food."

    Does that help?

    Also, with endocrine disrupting chemicals (EDCs), the timing may be more important than the dose. EDCs act like natural hormones, and those only have effects if there are receptors in the body. During development, the numbers of receptors change over time in different organs. A high dose of EDCs or natural hormones will have no effect if there are no receptors at that time of development. At another time, if there are a lot of receptors, there may be an effect from a low dose (and that effect may be permanent, and even appear until later in life). So in a study like this, which dosed the animals over a period of time, it may be that the effect would be seen with a lower dose at only one specific time of development, but we don't know that time yet. That would require more studies. A lot of research now is working to identify these "critical windows of susceptibility," that is, the time points during development when the dose would cause a change. For the immune system, it may be different than the pancreas, for example.

    Also, here are a number of other studies on BPA and diabetes/immune system. Most are type 2, but some may be relevant for type 1 as well (e.g., the ones showing effects on the beta cells). I'm leaving out all the studies on BPA and weight gain... there are lots more where these came from. Apologies if I've missed a few...

    2011. Does the plastic chemical bisphenol a contribute to type 2 diabetes? Ann.Intern.Med. 155(6):I36. http://www.ncbi.nlm.nih.gov/pubmed/21930838.

    Adachi T, Yasuda K, Mori C, Yoshinaga M, Aoki N, Tsujimoto G, Tsuda K. 2005. Promoting insulin secretion in pancreatic islets by means of bisphenol A and nonylphenol via intracellular estrogen receptors. Food Chem.Toxicol. 43(5):713-719. http://www.ncbi.nlm.nih.gov/pubmed/15778011.

    Alonso-Magdalena P, Laribi O, Ropero AB, Fuentes E, Ripoll C, Soria B, Nadal A. 2005. Low doses of bisphenol A and diethylstilbestrol impair Ca2+ signals in pancreatic alpha-cells through a nonclassical membrane estrogen receptor within intact islets of Langerhans. Environ.Health Perspect. 113(8):969-977. http://www.ncbi.nlm.nih.gov/pubmed/16079065.

    Alonso-Magdalena P, Morimoto S, Ripoll C, Fuentes E, Nadal A. 2006. The estrogenic effect of bisphenol A disrupts pancreatic beta-cell function in vivo and induces insulin resistance. Environ.Health Perspect. 114(1):106-112. http://www.ncbi.nlm.nih.gov/pubmed/16393666.

    Alonso-Magdalena P, Ropero AB, Soriano S, Quesada I, Nadal A. 2010. Bisphenol-A: a new diabetogenic factor? Hormones.(Athens.) 9(2):118-126. http://www.ncbi.nlm.nih.gov/pubmed/20687395.

    Alonso-Magdalena P, Vieira E, Soriano S, Menes L, Burks D, Quesada I, Nadal A. 2010. Bisphenol A exposure during pregnancy disrupts glucose homeostasis in mothers and adult male offspring. Environ.Health Perspect. 118(9):1243-1250. http://www.ncbi.nlm.nih.gov/pubmed/20488778.

    Batista TM, Alonso-Magdalena P, Vieira E, Amaral ME, Cederroth CR, Nef S, Quesada I, Carneiro EM, Nadal A. 2012. Short-term treatment with bisphenol-a leads to metabolic abnormalities in adult male mice. PLoS.One. 7(3):e33814. http://www.ncbi.nlm.nih.gov/pubmed/22470480.

    Cipelli R, Harries L, Yoshihara S, Okuda K, Melzer D, Galloway T. 2013. Bisphenol A modulates the expression of Estrogen-Related Receptor-alpha in T-Cells. Reproduction. http://www.ncbi.nlm.nih.gov/pubmed/24231368.

    Fenichel P, Chevalier N, Brucker-Davis F. 2013. Bisphenol A: An endocrine and metabolic disruptor. Ann.Endocrinol.(Paris) http://www.ncbi.nlm.nih.gov/pubmed/23796010.

    Gong H, Zhang X, Cheng B, Sun Y, Li C, Li T, Zheng L, Huang K. 2013. Bisphenol A accelerates toxic amyloid formation of human islet amyloid polypeptide: a possible link between bisphenol A exposure and type 2 diabetes. PLoS.One. 8(1):e54198. http://www.ncbi.nlm.nih.gov/pubmed/23372685.

    Hectors TL, Vanparys C, van der Ven K, Martens GA, Jorens PG, Van Gaal LF, Covaci A, De CW, Blust R. 2011. Environmental pollutants and type 2 diabetes: a review of mechanisms that can disrupt beta cell function. Diabetologia 54(6):1273-1290. http://www.ncbi.nlm.nih.gov/pubmed/21442161.

    Kim K, Park H. 2012. Association between urinary concentrations of bisphenol A and type 2 diabetes in Korean adults: A population-based cross-sectional study. Int.J.Hyg.Environ.Health http://www.ncbi.nlm.nih.gov/pubmed/22921714.

    Lang IA, Galloway TS, Scarlett A, Henley WE, Depledge M, Wallace RB, Melzer D. 2008. Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults. JAMA 300(11):1303-1310. http://www.ncbi.nlm.nih.gov/pubmed/18799442.

    Liu J, Yu P, Qian W, Li Y, Zhao J, Huan F, Wang J, Xiao H. 2013. Perinatal Bisphenol A Exposure and Adult Glucose Homeostasis: Identifying Critical Windows of Exposure. PLoS.One. 8(5):e64143. http://www.ncbi.nlm.nih.gov/pubmed/23675523.

    Ma Y, Xia W, Wang DQ, Wan YJ, Xu B, Chen X, Li YY, Xu SQ. 2013. Hepatic DNA methylation modifications in early development of rats resulting from perinatal BPA exposure contribute to insulin resistance in adulthood. Diabetologia http://www.ncbi.nlm.nih.gov/pubmed/23748860.

    Nadal A, Alonso-Magdalena P, Soriano S, Quesada I, Ropero AB. 2009. The pancreatic beta-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes. Mol.Cell Endocrinol. 304(1-2):63-68. http://www.ncbi.nlm.nih.gov/pubmed/19433249.

    Perreault L, McCurdy C, Kerege AA, Houck J, Faerch K, Bergman BC. 2013. Bisphenol A impairs hepatic glucose sensing in C57BL/6 male mice. PLoS.One. 8(7):e69991. http://www.ncbi.nlm.nih.gov/pubmed/23922885.

    Richter CA, Birnbaum LS, Farabollini F, Newbold RR, Rubin BS, Talsness CE, Vandenbergh JG, Walser-Kuntz DR, vom Saal FS. 2007. In vivo effects of bisphenol A in laboratory rodent studies. Reprod.Toxicol. 24(2):199-224. http://www.ncbi.nlm.nih.gov/pubmed/17683900.

    Robledo C, Peck JD, Stoner JA, Carabin H, Cowan L, Koch HM, Goodman JR. 2013. Is bisphenol-a exposure during pregnancy associated with blood glucose levels or diagnosis of gestational diabetes? J.Toxicol.Environ.Health A 76(14):865-873. http://www.ncbi.nlm.nih.gov/pubmed/24053363.

    Rogers JA, Metz L, Yong VW. 2013. Review: Endocrine disrupting chemicals and immune responses: a focus on bisphenol-A and its potential mechanisms. Mol.Immunol. 53(4):421-430. http://www.ncbi.nlm.nih.gov/pubmed/23123408.

    Ropero AB, Alonso-Magdalena P, Garcia-Garcia E, Ripoll C, Fuentes E, Nadal A. 2008. Bisphenol-A disruption of the endocrine pancreas and blood glucose homeostasis. Int.J.Androl 31(2):194-200. http://www.ncbi.nlm.nih.gov/pubmed/17971160.

    Ryan KK, Haller AM, Sorrell JE, Woods SC, Jandacek RJ, Seeley RJ. 2010. Perinatal exposure to bisphenol-a and the development of metabolic syndrome in CD-1 mice. Endocrinology 151(6):2603-2612. http://www.ncbi.nlm.nih.gov/pubmed/20351315.

    Sabanayagam C, Teppala S, Shankar A. 2013. Relationship between urinary bisphenol A levels and prediabetes among subjects free of diabetes. Acta Diabetol. http://www.ncbi.nlm.nih.gov/pubmed/23636267.

    Sakurai K, Kawazuma M, Adachi T, Harigaya T, Saito Y, Hashimoto N, Mori C. 2004. Bisphenol A affects glucose transport in mouse 3T3-F442A adipocytes. Br.J.Pharmacol. 141(2):209-214. http://www.ncbi.nlm.nih.gov/pubmed/14707028.

    Shankar A, Teppala S. 2011. Relationship between urinary bisphenol A levels and diabetes mellitus. J.Clin.Endocrinol.Metab 96(12):3822-3826. http://www.ncbi.nlm.nih.gov/pubmed/21956417.

    Silver MK, O'Neill MS, Sowers MR, Park SK. 2011. Urinary Bisphenol A and Type-2 Diabetes in U.S. Adults: Data from NHANES 2003-2008. PLoS.One. 6(10):e26868. http://www.ncbi.nlm.nih.gov/pubmed/22046388.

    Singh S, Li SS. 2012. Epigenetic effects of environmental chemicals bisphenol a and phthalates. Int.J.Mol.Sci. 13(8):10143-10153. http://www.ncbi.nlm.nih.gov/pubmed/22949852.

    Xu H, Yang M, Qiu W, Pan C, Wu M. 2013. The impact of endocrine-disrupting chemicals on oxidative stress and innate immune response in zebrafish embryos. Environ.Toxicol.Chem. 32(8):1793-1799. http://www.ncbi.nlm.nih.gov/pubmed/23606268.

    Yurino H, Ishikawa S, Sato T, Akadegawa K, Ito T, Ueha S, Inadera H, Matsushima K. 2004. Endocrine disruptors (environmental estrogens) enhance autoantibody production by B1 cells. Toxicol.Sci. 81(1):139-147. http://www.ncbi.nlm.nih.gov/pubmed/15166399.

    OK you get the idea... that's why I don't think BPA is "safe."

    Sarah
     
  4. joshualevy

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    Yes. I think it shows very clearly that these guys are not safety researchers, but rather fear mongers. If someone actually cares about the safety of a chemical, they will test it at the levels that people are actually exposed to it (and somewhat higher, as a safety margin). Someone who is selling fear just wants scary headlines, so they will target a dose that causes problems, even if they know that no one actually gets that dose!

    Their statement reinforces my summary that BPA does not cause type-1 diabetes at the doses that people actually get. In this case, they tested 20 times larger doses, and 200 times larger doses than people actually get, and both were still safe (in terms of not causing type-1 diabetes). The 2000 times normal dose was not based on what people actually get; it was just a manipulation to generate scary headlines.

    Joshua Levy
     
  5. sgh

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    sorry, disagree again

    They are toxicologists, not "fear mongers." This is what toxicologists do, they study the effects of toxic chemicals, at various doses, at various times, in various species or cells. They are not safety researchers, no, that is not what they do. That is what risk assessment is, to take the results of dozens of studies like this, determine human exposure levels, figure out hazard (hazard x exposure = risk). This study is not a risk assessment study. It is a first attempt to start to identify possible hazards relating to T1D. There is no way to make any conclusions about safety from this study.

    Sarah
     
  6. sgh

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    BPA expert says the dose is within possible human exposure

    I asked a scientist who studies BPA about the exposure issue in this paper. Here is the response:

    To get a sense of the dose they used, we have to convert the mouse mom exposure to human
    equivalent. Just dose of BPA per kilogram body weight. It's a standard way to think about doses.
    So, what’s the dose here?

    A) 10 milligrams BPA/Liter of drinking water — this dose showed the effect in this paper.

    Yes, but how much water does a mouse drink a day?

    According to some published info:

    B) In a day, about 10 ml water consumed/100 gram-mouse-weight …. and that equals 100 ml of water/kilogram body weight = 0.1L water/kg body weight.

    Now, the math:

    C) 10 milligrams BPA/L water X 0.1L water/kg body weight = 1 milligram BPA/kg body weight

    So that's the dose. 1 milligram BPA/kg body weight = 1000 micrograms BPA / kg body weight

    Now, the EPA “reference dose” is 50 micrograms BPA/kg/day, which is the believed “safe” daily
    oral dose in humans, for a lifetime.

    So the mouse mom dose that causes problems is 20x the reference dose. For risk assessment, the EPA, I believe, wants to keep ~ 100x dose cushion between mouse studies and human studies. That is, if you found bad effects in rodents at 1000 micrograms/kg, like in this study, you would want to keep humans from getting more than 10 micrograms/kg. EPA currently
    thinks 50 micrograms/kg is fine. So that's a problem.

    However -- urine levels of BPA suggest that people generally get much less exposure than the
    reference dose. So maybe it's fine?

    BUT, The Plot Thickens — There are sources of BPA which may not come in orally. “Orally” is a tricky word by the way. When the word ORAL is used, it almost always implies that the BPA comes in through the stomach/intestines — i.e., you swallowed it. Important because if so, it then
    goes right from the GI tract to the liver where the liver 99% inactivates it. (is 99% enough, by
    the way? -- maybe/probably).

    Anyway, a recent paper looked at sublingual dosing in dogs (sublingual = under the tongue) and it was equivalent to giving BPA intravenously, or at least pretty close. [yes, sublingual is oral, in a
    sense, but it’s not what people usually mean by ‘oral' exposure]. The reason is that a chemical
    that can get in sublingually goes straight into the blood circulation, like when heart patients
    put nitroglycerine under the tongue.

    And it’s also likely that thermal paper (like from receipts) is going to be important.

    Exposure via thermal paper could (maybe) result in:

    1) oral (e.g. absorbed by stomach/intestines - by contaminating your food) and/or
    2) sublingual (same) and/or
    3) transdermal (through the skin).

    The amount of each is unknown at this point. Neither sublingual nor transdermal is intercepted
    by the liver like the swallowed food/water is. The liver does (most) of the inactivating. It’s called
    the liver’s “first pass” metabolism, or “first pass effect”. [Search on those terms if you want
    to learn about it. Very important concept in drug development and toxicology both.]

    BPA that gets into the bloodstream through any route will eventually circulate through the liver,
    and so eventually it’s all gone. But BPA, if it comes in those other ways, like through the skin,
    gets a free shot at the bloodstream, and therefore, whatever target tissues the blood has
    contact with -- i.e., pretty much everything. At whatever dose made it through. So did enough get
    through? Always the question.

    But that’s how it might be possible for humans to end up with blood levels *of the active compound* (pre-liver breakdown) similar to rodents that *drink* a bigger dose. Of course, there could be some sublingual there as well, if mice are similar to us in that way.

    So — yes - it’s possible that humans could be exposed to the equivalent blood levels of BPA that
    the 10 milligrams/L group got in this experiment. The dose in the paper could turn out to be
    realistic.

    We can't say for sure yet. "Oral" BPA wouldn't do it at current population exposures. The BPA would need to come into us through skin or sublingually or otherwise bypassing the gut. We need to know what thermal paper and friends can do to blood levels. We’re working on it. Will know more soon.
     
    Last edited: Dec 12, 2013

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