About Correlations: Alcohol and Diabetes/BPA and Endocrine Disruption

From a purely health-oriented perspective, alcohol is one of those things where a little seems to be good and more than a little puts you at risk for a bad health outcome. One of the positive things small regular intake can do for you is protect you from diabetes. There is good epidemiological evidence that this is the case. Light drinkers are less likely to develop diabetes than those who abstain.

Samples prepared for analysis. 

As most people know, just because two things occur together does not mean that one caused the other. Correlation and causality are two different things. It is important to keep this in mind when reading about human health studies in the news. Epidemiology is a wonderful tool however, and provides clues to problems that might have gone unnoticed. In addition to identifying potential problems correlational (and epidemiological) studies are important in evaluating how a problem identified in the lab may be harming people in the real world. Are light drinkers more likely to eat better, exercise better, be healthier than those who drink more alcohol or even none at all?

An important next step is figuring out why the correlation exists.  Here is a case where epidemiology observed something (low alcohol = less diabetes, high alcohol = more diabetes) and experimental study identified a physiological reason that explains those observations.    He et al. (2007) discovered that light alcohol intake activates a biochemical pathway that has a positive influence on removal of blood sugar from the blood stream. Higher alcohol intake disrupts glucose management by activating an additional protein that blocks the positive effects seen with light alcohol intake.  This discovery helps explain why you can see two different outcomes with alcohol.  At first light it may have seemed that scientific studies conflicted each other.  The appearance of contradiction may lead some people to throw up their hands and decide to disregard health news or science in general.

Sometimes we need to keep working at the puzzle.

There may be a similar issue with environmental contaminants.  Sometimes a relationship is observed and someone publishes on it, and there there are a flurry of other studies that confirm or don't confirm the relationship, expand it or limit it.  Identifying the mechanism and understanding how it works under varied circumstances becomes essential.  There are now many correlational studies that show that Bisphenol A (BPA) intake is associated with health problems.  There are also mechanistic studies that show how BPA interacts with estrogen receptors and causes things to go arwy.  One could stop here and take steps to remove BPA from use.  Environmentalists and children's health advocates could claim victory.  This might result in fewer birth defects, less obesity, less diabetes, fewer behavioral problems in children etc.  But it might not.

Plastics are more complex than they seem.  Even without BPA many of the chemicals that go into or are released from different plastics may be may activate estrogen receptors.  Would people be exposed to less estrogenic chemicals if BPA is banned?  We still don't know.  While many studies have used data on concentrations of BPA or BPA-metabolites, to the best of my knowledge no one has looked at total exposures to estrogenic chemicals originating from plastics.  (There are also estrogenic chemicals from sources other than plastics too).   Does removing BPA from a plastic actually make it less estrogenic?  Is BPA, rather than other chemicals coming off of plastics, the main source of dietary exposures to estrogenic compounds?

Plastics are amazing, really, and have made many positive and important contributions to our economy and quality of life.  For information on how plastics benefit the environment and contribute to quality of life take a look at this pdf from the British Plastics Federation.  Its taken tremendous effort and ingenuity to develop polymers.  We can figure out where they might cause problems in the environment or in human health by continuing polymer research and including within, cell and molecular studies.  We should not have to leave epidemiology to discover problems that could have been avoided after the fact. 

He L, Marecki JC, Serrero G, Simmen FA, Ronis MJ, & Badger TM (2007). Dose-dependent effects of alcohol on insulin signaling: partial explanation for biphasic alcohol impact on human health. Molecular endocrinology (Baltimore, Md.), 21 (10), 2541-50 PMID: 17622585

Nguyen KH, Lee JH, & Nyomba BL (2012). Ethanol causes endoplasmic reticulum stress and impairment of insulin secretion in pancreatic β-cells. Alcohol (Fayetteville, N.Y.), 46 (1), 89-99 PMID: 21840159

What are Endocrine Disruptors: an introduction.

The next several posts will be devoted to the subject of endocrine disruption with a focus on environmental chemicals that interfere with sex steroids, chiefly estrogens and androgens. Most people are probably familiar with estrogen and testosterone. These are steroids produced by the human body (and the bodies of other species) that play important roles in sexual development and reproduction. They also play many other related roles, influence growth and tissue maintenance, neurological function and behavior.

 An endocrine disruptor is a chemical agent that interferes with very complex, inter-regulating and intertwined endocrine systems. Interference with one steroid hormone can produce chain reactions that impact other hormones that, in turn, influence other systems and other hormones. For example, Bisphenol A, an estrogen mimic will change production of Prolactin (Steinmetz et al. 1997).

A young boy ponders something.

The effects of endocrine disruptors can be strongest during critical periods such as fetal development, infancy, adolescence, conception and pregnancy. These are times of important changes that will have long-term consequences for a child (fry, larvae, pup, chick etc.) and its future children. Thousands of chemicals have been found to be endocrine disruptors. Some of them are very resistant to degradation and remain in the environment and in people's bodies for decades or longer. Many of these are no longer in use even though with can still easily detect them. They were found to be a threat to health and were banned and/or replaced with something less dangerous. There are many other chemicals in use that have not been tested. There are others that are current foci of research and debate. These chemicals were not developed to cause harm to humans (at least not most of them), rather they were found to be harmful after they were already in use. An example that you may be aware of is the plastics additive Bisphenol A.

Bisphenol A is commonly called BPA. After years of debate and conflict among interested parties BPA has been banned from baby bottles in the US. Manufacturers are adapting and produced new products. Consumers can easily find BPA-Free materials and it seems likely that BPA will leave many markets.  While BPA may be in decline the issue of endocrine disruptors is far from resolved. The plastic products used to make some BPA-Free plastics also appear to be endocrine disruptors (Yang et al. 2011.) Some of them appear to be more disruptive than the BPA-laced plastics they are meant to replace.  It would be better to produce Endocrine-Disruptor-free products Instead of  BPA-Free products

It is very difficult to pull something out of the market once it is already there. People's livelihoods have become dependent on continuing use, reputations are at stake, there may be millions of dollars spent on legal fees,  on efforts to fund studies that would show that the product in question was harmless after all, and then more time and more money spent arguing why banning a product would be unfeasible and not worth the cost of replacing it, developing alternative technology, or cleaning up environmental messes. Banning chemicals after they become part of the economy is hugely wasteful, makes people on both sides of the playing field upset and erodes public confidence. We may discuss this in greater detail later, but for now, just be aware that the chemical problem of endocrine disruptors is also an economic and then a political problem as well. This should be resolved eventually, but until then, we may have a very interesting, and for some a painful, ride.

Steinmetz R, Brown NG, Allen DL, Bigsby RM, & Ben-Jonathan N (1997). The environmental estrogen bisphenol A stimulates prolactin release in vitro and in vivo. Endocrinology, 138 (5), 1780-6 PMID: 9112368  

Yang CZ, Yaniger SI, Jordan VC, Klein DJ, & Bittner GD (2011). Most plastic products release estrogenic chemicals: a potential health problem that can be solved. Environmental Health Perspectives, 119 (7), 989-96 PMID: 21367689

Crossfit and the Search for the Perfect Diet: Aboriginal Australians and the Swiss

Perusing Google News this morning I came across an article claiming that "Research Shows CrossFit Diet/Exercise Reduces Risk of Heart Disease".  I clicked on that one immediately because, to the best of my knowledge, no scientific research has been published on relationships between high intensity CrossFit-type training and cardiovascular disease. If one were to do a search today on Web of Knowledge using the search term "Crossfit" you would get a single hit:




















Jansen, J., van Dam, N., Hoefsloot, H., & Smilde, A. (2009). Crossfit analysis: a novel method to characterize the dynamics of induced plant responses BMC Bioinformatics, 10 (1) DOI: 10.1186/1471-2105-10-425

I'm sure the intentions of whoever wrote the press release were good . . . but . . . it is quite a stretch and I hope no one takes it seriously. Still, interesting that it made it into Google News. The research the author discusses has nothing to do with Crossfit. The press release does, however, attempt to associate a high-fat diet (promoted by some Crossfitters as healthy than other diets) with lower incidence of cardiovascular disease by comparing incidence of disease between residents of Switzerland and Australian aboriginals living in modern Australia. The claim was that a high-fat dining Swiss have less cardiovascular disease than the presumed low-fat dining Australian Aboriginals and that, therefore, high-fat diets are healthier than low-fat diets.


I have not looked up the statistics for the Swiss, but Australian Aboriginals have been suffering increasing rates of cardiovascular disease over at least the last 30 years.  Few modern Aboriginals are likely to be following a traditional Aboriginal diet. It is extremely unlikely that the increasing rate of heart disease observed in Australian Aboriginals has been caused by low intake of dietary fat. Aboriginals are suffering from increasing obesity and diabetes just like so much of the rest of the world. The high incidence of cardiovascular disease in Aboriginals may be due to genetic factors and a change to a Western-type diet but extremely unlikely to be caused by a low-fat diet (especially since they are not eating this way anymore anyway).  There are also obviously many other differences between the Swiss and the Aboriginals (differences in poverty levels, availability of lederhosen and differences in other possibly important variables like intake of strong coffee and chocolate).

This is all silly until one considers the disservice being done to readers who key into a health-related article's authoritative words (Research, World Health Organization, Medical, Clinical, Science) and believe the message makes sense.


 Rowley K, Walker KZ, Cohen J, Jenkins AJ, O'Neal D, Su Q, Best JD, & O'Dea K (2003). Inflammation and vascular endothelial activation in an Aboriginal population: relationships to coronary disease risk factors and nutritional markers. The Medical journal of Australia, 178 (10), 495-500 PMID: 12741936

 O'Dea K (1991). Westernisation, insulin resistance and diabetes in Australian aborigines. The Medical journal of Australia, 155 (4), 258-64 PMID: 1875844

Breastfed infants metabolize perchlorate?

This is a test post to check whether or not research blogging can pick it up. This (below) is actually a very interesting article. Shelor et al. 2012 report significant differences between perchlorate excretion in breast and formula-fed infants, and provide evidence that bifidobacteria, which are common in the digestive tracks of breast fed but not formula-fed infants, drives breakdown of perchlorate. This is important because breastfed infants are thought to be a group most vulnerable to the effects of perchlorate exposure. Perchlorate is an iodine-uptake inhibitor. Since iodine is needed for formation of thyroid hormones, and thyroid hormones are important in brain development any agent that limits the body's ability to take up perchlorate can cause neurological impairment. Shelor, C., Kirk, A., Dasgupta, P., Kroll, M., Campbell, C., & Choudhary, P. (2012). Breastfed Infants Metabolize Perchlorate Environmental Science & Technology, 46 (9), 5151-5159 DOI: 10.1021/es2042806

What are we fighting when we strive to "Just Do It?"

Cody Zamaripa: not really a Master, but he definitely pushed it. We are fighting a lot. There are times we may be fighting a bad attitude, discouragement, lack of confidence, drive or our own personalities, but we are, at times, also fighting a very complex regulatory system designed to protect us from severe self-induced damage. Fatigue can be defined as reaching a point where the body seeks to slow down or stop. Exhaustion is that point where a person (or animal) is unable to continue. The most important factor driving suppression of motor activity is believed to be brain temperature. In an untrained person, exhaustion may occur when core body temperature reaches 100o to 102oF(~38o to 39oC) while a highly trained person may not reach exhaustion until body temperature has reached 104oF (~40oC). Interestingly, it’s not only humans who are stopped at these temperatures. Internal temperatures of ~104 oF will stop other animals whether sprinters (Cheetahs) or the generally more placid and possibly endurance-oriented (Goats) (Taylor and Rowntree 1973). And yes, I’m sure you’re wondering: temperatures were measured rectally, and the animals ran on a treadmill while wearing masks so oxygen and carbon dioxide levels could be assessed. The research team also cranked the heat up. Cheetahs ran for shorter periods when the room was hot. The authors of this paper concluded that the duration of a Cheetah’s sprint is limited by core temperature, which is influenced by air temperature. Keep this in mind when you are working out in the summer with no air-conditioning. There are other factors that are also thought to play roles in regulation of intense physical output. Working muscles send feedback to the brain, and in most of us, they are not yelling “Go! Go! Go!” At first they are saying things like “we need more oxygen over here” and “pump the heart faster.” Unfortunately you maximum output can only go on for as long as you have the necessary materials to keep the system running. Your maximum obtainable heart rate will matter. That may be one you cannot make “just do it.” although you can improve your ability to pump blood with training. Blood concentrations of important factors or metabolites, and depletion of working materials, are also detected by the brain. Changes in concentrations and availability of neurotransmitters, endorphins, cytokines and a build-up of ammonia in the brain occur during continued intense exercise change. Cerebral energy use increases requiring more oxygen, while blood flow will decrease by about 20% due to constriction of brain arterioles. Low oxygen, loss of neurotransmitters, and accumulation of waste products can cause a problem that is truly “all in your head” but a real problem none the less. An increased need for oxygen and fuel in the brain may be part of what causes someone to want to slow down or stop. Increasing oxygen intake may improve performance not necessarily by providing muscles with additional oxygen, but in providing the brain with what it needs to keep the system running. Depletion of brain glycogen and excessive use of lactate as an alternative brain fuel may also signal fatigue. This may happen faster in untrained athletes. Physical training is, after all, about much more than simple strength and endurance. It includes getting all systems, including subtler aspects of physiology like the ability to dissipate heat, produce lactate, carry oxygen and oxygenate the brain, to work as efficiently as possible. We can reach our limits, but our brains rarely stupid enough to allow us to go beyond them and recklessly run our bodies off the edge of a cliff. The brain also likes to know what’s going on and practice (going through the motions) and rehearsal are important to performance. Rehearsing movements before a WOD may be as important as traditional warming up. It preps your system for what it is about to do and lets it know what is coming. Even imagining movements may help improve strength output and performance (Jeukendrup et al. 1996). We can improve performance intelligently rather than fight what we imagine to be a lack of mental toughness, or allow ourselves be discouraged. We can keep cool and well-hydrated. We can be patient enough to recognize that our physiological and biochemical systems are becoming more efficient as we train, even if our speed or strength has plateaued, and not give up on long-term goals. Finally, encouragement and cheers can help people achieve their maximal level of oxygen consumption (Nybo & Secher 2004) and maximum performance. This may be especially true if they are new to Crossfit and have type A personalities. New Crossfitters may be putting superhuman efforts into their workouts and should be congratulated and admired for these as much as our seasoned champions.

Taylor CR, & Rowntree VJ (1973). Temperature regulation and heat balance in running cheetahs: a strategy for sprinters? The American journal of physiology, 224 (4), 848-51 PMID: 4698801 JEUKENDRUP, A., SARIS, W., BROUNS, F., & KESTER, A. (1996). A new validated endurance performance test Medicine & Science in Sports & Exercise, 28 (2), 266-270 DOI: 10.1097/00005768-199602000-00017 Nybo, L., & Secher, N. (2004). Cerebral perturbations provoked by prolonged exercise Progress in Neurobiology, 72 (4), 223-261 DOI: 10.1016/j.pneurobio.2004.03.005

Estrogen and Progesterone in Waterways

In the last post, I was speculating about how estrogens from effluent might end up in way water ways and end up increasing the incidence of prostate cancer. I wondered if the problem (if it there is anything more than a chance association) might be progesterone from birth control pills rather than estrogen. Progesterone is markedly non-soluble in water so it seemed unlikely at first thought. Poking around a little, progesterone might end up in sewage effluent after all. The three studies below report on fecal and/or urinary progesterone, conjugated progesterone or "progesterone metabolites" in animals. So . . . maybe progesterone contamination of water might be relevant. And, not all sewage is filtered and treated. I recently watched someone emptying a truckload of portapotties into one of our local creeks. (Yes, I called the police, who told me it was not their problem.) Don't know if anyone has looked at this or not. If you know, please have at it in comments.

deCatanzaro D, Muir C, Beaton EA, & Jetha M (2004). Non-invasive repeated measurement of urinary progesterone, 17beta-estradiol, and testosterone in developing, cycling, pregnant, and postpartum female mice. Steroids, 69 (10), 687-96 PMID: 15465115 Kinoshita K, Inada S, Seki K, Sasaki A, Hama N, & Kusunoki H (2011). Long-term monitoring of fecal steroid hormones in female snow leopards (Panthera uncia) during pregnancy or pseudopregnancy. PloS one, 6 (5) PMID: 21559303 Brown JL, Wasser SK, Wildt DE, & Graham LH (1994). Comparative aspects of steroid hormone metabolism and ovarian activity in felids, measured noninvasively in feces. Biology of reproduction, 51 (4), 776-86 PMID: 7819459 google-site-verification: googleaa234ad89e44d776.html

Response to a friend on significance of Triclosan in drinking water

Sorry Friend. That was a poor response to your question about the significance of Triclosan following news of the chemical as an androgen blocker in water.

Triclosan is a thyroid disruptor and according to recent reports, an androgen blocker. As an anti-androgen, exposure could be important to male fetuses, since it could potentially interfere with development of the genito-urinary system, which could mean birth defects like hypospadias, small phallus, or non-obvious problems like changes in numbers and proportions of cells that would, later in life, produce sperm and testosterone. Thyoid inhibition has its own effects on development of the male reproductive system as well. So there might be some interesting interactive effects if both thyroid hormones and androgens are impacted. If that would occur you'd see reduced fertility. In an adult lowered testosterone would lead to other problems.

Blocking androgens, on the upside, might lead to less prostate cancer. It would be interesting to see if Dial Soap or other triclosan-containing products use this as a marketing point. "protects against body odor, gingivitis AND prostate cancer" Let's guess not.

Lastly, there was also an article out recently that associates rates of prostate cancer with presumed levels of estrogen (presumably from urine from women on birth control) in water supplies (Margel & Fleshner 2011). This was unexpected to me, until I thought about the pathway through which testosterone is produced. Testosterone can be synthesized from Progesterone, which is also present in birth control pills. So, it may be the progesterone, rather than estrogen, that is causing the problem. Progesterone is not water soluble, so its unlikely to be found in water systems unless conjugated to something else or incorporated in something else, so this is just speculation on my part.

Back to Triclosan. You can find some basic information on what kinds of products contain Triclosan at the Environmental Working Group Website. Its dated 2008, but the basic information may be useful.

For all of this, note that, for Triclosan, the picture is far from clear, as recent papers also report Triclosan enhancing androgenic activity in vitro (Christen et al. 2010) and as having estrogenic activity (Jung et al. 2011). Neither of those qualities is desirable in an environmental contaminant.
Best wishes,

Margel, D., & Fleshner, N. (2011). Oral contraceptive use is associated with prostate cancer: an ecological study BMJ Open, 1 (2) DOI: 10.1136/bmjopen-2011-000311

Christen V, Crettaz P, Oberli-Schrämmli A, & Fent K (2010). Some flame retardants and the antimicrobials triclosan and triclocarban enhance the androgenic activity in vitro. Chemosphere, 81 (10), 1245-52 PMID: 20943248

Jung EM, An BS, Choi KC, & Jeung EB (2011). Potential estrogenic activity of triclosan in the uterus of immature rats and rat pituitary GH3 cells. Toxicology letters PMID: 22062131

Rostkowski, P., Horwood, J., Shears, J., Lange, A., Oladapo, F., Besselink, H., Tyler, C., & Hill, E. (2011). Bioassay- directed identification of novel antiandrogenic compounds in bile of fish exposed to wastewater effluents. Environmental Science & Technology DOI: 10.1021/es202966c