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Endocrine disruptors—the one true cause?

A common theme in alternative medicine is the “One True Cause of All Disease”. Aside from the pitiable naivete, it’s implausible that “acidic diet”, liver flukes, colonic debris, the Lyme spirochete, or any other problem—real or imagined—can cause “all disease” (in addition to the fact that most of these ideas are intrinsically mutually exclusive).

One of the popular new ideas in this category is that of “endocrine disrupting chemicals” (EDCs). These are chemicals in the environment that physiologically or chemically mimic naturally occurring human hormones. That some environmental substances are chemically similar to human hormones is indisputable. That these substances can have a real physiologic effect in vitro seems to hold up. How much of an effect these chemicals may have in real human populations is an open question.

And unlike many similar ideas, there are a lot of plausible questions that are under investigation. And this is where I fear our colleagues in the media lose it. The media can be an effective source of public health information, even a tool to improve public health, but when the media unleashes a torrent of premature speculation, science and the public health lose. This is where the Times’s Nicholas Kristoff comes in. On Sunday, he asked these questions:

The battle over health care focuses on access to insurance, or tempests like the one that erupted over new mammogram guidelines.

But what about broader public health challenges? What if breast cancer in the United States has less to do with insurance or mammograms and more to do with contaminants in our water or air — or in certain plastic containers in our kitchens? What if the surge in asthma and childhood leukemia reflect, in part, the poisons we impose upon ourselves?

We have many examples of human-made environmental chemicals causing disease.  Often, a cluster of disease is identified, and then a common exposure is found, and further study confirms a likely causal relationship.  For example, in the 20th century, thousands of people in Minamata, Japan fell ill and died from a mysterious neurological ailment.   Investigation found that industrial methyl mercury contamination had entered the seafood chain  and was the responsible agent.

Conversely, suspect contaminated regions can be identified, and then clusters of disease can be sought.  This is a bit trickier, but still a legitimate way of investigating a relationship.  The Michigan PBB incident in one such example in which health effects were hard to nail down.  Cigarette smoking as a cause of cancer was a bit more clear.

A less effective way to approach this type of problem is to have neither a clear disease cluster nor a clear exposure group.  This is the mistake made by Kristoff.  He relates EDCs to several problems, but focuses on breast cancer, drawing a line from EDCs to early puberty, to longer time from menarche to menopause, to increased breast cancer rates.  While this is not implausible, it’s pretty damned tenuous.  In order to see if EDCs are really causing breast cancer in significant numbers, we should establish both a correlation between exposure to specific chemicals and excess cases of breast cancer. We should also have a laboratory model for the connection.

The problem here from a science-based medicine perspective is not the implausibility but the oversimplification and naive, hyperbolic conclusions.  Kristoff cites a 56-page report from the Endocrine Society, which was much more circumspect and called for further study of the issue.  I can understand the desire to communicate an important health story to the public, but choosing an emotionally charged issue like breast cancer and linking it to everyday substances that everyone uses blurs the issue more than it clarifies.  It incites emotion without asking clear, important questions.

When I’ve talked to experienced public health experts about EDCs, they’ve given me a noncommittal, “yeah, there could be something to that,” but none that I’ve read have been willing to call this a major public health threat.  We know the causes of lots of cancers.  We know how to screen for many important cancers, which allows for early detection and treatment.  Some cancers we can actually prevent by limiting environmental exposures;  many lung cancers could be prevented by eliminating exposure to cigarette smoke.   Whether any cancers can be prevented by banning putative EDCs is a question that’s barely been asked, much less answered.

Posted in: Science and Medicine, Science and the Media

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31 thoughts on “Endocrine disruptors—the one true cause?

  1. Kausik Datta says:

    In order to see if EDCs are really causing breast cancer in significant numbers, we should establish both a correlation between exposure to specific chemicals and excess cases of breast cancer. We should also have a laboratory model for the connection.

    Very well put. This is the issue that I had with the Kristoff article this morning.

    I think one important aspect of this debate needs to be emphasized consistently at the present time. Overall, there are some indications that some endocrine disruptors may alter reproductive hormones (leading to secondary effects on sperm genesis, capacitation, and fertility in males and carcinogenesis in females) as well as thyroid hormones. However, these results must be interpreted with care, in view of the paucity of human studies and the fact that numerous reports did not reveal any adverse effects on human physiology, just as many studies seemingly did. This caution seems to be amply reflected in many of the papers archived in PubMed (as of this afternoon, a search with “endocrine disrupting chemicals” brings up 2730 reports of which 585 are reviews).

    Of course, further investigation is needed before a firm conclusion can be drawn. However, Dr. Lipson, I wonder if it is not prudent to try to limit human, especially perinatal, EDC exposure.

  2. windriven says:

    “What if breast cancer in the United States has less to do with insurance or mammograms and more to do with contaminants in our water or air — or in certain plastic containers in our kitchens? What if the surge in asthma and childhood leukemia reflect, in part, the poisons we impose upon ourselves?”

    Hey Nick, what if all brain cancer is caused by reading the musings of scientifically semi-literate journalists?

    There are innumerable unintended byproducts of industrial activity and these are sometimes both insidious and powerful. When the extent and consequences of these are poorly understood, even by those expected to be experts, ‘what if?’ becomes an easy ticket to outrageous fears.

    Remember the sci-fi movies of the 1950′s? Many of these involved the plot device that nuclear (nucular for those of you living in Crawford, TX) arms tests would cause genetic damage that would lead to gigantic insects, spiders, animals, and in at least one case, carrots (The Thing (or maybe that was aliens)).

    Exposure to nuclear radiation and to the long-lived detritus of nuclear testing leads to all sorts of unpleasantness but, so far as I know, not to gigantic cockroaches. But not knowing what to expect, people project their worst fears.

    So the problem is that while fear-mongering might sell a few newspapers it does nothing to improve the public welfare and it leads to “One True Cause of the Week” thinking. This week vaccination is the cause of all things dangerous and vile. Next week it is endocrine disrupters. A week later it will be gamma radiation from sunspot activity.

    The prudent course of action on a broad scale is to minimize what economists call negative externalities and to research causal links as they become apparent so that the externalities can be eliminated or at least internalized.

    On an individual level it means learning what one can, keeping things in perspective, and leading a balanced and active lifestyle.

    If you meticulously avoid every silly thing that is supposed to be bad for you, you still aren’t going to live forever. Though living in perpetual fear might might feel that way…

  3. EricG says:

    depsite the reservations presented, I look at this topic as dually satisfying to sbm and woo. though, i suspect that the woo-meisters may be reluctant to give up what is ulitmately their non-factual ideology.

    we’ve heard about “toxins” forever now. challenged, a “toxer” will always cite some burst of “man-made chemicals” and other nefarious substances that poison you. Well, they are out there…are we giving credence to the toxer movement by vetting some of their fears? to my knowledge, there are a variety of man made things that do mess with us…BPA, high fruc corn syr, hydrogenated oils, antibiotic super dose in livestock and so on (no expert…feel free to correct that list).

    In the mean time there are of course 100′s of food additives and building materials that are perfectly fine. I suppose I do not need to add, that despite the diseases we encounter, we are living, in the US, an average of 77 some odd years…not too shabby.

    Does a sbm verification of “toxins” inevitably fuel the fire? Or can we hope that a list will accumulate over time and naturopaths everywhere can accept xanthan gum and amalgam fillings?

  4. windriven says:

    @EricG

    High fructose corn syrup? What evil is that supposed to beget?

    “Does a sbm verification of “toxins” inevitably fuel the fire?”
    Nope. Semi-literate hacks rattling their tin cups may fuel the fire by misusing or sensationalizing scientific analysis of materials with negative health consequences. Woo-meisters may twist and distort scientific findings to promote their vaguely Freudian ‘purges’ and ‘cleansings.’ But the heart and soul of science based anything is simply to fuel the fires of truth and understanding, not those of fear and superstition.

  5. Zoe237 says:

    Thanks forr this response! I read that article last night was wondered if this website would comment.

    I also wonder SBM reponse to Stephen Milloy’s “junk science” website. Seems like he thinks just about everything is junk science, including research on passive smoke and DDT. It seems like this website doesn’t like the “toxin” scare tactic approach, but there must be some circumstances in which it is true.

  6. Peter Lipson says:

    I’m not sure that your generalization is correct. Of course there are many toxic substances that cause significant health problems. It may turn out that there are so-called EDCs that have measurable health risks, but at this time, the evidence isn’t there.

    There isn’t as much as a plausibility problem here as a lack of data problem.

  7. JerryM says:

    Endocrine disruptors? bah humbug.

    We all know the Daily Mail causes cancer!

  8. David Gorski says:

    Kristoff’s article is dubious at best, crap at worst. For one thing, the claim that breast cancer rates have skyrocketed is pure nonsense. The rates were slowly climbing over the last 50 years but since 2002 have plummeted, most likely because of the decrease in the use of hormone replacement therapy in the wake of the Women’s Health Initiative study. It is true, however, that rates of noninvasive cancer have increased markedly; this is most likely due to the effect of screening mammography, which picks up early noninvasive tumors very well.

  9. David Gorski says:

    I also wonder SBM reponse to Stephen Milloy’s “junk science” website. Seems like he thinks just about everything is junk science, including research on passive smoke and DDT. It seems like this website doesn’t like the “toxin” scare tactic approach, but there must be some circumstances in which it is true.

    The problem with Milloy is that he’s an industry apologist, if not an outright shill. If you ever want to know what side he will take on an issue of health, simply ask yourself what side industry takes. Of course, sometimes he will be correct (for instance, in concluding that anti-vaccine activists are pseudoscientific loons and in criticizing alt-med), but in those cases he tends to come to the right answer for the wrong reason; i.e., through ideology, not science. Most of the time, however, he is outrageously, hilariously wrong.

  10. Scott says:

    High fructose corn syrup? What evil is that supposed to beget?

    Health evils I’m not sure about, but many people think it doesn’t taste as good as real sugar, and it’s certainly more expensive. The things politicians do to buy votes in the Iowa caucuses…

  11. Zoe237 says:

    “The problem with Milloy is that he’s an industry apologist, if not an outright shill. If you ever want to know what side he will take on an issue of health, simply ask yourself what side industry takes. Of course, sometimes he will be correct (for instance, in concluding that anti-vaccine activists are pseudoscientific loons and in criticizing alt-med), but in those cases he tends to come to the right answer for the wrong reason; i.e., through ideology, not science. Most of the time, however, he is outrageously, hilariously wrong.”

    Thanks. That’s pretty much what I thought. Interesting how often smart people can be biased and wrong so often.

  12. Scott says:

    It’s arguably easier for smart people to be biased and wrong. If a person gets too used to being right, it’s hard to keep the possibility in mind that you really might be wrong this time.

    That’s why skepticism is so important – it provides a solid framework for trying to keep overconfidence in check. Much like the scientific method, really.

  13. edgar says:

    I think it speaks to the difficulty of environmental research as a whole. With the exception of a few extreme cases mentioned above, it is nigh but impossible to show a causative link between chemicals and disease. I would never say that there isn’t a link, though. Nor would I say that there is. I also don’t understand why SBM doesn’t have toxicologists and other specific experts writing posts about these issues.

    I see this as a black hole of research, and there needs to be a way to address this. In this particular example, I am hoping the results from the Sister Study might shed some light on the chemical/breast cancer question.

  14. EricG says:

    windriven-

    fair enough. Am i correct in assuming that because you only acknowledged HFCS that the remainder are reasonably understood as something that *may* mess with your endocrine system?

    As far as HFCS, perhaps that was toeing the line a bit too close. Again, im no expert but I have read that HFCS is metabolized in a way that would yield more fat had you otherwise ingested the same amount of…say, regular old corn syrup. Or maybe the natural confound is that, *because* hfcs so easily adds more sugar calories per volume, if you make a habit of eating hfcs laden products, you will gain more weight than otherwise. That statement, I am sure, is subject to a 1000 different caveats. An endocrine disruptor? yea, probably not. Bad for you? Quite possibly….?

    I 2nd the question on a Tox expert. Some things are bad, some things not so bad, some unequivocally safe….whatever that truth may be, inquiring minds would like to know!

  15. EricG says:

    “is metabolized in a way that would yield more fat had you otherwise ingested the same amount of…say, regular old corn syrup.”

    that should probably read:

    …had you otherwise ingested the same *caloric value* of regular corn syrup…

    obviously if you ingest more sugar as an alternative, you are more likely to retain more fat.

  16. Calli Arcale says:

    High fructose corn syrup is one of the major “boogiemen” right now, often abbreviated HFCS. (Side-note: has anyone else noticed a tendency for people to use the acronym when they’re trying to make it sound scary? Some things without acronyms have even been given acronyms, and I’m starting to think there may be a pattern. Sure, there are legitimate uses of the acronym, but sometimes I wonder if the fearmongers have noticed people find it scarier if they use an acronym. Makes it look more artificial.)

    Corn syrup has largely supplanted granulated sugar (whether cane or beet) in many industrial applications. This is partly because of convenience (it’s easier to work with, as its already in liquid form) but mostly because of its huge overabundance. It’s cheap. It’s only cheap because of corn subsidies, of course. It’s the same reason why corn ethanol became popular. Not because it’s the best choice, but because we’ve got actual mountains of corn lying around, waiting to be used.

    There are some who say that corn syrup is worse for you than sucrose, and some studies have linked it to an increased risk of diabetes*. It is processed slightly differently from sucrose, but i think the main reason it’s linked to diabetes is because there’s so much of it, particularly in beverages, where it’s easy to consume large quantities without really thinking about it. It’s really just a different form of sugar, and as long as you know that, you can make intelligent choices about how much of it you really need in your diet. The only real reason it’s a problem, in my opinion, is its sheer abundance. Replace it with sucrose or even a “natural” sugar like honey and you don’t really solve that problem.

    *Mind you, the same things were being said about sucrose years ago, and many folks will still rail against “refined sugar”. Some say the only safe sugar is cane molasses. Others say you should use honey and nothing else. I haven’t seen anybody laud maple syrup above all other sugar forms, but maybe that’s because of the price tag.

  17. EricG says:

    Calli,

    thanks for the input. I gather that I have fallen to some sort of “a sugar, is a sugar, is a sugar, is a sugar…all except for THAT sugar” trick.

    it would appear that the sugar calories per gram is the suspect here and because hfcs packs it in, it eventually (and perhaps rightfully so) receives a lot of blame.

    So, in advising against a hfcs laden product, it is probably more sound to simply say, “hmm, yes, that is basically junk anyway that is nutrient devoid. hfcs is just your run of the mill super sweetener that ends up making you fat.”

    Sound about right?

  18. edgar says:

    I would think glycemic index would be a factor as well, right?

  19. daedalus2u says:

    Steve Novella had a post on HFCS.

    http://www.theness.com/neurologicablog/?p=568

    I think much of the hype is completely overblown. Sucrose is a disaccharide of glucose and fructose. Corn syrup is 100% glucose, HFCF is ~55% fructose 45% glucose. When starch is digested it becomes 100% glucose in the gut. Apple juice has a lot more fructose in it than does HFCS.

    Once the sugars get into your blood stream, whethery they came from sucrose, corn syrup, HFCS, or starch is unimportant. The form you eat them in may change the rate of absorption, but not the molecular form of how they are absorbed and transported by the blood.

    Glucose is probably somewhat better because glucose is what the liver makes and stores and what muscle stores too.

  20. cha says:

    i like you’re blog but think you’re off base with this one. in this case the science is in favor of a link of BPA with disorders associated with altered hormone activity. Hundreds of animal studies–not in vitro studies–have shown effects at doses seen in the environment. And human studies assessing higher doses–such as the recent example of men exposed to BPA in a factory in china-also show an effect. It probably isnt a big deal if you are a 60 year old guy, but if you are pregnant and in your first trimester it would be prudent to pay attention to the data and avoid plastics with BPA. The concern among endocrinologists and especially people who study early fetal development is not theoretical, but real.

  21. Kausik Datta says:

    …the science is in favor of a link of BPA with disorders associated with altered hormone activity. Hundreds of animal studies–not in vitro studies–have shown effects at doses seen in the environment…

    Would you be kind enough to point to some references to these studies that ‘have shown effects’? Which effects are these exactly? Most of the studies I came across seemed to urge caution in interpreting the results.

  22. Mark P says:

    Seems like he thinks just about everything is junk science, including research on passive smoke and DDT

    We need to be careful to distinguish between junk science and being wrong. There is plenty of junk science that reaches the correct conclusion, or at least close to the correct conclusion.

    I would bet a fair amount of the research on passive smoking would fall into that category. And I’m pretty sure it is commonly agreed that the original slurs on DDT were massively exaggerated. Loopy or shill, anyone can probably find loads of junk in those two fields. I would have chosen other examples.

    Too many people are quite prepared to accept junk science so long as it agrees with what they believe to be true. Including those of us on the side of SBM.

  23. Ash says:

    cha, while there have been studies showing effects of BPA at low (environmental) doses, these have pretty much all been based on injection of BPA directly into animals; human exposures are normally from ingestion, which results in completely different pharmacokinetics (which is why these studies have generally been rejected by regulatory agencies reviewing BPA). That’s not to say there aren’t potential effects from BPA at low doses, particularly for infants who may not metabolize BPA effectively, but the existing studies aren’t very good for showing at what doses those effects might occur. BPA toxicity is one of those politically charged areas, where you have industry trying to show it is safe (and, I suspect in at least some cases, designing studies that they know will not show toxicity) while groups like Environmental Working Group use fairly poorly designed studies to demonstrate it isn’t (most of their studies seem designed to always give the conclusion that a substance is dangerous).

  24. trrll says:

    I am very skeptical of endocrine disruption in man, at least insofar as common environmental levels of exposure. The plausible exposure seems very small compared to endogenous hormone levels. Endogenous steroids are already so potent that it is difficult to imagine that environmental steroid mimics would be substantially more potent. To take it seriously, I’d need to see some pretty clear experimental results establishing a mechanism for such high-potency effects of putative endocrine disruptors in vivo.

    I can’t help remembering that a few decades back, there was a lot of concern that with the massive increase in the variety of synthetic compounds in our environment, many of them mutagenic (at least in simple bacterial assays) that we would see a huge increase in cancer and other adverse effects due to chemical contamination. It really doesn’t seem to have happened. In terms of consequences for human health, I can’t think of anything that compares to lead or asbestos–both natural substances with a long history of use.

  25. daedalus2u says:

    trrll is right, the levels of endogenous steroids is much higher than exogenous endocrine mimetics and those mimetics have much lower affinities for the various receptors. However there is no threshold for an exogenous disrupting signal to perturb an endogenous signaling pathway because the endogenous signaling molecule is already at the concentration where changes in that concentration have physiological effects.

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1566346/?tool=pubmed

    It was this paper that made me realize that the same no threshold effect for disruption by EDCs is also true for nitric oxide signaling. NO is used by a lot more pathways in a lot more tissue compartments, but the principle is the same. If the signaling molecule is already in the “active range”, where changes in its concentration produces physiological signaling, then a change in the basal level will produce perturbations to that signaling.

    DDT did have massive endocrine disruptive effects in birds. It wasn’t the DDT, but rather a metabolite DDE that caused egg shell thinning. If DDT use had not been drastically curtailed, many birds of prey would have gone extinct because the lipid soluble metabolites moved up the food chain.

  26. snfraser says:

    There is a great deal of research showing that much of the endocrine disruption talk is bunk in terms of potential health effects in humans. Some common targets of this bogus health scare include BPA. There is in fact a great deal of evidence showing BPA is not at all harmful to humans.

    http://www.informaworld.com/smpp/content~db=all~content=a908974039

    See also for a different plastic:
    http://www.acsh.org/factsfears/newsID.1237/news_detail.asp

    In the case of phthalates and BPA, at least, the science is quite clear.

  27. David Gorski says:

    I’m not sure I’d be so fast to cite ACSH (on whose board of scientific advisors Dr. Kamrin, the author of the review article you cite is listed) for evidence on this issue; it’s a bit too closely aligned with industry for my taste and, from my following its writings and positions, is a bit too much of an apologist for the pharma and chemical industries.

    With the exception of tobacco (although, I might add, less and less the issue of secondhand smoke), if you want to guess beforehand what ACSH’s position will be on a given environmental, nutritional, or medical issue, simply ask what the position of pharma, chemical, or food industries would be and you have at least an 80% chance (if not a 90% chance) of guessing correctly or nearly correctly. Of course, it’s possible that the industry position on this issue is actually the correct one (as it is on vaccines, most alt-med, and such), but I’d prefer a more unbiased source myself. revere has actually done a series of very good posts on BPA over at Effect Measure, and Steve Novella has also written on this.

    Come to think of it, the Endocrine Society summary statement referenced by Peter is a pretty good summation of the state of knowledge in this area. The fact is that, for breast cancer at least, teasing out environmental factors is very difficult, as there appear to be susceptible windows during breast development when the mammary tissue is more sensitive to various hormones and chemicals. That’s part of what makes it so hard to figure out these associations. I would agree that, if BPA or other endocrine disruptors are linked with breast cancer, it is likely not to be a huge effect, certainly not on the order of DES (or we would have noticed unequivocal evidence of it already). However, I don’t think we have enough evidence to definitively absolve or indict these chemicals of having a significant effect.

  28. snfraser says:

    Notwithstanding the fact that scientific fraud is highest in the medical sciences, and that pharmaceutical companies and researchers have engaged in shoddy practices, and that pharmaceutical funded research typically shows higher success rates for a given medication than independent reports…

    I don’t think you are being particularly fair in dismissing the findings of a peer reviewed report only because of industry ties. Caution is warranted if one study is one’s only source (that’s science for you). There have been no compelling scientific studies showing harmful effects of BPA or pthalates in humans. This is what the FDA has said, and they are currently reviewing these 2008 conclusions because of some hype.

    If your standard is ‘unbiased’ data, then you must also remove the work of Van Saal and his rodent studies, because he has been a large proponent of this particular health scare.

    My main point is that the original post, and your comment, implies that there has been little research on these particular chemicals. As these reports show, there has been a heck of a lot of research over the last 50 to 60 years on BPA and phthalates, at least. I would suggest that there is a rather large body of scientific evidence and that it shows there is no harm to humans from these 2 chemicals. I can’t speak for soy products or any other alleged ‘disruptors’.

    You are probably correct that any effects are trivial. In fact this is the conclusion of the European Union. They essentially suggest that ‘the poison is in the dose’ and that extremely large doses (>500mg/kg bw) of BPA are required to have any effect in rats.

    Finally, ACSH does tick me off some times, but their conclusions on this issue are consistent with the FDA, European Union, etc.

  29. Angora Rabbit says:

    >>trrll is right, the levels of endogenous steroids is much higher than exogenous endocrine mimetics and those mimetics have much lower affinities for the various receptors.>>

    Not disagreeing with you but adding some caveats. It’s not just a question of concentration, but also affinity for receptor, metabolic clearance rate, and a few others. Recall that an endogenous ligand has to come *off* the receptor at some point so that signaling can end. In contrast, a synthetic ligand could have a tighter affinity for receptor, and this could enable it to activate at lower concentrations than the endogenous ligand. This is the basis for many pharmaceuticals, as one class of example; indeed, binding affinity figures large in drug potency, because that means you need less drug to have an effect.

    As an endocrine disruptor example, consider TCDD (the most potent form of the chemical class loosely referred to as dioxins). TCDD has a tight affinity for its receptor and is unfortunately a toxin precisely because of the unhappy coincidence that it binds and activates a transcriptional effector (the aryl hydrocarbon receptor, or AhR) so well. TCDD’s potency is further boosted by its stability due to its chemical structure, which precludes the usual liver disposal. Curiously, we still don’t have a convincing idea of *what* is AhR’s endogenous ligand. So here’s an example where it takes very low quantities of a synthetic ligand to activate its receptor, with the caveat that we don’t yet have a framework for thinking about concentration as the endogenous ligand remains unidentified (and not for a want of looking!)

    The bottom line is that the situation is complex, and modified by more than just concentration. Also considered is the compound’s absorption, metabolic clearance, the potency of metabolites, receptor affinity, and the modifiers of age and gender, both of which can significantly affect the aforesaid factors. Also toss into the mix genetic heterogeneity, which can modify individual sensitivity by affecting these factors as well. This is why it can be a real challenge to obtain a clear answer on risk, and also is why recommendations tend to err on the side of caution, because a given individual is unlikely to know his or her variability on these factors. Recommendations are instead asked to evaluate risk at the level of population.

    Hope this helps a complex subject.

  30. trrll says:

    daedelus, I looked at the paper you cited, but it has massive problems. To begin with, it tries to estimate the endogenous estradiol level in the eggs using Scatchard analysis. I couldn’t believe that I encountered a paper published as recently 1999 using a technique that was abandoned decades ago due to the fact that it uses a transformation that violates the assumptions of linear regression, and as a result produces unreliable and biased results. Trying to extrapolate to the x-origin the way they have done is nuts, and their error estimates in that measurement are completely invalid. This sort of analysis was only defensible back when most investigators did not have access to computing equipment more powerful than a hand calculator. Besides, why try to measure endogenous estradiol that way, when highly sensitive immunoassays have been available for years.

    And even if you assume that in spite of defective methodology they somehow managed to get the right numbers, the estradiol doses they are giving are an orders of magnitude above their calculated endogenous estradiol level. They make a big deal out of the fact that there is no threshold at their high doses of exogenous estradiol. That’s fine; for the most part, thresholds are not real in a mathematical sense, they just reflect the dose at which an effect falls below the noise level, or becomes negligible for all practical purposes. But even using their model, if the concentrations were reversed such that the exogenous dose/ED50 was, say 10% of the endogenous dose, the effect on the percent female would be negligible. This is easily calculated from their mathematical model. You still end up with the conclusion that to produce an appreciable perturbation, the dose/ED50 of an estrogenic compound must be at least roughly comparable to the dose/ED50 of endogenous estrogen. Basically, to have a small percentage change in the normalized (to its own EC50) concentration of an agonist result in more than a small percentage change in the biological effect, you need some sort of extraordinarily powerful positive feedback, which is pretty rare (and which they don’t have in their system or their data would not have come close to fitting a Michaelis-Menten curve).

  31. trrll says:

    “Recall that an endogenous ligand has to come *off* the receptor at some point so that signaling can end. In contrast, a synthetic ligand could have a tighter affinity for receptor, and this could enable it to activate at lower concentrations than the endogenous ligand. ”

    The problem with this hypothesis is that the endogenous hormone ligands for endocrine receptors already have very high affinity, with dissociation constants typically in the nanomolar or even tenth-nanomolar range. This is probably very close to the maximum affinity achievable for noncovalent binding of a small-molecule ligand. So it is not particularly plausible that endocrine disruptors will bind at lower concentrations, or occupy the receptor for longer, than the endogenous hormone ligands. I don’t know of any xenochemical with much greater affinity for endocrine receptors than the endogenous ligands. TCDD, for example, has an affinity in this same concentration range, although since it does not seem to bind to an endocrine receptor, the issue of the toxin having to compete with a relatively background concentration of an endogenous ligand may not apply.

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