The Debate Over Low Doses: Hormesis & Human Health

February 9, 2005
3:00 pm US Eastern Time

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Call Transcript

1. Welcome - Call Moderator: Michael Lerner, PhD, President, Commonweal Welcome everyone, to this call is on the very important issue,of hormesis. Ted Schettler, our first speaker is going to give us a science update of a perhaps broader nature.

2. First Speaker - Science Update: Ted Schettler, MD, MPH, Science Director, Science and Environmental Health Network Good morning, everyone. I wanted to bring your attention to a paper on the interactions between PCBs and phthalates, in relation to human sperm motility, by Russ Hauser and colleagues at the Harvard School of Public Health and Mass General Hospital and co-author Antonio Calafat from the CDC, recently posted on the Environmental Health Perspective’s website, from January 2005. These scientists had previously reported an inverse relationship between sperm motility and exposures to some PCB congeners. They had also reported an inverse relationship between sperm motility and exposure to some phthalate esters. They also noted that some, but not all, PCBs can inhibit an enzyme that’s responsible for glucuronidation of phthalates in humans and glucuronidation is a major mechanism that humans use for excreting phthalates. They postulated that there might be a greater-than-additive interaction between phthalates and some PCBs. That is that men with higher levels of some PCBs that influence enzyme levels, might have a greater impact on sperm motility, from a given phthalate level -- because of the influence of PCBs on phthalate metabolism. They were interested in that interaction. In their sample population, they measured PCB levels in the blood and phthalate metabolites in the urine. Then they used a statistical technique, which I think we might want to consider using in other circumstances. It enables them to estimate the relative excess risk, due to interaction. There was a significant higher or more-than-additive risk of poor sperm motility in men with combinations of above-average PCB levels, and above-average levels of some phthalates. In other words, some PCBs alone correlate with decreased sperm motility and some phthalates correlate with decreased sperm motility. But when they’re mixed together, the impact is greater than the sum of the two, because of the interactions. Russ and his colleagues postulated that the enzyme-inducing PCBs are actually converting the PCBs to an intermediate -- which is then inhibiting the enzyme that’s responsible for glucuronidating the phthalates. And there’s some data to back that up or to support that hypothesis. But what are the implications of this work? Clearly, further work will need to be done to confirm these findings, and study the mechanisms. But the larger point is that people are exposed to mixtures of chemicals -- not single chemicals. Those are often started in lab animals. Risk assessments that are based on results from single-chemical experiments fail to account for these interactions. For phthalates, for example, reference doses that are based on single-chemical experiments and controlled laboratory animal tests will really not be as protective as they’re intended to be in large populations of people. I’d also suggest that these interactions ought to be looked at in other kinds of mixtures -- not only having to do with chemicals, but also interactions between nutritional factors and chemical exposures, as well as social factors and other influences, on health outcomes. So it’s a statistical technique that I think has a broader application to wider areas of interest. Michael Lerner: Ted, thank you very much for that very interesting science update. So, starting our presentations on hormesis, beginning with Pete Myers.

3. Second Speaker: Pete Myers, PhD, CEO, Environmental Health Sciences I’m going to very briefly frame what the discussion on hormesis is about. I should begin with the comment that the person who has been the chief champion of the idea of hormesis was invited to be on the call, and initially expressed an interest in doing so, but subsequently changed his mind. So unfortunately, Ed Calabrese won’t be joining us as a speaker today. On the other hand, if he is listening, I would invite him to join in the discussion. Hormesis: What is it? Well, we all know that the central dogma of toxicology is that the dose makes the poison. The more of a substance there is, the larger an effect you can expect. Dr. Calabrese years ago stumbled accidentally -- as often happens in science -- across a very unexpected result, in which he observed that in a particular experimental system with which he was working, in plants -- he found unexpected behavior and unexpected stimulatory effects at the very low end of the dose-response curve. So instead of dose making the poison, he found this enhancement of effects way down at the very lowest end of the dose-response curve. If you all are familiar with the shape of these curves, fine. If you’re not, there’s a really good paper, "Toxicology Rethinks Its Central Belief: Hormesis Demands a Reappraisal of the way Risks are Assessed," that Calabrese has in Nature, that was published two years ago, that does a good job summarizing what he means, and what the observations are that back up the notion that under certain circumstances, you find these unexpected responses at low doses. There are a couple of things that we need to explore in the talk, today. I know that Dr. Vom Saal and Dr. Tickner will be picking up pieces of this. One of the issues is that, for example, you read a thought piece by Calabrese and Baldwin and you’ll find that they emphasize the stimulatory positive effects of a hormesis response. Is it possible that there are negative effects also occurring at the low-dose end of the response curve? There are a lot of scientific questions related to that. Additional scientific questions related to, “Well, if it’s happening…” and it is clearly happening. Calabrese has presented examples of over 5,000 of these unexpected stimulatory effects at low doses in different systems, ranging from animals to plants. It’s clearly happening. Well, why is it happening? What are the biological mechanisms that lead to this very unexpected result? The second question is, “Well, what do we do about it?” If, as Calabrese maintains, this is really about good things happening at low doses, then does that mean that we have to rethink our standards for regulating chemicals at low doses? Today a lot of emphasis is put on reducing the exposure levels to very low levels, but at the low end of the dose-response curve. He models in this Nature piece that, “Well, perhaps we are overly concerned about those exposure levels,” but in fact we might accept some of the contamination existing at superfund sites, once it gets beneath some threshold, because beneath that threshold, you might even see something good. I know that Dr. Tickner will be addressing those types of policy questions. What does it mean in the real world, where we actually are exposed to compounds within the range of doses where a hormetic effect should be expected?

4. Third Speaker: Fred S. vom Saal, PhD, Professor, University of Missouri, Columbia, Division of Biological Sciences I’m going to focus on the low-dose effects of environmental estrogens, starting with what is known as the overcompensation hypothesis of hormesis. Because the generally accepted hypothesis for this hormetic curve is that overcompensation occurs during the repair of damage caused by toxic insults - such that the organism is more ready for another insult than if overcompensation didn’t occur. So this is viewed as an “evolved” mechanism, that is an adaptive response, to protect hormeostatic systems. It’s presumed to be a highly regulated, optimized process -- conferring biological insurance policy for the next insult. Even though there’s no mechanistic understanding of hormesis, potential mechanisms are stimulation of enzymes that repair DNA -- or eliminating tumor cells or damaged cells. One of the problems with this is with regard to endocrine disruptors that act by activating or inhibiting transcription of genes. None of these endocrine-disrupting events are recognized as damaged by cells. There’s no mechanism for a cell to know whether, in fact, the activity being initiated is due to endogenous or an exogenous hormonal trigger. Another problem with this view of hormesis as a tightly regulated overcompensation is that this can’t be applied to embryos where homeostatic systems are being established but not fully functional. So the adaptive model of hormesis is clearly based on adults -- not anything to do with embryos -- where, for endocrine disruption, we have a primary concern. So what about the idea that Pete raised about “beneficial effects” of these low doses and its application to risk-assessment? To really understand risk, we need to look at all examples of low-dose effects of endocrine disruptors, for instance -- none of which can be considered to be beneficial. This is covered in the article that I had written with Belke and Oldman. In contrast, Calabrese and Baldwin, in their Nature commentary, go on to propose that the public has been unnecessarily frightened by assumptions underlying risk-assessment. And instead of protecting against low doses, in fact, this fear should be replaced by the recognition that low doses are beneficial. It’s important that benefit or harm isn’t part of the definition of hormesis. Hormesis is a description of a particular type of dose-response relationship. Hormetic dose-response curves are, in fact, common for endocrine disruptors. We don’t dispute this, and in fact, think that regulatory agencies need to take this into account in risk assessment. Basically, the premise by regulators is that as dose moves from a very high level down to a threshold, below that threshold, you can reach a safe exposure level. The dose-response curve is always assumed to be monotonic. For estrogenic endocrine disruptors -- starting from a maximum-tolerated dose, for instance -- you would go through a range of toxicity, down to an area where there’d be no more toxic response. But that’s where you’d begin to pick up receptor-mediated responses. None of these receptor-mediated responses are currently part of the existing paradigms for looking at effects that are only examined at very high doses. So this whole approach contrasts with what is proposed by Calabrese -- that acceptance by the EPA of hormetic curves would lead to acceptance of a threshold model. We respond that, in fact, it should lead to rejection of the threshold model, because the system under attack by these environmental estrogens is already above threshold induced by endogenous estrogens. Dan Sheehan in EHP 1999 has a wonderful article on this.

5. Fourth Speaker: Joel A. Tickner, ScD, Assistant Professor, Department of Community Health and Sustainability, Lowell Center for Sustainable Production, School of Health and the Environment, University of Massachusetts, Lowell There are a lot of people on this call who have dealt with the issue of hormesis a lot more than I have. So I’m going to try to frame some issues about the use of hormesis in policy and risk-assessment policy. This discussion builds on a discussion we’re having with a very multidisciplinary group of scientists in Massachusetts. Myriam Laura Beaulne, who is on the call, has been helping to coordinate that for us. I think the first question here is, “Is hormesis gaining ground in scientific circles?” Are we giving too much credit or too much concern to the issue? Our discussion has really been, at least in the mainstream scientific community, that hormesis hasn’t gained a lot of ground, yet. Certainly, it’s getting a lot of press in the generic press. Certainly, it’s very good for those who don’t want chemicals regulated. But the question is, “Are agencies hearing hormetic arguments, now?” Is the general toxicology or epidemiology community accepting this? We would say, “Probably not, yet.” The concern that Fred was raising is really, I think, in cancer risk-assessment -- where a lot of the debate is about eliminating the non-threshold assumption in cancer risk-assessment. Another issue is that this certainly has not been shown to be a generalizable hypothesis. If you look at the databases upon which Calabrese and colleagues argue that hormesis is generalizable, most of these cases are plants and lower mammals. There’s very little, if any, epidemiology. And there’s much of the database that we don’t even have access to, because it’s confidential. Also, there’s no mechanistic explanation for hormesis. The theory of hormesis still isn’t clear, and there’s no clear definition, at this point. So we’re really not quite sure what hormesis even is, at this point. That leads to a number of reasons why it would be very irresponsible to integrate hormesis into regulatory policy. I started from a sort of fundamental, principal public health, which is protecting those most vulnerable in a population. There’s a series of points. The first is human variability. We know that there’s age, genetic, socioeconomic vulnerabilities and variability in a population. We know that certainly there might be a hormetic effect in a single individual. But are there other individuals in the population that might have a negative effect from that same dose? We just don’t know. But we must consider those with compromised immune systems, or those with lower socioeconomic status. The second point Ted raised quite clearly is we’re not exposed to single chemicals. We have a background of substances. And many substances cause toxic effect through similar modes of action. So we have the issue of interaction. Next point is that the database on which hormesis is based is based on single endpoints. We know that a single toxic chemical at a single dose can cause multiple endpoint damage. So while one effect might show a hormetic positive response, another effect might show a negative response. Also, stimulation may just be an indicator or a precursor of an adverse effect. We don’t know whether stimulation is actually a good thing or a bad thing. Next, it’s impossible to control exposure at "therapeutic" levels. Assuming the idea of hormesis means that you have to be able to control exposure at therapeutic levels, and we know that we’re exposed to toxics through multiple sources -- workplace, food, air, products, et cetera. The next point, which I think is very important, is what I call the “opportunity costs of chasing ghosts.” Of course, hormesis is very appealing to the regulated community, because it’s an opportunity to delay regulations. It’s part of what we would call and “evolution on the argument of the safety of chemicals.” The last part of that evolution was the idea that, “the mechanism makes the poison.” Now, we’re at, “the low doses might actually be good for you.” It delays investment in prevention. There are the costs of delay of chasing hormesis -- our cost to health. Not cost to industry. Then finally, it’s quite an anti-precautionary way of thinking about policy. So, in the end, if we were to accept hormesis as a part of the regulatory paradigm, we should be treating those chemicals that are argued to have hormetic effects, like drugs. We should be conducting clinical trials. There should be dose control, and there should be, obviously, informed consent. So there are a series of requirements before we could ever accept, responsibly, hormesis in the regulatory paradigm. You’d need to have clinical trials. There would have to be no variability. You would have to have controlled-exposures. You would have to have controlled background. You would have to demonstrate that there is a beneficial effect. And that that exposure couldn’t lead to another problem side effect, like a drug. So in the end, hormesis is a very interesting academic exercise, as Fred was explaining. The problem is really the low-dose harmful effects of chemicals. Finally, do we need to worry? We need to be cognizant of this happening, and respond. But remember that the vast majority of the literature on hormesis is from a single person. The database is weak. So we need to respond, but not worry too much, at this point, I think. We need to be clear that this is a problem, and we need to respond to it. But I don’t think we should give it so much credence. Michael Lerner: Joel, thank you very, very much. I just want to re-emphasize the efforts we made to encourage Dr. Calabrese to be on the call. Because truly, our goal is to raise the level of public and professional dialogue about how the environment affects human health. So it would’ve been truly wonderful to have him on, and to be able to respond to these thoughtful comments.

6. Open Discussion: Michael Lerner: I want to start with some of the scientists on the call. Theo Colborn is the co-author with Pete Myers and Dianne Dumanoski, of Our Stolen Future. You’ve been deeply involved in these issues. Would you comment on what you’ve heard, and on the issue?

Theo Colborn, PhD, President, TEDX, Inc.: Thank you, Michael. I was very pleased to hear what Joel just said, because I didn’t think anyone else was thinking like that. I think his argument is very strong, and something we should take it into consideration. Hormesis is too vague. It’s too difficult to deal with. As he said, it would be almost impossible to incorporate it into any kind of risk-analysis or risk policy. We simply haven’t even gotten to the point where we’re even looking at the important things. Like, “What happens during development, to then get bogged down into something this discrete and maybe trivial?” It may not be -- but right now, it seems to be. I hope Joel is right. Myriam Laura Beaulne, Biologist and Environmental Health Organizer, Clean Water Fund and Clean Water Action, The Alliance for a Healthy Tomorrow: I appreciate Dr. Vom Saal’s bringing specific examples of negative effects, because those have been sort of hidden from us. A lot of examples of potentially positive effects have been brought in the work that Dr. Calabrese has published, but I think we need to have a more subjective view.

Shanna H. Swan, PhD, Professor, University of Rochester, Department of Obstetrics and Gynecology, and Department of Environmental Medicine and Department of Community and Preventive Medicine: I’d like to suggest that the negative effects of low doses, or what we call the negative effects of hormesis -- I agree with Fred, that benefit and harm have no part of the definition of hormesis -- are not new or surprising. And I invite Fred, if he could take us through the numbers of studies that have demonstrated harmful effects of very low doses.

Fred vom Saal: Yes. Actually, I take a slightly different view from Theo and Joel on this, in that I totally agree that hormesis as it’s being proposed is being overblown. But just for a chemical that I’m working with -- bisphenol-A, an estrogenic chemical used to make polycarbonate -- there are 11 examples of low-dose disrupting effects of physiological processes that can never be considered. None of them could be considered as anything but adverse. We’re talking about proliferation of prostate cancer cells, induction of calcium influx, and disruption of cell function at phenomenally low doses of this chemical. Then, as you move to 100-1,000-fold higher dose, these effects go away. And if you started from high doses and moved down from very high doses, you would not see them. They just wouldn’t appear in a standard tox test. As I say, there are 11 major papers published, showing these kinds of dose-response curves.

Joel Tickner: I think both Theo and I weren’t opposing what you were saying, Fred. The definition for hormesis doesn’t indicate bad or good. But it’s been co-opted to indicate bad or good. So certainly we know there are low-dose impacts of chemicals. We know that the U-shaped or bi-phasic dose response is common, in some cases. We shouldn’t ignore it. The question is, “Should we give credence to the idea that exposures may have beneficial effects?”

Fred vom Saal: The response I would say is that we have to come up with a strategy that promotes the idea that risk-assessment has to accept that there are dose-response curves other than monotonic functions, that essentially discredit the linear threshold model of risk-assessment for non-carcinogenic chemicals. We have to do that while disassociating ourselves from the nonsense associated with hormesis.

Theo Colborn: Fred, you just said what I was trying to imply. What you’re trying to do is very important. And we haven’t even gotten to that stage, yet, where there is evidence -- solid evidence -- and a lot of studies repeatedly saying that chemicals at extremely low doses do have these developmental effects. But we haven’t been able to get that concept across. I’m like Joel. We just shouldn’t give credence to hormesis, and just hang in there.

Pete Myers: I’d like to refer everyone to a paper that Fred has written, "Large Effects from Small Exposures: Mechanisms for Endocrine-Disrupting Chemicals with Estrogenic Activity." While it’s true that in the vast majority of cases we don’t understand the mechanisms that are lying behind the responses that Calabrese has published as being hormetic, in fact, there are some very clear mechanisms known about the responses of genes to low doses and changes in gene expression, that are described in Fred’s paper. It’s very clear that these low doses are altering gene expressions. Because gene expression under the control of at least the estrodial and similar hormones operates through a system that saturates -- where you’ve got a number of receptors, you fill them all and don’t get any more response -- this is exactly what we would expect to see, in systems like that. So it’s entirely plausible to me that under certain circumstances, some of the genes that are being turned on at those low doses are causing beneficial effects. But as Fred and others on this call have pointed out, it’s no guarantee that only the beneficial effects are going to be turned on.

Albert Donnay, MHS, University of Maryland, Department of Toxicology and MCS Referral & Resources and Donnay Environmental Health Engineering: From my perspective, hormesis is not at all trivial or something that we should ignore, nor is it vague. The idea of the U-shaped curve is very specific. Two areas I think of are in public health terms, where there’s already quite a lot of epidemiologic data, and more coming all the time. I’ll give you an example of a new result I just heard last week at Maryland on the effects of alcohol at relatively moderate doses, and the effects of exposure to tobacco smoke, or smoking. In alcohol, we’ve seen low doses associated with better cardiovascular conditioning in the elderly, as well as a study done at Maryland finding that post-menopausal and peri-menopausal women who drink moderately have fewer hot flashes that don’t drink at all, or women who drink heavily. The mechanisms are unknown, but the effects are there, and they’re the subjects of media reports -- and not yet -- and I doubt ever -- regulatory policy. But it’s clear that we should just look across the whole range and spectrum of effects. There are some very serious toxins that have tremendous public health impact that industries involved with their production like to see these reports, and promote them.

David Wallinga, MD, MPH, Director, Antibiotic Resistance Project, Institute for Agriculture and Trade Policy (IATP): I just want to point out the incredible double standard at work, in terms of new science around non-linear dose-response functions for carcinogens, and new science regarding a U-shaped dose-response function for non-carcinogens. In the first case, EPA has been working for years to weaken a fairly health-protective presumption and risk-assessment, largely on the basis of science that’s generated by the industry. Namely, that carcinogens previously assumed to have a linear dose response function, in fact, act more like a threshold carcinogen. EPA’s been trying to “harmonize” -- that’s their term -- harmonize the risk-assessment procedures across carcinogens and non-carcinogens, in that way. But here, we’re talking about new science that indicates, possibly, a rationale for strengthening the risk-policy presumption underlying risk-assessment for non-carcinogens. But it seems like we’re holding that new data to a different standard than the new data on the threshold carcinogens.

Michael Lerner: Thank you for that comment, David. I’d like to come back to our colleague from the Albert Donnay’s comment on alcohol and cardiovascular risk. Is there somebody among the presenters who’d like to respond?

Theo Colborn: For me, hormesis is probably the lowest dose you can be exposed to. With the alcohol, a drink a day, or something like that isn’t the same as a very, very low-dose exposure. Is that truly called hormesis? Is that what is being considered hormesis, now?

Albert Donnay: What is hormetic is the shape of the curve. If there’s a specific endpoint of response that you’re looking at, as you move along the dose spectrum, at one end, you get a response in the positive direction. At the other end, you have a response in a positive direction, but it dips in the middle -- or vice-versa. The curve can be an upside-down U. It just depends on if you’re looking for what you call a positive or negative effect. But the idea is that at some point, the curve is convex or concave. There’s a hole in the curve, where your effect reverses itself.

Joel Tickner: I don’t think there’s a lot of controversy about it happening. The question in your case of alcohol is that a person -- an individual -- controls their intake of alcohol. They don’t control their intake of toxic substances in their environment. So there is a difference, of course. We know nutrients operate on sort of a U-shaped dose-response. But you’re also controlling those. So, there is an issue. I don’t think anyone doubts that it’s happening. We know it’s happening. How much it’s happening is in doubt. The mechanisms by which it’s happening, sometimes, are in doubt. But the question is could you use it as a generic phenomenon in chemicals risk-assessment for environmental occupational purposes?

Michael Lerner: Albert, I’d like to give you a chance to respond. You’re the one saying Calabrese’s position is not trivial, and a number of other people have said it is. So what is your response to Joel’s comment, or do you have any further comment? I just think it’s very important for this voice to be present in the call.

Albert Donnay: In public health terms, that’s where I’m coming from. We have examples that involve toxins, whether by choice or not by choice. I certainly agree that’s a critical difference. Alcohol is by choice. Ozone and carbon monoxide are not by choice. We have to see those as toxins that affect huge parts of the population that behave in this way. Whether they’re regulated by industry alone, or regulated by government as well, I think we need to be aware of the whole spectrum of hormetic effects in public health -- not just looking at endocrine disruptors or effects on fetuses or animals. I support Calabrese’s view that this can be found almost anywhere you look for it. We can’t have an across-the-board response to it, therefore. We have to take them case-by-case. And I like what I’m hearing from the other presenters, who’ve pointed out that in many cases, the effects you see of the very low doses are just as negative as the effects of the high doses. I fault Calabrese for always only looking at what he calls, “positive low-end effects.”

Jack Leiss, PhD, Chief Epidemiologist, Constella Health Sciences: I also think this is not trivial from an epidemiologic perspective -- but for a different reason than what has been mentioned, before. That is, I think it just really adds to our emerging understanding of the complexity of the exposure, and the complexity of effects. I think as many of the people on the call know -- one of the biggest problems with epidemiologic studies of environmental exposure is a difficulty in measuring the exposure and not completely knowing what effect to look for. What’s a relevant exposure? I think that actually is important from an epidemiologic point of view.

Karen Florini, Senior Attorney, Environmental Defense: I’d like to try to tease out something that both David Wallinga and Theo Colborn alluded to. What are we talking about, in terms of “low?” Non-cancerous effects use a threshold model, anyway -- for the most part. So is the hormetic effect alleged to occur above or below those thresholds? Another way to look at this is whether it has any implications beyond cancer risk-assessment?

Fred vom Saal: I have some data that I could use to answer that question. The presumed no-effect dose for bisphenol-A is 5 mg per kg body weight. And the no-effect or presumed reference dose used by the EPA is now 50 micrograms per kg. But 50 micrograms per kg puts an amount of bisphenol-A into the blood of a developing mouse that’s about 10,000 higher than levels that can actually stimulate responses in target tissues. The lowest dose of bisphenol-A so far to cause a really dramatic change in cell function is 230 centigrams, or essentially 0.23 parts per trillion. So you are down at a level that 20 years ago, people would have locked you up for suggesting could possibly cause an effect of what is being described as an extremely weak estrogenic chemical. Marcia Marks:I just wanted to say that the nuclear industry has been putting out a lot of information on hormesis lately. I think it’s very much related to the Administration pushing for 50 more nuclear reactors, and the increasing nuclear defense and, of course, the waste and everything that the public is going to be exposed to. Fred made a comment himself about tests being done based on adults. My understanding was that most tests on chemicals and other things are done on a 170-lb male.

Joel Tickner:Well, they assume the 170-lb man. I mean we don’t do test on 170-lb males except on controlled experiments. That’s generally the assumption in risk-assessment as we’re looking at adult risk or adult exposures.

Robert Gould, MD, President, San Francisco Bay Area Physicians for Social Responsibility: This actually follows on what Marsha Marks just mentioned. We’ve actually encountered, on the nuclear side of things, the hormesis arguments are being used rather commonly and by federal agencies. We’ve had experience, for example, close by here, in the Lawrence Livermore Lab, which was investigating under ATSDR, a number of tritium accidents over the last 40 years, which resulted in about a million curies being released. Scientists at ATSDR were incorporating arguments into the reports -- the investigation that they had done for the agency, as to the health effects. So this actually has been a problem on the radiation side of things. At this point, in terms of radiation exposures, most scientists adhere to the fact that there is no “safe” level of radiation. Yet again, federal scientists are beginning to bring these arguments in. So I think it’s important to highlight that as we’re discussing chemicals. I wonder if anybody has any comments, among the presenters, on hormesis, but on the radiation side.

Joel Tickner: I’m not a nuclear-radiation person, but this is the one area where it has been argued for decades. There is some work by folks -- Leslie Stainer who is an epidemiologist at the University of Chicago has written a bit, sort of saying it’s premature to argue hormesis on radiation, as well. So there actually is some literature now, responding to this concern.

Michael Lerner: Anybody want to support the idea that perhaps in the nuclear area, hormesis is real and could have a positive benefit? Anybody want to make the nuclear industry argument in an authentic way? After all, maybe it doesn’t mix with other chemicals, in the same way. I’m just trying to ask why that’s been argued for decades -- and is it different from chemicals?

Nancy Evans, Health Science Writer/Editor/Consultant/Filmmaker: I’m not a scientist, but I do know that there has always been the argument from the health professionals involved in radiology, that low-dose exposures are irrelevant and really won’t hurt you. So much so that the American College of Radiology is challenging the addition of X-radiation to the National Toxicology Program’s List of Known Carcinogens. You have to weigh the risk and the benefit. But there is always a risk. So it is an argument that radiation professionals use. They don’t use the word, “hormesis,” but they say low doses really don’t matter.

Rachel Massey, MSc, MPA, Research Associate, Global Development and Environment Institute, Tufts University: I have a comment about definitions. The one thing that I noticed was that there seemed to be some inconsistency in how hormesis was being defined, just within our discussion. I think we need to be really clear about whether we’re using the word hormesis to mean positive effects at low doses, or whether we’re using it to mean effects of any kind -- special effects of any kind -- at low doses. We’ve been discussing both of those things. But when Joel, for example, says, “Hormesis isn’t something we need to take seriously,” clearly he’s talking about the notion that only positive effects occur. When you say, “Good or bad is not in the definition of hormesis,” then you seem to be talking about something broader. So I think it is really important for this debate that we know exactly what we mean, by the word.

Joel Tickner: This is actually a good point that Linda Birnbaum, who is a toxicologist at the EPA brought up on a call that Environmental Media Services put together, that I think Pete was involved in. Which is to say, just get rid of the name, “hormesis” because it carries baggage. We should be talking about low-dose effects of chemicals, or low-dose beneficial effects. Maybe Ed Calbrese should be arguing -- not hormesis. It’s been interpreted by the conservative pundits. There’s a whole literature out there now on the economic cost-benefit analysis of hormesis, that is just the most academic exercise. But it’s being framed that way. If you look at industry journals like The American Industrial Hygiene Association Journal, you’ll see that these industry and industrial hygienists are talking about hormesis and suggesting, “maybe we should expose workers a little bit more, because that might be good for them.” You’re right. We need to be careful with the definition and maybe just throw it out, but respond to the fact that hormesis is generally being considered out there -- beneficial effects of low doses.

Fred vom Saal: Technically, Calabrese identifies hormesis as, “low-dose stimulation above baseline levels followed by, at higher doses, inhibition below baseline levels,” where you get into the realm of overt toxicity. The problem is that hormesis, in that respect, is thought of as the response of a particular set of cells or a tissue or something within an organism. Calabrese also applies this concept to population data. Then, he goes on to apply some kind of similar mechanism to events going on like survivorship curves -- as well as events going on within a specific cell. To me, conflating those two makes it almost impossible to really understand what he’s considering to be hormesis. So there is an inherent problem with trying to figure out just what the heck hormesis is.

Ted Schettler: Could I just add to that comment by going back to Albert Donnay’s point about the protective effects of low-dose alcohol, in terms of cardiovascular risk? We’re also there looking at a rather apical endpoint in an organism -- not at a cellular level and not at a population level, necessarily. But at an organism where you probably have a superimposition of various dose-response curves that represent various mechanisms. So at relatively different doses, you see the emergence of different toxic or salutary effects -- depending on where you are in the aggregation of those dose-response curves. So that’s yet another complication in terms of trying to figure out what phenomenon we’re actually talking about, here. Michael Lerner: I want to interject a question for you, Fred. I’m sure there are others on the call who would ask this. This is outside the realm of normal science. As somebody in my career who’s devoted to studying complementary and alternative medicine, this debate -- I’m sure -- reminds us of the debates over homeopathy. I ask not to introduce homeopathy into CHE discourse, because it is not a scientific discipline, and should be separated out. But it is a tradition of clinical medicine with deep roots in Europe and widely practiced in Europe. I just want to note the whole issue about hormesis raises some of the sort of fundamental precepts of homeopathy as a therapeutic discipline. Do you have any thoughts or comments on that?

Fred vom Saal: The problem with homeopathy is you’re talking about doses where people are down at 10 to the minus -35th molar, in other words, maybe a molecule in a swimming pool. Hormesis -- I perceive -- as being a little different from that, it got essentially killed by homeopathy, of course, back in the ‘30s. We can actually model effects of the hormones -- the endogenous hormone estrodial in a developing fetus at about a molecule-per-cell. The amplifying effects of endocrine-response systems are so unbelievably phenomenal that literally, a single molecular event can lead to a detectable output. Some people might consider that as something associated with homeopathy. Yet, homeopathy really comes at this from levels so far below that, that I don’t know if there’s a connection.

Michael Lerner: I think if there were a homeopath on the call, they would say that actually homeopathy uses a variety of doses, some of them, as low as you’ve described -- but others, higher.

Iris R. Bell, PhD, MD, Professor of Psychiatry and Psychology, Director of Research, Program in Integrative Medicine, The University of Arizona College of Medicine: I just feel compelled to jump in here about the issue of homeopathy, because as you know, I do research on homeopathy. I had previously done a great deal of work with low-dose sensitizations in vulnerable populations. My feeling about homeopathy, if you actually get into the literature right now, and you see some of the newer work that we’ve been doing and some other groups have been doing, it’s very clear that you can demonstrate non-linear dose-response curves, both below and above Avogadro’s numbers. I think it is potentially quite different, in terms of what you’re doing when you’re past Avogadro’s number. But the movement is to really look at the network structure of the water molecules in the solvent, rather than the original molecules. There really is some basic science evidence that is credible -- suggesting that the structure of the water, and the physical chemistry properties of the water have been altered by the preparation of the remedies. Beyond that, in countries like India, they are using homeopathic prepared arsenic to treat the endemic arsenic poisoning in the populations. And they have data to show on both animals and people that it increases the excretion of the arsenic. So I think we have to step back and say that if homeopathy eventually receives some serious scientific consideration, it opens up the possibility of using hormetic-like phenomena.

Albert Donnay: I want to comment that in homeopathy, looking for a low-dose and finding an operative low-dose response doesn’t mean it’s hormetic, unless there’s also a higher dose that produces the same effect. Because it’s a U-shaped curve, it’s not hormetic unless you get the same effect -- whatever endpoint it is -- at a very low dose and a much higher dose, with some gap in the middle where you do not get that effect. I don’t think that’s planned, for homeopathy. Iris Bell:I don’t want to get into that whole argument about it. But there’s a tremendous importance of individual differences, coach factors that we really haven’t addressed in the hormesis, and haven’t been addressed very much in the hormetic literature. I think that’s one of the most-important lessons, scientifically, that homeopathy might be suggesting for us for future research.

Michael Lerner: That’s, I’m afraid, the last comment -- just because of time. I just do want to delineate something. Normally on CHE calls, we don’t discuss complementary and alternative medicine. The reason I introduced the issue -- and I’m glad I did -- is that there is an active relationship between these two fields, one in mainstream medicine, and the other in complementary medicine. They need to be very carefully distinguished. But I think there is a further conversation here that those who share these two interests might want to have. I felt this was an extraordinarily interesting call. I want to thank all of our presenters, Ted Schettler, Pete Myers, Fred Vom Saal, and Joel Tickner. We look forward to seeing you next time on our national partnership call.