RHR: Dr. Chris Shade on Mercury Toxicity

At CCFM, we use Dr. Shade’s test methodology and protocols for metal toxicity, and a pretty high percentage of our patients are dealing with it on some level, and we’ve found the protocols to be really effective. Several patients stand out in my mind in terms of people who’ve had quite high levels of mercury or other metals, and then within several months of the protocol and retesting them, watching those drop below the normal levels and watching their symptoms improve. It’s exciting as a clinician to have access to new tools that I feel like I can rely on and are evidence based and aren’t going to cause any harm!

In this episode, we cover:

4:29  Dr. Shade’s Background
10:06  What mercury does to your body
15:55  How we get exposed to mercury
32:20  What determines an individual’s sensitivity to mercury
38:04  Testing for mercury

Chris Kresser: Hey, everybody, it’s Chris Kresser. Welcome to another episode of Revolution Health Radio. Today I’m very excited to have Dr. Christopher Shade as a guest on the show.

Dr. Shade obtained a bachelor’s and a master’s degree from Lehigh University in environmental and aqueous chemistry and a PhD from the University of Illinois, where he studied metal-ligand interactions in the environment and specialized in the environmental and analytical chemistries of mercury. During his PhD work, Dr. Shade patented analytical technology for mercury speciation analysis and later founded Quicksilver Scientific to commercialize this technology, and it’s the lab that we use for heavy metal and mercury testing, as you’ll learn in the show. Shortly after starting Quicksilver Scientific, Dr. Shade turned his focus to the human aspects of mercury toxicity and the functioning of the human detoxification system, and that’s what we’re going to be talking about today.

So without further ado, let’s begin the interview.

Chris, it’s such a pleasure to have you on the show. I’ve been wanting to do this for a long time, and I’m glad we could finally get our schedules to synch up.

Dr. Christopher Shade: Absolutely, Chris. I’m glad. I’ve been looking forward to talking to you for a long time as well, so this is great.

Chris Kresser: Great. I think this is going to benefit a lot of people—myself included—especially when we get into the discussion of selenium and mercury because that’s something I’ve written a lot about, and I understand I need some re-education on that topic based on the conversation that we were having before! And like I said, I always look forward to that. One of the things I love about my job is that I never stop learning, and I guess that’s why they call it a “practice.”

Dr. Christopher Shade: Yes.

Chris Kresser: I think I would be bored to tears if I didn’t get a chance to do this sort of thing every day.

Dr. Christopher Shade: Absolutely. It’s amazing when you see integrative medicine over the last 30 years, so many things that have come and gone, and often you see some clinical manifestation, you get a mechanistic explanation for it, and it’s wrong, but it sounds good and so we run with it, and there’s some truth to it, but time just brings clarification to these things.

Chris Kresser: Yeah. One of my favorite quotes is that the history of science is the history of most scientists being wrong about most things most of the time.

Dr. Christopher Shade: There’s an equally good one that science proceeds one death at a time.

Chris Kresser: Exactly. Yeah, both equally true, so let’s kill some things and correct some misconceptions here. But before we do that, I want to ask you just a little bit about your background and how you got interested in all this stuff.

Dr. Shade’s Background

Dr. Christopher Shade: Yeah, I come from a very holistic background. I was originally sort of a very reductionist scientist, and I sort of had this spiritual awakening and was disenthralled with science, and I went into organic farming for a while, and I was into sustainable agriculture, and I really liked that and looking at ecosystems and how soils and microbes and plant matter all come together. And from there I actually was a farmer for a while, and then I left that and went back to grad school and was looking at nutrients in stream waters near agricultural areas, and that brought me to looking at the University of Illinois, a big ag school, for a PhD.

And when I was there, I was interviewing with some ag people, and they put me through into an interview with a guy who was a modeler of global mercury cycling and a modeler of how mercury moves through the environment. His name is Bob Hudson, and he was fascinating. In five minutes with him, he taught me more than I felt like I had learned in my whole master’s degree. He just tied everything together so nicely, and he said, “Hey, are you good in the lab?” And I said, “Aw, yeah, I’m great in the lab.” And he said, “Well, we need new analytical methods for mercury because the ones that are there are so difficult. Can you design me a new mercury speciation method?” That means separating different forms of mercury in the analysis. I didn’t even know what was ahead of me, but I said, “Of course, I can do that.” And the rest is history.

Chris Kresser: Right.

Dr. Christopher Shade: I went to work for him, and in doing so, I learned everything about mercury. All the best mercury chemists were in environmental chemistry at the time because the government wasn’t giving any grant money for clinical mercury research. They were putting it all into environmental mercury research, so all these good oceanic chemists and aquatic chemists and biological mercury guys all came together. We had mathematic models of how mercury moved through the environment when it bound to this, when it bound to that. It goes up into the air as this. It rains down as that. So it was a really sophisticated understanding during which I developed and patented this mercury speciation analysis that we do.

But when I came from there into starting a company based on that patent and I wanted to get from the environmental testing I was doing back into clinical testing, I started meeting the people in integrative and functional medicine, and I found that the understanding of mercury analysis and mercury toxicity wasn’t very advanced. It was very much a black box. The body’s the black box, and if I put the chelator in, the mercury comes out. And if it comes out, that’s bad, and if it doesn’t come out, that’s good—where actually it’s kind of the other way around sometimes—and there was no good mechanistic understanding. This is what we said. They had clinical observations of mercury toxicity that were true. They saw that people got better when they detoxed, and they tried to create a story in between, but the story was fundamentally flawed. So I really endeavored to bring clarity to the story, and when you bring clarity to the mechanism, you come up with better solutions to the problem, and that’s really what I’ve been doing for the last six or seven years.

Chris Kresser: Yeah, I want to thank you for that work because we’ve definitely been the beneficiary of it in our clinic, as you know.

Dr. Christopher Shade: Yes.

Chris Kresser: We use your test methodology and protocols for metal toxicity, and a pretty high percentage of our patients are dealing with it on some level, and we’ve found the protocols to be really effective. Several patients stand out in my mind in terms of people who’ve had quite high levels of mercury or other metals, and then within several months of the protocol and retesting them, watching those drop below the normal levels and watching their symptoms improve. It’s exciting as a clinician to have access to new tools that I feel like I can rely on and are evidence based and aren’t going to cause any harm!

Dr. Christopher Shade: Yeah, that was a big thing. I was originally just getting into testing, but of course, I worked on myself, and I started taking DMSA and I had all these amalgams, and it just got me really sick.

Chris Kresser: Yeah.

Dr. Christopher Shade: So I got the amalgams out and kept taking the DMSA, and it just kept getting me worse and worse and worse. And it was at that low point, the sort of dark night of my biochemical soul, that I saw that I had to approach it totally differently, and that was what gave rise to this system we have upregulating the glutathione system and all its components. It’s really nice that that does so many more things for you than just moving mercury out of the body.

Chris Kresser: Right, the side effect of feeling better is a good side effect!

Dr. Christopher Shade: Great side effect!

Chris Kresser: That’s what we go for in functional medicine, right?

Dr. Christopher Shade: That’s it!

Chris Kresser: You treat the root of the problem, and things spontaneously improve instead of side effects that require other drugs.

Dr. Christopher Shade: Another drug, yeah.

What Mercury Does to Your Body

Chris Kresser: Yeah. Anyway, let’s take a step back since some people listening to this podcast are probably not familiar with just the basic physiological effect that mercury has on the body. We don’t need to go into excruciating detail here, just kind of a 101, 2- or 3-minute summary of how mercury really screws us up when it gets into our body.

Dr. Christopher Shade: Yeah, it’s really better to keep it at a broad summary because mercury is one of these things that has such a broad target that it tends to hit the weakest link in your chain.

People talk a lot about enzymes that are in the body and how enzymes regulate different processes, and they’re basically there to make chemical reactions happen that wouldn’t be favorable unless an enzyme was tying pieces together to make it happen. And one of the keys of these enzymes are what are called sulfhydryl groups. It’s a certain kind of sulfur, and in the enzyme, enzymes are proteins built of amino acids, and it’s the cysteine groups, the amino acid cysteine within the protein structure, that have this sulfhydryl group. And the sulfhydryl groups are very good at moving electrons around, and they’re very good at holding metals in place, metals that you want to use, like copper and zinc. But unfortunately, the thing that has the greatest affinity for them is mercury, and so mercury can get stuck onto them and maybe displace the copper or the zinc that was supposed to be in there. Or if it’s an active site that’s supposed to be moving things around, it stops it from doing its job. So mercury is good at stopping enzymes that happen.

To get more specific about places in the cell and places in the body where this blocking occurs, one of the most fundamental places it occurs is in the mitochondria, where it can disrupt the harmony of the mitochondria. In a harmonious mitochondrion—if you picture the mitochondrion like a furnace—you’re feeding wood into the furnace and it’s burning it up and creating heat that you use for work. Like in a steam engine, you use it for work or you heat the house with it.

Chris Kresser: Mm-hmm.

Dr. Christopher Shade: But what happens when you disrupt the controls on that fire, the fire starts coming outside of the furnace and burning the basement or burning the kitchen that it’s in. So instead of generating ATP, which is cellular energy, there’s what’s called a decoupling of the electron transport chain, and now the energy that’s moving through the electron transport chain spins out the side and becomes free radicals. Now, a little bit of free radicals is good, but what you want is a lot of ATP and just a little bit of free radical.

Chris Kresser: Right.

Dr. Christopher Shade: But in this case, it goes the other way, and you get a lot of free radical and just a little bit of ATP. And so that dysfunction in the mitochondria leads to the most classic symptom of metal toxicity, which is fatigue, just slowing down energy production, so that chronic fatigue. And one of the ways that mercury does this is by attacking the antioxidant system in the mitochondria that’s keeping this furnace in check. There are special antioxidant molecules in the mitochondria, and they’re able to handle the normal free radicals that are generated through respiration, but they’re not able to handle metals, and the metals which specifically target them are mercury, cadmium, and arsenic.

Chris Kresser: Mm-hmm.

Dr. Christopher Shade: Now, it’s important to remember those three because they’ll come up in our narrative a couple of times because the glutathione system is very good at detoxifying those three. And conversely, they’re very good at attacking things that the glutathione system would normally protect. So the mercury is wearing out the mitochondria, and that could be through the whole body.

Another target that’s more of an organ target would be the thyroid, and there’s a similar effect there. In the thyroid, it blocks the conversion of T4, which is the hormone that comes out of the thyroid. It blocks the conversion of T4 to T3, which is the one that’s active in the rest of the body, turning up the respiration in the rest of the body. So there’s another thing where it’s bringing fatigue, possibly weight gain. It’s slowing down metabolism.

Then let’s hit one third very common target in the body, and that’s the brain. The most well-defined target in the brain is the NMDA receptor, which is the glutamate receptor. In your brain, the symphony of neurochemistry in your brain is most dominated by the yin-yang pair of GABA and glutamate, where GABA is a calming neurotransmitter and glutamate is an activating neurotransmitter. But when glutamate is hyper-expressed, as happens with mercury toxicity, you get high levels of anxiety. You’re overstimulated and your body is stuck in what’s called sympathetic autonomic tone, where it can’t relax, it can’t repair, it can’t digest. It’s just running, running, running, in fear all the time. And so there’s this combination of fatigue in the body while hyper-stimulating the neurology that’s sort of the most common presentation of mercury toxicity.

Chris Kresser: Well, that sounds like a real perfect storm.

Dr. Christopher Shade: Yeah, it really is!

 

 

 

 

How We Get Exposed to Mercury

Chris Kresser: Let’s talk about the major routes of exposure for mercury, in particular. We have dental amalgams.

Dr. Christopher Shade: Yes.

Chris Kresser: Many of us grew up with mercury amalgams in our mouth, and some people still have those in their mouth. And then, of course, we have seafood.

Dr. Christopher Shade: Yeah, and those are really the big two. In a lesser level there’s also exposure to mercury from vaccines, but the mercury in vaccines is progressively being taken out and being replaced with aluminum, which has its own problems, but it is really dominantly those two, though I will find occasionally exceptionally high levels in people and find out that they are using skin lightening creams. These tend to be Latin Americans and Asians, where there’s a premium placed on porcelain-white skin, and these topical creams break down the melanin, so they make you whiter, but the one that we just had a case of and we analyzed the cream, it was 2.6% mercury. That’s 2.6 parts per 1000 mercury versus a fish that would be maybe 1 part per million to 1 part per billion mercury.

Chris Kresser: Wow.

Dr. Christopher Shade: Aside from those rare cases of those skin creams, it’s fish and it’s amalgams.

With amalgams, it depends how many amalgams you have and how much surface area they’re covering, and that mercury is coming off as a vapor all the time, being inhaled into the lungs. You have 80% absorption into the blood lipids, and it’s transported through the whole body. Now, it’s not actually toxic as that mercury vapor, but when the vapor then oxidizes or rusts to become the salt, inorganic mercury, that’s when it starts sticking onto enzymes and membranes and interfering with biochemistry.

Chris Kresser: I just want to highlight that because I think there’s some misunderstanding out there about dental amalgams and how they cause problems. I’ve even heard dentists in the past saying, “If the amalgam’s intact and the tooth is healthy, there’s no problem.”

Dr. Christopher Shade: Right.

Chris Kresser: “The mercury’s not seeping into the body.” But it’s actually the vapor, as you said, that’s being swallowed and contributing to most of the exposure for people.

Dr. Christopher Shade: It’s actually the inhalation of the vapor, is how you’re getting it. So there are two things happening from the amalgam: There’s a vapor coming off that you inhale, and that’s your route in for the vapor, and then there’s a corrosion product that’s happening on the surface, a rusting on the surface, and you’re swallowing that. Now, the stuff you swallow you don’t absorb much of, but it irritates your whole digestive lining, and when we talk about detoxification, we’ll see that that’s actually blocking detoxification. One form, the vapor, is going in and forming mercury inside your body, or forming inorganic mercury inside your body. The other form you’re swallowing, and it’s blocking the route out.

Now, in regards to the claim that mercury is stable inside the amalgam, mercury evaporates from the liquid mercury—that liquid, silvery stuff—at a fairly high rate. Now, when you combine it with silver and copper and zinc, like you do in a mercury amalgam, it then evaporates at a much lower rate. It doesn’t not evaporate. It evaporates at a much lower rate. In fact, when I was in environmental mercury analysis, when you’d go to tradeshows and the people would show you their mercury analyzers, they’d say, “Do you have amalgams?” And you’d say, “Yes.” And they’d go, “Blow in it!” And you’d see the mercury levels rise up. That is just the sort of thing that they’re hiding around, that it’s stable when they’re put together, and it’s just not true. It’s just not as volatile as it is when it’s that liquid mercury.

Chris Kresser: Right. All right, well, let’s talk a little bit about seafood. This is where I think I’m going to get some education from you! I know you don’t agree with or at least you have a different understanding than Nick Ralston, whom I’ve interviewed in the past and talked to at length about the protective effect of selenium with mercury. We were talking about that before the show. Maybe it would be fun at some point to have a kind of roundtable discussion, but I’m really curious to hear your perspective and what I’m missing in this whole understanding of the relationship between selenium and mercury.

Dr. Christopher Shade: Yes.

Chris Kresser: And maybe even before we go into that, just talk a little bit about fish and seafood and what the biggest concern is in terms of mercury.

Dr. Christopher Shade: Sure. OK, so the mercury in the fish is not in the fat. A lot of toxins are in the fat, and a lot of people think it’s in the fat, but it’s actually in the proteins, and again we go back to this story of cysteine, the amino acid that is part of the protein structures, and it has this sulfhydryl group, and the sulfhydryl group has a high affinity for mercury. So the methylmercury sticks to it, and when you eat it, you digest the proteins and you hydrolyze all that protein into amino acids, and then you have free cysteine and it still has the methylmercury stuck to it.

Now, it just so happens that methylmercury bound to cysteine looks, to your body, a lot like methionine, another amino acid. So you have molecular mimicry and you have absorption of the methylmercury cysteine through amino acid transporters in your GI tract, and that’s why you get 95% uptake of mercury from fish. OK? And then it distributes through the body, and it moves around as an amino acid until it jumps ship from the cysteine and lands on some other binding group, which is usually some other sulfhydryl group.

Now, it can also bind on selenium groups. The only thing that binds mercury stronger than a sulfhydryl group is a selenol group, which is selenium with a proton on it. And there are analogs of sulfhydryl groups called selenols. So there’s cysteine and then there’s selenocysteine, and selenocysteine is put into some very special antioxidant molecules, like glutathione peroxidase and thioredoxin reductase. One of the targets of mercury are these enzymes, thioredoxin reductase and glutathione peroxidase, and when you knock out all of the thioredoxin reductase, it’s very damaging to the organism because it stops you from being able to replicate DNA and it stops a number of different processes, and so it’s very toxic to the body. And what you need is a constant supply of selenium to then rebuild that thioredoxin reductase and the glutathione peroxidase, these things called selenoenzymes. So selenoenzymes are one of the targets of mercury, but not the only target. And so if your diet is high in mercury and low in selenium, you quickly deplete these selenoenzymes, and that becomes a major aspect of the toxicity of mercury in that situation, where you’re low selenium, high mercury.

Now, Nick Ralston had been doing some very nice studies where he was selenium depleting—and this is the part that is not conveyed right—he was selenium depleting mice and then feeding them mercury, and they had these toxic manifestations, very bad ones that would kill them eventually. And then he would slowly bring up their selenium status, and they would be less reactive to that mercury. And so when you look at that, it looks like selenium protects you from mercury toxicity, but what it is is that selenium depletion makes you more susceptible to mercury toxicity.

Now, this isn’t the first time these studies were done. These studies were done back in the ‘70s—maybe it was the ‘80s; I’d have to look back to the studies—and what they found was that the selenium deficient animals were super-susceptible to mercury. And then as they raised them up to selenium repletion in the diet, where they had enough selenium, they went up to a normal susceptibility to mercury. And then as they raised the selenium beyond the nutritional needs, they did not get any further protective effect.

Chris Kresser: Mm-hmm.

Dr. Christopher Shade: So it’s not that the selenium blocks all toxicity, but the selenium blocks this extra toxicity that comes about from selenium deficiency. And so when you hear Nick Ralston talk, he’ll talk about fish-eating populations that don’t really have other selenium sources in their diet, and so their selenium-mercury balance was dependent on the fish, and if they were eating low-selenium fish, they tended to have more problems than people who were eating higher-selenium fish.

Chris Kresser: This is, like, people in the Faroe Islands in the study that was done there that you’re referring to?

Dr. Christopher Shade: Yeah. They had more toxicity versus the one in the Seychelles that had more selenium and less toxicity.

Chris Kresser: Yeah.

Dr. Christopher Shade: But the guys in the Faroes also had a lot of PCBs, so there was an added thing there. And then that conversation started to turn towards, if there’s enough selenium in the fish, it binds all the mercury and you never absorb it, it’s all bound to the selenium, and that’s just patently untrue. There has been a lot of work proving that the predominance of the mercury is bound to cysteine groups that are sulfhydryl groups, so you will absorb them.

So again, just to recap that, if there’s not enough selenium in your diet, you’re going to be extra-susceptible to mercury. And if the mercury is coming from fish and there’s not enough selenium in the fish, you’re still going to be selenium deficient and you’re going to be extra-susceptible to mercury toxicity. But once you get enough selenium, it’s not like you’re immune from mercury toxicity, and there are a lot of guys who have had a lot of mercury toxicity just from the fish even though they have good selenium levels. And so I get a little worried when the conversation starts simplifying itself, and I’ll say that Nick does like to simplify it. We go to the global meetings together, and I see him every two years, and the last time I talked to him about this and I said just that, he said, “Yes, that’s true.”

Chris Kresser: Mm-hmm.

Dr. Christopher Shade: Yet the narrative continues saying that if there’s enough selenium in the fish, it doesn’t matter how much you eat.

Chris Kresser: So what do we make of the studies—let’s just think about maternal seafood consumption, for example, because that’s obviously one of the biggest concerns, is childhood development. I mean, as a parent, that’s a huge concern for me, that my child is safe, and that’s, I think, what’s on a lot of people’s mind. I’m aware of, I think, four kind of big reviews that evaluated the effects of maternal mercury exposure from seafood on subsequent child development, and I think one of those was the Faroe Islands study, one was the New Zealand study from the late 1970s, and then there’s the Seychelles study and another one in the UK. As far as I could tell from looking at those studies, the Faroe and New Zealand ones definitely showed harm.

Dr. Christopher Shade: Right.

Chris Kresser: But they were selenium-deficient populations, which would make sense. And then the Seychelles and UK ones not only found no adverse effects from consuming seafood, maternal consumption, but they actually noted neurological and developmental impairments among children whose mothers had avoided fish consumption. So what do we make of that?

Dr. Christopher Shade: Let me be really clear that I’m not saying, “Avoid seafood.” The only rational discussion of this is that you manage the mercury levels that you bring in because there’s a hundred-fold variation from the top of the mercury scale to the bottom in terms of the seafood, so I just want to go on… because I don’t believe in abstaining from seafood because of this.

But one of the problems… so you see this broad population study, and you say, “Wow, broadly, New Zealand and the Faroes had problems, broadly, England and the Seychelles did not have problems, and so that’s all there is to the story.” But the genetics, the subpopulations that are super-susceptible to the problems are, by far, the most important thing. When we look at this population, we put everybody into a statistical thing alone. Some group of the population that’s 10 percent of the population or 15 percent of the population that’s ultra-susceptible, they get lost completely.

Chris Kresser: Yeah.

Dr. Christopher Shade: This is most clearly evident in what was called the Casa Pia Study, the Children’s Amalgam Study in Portugal. They took this population of orphans, and they did half of them with amalgams, half of them with non-amalgam composite, and they tracked them for a while. And there were some funny things that happened with the urine, but when they looked at their neurological scores, they didn’t see any difference on the composite between the amalgam and non-amalgam group, and so the pro-amalgam people were like, “See? I told you there’s no problem.” But then when they went back in and they looked at some genetic subtypes that they believed would be more susceptible to mercury toxicity, they found a profound effect of the mercury—and these are not at massive levels. These are at levels that most of us are exposed to here if we have amalgams. They found profound neurological deficits and developmental delays of two to three years in this subtype, and it’s hard to get exactly what the percentage was on the subtype, but it looked like it was about 10 percent.

Chris Kresser: Yeah.

Dr. Christopher Shade: But you don’t see that when you look at everybody all together. And so these population studies are a good first cut, but we should not be determining everything we do based on that when we know so much about nutrigenomics and how different gene sets are going to make us more susceptible to things. There was a company that was going to come out with a gene panel that was all about mercury susceptibility so you could see if I’m a more susceptible one, then I’m going to be more careful about limiting my fish consumption to the bottom of the food chain, and if I’m less susceptible, I’m not going to worry about it as much. That’s where these narratives really have to be going. We have to get away from these archaic large-population studies and just extrapolating and saying, “Oh, everything’s fine.”

Chris Kresser: I couldn’t agree more. In functional medicine, we say we treat individuals, not populations.

Dr. Christopher Shade: Exactly. And we’re getting all the tools to do that now.

Chris Kresser: Yeah. Another example where that plays out is with studies on the effects of dietary saturated fat on cholesterol levels. On average, actually, despite popular belief, saturated fat has kind of a null effect on cholesterol, if you look at the most recent large-population studies, but I can tell you unequivocally that there is a subset of people, particularly ApoE 3/4 and 4/4, whose cholesterol will skyrocket if they go on a low-carb diet that has a lot of saturated fat in it, and I’ve seen that with testing.

Dr. Christopher Shade: Right.

Chris Kresser: And then we switch those people to a higher-carb, what I call a Mediterranean type of paleo diet, and their cholesterol goes right back down, so it’s the same kind of phenomenon.

Dr. Christopher Shade: Right, we kind of fell into that with the paleo thing, like, “Oh, everybody can do this meat-all-day thing!”

Chris Kresser: Right.

Dr. Christopher Shade: And you know, I fell into that, too, and I found I had to go Mediterranean, and that does best for me.

Chris Kresser: Yeah.

Dr. Christopher Shade: So we’ll just get better and better as we go at picking this all apart.

What Determines an Individual’s Sensitivity to Mercury

Chris Kresser: Yeah. So since we already touched on this, let’s talk a little bit more about what the factors are that determine an individual’s sensitivity to mercury.

Dr. Christopher Shade: Well, one of my favorite papers when I teach to use for this was a cell culture study where they had a big bank of these different cell types and they were assaying them for resistance to metals. And they found this cell type that was resistant to cadmium, mercury, and arsenic—remember, those big three I talked about.

Chris Kresser: Mm-hmm.

Dr. Christopher Shade: And then they took apart the biochemistry in the cells and they found that they had high amounts of glutathione synthesis, high amounts of glutathione S-transferase, which is an enzyme which will take the metal away from a cellular protein where it’s interfering and link it onto glutathione, so that’s transferring it to glutathione, and then high amounts of a shuttling protein that pushes it out of the cell. So if the cells had the glutathione, could transfer the metal onto the glutathione and shuttle it out of the cell, they could live in a lot of mercury, cadmium, and arsenic, so they had resistance. But then when the scientists went in and slowed down any one of those three processes, these cells then could not live with that same amount of metal. So they lost their resistance. They gained sensitivity to the metal.

So the way that your intracellular detoxification and antioxidant mechanisms works determines your susceptibility on that level to the toxicity of the metal. So if you have low expression of glutathione synthesis, low expression of glutathione S-transferase, and low expression of those transport proteins—and that can be from single nucleotide polymorphisms, or it can be from some epigenetic factor that is blocking the expression of those, and maybe we’ll talk later on what some of those factors are—but if that system isn’t working for you well, then those metals are going to hit the sensitive spots that create the toxic effects, so you’re going to have sensitivity to them.

However, there’s also immune sensitivity. Some of the labs that measure the immune sensitivity—you have Cyrex Labs; they do antibodies to mercury compounds. Then ELISA/ACT labs and the MELISA test. I think that’s done by Pharmasan—

Chris Kresser: Yeah.

Dr. Christopher Shade: —are looking at T lymphocyte reactivity to different metals. Once your immune system has seen this as an allergen, you’re going to have immune reactivity to the metal on top of the toxicity. And one of the downward spirals that happens then is the immune reactivity causes this hyperinflammatory situation, and the inflammation actually turns down detoxification.

Chris Kresser: Right.

Dr. Christopher Shade: And this relationship between inflammation and detoxification is a calculated relationship in nature because if you’re killing an invading bacteria or fungus, you have to turn down your antioxidant activity—and detoxification is part of the antioxidant activity—so that you can turn up your expression of pro-oxidant compounds, like hydroxyl radicals and peroxyl radicals that you’re using to kill these organisms.

Chris Kresser: Right.

Dr. Christopher Shade: So if something creates an immune reaction, it actually turns down detoxification. And so then you’re going to have the double whammy of the immune reaction to it plus the lowered cellular protection against it. So there are a couple of things that can really make you hypersensitive to a small amount of mercury.

Chris Kresser: So we have broadly maybe four categories, and correct me if I’m wrong: We have the determined toxicity of mercury. We have the intake or exposure, whether that’s coming from amalgams or seafood or another source, skin creams or something else, industrial perhaps. Then we have the individual’s detoxification capacity, which, of course, is a whole other conversation, all the factors that influence that. Then we have the genetic and epigenetic environment for each person, genes and gene expression that are regulating their sensitivity. And then we have immunological reactivity or lack thereof, and those are all working together to determine what happens when someone takes a bite of fish or has mercury in their mouth.

Dr. Christopher Shade: Bingo. That’s an excellent summary of it right there. We should probably write that up.

Chris Kresser: All right! Well, we could spend, I’m sure, an entire podcast talking about each of the single topics that we’re covering, but I want to use this as a kind of intro/review, and then I’ll have you back on, if you’re willing, at some point, and we can dive more deeply into topics that people want to hear more about.

Dr. Christopher Shade: Absolutely.

Chris Kresser: But I definitely want to talk about testing.

Dr. Christopher Shade: Sure.

Chris Kresser: Because I think this is one of the areas where there’s the most misunderstanding. You mentioned earlier the evolution of mercury toxicity in alternative and functional medicine, and of course, I have a number of patients that come to me and they show me a test that they’ve had done recently, and for that test they did a challenge.

Dr. Christopher Shade: Right.

Chris Kresser: And they say, “Look. I did this challenge test, and it said I have mercury, and my doctor put me on DMSA.” So leaving aside the DMSA part for now in terms of treatment, let’s talk about using chelators to provoke metals and then testing that way. What are the problems with this approach?

Testing for Mercury

Dr. Christopher Shade: Right, and I’ll give just a brief summary of the history of the testing. Originally there was your sort of traditional testing of either blood or urine, and then there was hair testing. And all these testings were tested as total mercury, so all forms of mercury all came together, so the dialogue did not yet incorporate the idea of methylmercury versus inorganic mercury and where they go, so there was only blood, urine, and hair. And for urine—and blood, really—the testing was kind of crude. One, they couldn’t separate different forms, but they couldn’t measure very low, and so people only showed mercury in their blood and urine if they had a lot of it. And so people were looking for a better way to see the difference between people who had chronic exposure versus the acute industrial exposure where the levels were very high.

So this thing arose called the challenge test, where they would take a chelator, like DMPS or DMSA, and this would take mercury from the bloodstream and make it more soluble and more kidney filterable so that it would move into the urine and the urine levels would come up. So you went from these tests where you couldn’t see much mercury in most people because the detection limits, the level at which they see the mercury, were too high. And you give them a chelator, and the levels come up to where they can see it.

Now, when we had bad testing, that was pretty useful because it brought the horse race—I’m calling it the horse race between who has the highest, the next highest, the next highest, and the lowest mercury—it brought the horse race up where we could see it. Now, one of the problems was that they kept the reference ranges from unchallenged urine. So they created a reference range from just the general population, and, say, it went from zero to 9—9 was really high and zero was really low—and they gave you the chelators, and no matter what your level was, it went way up. It might go tenfold up, it might go a hundredfold up, and so people would go up to the top of this reference range really easily because they were comparing it to non-challenged urine. So all of a sudden, somebody with very little mercury exposure is showing at the top of the range. Now, you look at someone who had good exposure, and they go way off the range, so the top of the range was really like 9 looked really high, but then compared to someone like Mark Hyman, when he first did a challenge test, he got a 287, I think. 287! I mean, he’s 28 times over the top of the range. Now, that’s high, but so many people looked at them getting up to 9 and said, “Oh, my God, I’m off the chart!” So all of a sudden, everybody’s off the chart, and in fact, there was one guy who went and measured a thousand doctors, he told me, with the challenge test, and he said, of that… Well, tell me, Chris, how many do you think were off the chart?

Chris Kresser: 999?

Dr. Christopher Shade: 950! Pretty close!

Chris Kresser: Not far off!

Dr. Christopher Shade: So you do a challenge test and 95 percent of the population rank high, and the problem with that is it becomes an excuse to treat everybody.

Chris Kresser: Yeah. That’s a big red flag for me. Whenever I see a lab that only returns positive results, I get very nervous.

Dr. Christopher Shade: Yeah. All of a sudden, everybody’s an excuse to treat, and that’s why the federal authorities got into that and started calling it fraudulent. That’s why it earned its place on Quackwatch and stuff.

Chris Kresser: Yeah.

Dr. Christopher Shade: And so that was one of the things that we wanted to get away, is this making everybody high. But the second problem is that it’s really stressful on the body. Precisely the people who need the intervention the most are the ones who can deal with it the least.

Chris Kresser: Right.

Dr. Christopher Shade: So when we do our testing, there’s one part, the urine-to-blood ratio, where you see if the transport system in the kidneys that moves mercury from the blood to the urine is working. And when it’s not working, you’ll see a lot of mercury in the blood and very little amount in the urine. Well, those are the hardest people to detox because every time you move stuff around, it’s not getting out well, and they become very symptomatic. But those transporters are also needed for DMPS and DMSA conjugates, so there, you give them a bunch of DMPS, they actually don’t put a whole lot into the urine, so you don’t think they’re high, but you start redistributing it through the body and making them extremely symptomatic. I can’t tell you how many people I’ve seen that have crashed and burned after a challenge test.

Chris Kresser: Yeah, that makes sense. I mean, earlier we were talking about how sick you felt taking DMSA.

Dr. Christopher Shade: Awful.

Chris Kresser: Yeah, and so the fact that people who are most toxic are loading themselves up with that for the test, that’s a bad situation.

Dr. Christopher Shade: Yeah, and I was taking it, and I was measuring my urine, but I was new to all this.

Chris Kresser: Yeah.

Dr. Christopher Shade: I didn’t know what I was doing. I couldn’t measure the blood, couldn’t see those urine/blood ratios, and I wasn’t getting a lot out, so what did I do, Chris?

Chris Kresser: Took more!

Dr. Christopher Shade: Took more!

Chris Kresser: Yeah, exactly. That’s often what happens.

Dr. Christopher Shade: This is what we type A personalities do! We just throw a little more in there!

Chris Kresser: Mm-hmm.

Dr. Christopher Shade: And I just kept getting worse and worse and worse until I was at Colorado Functional Medicine meetings and there was a sequence of Bob Rountree and Nigel Plummer from Pharmax talking, and they were talking all about the gut and the importance of the gut and immunity and how the gut is trying to read the signals in the immune system, and the GI tract is reading those signals, and I realized that it was really we had to clean all the metals out of the GI tract and focus on detoxing through the GI tract and not going through the kidneys, and that was where I developed our whole system.

Chris Kresser: Great. Well, let’s talk, before we go further, a little more about the Tri-Test that you developed as an alternative to the challenge testing and just straight up serum or hair or urine testing individually, and what the Tri-Test accomplishes that those other methods don’t.

Dr. Christopher Shade: Yeah, and this will sort of follow up on our previous question about what the shortcomings of other testing were. Blood was used a lot then, but it was hard to correlate blood levels with symptoms, just like it was also hard to correlate urine levels with symptoms. The most symptomatic people didn’t seem to have much in their urine often, and it wasn’t always the people with the most blood that seemed the most toxic, and that’s because they were putting all the different forms together. And when we do what we do, what we do is called mercury speciation, so we separate methylmercury from fish from inorganic mercury, which is dominantly coming from amalgam. And when you separate them, you see that for a given body burden, the blood carries a much higher level of methylmercury than it does of inorganic mercury. It’s carrying a level of methylmercury that’s proportionate to the body burden. It’s also carrying a level of inorganic mercury that’s proportionate to the body burden. But these two are almost like different metals, and the relationship of the distribution between what’s in the tissues versus what’s in the blood is different for the two.

Chris Kresser: Mm-hmm.

Dr. Christopher Shade: There’s always more in the tissues than there is in the blood, but that difference is more exaggerated with inorganic mercury, where a certain amount of inorganic mercury in the blood represents a much larger amount in the tissues than the methylmercury does in the blood. So if methylmercury is 10:1 tissue-to-blood, inorganic mercury is probably 100 or 150:1.

Chris Kresser: Wow.

Dr. Christopher Shade: So when they were just measuring blood, total mercury was dominated by the fish consumption, and so you could have a lot of amalgam mercury and eat no fish, and it would look like your blood was low. You could eat a lot of fish but have no amalgams and not be breaking fish mercury down into inorganic mercury, and it’ll look like you have a lot. But what we found is the pool of inorganic mercury in the blood is the most significant determinant of the symptomology of the person. So when we separate these two, we see typically larger amounts of methyl than inorganic, and we had to get those away from each other to see that. And now we can track these pools independently like they’re different metals.

And then, when you look at urine and hair, urine is all inorganic mercury, and because the blood was dominated by methylmercury, it didn’t appear that the blood and the urine were really related. But once you separate those two forms in the blood, the inorganic mercury in the blood should be directly related to the mercury coming out in the urine. They should be at a direct ratio. And as the blood inorganic mercury goes up because of your increased load, the urinary inorganic mercury should be in lockstep with it at a ratio, and when you look at our Mercury Tri-Test, you see a graph with a diagonal line that’s a ratio. And what happens to people is they get damage to the transport system that moves the mercury in the blood into the urine, so you can’t move it into the urine. So you have a low amount in the urine, but high amount in the blood. These tend to be the people that are the most symptomatic, and this clues us in that these people need support to the kidney. And as an important aside, the way that that’s been created in animal models is a combination of metals and lipopolysaccharides.

Chris Kresser: Right. Gut problems.

Dr. Christopher Shade: Exactly. Lipopolysaccharides are also called endotoxin. Endotoxin are parts of gram-negative bacteria, and they create huge inflammatory reactions in the body, and they’re synergistic with metals. You should see the data. Lipopolysaccharides alone don’t cause this kidney problem, mercury alone causes a little kidney problem, but the combination really blows out the kidney. And in the animal models, the urinary mercury is low, but the whole body burden is high. And as you just said, the most common source of lipopolysaccharides to the bloodstream is a leaky gut.

Chris Kresser: Yeah. And I can tell you and all of my listeners that we test for that. One of the Cyrex panels tests for antibody production to lipopolysaccharide, and it’s not at all uncommon to see that, which would be indicative of efflux of endotoxin out of the intestine, into the bloodstream. So it’s, unfortunately, more common than we’d like to believe.

Dr. Christopher Shade: And then in those people, you’re going to be much more likely to see that deflected urine-to-blood ratio, where the kidney detoxification has been blocked.

Chris Kresser: Mm-hmm. Well, let’s talk a little bit about… you mentioned earlier cadmium and arsenic, and these are also toxic metals—and copper. Copper, like many other nutrients, there’s a U-shaped curve.

Dr. Christopher Shade: Right.

Chris Kresser: We need just the right amount, not too little and not too much. So let’s talk about some of the metals that have a synergistic effect with mercury toxicity or an additive effect that we need to consider in the picture here.

Dr. Christopher Shade: Right. There have been several different studies on this over time, and certain things are very consistent, and others are different—for instance, lead and mercury. Some of the testing has shown it’s synergistic. Others have shown it additive. But what’s very commonly synergistic is cadmium.

Chris Kresser: Chris, before we go on, I just realized some of the listeners might not understand the difference between synergism and an additive effect.

Dr. Christopher Shade: Right, so additive effect is 1 plus 1 equals 2. Synergistic effect is 1 plus 1 equals 4 or 5. It’s a much worse effect. For instance, when we’re talking about mercury and lipopolysaccharides together, the sum of the two, when you put the two together, you have about an eightfold increase in the damage that the mercury was causing, where lipopolysaccharides alone didn’t cause any damage. That’s an example of a synergistic effect, where the damage is way greater than the additive amount of their parts.

Lead and mercury are usually shown to be additive and sometimes said to be synergistic, but cadmium is always synergistic, nickel is always synergistic with mercury, and one of the interesting things to find was that copper was synergistic.

Copper, as you said, is a nutrient mineral, and when it’s low, we have problems and we want a nutrient repletion. We want enough copper. But when we get too much copper, especially when we get copper in excess of zinc, where copper is really high and zinc is really low, then the copper starts to become a toxic metal. Copper, in the last bunch of testing that I saw, was synergistically toxic with cadmium, arsenic, mercury, lead, nickel—it was synergistically toxic with everything. In our testing, when we do the blood metals panel, we’re looking at the sort of percentile that the copper is at in the blood and the percentile that the zinc is at. And often you’ll see copper up at the 90th percentile and zinc at the 1st or the 5th percentile, and now we know that copper is going to be synergistically toxic with all the toxics, so even if you have just a moderate amount of arsenic and cadmium and mercury, you’re going to have a very toxic manifestation.

And copper, especially, is a very neurotoxic one. It creates a lot of the same symptomology that you find with mercury. I talked earlier about anxiety with mercury, but we also see paranoia and delusion with mercury, and that is the same thing that you see with copper, and those two together are actually super, super bad. One of the bits of trivia out there on this is that when William Walsh measured criminals for copper levels because he was very into copper, he was able to measure Charles Manson, and Charles Manson had the highest copper level on record of anyone he ever measured.

Chris Kresser: Yikes.

Dr. Christopher Shade: Yikes.

Chris Kresser: That’s a pretty potent argument for keeping your copper/zinc ratio in check.

Dr. Christopher Shade: It’s the Manson metal when it gets out of hand!

Chris Kresser: The Manson metal. I like that.

All right, so we could go on forever here. We won’t for our own benefit and our listeners’, but I want to finish up by chatting a little bit about treatment.

Dr. Christopher Shade: Yes.

Chris Kresser: Because this is another area where there’s a lot of controversy and misunderstanding. We’ve already touched on why chelators like DMSA may not be the best choice—certainly not the best starting point—so let’s talk a little bit about that and then what a better option is.

Dr. Christopher Shade: Yeah, and I think that was very well said there—”certainly not the best starting point.” There are plenty of capable practitioners who have made great strides with people with DMPS and DMSA, but these were chelators that were designed for industrial environments. DMPS was made for factory workers in the battery industry in Russia and Eastern Germany that were exposed to very high levels of lead and cadmium, and they were able to take these otherwise healthy people that were clearly just metal toxic and bring down those loads and get them back to work.

But the problem is a lot of the people that we deal with have multifactorial problems. There are some infectious problems, there are leaky gut problems, there are some kidney problems, and that’s leading to them accumulating toxins, like metals, and them being hyper-toxic or hypersensitive to those metals. So trying to grab those metals and say, “Well, that’s the only problem; let’s just force them out through the kidneys,” often leads to more harm than good. So if you remember back to the story that the cells become resistant to the metals when you have adequate glutathione, adequate glutathione S-transferase, and adequate transport proteins, we start by upregulating that part of the system.

I like to talk on a microcosm/macrocosm level. On a microcosm, that’s the cell and that’s the chemistry in the cell, and so that’s going to turn up the metal’s resistance of the cell as it pushes things out of the cell into the circulating fluids, but that’s also responsible for the macrocosmic effect of moving those metal-glutathione conjugates out into the urine flow, out into the bioflow. So on one level, we turn up the cellular resistance. On a larger level, we turn up what’s called the drainage or the movement of those out of circulation and into fecal excretion and urinary excretion. So upregulating of the glutathione system is the detox approach that we use.

Chris Kresser: Great. Yeah, and as I said before, we’ve found it to be very effective and not only that, well tolerated. Certainly some patients need to go more slowly than others and we need to adjust the doses with them. They need to pause sometimes.

Dr. Christopher Shade: Right.

Chris Kresser: But we do that with SIBO treatment. We do that with all of our treatments. It’s to be expected. But overall, we see that people get better over time, and we see the proof in the pudding, so to speak, with the follow-up test results.

Dr. Christopher Shade: Right.

Chris Kresser: Like I said before, it’s really great to have not only the testing, which helps us to better understand not only what the level of metals are in the body, but what’s happening with their detox mechanisms and, therefore, tailor the treatment accordingly, but then to have treatment options that can actually help people get well without harming them, which is, of course, a high priority!

Dr. Christopher Shade: Absolutely. And I have to say the best side effect of our detox is that it turns up the immune system. Often the people that have the hardest time, like, if you get into someone who just can’t make progress or they’re actually feeling worse, you take them immediately and you measure them for Lyme, different viruses, mycoplasmas, and what we get a lot of is people who had been testing negative to Lyme but were sure they had Lyme. You put them on the Detox Qube, and about a month into it, they’re feeling horrible! And they go back and they test again for Lyme, and they’re positive. Now, why is that? Did we give them Lyme? No. Lyme testing is all based on immune response, and the immune system is so down in these people that it can’t even react to the Lyme. And when we bring it up, it starts to react to the Lyme. And the negative symptoms are not actually the Lyme; the negative symptoms are the immune reaction to it. So now they know they have Lyme, they take a little detour, they start doing antimicrobials, and then as they stabilize, they come back onto the detox, they get rid of the metals, and they’re in step then.

Chris Kresser: From that perspective, it seems like it may make sense to treat metal toxicity before addressing some of the gut issues. Although, on the other hand, if you have a leaky gut and you have LPS going back and forth, then it’s going to be problematic.

Dr. Christopher Shade: Concurrently. Our whole system starts with low doses and moves up to high ones, so you maybe start a little bit ahead of time with the leaky gut, but often you have to get the metals out before that fixes itself, so you’re really going after the leaky gut while you’re at the low levels of the detox and not mobilizing very much, and that prepares you for going up into the high levels of the detox.

Chris Kresser: Mm-hmm. So here’s a question that a lot of patients are often concerned with, which is we do the testing, we find out they have high levels of mercury, and they still have dental amalgams, but maybe for financial reasons or where they live, they can’t get them, at least, all taken out immediately, and they want to know whether they can start treatment when they’re still present. And in the past, of course, the idea of starting chelation when you still had amalgams, was not great.

Dr. Christopher Shade: Oh, it was horrible! And I went through that all myself. I mean, I just annihilated myself doing that. But with this system, you can. As I said, you start low and you work up high. You’re not going to go to the highest levels of this while you still have amalgams, but you can do the earliest levels and not have a problem at all.

Chris Kresser: So last question—for this time, at least—I’m sure my audience is going to be clamoring for you to come back, so we’ll rope you in whether you’re ready or not! Functional medicine is fantastic, all this testing we’re talking about is fantastic, but as we all know, insurance isn’t paying for this, and it’s not a part of the conventional medical care system in the US and not in other countries, and we’ll get comments on the blog post for this podcast that say something like, “Geez, this all sounds really great, but I don’t have access to a practitioner that offers this kind of testing,” or maybe they can’t afford the test because they need to reserve their money for treatment.

Dr. Christopher Shade: Right.

Chris Kresser: So is there any risk in someone—a clinician or a patient—doing a therapeutic trial of, like, the Detox Qube protocol without doing the testing?

Dr. Christopher Shade: No. The difference is you have to listen more. You have to listen to your body and your symptoms more and be just more aware of how it’s going. The one thing that is difficult with treatment is when the urine-to-blood ratios are bad, so I would preemptively do kidney support with it. If you do the testing, you decide to add it or don’t add it. If you’re not going to do the testing, absolutely add the kidney support just as a prophylactic measure. And then just be aware of how the treatment is going, and don’t push yourself too hard. If you’re feeling very symptomatic, back up. But there’s no problem as long as you do that.

Chris Kresser: Chris, thank you so much for coming on the show. I’ve learned a lot, it’s been fantastic to have you, and I know my readers and listeners are going to appreciate it a lot.

Dr. Christopher Shade: Excellent. Thank you so much, Chris. I’m glad we finally caught up doing this, and I look forward to doing more.

Chris Kresser: Likewise. Talk to you soon.

Dr. Christopher Shade: Great. Take care. Bye-bye.

Chris Kresser: That’s the end of this episode of Revolution Health Radio.  If you appreciate the show and want to help me create a healthier and happier world, please head over to iTunes and leave us a review.  They really do make a difference.

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Thanks so much for listening. Talk to you next time.