So, I'm going to repeat a few things I said this morning. I'm not going to go into some of the depth that I did, but I will repeat some basic toxicology, because I think without it, it doesn't really provide a good basis from which to make some decisions. So, again, disclosures. I'm a consulting toxicologist. I evaluate exposures to chemical agents where there is sufficient dose and exposure to cause an adverse effect. That's my job. In practice, I evaluate the toxicity of metals to people, including metals that we're going to discuss today. So, I've been retained as an expert witness in cases involving chemical agents, including metals that we're going to talk about today. And my opinions, my expert opinions, are based on the foundational tenets of toxicology, including but not limited to exposure, dose, the threshold effect, things that I talked about this morning, a few points I'm going to repeat again today, this afternoon, and I'm also receiving an honorarium for this. As I did this morning, in terms of the second disclosure, probably quite important here is that this is an introduction to metal toxicology. I'm going to give you—I have quite a few metals I can talk about. Frankly, I only have an hour, and I don't know if I can go through every one reasonably well, but if you want to take a look at the metals that I don't talk about, they're still in there. The things that I look at as a toxicologist are the symptomatology, the occupational setting, hobbies, medical reviews, medication reviews, that is, objective testing, air, blood, urine, medical history, view of the toxicological information, and I will point that out. Learning objectives for this afternoon. I'm going to identify the most important metals, at least in the occupational setting. Again, that's a fairly large list, and there's a lot to each particular metal, as I'll talk about in a second. We're going to talk about routes of absorption, the general toxic effects of metals, the basic treatments of metals, application of occupational standards, and discussion of surveillance procedures for various metals. One of the things that I will tell you is that our field is continually expanding, like every other medical field, and so while I might provide numbers and values that are here related to exposures and doses and things along that line, my point here, as I've said earlier today, is we always double-check, make sure that things haven't changed, but double-check to make sure that the values are what they are. They haven't gone down or they haven't gone up, and I encourage and recommend anything that I put in this particular session be always double-checked for your own use. Maybe to give you a little bit of an understanding of priorities, this is the CERCLA priority list of hazardous substances. I've highlighted metals. All of these I have in my presentation, and so we'll talk a little bit more about those in a minute. Again, as I did this morning, sources of toxicological information, same list that I had this morning. Again, I want to point out ATSDR, the toxicological profiles, Casret and Duhl, the disposition of toxic drugs and chemicals in man I think I find as an important source of information. I'm going to talk about my slide earlier today. Health risk is related to exposure by hazard. A lot of the hazards we will identify, a lot tend to have either respiratory or neurologic components to them. But again, that's the hazard. That means to a toxicologist, what is the worst effect or what's the effect that we've got to be protecting the population from? So we want to know what that is so that we can actually protect the person from it. So hazard doesn't talk to you about the dose. It doesn't talk to you about the exposure. And as I've said this morning, and I'll repeat again, these are the fundamental tenets of toxicology. So just saying carbon disulfide or telling me that manganese could cause X, Y, and Z type of neurotoxicity isn't sufficient to a toxicologist because we're going to come back and we're going to say, well, how much? Under what conditions? Under what exposures? So again, health risk is related to exposure by hazard. Clearly, we want to know what the hazard is, but we also want to know what the exposure is. This is, again, my friend Paracelsus. Now, I did take liberty to maybe make the quote a little bit more understandable. All substances are poison. There is none which is not a poison. The right dose differentiates a poison from a remedy. Boy, that is so important. And again, from a public health, from a medical perspective, to educate your clients, your patients, your employers, whatever it is about these fundamental rules are so important. You'll probably get patients, and you have gotten patients that say, well, I was exposed to arsenic at work. That may be true. And the question is, we have to figure out how much, how frequent, and what it was, and what form it was. We'll find that out in a minute. Again, because of the analytical techniques, some of which we talked a little bit about drugs of abuse and drugs that could impair behavior in many ways, presence doesn't mean toxicity. There are guidelines. There's cutoffs that someone has set somewhere. Sometimes what we will do is look and figure out why did they set it at that particular level? Is there some physiologic? Is there some toxicological perspective that gives us that information? And that helps us understand what those levels are, and we'll talk a little bit about that. Toxicokinetics, you probably have had pharmacology at least three quarters of it or two semesters or something like that. So we just toxicologists just took the words and kind of updated it toxicokinetics. This is the absorption metabolism distribution and excretion of chemical agents. This is important for any chemical agent, but it's going to be important primarily in these conversations that we're having today about metals. There is the source of metals through ingestion, dermal contact, and inhalation. I think in an occupational setting, I would say inhalation seems to be the most common. That doesn't mean it's the only one. I'd say dermal is an important one for some of the metals. And ingestion seems to be either accidental or things like hand-to-mouth behavior. For example, if you're working in a dirty environment, that would be obviously another way to get things into the body. As I said earlier, it's the internal dose that becomes the most important for us. The metabolism is important for us. We want to understand how this chemical is either detoxified, which is usually the case, or this excursion into toxicity for a period before it actually gets detoxified. And then that's our metabolism and the distribution as to what organs. Some organs preferentially uptake metals. Depends on the metal. It depends on the species of the metal as well. We'll see, for example, mercury can come in elemental, inorganic, inorganic forms. They all have some degree of neurotoxicity, but the location in the final resting spot for mercury really depends on what form it's in. I mentioned this earlier today, the concept of threshold. It applies for metals as well, meaning that the dose-response curve is as you increase the dose, you get a bigger response. In this case, the response could be some form of neurotoxicity. So toxicologists like to drill in as far as we can as to what the neurotoxic effect could be. Is it a particular structure in the brain, like the hippocampus, or is it some other function that's going on? And that's the response that we'll be looking for. Additionally, as I mentioned earlier today, is that the dose-response curve. So these are non-cancer. Some of the metals can be cancerous, like chrome-6. So that gets evaluated in a particular way, as I mentioned this morning. But in this afternoon, we're going to talk more about non-cancer effects. And so even more, this dose-response is important. And so the non-threshold and threshold effects become really important because there are levels at which the body can protect itself adequately. Until those enzyme systems are overrun, the body is pretty good at detecting those things and getting rid of it. I mentioned these terms before, but it becomes important here. We want to look at good-quality studies for which we can find a no-L or no-L or low-L. The no-L is a no-observable effect level. That's a dose in a good study. These are animal studies, predominantly, where we find no effect. There are studies now that we can find with human populations that we can find levels that have no-Ls that are attributed to a particular study. That can occur, but the study has to be done quite well. It's a very valuable piece of information if we can find that, because it tells you that whatever that no-L dose is, there's no observable effect. That means no physiologic effect, clearly no adverse effect from that particular dose. And so we know that that has no effect on the body. The next level is a no-L, which is a no-observable adverse effect. So, in this case, we could see a physiologic effect, but we're not seeing an adverse effect. And that's another level that we can use as well. And then the low-L, as I mentioned this morning, is the lowest observable adverse effect level. It means it's the level at which—and typically toxicologists look for all the studies that are about a particular agent, and we'll look for a study that's well-designed. We'll look for studies that repeat the same type of study, and then we'll pick the lowest observable adverse effect level for the most sensitive endpoint, thereby protecting all other endpoints, including the most sensitive endpoint. This is a bit of a repetition, but I think these are the clear toxicological tenets of what we need to be thinking about. And I'm hoping that the first questions that you're thinking about as you get into your career in occupational medicine is, when someone presents something such as a chemical exposure, yes, it's good to know the hazard. The next question is, how much? How frequent? What and what kind of effects are we seeing? That becomes really important. There's been many, many cases where I've looked over their medical records, and all I see is exposed to solvent or exposed to mercury or exposed to whatever. That's it. Their final diagnosis is chemical poisoning of some sort. It doesn't work for toxicologists. We've got to look to see that there's more substantive work on that. The normal distribution of toxicant susceptibility, our friend the bell-shaped curve—when we look at doses like the low-als, the no-als, and things like that, we also take into consideration the population variability as well, and that's part of the assessment we do for those doses. You are familiar with the different types of exposures, whether they be acute, subacute, chronic. There are quite important definitions to a toxicologist at this particular time, because we're looking—there are acute exposures, of course. High-dose—someone mentioned RADS earlier today—RADS, reactive airway disease syndrome. The point that was put in that particular slide is you have to have a very high dose of an agent that actually does some kind of damage. It's an acute response, and it's an acute exposure. That's important. But a lot of the things that we're seeing in the occupational setting is subacute, subchronic, and chronic. And the way that we define these, particularly when we're looking at animal studies, is by these number of days—14 days or continuous dosing, repeated dosing for 90 days, or chronic, which is anywhere from 6 months to 2 years. These are what we call repeated dose studies. Why is that important? Because we're interested in what happens to the animal, to its person, on repeated doses. That's more common and more consistent with what the occupational patient will be showing you. It's the repeated doses that become more important to that. How is the body handling that over a particular time? This is a little more important, obviously, in the non-cancer realm, the possible chemical interactions. And you may have remembered these from pharmacology. There's additive synergistic potentiation antagonism. I've got little mathematical ways of explaining that and a few examples of where those occur. The way toxicologists think about it—so if you have a worker that's working with a number of different chemicals, we'll look at all the chemicals of exposure. And then what we do is we add together the toxicological data. It's actually a quantitative approach as part of our toxicology assessment. We think of that, again, as I mentioned before. We want to be protective of public health. And so the easy way to do this is to look at it from an additive perspective. Now, you could say, well, boy, you just missed synergism. Well, we do look at synergism, but we don't see it commonly. We do have examples, particularly in the—I mean, I'm giving you one—CCL4 and ethanol. That's one where we can see potentiation, but that's not necessarily a workplace. That's a workplace plus—unless someone's drinking on the job—that's workplace plus home behavior, I guess would be—to put it that way. We could see potentiation, which is one chemical that doesn't really have an effect, but then with the addition of another one, the effect does occur. Antagonism is also very more common than synergism, where we will take one or two chemicals, and they'll actually take away the toxicity of another compound. Those are examples. So we do, as toxicologists, consider these. We look for synergism, and if there is synergism, we use it. If there is potentiation, we use it. But the typical way, without any evidence of that, is that we just add all the chemicals together and ask the question, is it causing the effect that we are seeing? I have a few more types of antagonism. You can read those to get a better sense of those values and understanding, but I think covering those first few are the critical ones. One of the things that you're running into now a lot are the occupational guideline values. They come by many different names. They come by different organizations. They have different meanings. We heard the term IDLH earlier today. We have TWAs. We have OELs. We have PELs. La, la, la. Lots of acronyms in our particular area. I like to divide this into the occupational group and then the public group. With the public group, we also have guideline values. Again, they have specific names, like an RFD, an ADI, an MCL, or a TDI, by the various, as you can see, U.S. federal institutions, EPA and FDA, for example. There is a difference between occupational and public. We will use both to kind of help our thinking. Let me explain. Public, meaning what would be the exposure to someone living in their house or living in their house in a neighborhood that is downwind of a facility, for example, some kind of a factory of some sort. And these public ones are used in those situations. Occupational guidelines, though, have pretty specific definitions. They usually, in general, are five days a week, eight hours a day, for weeks or years of exposure. Some of them are emergency-type responding. ERPGs would be one example. Another one is—I call it the EGLE. It's A-E-G-L, acute exposure guidelines. And those are helpful for things like exposures for 10 minutes, for an hour, for five hours, for four hours, and for eight hours. That's where you can get a little more information. But these are values. The other part of these, for example, these would be different values for different media. What do I mean by that? If you're a worker in and breathing air, then you'd have toxicity guideline values for concentrations of chemicals in air. If you have drinking water, you could have water concentrations that are set at a certain level. So we have those particular ways of looking at it. I think the point here is, what are those levels set by? And I showed you this, and I'll show it again with a different emphasis, is I'll take an example. Now, this is the derivation of a reference dose, which is a public, but it applies to occupational as well. You take a study, and in this case, it's a L-O-A-E-L. I've got a dose of 0.0085 milligrams per kilograms per day, so it's a repeated study dose. And we look at the quality of that study, and we say, how was that study done? In what animal? And how good is the database for that? So you take that level, which is a low L, and now we apply safety factors. We also call those uncertainty factors. I don't know why it's called an uncertainty factor, but it is. I like the word safety factor, because what you're doing is you're taking that dose and you're dividing it by this uncertainty factor. So in this particular case, we actually take the 0.0085, divide it by 300, and we come up with an acceptable exposure. And that's whatever it is. It looks like 3 times 10 to the minus 5 milligrams per kilogram per day. That's the reference dose. And that reference dose, then, is a dose that we can use in an exposure scenario, whether it's inhalation, ingestion, whatever, and we can use that as a way to determine. And this one is for the public, not the occupational, but the occupational is developed the same way. The other thing we can do with that reference dose is then take an average body weight, which is 70 kilograms. We can differentiate that by sex, and I think the 70 has gone up to 80. I've seen that being used these days, but it really doesn't have a huge effect on the final answer. And then you take some consumptions. In this case, it's drinking water. The average person is taking 2 liters a day. If the person isn't taking 2 liters a day and tends to take more, then you can adjust that as necessary. And we come up with a drinking water equivalent level of one part per billion. So we could set a level. And so when we talk about these guideline values that I have here, this is how we get them. There is an implication, and that was said earlier today. If you have a guidance, let's say a worker exposure level of 5 milligrams or 5 parts per billion of chemical X in the air, and a person was exposed to 4 parts per billion, we're not concerned because there's a safety factor added to it. Likewise, if it's 5 and you got 7 or 8, we're not concerned because we've got a 300-fold uncertainty factor. You can then start to make better critical evaluations between a toxicity guideline value and the exposure that occurred, because we also know what the lowest observable adverse effect level is as well. So these are things that we can use to come up with these values. We use the same format that we did this morning, a hazard assessment, a dose response assessment, exposure assessment, and risk characterization. And here, this is where we start to think about what are the effects in metals. And the sources of exposure, reducing exposures, and chemical forms become really important for metals. Sources of exposures, specifically via inhalation, are grinding, sawing, sanding, aerosols, mists. We're exposed to many of these metals, by the way, through our daily activities in food or just living in an industrial society. So it's also important, as I kind of pointed out at the beginning, to reevaluate your patient to understand what that patient might be normally exposed to. The reducing exposure, obviously somehow limit the exposure through PPE, through environmental systems, through engineering systems, through administrative systems as needed. But here's where it really becomes interesting with metals, is that the chemical form becomes super interesting because adding a carbon molecule to a metal will change the toxicology quite dramatically. If it's inorganic form, that will also do it. And the other part is the valence. What's the valence of that particular metal? That also influences toxicity. As I just mentioned, we're always exposed to metals in air, water, and food. We have naturally occurring levels of metals in soil and groundwater. So again, just because someone says they were exposed, take into consideration where you might be located. And I'll show you a couple of examples in a second. What's a metal? A metal has these properties. It has high reflectivity, high electricity conductivity, high thermal conductivity, and mechanical usability and strength. Just to point out, there are naturally elevated levels of arsenic and mercury depending on where we live. So on the left hand with the little orange dots, you can see high levels of arsenic that are found in soil. So the Southwest United States tends to have that. If we look at mercury emissions, and this would be mostly inorganic mercury, you can see much of the developed world in Asia has high levels of it. I live in Seattle, Washington. One of my colleagues who does a lot of testing, we find mercury emissions, there's nothing West of us except something called the Pacific Ocean. So why do we get mercury in our mountains, in our mountain snow? It's because it's coming from Asia, it's being transported globally through that way. So we are getting, we have to think about the mercury exposures from just sources that we really can't control. Commonly known industries, this is not an exhaustive list by any stretch of the imagination, but at least metals are used in construction, automotive, aerospace, electronics, glass, plastics, and by-products of activities of power generation and catalysts. I think some of my neighbors are getting their cars, whatever they call it, the exhaust removed because of a rare metal. What, do you know what it is? Yeah, catalytic converters, yeah. Don't just tell me. I think it is. Yeah. You got weird neighbors. There's several of our neighbors that lost their catalytic converters. The thing about the biological activity in general is that the elements can either lose one or more electrons and that makes them quite reactive. They're also form-stable sulfhydryl groups and they alter structure of proteins and enzyme systems. By the way, some of the ones that I'm gonna talk about are also essential for normal metabolism, cobalt, zinc, chromium, and manganese. So the metals in this lecture with that preamble, and if you remember dose-response, I'll feel like I have made a great impact to my colleagues here, my physician colleagues. I'll be super happy about it. The major toxic metals are arsenic, beryllium, cadmium, chrome-6, lead, mercury, nickel. Essential metals with potential for toxicity are cobalt, manganese, selenium, chrome-3, so different valence forms here for between chrome-6 and chrome-3, and zinc. And minor toxic metals are thallium and vanadium. I'm gonna give you a way to look at all of these things because I've put together information on every one of these and I wanna be observant of my time so I don't know if I can really go through every one but I will, and I don't wanna bore you to death with the same things over and over again, but I will pick and choose a few and then if you have other questions we can look at those as well. So each model comes in several different forms. We call them species and they are metallic or elemental, inorganic, organic. They can be fumes, vapors. They can also be, I suppose, aerosols. They're also sometimes a gas. So quite a variety of different ways that a metal can exist and each one has a particularly different way of toxicity. So let me just start here. This is arsenic and let me just kind of give you the format of how I go through these and I'll just start it with arsenic and then I repeat the same approach over and over. First of all, the start of each one has a little picture of the metal. I also conveniently put a periodic table so you know where it sits in the periodic table for you. I give you the atomic number. You can play with that. I have a first slide here that's just general information about arsenic. So let me just point through this, go through this. It's naturally occurring. We've already seen that. Inorganic arsenic is used to preserve wood, was used quite a bit with something called copper chromated arsenic for residential purposes. So some of your older houses that have, oh, decks, for example, and sometimes playground type things like swing sets that were built before 2003, if that's, it's not that old, they could have copper chromated arsenic as a preservative in the wood. Also, some of these are used in marine pilings, for example, because they're quite good at preserving those kinds of structures. Organic compounds are used as pesticides. In our state, state of Washington, on the east side of Cascades, there's a large, large agricultural area that has many different types of crops. Some of them are things like apples and cherries and things along that line. And historically, if we go back in time, these arsenic type compounds were used as pesticides. And so some of the soils that are used in, that are found in agricultural areas will have higher levels of some of these metals. It's used in ceramics and electronics as arsene gas and lead acid batteries. And here, I think maybe the most kind of somewhat interesting point is it was a very good agent to kill people, murder. It's tasteless, it's odorless, and it's still used by some of the people that want to get rid of their folks today. And there have been a few cases in the media of that occurring. Interestingly, back in the Middle Ages, it had symptoms similar to cholera. And so you couldn't really tell the difference if you were being poisoned or you had a disease. These are, this is the next slide that I put together, and that is what are some of the occupational exposures, the high areas of occupational exposures for this? So mining and smelting, pesticide manufacturing and applicators, glass manufacturing workers, semiconductor workers, and wood treatment workers. The next slide I have is just a image from the European Union's research, and distribution is called ECHA. I have the website down below at the bottom. What I like about the European ECHA group is that they have pulled together a lot of information that I think is useful. So again, when you want to look, if you suspect something and you need some information as quickly as possible and is reliable, it's a little harder to go through Daskessrit and Duhl. It's a little hard to go through ATSDR because you got to read those documents. This one is a little bit more, I think, user-friendly. So I put these in there for your own use and you can use that. And it usually summarizes some of the issues related to the particular one. This one is arsine gas, and they have hazard classification and labeling. Again, when someone says hazard classification and labeling, it's identifying a hazard, not the dose or the exposure. Then I have a table for which each one has kind of the following things to the degree that it's available. I have the form, whether in arsenic it's organic or inorganic, the roots of absorption. And I try to work the levels that I think are most frequent from the top to the bottom. The distribution, meaning where does it go in the body? And so in this case, soft tissues, mainly liver and kidney, potential for storage in hair and nails, and for prolonged retention in lungs after inhalation. Gives you that major clinical effect. And here's where it becomes a little more tricky. And this is why when you ask a patient and a patient says they're exposed to a metal, the next question besides how much and how frequent is what form is it? What is it? Because this is where we'll start to get really important to differentiate the species. In general with arsenic, we'll get oral, you'll get nausea, vomiting, diarrhea, abdominal pain. For chronic oral, you'll get fatigue, weight loss, weakness, and anemia. Long-term dermal, you'll get skin changes. And I'll show you a couple of images in a second. And arsenic is a carcinogen. And so the worker exposure values actually consider not a non-cancer, but a cancer effect for those species, lung, skin, bladder. In terms of metabolism and excretion, I kind of give you a general sense of that. Methylation in the liver, excretion mainly via urine, with a half-life of around 10 hours. So you could use urine as a potential biomarker of exposure. These are just some of the dermal effects, long-term, chronic. Seems to me that you would see those things, particularly in the nails and alopecia, as more common, unless the exposures are super high. Clinical aspects to consider. Urine arsenic levels can be an indicator of acute exposure. Remember, we only have a half-life of around 10 hours or so. You'd have to consider when the sample was taken. And this goes with everything I say for these toxicants, is the half-life of these things. But it can be an indicator of acute exposure, and it's probably worth taking a look at it. And I give you two subtypes of those for specific ones. One needs to be cautious, though, about urine levels. Because some foods, especially seafood, contains organic arsenic. So let me unpack that a minute. So if you're gonna do a urine analysis, make sure you understand what you're asking for. So it could be very specific. You could be looking for inorganic or organic. Usually costs more to do that. What the easy way is is to get total metal concentration. What do I mean by total? It means whatever form it's in, you measured it. So if someone had a nice dinner of prawns or shrimp, they have high levels of arsenic. I mean, high relative to other food sources. And if a person gets tested within a day, they could show arsenic levels in the mercury, especially if it's total. So again, it's really important to find out exactly what the metal species is being tested for so you can accurately understand what it means. I've added some other lab findings from a clinical perspective as well. Treatment. Treatment is for both acute oral. And again, I would suggest, because treatments might change, that you contact your poison control center or you contact your pharmacist in the hospital or whatever your person is in order to understand exactly what the potential, the best treatment is under these considerations. The last slide I have in a particular chemical metal deck is regulations and guidelines. And here we have ACGIH, which is a worker level. And here they have arsenic and inorganic compounds at 0.1 milligrams per cubic meter. So it's an air concentration. And a TWA is for a time-weighted average, which means eight hours a day on average over a period of time. And what 0.01 milligram per cubic meter means, that's level and safe, and below is safe for a worker to be exposed to. It does not mean it's a blue line that says if you meet that or exceed it, you have been poisoned. I've included NIOSH, OSHA, and other ones for specific arsenic compounds. And the same thing I've said about urine tests that would apply for air is what was measured in the air? Was it total arsenic or was it a species of arsenic? So again, I'm just kind of going through these slides. I'll hit these, what I think are a few interesting ones that you may have that are fairly common. Some are not as common, but I want to hit them anyway. And I'll just kind of pick and choose what I think is correct. Anything I miss, the format's the same. So here's lead, naturally occurring, 38th most abundant element on the Earth's crust. Interesting, again, that this thing, this particular metal is all over the place. Lead compounds primarily contain lead in the divalent form. So again, valence becomes important. There's the advantage that metallic lead is resistant to corrosion and combined with other metals to form alloys. Lead alloys are used in battery shields from radiation, water pipes, and ammunition. I ran into, I thought was an interesting case when I was in South Africa, working in South Africa, when we came across a very high blood lead level. I'll explain that in a second. And it was a worker who had been working by removing the wires in tires and also had bad dental hygiene or didn't have any dental hygiene. And so ended up taking, being able to find lead, pulling the lead out because it's malleable, sticking it in where his caries were as a way to deaden the pain, which actually apparently, which worked. It's kind of a acid, kind of killed the nerve. It was a great entry into the body. It's not one that I'm gonna offer here as a way to do it, but it was an interesting case. And his blood levels were around 40, 45 milligrams per deciliter. I'll throw in, it's in the rubber and tires also. It's in the rubber and tires? Absolutely. That's why we worry about the ground up tires that they put in the base, in the athletic field at high schools. Because those kids ingest those little pellets while they're, you know, when they get tackled. Yeah, yeah. That's it. In fact, several high schools have removed all that stuff and replaced it with, there are non-lead options available, but they're more expensive. So some schools that have money have replaced them and some schools that don't, well, their kids are getting a little lead poisoned every year. I'm hoping other people have heard your comment. This was one of the people here who said that it's also found in tires and on some athletic fields, some of the older athletic fields that may have ground up tire as part of their astroturf, I guess would be, is what it is. And so that you could get oral exposure by getting pieces in your mouth when you're being tackled. Occupations with higher potentials of exposures, construction workers, battery manufacturer workers, smelters, refinery workers, plumbers, and shooting range instructors and users. ECHA has a nice review of this. Again, the first page of this is providing hazard information. On carcinogenicity, lead is not well, is not confirmed, I think that the approach that people have been taking has been to consider it. It's a level C, if you remember what we talked about this morning, group C. But it's enough that some people are putting it on their websites just to give us some information. And it is a reproductive toxicant. In terms of inorganic versus organic, I'd say the organic has the greater potential for dermal exposure or dermal absorption than the inorganic form. The inorganic has a greater potential from inhalation and oral. Blood, some food items, for example, will have any metals in it. I mean, anything you plant in the ground is going to grab metals from soil and put it into their system. So blood, primarily bound, lead is primarily bound to red blood cells with a half-life of about 35 days. Tends to go to soft tissues and bony trabeculae with a half-life of 40 days. As you can see, as it gets stored in the body, it tends to stay longer. In bone cortex, it actually has a half-life of 19 to 20 years. Here again, interestingly, another lead story from an aviation perspective is, because we have been exposed to lead probably mostly from our diet and exposures, but also it used to have leaded gas until 1973, I think it was. And so when we look at blood lead levels, we can see a very big decrease since the elimination of leaded gas. But that led to some of us that are in the age category that we were exposed, we could send up astronauts that would be in that age range. And one of the things that they noticed was that in weightlessness, because of the microgravity, bone tends to desorb. And so the minerals in that actually start to go into the bloodstream. And so blood lead levels start to creep up a little bit, primarily because of lack of gravity. And as you know, putting on, keeping bone healthy and safe. On clinical effects, inorganic is central nervous system defects at a sufficient dose. And I try to put this out again over and over is it has to be a certain sufficient dose and exposure. There's a peripheral neuropathy, there's anemia, reduced fertility, hypertension, and so on. And with organic is encephalopathy and neurocognitive defects. So there's a little mixing of the two different forms, but it is important. Now, the one thing that you will come across, I believe, because many of the organizations certainly in the United States, maybe in other countries, the European countries as well, is that some say that there's no safe dose of lead. And if I think that's primarily, so the good news about that is, is that you work towards minimizing exposures. I think that's a healthy approach to it from a public health perspective. I think the other side of the coin is, is that it doesn't really follow the toxicological tenets. And we can't come across that many things that are in contradiction to that. So it's important to think about the dose still here. There are guidelines that people are saying, and we'll talk a little bit about those guidelines, but there's just no way possible that you can eliminate lead from exposure. Clinical aspects to consider for workers. Medical removal from workplace when exposures of the blood lead level is greater than 50 to 60 micrograms per deciliter. I think I said milligrams before. It's micrograms. I apologize for that. There is an expert panel in 2007 that recommended the removal for a single blood lead level greater than 30 micrograms per deciliter or two successful levels over a four-week period greater than 20. Long-term goal is to maintain blood lead levels less than 10 micrograms per deciliter, and that's what most entities are looking at at 10 and below and keeping it that level. Women with childbearing years, in childbearing years, maintain blood lead levels less than 5 micrograms per deciliter, reduce lead exposures when it's greater than 5, and then medical removal from the workplace of any woman with prenatal blood lead levels greater than 10 micrograms per deciliter. The reason is that lead does cross the placenta and will be transported to the developing fetus, and, again, from a neurological perspective, that makes a lot of sense to keep the levels as low as possible. Chelation therapy, calcium disodium, ETDA, EDTA, or DMSA could be used with people with very high levels. Again, I would recommend you always check if you get some levels like that. Check with your pharmacy. Check with your poison control center. Check with people to see what the best treatment is. Again, what we have are the levels, occupational levels. I have, in this case, all worker levels. I have TLVs. I have, and you can see there's a difference between lead, lead chromate. Lead chromate is chromium, just to give you some examples, and you've got different exposure levels. Again, these imply that anything at these levels and below are safe under the worker, under worker exposures, and I think that's an important thing to keep in consideration. Moving on to mercury. I think mercury is quite an interesting one, and I remember as a, I don't know, middle schooler, it was such an interesting thing to take some elemental mercury and pour it in your hand and then somehow take a dime and make the dime shiny. Oh my gosh, as a toxicologist, I'm going, no one knew what they were doing at that time, including me. Maybe that's why I've suffered so much in my life. Maybe I've got my CNS malfunctioning for some reason, but anyway, the inorganic, the elemental is a vapor. It comes off as a vapor, and exposure is quick, fast, and quite effective from that perspective. I had a staff of mine who broke a mercury thermometer, and I know mercury thermometers are getting rare. She called me and she said, well, you know what, I said, how did you clean it up? And she said, well, I took the vacuum cleaner and I cleaned it up. And I said, oh my God, shut your wind, shut whatever room that was, close the door, and don't go in. You need to have some people come in because all that it is just take the small droplets, made them even smaller, and spurred it all over the place. So very interesting from that perspective. We also have elemental, inorganic, and organic mercury. Here's the ECA chart. Here's the hazard classification. I won't go into that. These are the occupations that are important. I think the one here would be dental workers, but again, I think the dentist industry has been working towards reducing exposures to their workers. But it's still, people still have amalgams, for example, and so there is some potential exposure from that perspective. This is where I think is super interesting is the form really does have an effect on toxicity, and the database is really quite articulate in that area. You have inorganic mercury, like mercury salts, you have elemental, which I mentioned, and we have methylmercury. In general, most of our mercury that we're exposed to on a day-to-day basis is methylmercury. I point out again that if you have some kind of biologic sampling done, like in urine or blood, again, if you just ask for mercury levels, you're just going to get total mercury, and that's not going to be very helpful because we want to know what species the mercury is in. Methylmercury is mostly ingestion. You probably have seen this with eating tuna, for example, tuna, which be a top consumer, and so methylmercury bioaccumulates through the food chain, and when we eat tuna, we are eating the product of the tuna eating that mercury over its lifetime, and it will then get into our bodies and then also get... will also accumulate in our bodies as well over time. Elemental readily crosses the blood-brain barrier and accumulates in the CNS and kidneys, and then inorganic is found much more in plasma and kidneys and does not cross the blood-brain barrier. So, here again, you can really see the differences between these species. On the major clinical effects, for inorganic, you have kidney effects, GI effects. On elemental, it's CNS. On methylmercury, it's CNS and developmental effects. So, not only does methylmercury bioaccumulate, it can also then be transported from maternal to fetal tissues. Mechanism of action is probably going into too much of a deep dive, but toxicologists like to do it. What we see is, like you would in pharmacology, is where does this particular agent go, and what does it affect? And so, with inorganic mercury, it's the proximal tubular necrosis, hence the kidney effects. With elemental, it goes to brain tissue and interacts with neurons. And then the same thing with methylmercury from that perspective. Metabolism and excretion, nothing I want to point out there at this point, but you can take a look at that. Clinical aspects to consider. 24-hour urine, normal is less than 10 micrograms per liter. Hazardous is greater than 200 micrograms per liter. And I think I have a typo here. It should be deciliter, not liter. Poisoning symptoms, greater than 300 micrograms per deciliter. Blood, it reflects methylmercury as well as inorganic and organic forms. I was on a case recently where someone had attributed being poisoned by one of their partners using mercury, and we took a look at their blood mercury levels. And again, they only did total mercury. And when we looked at that, most of the mercury in the person, given the hobbies, which were none, given the workplaces scenario, which didn't attribute anything, would have been methylmercury. And that's not a poison that people have their hands on. It's not a poison that is used to hurt people like arsenic is. And so I was confident that that mercury was actually related to ingestion of fish as opposed to anything else. When we get into occupational levels, we have OSHA and NIOSH levels. And again, it goes by, in this case, there's some industry components. So shipyards and construction have the particular ones. NIOSH has mercury vapor, organic compounds, and then IDLH levels for immediately dangerous to life. So here I am, again, I have many more metals to go through, and I have the same kind of process of the first page, second, third, fourth, and fifth. I don't know. Does anybody want to suggest a metal to go through? Because I'm worried that I'm going to intoxicate you with my voice. What other metals do you have? I can go back to the... Here's the list. Arsenic, beryllium. Maybe ones that show up on tests a lot. Okay. Well, certainly the ones I gave you would come on a test. Let me go to chrome. How's that one? You could find cadmium on it as well. I think any of them, certainly any of the ones on the first on the first column would be important. So here at chrome is really interesting because chrome has different valence, and the valence really is really important in terms of toxicity. So hexavalent chrome is chrome 6. Roots of chromium is chromium 6. So hexavalent chrome is chrome 6. Roots of absorption are inhalation, dermal, and oral. Distribution is to all organs of the body with high levels in the liver, spleen, and kidney. There's potential of storage of chrome in the hair and nails. The thing about chrome 6 is once you get it in the body, once you get it in the body, it goes from chrome 6 to chrome 3. And that metabolism takes away its carcinogenicity. So it's a bit of a tricky metal from that perspective. That said, if chrome 6 is in its hexavalent form for long enough, and you could ask me how long is long? I don't know. Some of the studies that we're talking about depend on some of the enzymes that are available for the transformation of the valence from 6 to 3. That said, chrome 6 does occur because people are, workers are using chrome 6 in occupational settings. So they would be exposed to chrome 6. And there is, until it's detoxified to chrome 3, it's still active as chrome 6. So a couple of things here. So the distribution, and there's, the point here is that there's retention in the lungs after inhalation. You can get, and I think someone mentioned nasal septum. You can actually get ulcers in the nasal septum and the perforate for people that are exposed to quite a bit of chrome 6. You do have it considered a human carcinogen for lung cancer. And it does get deposited into the alveoli of the lungs. The other interesting thing about chrome 6 is it's a sensitization agent. It, on skin, it will cause contact and allergic dermatitis as well. And the little picture to the left kind of does a little bit of justice to that demonstration. We have, I was part of an expert panel for EPA on the allergic aspect of chrome 6. And it was, it's a pretty good sensitizer from that perspective. Now I say that, and I'm going to go to chrome, where did my chrome 3 go? Well, you get that you're, at least you're getting, well, I just, I must have just done chrome 6 because chrome 3 is, it's a, it's an enzyme. It's a metal that we need for metabolic, normal metabolic functions. So once it turns to 3, it's part of our, our, our normal metabolism. And it's a, if you take vitamins, you'll see chrome as part of your vitamin supplement. That's, what's interesting about it. What other one could be on a test? I didn't, yeah. Randy Peters, Pittsburgh. I don't know if you remember, but back in the nineties, taking chromium, I think it was picolinate was an incredible rage for weight loss. I'm curious if you saw any bad effects from that or if you, if you had any experience with that. I, that's very interesting. And I, I'm not familiar with that. Thank you for letting me know. Yeah. The, the, the, it was a fad thing. It was, I don't know that it was supported, but some, some woo woo person said that it was implicated in improving insulin sensitivity by, because it has a, it plays a role in insulin, mediating insulin release from the pancreas. And when people hear, oh, chromium helps with weight with insulin, they just went nuts on it. It was big in Pittsburgh. I don't know if it was big anywhere else, but. That's interesting. I think the, you know, the big question there would be whether, I mean, a Chrome, if it's in the, if it's in the Chrome 3 version, then you have just general toxicity that could be a concern. If their manufacturing process wasn't so good and they had bits of Chrome 6 in it, then that becomes a bigger issue. But that's, but I don't know that. All right. Someone said zinc, an essential metal, zinc deficiencies result in severe health consequences. That's the deficiency of it. Sink toxicity is relatively uncommon and occurs at very high exposure levels. The uses are, you know, in pigments, welding, wood preservatives, things like that. Occupational, most fumes from welding, occupationally fumes from welding that have zinc in the welding could be a potential exposure, but the toxicity is not particularly high. Now, did I get this right? Metal fume fever is zinc, right? I was worried that when I saw you give that presentation, I was hoping I didn't miss that, and I didn't, so that's good. Inorganic and organic forms of mercury, metal fume fever, which was talked about earlier today, short-term fever, chest pain, chills, cough, dyspnea, nausea, muscle soreness, fatigue, potential neurotoxicity, neuronal cell death, but I think it has to be pretty high in order to get to that level, and excreted in feces and urine. So, you could do a urine test to find levels of zinc. Widely distributed in the body, muscle has 60%, bone 30% of it, hair about 8%. I mentioned metal fume fever, and these are the levels of exposure that are safe, and you see they're 1 milligram, 5 milligrams, 10 milligrams. Those are pretty high occupational exposure limits for that. Is there a question you had specifically about zinc? I was just thinking, we get a lot on our neurology boards, like zinc toxicity, because it kind of inhibits copper, like some of the combined degeneration, spinal cord weakness, bad sensitivity, stuff like that. And what would be, how would a person be exposed to zinc in your experience? Yeah, I was interested to see, I guess, I mean, we rarely see it in clinical practice, but I'm guessing by diet, maybe? Yeah, yeah. Seems like it's at really, really high levels. Yeah. I'll just go up front so that people at home can hear us. The big risk for zinc is people that weld on galvanized, and that's the huge exposure, because when you heat up galvanized metal, all the rainbowy stuff on the outside of your trash can, called a metal trash can, that's galvanized. And all the things on the side of the road, all those are galvanized metal. And if they heat them to weld, they're going to aerosolize that and turn it into a fume. I'm using the industrial hygiene definition of a fume, which is the exact right size to get it into your lungs. And then those people will get a dose. So to get all these other effects you mentioned, it's a huge dose. It's a huge dose. The welders will usually get the metal fume fever. And from welding on galvanized, they all know it's a hazard. If they use a respirator, it fixes the problem. The teeny tiny little problem is, if you wear a respirator when you're welding, you've got a good chance for catching something on your face on fire. And so that's where it gets complex, is you've got to come up with a solution that will let you have respiratory protection without catching your face on fire. And it's doable, but it does require some thought and some support from the employer to be able to do it in a way that's safe. So that's where metal fume fever comes in at. And I've never seen anybody with more higher levels. But the weird thing about metal fume fever is you don't get sick right away. You get sick a couple hours later. And I hear crazy, like, I'll just make sure I'm upwind of the thing I'm welding on and just let the wind blow it all away. And so that's, it's going to work. You may get away with that most of the time, but not all the time. I hope that's helpful. That puts it in perspective. Anybody else want to, I think I have one more metal that I could go through. You got about two minutes. I have two minutes. With that, I won't go through another one. I'll just say, again, I have all these metals. I've gone through what I've done for each one of them to provide you with information. If you want to know what I think would be examples of metals that you could see on a test, let me give you my best professional opinion. I'll just go to the, I'm not just, well, here it is. Well, he goes really fast. I'd say the ones that he covered, arsenic, lead, mercury, and zinc are probably the most likely ones you're going to see on a test. And they're also the most likely ones you're going to walk into your clinic. Arsenic is kind of specialized, but lead, mercury, and zinc, you will see in clinic. You might see chromium, chrome 6, but that's being really managed quite well. Maybe nickel. The biggest thing with nickel are dermatitis, dermatological reactions. It's a sensitizer for skin. And so you could see people wearing jewelry that have nickel in it instead of completely gold or whatever the metal would be. Thallium and vanadium, these are pretty rare things unless you're working in a, unless where you're working, you have industry that is very specialized, like in semiconductors or in producing electronic equipment for computers. Cobalt, manganese, selenium, chrome 3, and zinc. We've talked about chrome 3 and zinc, selenium, manganese, cobalt. Generally, these are going to be, as the title says, a lot of these are going to be essential metals with the potential for toxicity. And that means these are part of our body, but if you have too much, then we get into the toxicity, just like Paracelsus would say. So, I'd say the major toxic metals I'd focus on mostly, and zinc, because of the occupational exposure and metal fume fever. With that, I will come to a close. I have more slides, but you can look at those at your leisure. Okay, thank you very much. And I especially want to say, this is, the resource he gave you is an amazing review of the metals that's in the talk, and I, that's in his notes for the slides we didn't quite get to. And I would strongly encourage you to look at that if you were getting ready for some sort of an opportunity to show people what you know.

metal toxicology

toxicological principles

occupational health

metal absorption

inorganic arsenic

blood lead levels

methylmercury

hexavalent chromium

metal fume fever

safety data

regulatory guidelines