Good afternoon and welcome to today's webinar, Update on Arsenic, Health Effects Monitoring Prevention, What the Occupational Environmental Medicine Practitioner Needs to Know. My name is Danielle Feinberg, and I'm with the American College of Occupational and Environmental Medicine. There are two features available to communicate with our panelists and other attendees. You may post general messages in the chat feature. Messages can be shared with either the panelists or all participants. Use the drop down box to select who you want to share your message with. Go ahead and give it a try by introducing yourselves to our panelists and attendees. Let us know your role and where you are from. Questions, on the other hand, should be submitted in the Q&A box. Panelists are monitoring this box for questions, so please be sure to post all questions here and not in the Q&A box. If you are not familiar with ACOM, we are a membership organization that promotes the health and safety of workers, workplaces, and environments through education, research, development of public policy, and advancing the field of occupational health. Before we get started, just a reminder that we are recording today's session, and an email will go out with the link of the recording to all registrants. We are delighted to have Dr. Rose Goldman with us today. Dr. Goldman is the Associate Professor of Medicine at Harvard Medical School and Associate Professor of Environmental Health at the Harvard T.H. Chan School of Public Health. She is the founding chief of Occupational and Environmental Medicine at Cambridge Health Alliance and currently Director of Faculty Affairs for the Department of Medicine. Her career has combined clinical, occupational, and environmental medicine, with a focus on toxicology, with public health and education, and has authored... Excuse me. And Dr. Goldman, excuse me, is joined by Dr. Kushinga Butte and Dr. Shilpa Gowda, who aided in the planning of this webinar. We're glad you are able to join us, and we're looking forward to a fantastic webinar. I will now turn it over to Dr. Goldman. So, let's see. Hope everybody can see the screen. I'm quite delighted to be able to join all of you to discuss one of my favorite topics, which is arsenic, which other than some movies like Arsenic and Old Lace and things like that, you may wonder, well, what are we doing talking about arsenic? But it's actually a fascinating topic and one that's in the news quite a bit these days and worthwhile for all of us to know something about. And I'm going to structure the presentation today in a way that I hope is really practical. There are many people on this session today, and we are in many different settings doing occupational environmental medicine and or toxicology. And so the question is, how might we be confronting some arsenic questions? Well, for one, the most obvious that we may be confronted with some exposure and health effect questions related to employees who are actually working in settings where there could be potential arsenic exposure. The second thing is that some of us may be doing medical surveillance, either for companies or worker groups that have potential arsenic exposure, and we really need to know what we should be looking for and how to do medical surveillance. The other thing that comes into play here is there are environmental arsenic exposures, and we need to understand where those could be coming from, drinking water, food, and We may be getting direct questions about that, or it may be impacting how we're evaluating workers. Some of us might be doing toxicological consultations for high urine arsenic or actually for poisoning. And lastly, there may be toxicological questions that are related to cancer patients who are now getting arsenic chemotherapy for leukemia. So my learning objectives, what I hope we'll accomplish today, is that when we finish today, you'll have a better understanding and way to describe and contrast the different forms of arsenic, knowing more about the toxic forms and the relatively non-toxic forms and how those come into play in our work, be able to describe the manifestations of acute and chronic arsenic exposure. And a key thing I really would like to accomplish today is to really know what is the appropriate biological monitoring test to order for arsenic and how to interpret these results. So let's begin by just talking about what is arsenic. And it's actually a naturally occurring metalloid. It's distributed in the earth and the water. I was once in Alaska and I did a walk to the mines where they were mining for gold. And it happens that gold and arsenic and antimony can run in the same rocks. I picked up a few rocks, but the ones I had seemed to have more antimony and no gold, sadly. And there are different forms. There's an elemental form of arsenic, but that rarely exists in nature. And so there are the inorganic forms that are trivalent and pentavalent that we'll be talking more about. And then as they get metabolized in the body, they produce methylated metabolites that are quickly excreted. But to confuse things, there are also organic forms that are in fish and seafood and various other foods that can confuse our situation and assessments. And lastly, there's a very toxic gaseous form of arsenic known as arsine gas. So let's begin by talking about the toxic forms of arsenic. And these are the inorganic forms, the trivalent arsenite, which is the more toxic between that and the pentavalent form. In the metabolism, when one is exposed to the pentavalent form, it ends up getting reduced to the trivalent arsenic third. So they basically are very similar then in some of their toxicity. We're going to see a chart soon, but basically the metabolism of these inorganic forms leads to the generation of metabolites, monomethylarsonic acid called MMA and dimethylarsinic acid, DMA. And these are the ones that are quickly excreted. And some of them like DMA are somewhat less toxic than arsenic. But interestingly enough, DMA is also called cacodylic acid and is used in laboratories and frankly available on the internet. So these are forms that are out there for the public to use as well. Now arsine gas, which can sometimes be generated when acids are on certain metals that contain arsenic, and also in certain procedures in the computing chip industry. This is a very potent hemolytic agent. It has no odor. It can be breathed in. The worker or the individual doesn't even know what's happening. And then they collapse several hours later because their blood has basically been destroyed. So it's a very toxic agent, which hopefully none of us will ever be confronting this as a poisoning incident. Now there are other forms that are in the organic category that can be toxic. Oxarsone and some other organic arsenicals are put into chicken feed as a way to suppress some microbes in the chicken. The issue there is, and it also gets out into the soil around there, and there could be exposures that way, reportedly that by the time the chicken comes to the food platter that this form of arsenic is out of the meat. But this is something that has been of concern. The other thing to know about the organic forms is they're very well absorbed from the GI tract. They can also be absorbed from dust, and they're quickly distributed through the body. They go to the liver, kidney, muscles, skin, hair, but very quickly cleared from the blood. Then they go to the liver where they're metabolized and produce the MMA and DMA, and then they're quickly excreted through the urine. The other thing to know is that they also cross the placenta. Well where will we find arsenic? What are these exposure sources? Well certainly there are work settings. Smelters was the classic one producing the arsenic trioxide dust. Mining, as I mentioned, and the mining not only exposes the workers, but it can expose the surrounding community if there's contamination. Some of the coal-burning power plants, because they're burning a coal that may have arsenic in it. The production of circuit boards and chip manufacturers sometimes uses gallium arsenide. Then in the semiconductor and metals refining industry, there may be either the production of arsenic gas, or it's used as what's called a doping agent in the process of creating the atmosphere in which the microchip is produced. Interestingly enough, we should also be concerned about healthcare workers who are given chemotherapy, just like we would be concerned about them being exposed to chemotherapeutic agents. Since arsenic is used to treat promyelocytic leukemia, this would be another important thing to be aware about and to be sure that those workers are protected. There's also the production of CCA, which is used as a wood preservative. And then there are pesticides and herbicides that had arsenic in them. These were banned by EPA here in America, but they may be still used in other countries. And people sometimes have these old products on their shelves from the past. We actually had a situation of accidental poisoning many years ago here in Massachusetts from that jar of it being mistakenly given as water to a baby. On the environmental side, a big exposure to be concerned about comes from well water, because arsenic can get into the groundwater. And so it can be there both from natural sources as well as from industrial ones. More and more recently, we're becoming aware of small amounts of inorganic arsenic that are in foods, particularly rice, food that is grown in moist and water area where you actually might have arsenic in the water. And we're also finding it in some drinks, like apple juice has come to the forefront. Now if we take a quick look in America, this was something that came out in 2005, but what you'll see here, there are various locations in America where you would see levels of arsenic even greater than 50. And we'll talk about how we think about what's an acceptable level to arsenic. There is no natural arsenic in the body. Some metals like manganese do have a role in the body, but there's no role for arsenic. And so our level that's really normal is zero for inorganic arsenic. And it's also carcinogen, which we'll talk about later. So then the issue is what's an acceptable level. And right now, what's considered acceptable is somewhere 10 or less. And so we can look and we can see that there are many parts of America that have greater than that amount of arsenic in the well water. And in fact, around these parts, if you look at New Hampshire, because I've seen some people from New Hampshire who have been concerned when they've discovered that their well water has elevated levels of arsenic. And that's also a point for prevention that we'll be talking about, because if you know you have it in your water, then it would be important to either dig another well or put on a filter. Worldwide, there's also problems with arsenic in the drinking water. And we'll be talking a bit more about that, but you can see different locations worldwide where there are also problematic levels of arsenic, and in some locations in the hundreds in the water. So getting back to these forms of arsenic that are toxic, we have the trivalent, the pentavalent, the metabolites, the arsine. But I also want to note, as we mentioned, that these toxic forms get metabolized in the liver and are excreted in the urine. And this is really important for us to understand a little bit about this process, because when we go to do the biological monitoring tests, we need to know what we're looking for and what it means. So if we look at this process, we see that the pentavalent form of arsenic will get metabolized to this trivalent form, which will then go through more enzyme manipulations and then become monomethylarsonic acid and then get further metabolized over here to DMA. And then the DMA and the MMA and a little bit of residual inorganic arsenic will all be coming out in the urine. And when we do testing, which we'll be talking about, these would be what we consider the inorganic forms, even though these are technically organic because they have carbon, but they're derived from the inorganic arsenic. So why is arsenic such a big problem? Oops, let me just go back there. And that's because it's actually going to bring us back to a little biochemistry here that inorganic arsenic ends up inhibiting numerous enzymes, the cellular pyruvate dehydrogenase, succinate dehydrogenase, leading to ATP energy production. You may be scratching your head and trying to go back some years to the Krebs cycle or citric acid cycle, but this is the energy machine of the body and inorganic arsenic is really interfering with that. It ends up substituting in some of the places for phosphate metabolism, it interferes in signal transduction pathways, and also alter gene expression and other effects that may be part of the story for why it becomes a carcinogen later on. So all of these effects and the acute exposure lead to decreased energy production, cell death, endothelial injury, and increased risk of cancers. Very potent toxicant. And here is just a little reminder here of where pyruvate is coming in during this chemical process, coming through here to create the acetyl-CoA, and arsenic is interfering with the regeneration of this lipoamine over here. And so this is really interfering with this usual energy producing cycle in the human body. And if you forgot what the Krebs cycle looks like, here it is up here, I never thought I would be necessarily looking at that again, but here you have it. And that's where arsenic is wreaking its havoc acutely. Now, the other issue here that we need to be aware of is that there are forms of arsenic that are relatively non-toxic. And unlike mercury, which methylmercury and those organified mercury forms in fish are toxic, in this situation there are forms of arsenic in fish and seafood that are basically either minimally or non-toxic. For example, arsenobutane is the predominant form in most fin fish and shellfish. It doesn't get metabolized, it comes in and it goes out right away into the urine. There are also another form of these arsenic compounds called arsenosugars, arsenolipids, that are found in some forms of algae, crustaceans, mollusks, and they might be metabolized to a small extent to produce DMA, but also very quickly excreted. And it's not clear if they have really much or any toxicity, and it's not clear if you could even eat enough of this to begin to have an effect of it. These other forms are also found in other foods, mushrooms, other foods, and even when I've told patients or they've sworn that they have not eaten any fish, you can still have these compounds in other foods. And I can tell you that if you've had a fish meal within a couple of days of getting the test, you can have like a thousand micrograms of total arsenic in the urine. So the major reason we need to know about this, and I can't stress it more strongly, is that when we do the biological monitoring tests and we order that urine for arsenic, if we get a total arsenic, that level that we get of that arsenic will include both the toxic and the non-toxic forms. And that can lead to confusion for the patient and actually some pretty problematic outcomes. So going back to the clinical symptoms of inorganic arsenic poisoning, what is it that we see if somebody really is poisoned? If you take it and you ingest some inorganic arsenic, the symptoms will begin within minutes or hours. And usually it's described as starting with severe gastrointestinal symptoms or watery diarrhea. It's described as looking almost like cholera, followed by dehydration. It has cardiac effects because it has a prolonged QTC interval. People then go into cardiac arrhythmias, hypotension, they can go into coma, and certainly people die. It has been an agent for suicide, homicide, and certainly has been problematic for some accidental ingestions. The arsenic supposedly tastes a little bit sweet, and so it's easily disguised in drinks or other things like that, or not detected in an accidental poisoning. Now when people survive, this is usually a medical emergency, they're in an ICU if they really have poisoning. And when people survive, this is a situation where they may be left with that peripheral neuropathy that we've heard about, the significant sensory motor neuropathy. It's described as being painful, something like diabetic, and people can have effects on their mentation and cognition after surviving this. Now there could be a subacute presentation if someone is somehow ingesting or trying to be poisoned more chronically, and just having a more chronic GI illness, some undiagnosed other symptoms, anemia, abnormal liver function tests. I have seen descriptions where somebody's trying to poison somebody sort of chronically and they're coming in with these kinds of symptoms. It's not easy to diagnose it first blush because it's somebody who's having diarrhea and gastrointestinal illnesses, some other vague symptoms, anemia, abnormal liver function tests. So it really requires somebody calling attention that this could be arsenic to call attention to it for somebody to think about it in this sort of acute setting. And again, most of the scenarios for this type of poisoning tend to be suicide attempts, homicide, and accidental ingestions. Now moving on from that, we have a situation of chronic inorganic arsenic poisoning. And this varies from low levels, but low, I'll put that in quotation marks. This is a scenario where people are drinking water that has a large amount of inorganic arsenic in it on the order of hundreds of micrograms, definitely above 100. And in this situation, there has been an example of a terrible situation that occurred, particularly in the area of Bangladesh and India, where tube wells were drilled to go to the groundwater as an effort to help combat infections, particularly from cholera, when people would be using their source of drinking water from the surface water. So the idea was to drill these deep wells, and therefore you could get this water that wouldn't be contaminated with those microbes. Well, the good news was that the water wasn't contaminated by the microbes, but it wasn't checked or thought about at the time, I guess, that there could be contamination from arsenic. Because remember, we discussed that arsenic can be in some natural environments and rocks. And so what happened was that millions of people in this area have developed chronic arsenic poisoning. And this is from levels that are in the hundreds. And what you see here is, and this has been described both by doctors in Bangladesh and India, as well as people from America and other places that are going to try to study the situation, as well as to try to figure out ways to help people. But basically, what you see here is some people have these spots that are hyperpigmented, sometimes called melanosis. Some people actually have it where there's less melan and it looks like little white spots all over. And then there is cavitotic lesions that tend to be mostly on the hands and the soles of the feet. And of course, this also increases the risk markedly for developing skin cancer. And from studying situations like this, where people are having this kind of chronic, ongoing arsenic poisoning, what you see here when looking at these populations, you see that a lot of people have abnormal liver function tests. There have been studies that have looked at the people who have these high levels of arsenic in their water and finding a correlation between that and the development of high blood pressure and mortality from heart disease. Some of them actually have been found to develop this kind of stocking glove peripheral neuropathy. The other big problem with arsenic at this level, which doesn't kill at the moment, is the latent problems of increased risk of cancer. And the big ones are skin, bladder, lung. And actually, this is recognized as a grade one probable human carcinogen. And so the issue is, in some ways, there should be no exposure. But trying to find a balance to what's feasible and what would be a reasonable or acceptable exposure. So in America, and actually in Europe, the acceptable level in drinking water was reduced from 50 to 10. And we'll talk a little bit more about preventive measures in a later part of the talk. These kind of chronic exposures also have an effect on the bone marrow, can cause a megaloplastic anemia, leukopenia, thrombocytopenia, and sometimes even rapid decline and going to hemolysis. The other thing that has been discovered in studying these larger populations of people who have arsenic poisoning is increased development of diabetes mellitus. Also peripheral vascular disease associated with gangrene. Many might remember that old term Blackfoot disease. And that's from very, very high exposures when you get to that level. And in addition, because inorganic arsenic can cross the placenta, there's also been found increased adverse pregnancy outcomes. And of course, now there's exposure to the developing fetus, and more concerns about the children who then are born and whether or not there may be increased risk of cancer for them, as well as some cognitive issues. So let me get to now an important point in this talk. And the practical point is, what are the diagnostic tests that we can use for arsenic? And in this situation, the best media here is urine. But we have to understand what we're getting when we do a urine test. Because arsenic comes in and goes out very quickly, when we do the urine test, what we're measuring is basically the arsenic exposure at the present time. So if somebody's worried about an exposure that happened a couple of months ago, this is not going to give you the answer. And it needs to be collected in a metal-free container, not an acid-rinsed one. You can do a spot sample. You don't have to do a 24-hour, unless you're really treating the person in the hospital for poisoning. And if you check a creatinine at the time, you can adjust for concentration. And the reason that's helpful is you can compare time to time. And this is useful to do, as long as the person doesn't have renal failure, because most people excrete a steady amount of creatinine every day. And so you can come to a measurement, which is micrograms of arsenic per gram of creatinine. And so it corrects for concentration. And the other thing is, it's really quick how arsenic comes out. Two-thirds is eliminated in the first five days, if you stop the ingestion, and 30% with a half-life of about a week. And there is a small amount that will come out slowly later. The important point is when you just order a urine arsenic, you're going to get a total arsenic. And this is where I would strongly advise, if not plead, when you order the test to ask that it be speciated. That is, they'll give you some kind of result of inorganic arsenic. And sometimes it's just inorganic arsenic in total. Sometimes it's inorganic arsenic and metabolites or non-organic. So this is a very important point, and I'll show you some cases to help illustrate this. Now, the blood is usually not that helpful. First of all, you can't really speciate it, and it goes out of the blood so quickly. It may be useful to do blood, of course, if you're treating somebody with acute poisoning who's in the hospital. But for most of what we're doing as occupational and environmental medicine practitioners, we're not really going to be measuring it in blood. Then we get to the question of hair and nails. Now, sometimes people decide they want to send their hair off for, we've probably seen this measurement of 20 different things in their hair. So that can be very inaccurate. In the case of really trying to assess somebody for arsenic, there can be a role for hair, but we have to understand how it's used. Most of the time that hair and nails is used is in the setting of a research study. Interestingly enough, it is only the inorganic forms that get deposited in the hair and nails, not the organic forms. So on that point, that's a strength of doing this. However, a downside of doing hair is that if you have external exposure, the hair follicle will still bind it. So if you're worried about drinking water and the person is showering, or you're worried about workers in a smelter who have hair exposure, they might still be getting exposed on their hair. So we have to think about the situation where it may be useful. Fingernails have also been used, and they grow more slowly. A scalp hair might give you back a month if you have a seven meter of hair on your head. Fingers go for three to four months, toenails six to nine months, and that's why you'll see some research that's done using these kinds of more long-term measures. Other tests, such as blood counts, liver function tests, looking for that. Health effects may be also reasonable. So what are some common presentations that we might be seeing? So I'm just going to run by two just to show you some examples. But basically, what I've been seeing is patients who have various symptoms, maybe even a peripheral neuropathy, and they can't have it quite figured out. So the provider orders urine for heavy metals, and this is really a problem. And what is in the urine for heavy metal screen? Well, you get a total arsenic, you get cadmium, which doesn't relate mostly to most of the symptoms, you get a lead in which urine lead is not the best measure, and you get a urine mercury in which that form of mercury would be more metallic. And so you might want a blood and urine. So just ordering a urine for heavy metal screen is really not that helpful, and in fact, has caused a lot of problems where people think they're getting arsenic poisoning. So let me give you one example here of a woman who I got called about and eventually wanted to see me because she had a 24-hour urine test for arsenic. And what came up is that she had a total arsenic of 125.7, which was above the reference range of 35. So she was concerned, where am I getting poison? What kind of treatment do I have to have? And I can tell you, I've seen people who have undergone unnecessary chelation by a neurologist, people who have been accused of poisoning a relative. There are consequences to misinterpreting these tests. So what's the problem here? The problem is that we have no idea what this arsenic of 125 means because it's a mixture of the non-toxic species as well as the inorganic. So how do we approach a patient who has questions about arsenic in the outpatient setting? Well, first of all, we take a history and then we do the physical exam. And then we look at a biological monitoring test noting the timing and speciation and seeing if it's the occupational environmental assessments, do we have any data, the level of arsenic in the air, level of arsenic in the water? So in the history, we usually go down a bunch of questions. Do they live near an industry smelter? Are they doing art projects? There can be arsenic in certain pigments like Paris green, pesticide use, finding a big chunk of CCA wood and burning it, contaminated well water, taking an arsenical medication or some supplements. I don't totally always rule out a possibility that the person could be getting deliberately poisoned. I was involved in a forensic case at one point. So I don't totally doubt that, although usually the levels are much higher in the urine. And then asking about the diet, are they eating a lot of chicken? Are they eating a lot of rice? What else is in their diet? And then just doing the physical exam, looking for any skin lesions, noticing the heart rate, QT interval, abdominal exam liver, doing a good neurologic exam, and then looking at the biological monitoring test, or if there hasn't been one order, depending on the timing of the presumed exposure, maybe ordering it with speciation and looking at if there's any results that they have from water tests or air tests. So if we go back to this first patient example, here we see that she had a 24 hour urine test for arsenic, that was a 125.7. But this particular lab did end up doing a reflex fractionation, which is wonderful when they do that, they don't always. And what you see is in 123.5 was all organic. And then the, this lab particularly also measured inorganic and methylated, which was zero. So the conclusion for this person is that she didn't have a sore, she had no physical findings, and she had a urine with no inorganic arsenic. So basically, she doesn't have arsenic poisoning. And that raises where this reference level comes from. And how do we interpret an inorganic arsenic result? Well, if we turn to America, the CDC and Hanes actually does testing of our population, a sample of our population, and reports it in tables. And in the most recent table that looked at samplings from 2015 to 16, and they reported some tables as arsenic per liter and some as arsenic per gram of creatinine, which is probably a bit more accurate, we can see that the total arsenic levels, the mean is about 6.2 in the 95th percentile up in the 50s. Whereas inorganic arsenic, interestingly, still has a mean of about six, but a 95th percentile that's much lower. Now the ACGIH recommends a biological exposure index of 35 micrograms per liter. And that's looking at inorganic arsenic, plus the methylated species. And that number of 35 is meant to correlate sort of approximately with what you would be excreting if you were exposed to the current acceptable air level of 10 micrograms averaged over an eight-hour period. Let me just tell you another interesting patient example about how things can play out. I was called about 53-year-old mechanic in the semiconductor industry who works on ion machines. He went to China to work on a machine, but in that situation, he didn't have on any protective gear. While there near the end of his session, he developed nausea, vomiting, diarrhea that persisted when he came back to the United States. So he went to the emergency department of a local hospital. And this might've been about within a week after this possible exposure, because he was concerned about arsenic poisoning. So in the emergency department, he looked reasonably well, but a bit dehydrated. He had a normal EKG, no prolonged QT, normal chemistries and LFTs, but they called to the poison center and I got called in on this. And the question was, well, what do we do now? Should he be chelated? So I'll let you all ponder for a minute what you might do with him. But after we pondered it, we just decided there wasn't enough evidence here that he had arsenic poisoning and also that what would we be treating anyway, that levels may be low. So they drew a spot arsenic level. We didn't think he should be treated with the antidote like DMSA. And it's also very hard to get that immediately anyway, but we did have enough of a concern to admit him to the hospital overnight. He needed some intravenous anyway, because he'd become dehydrated and also to have some cardiac monitoring, just to be sure that even if he had something that everything was really okay physiologically. We did get back the results of his labs four days later. And you can see at that point, the total arsenic was 31 and 19 per gram of creatinine, 19 micrograms, but the inorganic and methylated fractions were non-detectable. The organic fraction was measured at 24, which is a little less than 31. So you wonder if he did have a little bit of inorganic, but for the most part, this didn't reveal at least at that point, acute arsenic poisoning. However, he was still concerned that the illness that he had was arsenic poisoning. And so he wanted a further evaluation. So he came to see me in our occupational medicine clinic. Interestingly enough on further history taking, he ended up reporting that he had a temperature to 101 when he was initially ill. He had a normal exam, and then the question was how could we evaluate him for maybe an exposure that happened a couple months before? Well, the choices that you have are fingernails, but you have to send them, and Mayo Clinic will do it, but you have to have clippings from 10 nails, and frankly, his nails were clipped down quite closely, so we wouldn't be able to get much. Then the question was scalp hair. Well, first of all, he could have had external exposure, and he didn't have much scalp hair. However, one can collect hair from other places, such as pubic hair, and we put him in an exam room by himself with the scissors, and he collected a sample, which we sent to the Mayo Clinic, and this is a very focused assessment of one element in the hair, and that can be more accurate, but basically, the main thing here was that none was detected, so in some ways, we hoped we could be a bit reassuring to him that at least going back at least perhaps a month or two, we didn't find any evidence of residual arsenic poisoning, and so we thought putting it all together that he most likely had an infectious GI illness. I'm not going to dwell a lot on, I'm running out of time here, treatment, because we really don't encounter that too much in our occupational setting. I will say if somebody's really acutely poisoned, they should be hospitalized with monitoring. There are different medications that can be used to treat them, BAL if they're really seriously ill, Suximir, which is an oral analog, and another agent, which is not FDA-approved in America, which is actually a very good agent, DMPS. For chronic arsenic intoxication, there's no clear evidence that giving a key later really helps that much once you've removed the person from exposure, so we don't generally recommend that. So I want to end by talking about prevention, and this is where it's really key. We need to control the work exposures. OSHA put forth a regulation back in 1974, and it was recently updated. The trigger, action trigger, is 5 micrograms per meter cubed over 8 hours, and the PEL is 10, and a medical exam gets triggered if you're over the action level for 30 days. It's a history and an exam, but no biomonitoring, interestingly. Other organizations do recommend biomonitoring, sometimes at the end of the work shift. ACGIH recommends a BEI of 35, but just to show you how there are differences in what different locations think is acceptable, Germany is at 15, the European chemicals, Europe is at 10. So you can see that there could be some discussion over what level will be acceptable, because this is, as I mentioned, a carcinogen. Then there's control of environmental exposures, EPA lowered it from 50 to 10, with some risk assessment analysis that showed you don't eliminate all potential increases in cancer, but trying to find a balance between the number of increased cancers being low and the feasibility of implementing this more practical. WHO also has a recommended limit of 10, but New Jersey and other states are really considering lowering it to 5, because it is a carcinogen. And then FDA has gotten very involved now with testing of food. There's been concerns about small amounts of inorganic arsenic in rice, particularly since that has been the first food in the past for infants and toddlers might be eating these rice products. So AAP, the American Academy of Pediatrics, has advised against rice as the first food for infants, and FDA has now recommended that we not have any more than 10 micrograms per liter in apple juice. And the 10 is meant that somebody could drink, I think, one or two liters a day for a lifetime. That's where that comes in, how many extra cancers you would get. So what are a summary of my takeaway points? Number one, I would say please avoid ordering urine for heavy metals. I don't see it as that useful. If there's a certain metal you want to measure for whatever particular reason, order the one that you need in the proper way. If you're doing arsenic biomonitoring, a random sample for most cases is okay, and add the urine creatinine so that what you get back is a microgram per gram of creatinine. And please, when you do the order, request speciation unless the lab has an automatic reflex program, and they may not do it unless they have a level above 35. Don't rely on telling people just don't eat fish or seafood for two days. I have had many patients who have sworn they didn't do it, and yet they have an elevated level, and one person, even when I sent her toenails off and nothing came back, she still believed she had arsenic poisoning from a random heavy metal test that showed a high level of total arsenic. For medical surveillance, if you're using urine samples, it's important to get an exposure history, a diet history, and if at all possible, to speciate if the total amount is above a certain level. So you can build that in as a reflex. And lastly, inorganic arsenic is a carcinogen. So technically, there's no safe level, but the lower the exposure, the better, and to the extent possible. We live in the world, we're not living in a bubble, and so there may be situations in which we do have small exposures to inorganic arsenic. So here are some useful references that I've put together. I also want to point that there was a really good article that got written from ACOM. I think I have it in here on the JOEM, and I hope that you will find some of these articles useful, and I hope this has been a useful chat, and I'm going to stop sharing right now. I'll turn it over to our moderators. Thank you so much, Dr. Goldman, I greatly appreciate that. I did see as we were going through, and again, I want to encourage everyone, if you have some questions, please type those in the Q&A box on your screen. We have three thus far. The first one says, would you ever have a patient change their diet for a while, i.e. not eat fish, and then retest and speciate to see if the urine arsenic changes? So that's a good question, but really, I don't find it as useful. If you can't speciate, surely that's something you could do. For most patients, I mean, I don't bother doing that. I'm able to get a speciated sample. I explain the situation to the patient, and then when we get it back, and it's all this non-toxic or organic form, and there's no inorganic, that's very reassuring to them. But I do have to tell them, the sad thing is sometimes what happens is they've gotten a urine the week before, their doctor gets this high level. They call me, and I say, speciate it. And by the time they try to call the lab, they've thrown the sample out. So that's why the easiest thing to do is do it from the beginning. But if the patient is, some people are convinced they're getting currently poisoned, I don't bother telling them to avoid fish, because there's other foods that could be these non-toxic forms. So I just go straight to getting another urine and saying, speciate. But that's a really good question. Next question. In Boston, do you ask about the consumption of lobster and other shellfish? Is the peripheral neuropathy associated with arsenic sensory or motor, and how long does it last? Well, that's a good question. According to the lobster, I think most of the arsenic that is in lobster is going to be the organic form. There may be in certain forms of shellfish, like I said, the DMA form. But again, I'll get the history so that I can help explain why we're measuring what we're measuring, but then I will still speciate. And then when I get that result back, I can discuss with them the meaning of it. And the second part of the question was, let me see, what was the second part of the question was? Is the peripheral neuropathy. Oh, the peripheral neuropathy. What I understand, and these are from past episodes of poisoning, I have to say I haven't seen somebody with such severe poisoning myself. But what is described in the literature is both a sensory motor. And so you should not see reflexes at the ankles. And for people that survive the poisoning, they also describe the sort of a burning sensation and lack of sensation. This is a very, very rare phenomenon. So even though neurologists and everybody is always checking for arsenic, it's actually a rare phenomenon. Urine test for current exposure. Did you say it would test the total arsenic of all types? Well, when you get the urine, a lot depends on your lab. And so you need to look into how your lab reports it. If you don't write anything, what you'll get back is total arsenic. Now depending on the lab, for example, they will do things in a different way. One laboratory that we use, what I get as a report is inorganic arsenic and total, period. Now that lab has told me that the inorganic is they put together the inorganic species and the metabolites. Another lab, on the other hand, like what I showed you from that other patient, comes out with a report that's inorganic, total, inorganic, and organic. And what that lab means is that the inorganic is the inorganic species plus the methylated. And the organic are those things like arsenobutane and those others. To actually have it speciated further to arsenobutane or arsenosugars, I'm not aware that our usual clinical laboratories do that. I have seen it. One of the papers that I recommended to you has done some assessments like that. But I think that would be much more of a research tool. So we don't have that tool at our fingertips. So what we need to know is how the lab is doing it and how to interpret it. And that information that I've given you is about usually the best way. But if you have any doubts, you can call the lab and ask them what they mean. Some actually label it as inorganic, methylated species, organic. But that's what they mean from the display that I showed you. We have a question. What was the story in Arsenic and Old Lace? Was there plausible poisoning? Or is this simply Broadway entertainment? Oh, boy. I'll have to go back and see that to remember. There are several movies that relate to chronic poisoning of people. And sometimes the cadavers have been even dug up, to tell you the truth, to look for episodes of it. Because if you keep chronically poisoning the person, you can eventually get them to be more and more ill. So I'm sorry I don't remember the name, but there's actually several movies about people that have died with arsenic poisoning and some whodunits. And I see that my colleague, Michael Kosnick, has something. I don't know if Michael wants to... It said, the NAS, as long ago as 2001, issued a formal risk assessment for arsenic carcinogenicity and concluded at water ingestion at the MCL of 10 micrograms per liter, the lifetime excess cancer risk, lung plus bladder, was approximately 1 in 300. This is higher than for any other carcinogen than EPA regulates. The OSHA standard, which would tolerate even higher exposures, was not based on a formal risk assessment. Shouldn't this be emphasized in the context of public health? Thank you, Michael. I totally agree with you. We've shown this risk assessment table. Thank you for bringing that up. It is much higher, 1 in 300, than the usual 1 in a million or 1 in 100,000. And I'm not sure that... I think this was accepted as a feasibility, that it was going to be too expensive for various places to be able to control the arsenic levels lower than that. So I'm not sure, back then in 1971, what was the year that that came through. That was... Oops, it's already gone. But I think that has been very controversial, actually, and I'm glad you brought up the exact number there. And I think that's the reason that other states, like New Jersey, are putting in, they're lowering it to five, which sounds like it would be much more reasonable. And I think that people who have well water, and particularly if they have children that are drinking the water, there's been more and more concerns about that. So I do agree, I'm not totally aware about how that got through, but I have a feeling from a chart that I saw about it, that it had to do with how much money it was going to cost to lower it to five. And for the chart that I saw, the amount of money that it would cost to lower it to five, and the number of cancers that were less, the people making the decision didn't think it was worth the extra cost. So I'm not saying I agree with that at all. And I think it is something that may be worth revisiting. But at the time that there was a decrease from 50 to 10, you may remember it, there was a lot of pushback, even going from 50 to 10, and Europe had been way ahead of America to do that. So maybe we should be relooking at it and trying to advocate for at least pushing it down to five. But thanks for bringing that up, totally on the mark. Excellent. And this is our last question, and then we do want to move forward and be respectful of everybody's time. Thank you, Dr. Goldman, for a very interesting presentation. Rice is a major staple of many diets and food products. To minimize ingestion of arsenic at a level of concern, what is the recommended average weekly amount of servings of rice for most? Are specific types of rice known to contain less arsenic than others? Which geographic regions may be preferable sources of rice to reduce arsenic exposure? That is a totally very important question. I've been concerned about that as well. There was an article in a Consumer Report, and I can also post later, and it may be one of the references that I have, looking at different forms of rice from different locations. And yes, you are correct, that rice from different locations has different levels of arsenic in it, and rice, and it depends where it's grown. And there are sort of tables and things that have come out from different organizations listing that. However, I think the major issue here is less for adults who are eating maybe a few cups of rice, but you're right, worldwide people do eat rice with every meal sometimes. And so knowing whether that rice has some level of inorganic arsenic would be important. The other reason this became very important is that the first food for infants has traditionally been rice, and also there's been something called rice syrup, which is even more concentrated. And so for that reason, there's been greater attention called to it, but not all rice everywhere has this problem. And there's one of the references that I posted, not to make a plug, I don't get any kickback from Consumer Report, but they've been trying to monitor and test different forms, different rice, to see what the levels are, and maybe FDA has even started doing that as well. Great question. Dr. Goldman, on behalf of the ACOM leadership, thank you for presenting today. As a reminder to all of our registrants, today's webinar was recorded. A link will be sent out to everyone. Please check the ACOM website often for new webinars. The American Occupational Health Conference is taking place in Salt Lake City, Utah, May 1st through 4th, 2022. Registration is now open. Please visit acom.org backslash A-O-H-C. To all of our participants today, thank you so much for joining us. We hope that you found this educational and informative. Please be safe, stay warm if it's chilly where you are, and have a great day, everyone. Thank you.

webinar

Dr. Rose Goldman

arsenic

health effects

monitoring

prevention

toxicity

exposure sources

biological monitoring

prevention measures