Richard Plois, Ph.D., M.S., Chief Toxicologist, Pharmacologist, Founder, and President of Intertox, Inc., is an expert in neurological, aerospace, endocrinological, respiratory, reproductive, developmental toxicology with over 30 years of experience assessing the risk to humans exposed to chemical and biological agents via food, water, consumer products, therapeutic agents, and the environment. He has conducted over 750 toxicological assessments that include single and mixtures of chemicals. Rick and I go way back. I've been so impressed with him. This is just a wonderful presenter for us to have. We've actually worked on the Navy F-18 and T-45 physiological episodes. I worked on it before I got out of the Navy, and then Rick worked on it with a root cause analysis after I had left. And not only that, Rick is the father of Aerospace Toxicology Association. It's a brand-new, as-an-affiliate organization, and his initiative has got that up and running. His father and brother are aviators. His brother's a flag officer in the Air Force. And he truly, Rick, does have a passion for aerospace medicine, and we're so honored to have him come here and present to us twice, now and then later on. So, cancers and then metals later on. So, this is absolutely fantastic. Good morning, everyone. I'm very happy to be here. Thank you, Chris, for the wonderful introduction. It has been wonderful to be able to work with you and all of your colleagues on a number of issues, aviation obviously being a passion of mine. I'm from Seattle, Washington, so I've come from the Pacific Northwest, where we do have our rain events. Not as much as California, though, at least at this point. A couple of things I want to start off is just some disclosures about who I am and what I do, so that we're clear about that. I am a consulting toxicologist. I've been practicing roughly 30 years or so. I evaluate exposure to chemical agents and determine whether there's a sufficient dose and exposure to cause an adverse effect. That's kind of my job. In my practice, I evaluate the toxicity of metals. I look at a bunch of other chemicals, like solvents and things and many different things, including the things that we're going to talk about today. I have been retained as an expert witness in cases involving chemical agents, including metals, including a whole bunch of different chemicals. So I just want to be clear about that. Some of the things that we talk about today, I've been an expert on. My opinions, though, are based on foundations of toxicology, which we're going to go through because I think it's so important. And it's including but not limited to exposure, dose, threshold, effect. And I conduct my toxicology assessment according to global recognized guidelines. And for today, I do receive an honorarium. So one of the things that we're going to cover, and there's a lot of information here. My question here is, this is the cancer course, right? Of course, the cancer risk, yes, sir. Yeah, and this is the slides for cancer. Is that correct? Okay, it is. For some reason, there's some mix up on the slides. Anyway, so the way I think about it as a toxicologist, I consider symptomatology, occupational setting, hobbies of the person, medications review, objective testing, including air, blood, urine. We'll talk a little more about that, medical history, and review the toxicological information. And I'll go into more depth on these things. And of course, when in doubt, call a toxicologist. That sounds maybe a little self-biased here. But the point is, the thing that I've been able to look at for 30 years is when I take a look at how physicians are conducting their toxicological evaluation, there could be a lot of opportunity for understanding the way that we do that, I think, which would be helpful for how you do what you do. One of the things about toxicologists is that we're conservative, like you. We are on the side of, and we err on the side of protecting public health. We review the literature. We consider higher air concentrations. We consider higher doses when we're making our evaluations, and I'll talk more about this. And we consider longer periods of exposure. In other words, if you have a higher dose, a longer exposure, and higher periods and higher concentrations, that's going to lead to an erring on the side of public health. The objectives today is to talk about carcinogens in the occupational setting, how we do our toxicological risk assessment, how we apply applicable occupational standards, and discuss a little bit about surveillance procedures for various compounds. So we'll talk about an introduction, general talks, studies using cancer toxicology, and then cancer and occupational medicine. So I know you all are aware of this, but it's also helpful for toxicologists. Cancer is a disease characterized by mutation, modified gene expression, cell proliferation, and aberrant cell growth. There are multiple causes of cancer that have been established, including infectious diseases, radiation, and chemicals. And my next slide pretty much kind of helps put what we think of as toxicologists in terms of perspective on cancer. And I think you can see from this particular document from Kasseret and Duhl that diet accounts for a lot. Tobacco accounts for a lot. And when we look at industrial products, for example, we're looking at around 1%. Occupational exposure is around 4% of all cancers. So I think it's important, then, when you're thinking about working with your patients in cancer, what it is that might be causing the cancer. We're here in occupational medicine, so we're focused. Basically, our flashlight is focused on this area of work, but it's broader than that. Just to give you another example, take a look at these. Large doses of natural chemicals can cause cancer in animals. I'm sure you're quite aware of any of these, and you may have had these for breakfast or you may have had these for dinner yesterday or whatever. And the point here is that, again, while we're focused on occupational, there are other bigger, important causes related to cancer in humans. A little bit of the history of toxicology and cancer. We go back to the chimney sweeps back in 1775 with Percival Pott. You may remember that in some of your early epidemiology courses that you've taken. And in that case, it was soot and chimney sweeps that were getting scrotal cancer at the time. Well, you can take a look on this particular thing all the way forward. What we see from a chemical standpoint are things like arsenic, coal tar, uranium, soot, what else here, benzene, nickel, chromium, coal tars, just to name a few, which tend to be more on the occupational perspective. But that's kind of the history of it. I know you're aware of the terminology, so I really won't spend a lot of time on that. But I think it's important to consider what it is, because when we start looking at animal studies, it's important to understand what it is that they're actually detailing in those studies. I think this is a little bit more interesting in terms of the process of arsenogenesis from a toxicological perspective, is that you have a normal cell, you have an initiated cell, you have a lesion, and then depending on what happens, you have potentially cancer. So from a normal cell to an initiated cell, there is an initiation occurrence. And that could be a mutation, it could be DNA damage, it could be one of these things. Again, from a toxicologist's perspective, we want to know what that is, because it helps us understand the potential for causing a cancer. Then after the initiated cell to the focal lesion, well, those cells could just die, which would probably be a good thing. In other words, the damage is sufficient that actually the cell dies, apoptosis. On the other hand, it could not be. It could be just a wound, if you will, such that the cell continues to live and proliferate, and that's where you get into different types of neoplasms and tumors. One of the things that I think is probably useful for all of you is what sources do we use? And I think that's going to be an important part for what you can consider when you want to look more on chemicals causing occupational cancers. The ones that I think, and all of these are very good, some that you're probably aware of with ACGIH, NIOSH, OSHA, things like that. But I also want to point you towards the bottom of this. Toxicological profiles by ATSDR. CDC is a good source. The disposition of toxic drugs and chemicals in man, the 12th edition, I think, is what's current, if you've seen that one by Bassett. And our Bible of toxicology is Cassaret and Duell, which is up to its 9th edition. And it's heavy in toxicology. I'm not going to shy away from the point that it has a lot of details. These things are detail-oriented, which may be more than what you want to read. But from a toxicological perspective, we found this super, super helpful to understand what's going on. So I point this out. I want to say one thing about these. I've given you documents, and so something like an ATSDR document, for example, is a good source, a good summary. What we need to do as toxicologists is go back into some of the studies that have been reported in there and make sure that it was translated correctly, that the data was understood correctly. And so while it might be considered a strong document, we always want to go back and look at the actual study to see if we can agree with the interpretation. You'll hear that more and more as I move into this conversation. So another way we look about this is health risk. If we want to look at health risk, there's two components here, exposure and hazard. So if we look at a chemical like benzene, for example, benzene has a hazard depending on what the amount is. You know, you could get CNS effects. You can get certain cancers over as an endpoint. So we want to know what the endpoint is for a particular chemical, and there are pretty specific. But the other side of that is the exposure, and exposure is dose and time. So we could have something like plutonium, for example, put it in a bottle, a container that doesn't allow the radiation to be released, or exposure to the compound. And as long as it's in that container, the exposure is zero, the human health risk is zero. So just to use that as an example, exposure becomes a very important part of our work in toxicology. Another thing that I think is really important in the work that we do is to consider a statistical problem that we run into all the time, and I know you all run into all the time, and that is 0.05 as a statistical component. Oh, my goodness, we are just always looking at this a little bit more carefully, because the way we see it is there's a statistical significance, and some could even argue whether 0.05 is adequate enough. Some are suggesting 0.001, 0.005, 0.0001. In other words, what's the magic by 0.05? But that's a statistical point. It's not a clinical component. That's the way we talk about it, is we're interested certainly in statistical components, but that doesn't mean that it's causing the clinical effect that has been announced. So I always want you to be thinking about that. This is a publication bias. One thing in toxicology, I would say, is the fact that my colleagues, my brothers and sisters in general, in toxicology, we're motivated, and the reward system is such that we find problems, which is good. I mean, that's a good thing what toxicologists do is find things that are causing human health issues. Just as important to me is things that are not causing human health effects. So finding no effect is as important as finding an effect. And if we only find effects, then I think there's a concern in my mind from a toxicologist's perspective is what's appropriate, what's safe, what's not safe, things along that line. So there is a publication bias, I think, in our field that I think physicians and clinicians should be aware of. One other thing that I would say is, boy, we generally talk about small things. And to put it in perspective, we're talking in general about concentrations and exposures in the part per billion category. That's not very much. And here to illustrate that is an Olympic-sized pool. And if you put one teaspoon of sugar in an Olympic-sized pool, it's two parts per billion is the concentration in that. And that is not very much. And so when we're talking about concentrations in air that's in parts per billions or in water that's parts per billions or whatever it is, the unit, just please remember that it is a small amount. And with toxicology, as you're going to find out, the dose makes the poison. So we'll go into a couple of components here. This, I think you've looked at and seen before, exposure routes, oral inhalation, skin. Talk more about these as we go on. But here, I think, is another important point, and that is air concentrations or water concentrations or food concentrations or soil concentrations. Remember, when you see some data, if you do see data, let's say we're looking at a concentration in this water of something, and that's the test result that you get. So that's in the glass, that's in the water. Here it is out there in the web land. It's in the water. But what we're interested from a toxicologist perspective is what's the dose, the internal dose. So if something is dissolved in water, and it is dissolved in water, likely it's going to be pretty well absorbed into the gastrointestinal system. However, if it's not very well absorbed, then whatever is in the water is not necessarily going to be what gets into the body. Then we have the detoxification. So we have a potential dose that is in the water that could get in. And that's important to think about because there's a lot of things that are going to go on, absorption being one. Number two is once it's absorbed, then what happens to it metabolically, the distribution of that particular compound. And that becomes more interesting to us because there's metabolism that will go on, especially if it gets brought into the liver quite quickly. We're going to start to metabolize that. And that is a detoxification process in general. There are exceptions to that where actually the agent becomes the toxic agent because of the metabolism. The body can't quite figure out exactly what to do other than metabolize it. And that's what happens. There is then finally an internal dose that gets distributed throughout the body. And from that perspective, what we're saying, that's the biologic effective dose when it particularly hits the organ. So if it's a brain, neuron, cardiac cell, whatever, that's the dose that we're most interested. But I say that because most of the time we get concentrations in some material, like you'll get it in air if you're in a factory, for example. And that will be the guide that would say, was it toxic or not? And there's more to do than just look at an air concentration. Well, here's the father of toxicology, only about 500 years old, Paracelsus. What is there that isn't? So this was in German, so someone translated it to English, so it's a little awkward. What is there that is not poison? All things are poison and nothing is without poison. Solely the dose determines a thing that is not a poison. I think this is so important. This is kind of one of the major tenets of toxicology. You learn this in pharmacology as well. The dose makes the poison. Not enough, you don't get a therapeutic effect. The right dose gives you a therapeutic effect. Too much is a toxic effect. Same thing in environmental agents or occupational exposures as well. The other point here to make, and we'll go through this a little bit more, is the dose-response relationship. And we'll talk a little bit more and we'll kind of dissect it, because it's important to understand that as you move forward. The other thing is presence doesn't equal toxicity. We have today, here's some other brothers and sisters that are called chemists that are out there working their tushes off, so to speak, to come up with machines that can measure things in such small quantities. That's their job. They love it. They're doing a great job. They're finding things in parts per quadrillion now. Again, the fact that you can detect it doesn't mean that it's toxic. And this is an area that I think is important also with your patients, is to remind them that the media that is saying things such as headlines about, you know, coffee causes cancer, coffee doesn't cause cancer, you know, you name it, you see it almost weekly, is not helpful from a toxicology perspective. It is not providing. In other words, like, it may or it could or it might. These are not scientific terms that we use. We want something more definitive. And I think we all have the obligation in order to figure out how to explain toxicology and how to explain exposures to chemicals. Given the fact that everything on the planet is chemical, given the fact that we're all exposed to chemicals, I like Dr. Peters, I think, was the last person who said, if you tell someone not to be exposed to a chemical, what do you do? I'm drinking water, H2O. So, and it will kill me if I drink enough quickly enough, it will kill me. All right. So, one of the things on this is the idea of detoxification. So, one way to look at it is chemical and drug at low doses, there's protective pathways that actually work. That's the beauty of the human body. We've got protective mechanisms that work really quite well. And at low doses, they're doing their job. Where it becomes unbalanced is high doses, protective pathways then become overwhelmed, and that then starts the toxicological cascade of the potential adverse health effects. So, I think it's important here. I've identified phase one and phase two enzymes. For those that are super interested in the detoxification mechanisms, you can look those up and have fun with them. As I said, I want to talk a little bit more about dose response, and there's a couple slides here that I'm going to talk about. One is called a threshold. And so, the S-shaped curve, and you can see this, there's the response that goes from zero to 100, 100% response. Let's just put it percentage. And then the dose or concentration, it increases. It goes to the right. What we see very, very often with most chemicals is an S-shaped curve. And when we see the S-shaped curve, you see there's a period below which there's kind of a flat line, and then the rate of response increases with smaller doses to the point where it maximizes whatever chemical effect or whatever response that you're going to see. So, there is a principle in toxicology called threshold effect, or the approximate threshold, which basically says, how do we, how can we determine what, if I go back to my last slide, where everything is actually working quite well in the body, there may be exposure, but the effects are nothing. There's nothing that can be registered. And so that is what we consider a threshold. When we think about threshold effects, which is we can find in the toxicological literature, in other words, going back to the original studies to see if they were done well, we can find threshold effects. Now, they might be in an animal, like a rat or a mouse, but we can apply some safety factors to it, and we'll still have this concept of a threshold effect. Another way to look at it is, coming from Seattle, we have a football team up there you may have heard of. It's called the Seattle Seahawks. And I like this concept here because, just like, I guess we're here in Kansas City, where they also have a football team, I guess. The concept of any stadium is you've got a seat, you've got chairs where people sit. And if you use the analogy that a person is a chemical agent, like one molecule of a chemical agent, they all have to find their seat in order to fill a stadium. And if we use filling the stadium as a representative of enough of a dose to cause an effect, this is what we're talking about. So we have something called the 12th man in Seattle. And if you had one person—and the idea of the 12th man is the stadium, people yelling in the stadium so loud that the other team can't think, I think, is what they're trying to do. But so the concept here is if you only have one person in the stadium yelling at the top of his or her lung, it's not going to have an effect. You're not going to see anything. And if you occupy 68,000 seats and everybody starts yelling, you're going to have an effect. So again, that's another principle, another way to look at those response. A few molecules, probably not much. You could maybe fill up a quarter of the stadium still, not much. Maybe you hear something, but not enough to cause an effect. Now, with cancer, we have a little bit of a different approach to it. And that is—usually it's called a—it's kind of a straight line. It's—we will use a term called cancer slope factor here. And the cancer slope factor is an approach to public health toxicology. And it goes something like this, is that if you follow this, you can say pretty much any dose would be enough to cause cancer. We use that because—not we, but many agencies around the world have used that because they believe that a single molecule—and it's certainly health protective if you think of a single molecule could potentially cause cancer—is to use that method in order to make that determination. That's the approach that we take, and I'll talk a little bit more about how that—what the results look like. The problem is, is that it erroneously assumes that there's an increased cancer risk at any dose. And again, what we do see in studies is a dose response from that perspective. Now, so we can see a dose response, so that's toxicology knowledge. The way that we protect against it is to use a cancer slope factor, which goes through zero from that perspective. So that's another example of protection in terms of the way that we do our work. One of the things to talk about is chronic exposure—the types of exposures. I'm sure you're aware of many of these—acute, subacute, chronic, subchronic. You've probably seen animal studies. What is important here is that with an animal study, you have controlled doses of a specific chemical. We can do dose response curves, and we can look at the severity of effects from that perspective. But here's another way to look at this low end of the dose response curve. We've got different acronyms. One is NEL, another one is NOEL, another one is NOAL, and the other one is LOAL. You can practice those after this class. They're pretty self-explanatory. NEL is no— It's self-explanatory. No observable effect level, so that's a NOEL. A no effect level is an NEL. A NOEL is a no observable effect level. So you can see the distinction between it. The NOEL would be something you would find from an experiment. You'd find that there's no observable effect. Now, that doesn't mean that the animal wasn't dosed. It doesn't mean that the animal didn't receive it. It was that whatever you're looking for, whether it's clinical parameter, pathologic parameter, or whatever, you don't see any effects. No observable adverse effect level, a NOEL, is a little bit higher dose. And what that means is that there's no observable adverse effect level. Again, toxicology studies look for that as well. In a good dose-response study, we want to be able to see these different levels. So it doesn't mean that there isn't an effect. So there might be a clinical effect of some sort, some minor effect, but it's not an adverse effect. And then the NOEL is the lowest observable adverse effect level, meaning it's the dose at which was demonstrated there was an adverse effect, but it's the lowest dose that we found for that effect. Why is this important? First of all, when we start looking at toxicology studies, we want to know what these numbers are, because that helps us understand what the potential health effects are. Number two, we also want to find the adverse effect, and we want to find the most sensitive adverse effect. So the LOAEL, the LOAL, helps us a lot. First of all, it's the most sensitive effect. Second, we go for the lowest LOAEL we can find for the most sensitive effect. Again, these are ideas towards protection, because if we protect against the most sensitive effect, all the other effects are then prevented. So these are numbers that we want to get from studies. These studies are really important from that perspective. What we do then is we apply safety factors as well. And these safety factors can go from numbers of, I say, 1, 3, or 10. That's for extrapolation from animals to humans or extrapolation from a LOAEL to a NOAEL. How good is the database? Blah, blah, blah. So we apply these, and these numbers can be really quite high. They can be 300, 400, 300, 900, 1,000, sometimes 10,000. So whatever we find, we then lower the dose in order to come up with acceptable levels. In terms of animal testing, I'm going to just run through these slides. You can look at these at your own leisure. What's important is that animal testing for carcinogens in particular, but also any kind of chemical testing, is really changed between anything before 1970 and then after 1970. And these are important when you take a look at these studies when you're thinking about this and something we look at. You know, a study that only gives a single dose, for example, doesn't tell us a whole lot. We want to see a varied dose for the things that I was just talking about. In today's practice, you have at a minimum three doses, and you have enough animals per group, all this kind of stuff. So you can look through these. It's an important thing to consider. I have all of the slides there. Now, human studies is a little bit different, because here we get into this idea. And with occupational, we're not talking about doing clinical studies with people on these things. The best studies that we're going to do are something called epidemiology studies. And these are studies that are used a lot. And again, it's really important to take a look at the quality of these studies in order for you to make a good understanding of what the potential health effects is for a cancer agent. First of all, an epi study can provide an association. It's not cause and effect. Animal studies can give you cause and effect much more often than a human study. But epi studies are an association, and they're helpful, especially when they're done well. But they cannot provide causation. And so if you're making a determination based on epidemiological studies, just be thoughtful about the fact that these are association studies. And it's so hard to manage a bunch of different variables, which we'll talk about. The types of outputs that come out here are, in some cases, some absolute measures. There's some risk differences. There's some population attributable risk. There's some relative risks and odds ratio. There is a hierarchy of different types of epidemiological studies, and I think this is important for you to consider as well. One is called the clinical trial. We'll go through these. This is not going to be—this would be happening if you had a drug. But the idea here is to take your target population. You treat them with a vaccine, let's say, or the other ones would provide a placebo, and then you figure out what's the cases of the outcome. Pretty straightforward. Well done. Usually managed pretty well from a population perspective. A cohort study, also called a nested case control or a case cohort study, is different. You have a target population. Within that population, you have some that are exposed and those that are unexposed, and then you look for the disease outcome. And time is a variable that is looked at. Again, this would be a second-best epi study. So if you're looking for studies, go see if you can find these before you find anyone else. The other one is called a population-based case control study. And in this case—yeah, there we go. You're kind of going backwards in time, whereas if the other one was going forward in time, you take a population, you look at those that were diseased versus that were not diseased, and then you take a look at those that were exposed that were diseased and those that have the disease that were not exposed, and you can basically understand it. So what I'm trying to show you here is what's important to think about when you're looking at these studies in terms of how do they help you make a decision of cause and effect? How does it help you with your understanding of the practice of medicine as you do that? Cross-sectional studies. These are not quite the lowest form of study, but basically you take a target population, you look at those that were exposed with those with the disease and exposure, and you come up with it. There are a lot of these studies that are easier to do. Every one that I've said, if we go back up the pyramid, are much, much harder to control. And then last are anecdotal reports and opinions. This is where I put case studies, for example. They can be super interesting and super helpful, but, I mean, it's usually one person or maybe a handful of people, not a population. So many of the things that we see as toxicologists, when we are asked the question, can you provide scientific evidence of causation or can you not provide, is there any causation that can be attributed to this, is important. So, we take all of the data that we've said so far and we put it into our human health risk assessment. It's a fancy word that we use. It's toxicology assessment. And when we do reports, we basically kind of go through everything that I've said so far plus this next few steps. And there are four parts of it. One is called the hazard assessment. Basically, what chemicals are we talking about? And what's the end point? What's the cancer end point that we're looking at? Dose response. Look for the studies that provide some information on dose response. Carcinogens, one way or the other. Exposure assessment. What do we know about how long it takes and how much it takes over time? And then we do what we call the risk characterization. And that's the way we do it. And this is a globally accepted way. Europe does it. Most countries, industrial companies, countries have used these procedures wherever they go. There's a lot of documentation that goes to this. This is just a little bit of it. There are cancer guidelines. There's chemical mixture guidelines. There's developmental toxicity guidelines. There's mutagenicity. Blah, blah, blah. All of these things are guidelines that we use. When you send your taxes to your account, they have to follow certain procedures. Just like you have to follow certain procedures, we have to follow certain procedures that have been identified. When we look at exposure parameters, we look at air, water, diet, dermal. And we put fish consumption in this just to illustrate the fact that if you're looking at mercury, for example, does your patient fish? Where are you in this country in terms of that? Because methylmercury, for example, not a carcinogen, but it will bioaccumulate. And if you're eating fish, it'll get into your body and it'll stay in the body. So anyway, we do that. We look at, in this case, it's a reference dose, but it illustrates the way that we look at the world. In this case, this is an example of a chemical with a low L. I give you a milligrams per kilogram per day. We divide it by uncertainty factors because maybe the database isn't that strong. Maybe it was a low L. The end point is important. We then come up with a dose of milligrams per kilogram per day. And then we can actually turn that into a drinking water level, for example, by using a standard weight and two liters a day. So we can take that reference dose and actually put it into a value. EPA has ways of looking at this. So if there's interspecies difference, we can divide it. We can take a dose of a low L of 500 nanograms per kilogram per day and then continue to divide it down for intraspecies or low L to no L and for kind of extrapolation. So anyway, for a cancer risk, what we do is we have a little simpler equation. We have risk equals intake times the cancer slope factor. So if you go back to my one slide, which has a straight line, we can find the slope of that line, and that line then identifies it. And when we come up to acceptable exposures of cancer risk, we come into this really interesting way of describing it. So one of them is—these are EPA guidelines, and they use them also for worker exposures as well. There's 1 times 10 to the minus 4 risk, and then there's 1 times 10 to the minus 6 risk. So what we do is we take this cancer risk, and we've actually developed a level at which we expect or predict based on these scientific studies of cancer. And what do we mean by that? So 1 times 10 to the minus 6, that's probably the easiest one to talk about, is called de minimis, meaning that we don't—the expectation of a cancer at that level is, I don't know how to say it, hard to find, hard to relate to, hard to accept, hard to understand. So 1 times 10 to the minus 6, where exposures can go to carcinogens all the way up to 10 to the minus 4. So what I did here is I give you an example. So if chemical X has a cancer risk of 2 times 10 to the minus 6, that's from experimental studies, okay? So we get that from experiments. And just to point out, toxicologists, again, there are a lot of cancer studies, so we go for the one that's the best designed, the best conducted, has several doses, exposures are appropriate. We think about all of these things. So does US EPA and all these other agencies. It comes up with a cancer slope factor. Now what we do is we put this into perspective with what's the average risk of developing cancer in the US. I've seen it's 1 out of 2, sometimes 1 out of 3. I'll use 1 out of 3. If we just change that to a decimal, that's 0.333333333. So what is the incremental risk due to exposure chemical X if it has 2 times 10 to the minus 6? You go from 0.000002 plus 0.3333333, and you come up with 0.3333335. So, again, to demonstrate the kind of work that we're doing in terms of protecting public health from cancers, from carcinogens, is to use this approved method. And to give you a perspective of how conservative it is, here's an example of taking that. This is developing cancer. That's it. Deaths, not anything else, is just developing cancer. So I will kind of move into more examples of carcinogens in cancer. But one thing I want to talk about is uncertainty. And uncertainty is an example of a term that we use in science. You probably use it in medicine as well. I don't know if we have the same definition, but we might. But I do know that toxicologists calling something and saying we're talking about uncertainty and the public and talking about uncertainty is completely different. So one of the things in science is we can't know everything, right? We just don't know everything. And so we try to quantify what we don't know. Or, if we can't quantify it, we at least want to say it. When I say that there's some uncertainty about chemical X causing cancer, it doesn't mean that I believe that it doesn't cause cancer or that it does cause cancer. I'm more specific as to what it is that we don't know that would be helpful to know so that you have a complete package of information as a physician or as anybody that else is interested. You have a complete package of what we know versus what we don't know. And it helps you, I think, put more certainty on what you did. So we use the term uncertainty. It's not the layman's term. It's more specific to the area that we do. I think a lot of science does that. I know physics people do it. Chemistry people talk about uncertainty. They don't seem to run into problems that toxicologists say, well, here's some uncertainty. And they go, oh, my goodness, you probably don't know what you're talking about then. So we're working on trying to get the definition of uncertainty parallel. Anyway, that's us. I'd be interested if you guys had that. So let's talk about lists of cancers and association with chemical agents, really the meat of it. That said, all that I've said to you thus far is so critical to coming up with these lists that if that's not part of it, I think I'm not giving you enough information as a toxicologist. So there's some fantastic sources. I've just put out three here that you can go ahead and look up. IARC. Canadians have a great site. U.S. has excellent resources on it. If we go to OSHA, they have definitions of it. You can read these definitions of it. It is what it is. What's maybe a little more important here is this idea of groups of carcinogens. So here I'm giving you on this slide IARC's classification of carcinogens. And you break them down into different groups. Group 1, group 2A, 2B, group 3, and group 4. And the points of this is that scientists have come up, toxicologists have come up with different classifications depending on the evidence for carcinogenicity. And with that, the highest, group one, is evidence of carcinogenicity. So there's actually human evidence of it. So if you come across a group one carcinogen, the evidence is pretty quite strong and it has human health, excuse me, it has human health implication, not implications, but evidence as well. Where you tend to see a lot more is in the group two A's and two B's. So this should give you at least some thinking about the quality of work. You should do it with group one as well, frankly, but group two is some limited evidence of carcinogenicity in humans, but there's sufficient evidence in experimental animals, that's group two A. And two B is kind of limited on both of those. Group three and four tend to be ones that are not important for carcinogenicity. EPA does the same. They have group A, B, C, D, and E. And so there's actually a consistency between that. OSHA has a list of carcinogens that from a workplace perspective, I suspect you've seen many of these or know of these, and they have derived these levels based on the way that they have evaluated the literature. And then what I think is more intriguing, which I think is helpful is, and this is by IARC, it basically starts to differentiate organ site by chemical. I think this is where this is super helpful because when we're talking about a therapeutic agent, we want it to hit a target. We know that it'll hit other structures in the body, but we also know that it should hit a target in order to be a therapeutic effect. We think the same thing with chemical agents as well. And again, it's a dose response effect, but we're looking for things that are the lowest dose that cause an adverse health effect and we can manage it. But it would also look at a specific organ. If you increase the dose so high, you're gonna get a lot of organ involvement, and that's not particularly helpful. But if you look at it from a more strategic standpoint, now we can start to look at it. So I just wanna go through some of these things, what I've done just to help you see this. I hope it comes in your handout as I've identified different structures from an occupational perspective and the chemicals that have been listed. And there's two categories here, carcinogenic agents with sufficient evidence in humans and agents with limited evidence. And I've gone, and on the other side, I pointed out different organ structures. So I think what's kind of interesting here is if you can start to walk through some of this, you'll see some consistent chemical agents over the next few slides. But you will also see some things like rubber production, which it's got a lot of chemicals, I suspect. So it's a little bit hard to figure that out. I think the ones that tend to be interesting are ones where they have strong evidence of exposure. Again, it's always important to go back to the original studies to see how they came up with that. The ones that I think will be important specifically in the occupational would be obviously lung, nasal cavity, larynx, not much there, and digestive systems, to name a few. Skin, and here we have a fair number of them. And then some other individual compounds. Asbestos, you see a lot. Painting, you see a lot. You see formaldehyde a lot. You see welding fumes on some, silica dust on some, arsenic, to name a few. And I want to point out one thing I think is super interesting. I have a little green box by this one. And I raise this because a couple of reasons. One, if you look at these, there's no chemical agents that affect the thyroid gland. Radiation has been demonstrated in humans to cause thyroid cancer. What I run into sometimes is, in medical records and things like that, this is just to illustrate a point. Well, I'll look for the organ that has been affected by the cancer, because we can find the cancer in an organ. But then the question is, what about the chemical and the agent? And so I bring up thyroid gland primarily because I have seen thyroid cancers diagnosed by physicians as caused by a chemical agent. And so where I think this is super helpful is to help you understand where these organ systems are relative to a chemical agent. I think that should help that perspective. All cancers, 2,3,7,8-etrodioxin, that is a compound that is a material that has been shown in many occupational settings related to combustion processes. So in terms of, I said, health risk equals hazard times exposure. So you could do a couple of things. You can do several things, and I believe you've already seen some of this. Reduce exposure. Engineering things are great. So engineering controls, work practice controls, administrative controls and personal protective equipment. We've seen, again, where people have had appropriate PPE, yet they have a cancer of an organ that has been suggested by a physician who have caused that. A, it doesn't fit the right organ. B, you've got PPE that would obviously prevent that. Now, of course, we'd need to look and see what the history of PPE use is, but those are the kinds of things that we'd be thinking about. WHO has set out some principles for screening populations. The health impact has to be important. The idea here, it's almost like medical monitoring. When do you do medical monitoring? When is it helpful? And it's helpful if you can actually have a diagnostic test that is reliable, specific, and sensitive to the endpoint that you're looking for. And if you don't have that, then I think screening has been considered less effective. Also, the idea of accepted treatment, suitable tests, policies, and facilities for a diagnosis. In terms of assessing risk from toxicologists' perspective, not a physician's, is the patient history, the occupations, onset, length, carcinogenicity. We also add hobbies, we add therapeutic agents. We also look for other explanations and causes. And again, this is your domain, not mine, but observation, lab work, histology, anything in terms of objective testing is super helpful for us. That's really where it is. Some people have brought up the Bradford Hill, they call them criteria, they're really guidelines. And it's something to think about. There are nine of these, the strength of association, the consistency, the specificity, temporality, biological gradient, plausibility, coherence, experimental. If you look for Hill, 1965 is when he wrote this. It would be a good source of information to think about causation relative to a compound. These are the nine guidelines he suggests that are used in that approach. And with that, I think I have come to the end of my presentation. Any questions, please? I have a question from one of our online panelists. Dr. Fraser asks, can you speak to Agent Orange, burn pits, and Havana syndrome? That is a very, very, very broad question. That's a very broad question. I'm interested in it. I mean, I'm curious why you're interested in all of those three. So I don't know what to, is there more to the question than just, what can I say about it? I used to have seen a response yet. Okay, well, I can say one thing, and that's burn pits. I can, but it's a limited response, is I was part of the government's review of research in burn pits. As a neurotoxicologist, I was asked to review studies on behalf of the military as to whether the studies that were being presented were designed to answer questions about burn pit exposures. That's all I could say. From a neurotox perspective, very interesting stuff from both psychological as well as neurotoxicological. Can you hear me? Oh, I can hear somebody. Hi, I was the one that posed the question. So I am doing compensation and pension exams for the VA, and they recently passed that burn pit legislation. And with that, it also encompassed the people with other things like Agent Orange and so forth. So basically they're all being considered, like reevaluated and whatever. So I was just curious, there's been so much controversy over Agent Orange, and recently they published saying Havana syndrome is not really a thing. So I just thought maybe you would have some more interpretation of the evidence if you are familiar with it. Yeah, so thank you, Dr. Fraser, for asking the question. Let me respond a little bit more. So I mentioned the burn pit stuff. That's my experience. I think it's a super hard question because as I understand, burn pits would include a whole host of different compounds at temperatures that are not similar to one another. And so you have potential combustion byproducts that could be quite diverse. That's my understanding. So I'm not adding a whole lot more to it. Agent Orange, you have the potential for production of 2378 TCDD, which I kind of mentioned at the end. That's one of the things that pops up, but it's important to understand what the agent was at the time to understand whether there was sufficient levels, if any. And then third on Havana, I know nothing about it other than I believe it had to do with some electromagnetic radiation, but that could be completely wrong. Yeah, my understanding is it was EMS too. Yeah. My question about CT scans and cancer, just this is not occupational related. I mean, but more about as an ER physician, we scan a lot of people. And some people have way too many scans. And I'm just wondering what your interpretation on some of the cancers, the thyroid cancer, breast cancer, and some of those things that we are worried about inducing in patients. By giving too many exposures to radiation is what you're saying? Yeah. Yeah, I'm not the expert in radiation. I'm sorry to say I can't help you there. Other than the exposures, the metabolism, all of the things that we have all probably learned are important. So reducing exposure is a key part of reducing exposures to these agents, that's correct. But I do believe that I would suspect you have a radiation medical physicist or something like that related to your facility that you could ask these questions to. Yes, we do. And like I said, it's not really occupation related. Yeah. Well, thank you for your questions. Randy Peters from Pittsburgh, can you hear me? Yes. Oh, wow. This is also, and I apologize, this is also a very general, not purely occupational question. One of our hospitals in Pennsylvania is right across the state line, so literally just a few miles from the site of the East Palestine, Ohio crash. We're trying to do some just general public safety. We're basically trying to cop, how should I say, we're trying to do education to offset the possibility of propaganda and conspiracy theory stuff. It would help me a lot if you could just say as one of the leading toxicologists that you feel comfortable with the work that the EPA does in clearing and making sure. Admittedly, they're going to need to watch those sites for a very long time and do further testing. I would just like more ammunition than my own limited fund of knowledge in saying that the government approach to the crash and monitoring has been appropriate thus far, if you can, if you feel comfortable doing that. Yeah, that's a, I think you raise a very interesting question. First of all, we are, we, my firm and I are not involved with this issue at all. So I don't have data to say anything. So I point that out. I only know what I read in the paper, and I, as you know, I have a little skepticism about science in major newspapers in terms of sometimes the quality. I also know about outrage that occurs in situations where people get very frightened by situations. And this one certainly has, from what I can tell, pretty robust level of outrage for lots of reasons. One of them is the chemical exposure. In general, I'd say EPA does a good job. I suspect that the outrage is causing a whole bunch of entities, including probably the railroad, probably EPA, probably the state, to do a lot of testing, which I think is good. It probably is more than is needed, but that's a bit of a guess. But I think the outrage is driving more and more testing to be done. I don't know if that's helpful or not, but that would be my assessment. I would not expect you to have a definitive response. That's very helpful. Thank you so much. I really appreciate it. You're welcome. Thank you for asking. This is Conrad De Los Santos. I have a question concerning threshold and non-threshold responses. Would benzene be considered, benzene exposure, either acute or chronic, be considered a non-threshold response? Well, it's a controversial one. I think for non-cancer, there's a threshold effect. For cancer, we assume a no-threshold effect for doing our work. Can you elaborate what you mean by that? Yeah. So if we're looking at benzene from a non-cancer standpoint, then the traditional dose response threshold effect would take place. In other words, there would be an exposure at which there would be no non-cancer health effect. Let me stop there for a second. Does that make sense to you? It does. But what about if a patient is starting to develop changes like bone marrow dysplasia after potential benzene exposure? Well, then that would be a different thing. So when I think of benzene exposure, for example, here's a simple one we're all exposed to. As we go to the gas station, we fill our car up. We're exposed to benzene at that point. My guess is the exposures that we receive at that point are low, below a threshold. Our body enzyme systems are able to do it. If you're starting to see some pathologic or clinical parameters change, and you think it's due to benzene, I think you're obligated to look into that much more thoroughly. OK. Is that helpful? It is. I was just trying to relate it to non-threshold versus threshold, and whether it's something that's like a group A or a group 1, depending on whether you're looking at EPA or OSHA. Would something that's a known carcinogen kind of fall within the non-threshold response, being that no amount is a safe amount? Well, I don't think it's possible to not have benzene exposures on our planet, sorry to say. So I think that's it. But I think, let me make sure I'm understanding your question, because it's possible I am or I am not. You have a, let's say, patient. And the patient works in a facility that uses or has benzene exposure, right? I would expect there to be air samples of benzene. And so that's either a yes or no. I would expect, then, those levels of benzene to be either above worker exposure levels or below worker exposure levels. You have to consider on an individual basis whether a patient is, for some reason, more sensitive than the average person, but not by 10,000-fold. I'm just talking about tenfold. For some reason, you have some information that would say that. Then, if they are being exposed over longer periods of time to levels that are unsafe, and you're starting to see some clinical parameters, I think, then, you need to continue to work that protocol to find out, are those clinical changes consistent with benzene exposure? Right, no, we're saying the same thing. And according to your list of classifications, it shows hematopoietic, lymphoid, and related tissue. So if you saw damage to that target tissue, then, EPA happens to have a benzene limit of five parts per million. If you knew that patient had exceeded five parts per million over a year, then, I guess, the presumption would be it's from the benzene exposure. Well, I think you're working towards building that as a causative effect. Again, how much more over worker exposure levels, not EPA levels, but worker exposure levels. You could also use EPA levels which are more residential, which might provide some insight. But again, those have such great safety factors that it would be important to think about. Very good, thank you. Yeah, happy to, if you want to talk offline or something like that, I'm happy to, yeah, more. Very good, thank you again. Yep. Thank you. Thank you. Thanks, sir.

toxicology

risk assessments

chemical exposures

biological exposures

carcinogens

occupational settings

public health

IARC

clinical significance

Agent Orange