[MUSIC] Welcome to module four of Chemicals and Health. My name is Dr. Clifford Mitchell and I'm an occupational physician by training. And I work for the Maryland Department of Health and Mental Hygiene and I have a faculty appointment at the Johns Hopkins Bloomberg School of Public Health. Today, I'm going to talk about the health effects of chemicals, specifically how do chemicals affect our health and how do we figure out how that happens. We have four objectives for this part of the module. First, to discuss the different types of health effects that chemicals can cause. Secondly, to describe various health endpoints. Third, I'm going to introduce the Center for Disease Control's Environmental Public Health Tracking Network, which is a way of looking at chemicals, chemical exposures and health, and trying to put them all together. And finally, I'm going to talk a bit about the difference between association and causation as we discuss our understanding of whether a chemical is actually causing a problem. Or whether what we're observing may not necessarily be directly related to a cause. So let's start with talking about various types of health effects that chemicals can cause. So, there are many different ways to think about health effects. And, as you know, since chemicals are all around us, we use chemicals in the form of medication, we use chemicals in our environment, do many things including serve as building materials and serve as products that we use every day. There are many different ways we can potentially be exposed and there are many different ways chemicals can affect us. Some of these are beneficial, some of these are harmful. Some of these happen right away, some of these take a while to happen. And so, we're going to talk about some of these impacts, the difference between acute and latent, a transient effect versus one that is chronic. Or a beneficial effect versus one that is not necessarily helpful. So, first, some terms that are commonly associated with chemical usage. One term that people use a lot is the idea of an acute effect as opposed to a latent effect. Now, an acute effect usually is something that happens relatively short-term. That is to say, in the period of immediately, in days or months, but it isn't usually something that we think of in terms of years. So if you look at the graph and the green line, that represents a line where the effect may be very, very short and may be over in a period of a couple of months. But we don't expect it to have a long-term effect. By contrast, a latent effect is one where, for some time after the chemical exposure, we see no effect whatsoever. That can go on for days, months, or even years, and then we can see the effect. For example, if you look at carbon monoxide poisoning from a stove that was left on, but that was not burning correctly, that effect would happen very, very quickly, in a matter of minutes or hours. By contrast, if you think about the effects of a chemical such as asbestos that workers were exposed to for many, many years, that can be an exposure which happened 20 or 30 years ago. And it's not until 30 years later that a worker would discover that he had, or she had, significant asbestos-related disease. So, that would be an example of a latent effect. Now, we also sometimes see the idea of a transient health effect versus one that's long-lasting or that is chronic. So, again, think about the example of carbon monoxide. Generally speaking, if someone is exposed to carbon monoxide, a health impact is going to be immediate. People will feel dizzy. They'll feel sick to their stomach. They'll develop a headache. More severe cases can lead to difficulty with breathing, trouble with thinking, unconsciousness and even death. But those impacts are very, very rapid from the time of the exposure to the impact. By contrast, if you look at something such as the effect of smoking to cause chronic obstructive lung disease such as emphysema, or what's called COPD, that's an impact that can be chronic. It represents permanent damage so that the impact will not only develop more slowly, but in addition, may last for a very, very long time or for the person's entire life. Third, I'd like to talk a little bit about the idea of dose response or the idea that the dose makes the poison. This is a concept that's very, very important. We use chemicals all the time in the form of medication and those can be very, very beneficial. But it is almost always the case that if you take too much of something or you're exposed to too much of something, the body's ability to metabolize or process that chemical can be overwhelmed and then it can lead to severe health problems. So, for example, if you look at a medication like Tylenol or acetaminophen, which is a common chemical used for pain relief, that's a drug that, taken in correct amounts, is very, very beneficial. It helps to reduce pain, helps to reduce inflammation. But if you take too much of it, it is metabolized in the liver and at certain point, it will overwhelm the liver's ability to process it. Then, you can actually cause permanent or temporary liver damage and even death. So, it's very important to follow the recommendations of the manufacturer or of your physician or healthcare provider in terms of taking the right amount of medicine. The same thing applies to chemicals that we're exposed to in the everyday, where the body ordinarily is able to process many of those and eliminate them, but if you have too much of that, it can overwhelm the body's ability to process those chemicals. Now let's talk about some health endpoints and here, I'm going to talk about a variety of terms. The important idea is that these terms are used by health scientists, epidemiologists, physicians and others, and I just want you to be familiar with them, but not to concentrate too much on the specific mechanisms. We've already talked about the idea of acute toxicity or repeated dose toxicity. I'm also going to talk about a number of other possible toxic mechanisms. They can include mechanisms that have to do with the immune system, the reproductive system, the cells, genes, or DNA, or various other body systems. So, first, we've already talked a little bit about acute toxicity. The important thing here is that this is a process that occurs relatively rapidly. Now, even with an acute toxic event, you can have permanent or long-term damage. So, people may have, for example, both an acute and a chronic problem as a result of an exposure or in some cases, it may be just an acute exposure leading to acute health effects and then the effects are gone. By contrast, what happens, and we talked about this with Tylenol or acetaminophen already, if the body takes a while to process a chemical, it can be a repeated dose that leads ultimately to the toxic impact. So, for example, you can take a single dose of Tylenol or acetaminophen, the generic name, and your body will process it. But if you keep on being exposed repeatedly, at some point, you can build up enough of the drug to cause that overwhelming of the body's metabolic system. So, it's very important again not only to take the correct dose, but in the right period of time. You don't want to take the medication faster or sooner than is recommended because when you do so, it's both the amount of the me, chemical and how quickly that it gets into the body that determines whether or not it will be appropriately metabolized. Let's talk about genotoxicity. This is a term that means that it affects the genes, or the DNA, of the cells in the body. Now, when this happens, it can have two different kinds of effects and that depends on what kinds of cells they are. because remember, the body has two basic different types of cells. One are what are called somatic cells, and those are the cells that make up your skin, your muscle, your nervous system, all the other parts of the body except the reproductive system. There are also reproductive cells. Those are the eggs and the sperm, and those are cells that, when they are combined, lead to a new person or a new fetus. So, if the genetic effect, the damage, occurs in one of the somatic cells of the body, that could potentially lead to a mutation which could ultimately, possibly lead to cancer. If the damage occurs in the cells of the reproductive system, the eggs or the sperm, those can lead to birth defects because the effect will not be seen until the birth of the child in many cases or in some cases. So, again, these are the two different kinds of effects. Now, cancer, or carcinogenicity, is the ability of a chemical to cause or make more likely the development of cancer in an individual. Now, the cancer itself is a very, very complex set of different diseases. Not all cancers are the same, not all cancers have the same causes, not all cancers behave the same way. And in many cases, we don't really know all of the things that contribute to cancer or cause cancer. We do know there are some chemicals that we've identified, either through animal studies or through people studies, epidemiology, that show very likely or definitively that a chemical exposure could lead to cancer. But in all cases, the question of whether an individual chemical exposure in an individual person will lead to cancer is almost impossible to predict because there are so many contributing factors that make cancer less likely or more likely. They include things like how your immune system functions, whether you have a genetic predisposition to cancer, whether or not you have some other kinds of exposures that combine with this exposure to make cancer more likely, and a whole host of other conditions. So, almost always, if somebody asks, did a specific chemical exposure cause my cancer, the answer is, we don't know, because there are so many contributing factors that it's very difficult to go backwards and predict. We do know for a very very small number of chemicals, such as asbestos or vinyl chloride, that the likelihood of developing a particular kind of cancer without an exposure to that chemical is so low that for all intents and purposes, if you have a likely exposure and if you have the cancer, it's more likely than not that that chemical exposure caused that cancer. But, as I said, that is rarely the case. Most of the time, cancers occur for many, many different reasons and in an individual, it's very difficult to predict whether or not a particular cancer was caused by a particular exposure. However, that being said, our knowledge is such that we try to look at a whole group of people and say, is a cancer likely or more likely to happen if you expose a whole bunch of people to a particular chemical. And when that is the case, even though we can't predict for an individual, we try to take steps to protect the population from this chemical because there is an increased risk of cancer in the entire population. Now, reproductive toxicity, like cancer or carcinogenicity, is a complicated process. The reason is that reproduction itself is a complicated process with many different steps. I already mentioned, for example, that you can cause damage to the DNA even before the egg and the sperm combined, and that can cause a mutation and a birth defect. In addition, once the fetus is developing, there are certain critically important developmental processes that can be affected by chemicals or drugs. Some examples of this that you may be familiar with, for example, are thalidomide, which can cause damage to the developing limb buds, resulting in small or malformed limbs. Also, DES, diethylstilbestrol, which is a chemical that was used many years ago for women and it caused problems in girls who were born to mothers who had taken DES. And it caused problems with the formation of the cervix and the development of the cervix. There are also chemicals such as lead, which can cause, at many different points along development, problems with the developing central nervous system. So there are many different points where you could interrupt or damage the process of reproduction. And at that same time, again, in most cases, when we look at birth defects, they are, like cancer, very complex to disentangle a particular cause. So, in many cases, unless we are relatively confident of the exposure and relatively confident that we can link a particular agent, when we have a child who has a birth defect, it's sometimes difficult to go back and figure out exactly what the exposure was that contributed to the birth effect. Now, many of you may have heard the term endocrine disruption. This is a term that's been relatively recent in the literature and it refers to the idea that we have hormones, chemicals that are chemical messengers in the body. Sometimes they are sex hormones like estrogen or testosterone. There are other kinds of hormones as well. These hormones can be, in some cases, chemically similar to or similar enough in structure to chemicals that are in the environment that the body sometimes is fooled and thinks that the chemical in the environment, once it's in the body, is similar to or acts the same as a naturally occurring hormone like estrogen. When that happens, these estrogen mimics, or these endocrine mimics, or endocrine disruptors can either block or exaggerate or somehow interfere with the normal signaling in the body that is what the chemicals are used for. That can cause a number of problems that we usually see or can see in terms of growth and development. Sometimes it's development or sexual differentiation. Sometimes it's a difference in terms of the way the hormones behave. And it's an emerging field which has caused a great deal of interest in the scientific community because there are many concerns that these persistent chemicals in the environment may be leading to these effects not only in people, but in various animals throughout the ecosystem. So, endocrine disruption is a concept that you'll see more of in years to come. Neurotoxicity I mentioned already in connection with lead. And one of the concerns about neurotoxicity is the thing that makes us human more than almost anything else is our brain and our central nervous system. It's a very complex and wonderful organ, but the nervous system is also susceptible to a wide range of environmental insults. For example, you can have short-term impacts on the nervous system from chemicals that block oxygen in the brain. An example of that would be carbon monoxide, that I already mentioned. But you can also have, for example, metals that can interfere either with the central or what's called the peripheral nervous system, which are the nerves in the legs, the arms and outside of the brain and the spinal cord. And that can cause problems either with motor coordination. It can mimic diseases like Parkinson's disease and it can also cause problems with the higher order of the central nervous system like thought processing. And so, lead, for example, or manganese, or other metals can have a wide range of impacts or effects on the central nervous system and the peripheral nervous system. And this is also true for a number of organic chemicals, such as hexane, which can cause permanent neurologic damage. I'm not going to spend a lot of time on other kinds of toxicity except to say that these are concepts such as damage to the immune system or interference with, or causing allergies, or concepts of chemical intolerance. These are a series of concepts that physicians use or healthcare providers use when they're looking at the effects of chemicals on specific parts of the body, such as the immune system. There can also be effects on the skin, which are related to the immune system and you can see a whole host of various responses. Suffice it to say that these are sometimes complicated processes and the important thing is that they are often very, very individual, so that you can have two people who are very similar, one of whom is very sensitive from the immunologic point of view to a particular chemical, which could be a naturally occurring chemical such as a peanut protein. And you can have a person, who is very, very similar who has no reaction whatsoever. So, a lot of these toxic responses or immunologic response are very, very specific to the individual. Now, I'd like to talk just for a minute about the Center for Disease Control's Environmental Public Health Tracking Network because this is a way that the nation has been trying to assemble a tool that people can use, as well as policy makers and healthcare providers, to better understand where chemicals are in the environment, as well as where health impacts are that we think might be related to chemical exposures. The important thing about the CDC Environmental Public Health Tracking Network is that it is a cooperative effort between states, between local jurisdictions, including some large cities, and the federal government to try to create a system where we have what are essentially consistent descriptions of chemicals in the environment. As well as health impacts that people can then go online to a web browser and look across the country or in individual states that are participating in the system and find a great deal about where chemicals are. And where people have health impacts that could be either affected by chemical exposures or that could, in some cases, be the results of chemical exposures. So, the important thing about this network is that it is really a cooperative effort which is really designed to allow the public, as much as possible, to understand the place in which they're living, the state in which they're living, the country in which they're living. And to be able to make informed choices, both individually and collectively, about how to appropriately balance the potential beneficial impacts of chemicals from the potential downsides of chemicals, and make good policy choices, both individually and collectively. So, here's a sort of an example of some of the things that you can do on the tracking network. This is a picture of elevated blood lead levels in states across the country. And this is for the year 2011. And not all states have data in the tracking network yet. Not all states are participating in the tracking network yet, but this is an example that shows you the power that using maps and charts, you can look and see how it is that lead and elevated blood lead levels distributed across the country by state. You can also go to the individual state portals and get a much better and more detailed understanding of where lead contamination or lead elevated blood lead levels might be within an area. So, this network also has much greater detail at the state level. Finally, just a word about the difference between association and causation. I've spent a great deal of time to date talking about the things that we do know. It's important to recognize just as I showed you, for example, the map of elevated blood lead levels, just because there you see a possible relationship, doesn't necessarily mean that there's a causal relationship. So, here's a chart that was produced, showing that over time from 1983 to 2013, the stork population has been growing substantially and at the same time, the human population has been growing substantially. So, I think you could certainly make a reasonable inference there that the story of the stork bringing children is clearly borne out by the increasing storks and the increasing kids. Obviously, we don't really think that the storks are bringing the kids, and as a result, this is an example of an association which doesn't necessarily relate to a causal relationship. So, it's a funny example, but I think it proves the point. Mark Twain, the famous humorist, said, facts are stubborn, but statistics are more pliable. And if you think about this in the context of our discussion, what Mark Twain was essentially saying, but much more eloquently than I, is that you can have a statistical association or a statistical fact which doesn't still lead you to understand whether there is a true causal relationship. To understand whether there's a causal relationship, you need several different things. You need research. You need observation. It's important to think about the fact that when we try to, as health professionals and scientists, provide useful information, we should always be careful to show when we are showing something that is a possible relationship that might be causal because we think we understand the mechanism or have an idea of the mechanism. We think there's an association that might be biologically plausible, but we don't have evidence for it yet. Or whether there's a association that while true, may not be related, so you may have true but unrelated facts. And our job as health professionals, as scientists, and as members of the public is to try to understand as much as possible which of those three conditions might apply when we're talking about the relationship between chemicals and health in general. So, I'll finish up by showing you some of the causal criteria Sir Austin Bradford Hill proposed many, many years ago when he delivered a lecture on the environment and disease. And he put together a set of criteria. And these criteria say that what you want to show, in order to be sure that there is actually some causal relationship between an exposure and an outcome, is to first look at the strength of the association. Then, the consistency. Do you always see the impact when you see the exposure? Third, specificity. When you're looking at the outcome, is it only associated with that exposure or are there many other possible exposures that could account for it? Next, temporality. If the outcome happens before the exposure, it's not likely that the outcome was related to the exposure. It's more likely if the outcome follows the exposure. Next is the idea of a biological gradient. This is the idea that the dose makes the poison. So, if you have a little bit of it, is there a little impact? And then if you have more of it, does the impact or the health effect increase? If it goes in an opposite direction, that's not necessarily saying it, there isn't a relationship, but it is more likely if you do see a relationship in which the increasing dose means an increasing effect. The idea of biological plausibility is, even if we can't account for a specific mechanism, does it make sense in terms of our general understanding of the way the body works that this might be an impact related to this exposure? Coherence is the idea that you have some kind of relationship between findings that you see in the laboratory and what you observe when you look at the person or a group of people epidemiologically. Finally, the idea of an experiment is, can you reliably reproduce the impact that you think is related to the exposure by showing it in an animal model? And then, are there analogous kinds of relationships, similar chemicals with similar kinds of impacts, that'll add strength to the idea that you have a causal relationship. In essence, those are Hill's causal criteria and if you can meet all or most of those, you can be much more comfortable that the outcome is the result of the exposure. Finally, here's some references for you to look at, to read, and think about. And at this point, we've covered all the objectives for the lecture. If you want more information on any of these topics, I would recommend these and other references to you. And if you have questions or comments, please use the discussion board. Thank you very much. [MUSIC]
