This next lecture is something of a grab bag, mainly involved with respiratory toxicology, and we'll look at some of the features of this also in a forthcoming lecture on occupational lung disease, but here we'll introduce some main points. We'll also touch on pesticide toxicity, and lastly, finish off with hepatic and renal toxicology. There's a few points to emphasize in respiratory toxicology, and I don't want to beat these into the ground, but I want to make some distinctions between nomenclature. Fumes are generally an aerosol of solid particles. These are condensed, vaporized material, usually coming from metals, so we can talk about lead fumes or zinc fumes. By contrast, vapors are gaseous phases of things that are usually in a liquid phase, and water vapors among these, and also we talk about solvent vapors, so when your patients, for example, talk about solvent fumes, technically they're really talking about vapors. The distinction in the clinic probably isn't important, but as we discuss these in detail, some of these will become a little more apparent. Dusts by contrast are particulates that are derived from solid materials. They can be inert or non-pathological. Nuisance dust, such as dust from dirt or from other organic materials like cellulose, oftentimes is likely not to cause any real problems. If these particles are greater than 10 microns, they can get deeper into the lungs, but they mainly just cause irritation of the airways. Over a long period of time, they might be associated with COPD, and we'll see that in the lung lecture. Organic dusts oftentimes are biologically reactive. These can cause immunologic reactions and lead to pulmonary diseases such as asthma, hypersensitivity, pneumonitis, or inhalation fevers, in this case organic dust toxic syndrome. And lastly are the mineral dusts, particularly bad actors are the fibrogenic dusts, and this really includes silica, asbestos, or coal. Dusts and other particulates settle in the respiratory tract. If they're greater than 10 microns, they'll usually impact in the nasal turbinates, in the nasopharynx, and oropharynx, and get cleared by mucociliary action. The nose will also scrub water-soluble pollutants and elaborate IgA or IgE. The graph over on the right shows what happens to deposition of particles that are 10 microns or smaller. The larger ones, 10 to 7 microns, will deposit in the larger airways, the trachea and the main stem bronchi, while the smaller particulates will be carried down into the respiratory bronchioli, and smallest particulates on the order of 1 to 2.5 microns will deposit out in the lower respiratory tree and in the alveoli. Right down into the lung parenchyma, this can set up inflammatory reactions as those particulates are engulfed by macrophages, and this is the mechanism by which they create inflammation and ultimately fibrosis and scarring, particularly in asbestos and silica inhalation. So we're going to leave the fibrogenic dusts for right now and pick up on them again in the pulmonary lecture. Right now we're moving on towards irritant injury, and this is generally from inhalation of gases or vapors. The site of deposition of a gas or vapor, and hence the symptomatology, is determined primarily by the water solubility of the material, as we'll see in the next several slides. Workers who inhale them can have symptoms within minutes to hours, and it's again dependent on where in the respiratory tree, either upper or lower, that these deposit out and do their dirty work. Because the nasopharynx and oropharynx are principally lined by mucus and other watery materials, highly water-soluble or polar gases will be absorbed in the upper airways and dissolve in them. So these are the materials that will cause primarily upper airways irritation. Very polar materials, such as acids, hydrochloric acid, ammonia, and oxides of sulfur. Some with medium solubility, like chlorine gas, may irritate the upper airways but may also get down into the mid and lower airways, the trachoponchial tree for example. And those with lower solubility, as we'll see in the next several slides, or which are nonpolar, are not scrubbed out by the mucus in the upper airways and are inhaled deeply into the alveoli and set up lung reactions. The two low water solubility toxicants we're going to discuss are phosgene and oxides of nitrogen. As we saw in the last slide, these are nonpolar materials which aren't well absorbed in the watery upper respiratory tract. The other take-home point is that they may lack immediate symptoms and patients, workers, may not become symptomatic until 8 or 12 hours after inhalation injury. Phosgene is really one of the classic inhalation toxicants and it was developed as a war gas in World War I. Soldiers who inhaled it oftentimes had delayed reactions, as we mentioned in the last slide, and wouldn't become symptomatic until 8 or 12 hours later. Exposures nowadays are primarily involved in accidents such as welding. If metals are degreased with chlorinated solvents and then subjected to high heat, phosgene will form as a pyrolysis product of these chlorinated solvents and it can be inhaled by the welder. As well, other chlorinated solvents, if they're burned, such as PVC plastics in fires, can elaborate phosgene as well, so it may also be a hazard to firefighters and other people involved with fire suppression. It can also be used in a variety of manufacturers. It's a reactive intermediate in the manufacture of dyes, pesticides, and other pharmaceuticals. So here's the interesting point about the chemistry of phosgene. It's a simple molecule. It's carbon and oxygen and two chlorine atoms, which is why it's formed by organochlorine materials and their pyrolysis. When it gets down deeply into the lungs, it slowly reacts with water and is hydrolyzed and it forms, as you can see from the molecule, hydrochloric acid and carbon dioxide, which is given off. The hydrochloric acid becomes the bad actor in this scenario, and if you can kind of imagine what application of hydrochloric acid to the alveolar cells and the lining of the lungs would cause, you can pretty much guess what the patient will present with. So what we're looking at here is this acute damage to the lung parenchyma from application of an acidic medium, eventually leading to non-cardiogenic pulmonary edema. As I mentioned, there's usually this delay because the hydrolysis is rather slow. You can have a normal chest X-ray and normal blood gas if the exposure has been fairly recent, but you want to hold on to and observe any patient in whom you suspect this inhalation because they may come back in rather florid acute respiratory distress four, six, eight hours later. Along similar lines, nitrogen dioxide is the other low water solubility gas that can cause diffuse severe pulmonary injury. It probably proceeds by the same mechanisms, which is to say hydrolysis in the lungs and forms nitric and nitrous acids in the lungs. There are other mechanisms for its toxicity as well. It's a heavier than air gas, and it's generally been termed silo fillers disease because nitrogen dioxide is a byproduct of fermentation of grain when it's put in a silo. When the farmer eventually empties out the silo, nitrogen dioxide escapes down the bottom and a big inhalation dose may be captured by the farmer. Similar to phosgene, it causes minimal upper airway damage, but can have later pulmonary effects, as I said, non-cardiogenic pulmonary edema, much the same as we saw under phosgene, repeated exposures, because farmers may be getting exposures across time repeatedly. They may develop bronchiolitis obliterans from a chronic lung injury. There's a number of disorders of farmers that we'll look at across this time, and I just want to leave you with a few thoughts as you look at these, because some of these can be confusing. Silo fillers disease is the name that gets applied to nitrogen dioxide inhalation from silage. Farmer's lung, which is a type of hypersensitivity pneumonitis, can also occur in and around silage, particularly because bacteria and fungi grow within the silage, and so can be essentially acquired in the same location. Organic dust toxic syndrome, which is probably secondary to endotoxin after harvesting crops, probably occurs in kind of the same or similar scenarios. And lastly, later on, we'll see hydrogen sulfide knockdown, which is very different from the silo, but occurs in pumping out in manure pits. So I'll leave you with those thoughts to keep from differentiating this from other disorders that farmers may acquire at work. So moving from the low-water solubility materials into the moderate to high-water solubility ones, we see again that these are generally polar compounds, such as acids, acid mists, and ammonia. One noteworthy point here is one that we see a number of cases every year, probably one every couple of months, which is in mixing household bleach and ammonia. You may see or remember labels that oftentimes tell you not to do this. This occurs from the generation of chloramine gas, and the typical scenario that we see is a cleaner in a restaurant or a big public area who has mixed two types of cleaners in order to clean out, for example, the restrooms. This generates chloramine gas, and because they're right proximal to the site of the work is that they may get a big inhalation dose and very severe, particularly upper and middle airway symptoms. Other causes of acute upper airway inhalation injuries are chlorine gas, which can be converted into hydrochloric acid when it comes into contact with water on the mucous membranes, and of ammonia, which has a huge variety of uses and causes much the same type of problems. There's a number of sequelae that can arise from these acute injuries, particularly if the dose is high or particularly severe symptoms result. These patients can go on to develop reactive airways, dysfunction syndrome, or RADS, which we'll talk a bit more in the lung disease lecture. Main treatment for irritant gas treatment is mainly supportive. Of course, you want to distinguish whether this was polar versus nonpolar, acids or ammonia versus phosgene or oxides of nitrogen. Obviously, get them away from the source of exposure. They need to be intubated if there's stridor evidence that the airways are closing or there's burns and otherwise general treatments such as oxygen mists, bronchodilators, and albuterol. As we mentioned under the skin disease lecture, if hydrofluoric acid has been inhaled, these patients will need to have nebulized calcium gluconate in addition to getting it via an IV. Next are the asphyxiant gases, which don't cause direct airway damage, but can cause hypoxemia either at a gross or more cellular level. Asphyxiants can be divided into two main types. There's the simple asphyxiants, which we see here, and the chemical asphyxiants, which we'll talk about in more detail. The simple asphyxiants are just gases that displace oxygen from the inspired air and reduce the amount of oxygen that you're able to inspire. Methane or carbon dioxide pockets were very frequent in underground coal mines, and this is the main reason, as you can see in the picture, that coal miners carried canaries and they were relatively more sensitive to hypoxemia, so when they would see them start to drop, they knew that they might have hit a pocket or otherwise reduced oxygen tension within the mines. Other asphyxiants besides these two are a large variety of other materials that can be seen in fossil fuel extraction, such as acetylene and propane, other areas where they you can get asphyxiant gas in high concentrations or any place that uses liquid nitrogen or solid nitrogen or carbon dioxide for freezing purposes, and if these are used in an enclosed room, these can asphyxiate people working in laboratories, for example, fairly readily. Symptoms related to simple asphyxiants are relatively simple. They cause hypoxia and all the attendant symptoms that come with lack of oxygen, ranging from headache and nausea to loss of consciousness and eventual coma. Treatment is likewise fairly straightforward, is just removal from exposure and replacement of oxygen. Nitrogen is somewhat interesting because it's in compressed air diving tanks. Divers may develop higher levels of nitrogen dissolved within the bloodstream. This can lead to a sort of hallucinogenic set of experiences, which is oftentimes termed rapture of the deep and is really fundamentally just a sign of a kind of a mild hypoxia related to the nitrogen and increased dissolved nitrogen from diving. In contrast to the simple asphyxiants, we're going to talk about three chemical asphyxiants. These interfere with the ability to carry oxygen, as does carbon monoxide, or in the cases of hydrogen cyanide and hydrogen sulfide, they bind to cytochromes, interfere with respiration at a cellular level and the ability to utilize oxygen in respiration. So here's a typical carbon monoxide case. This is a young man who works as a car mechanic. He begins to develop headaches and dizziness at work, and symptoms are noticeably worse in the wintertime, and they resolve at nighttime and on weekends, typical cases in occupational disorders. He's also a non-smoker, so there's no source via tobacco or cigarette use. And when evaluated, he has a carboxyhemoglobin level in the bloodstream of 21%. So a few take-home messages. This is a young person. They generally have no cardiac disease, and so his symptoms tend to be rather nonspecific rather than localized to the cardiovascular system. So if I told you to go out and get carbon monoxide poisoning, most of you would come to the same conclusion, which is either to run a combustion engine, such as an automobile, indoors or in an enclosed space, or to combust some other type of fossil fuel, be it wood burning, oil, or coal, in a closed space where there is little oxygen, and therefore the material is incompletely combusted. It's odorless, as we all recall, and there's no warning properties, so this is the value of carbon monoxide detectors, particularly when furnaces are malfunctioning. And in biomonitoring, we may have a little bit of carboxyhemoglobin in the bloodstream from outside sources, so the normal is going to be probably about 1%. Smokers, depending on the extent of their smoking, may be anywhere from 5% to 7% to 10% carboxyhemoglobin levels in the bloodstream. So carboxyhemoglobin is formed in the bloodstream from the reaction of carbon monoxide with hemoglobin. It's not irreversible, but it's very difficult to separate the carbon monoxide molecule from the hemoglobin, and it increases the avidity of hemoglobin for oxygen, and it doesn't dissociate as well. We'll see in the next slide the typical oxygen dissociation curve. It can also have some other effects. It can bind to mitochondrial enzymes in myoglobin, as well as to hemoglobin. It can increase platelet stickiness, and it can decrease arrhythmia thresholds. All three of these factors may lead to cardiovascular problems in somebody who already has preexisting cardiovascular disease, particularly coronary artery disease, and may be responsible for arrhythmias or an MI. Here's a typical hemoglobin oxygen dissociation curve. I think most of us can probably recite in our sleep that carbon monoxide shifts that dissociation curve to the left. What does that really mean? Well, it means over on the right side of the graph, at high partial pressures of oxygen, both carboxyhemoglobin and normal hemoglobin are pretty well saturated with oxygen regardless. What we really want to pay attention to is over on the left-hand side of the graph, where the tissues are relatively anoxic, or at least have low partial pressures of oxygen, and at those low partial pressures, normal hemoglobin becomes progressively desaturated fairly rapidly. Carboxyhemoglobin, by contrast, is more avidly hanging on to oxygen. So at those same low partial pressures of oxygen, the hemoglobin stays more saturated. You can see this on the line there. At about 30 partial pressure of oxygen, the normal hemoglobin would be about 50% desaturated, whereas carboxyhemoglobin is about 66% desaturated. In other words, more avidly hanging on to oxygen. This is what accounts for the tissues fundamentally starving for oxygen in the midst of plenty because the carboxyhemoglobin is not desaturating more rapidly. So the effects of carbon monoxide, particularly the cardiac effects, are somewhat dependent on pre-existing status and cardiovascular disease. You can generally see some cardiac compensatory effects, such as mild tachycardia, along with non-specific symptoms of mild hypoxia, such as headache and lightheadedness, at carboxyhemoglobin levels of 8 to 10 percent, particularly in a non-smoker. EKG disturbances and other rhythm disturbances, as well as anginal symptoms, will take over at higher levels. This is about 10 to 25 percent, again depending upon age, whether it's a younger versus an older person, and whether or not this person has already existing coronary artery disease. And again, it's also dependent on whether the person is a cigarette smoker. We mentioned that cigarette smokers are going to be chronically at 5 or 7, maybe 10 percent carboxyhemoglobin, so any additional carbon monoxide from an outside source is going to be additive. Individuals who have particularly bad or severe coronary artery disease may actually start to get angina with some moderate activity, even at low carboxyhemoglobin levels as 3 to 5 percent. This is a useful slide to look at, not necessarily because you have to commit these values to memory, but it shows the difference between how PELs and recommended exposure levels are calculated. The OSHA standard is a straight-up 50 parts per million for an 8-hour time-weighted average, so that assumes that people are going to be working 8 hours. NIOSH sets the recommended exposure level a little bit lower, and on the assumption that people might be working or exposed to carbon monoxide for greater than an 8-hour day, and so they set theirs for 10 hours. This recommended exposure level would be equivalent to about a 5 percent carboxyhemoglobin level, which would be reasonably protective of most workers, but not protect necessarily the elderly or people with pre-existing coronary artery disease. And they also note that carbon monoxide uptake will increase with physical exertion because that's going to increase minute ventilation, and so if there are jobs with high physical demands, NIOSH recommends that exposure should be more limited than this 10-hour day or a reduction in the exposure to carbon monoxide because of those physical demands. The ACGIH takes an even more conservative stance, and their recommendation is for a TLV at 25 parts per million, a bit lower than the NIOSH recommended exposure level, and this is equivalent to a BEI of about 3.5 percent carboxyhemoglobin, which is less than what you see in the NIOSH REL. They do this to be more protective of sensitive groups, such as the older worker, and the BEI may be useful in documenting significant exposure. In other words, if there's an exposure that yields a carboxyhemoglobin level of greater than that value, then you might begin to check ventilation controls and the like because of the possibility of an overexposure. The other potential source in the workplace for carbon monoxide exposure is through the use of methylene chloride. Methylene chloride, as you see, is a single carbon with two chlorine atoms, is used as a solvent, and apparently it's a fantastic paint stripper. Many individuals will use it in small shops and in household work for paint stripping, and it gets absorbed through inhalation, or it can also be absorbed through the skin. The interesting thing about methylene chloride, and very different from any other chlorinated solvent, is once it gets into the bloodstream, it's metabolized in the bloodstream to carbon monoxide, and then forms carboxyhemoglobin, so that individuals working in a poorly ventilated space, particularly using it as a paint stripper around a household or that type of work, might develop a high level of carbon monoxide poisoning. For example, carboxyhemoglobin levels up to about 10%. So here again, what I mentioned on the last slide is that you can get carboxyhemoglobin levels up to about 10% if you're working in a poorly ventilated space, as might paint stripping in a household, for example, contribute to. This may not be significant to a healthy person. Remember the previous slide, where carboxyhemoglobin levels up to about 10% might make someone mildly symptomatic with vague or nonspecific symptoms. Other risks occur if somebody has current coronary artery disease, and particularly they're exerting themselves, or if they're a cigarette smoker, in which the carboxyhemoglobin level might become additive. In other words, this may then put them up at a carboxyhemoglobin level of 10 or 12 or 15, even up to 20%. So this slide presents some of the typical symptoms of carbon monoxide poisoning. From the medical school textbooks, the cherry red skin is supposedly classic, although I've met toxicologists who claim they've never seen it, and that only a very small number of cases actually present with it. Most generally, the symptoms are nonspecific and flu-like, without the fever. There's headache, malaise, feelings of nausea, dizziness, or lightheadedness. And this is one of the points where you can see that carbon monoxide poisoning might be missed, unless you're specifically thinking of it. And to get a history or draw a carboxyhemoglobin level, many of these cases may present in emergency wards or in an outpatient or walk-in clinic. So it's got to be remembered that people who may be shutting the doors or working with combustible materials may be at risk for carbon monoxide symptoms. Most common are the cardiovascular effects, and we mentioned those before, so I won't go deeply into them there. They're on this slide. People with coronary artery disease, again, develop decreased excellent exercise tolerance and angina symptoms, and ventricular arrhythmias may get triggered at low levels in unhealthy people, and even in healthier people at higher levels in the 20% range. And this, of course, may lead to MIs, arrhythmias, sudden death, cardiac arrest, and the like. Neurologic symptoms are primarily the result of hypoxia in the central nervous system and can range at lower levels from headache and dizziness, progressing on upward to more much more severe symptoms, including ataxia, confusion, and coma. The delayed neurologic effects are interesting, and these occur mainly in poisonings that were severe enough to have caused hospitalization with loss of consciousness. The main one to remember in this group is Parkinsonism, along with dementia and a variety of other symptomatology that can be seen here on this slide. CT and MRI scans in severe cases will show decreased density in a variety of nuclei associated, again, with Parkinsonism. Reproductive health effects can be seen in carbon monoxide poisoning, and these are dependent upon the extent of poisoning and the timing. Fetal death can be seen in very high-dose cases in which the mother's health, consciousness, and the like have been affected. CNS defects may also become apparent, again, with severe poisonings, particularly in the earlier stages where CNS is developing. A more likely outcome, particularly of chronic or low-level persistent carbon monoxide exposure, is low birth weight, and you can think of this as analogous to cigarette smoking, which also supplies carbon monoxide on a low-level but persistent basis in the maternal circulation, and so the effects are the same with reduced birth weight because of relative hypoxia in the fetus. Treatment for carbon monoxide is generally consisting of removal from exposure, so there's no further carbon monoxide to be inhaled. Depending upon the extent and duration of the exposure, the usual half-life of carbon monoxide in the bloodstream is from two to six hours. If you give 100% oxygen inhaled, it will reduce the half-life to approximately an hour, and in severe cases where hyperbaric oxygen therapy is initiated, that reduces the half-life in the bloodstream to about 20 minutes. Carboxyhemoglobin is measured repeatedly during the treatment to get the individual certainly below 5% carboxyhemoglobin and further down, more ideal, particularly depending on their symptomatology, age, and general condition. So moving on to the other chemical asphyxiants, we come to cyanide, familiar as a poison to anyone who watches crime dramas or reads detective novels. It's used fairly extensively in the metal plating industry as well. It may be a byproduct within ores and so may be given off as a result of heat applied in gold and silver purification. It can also be a combustion byproduct of a variety of materials, and so firefighters in particular may become exposed to cyanide gases and airborne exposures. Works a little bit different than carbon monoxide. Instead of binding to hemoglobin and restricting the transport of oxygen, this works at the cellular level and binds to cytochrome oxidases, which block oxygen utilization, as we'll see in the next slide. Variety of nonspecific symptoms in general, particularly at low level or chronic exposures. Individuals can develop shortness of breath, headache, nausea, and dizziness, all from the hypoxia at the cellular level. So as I mentioned in the last slide, cyanide inhibits cellular or mitochondrial respiration, and I throw up a copy here of the electron transport chain, though I'm sure everybody recalls and knows it at their fingertips. Fundamentally, cyanide binds to iron in the cytochrome oxidase system and prevents the cell from using transporting oxygen. This stops oxidative phosphorylation and the cells begin to starve from oxygen and eventually die. Organs with the highest metabolic rate, so the heart and brain in particular, are affected initially, and so central nervous system symptoms will predominate, along with cardiac symptoms secondarily. The symptoms generally relate to increasing or progressive central nervous system toxicity, initially with feelings of anxiety and hyperventilation in an attempt to increase oxygen levels, followed by headache, dizziness, vomiting, and progressing again to loss of consciousness, ataxia, stupor, and the like, along with angina symptoms. And removal from the source is, again, the first line of treatment. Oxygen should be given after removal from the area. Clothing should be removed in case there's absorption through the skin. Supportive care, particularly if the victim is conscious, including oxygen IV fluids and antidotes, may not need to be given. If they're unconscious, they should be bag and mast ventilated. For the purposes of the boards for occupational medicine, the answer to an antidote is the hydroxycobalamin cyanokit. This is fairly clever. It's given intravenously, and it binds to cyanide, and the hydroxycobalamin forms cyanocobalamin, which is just pure and simple vitamin B12, which is just excreted in the urine. So it's forming a non-toxic end result product, which is fundamentally a vitamin, and simple excretion after that. There are a variety of other methods. I think these mainly apply to anyone doing toxicology boards rather than the occupational medicine boards, but I think in this case what you would really need to know is the kind of standard treatment now, which is to have the cyanokit, as we illustrate, available for treatment. All right, and the second of the major chemical asphyxiants we want to cover is hydrogen sulfide gas. The sort of typical scenarios for this, because this generally comes from decaying fecal matter, so a father and son are cleaning a sewage drain or a septic tank. Somebody goes down in underneath it, or a worker in the sewage system goes into the sewer, loses consciousness. Somebody comes in after them yelling, I'll save you, and goes in as well, and that person loses consciousness, so now it's down to the first responders to get an oxygen supply, in other words an SCBA, and to go in there to rescue them because it's a rather severe, rapidly acting asphyxiant. So this is the type of case scenario that you might see with HS. Hydrogen sulfide, because it's generally the result of decaying fecal matter, is noted by its rotten egg odor. It smells quite terrible, and it can be found in manure pits, it can be found in sewage work, as we mentioned on the last slide, and in farmers, again, with the manure trough around. It's a quick and rapidly acting asphyxiant, and so again another typical scenario is the farmer who goes to pump out the manure pit, which is underneath the barn, and all of a sudden hears a big BAM overhead, and then that's followed by another BAM and another BAM and another BAM, and what's happening is the cattle are becoming rapidly asphyxiated and falling over, knocked down and asphyxiated, and so what's the next course of action for the farmer is to run as fast as he can out of that manure pit area. For workers who are working around this material, there's dangerously some olfactory fatigue, in other words, you stop noticing the real terrible smell after a while, and you might be more susceptible if you don't notice high levels of it. At low levels, because of its odor, it's a mucous membrane and a respiratory irritant, and at more moderate levels, just as according to the same scenarios we've mentioned, it'll cause loss of consciousness and anoxia. It works much the same as does cyanide, blocking oxygen utilization through the cytochrome oxidase pathway, but unfortunately the antidote isn't nearly as clever or well known or even well developed. Generally it's supportive care, including giving oxygen. So moving on with our slides on respiratory toxicology, we're going to visit building-related illness, and as many of you know from practice, this encompasses a whole range of, starting with complaints really, up to illnesses associated with exposure to indoor air. To give you some historical perspective that may help in treating, recall that many buildings were built in the post-war era, and then in the 1970s we had an energy crisis that mandated us building tight buildings where you couldn't open windows, for example. You'd recycle the air so that you wouldn't have to heat or cool it, because that was expensive to do, and there was also poor air intake from the outside for the same reasons, and so a lot of air got recycled within buildings. Fast forward a couple of decades later, there was the dot-com bust, there was the Great Recession in the 2000s, now these buildings are 40 and 50 years old, there's been a lot of deferred maintenance because of the cost, there's been leaks in the roof, there's been water incursion, and nobody has spent much money in cleaning out the HVAC system. So what you get there is a buildup of a number of irritants. In particular, this is high carbon dioxide from the poor ventilation, because we're all giving off carbon dioxide in office buildings, high humidity or low humidity because it hasn't been adjusted, and a lot of dust because the HVAC systems aren't very well cleaned out. You tended then to get a lot of non-specific symptoms related to all these irritants and the high CO2 levels, including headache, irritability, fatigue, people doing head dives at their desk, nausea, some coughing and the like, probably from the dust and the like. NIOSH reviewed all their health hazard evaluations in which they were called in for indoor air problems and found that just over half of them were simply due to poor ventilation, so this is oftentimes the major component of indoor air problems. In the next slide, we'll look at some of the other potential illnesses that can arise from the indoor air, poor quality. So on top of the poor ventilation problems that I mentioned on the last slide, particularly things like carbon dioxide and related problems around ventilation, water incursion is a consequence of this delayed maintenance, encourages the growth of biologicals in and around these buildings. It can be on wall board, they can be on other areas of water incursion and materials that can be on the roof and entrained into the building by the HVAC system. Molds and fungi are responsible for hypersensitivity reactions, including asthma and HP, and some bacteria can grow and be entrained in the ventilation system or grow within the ventilation system. This in particular refers to Legionella, which can develop Legionella pneumonia, Legionnaires disease, or Pontiac fever, fundamentally the same disorder without the pneumonia. Of course, there can be a whole huge variety of other potential pollutants. You can have old asbestos tiles or ceilings, there can be other biologicals, there can be combustion byproducts. For example, if trucks are running their engines near an exhaust vent, mercifully most laws against smoking have taken effect and have very greatly reduced the extent to which environmental tobacco smoke becomes a problem in many buildings. Building related complaints may involve more than one person, so a group or a cluster of complaints should spark the need for building investigation. The principal way of investigating these is not to do a lot of testing on individual people, although you want to exclude or ascertain whether or not there are cases of hypersensitivity, such as asthma. But the main treatment and solution for building-related illness is generally to approach the source and the building and to try and find possible sources of contamination or the worker's symptomatology. So, a careful walkthrough with an industrial hygienist or a building scientist with attention to potential problems, which I list over on the right-hand side, is probably the most useful task in ameliorating building-related illness. You can do judicious sampling, you can look at carbon dioxide levels, you can measure humidity, and you can see what you find on a walkthrough, and that's going to be helpful. Less helpful are the testing for every type of mold, unless it's done very judiciously and it's done with an eye towards comparison of what's inside versus outside. As you see in the picture here, this is pretty obvious mold, and the solution for that is not to sample it or test it, but to clean it up. So, as I mentioned in the last slide, mold testing needs to be done judiciously, and there also should be outdoor air sampling if you're going to do indoor air sampling, the reason being that numerous mold species exist out in the outside world. And if they are the same as those seen inside, same in number and concentration, then it means there actually is a source of fresh air from the outside coming in. It's when they differ in species in particular, as well as concentrations between the outdoors and the indoors, that you know there may be a problem. Bulk sampling can only identify it, and as I mentioned in the last slide, identifying it, as you see in this picture, is just only giving you a reason to clean it up. Fundamentally, you've got the grandmother test for mold, which is that if your grandmother would point at it and say, that's mold, then you're looking at mold. And so the main thing is to try and remediate the mold overgrowth here, but also to look at the building and try and identify sources of dampness, water incursion, wet building materials, tear those out and remediate them. Mold testing in patients should also be done and used judiciously, and mainly if people have demonstrable illness, particularly if they're developing asthma, severe rhinitis, sinusitis, and related immunologic problems. You don't want to scatter shot a battery of them there, and many people will have false positives from prior sensitization. And you want to use those if the signs and symptoms accord, and if ideally you're getting the same information back from the building. There's a number of neuropsychological testings, mold provocation tests and the like, and those have so far not panned out. Just a word for those of you taking the boards, the boards tend not to like controversy, so what you see here is, I think, looking at indoor air quality with the idea of ameliorating the symptoms for the people who work there and of diagnosing specific disorders such as asthma that may be related to indoor allergens or antigens. Moving on, let's look at nanoparticles. These are engineered particles which are very, very small. They have dimensions from 1 to 100 nanometers, and they can be contrasted in size with even larger particulates, which are still small like PM2.5, and compared to those, these nanoparticles have greater reactivity. They can generate reactive oxygen species because of their small size and the fact that they actually tend to act almost in kind of quantum mechanical-like ways. They're very useful because they can penetrate through membranes, and so one application in the medical arena is to use them as skin-absorbing drug delivery systems. So they will penetrate through membranes well, and they're much more reactive. The problem is we don't know a whole lot, certainly about human disease and disorder or even human epidemiology, but in experiments with animal toxicology, they've proven to throw up some problems which look very bad, and to make a short story short, they can cause pulmonary inflammation and fibrosis in inhalation studies. They can also translocate from the lungs into the cardiovascular circulation, cause cardiac inflammation, atherogenesis, and thrombosis. Very worrisome, as I mentioned, that they can penetrate through membranes is translocation into the brain. Remember that the olfactory nerve tract is the one cranial nerve that actually has sensors and exposure to the outside world. All others are sort of mediated, like the optic nerve, but the olfactory nerve goes straight on outside, and the worry is that these can be taken up by the olfactory nerve and translocate along the neural pathways of the nerve to the brain and cause inflammation there. And lastly, rats injected with nanoparticles intraperitoneally have developed peritoneal mesotheliomas. I'd alluded to this on the previous slide, but this is a common question that boards like to ask. Particle size in nanoparticles is the main determinant of their reactivity and of their probable toxicity. So as size goes down, the surface-to-volume ratio of a particle goes up, therefore the surface area, which provides a substrate for reactivity of the particle, increases the smaller the particle gets, and therefore the smaller particles become more reactive, particularly in their ability to generate reactive oxygen species and to cause or set up inflammation. I noted on the earlier slide that there were a number of animal toxicologic studies that suggested potential very harmful disorders arising from nanoparticles, and we have really no information, no case studies, no epidemiology, giving us information on human health effects. Therefore, the precautionary principle goes into effect and controls are clearly warranted. Most suggestions have been for enclosure or isolation of the process from the worker entirely. This can be through robotics or through other enclosed areas in which no direct contact with nanoparticles occurs. It's not really clear whether personal protective equipment would be helpful. Respirators, for example, may be too gross, have a limited ability to filter out nanoparticles, and therefore may not be of any use. Gloves, by the same token, may not be entirely protective. Some of these particles may be able to translocate through latex or nitrile gloves, for example, and so we don't really know the best way to accomplish personal protective equipment. So enclosing and isolating is really going to become the mainstay of control for nanoparticles. As well, if you notice, some of the health effects that we're seeing in animal studies, and many of these are going to have long latencies like mesothelioma or other pulmonary conditions. As well, we don't necessarily know what we're looking for when we put in place the usual surveillance method. So we don't know whether surveillance programs are going to be adequate, because they may not be sensitive and we may not necessarily know what we're looking for. NIOSH has recommended that surveillance programs be established in materials that are linked to disease by these animal toxicologies, such as carbon nanotubes, which have been responsible in animal tox studies for fibrosis and mesothelioma. And they also recommend that companies establish exposure registries, which gives you a listing and the ability to contact workers who have worked with nanoparticles and to contact them years later or to follow them along for potential health effects. So moving from respiratory toxicology, we're going to look at pesticides. Pesticides are, in broad brush terms, anything that kills or eliminates something that's unwanted. So this can range from insecticides, which we tend to think of first, but can also be herbicides, for example, killing off weeds or other vegetable pests that may inhibit the growth of crops, or fungicides and even rodenticides. Routes of exposure can be many and varied. There's very effective and efficient absorption of most of these through inhalation, and most of them are also absorbed through dermal absorption. Regulations are an area of overlap, and when you have overlap, you may also have missing pieces. The FDA regulates pesticide residues in raw and processed food, and the USDA regulates those in meat and poultry, whereas the FDA is mainly concerned with crops. OSHA regulates workplace exposure in the manufacture of pesticides, but does very little to control application of pesticides, and the EPA is responsible for application of pesticides, but mainly their purview is in agriculture, and particularly in migrant agriculture, where large amounts of pesticides are applied to crops. I'll mention this here briefly, but there's also mention in the slides on government regulation. Pesticide regulation by the EPA is done under FFRA, which took effect in 1970, and requires a testing scheme for toxicity to register for them as a use, and these range from very highly toxic pesticides, which must be regulated, and applicators must take exams and courses in application, all the way down to things like pyrethrins, where there's just a cautionary statement, but no precautionary measures need be taken. So we'll look most at the insecticides, and mainly the cholinesterase-inhibiting insecticides. These are most commonly quizzed on, at least by virtue of the boards, and after that, the lower toxicity pesticides, organochlorines and pyrethrins. The insecticides that inhibit or deactivate acetylcholinesterase are the organophosphate pesticides and the carbamates. These are absorbed very easily and readily by inhalation, but mainly by dermal exposures that can be very readily absorbed through the skin, as well as conjunctiva and the mucous membrane. Recall very briefly that acetylcholinesterase regulates and down-regulates acetylcholine activity, and these pesticides which bind and deactivate this enzyme result in elevated acetylcholine, which then causes massive cholinergic stimulation. For carbamates, this is reversible. In organophosphate, this is irreversible, at least in insects, and we'll see the health effects in just a moment. The classic mnemonic for OP and carbamate pesticides is dumbbells. Those of you recertifying may remember memorizing this 10 years ago, and it's the mnemonic for uninhibited cholinergic activity. So, look at the top and bottom. It fundamentally opens up every pore and sluice in the body and causes diarrhea, urination, emesis, lacrimation, and salivation, massive outpouring of fluids, if you want to think of that, as well as emesis, which I neglected to mention there. It'll cause meiosis or small pupils, but the real bad actors are the ones in the middle, bronchorrhea and bronchospasm, as well as bradycardia. These are referred to as the killer bees. The other symptoms are quite unpleasant, but bronchorrhea and bronchospasm may cause asphyxia, and bradycardia may result in death as well. So, think of those as the killer bees within the dumbbells mnemonic. So, just to reiterate from what we saw with the symptoms on the previous slide, acute poisoning with OP pesticides or carbamates causes this acute cholinergic crisis, the parasympathetic overstimulation, including small pupils, bradycardia, and glandular hypersecretion. It can also have nicotinic effects, muscle weakness, and fasciculation, as well as central CNS effects, including early neural excitation, then late depression, and potentially seizures if the dose is high enough. The other interesting point about OP pesticides is through a very different mechanism, it can cause a delayed peripheral neuropathy. So, in someone who has sustained marked exposure to OP pesticides after they're done with the acute cholinergic crisis, two to three weeks later, this delayed peripheral neuropathy begins. It's a dying back axonal peripheral neuropathy, most noted in the legs and feet, but also in the hands and arms, and it has a long course. Its mechanism is the inhibition of an enzyme called neurotoxic esterase within the nerve cell. There was an outbreak of a number of these cases of peripheral neuropathy in the 1930s when an OP-like material was added as an adulterant into flavoring. This was a flavoring known as Ginger Jake, which flavored alcohol during Prohibition and caused an episode, an epidemic of paralysis at and about that time. So, treatment for OP pesticides consists first and foremost of decontamination, so remember this first. If you're given an order, remember that the skin has to be washed, clothing has to come off, because the potential for dermal absorption still remains as long as they still have their clothes. Following that, atropine can be given as an antagonist for cholinergic overload. This will dry up all the glandular secretions that we mentioned in the dumbbell slides, and it also, easy to remember, has the effect of reversing the bradycardia and returning it to a normal heart rate. So, atropine is really an antagonist, which means that it treats the symptomatology. Prelidoxime, or 2-PAM, is the actual antidote for OP pesticide poisoning, and rather than controlling the symptoms, this actually works to detoxify the organophosphate pesticide itself. It breaks the OP-cholinesterase bond and reactivates the enzyme acetylcholinesterase, which then goes back to doing its work in detoxifying and breaking down cholinesterase. It doesn't work for carbamate pesticides, as those proceed by a different mechanism than this OP bond, so they won't be useful. One board question that gets asked frequently is, OP pesticides that get used as nerve agents and bioterror weapons, so circle this or write it down or remember it somewhere, sarin nerve gas, which was used in the Tokyo subway attacks, and VX nerve gas, which has been weaponized as a potential bioterror weapon, are also related to organophosphate pesticides and can be used as bioterror weapons. So, if you're looking for an analogy between these two and OP pesticides, or the boards as doing that, that would be the proper answer. There's high natural variation in cholinesterase levels amongst individuals, and cholinesterase is inhibited by a number of medicines and drugs, it's inhibited by diseases and disorders such as liver disease and anemia. There are two varieties in the body, there's plasma cholinesterase, which gets termed pseudocholinesterase, and red blood cell cholinesterase, which more closely reflects nervous system levels. Some of these pesticides inhibit one more than the other, it's probably not important for the purposes of the board exam, but it's useful to know anyway if you're testing it and are given the choice, then red blood cell cholinesterase should be the one that gets tested. It returns much more slowly, and it again better reflects nervous system levels in acute or chronic poisonings. Some regulations for pesticide workers in California, with its big agricultural community as kind of a leader amongst these, mandate cholinesterase levels as a surveillance method, and this also mandates a baseline cholinesterase measurement, because recall from the last slide, we mentioned the high natural variability in cholinesterase levels, so this is just an illustration of that variability. You have two workers who are tested at baseline pre-application over on the left-hand side, and post-application, note that the yellow dot has dropped much more markedly than the worker represented by the white dot. Now if you had just taken post-cholinesterase levels, as you see over on the right side, you would have thought that the worker represented by the white dot had gotten overexposed, when it is in fact the yellow dot worker, because they had started off at a much greater baseline, so the white dot worker is likely not particularly greatly exposed, whereas the worker in the yellow dot may represent an overexposure. So this is the value of baseline measurements again. The organic chlorine pesticides are mainly notable for their high environmental persistence. They're stored in fat and they bioconcentrate up the food chain, so their use in killing mosquitoes in malaria-prone areas led to their bioconcentration up the food chain to small animals and eventually to predatory and raptor birds, and was the basis for the book Silent Spring, which noted that the larger birds were being killed off by this environmental persistence and bioconcentration of these pesticides. This had the consequence of banning DDT for most uses. It was banned in the U.S. in 1973 and most other areas about the same time. They are less toxic to humans than the OP pesticides, but they do persist and bioconcentrate in fat storage depots. Their toxicity is usually in high exposure or single overdoses. They can be neurotoxic and cause CNS irritability and seizures, as well as mental status changes, and there's evidence that they may be carcinogenic, causing liver cancer in animal models. Chlordecone was a special case of an organochlorine pesticide, which led to decreased sperm counts. This was picked up in the workers manufacturing this pesticide, who were exposed to much higher levels, and they're also, some were noted to have normal pressure hydrocephalus or pseudotumor cerebri. Hexachlorocyclohexane or Lindane might be familiar to many of you there. This is another organochlorine pesticide, which had clinical uses as a scabicide and other insecticides, and its use has been phased out because of its neurotoxicity, particularly the concern about seizures in children where it's used. Pyrethrins and pyrethroids are among the much lower toxicity insecticides. Fundamentally, you can get these at the DIY store for your flower garden. Pyrethrins are derived from chrysanthemums, and pyrethroids are the synthetic versions. They're very low toxicity compared to the other two we've been reviewing. They may cause topical paresthesias if you get it on your hands. They are skin and respiratory irritants for some people, probably with a mainly irritative but non-allergic component, and a few cases may cause allergic disorders, namely allergic contact dermatitis and potentially asthma, but their toxicity is much lower than the ones we've examined previously. This is a recap of the slides we saw in the skin lecture dealing with particularly dioxins. These were a byproduct and contaminant of the manufacture of chlorophenoxy acetic acids, 2,4-D and 2,4,5-T, which were used as an herbicide defoliant in Vietnam. These herbicides themselves can have skin and respiratory irritation and can cause a peripheral neuropathy. The main concern was along with dioxin contamination of Agent Orange, which was the combination of those two herbicides. These can cause chloroacne, which is seen in this picture, and if you go back to the skin lecture, you'll see President Yushchenko with his case of chloroacne from dioxin poisoning. These have also been found, particularly in the Agent Orange applicators in the U.S. military in Vietnam, to cause liver dysfunction and liver transaminase elevations and are associated with the development of soft tissue sarcoma and non-Hodgkin's lymphoma in individuals overexposed to these materials. The last few slides on pesticide toxicity. Some fairly toxic materials are used as fumigants, which exist as gases at room temperature and are used to treat wood insides of buildings and to essentially detoxify them from pests. These have a variety of side effects, including respiratory tract irritation and central nervous system effects. Probably the most notable one of this group, or at least the one to remember for the boards, is hexachlorobenzene, which was used in the 1950s and resulted in acquired porphyria, one of the few occupational substances or toxicants that causes a porphyria. As well, methyl bromide was used as a fumigant, and this has central nervous system toxicity. So we mentioned the herbicides again, particularly the chlorphenoxyacetic acids. I'll also say a word about Paraquat. This was used to spray marijuana fields, particularly in the 1970s, after which the marijuana was harvested before the Paraquat worked as a defoliant. Smoking marijuana with Paraquat applied led to inhalation toxicity from the Paraquat and led to pulmonary fibrosis, along with hepatic and renal damage. This isn't used very much anymore, marijuana being somewhat more legal, or at least there isn't quite the same war on it as there was in the 1970s. So this is mainly of historical interest. Moving along to the last set of slides is kidney and liver disease, which we'll deal with in turn. So the most familiar mechanism of liver damage is that induced by solvents in the occupational setting. Carbon tetrachloride is the main exemplar of this, although most of the other haloalkanes like TCE and CFCs can cause it. And fundamentally what happens is in cytochrome P450 oxidation and liver metabolism of these halogenated compounds, a chlorine atom is torn off of the original molecule and that leaves a free radical with a single electron. This can then peroxidate or otherwise directly injure and or damage cell membranes and cause other toxicity at cellular level and in large doses or in constant exposure will cause centrolobular necrosis and steatosis. This might be familiar to you from another clinical setting. Halothane hepatitis occurs via the same mechanism from inhalation anesthetics, which if you think about it are simply other halogenated alkanes. This slide is a rather large grab bag of materials including occupational exposures but also other extent conditions that can cause liver damage and steatosis. Main among them are non-occupational causes including obesity, diabetes, hyperlipidemia, and of course alcohol use. We looked at the mechanism of the halogenated hydrocarbons and their toxicity in the previous slide. Amongst the other ones to take note of are DDT and some of the organochlorine pesticides, vinyl chloride monomer which not only can cause liver cancer and angiosarcoma but also liver damage in non-malignant ways, and trinitrotoluene or TNT and some of the other nitro explosive compounds. This one is somewhat of historical interest and is the sort of thing the boards like because it's kind of a one-off. A compound called methylandianiline, which is an epoxy resin hardener, accidentally contaminated flour in England in the 1960s. Bread was made from this flour and this was ingested by a large number of people in and around the community of Epping in England and so this was termed Epping jaundice. This interferes with metabolic pathways in the liver, caused cholestasis, and led to this outbreak of jaundice. Again, not seen very common or frequently but one of those historical accidents that the boards like to take as representative of a single toxin or exposure. The liver has a very limited number of mechanisms of repair and following damage, steatosis or direct hepatocellular injury, it responds mainly with a fibrotic response. And so these are then the mechanisms that lead to cirrhosis. Carbon tetrachloride to mention again, and this goes for most of the halogenated hydrocarbons. Arsenical pesticides had a long history of liver toxicity as well. Most of these are banned, certainly in the developed world. Nitro explosive compounds such as TNT and of course down at the bottom, other factors outside the occupational setting including alcohol, viral hepatitis, and schistosomiasis. Fundamentally, anything that causes ongoing and prolonged liver damage will lead to this end response of cirrhotic liver. Lastly, when discussing the liver are the compounds that can cause liver malignancy, either hepatocellular carcinoma or hepatic angiosarcoma. The real classic for this in the occupational setting is vinyl chloride monomer, the precursor of polyvinyl chloride, which was noted to cause hepatic angiosarcoma. This was discovered when several primary care physicians bumped into each other and noted that they had patients with an unusual tumor and it turned out that these were two or three separate patients and they all worked at a plant that produced vinyl chloride monomer. Subsequent investigation confirmed and turned up more cases of hepatic angiosarcoma and the link was made subsequently via epidemiology. Arsenic, also responsible for hepatic angiosarcoma, and then a couple of outsiders from the occupational setting, anabolic steroids, and a compound called thoratrast, which was an alpha emitter used as a contrast medium in radiology into the 1950s and 60s and caused liver cancers, particularly biliary tract cancers, because it accumulated in the liver and was also responsible for leukemia and marrow malignancies. Hepatocellular carcinoma, probably most familiar from that being caused by hepatitis, so hepatitis B and hepatitis C, particularly in areas of endemicity. Hepatitis C is something of a tip of the iceberg problem because of the long latency of its causation for a hepatocellular carcinoma. And lastly, aflatoxin, which is derived from aspergillus and can be found on grain and peanuts and may put those workers at risk. Moving on from liver disease, we'll come on to renal disease. And without getting too deeply into the weeds on classification of renal disease, we want to point out a few factors. Main thing to remember here is the differentiation between renal tubular disorders and glomerular disease. Tubular disease happens generally proximally with occupational solvents and leads to low molecular weight proteinuria. This leads to excretion of beta-2-microglobulin. Please ignore the slide that says macroglobulin. I don't know how I didn't catch that all these years, but I am now. And this is distinct from glomerular disorders, which leads to heavier or higher molecular weight proteinuria, principally albumin. Interstitial nephritis can be caused by analgesics. Very few things in the occupational setting cause it. And finally, towards the end of this lecture, we'll get on to malignancy as well. So taking up renal tubular disease, as we mentioned in the last slide, either acute tubular necrosis or chronic renal disease leading to necrosis of renal tubulars is probably the most common injury from the occupational setting. This, as I noted, leads to low molecular weight proteinuria. And the main agents you really want to remember are cadmium and lead, along with mercury and possibly arsenic. And we'll look at cadmium in a little more detail in the next couple slides. Distinct from proximal tubular disorders, glomerular nephritis is going to be much rarer in the occupational setting. This leads to high molecular weight proteinuria or albuminuria instead of beta-2-microglobulin, as we see in the tubular disorders. The main thing you want to remember for glomerular nephritis is primarily mercury, with some evidence for organic solvents also causing GN. Interstitial nephritis is mainly remembered by being caused by a variety of analgesics, such as non-steroidals, and can occur in systemic diseases such as lupus. There's minimal proteinuria as compared to the glomerular and tubular disorders. And of recent date, although the causes and the physiology have not been well described, is Central American chronic kidney disease. This occurs in low-altitude agricultural workers in whom heat and dehydration may also be playing a role in addition to some potentially unknown factor at work. The two main toxicants in the occupational setting that you really want to have a good handle on are lead and cadmium. Looking first at lead, lead nephropathy can occur in acute high-dose exposures and lead to proximal tubule dysfunction and Fanconi syndrome with all the concomitants that you see here. More likely are the renal effects of long-term lower-level but chronic exposure to lead, which leads to a tubular nephritis along with some interstitial nephritis. This also leads not only to the proximal tubule dysfunction, as we see, but also into hyperuricemia and what's termed saturnine gout, saturnine having to do with lead. And so this impaired uric acid excretion can lead to, again, hyperuricemia and gout. Because of the chronic renal damage, this can lead to hypertension, and so it's something of an interesting question as to whether or not ongoing high lead level exposures in who are now older people led to an increase in hypertension along with chronic renal failure and potentially hyperuricemia and gout. And so suspicion might be for long-term chronic lead exposure in seeing someone who has developed hypertension with chronic renal failure and evidence of gout. Cadmium nephropathy is somewhat like lead nephropathy, but it is particularly interesting in its pathophysiology. This, again, causes proximal tube dysfunction, and we'll look at the mechanism on the next slide. There is also some element of interstitial nephritis. The main hallmark here, again, is low molecular weight proteinuria, and most of these individuals, if they're chronically exposed, will go on to develop this low molecular weight proteinuria, Fanconi syndrome, renal tubule acidosis, and primarily calcium wasting from the renal system. This can lead to stones, and it can also lead to osteomalacia and osteoporosis. Cadmium is used in battery making, for example, nickel cadmium batteries, also used in metal plating and as a pigment in a variety of colors. The toxicity is somewhat complicated after cadmium is absorbed in the workplace setting. It binds to albumin, and it's transported to the liver. In the liver, it induces production of a protein called metallothionine within the liver. It then complexes to this protein, and this cadmium thionine complex is then released from the liver, goes through the bloodstream, transported to the kidney, and accumulates in the proximal tubule of the kidney. There, it's very slowly metabolized and catabolized and releases cadmium into the cytoplasm of the renal tubule cell, so this leads to ongoing, prolonged, chronic proximal tubule damage. This cadmium metallothionine complex is much more nephrotoxic than cadmium alone because of its chronicity and slow release within the tubule system, and the nephropathy may not be reversible in workers who have had long-term cadmium exposure. The OSHA standard for cadmium is based on the fact that low molecular weight proteinuria is a marker for cadmium toxicity, and therefore beta-2-microglobulin should be checked. The OSHA standard mandates a check for beta-2-microglobulin, and this should be below 300 mics per gram of creatinine standardized. Blood cadmium and urine cadmium can be checked, although it's excreted rather rapidly from the bloodstream, and urine cadmium levels may not reflect ongoing or chronic toxicity. So lastly, under the renal system come the urologic cancers, and principally we know more about bladder carcinogens within the GU system than we know about renal carcinogens, and this particularly in the occupational setting. The dye industry, which was founded in the late 1800s, produced a variety of aniline and aromatic amine dyes, which were subsequently proven to be cancer-causing, specifically for the bladder. As well, these materials were made from coal tar derivatives, which may also have contained PAHs, and PAHs themselves are also bladder carcinogens, so that workers, for example, in coke ovens can also develop bladder cancer, although I didn't list it on this slide. There's a variety of other related aromatic amines, such as benzidine and aminobiphenyl, which also are bladder carcinogens. Renal cell cancer is less clear-cut, and most of the carcinogens are outside of the occupational setting that we know clearly are renal cell cancer-causing. Smoking, obesity, and hypertension tend to be the principal causes of renal cell cancer. Amongst the occupational carcinogens, trichloroethylene, or TCE, gets an IARC2A designation. This is a probable human carcinogen, but not a class I. Asbestos, cadmium, and uranium all have some moderate evidence, but less evidence than the big triad of smoking, obesity, and hypertension. So, these are not as well described, whereas what we know about bladder cancer is fairly clear, particularly with the aniline dyes and related aromatic amines. So, this concludes this toxicology lecture. Subsequent lectures will be on further toxicology, including more detailed respiratory disease, in which some of the same themes will be covered.

respiratory toxicology

building-related illnesses

environmental health

toxicology

respiratory irritants

asphyxiants

proper ventilation

maintenance

indoor air quality

treatment

exposure

oxygen