Hello, this is Dr. Francesca Litto, and in this part of the course we will be reviewing neurotoxicology, hematologic toxicology, and occupational cancer. So we'll start with a case. A worker presents with numbness and tingling in his feet for three years. This may be due to occupational exposure to A, methyl n-butyl ketone, B, formaldehyde, C, trichloroethanol, or D, methyl ethyl ketone. I'd like you to think about this case as we review the following slides, and in a future slide we'll discover the answer to this question together. Let's start our discussion with some general points about neurotoxicology. The health effects of exposure to neurotoxic agents can affect the central nervous system, or the CNS, and or the peripheral nervous system, or PNS. There's a strong dose-response relationship, meaning the more that you are exposed to, the more likely a more significant health effect. In addition, there's a temporal relationship where exposure precedes development of the associated health effect. Because exposure is generally to the entire body, either through inhalation usually, or dermal or skin exposure, this health effects resulting from exposure to neurotoxicants are usually non-focal and are symmetrical on both sides of the body. Luckily, improvement usually follows the cessation of exposure, with a couple of exceptions. For example, if a given neurotoxicant causes such a significant structural change, or in the event of significant loss of neurons, or irreparable damage to the neurons, it is less likely that function will recur. One specific phenomenon, called coasting, is related to exposure to the solvent n-hexane, and describes a continued decrement in function after exposure to n-hexane ceases. And that is due to the evolving health effect resulting from n-hexane exposure, which we'll talk about as we go through this discussion. Let's start our discussion of the neurotoxic agents by talking about solvents. Solvents are a category of organic chemicals that, in general, are in a liquid state at room temperature, but have varying degrees of volatility. They're very useful in a wide variety of applications, including in industry and in healthcare, because of their ability to dissolve other compounds. And although we'll talk about individual solvents on the next few slides, in reality, most exposures are two mixtures of solvents. Specific characteristics that will affect exposure, and thus impact the likelihood of health effects, include their volatility, which affects whether they're going to be in a gaseous state, and hence more likely to be inhaled, or in a liquid state, and hence more likely to be absorbed through the skin, as well as lipid solubility, which would affect their ability to cross lipid membranes. And we'll talk about that, again, on an upcoming slide. The major routes of exposure to solvents include inhalation, or skin or dermal exposure. Respiratory exposure, or inhalation, is the major route of exposure for most solvents, and key determinants of exposure and internal dose, including the solubility of the given agent in blood, and how it is taken in with increased workload. For example, if someone is exerting a lot of energy, performing a strenuous task, then their respiratory rate would be faster, and hence their uptake would be higher from an inhaled agent. Regarding dermal exposure, this is more likely for solvents that are liquid at room temperature, that is, those with low vapor pressure. Examples include the glycol ethers, dimethyl formamide, and DMSO, or dimethyl sulfoxide. DMSO is often used in veterinary medicine because of its ability to take other agents across the skin. It's also used, interestingly, to treat arthritic diseases in large animals, such as horses. In general, solvents are metabolized primarily by the cytochrome P450 system in the liver. This process, in most instances, results in inactivation or decreased toxicity of the solvent. There are some notable exceptions, including the metabolism of N-hexane and or methyl N-butyl ketone, which results in the more toxic agent 2,4-hexane dione, as we will discuss further. Carbon tetrachloride radical and benzene metabolites that we'll discuss in a later section of this presentation can also be created and or activated through metabolism by the cytochrome P450 system. So again, these are examples of increased toxicity and or formation of new agents during metabolism in the liver. Trichloroethylene, or TCE, is metabolized like alcohol by alcohol and aldehyde dehydrogenase. And a phenomenon called degreasers flush has been recognized in employees who drink alcohol and are exposed to trichloroethylene. This anabuse-like reaction includes facial flushing, headaches, and gastrointestinal symptoms similar to a person who is using the drug Antabuse or Disulfiram and then ingests alcohol. And it's thought to be due to competitive inhibition of alcohol and aldehyde dehydrogenase enzymes. Because of their lipid solubility, it makes sense that solvents tend to distribute in the body to lipid-rich tissue. These tissues include the brain, the nervous system tissue, the liver, and adipose or fat stores. Solvents are generally excreted via either exhalation of an unchanged parent compound in the case of inhalation as exposure. Solvents that are poorly metabolized, such as tetrachloroethylene, are excreted primarily by exhalation. Alternatively, solvents that are metabolized in the body can be excreted by urinary or biliary excretion of either the parent agent or a metabolite. And when we are looking at monitoring for occupational or environmental exposures to solvents, we use this in order to perform monitoring. So for example, for benzene, we can measure urinary phenol. That is what is measured according to the OSHA standard for benzene. There is also a biological exposure indicator for benzene, and that's TTMA. We could alternatively measure urine S-phenylmercapturic acid, and we would measure those in the urine of workers at the end of their shift. We'll define and discuss biological exposure indicators on an upcoming slide. BEIs, or biological exposure indices, are not regulatory levels. They are published by the American Council on Government Industrial Hygienists and are useful indicators of occupational exposure to given agents. This slide summarizes some of the solvents and their corresponding biological exposure indices. For example, for benzene, although the OSHA standard requires monitoring of urine phenol, you can see that biological exposure indices for benzene would include urine S-phenylmercapturic acid and urine transtransmuconic acid that I discussed on a previous slide. Also note that the metabolite of N-hexane, or urine 2,5-hexanedione, happens to be the biological exposure index for this agent. In this section of our presentation, we'll first talk about the acute and chronic effects of occupational exposures to various solvents in general, and then we'll focus on a few particular solvents. There's a good correlation between the lipid solubility of a solvent and its anesthetic effects, and we've capitalized on this in the past by using solvents including chloroform and diethyl ether as general anesthetics. Unfortunately, these two agents are difficult to control with respect to their dose response and risk profile, and due to this, they are no longer used as general anesthetics. The effects of solvents are similar to the effects of ethyl alcohol, which is also a solvent, on the central nervous system. Symptoms of acute solvent syndrome onset rather rapidly, within minutes to 24 hours, and include symptoms that, again, look very similar to those related to intoxication with ethyl alcohol, and those are listed on this slide. They can range from the mild, such as headache and confusion, to the very severe, such as seizures. Just like those folks who ingest ethyl alcohol, workers exposed occupationally to solvents can develop tolerance to the acute effects. In fact, when workers with consistent occupational exposure to solvents have weekend breaks or other times away from work, they may actually exhibit symptoms that are a lot like hangovers, symptoms of withdrawal when they are not near their usual occupational exposures to solvents. With chronic exposure to solvents, we see persistence of the health effects of acute exposure, as well as persistent slowing of psychomotor performance and mental health conditions, such as depression and irritable mood. Chronic solvent syndrome has also been called painter's syndrome, because painters historically have been an occupational group with significant solvent exposure, for example, due to the solvents in paint thinners. Toluene is a widely used solvent, and although the picture on the upper right-hand corner of the slide here does illustrate a container of toluene, as with many solvents, it's frequently found in mixtures. It can be found in gasoline and can be used as a substitute for benzene, as well as an ingredient in paint thinner. Because of the high likelihood that toluene is vaporized, inhalation is the most likely route of exposure. It makes sense, since it is likely inhaled, that respiratory irritation is an expected health effect. Because toluene is highly lipid-soluble, it makes sense that it causes central nervous system effects, which can include depression and cardiac arrhythmias with high-dose exposure. In chronic abusers, such as those who are huffing or glue-sniffing, neurobehavioral and cerebellar dysfunction have been noted. And akin to the fetal alcohol syndrome, a fetal solvent syndrome has been recognized in the children of women who recreationally sniffed glue. Cases of toxic encephalopathy have been reported in chronic toluene abusers, such as those who are glue-sniffing or huffing, and in case reports from some high-level inadvertent occupational exposures. This syndrome consists of a multifocal, diffuse white matter disease called leukoencephalopathy. And health effects associated with this include abnormal gait, incoordination, visual impairment, cognitive changes, increased reflexes, as well as tremor. All of these are consistent with white matter and upper motor neuron. Impairments. This slide contains some magnetic resonance images of the brain of a patient with toluene-induced leukoencephalopathy. And although interpretation of these images is beyond the scope of an occupational or environmental medicine physician, I wanted to include this as an example of structural changes that do correspond with the functional changes that we observe in patients who have this condition. Trichloroethylene is used in many industrial applications, including use as a vapor degreaser, meaning that it is used to clean surfaces prior to coating them. This process could be included, for example, in the manufacture of appliances such as refrigerators or washer and drying machines. Acute high-level exposure to trichloroethylene can result in toxic hepatitis or acute tubular necrosis, abbreviated as ATN on this slide. Chronic exposure has been associated with an increased risk of trigeminal neuropathy, resulting in decreased sensation and difficulty chewing due to neuropathy of the fifth cranial nerve. It's also been associated with an optic neuropathy. Alcohol potentiates trichloroethylene symptoms, as we discussed in an earlier slide, due to competitive inhibition of alcohol and aldehyde dehydrogenase, resulting in degreasers flush or patchy flushing of the face, which can also be accompanied by an antabuse or disulfiram-type reaction, including nausea and headaches. The two photos at the upper right corner of this slide are a before and after of an employee who's exhibiting degreasers flush. Trichloroethylene has also been classified as a class 2A or probable human carcinogen by the International Agency for Research on Cancer, or IARC, with associated risks of liver, biliary tract, and non-Hodgkin's lymphoma cancers. Styrene is a solvent used in many industrial processes, including those that manufacture plastics, resins, polymers, and the polystyrene packing materials that are shown in the photo at the right-hand corner of this slide. Due to its physical properties, it is most likely found as a vapor at room temperature, and hence occupational exposure is mainly through inhalation. Styrene is unique in that occupational exposure has found to be synergistic with occupational noise exposure, creating an increased risk of hearing loss in workers exposed to both occupational noise and styrene. Like many other solvents we've discussed, styrene is hepatotoxic and has also been associated with color vision deficiencies and neurobehavioral changes. On the next pair of slides, we'll hopefully get to the bottom of our initial review question. So we're going to be reviewing some toxicants associated with peripheral neuropathy in this section. Historically, when methyl ethyl ketone, or MEK, and n-hexane were added to glue, there was a noted increase in neuropathy in people who sniffed glue. Methyl ethyl ketone alone doesn't cause this neuropathy. However, it's hypothesized that methyl ethyl ketone, or MEK, causes more rapid metabolism of the n-hexane to its toxic metabolite, 2,5-hexanedione. Methyl and butyl ketone has the same toxic metabolite and thus can cause distal sensory symptoms that initially onset and later evolve into a mixed sensory and motor neuropathy. Although this isn't a course in chemistry, I'm hoping that the information on this slide will help you to better understand the relationship between these toxicants and their common metabolite. So on this slide you see the structure of n-hexane, a straight chain solvent, and below it the structure of methyl n-butyl ketone, a straight chain solvent that has a ketone group on it. On the bottom of this slide you see their common toxic metabolite 2,5-hexanedione. This metabolite is responsible for the toxicity to the peripheral nervous system from both of these compounds, and again this is one of the examples where a chemical particularly n-hexane is activated in the liver to a toxic metabolite 2,5- hexanedione rather than deactivated in the liver. Carbon disulfide is a volatile solvent, thus inhalation would be the most common route of exposure. Carbon disulfide is used in a variety of industrial processes including manufacture of viscose rayon, so it can be found in the manufacturing process for many textiles as well as items such as pantyhose and other products such as cellophane film and velour fabrics. Carbon disulfide is a compound that will become very familiar to you as we go through this course because it has associated health effects due to exposure in most body systems and for most body functions. I've listed some of those on this slide and you can see that regarding the neurological system exposure to carbon disulfide has been associated with the phenomenon of Parkinsonism which we'll discuss on a later slide as well as with psychosis and associated with the peripheral sensory motor neuropathy. One of the unique things about carbon disulfide is its cardiovascular effects, specifically its association with an accelerated risk for atherosclerotic disease and hence increased cardiovascular mortality, increased cholesterol, and high blood pressure. The histology side photographed on the upper right hand corner of this slide is meant as a reminder that carbon disulfide has also been associated with central lobular necrosis of the liver and that's exhibited in that histology slide. Observation of the health effects experienced by workers over time who were exposed to acrylamide monomer in the shoe industry, grouting industry, and the manufacture of coatings and things made out of acrylates provided an experimental model for a toxin-induced peripheral neuropathy. Exposure to acrylamide monomer has been associated with a sensory motor axonal degeneration that results in numbness and weakness as you can expect. Uniquely, this syndrome includes autonomic dysfunction and that is unusual among the neurotoxicants. Examples of autonomic dysfunction include excessive sweating or hyperhidrosis and orthostatic hypotension. Inorganic arsenic has been used as a poison throughout history and its use and the health effects associated with poisoning from this have been documented in the literature such as Madame Bovary, in movies such as Arsenic and Old Lace illustrated on this slide, as well as in terms including the French term Poudre d'Assonchon which refers to the use of arsenic historically for people who wanted to quicker inherit their family wealth by poisoning elderly family members. Occupationally, workers exposed would work in industries such as insecticide use in manufacture, smelting, and the electronics industry. Non-occupational exposure to organic arsenic is mainly through ingestion of seafood but that can contain some inorganic arsenic as well. Agents such as CCA, chromated copper arsenate, or Paris green contain arsenic and have been used to treat wood as preservatives so children who might gnaw on this treated wood would be at risk of inorganic arsenic poisoning. Drinking water contamination due to drilling of wells in areas with deep arsenic stores has been associated with development of arsenic poisoning in many overseas locations. In Taiwan and Mexico in particular, Blackfoot disease was noted and we'll discuss the particular skin health effects and other health effects of inorganic arsenic on the upcoming slides. Acute inorganic arsenic poisoning which would most likely result from ingestion either accidentally or perhaps in a purposeful suicide attempt situation results in acute gastrointestinal symptoms as well as acute neurological and cardiac symptoms. Here on this slide I have included a visual diagram of normal and prolonged QT intervals for your review. Inhalation of arsine gas classically produces hemolysis and resulting symptoms of abdominal pain, jaundice, and oliguria as well as shock due to the hemolysis. This can also result from stibine exposure. Ingestion of inorganic arsenic over time generally affects the skin and the neurological system although it's important to remember that inorganic arsenic has also been associated with a unique cancer of the liver called angiosarcoma. Subacute symptoms connected with inorganic arsenic toxicity include hyper pigmentation of the skin, hyperkeratosis which is what is illustrated on the soles of the feet in the upper photo on the slide here, as well as anemia and leukopenia. Peripheral neuropathy can also occur and Mies lines or horizontal lines on the nails as illustrated in the lower photo on the right-hand corner of this slide can result from multiple heavy metal exposures including that to arsenic. Blackfoot disease that has resulted from contaminated water ingestion consists of peripheral vascular disease and gangrene. Chronic symptoms associated with inorganic arsenic ingestion include peripheral sensory motor neuropathy, anemia, and skin cancers including Bowen's disease or in situ squamous cell carcinoma of the skin as well as a bronze hyper pigmentation of skin that has been noticed in people who have ingested water contaminated with arsenic over time. In contrast to inorganic arsenic, organic arsenic is non-toxic and as information will be cleared within days. It's interesting to note that levels of organic arsenic can be remarkably high in the urine from 12 to 24 hours after ingestion of shellfish and for this reason it's very important to request speciation or clarification of what type of arsenic inorganic versus organic is being reported in a urine arsenic lab result. Exposure to thallium can occur via skin or dermal exposure as well as through ingestion and results in a neuropathy of with loss of distal sensation within days of exposure. Notably people exposed to thallium may also experience hair loss and this is something that is unique to this heavy metal exposure compared with other heavy metals that we've been discussing in this section. The neurological system can further be affected by a chronic tremor including features of chorea or gentle irregular movements, abnormal gait as well as peripheral neuropathy and there can also be a neuropathy involving the cranial nerves in those exposed to thallium. In thinking about occupational or environmental exposures to mercury it's important to recognize that there are three distinct forms of mercury. Metallic or elemental mercury also referred to as quicksilver is the type of mercury found in traditional mercury thermometers and is the type of mercury that you can see in the picture on the upper right hand corner of this slide. This type of mercury is easier absorbed by inhalation as compared to by ingestion and thus the hazard during a mercury spill would be of inhalation of mercury fumes. Inorganic or mercurical compounds such as those used in plating and jewelry and those that might be used as disinfectants or anti-mold agents is very efficiently absorbed by ingestion. Organic or methyl mercury is absorbed much more efficiently by ingestion compared with inorganic mercury and is found in grain fumigants and is used as a fungicide. There is a very famous environmental disaster which occurred in Minimata Bay and the health effects of which were recognized in the 1970s and photographed in Life magazine by Eugene Smith. I'll be showing some of those photos in today's presentations as well as in the presentation on reproductive toxicology in the future. As I mentioned on the prior slide, elemental mercury is very efficiently absorbed through inhalation and acute symptoms of exposure generally involve the upper respiratory and gastrointestinal tracts. Chronic symptoms are best exemplified by the mad hatter with the tryout of classic symptoms of a tremor, gingivitis, or swollen gums as well as an odd effect called erythism. Sensory neuropathy and kidney or renal disease also accompany chronic exposure and the unique symptom of acrodynia or pain at the tips of the digits can also occur. Particularly in children we see a painful neuropathy with red cold hands and feet in those exposed. Inorganic mercury compounds have had a wide variety of uses. The photo of an old bottle of mercurochrome or mercuric chloride contained a red substance that was used as an antibacterial and antiseptic for minor skin wounds. Mercury has also been used in the preservative and tanning industries as well as to create red color when used as mercury dichloride in the production of fireworks. Mercury oxide containing batteries have been phased out in compliance with the 1996 mercury containing recyclable battery act promulgated by the EPA. Acute effects of exposure or ingestion of inorganic mercury include those on the gastrointestinal system and the kidneys. Chronic health effects mainly focus on renal or kidney disease. The reproductive health effects after ingestion of organic mercury in Minimata May, Japan became evident in the 1950s. Women who ingested fish contaminated with organic mercury gave birth to children with a cerebral palsy like syndrome, pictures of whom were published in Life magazine. Again the mothers were asymptomatic in most cases and these reproductive health effects mainly affected the children, both male and female children, of their mothers. Interestingly both cats and dogs who also ingested fish from this source were also affected with central nervous system symptoms. This slide includes a picture taken by W. Eugene Smith of a woman bathing her very impaired child. This child was one of the children that suffered from the cerebral palsy like constellation of symptoms due to maternal ingestion of fish contaminated with methylmercury from Minimata Bay, Japan. I've listed some of the impairments on this slide and we'll discuss this again in our discussion of reproductive health hazards. On this slide I've combined information about the different types of mercury we've discussed, their half-lives in human tissue, the matter of excretion for each type, and what body media is used for monitoring. Normal blood mercury is less than 10 micrograms per deciliter. Urine blood mercuries range between 20 to 50 micrograms per deciliter. The biological exposure indice for elemental mercury as measured in post-shift urine would be 35 micrograms per gram of creatinine. And when examining workers exposed to organic or methylmercury, blood levels are more useful than urine levels. And you can see that in the chart here on the lower right-hand side under monitoring for organic or methylmercury, which has the longest half-life in tissue, that we would monitor that in either blood or hair. Like carbon disulfide, inorganic lead toxicity affects multiple body systems and functions. I've listed some of them on this slide, and throughout our review course you'll be hearing about these, which hopefully will cement your memory of the different health effects of exposure to inorganic lead. Chronic exposure in adults leads to a constellation of functional symptoms, as well as a distal motor neuropathy, hypertension, reproductive health effects, renal disease, as well as, rarely now, lead lines on the gums. Lead lines are now rare due to the rareness of overexposure to lead. This slide was lent as a courtesy by Dr. Mike Levine, who works with workers who recreate colonial manufacturing processes and who do have continued exposure to inorganic lead. So on this photo you can see the bluish discoloration of the gum line. As we've discussed, the health effects of exposure to inorganic lead affect multiple body systems. In contrast, the health effects of alkyl or organic lead are mainly focused on the central nervous system and gastrointestinal system, and I've listed them here on this slide. Exposure to alkyl or organic lead might occur in some industrial applications, and there are still some small amounts of organic lead in gasoline, although overall alkyl or organic lead, in use in the past as an anti-knock agent, has been prohibited in the United States as well as overseas. Multiple toxic agents have been associated with development of a resting tremor. Some, like the neuroleptic drugs or lithium, are medications. Some, like carbon disulfide, which would be used or elaborated in the process shown on the right, which is an extrusion process making a cellulose fiber or a rayon fiber. Carbon monoxide and cyanide, which are gases, manganese, which is a heavy metal, and MPTP, which is a substance that was inadvertently created when some folks were trying to synthesize the drug Demerol. These folks ended up exhibiting symptoms that looked like Parkinson's disease, although they did not have the classic cause of deterioration of the substantia nigra. Their symptoms were thought to be associated to exposure to this substance, MPTP, and these cases provided an experimental model for the development of Parkinsonism. While Parkinson's disease is caused by a deficiency in the cells of the substantia nigra in the brain, Parkinsonism refers to a constellation of symptoms and impairments that are like those found in Parkinson's disease. Parkinsonism can be caused by exposure to chemical toxicants as well as MPTP, which was discovered in attempts to make synthetic Demerol. On this slide, I've listed and displayed a picture illustrating some of the classic features of Parkinsonism, as well as some of the agents that are associated with development of these symptoms. One of these, carbon disulfide, has been reviewed before, and again, is a toxicant that is associated with health effects in many organ systems. On this slide, I've summarized some additional neurotoxicants, as well as their corresponding health effects, highlighting unusual features of each to aid in your memory. Chlordecone, or Kepone, is an organochlorine insecticide that's no longer in use. An unusual health effect associated with chlordecone is opsoclonus, or unusual eye movements. Methanol has been associated with development of blindness. Several agents, including some we've discussed, like carbon disulfide and mercury, are associated with development of psychosis. Dimethylaminopropionitrile is associated with development of bladder neuropathy. And chronic toxic encephalopathy, that we discussed in the start of this presentation with respect to solvents, has also been associated with exposure to lead, as well as carbon disulfide. It's important to recognize that sleep disorders can have a serious potential impact on situational awareness and, thus, fitness for duty for safety-sensitive positions. Narcolepsy is a brain disorder that involves poor control of sleep-wake cycles. Signs and symptoms include periods of extreme daytime sleepiness and sudden sleep attacks that an employee cannot prevent. These can last a few seconds to several minutes. This is distinctly different from nodding off, as you might do during, say, an extended board review course. Cataplexy involves a sudden loss of muscle tone in addition to sleep onset. And thus, it can be confused with a seizure disorder. Cataplexy results from EDS or excessive daytime sleepiness. And so it's very important to clarify whether a person has a seizure disorder or a sleep disorder if they are displaying this type of behavior. Obstructive sleep apnea, abbreviated OSA, is a pulmonary disorder that can significantly impact an employee's ability to maintain situational awareness during the daytime. The American Thoracic Society and the American Association of Sleep Medicine estimate that between 3% to 7% of adults in the US suffer from some form of obstructive sleep apnea. Symptoms, again, include excessive daytime sleepiness and might include snoring or noisy breathing at night. Objectively, when examining a patient, we can note physical obstruction of the airway by the tongue or glottal structures when sleeping or in a sleep position. Obesity is a significant risk factor for development of obstructive sleep apnea. But you do not need to be obese to have obstructive sleep apnea. Diagnosis is made via a sleep study or a polysomnogram. And that results in calculation of an apnea hypopnea index, or AHI. An AHI of 5 to 15 is consistent with mild sleep apnea. An AHI of 15 to 29 is consistent with moderate sleep apnea. And an AHI of greater than 30 is consistent with severe sleep apnea. For an AHI of 15 or greater, the American Association of Sleep Medicine guideline recommends treatment. However, those diagnosed with mild sleep apnea who are experiencing excessive daytime sleepiness also would need treatment. Treatment consists of continuous positive airway pressure or CPAP, weight loss and surgery, and also may include use of an oral device for those with mild obstructive sleep apnea. During our discussion, we've talked about some of the health effects of exposure to agents, including solvents and heavy metals, that affect the cognitive function of the central nervous system, as well as the sensory motor function of the peripheral nervous system. On the next few slides, we'll talk about clinical objective test methods to assess the extent of health effects and or decrements in function related to these exposures and their corresponding disorders. On this slide, I've excerpted a table from the reference paper. You can certainly look at the full paper that is published in the journal Neurology that discusses the use of particular neuropsychological tests. Some of the more common ones are summarized on this slide. And some of them have also been imported into computer applications for use in clinics. Some of them test different functions. And so on the left-hand side of the slide, I've listed the particular central nervous system and cognitive functions that are assessed. And then on the right-hand side of the slide, I've listed the corresponding tests. Clinical objective testing tools to investigate the possible extent of peripheral nervous system disorders include nerve conduction studies and electromyography. On this slide, we'll talk about nerve conduction studies. First, a few parameters and definitions. To study motor nerves, we apply current to produce a compound muscle action potential. For sensory nerves, we apply a current to produce a sensory nerve action potential. In general, the amplitude of the signal received reflects the number of conducting fibers. And this would be reduced in loss of axon fibers. You can think about this in terms of an electrical cord comprised of a number of wires with a sheath. If you lose the wires, then you would not have a very strong signal conducted. The latency or potential speed or delay of a signal as measured from stimulus to a response would be prolonged in demyelination. So using our electrical cord example, the myelin is analogous to the plastic or other covering that contains the wires that make up the electrical cord. We also measure the duration of the response to a stimulus. And we're looking also at the conduction velocity. So this is related to the latency, right? If we have a delay in response, that could be related to demyelination. Also, a reduction in the speed of the response itself would be related to a demyelinating disorder. Additional parameters that can be measured in some nerve conduction studies, including late responses, specifically the F wave and the H or Hoffman wave. I've included the definitions of these waves on the slide for your review. It's important to note for our purposes that in demyelinating disorders, both the F and H waves are significantly prolonged or absent due to impaired conduction of nerve impulses. Whereas nerve conduction studies are used to investigate sensory or motor neuropathies, electromyography is used to investigate muscle weakness. Thus, combined with nerve conduction studies, electromyography can differentiate between a nerve problem and a muscle problem. Changes in the EMG or electromyograph signal correspond to changes in the number and the size of muscle fibers that are innervated by a single motor neuron. In nerve or neurogenic lesions, we would see polyphasic large motor units from a healthy muscle with a reduced recruitment pattern. In other words, if you have a signal that is faulty, then the response to the signal in the muscle would be reduced, but all the muscle fibers, which are healthy, would be responding. In a muscle or myopathic lesion, the signal is fine, but the recipient, the muscle, is faulty. So you might have a polyphasic response from the healthier cells with an early recruitment pattern. If you'd like to learn more about electromyography, I've included a reference to review in the Australian Family Physician. We'll now transition into a discussion of some hematologic disorders associated with occupational or environmental exposures, as well as a discussion of agents associated with development of cancers. Let's transition into this section with a review question. We have a 40-year-old home contractor presenting to your clinic with headaches, new onset hypertension, and anemia. Which of the following would be associated with this symptom constellation? A, use of paint thinner on furniture, B, removal of old insulation in an attic, C, sanding painted wood floors, or D, digging trenches for new pipes? This question serves as a good review of some of the topics that we've already reviewed and some that you will review as we go through this course, and is a typical type of question requiring you to understand the exposures that are associated with a given occupational activity or task. Going through the choices, choice A, use of paint thinner on furniture, would be most consistent with exposure to solvents. Choice B, removing old insulation, would be most consistent with exposure to asbestos fibers. Choice C, sanding painted wood floors, is a classic exposure scenario for exposure to inorganic lead dust. And this is the correct answer to this review question. Choice D, digging trenches for new pipes, is kind of a nonspecific activity that could be related to exposure to a variety of potential toxicants. But again, choice C is the best answer, given what we're going to be discussing about the effects of inorganic lead on the employee's health. Let's review one more case question. In this case, we have a 35-year-old pipe fitter whose labs reveal a hemoglobin of 8.5, a reticulocyte count of 0.5%, a white blood cell count of 400, and platelets of 19,000. So from this information, you hopefully have concluded that all of these indices are quite low. And the appropriate description for this syndrome would be a pancytopenia. It's not a thrombocytopenia, because not only the platelets are low, and it's not an anemia, because not only the hemoglobin is low. Pancytopenia can be due to exposure, classically, to benzene. So A, benzene, is the correct answer to this slide. Both lead and iron deficiency would be associated with an anemia. But again, in this case, all of the indices are low, and we have a pancytopenia. Arsine gas would be associated with hemolysis, but again, we have all of our indices low, associating a problem with the bone marrow, or a pancytopenia. So again, choice A, benzene, is the correct answer to this question. Benzene is a widely used solvent found in industries including rubber manufacturing and petroleum refining. Gasoline contains a small percentage of benzene, and due to its vapor pressure, exposure is most likely via inhalation. 20% to 50% of inhaled benzene is excreted via exhalation. As we discussed, benzene is one of the exceptions to the general principle that most solvents are deactivated by the cytochrome system in the liver. Toxic metabolites of benzene that are activated by liver metabolism include hydroquinone and benzoquinone. In order to understand the toxicity of these benzene metabolites on our hematologic system, it's important to understand how they work in the body. These metabolites destroy stem cells. So understanding that stem cells are the parents of all of our hematologic cell lines, it logically follows that a pancytopenia would be one of the health effects resulting from benzene toxicity. One of the metabolites, 1,4-benzoquinone, is hemotoxic and as well as genotoxic, binding to DNA, and has been associated with specific alterations in chromosomes leading to acute myelogenous leukemia. The DNA toxicity of benzene's metabolites increases the risk of blood dyscrasias, including aplastic anemia, the blood cancers, as well as other blood dyscrasias, including myelofibrosis, myeloid metaplasia, and paroxysmal nocturnal hemoglobinuria. It's important to note that although benzene exposure is associated with an increased risk of specific cancers, prior aplastic anemia or leukopenia are not required for benzene associated development of the blood cancers or the leukemias. Again, this is not a necessary continuum. The first health effect related to benzene exposure might be a diagnosis of a blood cancer in someone who has never had a diagnosis of aplastic anemia. While normal healthy bone marrow would appear red and full of cells, the bone marrow in the histology slide that is included on the upper right corner of this slide appears pale and you see really only a reticulated structure with very little red color in it. This is a bone marrow that is consistent with aplastic anemia in which there is a pancytopenia and all cell lines are decreased or absent. White blood cell counts in people with aplastic anemia are typically less than 500, platelets less than 20,000, reticulate counts less than 1%. And before we had bone marrow transplants, there was up to a 50% fatality rate for people who suffered from aplastic anemia. Although, again, this is not a necessary continuum, a person who has aplastic anemia may then go on to develop a blood dyscrasia and then a blood cancer such as leukemia. On this slide, I've summarized some other chemical exposures as well as the physical hazard of ionizing radiation and some medications that have been associated with the development of aplastic anemia. Understanding that ionizing radiation exposure causes physical damage to the DNA and understanding that chemotherapy agents are targeting rapidly developing cells, we can understand why exposure to these agents would result in a higher risk of development of aplastic anemia due to destruction of the bone marrow. I've included the diagram on the right not to scare you back to high school or college chemistry, but to remind you about the heme synthetic pathway to promote a better understanding of the effects of lead on this pathway. Lead binds to sulfhydryl groups and inhibits key enzymes in the heme synthetic pathway. These include delta-immunolevulinic acid dehydratase, ferroculatase, and uroporfin porphyrinogen decarboxylase. These result in a buildup of the precursors for these enzymes, including an increase in protoporphyrin 9, which binds with zinc to result in an increased level of zinc protoporphyrin, which as you recall is one of the indicators that we can monitor in workers occupationally exposed to lead. As exposure to lead impairs the heme synthetic pathway, it makes sense that anemia is one of the findings in workers exposed to occupational or environmental lead. On histology slides such as the one included on this slide, we see evidence of basophilic stippling. This is due to deposits of RNA, which are left as lead has inhibited the function of the nucleotidase enzyme that would normally break down this RNA. In addition, we would see elevated blood lead levels as well as elevated zinc protoporphyrin or free erythrocyte protoporphyrin. On x-rays of children, we may also see lead lines from lead deposits in the bones. Although x-ray fluorescence of adult bones is useful as a research and surveillance tool indicative of chronic body burden of inorganic lead, it is not useful as routine medical surveillance and is not part of the requirements of the OSHA lead standard. On this slide, I've summarized the expected lead level in adults, which would correspond with an increased risk of the health effects listed. For those of you who are preparing to take the core or preventive medicine section of the board exam, please note that the level of concern for childhood lead medical surveillance changed in 2012 from 10 to 5 micrograms per deciliter. This slide focuses on health effects in adults. You can see that at relatively low blood lead levels, we begin to see enzyme inhibition with progressively more severe health effects as lead levels get higher. It is rare to see frank peripheral neuropathy in acute lead exposure or encephalopathy in acute lead exposure now in the United States and some developed countries due to the implementation of occupational safety and health controls and the elimination of lead from gasoline. Currently, we might see these marked lead levels in workers with chronic lifetime lead exposure, especially those who have been working overseas. The porphyrias can be due to a genetic deficiency of enzymes, which leads to a buildup of heme precursors. Symptoms include photosensitivity as well as abdominal colic and a sensory motor neuropathy. In addition to genetic porphyrias, porphyrias can be acquired, also called the toxic porphyrias, after exposure to different toxicants. These are associated with liver injury and impaired hepatic synthesis of heme and have the same symptoms as the genetic porphyrias. On this slide, I've listed some of the agents that are associated with development of the toxic porphyrias for your review. As I mentioned during our earlier discussion of the health effects of exposure to inorganic arsenic, inhalation of arsine gas can result in the development of acute hemolysis and hemolytic anemia. Stivine gas, which results from the combination of antimony and ammonia, can also result in hemolytic anemia. Stivine gas is used in the process of manufacturing semiconductors. Inorganic lead exposure can rarely result in hemolytic anemia. And copper sulfate, which is a chemical as a root retardant, can be either accidentally or, unfortunately, purposefully ingested in a suicide attempt situation, leading to hemolytic anemia as well. Methemoglobin is formed when the normally ferrous iron in hemoglobin is transformed into ferric iron under oxidant stress. Many compounds, including the nitrates and nitrites, increase the risk of formation of methemoglobin in those who are exposed. Formation of methemoglobin results in a shift of the oxygen dissociation curve to the left, meaning that methemoglobin decreases the release of oxygen to the peripheral tissues. And it also increases the affinity of hemoglobin for oxygen. This situation results in a relative hypoxia. When methemoglobinemia is present, lab studies are consistent with hemolysis and anemia. In addition, on histology slides, such as the one shown on this slide, we see the presence of Heinz bodies, which consist of precipitated hemoglobin. Workers with glucose-6-phosphate dehydrogenase deficiency are at increased risk for formation of methemoglobin under oxidant stress. Treatment for methemoglobinemia includes removal from exposure, administration of supplemental oxygen, and in severe cases, administration of IV methylene blue. The myelodysplastic disorders are all characterized by poorly formed and non-functional blood cells. The myelodysplastic syndrome may lead to an acute leukemia or blood cancer. However, with respect to benzene, as we discussed, it is not necessary for a person to develop either an aplastic anemia or a myelodysplastic syndrome prior to being diagnosed with an acute leukemia or other blood cancer. We'll transition into our discussion of agents associated with increased risk of occupational cancers with a review question. A 59-year-old man is diagnosed with lung cancer. Related occupational exposures include A, bischloromethyl ether, B, aniline dyes, C, silica dust, or D, lead. The correct answers to this question are A and C. Both bischloromethyl ether and silica dust are associated with an increased risk for lung cancer. Aniline dyes are associated with an increased risk of bladder cancer. And although we have talked about many body systems that can be affected by occupational or environmental exposure to lead, lead has not been associated with an increased risk of any type of cancer. Up to half of all individuals will develop a cancer of some type during their lifetime. It's been estimated that between 2% and 8% of these cancers may be due to occupational exposure. Our current understanding of how cancers develop supports that cancers arise from development of a single abnormal cell. However, a cancer goes on to develop depends on several factors, including our inherent ability to repair damage to DNA, the presence of agents that inhibit or foster growth of a cancer, including those that might inhibit tumor suppressor genes, and the overall integrity of the individual's immune system. The International Agency for Research on Cancer, or IARC, periodically reviews scientific literature and other information and classifies agents into four categories listed on this slide. Category 1 agents are classified as human carcinogens, and these are agents for whom sufficient information on human carcinogenicity is known. Category 2 includes two subcategories. Agents in category 2a are categorized as probable human carcinogens, for which there is limited human data but sufficient animal data to support this classification. Category 2b, also known as possible human carcinogens, are those agents for whom both limited data on humans and animals have been reviewed. Those agents in category 3 are those for which insufficient data has been reviewed for classification as a carcinogen, and those agents in category 4 are those agents for whom sufficient data has been reviewed to support that these agents are not human carcinogens. On the next two slides, I've summarized some agents and their associated cancers. At the end of this presentation, I've provided two links to IARC publications that are useful as study aids. These two slides are not meant to be all-inclusive or exhaustive, and I also recommend that you consult other texts, including but not limited to the Ledoux textbook that John Meyer mentioned at the introductory lecture to this course. Again, this slide is the second of a series of two summarizing some occupational exposures or agents and cancers that have been associated with these exposures. Here's a question to review some of the information we've covered in this presentation thus far. Arsenic exposure is associated with which of the following? A, angiosarcoma of the liver, B, squamous cell carcinoma, C, peripheral neuropathy, or D, all of the above. So, so far in our discussion of neurotoxicants, occupational environmental carcinogens, and heavy metals, we've learned that arsenic exposure is associated with all of the above, including angiosarcoma of the liver, squamous cell carcinoma, and peripheral neuropathy. In addition, you can remember that vinyl chloride exposure is the other potential occupational exposure that is associated with the rare cancer, angiosarcoma of the liver. We'll end this part of our review with a discussion of several selected carcinogens. Formaldehyde has many exposure sources. It's widely used as a preservative and can be found as a resin as well as in particle board. And many of us were exposed to some form of formaldehyde during our medical training in Kadour labs. OSHA has promulgated a formaldehyde standard. And one unique thing about this standard is that it is questionnaire based. Specifically, workers are required to complete a questionnaire. And then that questionnaire is reviewed by a healthcare provider who then determines if any additional testing or evaluation is needed based upon the employee's responses. Formaldehyde causes irritation of the upper and lower respiratory tract. And it makes sense that it has also been associated with allergic dermatitis and asthma. Notably, formaldehyde has been categorized by IARC as a group one or known human carcinogen with an increased risk of nasopharyngeal cancer in those exposed. PAHs or polycyclic aromatic hydrocarbons are a group of compounds that are elaborated from combustion of fossil fuels such as asphalt and coal. Collectively, PAHs have been classified as carcinogens, with target organs being the lung, kidney, bladder, skin. And as well, PAHs were the responsible agent related to the development of scrotal cancer in chimney sweeps, one of our first historical recognitions of an occupational cancer. The OSHA standard for coke oven workers covers workers exposed to PAHs and requires a history, a physical exam of the skin. Objective testing is listed here. And importantly, urine cytology, as well as a urinalysis, which makes sense since the bladder is one of the target organs. It also follows that chest x-rays with a B reading and pulmonary function tests are required due to the effects of PAHs on the lungs. Workers can be exposed to vinyl chloride monomer during production of polyvinyl chloride, as well as in the plastics industry. Exposure is mainly by inhalation and the acute health effects on the central nervous system are similar to those we discussed for solvents. Chronic health effects include fibrosis of the liver and the relatively unusual cancer, hepatic angiosarcoma. You've learned during this discussion that arsenic is also a cause of this rare cancer. Those exposed to vinyl chloride monomer are also at risk of developing acroosteolysis, which is shown in the radiograph on the right side of this slide. You can see by looking at the distal phalanges that there is some lack of bone consistent with osteolysis. The skin of this person would also likely exhibit some scleroderma-like skin changes, and the person affected would also likely experience Raynaud's phenomenon. The OSHA standard for those exposed to vinyl chloride requires liver function testing, and the frequency of testing is based upon the length of an employee's exposure. And this is consistent with the carcinogenicity of vinyl chloride in that the latency for development of cancer would be not less than 10 years in general. So it makes sense that more frequent screening every six months is required for workers with 10 years of exposure. In addition to the Ledoux textbook and other references mentioned by Dr. Meyer at the beginning of our course, these references on this slide are useful in reviewing for the board exam and for your general knowledge in occupational and environmental medicine. I did verify that they were active earlier this year, and I hope that they are useful as study aids or review aids for you.

neurotoxicology

hematologic toxicology

occupational cancer

toxic agents

exposure routes

solvents

lead

benzene

carcinogens

formaldehyde

healthcare providers