Toxicology - Medical School Crash Course

TOXICOLOGY

Medical School Crash Course

PREFACE

This course is designed for the provider to develop a basic understanding of toxicology. The body can be exposed to a variety of toxins through skin exposure, breathing in toxic substances, and ingesting things that are toxic to them. There are medications that lead to toxicity in excessive amounts and many illicit drugs are actually toxic to the body. There are many environmental toxins people can be exposed to in the environment. Everyone is exposed to some extent to the adverse effects of things like ionizing radiation, workplace toxins, and toxic substances in the environment. At the end of this course, you will understand how and why these things can adversely affect the body.

The focus of chapter one in the course is to discuss the chemistry and toxicity of different inhaled hydrocarbons, including toluene and benzene both of which are used as solvents in many industries. The inhalation of these substances is a public health crisis because they are found in commonplace items that young people inhale as part of “huffing”. Vinyl chloride is a gas used to make polyvinyl chloride in certain industries and is also toxic at high enough doses. Finally, phenol can be inhaled or ingested and has toxic properties when enough of it is taken in by humans.

Chapter two in the course is about drugs that have known hepatotoxicity and nephrotoxicity. The most commonly used hepatotoxic drug is acetaminophen, which can lead to acute or chronic liver toxicity. There are, on the other hand, many nephrotoxic drugs. The basics of drugs that are nephrotoxic are covered in general, outlining the different drugs and medications that can adversely affect the kidneys. Specific drugs that have known nephrotoxicity include things like lithium, cisplatin, cyclosporine, aminoglycosides, amphotericin B, and NSAIDs. How these drugs are nephrotoxic as well as how toxicities are treated are a part of this chapter.

The main topic of chapter three is heavy metal toxicity. There are several heavy metals that are discussed, including lead toxicity and mercury toxicity, which are relatively common. Toxicity can also exist with arsenic, cadmium, and chromium to a lesser degree. Both children and adults can be exposed to these heavy metals, with effects on

different body areas. The main treatments for heavy metal toxicity of different types are chelation and avoidance of further exposure to the toxic substance.

Chapter four in the course introduces the topic of neurotoxins, which can affect the central nervous system and the peripheral nervous system. The biochemistry of neurotoxins is covered, including the biochemistry of some things talked about in prior chapters as they apply to neurochemistry. Some known neurotoxins, such as shellfish toxins and tetrodotoxin, which comes from pufferfish, are discussed as well as curare, which is a peripheral nervous system neurotoxin that acts on the neuromuscular junction.

Chapter five looks into carcinogenesis and the mechanisms of carcinogenesis. There are many human carcinogens that are classified as being likely or probable carcinogens in the environment. The labeling of something as being carcinogenic depends on which organization is studying these environmental agents. The chapter also covers the different molecular mechanisms by which a given substance is carcinogenic. Tobacco is a common substance that contains many carcinogens within the smoke and tobacco product so this is looked at as a model of something that leads to many different types of cancer in humans.

The focus of chapter six in the course is teratogenesis and teratogens, which are substances, exposures, and infections that can cause birth defects. These include many medications that, if used during certain points in pregnancy, can cause injury or death to the fetus. There are certain drugs that stand out, such as isotretinoin, which is marketed as Accutane, and thalidomide, which led to numerous birth defects in the 1960s. The different categories used to determine risk in pregnancy and lactation are covered in this chapter as well, as these categories can be used by physicians and patients to decide which medications are safe or not safe to take in pregnancy.

Chapter seven in the course discusses the effects of chemicals in the environment that are used to treat things like weeds, agricultural pests, rodents, and even pests that infect humans, like head and body lice. These are chemicals that can be found in residual amounts on agricultural products and other foods that are eaten by the consumer. Individuals who work with these products are also particularly prone to the chemical

toxicity seen with them. The effects of organochlorides like Lindane, used to treat head and body lice, is also covered in this chapter.

The topics included in chapter eight include fungal exposures and the different foodborne toxins that can be gotten from intake of organisms in foods that release toxins. Aflatoxins come from fungal contamination by certain foods, causing various clinical syndromes. Botulism is a severe but uncommon illness that is found when foods are ineffectively preserved. For various reasons, humans can also get Clostridium difficile infections from contaminated food, leading to a toxic gastrointestinal disease. The same is true of some strains of Escherichia coli that produce toxins. Finally, aromatic amines can come from meat, leading to carcinogenicity in humans.

The focus of chapter nine in the course is alcohol toxicity. While in most cases, this refers to ethanol poisoning and ethanol toxicity, individuals can become toxic and at lower concentrations of alcohol with both methanol poisoning and isopropyl alcohol poisoning. Both of these can be toxic at lower concentrations than is seen with ethanol toxicity. Ethylene glycol is another “toxic alcohol” that is seen mostly with accidental ingestion of the substance. The presentation and management of these toxicities are explained in this chapter.

Chapter ten in the course introduces the topic of the toxicity of ionizing radiation in adults and children. Radiation exposure can be acute, as is seen in wartime situations with atomic bomb blasts or when there is a nuclear disaster. Another type of radiation exposure is more chronic and can be seen in situations like radon exposure in certain homes. Radiation can cause a variety of cancerous and non cancerous changes in the body.

The focus of chapter eleven is the toxicity of certain illicit drugs. The toxicity of cocaine is covered, including what happens when a person takes in too much of the drug for whatever reason. Opiate toxicity is increasingly important as well as there has been a vast increase in the number of deaths due to opiates in recent years. Finally, the toxicity of methamphetamines is covered as this is also a common drug of abuse, carrying the risk of death when taken in high doses either intentionally or accidentally.

The subject of chapter twelve in the course is bioterrorism and the toxicological implications of this global problem. We discuss bioterrorism in general, including how to recognize it, what the emergency response should be, and the management of possible agents of terrorism. Some things used in terrorist attacks include anthrax, which is covered in this chapter, and ricin a toxin that has terroristic potential. There is a risk also of terrorism that makes use of the different hemorrhagic viral infections, such as Ebola virus, which is also discussed in this chapter.

Chapter thirteen in the course covers the basics of occupational exposures. There are many things a worker can be exposed to as part of their job, most of them related to the inhalational exposure to various things in the work environment. Exposures can lead to occupational asthma, which can happen in individuals who do not normally have asthma. Other major lung exposures include those to asbestos, silica dust, and beryllium. While personal protective equipment can be used, it may not totally prevent exposure. Hypersensitivity pneumonitis is another lung disease also related to exposure to certain things in the workplace.

The focus of chapter fourteen is animal and plant toxins. There is significant toxicity associated with snake bites that depend on the type of snake that bites the affected individual. There is envenomation from jellyfish stings as from other marine animals. Ciguatera fish poisoning is a specific marine poisoning covered in this chapter. Many different plants can be ingested and are causative of toxicity in children who ingest them. People of all ages can consume harmful mushrooms that can lead to toxicity as well.

Chapter fifteen in the course discusses different forms of endocrine disrupters. Endocrine disrupters basically mean estrogen disrupters, which are chemicals that mimic or inhibit estrogen in the body. These can be found in several sources. Plastics are a major source of endocrine disrupters, containing both phthalates and bisphenol A, also referred to as BPA. There are foods that contain phytoestrogens. The chapter talks about both the theoretical pros and possible cons of taking in these types of foods as well as what they do chemically to mimic estrogen.

Chapter sixteen offers a wide range of topics related to water and air pollution. It focuses mainly on the water pollution that faces the earth and on what things can contribute to the pollution of water. When it comes to air pollution, the chapter talks mainly about things that can be toxic about indoor air pollution. Sick building syndrome is a unique situation in which people have toxic effects because of indoor air quality. Cyanide poisoning mainly comes from indoor domestic fires. Carbon monoxide poisoning is also covered, which is also seen indoors and can be lethal when inhaled for a prolonged period of time or in high doses.

CHAPTER ONE: HYDROCARBONS, SOLVENTS AND VAPORS

The focus of this first chapter is to discuss the chemistry and toxicity of different inhaled hydrocarbons, including toluene and benzene both of which are used as solvents in many industries. The inhalation of these substances is a public health crisis because they are found in commonplace items that young people inhale as part of “huffing”. Vinyl chloride is a gas used to make polyvinyl chloride in certain industries and is also toxic at high enough doses. Finally, phenol can be inhaled or ingested and has toxic properties when enough of it is taken in by humans.

TOLUENE

Toluene is also referred to as methylbenzene. It is one of several aromatic hydrocarbons, used frequently as an industrial solvent in the making of certain chemicals, paints, rubber, and pharmaceuticals. It can be found in acrylic paints, gasoline, lacquers, varnishes, adhesives, glues, paint thinners, and airplane glue. It has a slightly sweet odor and is a highly volatile liquid. Routes of absorption can be inhalation (the most common means of absorption), transdermal absorption, and ingestion. Figure 1 shows the chemical structure of toluene:

Toluene abuse is common among young people who engage in “huffing”, “bagging” or glue sniffing. Individuals will soak a rage with a toluene containing substance and will place it over their nose and mouth. There will be a nearly immediate sensation of a buzz, high, or euphoria. Individuals who engage in bagging will also breathe in their exhaled air, resulting in hypoxia and hypercarbia, which adds to the feeling of disorientation.

According to OSHA (The Occupational Safety and Health Administration), there is an acceptable Permissible Exposure Limit (or PEL) of 200 parts per million. This is a time weighted exposure limit for an eight hour day. Levels of greater than 500 parts per million are very dangerous. Some people will be more sensitive to toluene and will have occupational asthma at acceptable levels. It’s the duration of exposure and not the actual level that can lead to asthmatic symptoms.

Because toluene is highly lipophilic, it can easily cross the blood brain barrier, accounting for its effects on the central nervous system. It binds to ion channels, inhibiting the NMDA (N Methyl D aspartic acid) type of glutamate channels. The overall effect is to decrease the metabolic function of the brain, in particular, the thalamus, pons, and hippocampus. It will increase the release of dopamine, particularly in areas of the brain that go to the cortex and limbic system. White matter toxicity called solvent vapor/toluene leukoencephalopathy involves permanent brain changes. Acute intoxication occurring when inhalation of toluene happens involves delusions, tinnitus, dizziness, headache, euphoria, hallucinations, ataxia, seizures, stupor, and death. Patients who overuse the substance over a long period of time can have gait and movement disturbances, neuropathy, decreased cognitive abilities, blindness, hearing loss, neuropsychosis, and tinnitus.

Toluene also has negative effects on the heart and lungs. A condition called “sudden sniffing death” involves a cardiac arrhythmia when inhaling toluene. There can be aspiration pneumonitis, acute lung injury, bronchospasm, and asphyxia. Toluene exposure can lead to nausea, vomiting, upper GI bleeding, and hepatotoxicity. A toxic hepatitis is possible. The kidneys are frequently damaged, particularly with renal tubular acidosis and renal failure. Lymphocytosis and aplastic anemia are possible as are skin changes, including chemical burns and dermatitis.

The muscle cells are directly affected by toluene toxicity. Patients will have rhabdomyolysis and increased levels of myoglobin in the blood. Hypokalemia stemming from renal tubular acidosis can lead to severe muscle weakness. Bone resorption and inhibition of bone formation is another musculoskeletal effect.

A major problem seen in toluene toxicity is sudden death. Most of these happen because of a cardiac arrhythmia; however, people can easily die from respiratory depression, anoxia, vagal simulation, asphyxia, aspiration, and traumatic death. Being startled, exercise, or sexual activity can release catecholamines, leading to arrhythmias. Fright and running are precursors to death.

Besides people intentionally using toluene, industrial workers can be at risk for this type of toxicity. Chemists, textile workers, painters, refinery workers, and workers in the rubber industry can have unacceptable exposures to toluene. Certain hobbyists will have an increased risk of exposure if not working in well ventilated areas. People who use alcohol will have decreased metabolism of toluene and increased levels of the toxin. Cocaine or other sympathomimetics can increase the chances of fatal arrhythmias.

Toluene toxicity is treated at the scene with supplemental oxygen and ventilatory support. Mouth to mouth is not recommended because the person overcome will expire toluene, which can affect the rescuer. Clothing should be removed and skin areas that are affected need irrigation. Mucus membranes, eye, and skin irrigation may be necessary and intubation may need to be undertaken. Propranolol and esmolol can be used to treat ventricular arrhythmias.

Patients may need fluid boluses to maintain urinary output. Vasopressors should be used with caution if they are sympathomimetic as this can lead to increased arrhythmia risk. Sodium bicarbonate may be necessary in severe acidosis; ions like calcium, potassium, and phosphorus need to be replaced if low. If the substance was ingested, induction of vomiting is not recommended as this can lead to aspiration pneumonitis; however, an NG lavage can be applied to decontaminate the GI tract.

STYRENE

Styrene is a thick, flammable liquid used to make products like plastic, rubber, pipes, fiberglass, insulation, food containers, carpet backing and automobile parts. It is a known carcinogen and is used to make polystyrene a part of plastic, including disposable containers and cups. The primary route of exposure is through indoor inhalation; however, it can be gotten in the system through food and water ingestion, skin contact, and outdoor air pollution. Tobacco smoke contains styrene. In most settings, the level is less than 1 part per billion, except in the plastic industry, where levels can be seen at about 100 parts per million.

The studies on styrene and cancer have been done or workers in the plastics industry, the styrene polymer industry, and the rubber industry. Most exposures happen in the plastics industry. Styrene is used in the rubber industry along with butadiene, which is itself a carcinogen so it can be difficult to separate the effects of each toxin separately. The most common cancer associated with styrene exposure is lymphohematopoietic cancer. For exposures around 1 part per million, the major associated cancer is leukemia. Other less commonly seen cancers include non Hodgkin lymphoma and Hodgkin lymphoma. Pancreatic cancer risk is statically higher in styrene exposure as are esophageal cancer, breast cancer, lung cancer, stomach cancer, cervix, urinary tract, larynx, and prostate cancer.

HYDROCARBONS

Besides toluene, any of the hydrocarbons can be inhaled in patients who have inhalant abuse. This is the second most widely abused illicit drug. It can lead to CNS depression or sudden cardiac death. Hydrocarbons are found in solvents, glues, gasoline, paints, and lighter fluid. Any aerosolized product contains hydrocarbons, which are sniffed, bagged, or huffed. It is a problem particularly seen in young children. Most of the time, these things are inhaled or ingested but a few people will inject it as part of a suicidal act. Figure 2 shows the structure of some simple hydrocarbons:

The mechanism of action of these hydrocarbons on the system is not completely known. Some believe that they slow the ion channels in axons generally, while others think that GABA receptor potentiation occurs because of cross tolerance between toluene, ethanol, benzodiazepines, and barbiturates. Chronic abusers will inhale hydrocarbons up to 4 times or more per day. Withdrawal symptoms are rare but tolerance and physical dependence are possible.

The two main systems affected are the CNS and the cardiopulmonary system. These toxins will cross the blood brain barrier because they are lipid soluble, reaching a peak level in the blood after 15 30 minutes. The main symptoms are euphoria, disinhibition, confusion, and disorientation. There will be gait disturbances, hallucinations, CNS depression, slurred speech, drowsiness, and sleep.

Hydrocarbons can sensitize the heart muscle to exogenous and endogenous catecholamines so that, when the person is startled, there is a risk of ventricular arrhythmias and sudden death. Excess catecholamine concentrations can also lead to coronary artery spasm and coronary thrombus formation, but this is less common. Patients can also develop asphyxia, aspiration pneumonia, or trauma-related injuries from hydrocarbon intake.

Renal tubular acidosis will lead to hypokalemia and hyperchloremia. Fluorinated hydrocarbon intake can lead to tracheal burns, esophageal burns, and facial injuries. Bone marrow damage is possible, leading to aplastic anemia and leukemia (particularly

from benzene). Toxic hepatitis comes from toluene exposure. These will cross the placental barrier, leading to microcephaly, hypoplastic midface, palmar creases, and other facial anomalies. Infants have features similar to fetal alcohol syndrome.

Patients who abuse hydrocarbons over a long haul will have loss of white matter and other CNS problems, including optic neuropathy, deafness, and peripheral neuropathy. Lung problems include pulmonary hypertension, reduced diffusion of gases, and restrictive pulmonary disease. Pulmonary toxicity is possible with lung inflammation and bronchospasm.

Recreational abuse can lead to significant pulmonary and neurological complications that can be persistent after the abuse has stopped. It is a cause of death in up to 2 percent of all deaths in adolescent males. More than half of the deaths are from sudden sniffing death, while the remainder are due to suffocation, accidental trauma, and aspiration. Death can happen even after the first use of the substances. Chronic use leads to irreversible CNS changes, such as demyelination, Parkinson disease, psychiatric disorders, spasticity, and cognitive decline.

When dealing with a patient with possible hydrocarbon toxicity, there must be a high index of suspicion as few will admit to this abuse. The odor of kerosene or gasoline is possible; acutely intoxicated individuals will have an altered mental status. Adolescents and children have the highest risk of this problem. Hydrocarbons are not screened for in toxicology screens. The exam may show a loud S2 from pulmonary hypertension and dark urine from rhabdomyolysis. Seizures and obtundation may be present. The affects of acute toxicity wear off after a few hours but chronic use will show a constellation of GI distress, muscle weakness, and neuropsychiatric symptoms.

As the labs will not show acute toxicity, labs should be drawn for evidence of rhabdomyolysis and acute tubular necrosis (hypokalemia, acidosis, hypercalcemia, and hypophosphatemia). The ECG will look for dysrhythmias and an echocardiogram may show cardiomyopathy and pulmonary hypertension. Restrictive lung disease is seen on pulmonary function testing. Neuropsychiatric testing will be abnormal. Neuromotor testing should be done when peripheral neuropathy is suspected.

VINYL CHLORIDE

Vinyl chloride is mainly used to make PVC plastics or “polyvinyl chloride” plastics and vinyl products. Acute exposure leads to CNS effects, such as headaches, drowsiness, and dizziness. Chronic exposure to vinyl chloride leads to liver damage with liver cancer a rare complication of vinyl chloride exposure. While most exposure comes out of the PVC industry, vinyl chloride is used to make some times of furniture, car upholstery, cable coatings, housewares, wall coverings, and car parts. Figure 3 shows the chemical structures of vinyl chloride and polyvinyl chloride:

Most exposures come from exhaust gases in factories that use vinyl chloride or in the air where vinyl chloride is stored. Air inside new cars contains vinyl chloride and drinking water may contain vinyl chloride if PVC pipe is used to transport water. Microbes break down trichloroethylene in ground water to make vinyl chloride in water sources and occupational exposure can happen when workers handle the chemical. It can be assessed in urine and tissues but this does not reliably predict the worker’s total exposure to the substance.

Besides headache, giddiness, and dizziness, the person will have irritation of the respiratory tract, renal and lung irritation, eye irritation, cardiac arrhythmias, and blood clotting inhibition. It takes long-term exposure to have liver damage and things like scleroderma like skin changes or Raynaud phenomenon. Peripheral neuropathy can be seen. It may affect male sexual performance and there is an increase in birth defects among women who have exposure while pregnant. Long term exposure can lead to angiosarcoma of the liver, which is otherwise rare in non exposed individuals.

PHENOL

Phenol is an aromatic compound found naturally in the environment as well as in manufacturing. The most common route of exposure is through the skin, although it is found in mouthwashes, throat lozenges, and antiseptic lotions. People who live near coal powered or petroleum fueled facilities and people who live near incinerators have a high risk for phenol exposure. It is a part of automobile exhaust so high traffic areas will have phenol in the air. Smog will increase the phenol concentration in the air. It is found in drinking water, ground water, surface water, hazardous waste sites, and urban runoff. It filters rapidly through the soil. It degrades quickly in air but is found for longer in groundwater.

It has been studied in mice with equivocal effects on offspring except for decreased fetal weight. Studies in wood industry workers show a slight increase in respiratory cancers and Hodgkin disease, as well as other cancers. There is an increase in pheochromocytomas and blood cancers in rats exposed to low doses. Because the risk is low, it is a Group D human carcinogen, which means it is not classifiable. The main affects to health are hypersensitivity reactions, asthma, and chronic bronchitis with repeated exposure. It is mainly an irritant to the respiratory tract but it can increase the liver transaminases with no obvious liver damage.

SOLVENT NEUROTOXICITY

Solvent neurotoxicity is also referred to as chronic toxic encephalopathy (CTE) or “chronic painter’s disease”. It involves chronic solvent inhalation in painters and other workers who have unsteadiness, psychological disturbances, and headache. It is attributable to slow damage or accumulation of damage to the brain from solvents, which are by nature lipophilic.

CTE or chronic painter’s disease is a diagnosis of exclusion and is mainly a clinical diagnosis based on a history of chronic solvent exposure. Many of these individuals will improve after being removed from solvent exposure. MRI imaging can show decreased signaling in the basal ganglia but will not show brain atrophy. Psychological tests will show decreased ability to think clearly. These will be evident on psychometric testing. Solvents have an effect on working memory, processing speed, and attention. These is some evidence that some cognitive deficits do not entirely resolve themselves.

KEY TAKEAWAYS

• There are thousands of solvents that share lipophilicity so they cross the bloodbrain barrier.

• Toluene toxicity is often seen in teens who inhale fumes as part of recreational use.

• Hydrocarbons of all types can cause sudden death by sensitizing the heart to catecholamines, leading to an increase in ventricular dysrhythmias.

• Many solvents are carcinogens, leading to an increase in blood cancers and other cancers.

• Workers at risk for solvent toxicity include painters and those who work with fumes of all types.

• Vinyl chloride toxicity leads to hepatotoxicity and a risk of angiosarcoma of the liver.

• Some of the CNS effects of solvents is reversible after avoiding the exposure to the solvents.

1. What is considered the most common means of absorption of toluene?

a. Mucus membranes

b. Transdermal

c. Ingestion

d. Inhalation

Answer: d. While toluene can be taken into the body through many different ways, inhalation intentionally is the most common way it is absorbed.

2. What is considered the Permissible Exposure Limit or PEL of an inhaled toxin?

a. The highest acceptable concentration of an inhaled toxin.

b. The level above which the toxin is considered to be carcinogenic.

c. The permissible level weighted over an 8 hour workday.

d. The amount above which there will be symptoms of toxicity.

Answer: c. The PEL is established by OSHA as a permissible upper limit that has been weighted over an 8-hour day.

3. What musculoskeletal effect is not seen with toluene toxicity?

a. Muscle spasms

b. Myoglobinuria

c. Rhabdomyolysis

d. Muscle weakness

Answer: a. Each of these can be seen in toluene toxicity; however, muscle spasms are not typically seen. Instead, hypokalemia can lead to muscle weakness.

4. What is the most common cause of sudden death in individuals who abuse toluene?

a. Asphyxia

b. Respiratory failure

c. Bronchospasm

d. Cardiac arrhythmia

Answer: d. Cardiac arrhythmias can happen in toluene abusers because it directly affects the heart rhythm, making this the most common cause of toluene-related sudden death.

5. Which type of cancer is considered to be most linked to styrene use?

a. Lymphoma

b. Leukemia

c. Pancreatic cancer

d. Esophageal cancer

Answer: b. While each of these is a type of cancer that carries an increased risk because of styrene use, leukemia carries the greatest connection to this type of exposure.

6. What is the main way that hydrocarbons get into the system?

a. Inhalation

b. Ingestion

c. Through the skin

d. Intravenous

Answer: a. The vast majority of hydrocarbons are absorbed via inhalation in the act of sniffing, huffing, or bagging.

7. What is the most common cause of sudden coronary death after hydrocarbon intake?

a. Acute myocardial infarction

b. Coronary vasospasm

c. Hypotension

d. Ventricular fibrillation

Answer: d. Each of these can be a factor in hydrocarbon ingestion leading to sudden cardiac death; however, ventricular arrhythmias and ventricular fibrillation after coronary sensitization to catecholamines is the major cause of death.

8. Patients with hydrocarbon intake will have renal tubular acidosis. What electrolyte abnormality comes out of this?

a. Hyponatremia

b. Hypokalemia

c. Hypocalcemia

d. Hyperkalemia

Answer: b. Hypokalemia and hyperchloremia come from renal tubular acidosis seen in renal injuries from hydrocarbon use.

9. What is not a feature of chronic abuse of hydrocarbons?

a. Asthma

b. GI distress

c. Muscle weakness

d. Neuropsychiatric symptoms

Answer: a. The constellation of GI distress, muscle weakness, and neuropsychiatric symptoms indicates the possibility of chronic abuse of hydrocarbons. Asthma in patients who do not already have asthma is not a symptom of this chronic problem.

10. Which system is most affected by vinyl chloride exposure over the long term?

a. Pulmonary Renal

c. Liver Musculoskeletal

Answer: c. Over the long term, the major risk of vinyl chloride exposure is liver toxicity and a rare form of liver cancer. This is listed as a class A carcinogen.