The list of substances, minerals, chemicals, toxins, etc. that are potentially toxic to humans is essentially endless, particularly if we remember Paracelsus' dictum, "sola dosis facit venenum," only the dose makes the poison. Virtually any substance can be toxic if taken in excess, even essential dietary elements. Iron is necessary for the formation of hemoglobin, and inadequate dietary intake leads to anemia but excess dietary intake can lead to hemosiderosis with resulting organ damage. Too much iron in the form of ferrous salts taken at one time can lead to acute poisoning. Is there a substance as innocuous as water? Yet water can be toxic if more is taken into the body than the kidneys can clear. Water intoxication can result from rapid excess ingestion as is sometimes seen in psychotic patients. It can also be an iatrogenic complication of therapy when nonelectrolyte solutions are given to patients with inappropriate antidiuretic hormone secretion or sterile water is used to flush operative sites. Water toxicity also occurs in marathon runners who over hydrate during their run. The excess water dilutes the intravascular volume and the resulting hyponatremia can be fatal.
Toxic chemical exposures, acute or chronic, can occur in the home, workplace, hospital, and the great outdoors. Some of these exposures are natural since numerous toxic substances are already present in the environment such as plant toxins or high arsenic concentrations in some groundwater. Others are man-made, both in regard to the origin of the toxic substance and the circumstances in which they are encountered, such as exposure to solvents in a chemical plant. Man-made substances also escape into the natural environment where they can become hazards as in the case of mercury released from industrial processes into the environment accumulating in the flesh of fish.
The determination that a particular substance is potentially toxic usually begins with the recognition of an apparent association between the use of or exposure to that substance and some malady. The association is confirmed by epidemiologic studies demonstrating that the malady is more common in exposed individuals than unexposed or in those with greater exposure than those with less. Animal models are utilized to support the association and to try to define toxic levels as well as set permissible levels for human exposure. This latter process involves exposing the animals to increasing quantities of the substance and determining the lowest dosage that produces an effect, the threshold dose, which is then used to define a permissible exposure level. Epidemiologic studies are complicated by many factors particularly those involving determining the actual exposure to the substance in questions in the subject groups and identifying an appropriate control group for comparison. Animal studies can be problematic since there are physiological differences between humans and other animals and it may be difficult to approximate conditions in the real world in the experimental setting. Many animal studies utilize exposures many times greater than what humans would experience. Particularly challenging are assessing the effects of long-term low concentration exposures given the long life of humans versus those of laboratory animals. It is in fact difficult to know what the long-term effects to low concentrations of many substances might be raising concerns about our ability to set permissible exposure limits to such substances.
Substances taken into the body are distributed within its various compartments, depending on the chemical properties of the substance. Water-soluble molecules like ethanol are distributed throughout the total body water while others that are more lipophilic move more easily into lipid-rich organs and tissues and are concentrated there. Inhaled particulate materials such as asbestos fibers lodge in the lungs where they do their damage. Most chemicals are metabolized to some degree and both metabolites and residual parent drug are cleared from the body through urine, bile, and/or feces. In some instances, the metabolite of the drug or chemical may be more toxic than the parent substance itself.
The misuse and/or abuse of drugs and medicines is a significant medical and legal problem in much of the world. Even appropriately used medications can have side effects or produce complications more serious than the conditions for which they were prescribed. It is well recognized that iatrogenic injury from medications is a major cause of morbidity and even mortality in both inpatient and outpatient settings.
Medications can cause injury in several ways. If an excess of medication is taken, an overdose can result. Drugs vary in their therapeutic index, essentially the difference between the dosage necessary to produce a therapeutic effect and what will be toxic. Drugs with low therapeutic indexes, like digoxin, have to be carefully monitored to prevent patient injury. Drugs with abuse potential are also likely to result in overdose since users may increase dosage to "improve" the pharmacologic effect they are seeking. Drug interactions can lead to overdoses. If one medication affects the metabolism or clearance of another, it can cause a buildup of the other with a resulting increase in its pharmacologic effects. The anticoagulant, warfarin, is an example of a medication whose effects can be augmented or diminished by numerous other medications as well as dietary substances. The simultaneous intake of multiple medications that have similar potentially toxic side effects sometimes leads to injury even when none of the medications is itself present in a toxic concentration. Sometimes the respiratory depressant effect of ethanol is the additional factor that changes an instance of abuse into a fatality.
Virtually all medications have side effects and some of these can be injurious. There are a variety of hypersensitivity reactions that can occur to medications ranging from minor to disabling or even fatal such as erythema multiforme (see Chapter 20). Erythema multiforme has been associated with a number of medications including barbiturates, penicillins, sulfonamides, and phenytoin. Acute allergic reactions from hives to frank anaphylaxis can occur. These usually involve an initial exposure with sensitization and then a reaction on rechallenge but anaphylaxis may occur without a history of an initial sensitizing exposure. Drugs with greater risk of such allergic reactions include penicillin. Iodinated radiocontrast materials may also cause anaphylaxis, though it is believed to be through a different mechanism as is that seen in individuals allergic to aspirin and other NSAIDs.
When medications are abused, they are often taken by individuals for whom they are not prescribed or, if prescribed, in quantities in excess of that which was prescribed. This may result in an overdose where the pharmacological effects of the drug are paramount. In a situation of abuse, moreover, not only may the quantities of the medication be supratherapeutic but also the route of administration inappropriate. For example, medication in pill form intended for oral ingestion may be ground up and injected intravenously (IV). With street or illicit substances, there are no standards of purity, and in addition to the drug/medication of interest, a variety of other substances may be, and usually are, present. While some may be inert, others are pharmacologically active and potentially toxic. It is also common for abusers to ingest multiple substances/medications at the same time further compounding the problem.
Abusers administering drugs to themselves and/or others put themselves at risk of a variety of diseases and complications beyond those related to the pharmacological effects of the drugs involved. The sharing of syringes and needles by IV drug users has been linked to the spread of infectious agents including hepatitis B and C, HIV, and malaria. Unclean needles and poor injection hygiene can lead to abscesses or cellulitis at injection sites. Right-sided endocarditis is seen in IV drugs abusers. The insoluble components of ground oral medications or materials used to "cut" street drugs become lodged in the microvasculature of the lungs where they induce a striking foreign body granulomatous reaction that can lead to right-sided heart failure, cor pulmonale. Inhalation of powdered cocaine can lead to nasal septal perforation.
Addiction to illicit drugs, legal medications, or alcohol is itself a serious problem with a significant cost to society in addition to the damage it does to the individuals involved and their families. The addict may be unable to function normally in society or support themselves and their families. Some resort to criminal acts and enterprises in order to maintain their habits. Those addicts living marginal existences are at risk of all the medical and nutritional problems associated with such a lifestyle. The production and distribution of illegal drugs is itself a criminal enterprise often associated with violence and users, particularly those that also deal drugs, may become victims. The classes of drugs most abused with the exception of ethanol are the narcotic analgesics, the stimulants, and the anxiolytics.
Narcotic analgesics: These include the medications extracted from the opium poppy, Papaver somniferum, mainly morphine and codeine. Heroin, diacetylmorphine, is not utilized clinically but is the main form of street opiate. A variety of synthetic opioids are also available and abused including hydrocodone, oxycodone, hydromorphone, oxymorphone, and others like fentanyl, propoxyphene, and methadone. These substances are respiratory depressants and taken in overdose may cause death via central respiratory depression. There is evidence that methadone and propoxyphene, a related compound, have cardiac effects as well. Generally apart from the serious consequences of addiction noted above and those of acute intoxication, these substances (in and of themselves) have little or no long-term/chronic toxicity.
Stimulants: Cocaine and amphetamines are the major drugs in this group. They are abused for their excitatory effects and their toxicity is felt to be primarily cardiac, with deaths resulting from lethal arrhythmias. They may also precipitate what is termed "excited delirium." This is not an overdose phenomenon but a drug-induced state characterized by bizarre, hyperactive, behavior often culminating in cardiovascular collapse and death. It often becomes particularly problematic when the bizarre behavior leads to law enforcement or bystander intervention and restraint of the victim. Following the collapse concerns are understandably raised that the fatal outcome was the consequence of traumatic asphyxia or physical injuries sustained in the course of the restraint.
Cocaine: It may be taken in the form of the hydrochloride salt, powder, or in a crystalline form, the free base. The latter is often referred to as "crack" because of the cracking noise it makes as it is heated prior to inhaling its vapors. It may be inhaled, snorted—intact, inhaled while it is heated—smoked, or injected. It is not ordinarily ingested except regrettably occasionally in an attempt to hide evidence with often lethal results. Cocaine and amphetamines raise heart rate, cardiac output, and blood pressure. Acute cerebrovascular hemorrhages have also been linked to their use. Cocaine may cause coronary artery spasm, and there is ample evidence linking chronic cocaine use to accelerated coronary atherosclerosis and cardiomyopathy.
Methamphetamine: It is often produced in-house "laboratories" from the over-the-counter precursor drug pseudoephedrine and has become a serious problem in many parts of the United States. This is not only because of its potent addictive potential and its pharmacologic effects but also because its clandestine production involves the use of explosive and corrosive chemicals. These "labs" are often located in homes and trailers where families including children may be living. Chronic methamphetamine users may exhibit evidence of premature aging and striking deterioration of their dentition. The latter has also been noted in cocaine abusers. Methamphetamine may be ingested orally, smoked or injected.
Anxiolytics: There are a large number of medications in this group many of which in addition to their antianxiety properties are utilized as sleep aids and muscle relaxants. The most widely prescribed are the benzodiazepines including alprazolam, diazepam, and chlordiazepoxide among others. They vary considerably in their fatal overdose potential but when, as is often the case, they are taken with in combination with other drugs or ethanol in a situation of abuse they may augment the respiratory depressant effects of the other agents.
Hallucinogens: Hallucinogens such as LSD are dangerous largely due to their mind-altering effects that may lead intoxicated individuals to seek out or unwittingly place themselves in situations where they may be physically harmed.
Inhalants: Another broad group of abused substances is the inhalants. Many of these are low molecular weight hydrocarbons that serve as the propellants in aerosol dispensers. Some inhalants are volatile solvents while others gases with various uses. The propellants include propane, butane, and isobutane as well as fluorinated hydrocarbons. Chlorofluorocarbons (CFCs) were once utilized as propellants but are now banned in most countries because of concerns about their effects on earth's ozone layer. Some CFCs, however, are still used as refrigerants and may be diverted for abuse in that form. When inhaled, "sniffed" or "huffed," for a high, these chemicals have the potential to destabilize the myocardium and consequently precipitate lethal cardiac arrhythmias. Volatile solvents like toluene in glue can have similar effects. Helium, nitrous oxide, and propane may also be sniffed. Asphyxiation may result if a volatile is utilized in a setting where it displaces the air that the abuser is breathing creating an oxygen-deficient atmosphere. This most commonly involves putting a plastic bag over the head to confine the fumes or utilizing a mask.
Acetaminophen: This commonly utilized analgesic and antipyretic deserves inclusion because of its potential for hepatotoxicity in overdose; as such it is the most common cause of acute liver failure in the United States and Great Britain. The drug came into wide usage as a replacement for aspirin in large part because of its much lower incidence of undesirable gastric side effects. Probably because of its availability, ingestion of large quantities in suicide attempts and "gestures" occurs frequently. In overdose, the liver becomes unable to conjugate the drug into the forms in which it is ordinarily excreted from the body in the urine. This leads to the formation of a toxic metabolite and cellular damage. Liver necrosis appears some days after the ingestion that histopathologically is characterized by bland central necrosis. This catastrophe can be averted by the administration of N-acetylcysteine within the first 8–10 hours of ingestion. This helps restore liver glutathione stores needed for the conjugation of the parent drug. Chronic alcohol abuse, fasting, and use of some anticonvulsant drugs can increase the potential for acetaminophen to reach toxic levels with heavy but otherwise nontoxic ingestions. Another important factor is the presence of acetaminophen in many different products. Individuals may be unaware of how many of the over-the-counter medications they are taking contain the drug and inadvertently attain toxic concentrations.
Alcohols: There are four alcohols commonly involved in human toxicity: methanol, ethanol, isopropanol, and ethylene glycol.
Methanol, methyl alcohol or wood alcohol, is most commonly used as a solvent. It is at times ingested, usually by alcoholics, as a substitute for ethanol. It is highly toxic and metabolized to formaldehyde and formic acid. It initially produces intoxication, and one of the potential complications of its use is blindness. It is metabolized by alcohol dehydrogenase and thus one of the treatments for methanol poisoning is to administer ethanol which competes with and slows methanol's metabolism.
Isopropanol, isopropyl or rubbing alcohol, is used as a disinfectant and a fuel. It is approximately three times as toxic as ethanol and like methanol is metabolized via the alcohol dehydrogenase pathway. Its major metabolite is acetone, and acetone levels in individuals who ingest isopropanol will approach the same levels that were initially achieved by the parent compound as metabolism proceeds. As with methanol treatment of isopropanol ingestion consists of the administration of ethanol. Like methanol, isopropanol may be utilized as a substitute of ethanol by alcoholics.
Ethanol, ethyl or beverage alcohol, is a widely consumed and equally widely abused drug. Produced via the fermentation of sugars by yeast it is the "active" ingredient in a vast range of alcoholic beverages including beers, wines, and the stronger distilled spirits. Ethanol in beverages is usually described in terms of the percentage of ethanol present per unit of volume. Beers range from 3.2 to 3.5% upward, wines 9% to 13% and distilled spirits 20% to 50%, although there are exceptions. Distilled spirits are sometimes classed by their "proof" which is a number that is equal to twice the ethanol percentage. The highest percentage of ethanol that can be distilled from an aqueous solution is 95 yielding a 190 proof "beverage." Ninety-five percent ethanol has a variety of laboratory and commercial uses including a solvent and disinfectant. Sometimes substances will be added to 95% ethanol to discourage its consumption—this process is called "denaturing" and the resulting product "denatured alcohol."
Ethanol is an anesthetic and in low doses has a disinhibiting effect. At higher concentrations, it affects coordination and in toxic dosages can lead to loss of consciousness, coma, respiratory depression, and death. Extensive studies have demonstrated that slowing of reflexes and loss of coordination begins in the vast majority of individuals at blood ethanol concentrations of 50 mg/dL. Consequently driving while intoxicated/driving under the influence (DWI/DUI) levels in the United States are set at 80 mg/dL, although this is usually phrased as .08%, a concentration of ethanol in the body of .08% by volume. In a "standard" 70 kg male, a quickly ingested standard drink (a drink consisting of a 12 oz beer, 4 oz glass of wine, or mixed drink containing an ounce of ethanol) on an empty stomach will produce a blood ethanol concentration of 15–20 mg/dL. Thus, such an individual would have to consume approximately four "standard drinks" in the space of an hour to be judged as DWI/DUI using the .08% level. Ethanol distributes throughout total body water and concentrations achieved after a particular dose will thus vary, depending on the weight of the individual. There is also data that indicate that women will experience a more rapid increase in blood alcohol after an equivalent ingestion versus a male of the same weight. Food in the stomach blunts the rise after ingestion and may lower the peak ethanol concentration versus intake with an empty one. Ethanol is metabolized in the stomach and liver primarily by the enzyme alcohol dehydrogenase to acetaldehyde that is then metabolized to acetic acid. Ethanol is metabolized or cleared at a rate of approximately 19 mg/dL per hour.
There is some variability among individuals in the intoxicating effects of alcohol, and chronic heavy users develop some degree of tolerance. Naïve drinkers are at risk of respiratory depression and death at concentrations of 350–400 mg/dL. Lower concentrations can prove fatal as well if they lead to loss of consciousness in a position where respiration is mechanically compromised or the inebriate vomits and cannot clear their airway. Acute intoxication can also lead to a variety of injuries through falls, loss of control of moving vehicles, or an innumerable variety of circumstances where the alcohol "altered" senses lead the inebriate into a dangerous situation or prompt him/her into an action they would not have undertaken in a sober state.
While mild regular ethanol consumption, 3–4 standard drinks per day, is not necessarily harmful and may even have beneficial cardiovascular effects, heavy chronic consumption, 10 or more drinks per day, is dangerous. Consequences may include alcoholic liver disease, gastritis, pancreatitis, and dilated cardiomyopathy. See Chapters 9, 10, and 11 for additional details. Alcoholics can suffer from skeletal muscle weakness and alcohol negatively affects the immune system leading to an increased susceptibility to infection. Heavy consumption is also linked to cancers of the oral cavity, larynx, and esophagus. Consumption of alcohol by pregnant women may lead to fetal alcohol syndrome in their infants characterized by microcephaly, facial dysmorphology and malformations of the brain, and cardiovascular and genitourinary systems.
Carbon monoxide: This colorless, odorless gas is the product of the incomplete combustion of carbon containing compounds and oxygen. It has an affinity for hemoglobin that is approximately 240 times greater than that of oxygen, and the resulting carboxyhemoglobin is unable to transport oxygen to the tissues. It also binds to mitochondrial enzymes and interferes with cellular respiration at the molecular level. CO in the body is commonly measured and expressed in terms of the percentage of hemoglobin saturation. CO bonding to hemoglobin is not an irreversible process but the equilibrium greatly favors it over formation of oxyhemoglobin. In individuals unexposed to elevated ambient CO there is only a fraction of a % carboxyhemoglobin in the blood. With CO exposure through cigarette smoking saturations of 5–6% can be seen. Symptoms of headache and nausea can develop at saturations of 20% and saturations over 40 can be fatal in individuals with preexisting medical conditions, while 50–60% is fatal in healthy individuals.
CO from internal combustion engines is a particular hazard to humans, although the addition of catalytic converters to automobile exhaust systems and requirements that those systems be intact have decreased the number of fatalities due to unintentional auto exhaust poisonings. Auto exhaust also contains other asphyxiant gases including CO2 and nitrous oxides so suicidal "poisonings" via exhaust run into the passenger compartment and closed garages still occur even though blood carbon monoxide saturation levels are not always elevated. Serious intoxications and deaths are seen when other types of internal combustion devices are utilized in enclosed spaces, for example, generators and gasoline powered tools. Motorcycles, lawn mowers, and other garden and home devices if run in a garage, shed, or basement can generate enough CO to produce poisoning and death. CO is also produced in varying quantities by portable heating devices that burn hydrocarbons. CO poisoning should be suspected in individuals presenting with symptoms of weakness, nausea, and headache during the heating season particularly if the symptoms are present in multiple household members. In these cases, the source of the CO is usually a heating system/device that has been improperly installed or when an exhaust vent becomes obstructed. In times of power failures, generators and inadequately vented gas-powered space heaters are often the culprits. Burning charcoal generates a large volume of CO, and when it is used for heat or cooking inside a dwelling can have tragic consequences. It may even be utilized as a means of suicide. CO poisoning is treated with oxygen. Inhalation of 100% oxygen decreases the half life of carboxyhemoglobin in the body from 4–5 hours to a little over 1 hour and under hyperbaric circumstances to less than half an hour.
Tobacco: Tobacco use, mainly in the form of cigarette smoking, constitutes a significant public health hazard in the United States and other countries. Cigarette smoking is felt to cause approximately 400,000 premature deaths yearly in the United States and as such the single greatest potentially preventable cause. Smoking has been linked to cancer, cardiovascular disease, pulmonary disease, and low birth weights in infants born to smokers. Smokers have a decreased life expectancy that is proportional to the number of years smoked. Many of the risks of smoking decrease significantly if the smoker quits.
It is estimated that 85% of cases of lung cancer are smoking related and smokers also are at greater risk of cancers of the oral cavity, larynx, esophagus, kidney, colon, and cervix. Consumers of smokeless tobacco products, chewing tobacco, and snuff are also at risk of oral cancer as well as gum and dental disease.
Coronary atherosclerosis is the primary cardiovascular consequence of smoking, and smokers have a greater incidence of sudden cardiac death. Atherosclerotic disease is not confined to the coronaries but may be noted in the aorta and other vessels. Respiratory complications in addition to neoplasms include bronchitis and chronic obstructive pulmonary disease, mainly in the form of emphysema.
These conditions are not confined solely to the smokers themselves. Nonsmokers who are exposed to cigarette smoke in the workplace or home may also be affected demonstrating an increased risk of lung cancer and coronary atherosclerosis versus the nonexposed. Children growing up in homes where cigarettes are smoked have a higher incidence of respiratory illnesses. Because smoking involves combustion it is an underlying cause in many fire and/or explosion related injuries and deaths.
Cyanide: Sodium and potassium cyanide salts are not commonly present in the home but are readily available in laboratories and utilized in industrial processes. Cyanide is a potent and fast-acting poison that binds to cytochrome c oxidase involved in cellular oxidative processes. It has been famously utilized for suicides and homicides—in the case of the latter particularly in fiction. When the salts are combined with acid, hydrocyanic gas is produced—this was the method utilized in judicial executions involving so-called gas chambers, and hydrogen cyanide gas was infamously employed by the Nazis in their extermination camps. Cyanide containing baits have been utilized to control "undesirable" animals in the wild such as feral pigs, foxes, and coyotes. There were a number of drug tampering incidents in the 1980s where capsules containing acetaminophen were removed from store shelves, refilled with cyanide, and then replaced. In one episode, never solved, seven people were killed. These tragedies led to extensive changes in the packaging of over-the-counter medications including moving away from capsules to solid tablets and tamper resistant packaging. Some plants contain compounds that can produce cyanide on ingestion. A notorious episode involved a quack cancer "cure" called laetrile made from apricot pits that resulted in cases of cyanide poisoning and notably uncured cancers.
Insecticides: Many of these compounds are neurotoxins and highly toxic to humans. Exposure can occur in agricultural situations or tragically in the home or shop when such chemicals are mishandled or improperly stored. The reuse of milk, drink, or other food containers to mix or store such chemicals has led to many unintentional poisonings. This is also the case for other substances in the home from detergents to plant fertilizers. Should containers normally containing food or similar consumables be reused for the storage of other substances, they should be clearly relabeled and never be stored near consumables. Conversely consumables should never be kept near potentially toxic materials.
Heavy metals: Those of primary concern are lead, mercury, and arsenic. These elements have and continue to have numerous industrial and other uses and are common in the environment.
Lead was once a common constituent of paint pigments and while now banned for that purpose in most parts of the world is still found in dangerous concentrations in some older paints. When lead containing paints deteriorate, the dust and flakes may be ingested by young children. Lead is neurotoxic, particularly in the young, and can lead to stunted intellectual development at levels of intake below those required to produce signs of overt intoxication.
Mercury is similarly highly neurotoxic to the developing human. This concern has led to recommendations that pregnant women abstain from or limit their consumption of fish that may contain higher concentrations of mercury because of contamination of the waters in which they grew. Top predatory fish like tuna are also considered potentially dangerous since they accumulate in their flesh the mercury contained in the smaller fish that they feed on.
Arsenic is an element that is naturally present in some areas of the world in sufficient quantity to contaminate water supplies without the assistance of man (Bangladesh being notable). These lower concentrations are associated with higher prevalence of certain cancers in the affected populations. Arsenic was once a common ingredient in insecticides and rodenticides where it caused both unintentional and intentional poisonings. It was a favorite poison in the middle ages and later to the extent that laws were passed to prohibit its inclusion in embalming fluids in order to prevent poisoners from claiming that the arsenic found in their victims was an artifact of the embalming process.
Occupational Chemical and Substance Exposure
Chronic exposure to a variety of chemicals and other substances in occupational or industrial settings has been linked to a variety of specific diseases: benzene to aplastic anemia and leukemia and vinyl chloride to angiosarcoma of the liver. Acute injury from contact with toxic chemicals or substances is a hazard in any occupation where such substances are present. Poisoning from pesticides, for instance, is a particular risk of agricultural workers.
Exposure to dusts among miners, welders, sand blasters, and others causes a group of pulmonary diseases termed the pneumoconioses. These dusts include coal, silica, asbestos, and beryllium as well as some metal salts. While there are differences in their pathogenesis and their histopathology, these conditions all primarily result in pulmonary scarring and can cause significant disability or death. Additionally asbestos has been linked to mesothelioma and cancers of the upper and lower respiratory tract as well as the gastrointestinal (GI) tract. Various industrial or agricultural organic dust exposures have been linked to hypersensitivity pneumonitis and reactive airway disease, asthma.
The burning of wood and fossil fuels releases large quantities of combustion product gases and particulate matter into the atmosphere that can cause or contribute to human disease. These gases include nitrogen and sulfur dioxides as well as carbon monoxide and dioxide. Within the atmosphere, the nitrogen and sulfur oxides may be further oxidized to sulfuric and nitric acids. In summer, nitrogen oxides and other hydrocarbons interact with solar radiation to produce ozone, one of the major components of smog. These elements are primarily irritants to the lower respiratory system and are particularly hazardous to children and individuals with preexisting pulmonary disease, especially reactive airway disease, asthma.
Many toxins of natural origin are present in the environment including the previously mentioned arsenic. These include toxic chemicals within food plants such as oxalic acid in the leaves of rhubarb and cyanogenic glycosides in cassava or manioc, an important staple in many parts of the world. Inadequate processing of the latter prior to consumption can lead to poisoning. Various mushroom species contain potent hepatotoxins. Most of these plant toxins do not pose a great risk to those buying their food in stores but are a potential risk to those who go out and harvest naturally growing edible plants. Misidentification of plants is the cause of numerous ED visits and some fatalities in the United States. Epidemic poisoning from ergot alkaloids produced by molds growing on rye and other grains was a common affliction during the middle ages and was called Saint Anthony's Fire. Aflatoxin B produced by a fungus that grows on peanuts and corn is one of the most potent carcinogens known and is felt to contribute to the high incidence of liver cancer in some parts of the world. In the United States, aflatoxin levels in milk are monitored because of potential feed-corn contamination. Animal tissues are not immune from risks. Both wild and domesticated animals harbor parasites and bacteria that can lead to human disease if the flesh is inadequately prepared like enterohemorrhagic Escherichia coli that causes hemolytic-uremic syndrome. Some fish and shellfish may accumulate toxins from the dinoflagellates that they feed on and their consumption can cause ciguatera poisoning.
Hormones: Hormonally active medications include oral contraceptives (OC), estrogens, somatropin, and others.
OC users have a higher risk of deep venous thromboses and resulting pulmonary emboli, although that risk is decreased with modern formulations. Some studies indicate a slightly increased risk of breast cancer in OC users who started using them at a young age. OC users had a decreased risk of ovarian and endometrial cancer. Benign tumors of the liver, hepatic adenomas are associated with OC use. Estrogen therapy for menopausal symptoms and osteoporosis prevention increases the users risk of endometrial cancer. The addition of progestin, a synthetic progesterone, decreases that risk but may increase the risks of breast cancer and various cardiovascular complications, venous thrombosis and dementia. Diethylstilbestrol (DES) is a synthetic estrogen that was prescribed to pregnant women beginning in the 1940s to prevent premature labor and miscarriages. Women who took DES during their pregnancy were later found to have an increased risk of breast cancer and their daughters a greatly increased risk of a rare vaginal and cervical cancer, clear cell adenocarcinoma, as well as an increased risk of breast cancer.
Somatropin, human growth hormone, used to be obtained from processing donated human pituitary obtained at autopsy. In 1985, several cases of Creutzfeldt–Jakob disease were diagnosed in individuals who had received the hormone and subsequently some 28 cases were identified. Somatropin is now synthesized rather than obtained from human tissues, so this is no longer a risk. This example demonstrates the risks inherent in using materials collected from human sources for therapeutic purposes. When biological source materials are pooled (as was the case for the pituitaries and also for HIV contaminated factor VIII and IX concentrates used to treat hemophilia), there is the possibility that a sample obtained from one infected individual can lead to the infection of many others. The development of screening tests and improved methods of processing such materials have minimized these risks.
Implicating drugs, medications, and toxins as causative agents in human disease can be a complicated matter. In the case of an acute fatal exposure, such as a drug overdose, the appropriate history and symptoms coupled with the finding of the offending agent in the blood and/or tissues of the victim in toxic concentrations usually suffice. This involves both the qualitative and quantitative characterization of the agent since the mere presence of a substance does not necessarily mean that it was the cause of the overdose. For forensic, legal, purposes drug identifications must ordinarily be confirmed by more than one independent methodology. In the clinical setting of a possible drug intoxication, qualitative "screens" are often run on urine. The results are useful in clinical decision making but positive results may be invalid for legal purposes unless confirmed by another methodology because of the possibility of false positives due to cross reacting substances. For some substances, quantitation is important in the clinical setting as it is essential for treatment decisions; for example, acetaminophen concentrations are measured to determine whether N-acetylcysteine will be administered.
Postmortem toxicology is further complicated by sample issues. Clean uncontaminated blood or urine can be obtained from living individuals for analysis but in the deceased the samples are often hemolyzed or even decomposed and cannot be analyzed by the same methods employed in the clinical lab. Drugs and medications in the living are distributed, often unevenly, within the various body compartments and this distribution is maintained by the circulation, the integrity of cellular membranes, and other active processes. After death, these substances often redistribute in the body leading to the finding of concentrations in some samples that are different from what they would have been at the moment of death. To avoid misinterpretations, the testing of samples drawn from different sites including tissues is required.
When attempting to implicate environmental factors, testing is required to demonstrate the presence of the substance in question in the air, food, water, etc. that is thought to be the source. Often, however, the substance is not present continuously in the environment or the concern arises years after the period of exposure may have occurred. The offending substance may not be stored in the body of its victims or by the time that the concern is raised may have been cleared. As the sensitivity and capability of testing methodologies improve, it has become possible to detect quantities of substance at levels orders of magnitude lower than previously with the not unexpected finding of chemicals that had not been detected before in environmental samples. The significance of many of these findings in terms of human disease causation is unknown.
HUNTING FOR ZEBRAS
During routine water supply testing, it was discovered that volatile organic chemicals, (VOCs), were present in some of the wells supplying water to a large military base. Initial results identified tetrachloroethylene (PCE) and trichloroethylene (TCE). Benzene was later also detected in one of the systems. The wells had been in existence for some 40 years at the time contaminants were detected, so hundreds of thousands of individuals had potentially been exposed This included the families (and children) of soldiers in who lived in base housing. Not unexpectedly many soldiers and their dependents who had lived or worked on the base have developed illnesses including cancers and many of them and/or their families attribute their illnesses to the chemicals found in the water. An extensive epidemiological study is currently underway to determine if there is an increased incidence of a variety of diseases in this exposed population versus a similar unexposed population.
Even if that study were to show that there was an excess of cases of a particular illness in this group can it be said that any one of those affected individuals developed illness solely due to the exposure? Imagine for illustrative purposes that the incidence of "malignancy X" is 3 cases yearly per 100,000 in the general population, and in the exposed group the incidence was found to be 6. Assuming that this difference was determined to be statistically significant and all other possible contributing factors could be ruled out which 3 of the 6 cases was actually due to the exposure?
This is one of the dilemmas that recurs repeatedly in attempting to attribute causation to environmental agents suspected (or, as is true in this example, known) to cause human disease. While it is often possible to implicate the contribution of an agent to the population burden of an illness, it may not be possible to prove that an individual instance of the illness was caused by the agent unless there is some marker of the condition that links disease occurrence to individual exposure. (For example, with lung disease and asbestos exposure where the co-occurrence of asbestos bodies and lung disease is probative.)
Nonetheless such specific attributions of individual causation are routinely made within the framework of legal and political systems. Individuals with conditions known or sometimes only suspected to have links to environmental factors are awarded damages or compensation for the failure of some agency or entity to prevent or ameliorate that exposure even when the scientific basis for that attribution is felt by many to be weak or totally lacking. This does not argue against the undoubted serious public health burden produced by a variety of environmental contaminants but highlights the scientific, legal, and political difficulties in dealing with the human costs of such damage to the environment. These are issues in which the pathologist may well become involved.