CHAPTER 52 Toxicology
Toxicology is a basic science that is concerned with information regarding poisonous substances and their toxic actions. This discipline draws on biology, chemistry, and medicine to coordinate knowledge regarding toxic materials. Toxicology strives to understand key features of biology relevant to adverse interactions of chemicals with living systems. A principal objective is to promote the safe use of chemicals, particularly among humans, whether encountered as medicines, as food additives or contaminants, as industrial materials, as household products, or in the environment. Topics of interest to toxicologists include analysis of toxic agents, identification of toxic effects, elucidation of mechanisms of toxicity, management of poisoning, characterization of potential chemical risks, forensic and legal applications, and timely application of knowledge to prevent potentially disastrous consequences of chemical use.
The toxicology of therapeutic agents is integral to their pharmacologic characteristics and is described in appropriate chapters of this text. This chapter reviews general principles of toxicology, summarizes key organ systems that are susceptible to toxic effects, and outlines prevention and management of acute poisoning. Toxic materials not described elsewhere in the text are reviewed, and relevant topics related to dental practice are discussed.
All chemical substances can cause harm or kill if encountered at sufficiently large concentrations over crucial periods of time. This statement embodies insight articulated by Paracelsus in the sixteenth century that dose is the major determinant of toxicity. A subset of substances has relatively specific toxic effects, however. These are considered very harmful based on human experience and are considered poisons or toxins. Beyond this base of experience exists a vast number of uncharacterized, potential toxicants. As of 2007, the Chemical Abstracts Service10 reported counts of more than 32 million organic and inorganic substances, 245,000 inventoried or regulated substances, and some 15 million commercially available chemicals. Because many of these are potentially toxic, this array dictates that toxicologists use some means of triage toward assessment of potential toxicants. At present, selection of chemicals for toxicologic testing is dictated by their potential for use, by funding of basic research on the chemicals, and initial evidence of their specific adverse effects.
The ultimate aim of toxicologic science in society is to guide safe use of chemicals. The definitions in Box 52-1 can assist in understanding and promoting concise communication in the approach to this objective. Safety is a negative entity—that is, the absence of threat of injury. As such, safety cannot be proved directly. Society often simplistically considers chemicals “safe” or “toxic.” Such naive characterization can preclude the rational judgment that enables safe uses of chemicals. Critical judgment requires understanding of the distinction between the terms toxicity and hazard to enable assessment of risks (see Box 52-1). Toxicologic assessment promotes safety by defining hazardous situations of use so that the unsafe use of chemicals can be avoided.
|Safety||Condition of being secure from threat of danger, harm, or injury|
|Toxicity||Property of grave harmfulness or deadliness associated with a chemical that is expressed on biologic exposure|
|Hazard||Threat of danger directly related to circumstances of use of a chemical|
|Risk||Expected frequency of occurrence of an adverse effect in a given situation|
A primary concern of toxicology is evaluation of risk. All useful chemicals have some degree of risk associated with their use. Toxicologic science has developed testing paradigms to define toxicity to assess potential risk. Benefits also must be considered relative to the risk of use. A high degree of risk may be acceptable when benefits are great (e.g., use of toxic but potentially life-extending drugs such as chemotherapeutic agents). Otherwise, risk may be unacceptable for less essential uses (e.g., food coloring). In contrast to the science inherent in testing methods, judgment of risk acceptability involves policy. Such judgment invokes economic, social, and ethical values and should consider factors such as needs met by a chemical under consideration, alternative solutions and their risks, anticipated extent of use and public exposure, effects on environmental quality, and conservation of natural resources.
Within such considerations is an issue of major importance to toxicology and to society in general, which is determination of cause-and-effect relationships. This objective of epidemiologic studies is elusive for chronic diseases, such as many types of cancer. Such diseases may involve confounded potential causes, such as chemical or viral exposure and genetic susceptibility factors. Uncritical publication of unscientific observations or incomplete studies leads the public to inappropriate conclusions, which should be characterized more correctly as hypotheses. Adequate processes for determination of causation, as opposed to simple unrelated association or correlation, require scientific discipline and judgment based on considerable experience.
The criteria developed by Sir Austin Bradford Hill36 provide a sound basis for consideration of causal relationships and should be considered a touchstone for expert opinion regarding cause and effect (Box 52-2). None of these criteria should be considered as absolutely essential, and they cannot be considered as proof of causal relationships. Their careful application during evaluation of potential cause-and-effect relationships can assist, however, in organizing knowledge toward a weight-of-evidence judgment and may provide an alternative interpretation for consideration.
From Hill A: The environment and disease: association or causation? Proc Roy Soc Med 58:295, 1965.
|Strength of association||Observed magnitude of the association compared with other relevant observations should be considered as a primary indicator in assessment of cause and effect|
|Consistency||Association of cause and effect can be observed repeatedly by others under appropriate circumstances|
|Specificity||Particular conditions produce the effect, or a specific group is affected. Bounds of causal relationship should be delimited|
|Temporality||Causation generally occurs before effect, whereas correlational effects can vary in temporality|
|Biologic gradient||Demonstration of a fundamental dose relationship provides convincing evidence of cause and effect|
|Plausibility||Some basis in previous knowledge provides a means of common understanding (remember, however, that all phenomena were novel at some point)|
|Coherence||Care should be taken that interpretation of cause and effect does not unduly conflict with scientifically established facts of biology and medicine|
|Experiment||Manipulation of accessible variables in the potential cause-and-effect relationship has an effect|
|Analogy||Previously understood examples provide basis for formulation of testable hypotheses|
As mentioned earlier, the relationship between dose and toxic response is the fundamental axiom of the science of toxicology. Studies are designed to ascertain dose-response functions associated with specific adverse effects. When simple all-or-nothing criteria, such as death, are used, quantitation of response is simple. More often, objectives require more subtle means of assessment, however, that are less readily quantified. Beyond simple indication of the quantity of material required for the toxic effect, dose-response relationships provide strong evidence of the causal relationship between the observed effect and the chemical under study, as noted previously.
Figure 52-1 presents three modes of display of idealized dose-response data to illustrate and describe the dose required for median response in subjects tested. These data are typical of quantal or all-or-nothing responses such as lethality. In this example, the dose axis is logarithmically spaced, and the data describe a log-normal distribution. Responses that arise from mass action, such as reversible occupancy of receptor by drugs, often are most easily plotted on a logarithmic axis. Alternatively, effects caused by limited biologic capacity, such as irreversible enzyme inhibition, can exhibit abrupt threshold-like effects and may be more easily analyzed on a linear dose axis. The rule is to plot the data to see what type axis is most applicable.
FIGURE 52-1 Various techniques for graphic display of quantal response versus dose data, including frequency of response (bottom panel), cumulative response (middle panel), and cumulative response linearized by probit transformation (top panel).
The lower panel of Figure 52-1 indicates distribution of responses across the dose axis, with a mean of 10 and standard deviation (SD) of one log10 unit. Response percentages include approximately 68.3% within ±1 SD of the mean, 95.5% within ±2 SD, and 99.7% within ±3 SD of the mean. The distribution indicates hypersusceptibility for individuals at the lowest doses and resistant responders at the highest doses. Such a plot gives a convenient way to visualize the distribution of responses across dose within the test groups.
The middle panel of Figure 52-1 plots the cumulative response versus dose across all treated groups. Here the response data are practically linear in the range from −1 SD to +1 SD for these ideal data. This plot provides convenient, accurate estimation of dose required for a 50% response, such as the median lethal dose (LD50). Real data are rarely so well behaved, however, because too few animals may be included for adequate definition of the sigmoid curve. Another disadvantage is that the sigmoid curve presents difficulty in estimating doses that elicit extremes of response, such as 1% or 99%.
An alternative presented in the top panel of Figure 52-1 uses the probit transform45 for the cumulative response. Probit units are derived by conversion of cumulative response percentages to units of deviation from the mean. The scale uses normal equivalent deviation units (NED), for which the mean is arbitrarily set to a NED value of 5 to give positive values along the axis. As is evident in the example, the probit transform linearizes the extreme values of the response function, which allows accurate estimation of doses affecting 1% or 99% of subjects exposed. In addition, the probit transform facilitates determination of the slope, which enables comparison of the dose-response function with other agents or responses.
Such plots are inadequate in dealing with issues of societal risk, however, for which policy often requires estimation of exposure posing a theoretic risk of 1 in 1 million, otherwise described as a 10−6 risk factor. Practical problems intervene, including the impracticality of experimental studies involving sufficient animals to define adequately the dose-response function at low response levels. A classic toxicologic experiment conducted at the National Center for Toxicological Research illustrates this point. Officially termed the ED01 Study,33 this experiment examined in detail the response function of mice treated with low doses of the experimental carcinogen 2-acetylaminofluorene. The study, sometimes termed the megamouse study, involved more than 24,000 mice to determine, with precision, the dose effective in producing a 1% tumor rate. This work advanced toxicologic understanding of the complexity of genotoxic and proliferative cellular events in chronic cancer bioassays. It also exhibited logistic difficulties in conducting statistical studies of low incidence and illustrated gaps in the evolving understanding of chemically induced cancer.
Dose-response relationships can vary with many factors, including differences within and among individuals. As described in Chapter 3, factors responsible for dose-response variations within an individual over time may include age and nutritional status, environmental influences, functional status of organs of excretion, concomitant disease, and various combinations of factors. Changes in pharmacokinetics of toxicants are a frequent basis for altered dose-response relationships. Known influences include increased toxicant bioactivation by enzyme induction,31 such as occurs in certain variants of cytochrome P45013 with exposure to phenobarbital or polychlorinated biphenyls. Conversely, inhibition of metabolic clearance is possible with interacting chemicals, increasing the pharmacodynamic action of drugs and chemicals.
Cytochrome P450 variant 3A4 is an important enzyme in human drug metabolism, and its presence in the gut and liver subjects it to inhibition by many drugs and dietary components, such as grapefruit juice.19 Conversely, substances are often less toxic by the oral route when administered with food as a consequence of less rapid absorption. The time and frequency of administration can be important in altering dose-response relationships through functional changes. Many compounds induce tolerance on repeated administration, whereas others can become more toxic with closely repeated administration. Receptor densities and sensitivity may vary with time or as a consequence of previous exposure. An example of the latter is the well-known tolerance that develops to long-term administration of opioids.
Responses among individuals differ as a consequence of different genetic traits, a subject of intense interest as knowledge emerges from the Human Genome Project, and use of efficient molecular techniques and transgenic animals becomes widespread in research. Recognition and understanding of relevant aspects of human diversity derived from functional genomic research offer potential for therapeutic gains.26 The rationale is to use appropriate drugs in patients best suited to benefit, and to reduce use in patients with genetic traits that might result in toxicity. These efforts have spawned new terms, including pharmacogenetics, representing characterized genetic differences in drug metabolism and disposition, and pharmacogenomics, used to describe the broad spectrum of genes that affect drug response. A summary is available25 that describes progress in determining genetic polymorphisms relevant to drug action and disposition. Known variants linked to altered drug effects in humans include phase I cytochrome P450 enzymes, phase II enzymes such as N-acetyltransferases and glutathione-S-transferases, small molecule transporters, drug and endogenous substrate receptors, and ion channel variants. Chapters 2 and 4 provide additional information on these topics.
Similar advances are likely to be applied to understand genetic differences that result in toxic effects aside from those that arise during drug therapy. Approximately 400 million individuals worldwide exhibit a heritable deficiency in the cytoplasmic enzyme glucose-6-phosphate dehydrogenase. Because this enzyme is essential to the cell’s capacity to withstand oxidant stress through production of reducing equivalents, sensitive individuals with this enzymatic deficiency have chemically mediated hemolytic anemia when exposed to oxidants.6
Of particular importance to the interpretation of toxicologic studies are interspecies differences, which may confound understanding and interpretation of results from animal models. Well-known differences in physiology, metabolic rates, pharmacokinetics of toxicant metabolism and excretion, and sites of toxicant action mediate these interspecies differences. Advances involving physiologically based pharmacokinetic modeling and use of predictive, mechanistically based biomarkers offer promise of augmenting, or in some cases obviating, conventional toxicity testing.
Toxicity can be classified by the amount of time required for development of the adverse effect. For this purpose, the term acute describes toxicity with a sudden onset, whereas chronic describes a long latency or duration. In epidemiology, this classification typically describes the time between exposure and onset of toxicity. Intoxication is an acute effect that results from ingestion of a large quantity of ethanol over a brief time. Alternatively, the progressive diffuse architectural damage to the liver known as cirrhosis occurs over years with chronic ethanol exposure. In experimental toxicology, these terms are used to refer to experimental paradigms involving the duration of treatment or exposure. Acute testing typically describes a single treatment, whereas chronic toxicity testing usually involves dosing or feeding a chemical over the lifetime of a species, as in a rodent carcinogenicity bioassay.
If exposure occurs repeatedly at intervals more frequent than the time required to eliminate a toxicant, the material accumulates in the body throughout the duration of exposure. Although each exposure may be less than toxic, accumulation may produce toxic concentrations if exposure continues for sufficient time. The primary determinant is the rapidity of elimination relative to the frequency and magnitude of exposure. Slowly eliminated toxicants, such as lipophilic chemicals or materials readily bound in tissues, have the greatest potential for accumulation.
Chronic toxicity may exhibit little or no apparent relationship to acute toxicity. In such cases, understanding of cause and effect requires careful study. Of the many examples of chronic toxicity, carcinogenesis currently is of greatest concern in society. Precancerous cellular changes occur and develop slowly and may remain undetected over long periods. Periodic dental examinations often play a significant role in detection of cancers of the oral cavity. Knowledge of patient habits with adverse potential health effects, such as the link between tobacco use and occurrence of oral lesions,75 assists the dental practitioner in being vigilant against such chronic toxicity.
Understanding of chemical toxicity requires knowledge of related chemicals that may be present as impurities because of manufacturing or exist as a result of environmental effects. A classic example is 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin, or TCDD), which was discovered in the herbicide mixture known as Agent Orange used in the Vietnam War. Although dioxin existed at low part-per-million levels in the herbicide mixture, the extreme toxicity of this contaminant in certain species created grave concern for contaminated areas. This concern led to a ban on the use of the herbicide 2,4,5-trichlorophenoxyacetic acid because TCDD is formed through a condensation reaction involving two molecules of 2,4,5-trichlorophenol. Dioxin also can be formed from other sources, such as combustion of municipal waste, iron ore sintering, and wood pulp and paper mills. The toxic actions of TCDD are mediated through its binding to the aryl hydrocarbon nuclear receptor,57 which regulates transcription of genes encoding cytochrome P450 enzymes in the CYP1A subfamily and several other genes that regulate cell growth and differentiation. Despite its extreme toxic potential in some species, epidemiologic studies regarding the effect of TCDD exposure on humans have been inconclusive to date.
The consequences of metabolism of drugs and chemicals after ingestion are extremely important. The following example illustrates the importance of understanding toxic effects relative to drug metabolism. Terfenadine is a nonsedating histamine H1 receptor antagonist that was widely used for relief of symptoms of seasonal allergy. This drug was removed from the market because studies revealed cardiotoxicity when terfenadine was given with erythromycin.93 The toxic interaction was traced to the antibiotic’s inhibition of the high-affinity oxidative enzyme system CYP3A in human liver and intestinal membranes.19 This interaction inhibited normal clearance of terfenadine, and the abnormally elevated concentrations produced toxicity in the form of a prolonged QT interval and the cardiac arrhythmia torsades de pointes. This antihistamine has been replaced with its active metabolite, fexofenadine, which apparently does not elicit this toxicity (see Chapter 22).
Toxic effects can occur at a site of exposure, such as dermal contact, or at some site remote from the point of chemical contact or entry. Local effects dependent on applied concentration are usually diminished by dilution with physiologic fluids and diffusion within tissue away from the site of application. The toxic effect depends on the nature of the interaction at the local site. If the effect is caused by reversible interaction with a receptor, such as that of a local anesthetic, toxicity is attenuated by diffusion, and the system is returned to a more normal state as the drug dissociates from receptors. For toxicants that act through destruction of normal cellular architecture, such as a caustic agent, return to normality requires repair of membranes and cellular structures.
Systemic effects are facilitated by transport within the body fluids and may be influenced by metabolism. Depending on whether biotransformation activates a protoxicant or detoxifies a toxicant, the effects of systemic processing can increase or attenuate toxicity. Compounds may be more or less toxic by the oral route than by other means of systemic exposure, as the first-pass effect of intestine or liver serves to activate or remove toxicants before distribution in the systemic circulation. Alternative systemic exposures, such as inhalation, are not modulated in this manner because systemic exposure occurs directly.
Most toxic chemicals exhibit specificity in their action on target tissues or organs because these targeted biologic systems reach crucial points in which their physiologic functions are interrupted under the influence of the chemical. This section presents crucial physiologic systems and their characteristics that are important in understanding organ-specific toxicity.
Given the primary importance in control of integrated function, the central nervous system (CNS) is a target of paramount importance for many toxicants. Individual neurons exhibit high metabolic rates and are unable to rely on anaerobic glycolysis. These characteristics make these cells susceptible to toxicants that adversely affect cellular respiration and energy production and lead to neuronal damage when central or peripherally acting toxicants interrupt neuronal metabolism, cerebral circulation, oxygen-carrying capacity of blood, or pulmonary ventilation.
A remarkable cell-selective neurotoxicant is 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an impurity discovered42 after attempted illicit synthesis and injection of a meperidine analogue. This compound is a protoxicant for 1-methyl-4-phenylpyridinium, which is formed by monoamine oxidase and concentrated by high-affinity carrier into dopaminergic neurons. The molecular target of 1-methyl-4-phenylpyridinium is reduced nicotinamide adenine dinucleotide dehydrogenase, and the interaction blocks the cellular respiratory exchange of electrons in mitochondria of cells. Its toxic actions result in destruction of dopaminergic neurons in the substantia nigra (see Chapter 15). Death of these cells produces symptoms strikingly similar to Parkinson’s disease, leading to loss of willful motor actions.
Loss of integrity of neuronal cell metabolism can alter neuronal architecture, particularly the myelin sheath of peripheral neurons. Such effects are common to many forms of toxicity expressed in the nervous system. Various compounds, such as tri-o-cresyl phosphate, acrylamide, and metabolites of hexane, cause degeneration of long axons that control neuromuscular activities. Termed distal axonopathy,39 this toxicity involves a “dying back” or retrograde degeneration of distal axons and leads to loss of control of motor functions such as gait. Other effects, such as sensory neuropathy and paresthesia, can result from similar effects of toxicants on small sensory fibers.
Because of the crucial roles of the elements of blood in delivering oxygen and maintaining immune function, toxic effects on blood or the hematopoietic system can be life-threatening. Of these, perhaps no poisoning is more common, preventable, or treatable with timely therapy than the toxic interaction of carbon monoxide (CO) with hemoglobin (Hb). This interaction blocks the vital oxygen-carrying capacity by formation of carboxyhemoglobin (CO-Hb). Characteristics of CO and its toxic effect on various tissues sensitive to anoxia have been concisely reviewed.86 Details of treatment, which involves displacement of Hb-bound CO with oxygen, are provided in the comprehensive text Medical Toxicology.89 In mild (CO-Hb <30%) or moderate (CO-Hb 30% to 40%) cases, therapy includes use of 100% oxygen by nonrebreathing mask until CO-Hb is less than 5%. Severe poisoning can mandate hyperbaric use of oxygen to hasten the exchange.
Another toxic effect that alters the oxygen-carrying capacity of erythrocytes is the formation of methemoglobin. In this toxicity, the heme iron is oxidized from the ferrous (Fe++) to ferric (Fe+++) state by exposure to oxidizing chemicals such as nitrites or aromatic amines.92 As with CO-Hb, methemoglobin is incapable of carrying molecular oxygen to tissues. Although the effects of resultant anoxia are similar, the treatment differs. The treatment involves use of methylene blue, as a precursor to its metabolite leukomethylene blue, a cofactor that enables erythrocytes to reduce methemoglobin in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH). This therapy has complications of potential hemolysis for treatment of infants and individuals with glucose-6-phosphate dehydrogenase deficiency92 because this enzyme is essential in the production of NADPH.
Other adverse actions affect the blood-forming cells of the bone marrow. Such effects can cause loss of immune functions mediated through leukocytes, as noted with induction of agranulocytosis during treatment with thioamide antithyroid drugs, such as propylthiouracil. Although rare, this adverse effect is devastating because it leaves the patient susceptible to sepsis. Aplastic anemia is a complication of therapy with the antiepileptic drugs felbamate and carbamazepine. This condition is very serious because the marrow loses the ability to produce cells. This potential effect requires vigilance for signs of blood dyscrasias and requires laboratory monitoring of blood cell counts during the first months of treatment.
Other adverse effects on the hematopoietic system include overexpression of certain types of cells, such as that noted in the development of acute myelogenous leukemia from benzene. Benzene is a toxicant commonly encountered in petroleum distillates such as gasoline and is considered a causative agent in human leukemia, probably through an active hydroquinone38 or benzoquinone53 metabolite. The process of leukemia development seems to involve preferential selection and clonal expansion of stem and progenitor cells through interaction of the toxic benzene metabolites by multiple independent genetic and epigenetic factors.
The effect of toxicants on the respiratory tract is largely determined by the area of intimate cellular exposure to inhaled chemicals. Such contact is dictated by the structure of the conducting airways and the physical and chemical properties of the toxicant. Larger particles and more water-soluble compounds deposit in the upper regions of the respiratory tract, whereas very fine particles and less soluble gases reach more deeply into the lungs.
Compounds that are rapidly absorbed or highly caustic generally affect the nasal passages. Formaldehyde has a detectable pungent odor at concentrations greater than 0.5 ppm and is highly irritating to the nasal passages. The nasopharyngeal region serves as a filter for particles 10 to 30 µm in diameter. Many of these particles are cleared upward by mucociliary action. Highly water-soluble gases, such as sulfur dioxide, dissolve in moisture present in the upper respiratory membranes and form irritating sulfurous acid. Less soluble compounds, such as oxides of nitrogen and ozone, penetrate more deeply into lung and generally exert effects at membranes in the smallest airways or alveoli. Particles smaller than 5 µm may travel well down into the bronchiolar region, whereas fine particles of 1 µm nominal size reach the alveolar region.91
Lung toxicity typically involves damage to the delicate architecture vital for efficient gas exchange. Because lung tissues contain many cytokines and immunologic mechanisms for particle clearance and tissue repair, inflammation is a common result of inspired toxic gases such as ozone. With severe acute injury, an exudative phase may progress to pulmonary edema, which alters ventilation, diffusion of oxygen and carbon dioxide, and perfusion. Severity depends on the extent of damage to bronchiolar and alveolar cells and the resolution of inflammation through mitogenic or fibrinogenic processes.
Chronic injury to the lung may result from inhalation of fine particles. Phagocytic mechanisms attempting to remove insoluble particles may produce tissue scarring and interstitial fibrosis, in which collagen fibers replace normal membranes and occupy alveolar interstitial space. This kind of injury is common with inhalation of silicate particles such as asbestos.64 These actions produce inflexible tissue, diminish surface area, and lead to poor surfaces for gas exchange. Another chronic lung toxicity is emphysema; its major cause is cigarette smoking. This toxic effect produces distended, enlarged air spaces that are poorly compliant but without fibrosis. The pathogenesis of this condition is not fully understood, but an imbalance between proteolytic activities of lung elastase and antiproteases seems to be involved.3 Lung cancer became a major concern with the increase in popularity of smoking; this health scourge of today was a rare disease a century ago. Smoking is believed to be the most important risk factor for this disease, presenting a 10-fold and 20-fold increase in risk for average and heavy smokers.91
The primary organs of toxicant elimination are the liver and kidneys. The liver provides the major site for metabolic transformation, rendering compounds generally more water-soluble and subject to more efficient excretion in urine by the kidney. The unique physiologic features of each organ provide crucial characteristics that are susceptible to toxic actions and subsequent adverse consequences of impaired function.
The liver possesses remarkable capabilities for regeneration. Hepatotoxicity often results in necrosis and loss of the vital capacities of the liver, however. Essential functions include protein synthesis, nutrient homeostasis, biotransformation, particle filtration, and formation and excretion of bile. Impaired production of proteins such as albumin, clotting factors, and lipoproteins may cause hypoalbuminemia, hemorrhage, and fatty liver. Toxic actions that alter glucose synthesis and storage often lead to hypoglycemia and confusion, whereas effects on cholesterol uptake may produce hypercholesterolemia. Altered biotransformation or biliary excretion of endogenous substrates such as steroid hormones or bilirubin may affect a wide variety of hormonal functions or cause jaundice.
As previously noted, various membrane and cytosolic enzymes in the liver provide the essential metabolic functions of oxidation and glucuronide, sulfate, and mercapturate conjugation for removal of toxicants. These reactions usually detoxify compounds, but occasionally metabolic products exhibit enhanced toxicity. Interactions can occur among effects of toxicants within the liver through induction of enzymes or depletion of metabolic resources. Acetaminophen has been widely used as an over-the-counter analgesic without adverse effects on the liver at therapeutic doses. In circumstances of glutathione depletion, however, which occurs with large acetaminophen overdose, malnutrition, or CYP2E1 induction by long-term ethanol use, a reactive electrophilic intermediate forms in sufficient amounts to produce covalent adducts that severely damage the liver (see Chapter 21).
The kidney plays a vital role in regulating extracellular fluid and excreting soluble wastes through filtration of blood, concentration of wastes, and elimination. To accomplish these vital functions, nephrons are composed of vascular, glomerular, and tubular components. The kidneys possess metabolic and regenerative capabilities, but these resources lead to renal failure when overwhelmed. Nephrotoxicity can be classified as acute or chronic. Acute renal failure can be caused by hypoperfusion from renal vasoconstriction, as elicited by the antifungal amphotericin B, or hypofiltration through glomerular injury resulting from cyclosporine and aminoglycosides. Numerous compounds, including nonsteroidal anti-inflammatory drugs, various antibiotics, and heavy metals, cause acute renal failure by nephritis, acute tubular necrosis, or obstruction. Causes of chronic renal failure from many of these toxicants include nephritis from inflammatory and immunologic mechanisms and papillary necrosis through ischemia or cellular injury. Compensatory mechanisms may include hypertrophy and induction of metallothionein synthesis in response to heavy metal exposure.
Prevention of chemical toxicity is a responsibility of the entire community. Governmental agencies and private corporations must act in concert to minimize toxic hazards in the workplace and the environment. In the home, parents have a responsibility to protect children from harm as they explore their surroundings. Numerous sources of information are available to aid families in protecting against accidental poisoning. Steps can be taken by practitioners to limit the possibility of accidental poisoning. Patients should be encouraged to keep all medications out of the reach of children, and drugs should always be kept in child-resistant containers. Information on the label of a prescribed drug should be understandable and include the name of the agent and clear directions for use. The prescribing physician or dentist should always indicate the purpose of the medication in the label information on the prescription. This procedure helps reduce confusion about drugs in the medicine cabinet and facilitates rapid identification of the drug involved in cases of accidental ingestion. Patients should be instructed to discard unused medication rather than attempt self-medication with drugs remaining from a previous course of therapy.
Diagnosis and treatment of poisoning are the purview of the physician. Principles of therapy for poisoning are summarized in Box 52-3 and apply to the management of any drug overdose. A dentist may be called on to provide emergency treatment of acute poisoning, however, within the practice environment or because of training as a health care professional.
BOX 52-3 First Aid for Poisoning
When acute poisoning is evident, help should be sought through the emergency 911 telephone service if available. For less critical situations, the community poison control center provides an invaluable service. These centers are equipped with extensive files describing the signs and symptoms of poisoning and recommended methods of treatment for most toxic substances distributed within the United States. Poison control centers can be reached by telephone on a 24-hour basis, and phone numbers are usually published inside the cover of telephone directories. If the toxic reaction is serious, expert medical assistance should be sought immediately. In addition, most major medical centers have drug information centers that provide information to practitioners about drugs and drug interactions.
Supportive therapy should be provided. Because hypoxia and shock are two common manifestations of serious toxicity, respiration and circulation must be monitored and assisted if required. For convulsions, physical protective measures may suffice along with the administration of oxygen to help avoid hypoxia. Intravenous diazepam is a drug of choice for pharmacologic control of continuing seizures.
Proper therapy to eliminate exposure to the toxin or reverse its effects depends on identifying the poison. Questioning the victim or the victim’s associates, searching for empty containers, or looking for physical signs on the patient (e.g., miosis or needle tracks for opiate or opioid overdose, burn marks in the mouth for ingestion of caustic chemicals) can be important in establishing the cause of poisoning.
Any obvious means of contact with the poison should be removed. For dermal exposure to chemicals, removal of contaminated clothing and repeated washing with soap and water are indicated. With ingested compounds other than petroleum products and corrosive substances, vomiting can be induced, but only in a conscious patient. Vomiting should not be induced for poisoning by petroleum products or agents producing loss of consciousness because of the risk of aspiration. Likewise, corrosive damage to the esophagus and gastric perforations may result from corrosive substances if emesis is induced. Modern practice is to avoid inducing vomiting because it does not reliably remove ingested poisons. Gastric lavage can be used by qualified personnel if care is taken to avoid aspiration of stomach contents by the victim. Prevention of absorption of many drugs within the gastrointestinal tract can be achieved by activated charcoal (10 to 50 g in water), and cathartics may be used to hasten the exit of drugs from the intestine. The merits and limitations of gastrointestinal decontamination measures have been reviewed in detail.15
Specific antidotes are available to treat poisoning by certain classes of compounds. Antidotes may be useful in preventing the absorption of ingested agents (e.g., Ca++ salts for F−), increasing their rate of elimination (e.g., dimercaprol for inorganic mercury), blocking specific receptors (e.g., naloxone for morphine), or blocking other toxic activity (e.g., N-acetyl cysteine for acetaminophen overdose). One specific antidote should be remembered by dentists. For ingestion of toxic amounts of fluoride, which might occur with prescribed tablets or with topical liquids or gels, the local antidote to prevent absorption is Ca++ (in milk, calcium lactate, calcium gluconate, or lime water). If necessary, 2 to 10 mL of 10% calcium gluconate may be injected intravenously t/>