Toxicology

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Chapter 7 Toxicology

The field of toxicology is a broad-based multidisciplinary science that examines the harmful effects of substances on living organisms, including humans. There are several major subdivisions of toxicology.

image Descriptive toxicology focuses on toxicity testing with the intent of defining the degree of risk associated with substances.
image Environmental toxicology involves the detection and understanding of environmental pollutants and their effects on humans and other organisms.
image Forensic toxicology is primarily concerned with detection and quantification of toxic substances for legal purposes.
image Mechanistic toxicology is focused on determining the mechanisms by which substances exert toxic effects.
image Regulatory toxicology uses toxicologic data to establish policies regarding exposure limits for toxic substances.
image Medical or clinical toxicology focuses on the diagnosis and treatment of toxic effects in humans.

This chapter focuses primarily on the concepts of medical toxicology. These concepts are similar in many respects, at least in principle, to those of pharmacodynamics and pharmacokinetics. This is not surprising, because any substance can be toxic under the appropriate conditions. Indeed, Paracelsus, an early toxicologist, stated, “All things are poison and nothing is without poison, only the dose permits something not to be poisonous.” In fact, even water in excess can exert toxic effects (water intoxication) by disrupting electrolyte balance. Thus toxicity may be associated with therapeutic agents and nontherapeutic agents alike.

General Principles

Terminology

Although toxicology has a long history, it is an evolving discipline, and consequently toxicologic terminology continues to evolve. There are ongoing efforts to standardize and codify toxicologic terminology (see Internet resources). The following are some useful definitions:

image Poison is any substance that may disrupt biologic function and potentially kill an organism.
image Toxin, by strict definition, is a poison of biologic origin that does not have the ability to replicate. However, the term toxin has been used more loosely. For example, environmental toxin has been used to describe toxic substances of nonbiologic origin.
image Venom is a toxin that is injected into the victim by some means (e.g., bee sting, snake bite).
image Toxicant is a general term that refers to any harmful substance and is generally interchangeable with poison.
image Toxicodynamics refers to the general concepts of pharmacodynamics (interaction with molecular targets and mechanisms of effects) as applied to interactions and mechanisms that generate toxic effects.
image Toxicokinetics refers to the general concepts of pharmacokinetics (absorption, distribution, biotransformation, and elimination) as applied to toxic substances.

General Mechanisms of Toxicity

Toxicity can be caused by both therapeutic and nontherapeutic substances. In terms of therapeutic drugs, toxicity may arise from a direct extension of the drug’s primary action. For example, central nervous system (CNS) depression or coma may occur with excessive doses of barbiturates used in the treatment of epilepsy. The toxic effect may also be unrelated to the primary therapeutic effect but related to the general pharmacology of the drug (nonsteroidal antiinflammatory agents may increase edema in heart failure patients). The toxic effect may also have no relationship to the therapeutic action of the drug (ototoxicity induced by aminoglycoside antibiotics).

Detailed discussion of the mechanisms of toxicity is beyond the scope of this text. Nevertheless, it is useful to identify several general mechanisms by which toxic effects occur. These mechanisms can be classified as follows:

image Physical. The physical presence of the toxicant triggers reactions that are harmful (e.g., asbestos fibers in the lung).
image Chemical. Toxicants react chemically with the tissues or body fluids such as blood to produce harmful effects (e.g., strong acids or bases cause burns).
image Pharmacologic. Toxicants interact with endogenous pharmacologic pathways, resulting in inhibition or overstimulation (e.g., botulinum toxin inhibits release of acetylcholine to cause paralysis).
image Biochemical. Toxicant reacts biochemically with cellular constituents to produce cellular damage (e.g., venom of many snakes contains phospholipases that destroy cell membranes).
image Genomic (genotoxic). Toxicant alters the genetic material of the cell, resulting in disruption of function. Genotoxic substances may be mutagenic or carcinogenic.
image Mutagenic (carcinogenic). Toxicants alter DNA structure or function sufficiently to cause mutations (benzene) or initiate and promote the development of cancers (polycyclic aromatic hydrocarbons such as benzo[a]pyrene, found in cigarette smoke).
image Immunologic. Toxicant may trigger an immune response that leads to cellular damage (e.g., penicillin-induced hemolytic anemia) or conversely suppresses the immune system, causing an increased susceptibility to infection (e.g., procainamide-induced agranulocytosis).
image Teratogenic. Toxicant alters fetal development, resulting in birth defects (e.g., phenytoin is associated with development of cleft lip).

Target Organs

Toxicity may be systemic, affecting the whole body, or it may be largely confined to select target organs, the so-called toxic effect organs. Some organs, such as the liver, brain, lungs, heart, and kidney, play a central role in poisonings (Figure 7-1). When toxicity is site specific, the word toxic is preceded by an indication of the specific target organ. Thus, hepatotoxicity refers to effects on the liver, nephrotoxicity refers to effects on the kidney, ototoxicity refers to effects on the auditory system, and so on. A number of factors interact to determine the susceptibility of organs to toxic effects. These include the organ’s anatomic location, blood flow, metabolic processes and activity, affinity for the toxicant, and capacity for self-repair. Major toxic effect organs include the following:

image Liver. The liver is exposed to a high concentration of toxic substances. Orally absorbed toxicants are presented first to the liver via the portal circulation. The liver also receives a large proportion of systemic blood flow. Enterohepatic cycling extends exposure to toxicants excreted through the bile. The high metabolic activity of the liver also results in the generation of reactive intermediates that may have toxic actions.
image Kidney. The kidney receives a high proportion of the cardiac output. Many toxic substances are excreted by the kidney. These toxicants are concentrated in the urine as fluid is reabsorbed from the renal tubule.
image Heart. The total blood volume passes through the heart. Thus it is exposed to all blood-borne toxicants.
image Lungs. The lungs represent an extremely large surface area for interaction with toxicants, particularly those that are airborne. The total cardiac output passes through the lungs, so blood-borne toxicants are also distributed extensively to the lungs.
image Brain. The brain is a critical target organ because of its central role in homeostasis. Thus toxicants that affect the brain may influence multiple systems and result in widespread systemic toxicity.
image

Figure 7-1 Major target organs.

Risk Assessment

Poisoning remains a significant public health issue that affects up to approximately 5% of the population per year in industrialized countries. Many countries have established national poison control centers that can serve as valuable sources of information. The World Health Organization maintains a directory of these centers (see Websites).

Because virtually all substances are potentially toxic, key questions in toxicology are how much risk is associated with a particular substance and under what conditions does this risk become apparent? In addition, the level of acceptable risk will vary. In some circumstances, very toxic substances (e.g., anticancer drugs) are used therapeutically despite their known toxic effects because the benefits of such treatments outweigh the risks. Accordingly, risk assessment is a primary consideration in the management of toxic events (Figure 7-2).

image

Figure 7-2 Risk assessment during management of toxic events.

Key factors contributing to risk assessment include the following:

image Hazard identification. What substances are involved and what are the adverse effects of each substance? Knowledge of the physicochemical properties, toxicokinetics, and toxicodynamics of the suspected toxicant(s) is invaluable in designing treatment strategies.
image Dose response. Is there a known dose response relationship for the toxic effects of the toxicant? Do toxic effects mirror plasma concentrations? At what dose (concentration) do toxic effects appear?
image Exposure assessment. Exposure assessment is a key process in determining the urgency and strategy for treatment of toxic events. Exposure assessment includes estimation of the following:

• Degree of exposure. An estimate of the degree of exposure is essential. This may be the dose of drug ingested, the concentration of chemical to which a patient was exposed, or some other measure (e.g., parts per million) of the amount of toxicant. Included in this assessment is whether the exposure was acute or chronic.
image Route of exposure. The route of exposure is an important determinant of both the extent and rate of absorption of the toxicant. For example, dermal exposure is generally associated with reduced rates and extent of absorption compared with oral ingestion or inhalation.
image Time since exposure. An estimate of the time since the exposure will be helpful in estimating the following:

• Degree of absorption at presentation.
• Usefulness of blood sampling. Blood sampling is useful for toxicants that exhibit a relationship between the plasma concentration and toxic effect(s). However, if the time of exposure has been long, it is most likely that plasma concentrations have reached a maximum value and are of lesser benefit compared with symptomatology in determining course of treatment.
• Value of certain therapies. The time since exposure will dictate to a certain extent the appropriateness of treatment approaches. For example, if the time since initial exposure has been very long, then therapies aimed at inhibiting absorption may have only a minor influence on the course of poisoning.

image Clinical status. In many cases, information about the degree and time of exposure may be lacking. In such cases, careful determination of the clinical status of the patient coupled with knowledge of potential hazards can assist in determining the type of toxicant (e.g., recognition of anticholinergic effects of mushroom poisoning), the suspected time course, and the treatment protocol. In addition, recognition of compromised airway, circulatory, or neural function requires immediate supportive measures.
image Patient characteristics. The specific characteristics such as anthropomorphic characteristics, genetic background, and preexisting conditions of each patient also factor into risk assessment. Some (e.g., weight) may affect the course of poisoning indirectly, whereas others may have a more direct effect (e.g., alcoholism) by influencing the production or elimination of toxic substances. Genetic polymorphisms may affect absorption, biotransformation, or elimination of toxicants.

General Strategies for Management of Toxic Events

In some cases of poisonings, there are specific treatments or antidotes available that prevent, interrupt, or reverse the toxicity. In such cases, hazard identification and knowledge of the toxicodynamics of the toxicant are critically important for selection of the appropriate antidote or treatment. Antidotes or specific treatments may act via a number of mechanisms including the following:

image Antibodies that neutralize toxicants or prevent their distribution to target organs (e.g., antivenin for snake bites)
image Compounds that sequester the toxicant, prevent its distribution, and promote its excretion (e.g., heavy metal chelators)
image Compounds that scavenge the toxicant to prevent its interaction with tissues (e.g., N-acetylcysteine [NAC] in acetaminophen poisoning)
image Pharmacologic antagonists that block receptors stimulated by the toxicant
image Pharmacologic agonists that stimulate receptors blocked by the toxicant
image Treatments that act physiologically to oppose the actions of the toxicant (e.g., pressor agents to reverse hypotension)
image Enzyme inhibitors that prevent the formation of toxic intermediates
image Enzyme activators that reverse enzymatic inhibition produced by toxicants

In addition to specific treatments, a number of generalized treatment strategies can be used in poisonings (Figure 7-3). These are toxicokinetic treatment strategies targeted at reducing or preventing the absorption of the toxicant, at reducing the distribution of the toxicant, at manipulating biotransformation to reduce formation of the toxicant, or at hastening excretion of the toxicant. These approaches rely heavily on the concepts of pharmacokinetics presented earlier, which will not be repeated here. These generalized approaches are very useful in situations in which there are no specific antidotes or the causative toxicant(s) and/or modes of action are not sufficiently well defined to allow application of a specific antidote.

image

Figure 7-3 General strategies in management of toxic events.

Reduction or Prevention of Absorption

Because the majority of poisonings occur via ingestion, approaches to limit absorption via this route will be discussed here. Approaches to limit absorption via other routes are generally common sense approaches. For example, moving the patient to fresh air if the exposure route was inhalational or flushing the skin with water in the case of dermal exposure. Several options are available to reduce oral absorption of toxicant. Collectively, these approaches are sometimes referred to as gastrointestinal (GI) decontamination.

Forced Emesis

Vomiting can remove toxicants present in the stomach. This approach may be useful if there is reason to believe that there is toxicant remaining in the stomach. This may be the case if the time since exposure is relatively short or if gastric emptying has been delayed. In the past, a number of approaches have been used to induce emesis. However, most have been abandoned. The most frequent method in current use is ingestion of syrup of ipecac.

image Mechanism of action
image Stimulation of sensory receptors in the GI tract
image Stimulation of chemoreceptor zone in the CNS
image Adverse effects
image Aspiration of vomitus into lungs
image Physical damage due to the act of vomiting (e.g., gastric tears)
image Impairment of other GI decontamination procedures since patient may continue to vomit for prolonged period
image Electrolyte imbalance
image Contraindications
image Ipecac should not be used with toxicants such as:
• Petroleum distillates (e.g., gasoline, furniture polish)
• Corrosives (strong acids, strong bases) (e.g., drain cleaner)
• CNS stimulants, because act of vomiting may trigger convulsions
image Unless a secure (intubated) airway has been established, ipecac should not be used in the following patients:

• Those who are unconscious
• Those with impaired airway reflexes

image Anticipated use of other GI decontamination procedures, because emesis would remove the treatments from the GI tract

In the past, the use of ipecac to induce forced emesis was promoted for GI decontamination in both hospital and home settings. Recommendations from a number of poison control organizations now indicate a much more conservative use of ipecac because of the potential for harm and the relative lack of evidence for definitive benefits. Available data suggest that ipecac may be of use in the following situations:

image In prehospital settings when there are no contraindications for use
image When the ingested toxicant poses substantial risk
image If no alternative means of GI decontamination are available
image When ipecac can be administered within 30 minutes of toxicant ingestion
image When there will be a substantial delay (>60 minutes) in reaching treatment facilities

Gastric Lavage

Gastric lavage involves placing a tube through the mouth (orogastric) or through the nose (nasogastric) into the stomach. Toxicants are removed by flushing saline solutions into the stomach, followed by suction of gastric contents.

image Mechanism of action

image Physical removal of toxicant

image Adverse effects

image Aspiration of lavage into lungs
image Mechanical injury caused by placement of the gastric tube
image Endotracheal placement (into the trachea and thus into the lungs) of gastric tube
image Electrolyte imbalance

image Contraindications

image Gastric lavage should not be used with toxicants such as the following:

• Petroleum distillates (e.g., gasoline, furniture polish)
• Corrosives (strong acids, strong bases) (e.g., drain cleaner)
• CNS stimulants, because the act of vomiting may trigger convulsions

image Unless a secure (intubated) airway has been established, gastric lavage should not be used in the following patients:

• Those who are unconscious
• Those with impaired airway reflexes

Although in theory gastric lavage would seem to be the most direct way of removing a toxicant, the available evidence does not support the routine use of gastric lavage. Gastric lavage may be useful in cases in which there has been very recent ingestion (30 minutes to 1 hour) of a life-threatening toxicant.

Activated Charcoal

Activation of charcoal by oxidization increases its adsorptive surface area. The large surface area of charcoal is capable of adsorbing many toxicants, thus sequestering them in the gut. Because only free molecules are able to diffuse across membranes, reduction of the concentration of free toxicant in the gut by charcoal greatly reduces absorption into the bloodstream (Figure 7-4). This treatment is administered as a slurry of the activated charcoal powder.

image Mechanism of action

image Toxicant molecules adsorbed to charcoal are not absorbed
image May increase elimination by decreasing free concentration of toxicant in gut
image May interrupt enterohepatic cycling

image Adverse effects

image Vomiting, particularly with premade solutions containing sorbitol (seen in up to 40% of patients)
image Aspiration; charcoal can cause marked lung damage
image Reduced absorption of other drugs or antidotes
image Constipation

image Contraindications

image Patients at risk for bowel perforation (e.g., ingestion of corrosives)
image Toxicants with significant potential for aspiration (e.g., petroleum distillates)
image Toxicants that are not adsorbed to charcoal

• Alcohols
• Iron
• Highly polar molecules and salts

image Unless a secure (intubated) airway has been established, activated charcoal should not be used in the following patients:

• Those who are unconscious
• Those with impaired airway reflexes

image

Figure 7-4 Activated charcoal reduces drug absorption.

Available data suggest that activated charcoal is effective at reducing the absorption of many toxicants. This treatment may be administered as single-dose activated charcoal (SDAC) or repeated as multiple-dose activated charcoal (MDAC). However, the efficacy of SDAC charcoal at preventing drug absorption is very time dependent and decreases rapidly with time from ingestion. SDAC is most effective if administered within 60 minutes of toxicant ingestion. MDAC is most frequently used in cases of poisoning with controlled-release substances, with the goal of binding toxicant as it is released from its formulation. In addition, MDAC also may be of benefit in increasing the elimination of toxicants. Current recommendations suggest that activated charcoal should be used in the following situations:

image When the toxicant is potentially fatal
image When no contraindications to its use are present
image If the toxicant binds to charcoal
image If the time since ingestion suggests toxicant is still present in the GI tract

Whole Bowel Irrigation and Cathartics

Whole bowel irrigation and cathartics are used to prevent the absorption of toxicants by increasing GI motility and passage of the GI contents, thereby reducing the time available for drug absorption. Cathartics use osmotic substances to draw fluid into the gut and produce diarrhea. The most commonly used cathartic is sorbitol. Available recommendations currently discourage the use of cathartics as sole therapy for poisonings because of the associated dehydration and electrolyte disturbances. Accordingly, cathartics will not be discussed further.

Whole bowel irrigation (also called whole gut lavage) is an evolution of the cathartic concept. This approach combines oral administration of high–molecular-weight substances, generally polyethylene glycol, with iso-osmolar electrolyte solutions (e.g., Golytely). This combination tends to prevent systemic electrolyte disturbances that complicate the use of cathartics alone. Large volumes of these solutions plus water are administered orally or by gastric tube.

image Mechanism of action

image Increased volume in GI tract promotes voiding
image Administration is continued until rectal discharge is clear

image Adverse effects

image Nausea, vomiting
image To date, systemic electrolyte disturbances have not been reported

image Contraindications

image Patients with impaired bowel function (e.g., ileus) or perforation
image Patients susceptible to aspiration if vomiting occurs

Whole bowel irrigation has been shown to decrease the bioavailability of certain toxicants. Although there are no consensus statements regarding specific indications for whole bowel irrigation, this approach may be best suited for intoxications for which the other methods of GI decontamination may not be appropriate. More specifically, whole bowel irrigation may be particularly useful in cases where there has been a long time lag between ingestion and treatment and in cases in which toxicants are released slowly. Current recommendations

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