Toxicokinetics is the study of the movement of toxic substances within the body (ie, their absorption, distribution, metabolism, and excretion) and the relationship between the dose that enters the body and the level of toxic substance found in the blood or other biologic sample. Toxicodynamics is the study of the relationship between the dose that enters the body and the measured response. Simply put, toxicokinetics is the study of the effect of the body on the substance, and toxicodynamics is the study of the effects of the substance on the body. The magnitude of a toxic response is usually related to the concentration of the toxic substance at its site of action.
The bioavailability of a toxic substance indicates the extent to which the agent reaches its site of action. In some instances, an agent will be inactivated before it reaches the site of action. For example, when cyanide is taken orally, it is absorbed and passes to the liver, where the enzyme rhodanese may detoxify a portion of the ingested cyanide. On the other hand, if the cyanide in the form of gaseous hydrocyanic acid (HCN) is absorbed through the pulmonary circulation, it goes directly to the brain, where it may cause damage due to hypoxia.
Cell Membrane Permeability & Cellular Barriers & Cell Signaling
Absorption, distribution, metabolism, and excretion all involve passage of toxic agents across cell membranes. Permeability is dependent upon a toxic substance's molecular size and shape, degree of ionization, and relative lipid solubility. The distribution of some toxic agents is altered by unique cellular barriers, for example, the blood-brain barrier, the blood-testis barrier, and the placenta, which may exclude toxic substances.
Bone is an important deep reservoir for many heavy metals (especially lead) and for radioactive materials, and the effects of these materials can persist long after they have left the circulation. This storage property can be used in determining previous exposure and toxic burden. Substances rely on many different cell signaling pathways to induce toxicity. These pathways include G-protein coupled receptors (for muscarinic receptors that are susceptible to organophosphate agonism), ligand gated ion channels (used by nicotine) and intracellular enzymes such as soluble guanylate cyclase (used by nitrovasodilators such as nitrate).
The rate of absorption is dependent on the concentration and solubility of the toxic agent. Absorption is enhanced at sites that have increased blood flow or large absorptive surfaces such as the adult lung and gastrointestinal tract.
A. Gastrointestinal Absorption
The amount of absorption through the gastrointestinal tract is usually proportionate to the gastrointestinal surface area and its blood flow and depends on the physical state of the agent. Most toxic substances are absorbed in the small intestine. Therefore, agents that accelerate gastric emptying will increase the absorption rate, while factors that delay gastric emptying will decrease it. Some toxic substances may be affected by gastric juice; for example, the acidity of the stomach may release cyanide products and form hydrogen cyanide gas, which is even more toxic than the cyanide salt.
The most common route of occupational exposure is pulmonary absorption. Gaseous and volatile toxic substances may be inhaled and absorbed through the pulmonary epithelium and mucous membranes in the respiratory tract. Access to the circulation is rapid because the surface area of the lungs is large and the blood flow is great. The nasal hair, the cough reflex, and the mucociliary barrier help prevent dust particles and fumes from reaching the lung.
The solubility of gases affects their absorption. Highly water-soluble gases such as ammonia and sulfur dioxide are absorbed in the upper airways and cause marked irritation there. This serves as a warning and may help limit the injury to the lung because the victim leaves the site of exposure. In contrast, noxious gases of lower water solubility such as nitrogen dioxide and phosgene, which have few early warning properties, can reach the bronchioles and alveoli and cause delayed injury (Table 16–3).
Table 16–3.Irritant gases. ||Download (.pdf) Table 16–3. Irritant gases.
|Low Water Solubility (poor warning properties) ||High Water Solubility (good warning properties) |
|Ozone ||Ammonia |
|Phosgene ||Chloramine |
|Nitrogen dioxide ||Sulfur dioxide |
|Nitric oxide ||Nitric acid |
C. Percutaneous Absorption
Many toxic substances can pass through intact or broken skin. The amount of skin absorption is generally proportionate to the surface area of contact and to the lipid solubility of the toxic agent. The epidermis acts as a lipid barrier, and the stratum corneum provides a protective barrier against noxious agents. The dermis, however, is freely permeable to many toxic substances. Absorption is enhanced by toxic agents that increase the blood flow to the skin. It is also enhanced by use of occlusive skin coverings (eg, including clothing and industrial gloves) and topical application of fat-solubilizing vehicles. Hydrated skin is more permeable than dry skin. The thick skin on the palms of the hands and the soles of the feet is more resistant to absorption than is the thin skin on the face, neck, and scrotum. Burns, abrasions, dermatitis, and other injuries to the skin may alter its protective properties and allow absorption of larger quantities of the toxic substance.
The pH of the substance can affect the degree of tissue injury and ultimate skin. Highly acidic substances can cause an immediate coagulation-type necrosis that creates an eschar, which tends to self-limit further damage. In contrast, highly alkaline substances cause a liquefactive necrosis with saponification and continued penetration into deeper tissues, resulting in extensive damage.
The eye is also a ready site of absorption. When chemicals enter the body through the conjunctiva, they bypass hepatic first-pass elimination and may cause systemic toxicity. Early decontamination of the eye may thus prevent systemic as well as local damage.
Distribution of Toxins in the Body
After absorption, toxic substances are transported to various regions of the body. Some are removed by the lymph, and some insoluble compounds are transported through tissues such as the lung via cells such as macrophages. Most toxic substances enter the bloodstream and are distributed into interstitial and cellular fluids. The pattern of distribution depends on the physiologic and physicochemical properties of the material. The initial phase of distribution usually reflects the cardiac output and regional blood flow. Agents that penetrate membranes poorly are restricted in their distribution, and their potential sites of action are therefore limited. The blood-brain and blood-testis barriers limit the distribution of water-soluble but not lipid-soluble chemicals to these organs. Distribution may also be limited by the binding of toxic substances to plasma proteins. Toxic agents can accumulate in higher concentration in some tissues as a result of pH gradients, binding to special cellular proteins, or partitioning into lipids. Some agents accumulate in tissue reservoirs, and this may serve to prolong the toxic action, for example, lead may be stored for years in bone and may be released later. Some properties allow for substances to be removed by extracorporeal means such as dialysis. Substances with a small volume of distribution, low molecular weight, high water solubility, and low protein binding are more likely to be removed by dialysis.
Before a toxic substance can be excreted, it may require metabolic conversion (biotransformation), for example, to a more water-soluble substance that can be eliminated in the urine. The most common site for biotransformation is the liver, but it can also occur in plasma, lung, or other tissue. Biotransformation may result in either a decrease (detoxification or inactivation) or an increase (activation) in the toxicity of a compound. Differences in the metabolism of toxic substances account for much of the observed differences between individuals and between animal species.
Biotransformation occurs in the liver by hydrolysis, oxidation, reduction, and conjugation. Microsomal cytochrome P450 metabolizing enzymes play a key role in the process by primarily catalyzing the oxidation of toxic substances. The activity of the CYP450 enzyme system can be increased (induced) by many environmental and pharmacologic agents. Individual differences in microsomal enzyme activity and susceptibility to induction are genetically determined and account for the marked variability in bioavailability of many toxic substances. Other factors that regulate key liver enzyme systems are hormones (which account for some gender-dependent differences) and disease states (eg, the presence of hepatitis, cirrhosis, or heart failure). Because the activity of many hepatic metabolizing systems is low in neonates—particularly premature neonates—they may be much more susceptible to toxic substances that are inactivated by liver metabolism. Inefficient metabolizing systems, an altered blood-brain barrier, and inadequate mechanisms of excretion combine to make the fetus and neonate more sensitive to the toxic effects of many agents.
A. Pathways and Mechanisms of Excretion
Toxic substances are excreted either unchanged or as metabolites. Excretory organs other than the lungs eliminate polar (water-soluble) compounds more efficiently than they eliminate nonpolar (lipid-soluble) compounds. The kidney is the primary organ of elimination for most polar compounds and metabolites. Excretion of toxic substances in the urine involves glomerular filtration, active secretion, and passive tubular reabsorption. Alkalization or acidification of the urine may dramatically change excretion of some agents. When tubular urine is more alkaline, weak acids are excreted more rapidly because they are ionized and passive tubular reabsorption is decreased. In contrast, when tubular urine is made more acid, excretion of weak acid is reduced.
Many toxic substances metabolized by the liver are excreted first in the bile and later eliminated in the stool. After biliary excretion, some substances are efficiently reabsorbed into the blood, a process known as enterohepatic recirculation. This recirculation can be a cause of repeat exposure and injury. This process can be interrupted by the use of binding agents, such as activated charcoal given in multiple doses. Toxic substances can also be excreted in sweat, saliva, and breast milk, and there may be some minor removal in hair or skin.
Clearance is the rate at which a toxic agent is excreted, divided by the average concentration of the agent in the plasma. Most toxic substances are eliminated as a function of concentration, ie, a constant fraction of the toxic material is eliminated per unit of time, a process known as “first-order” elimination. If the point of saturation is reached, the body will no longer be able to eliminate a constant fraction of the material but will instead eliminate a constant amount per unit of time, a process known as “zero-order” elimination. Under these circumstances, the clearance becomes quite variable. Note that clearance is a measure not of how many milligrams of toxin is being removed but rather of the volume of fluid that is freed of the toxic agent per unit of time.
C. Volume of Distribution
The volume of distribution is calculated by dividing the amount of the toxic substance in the body (eg, a known dose) by the concentration measured in the blood. This number is not necessarily a physiologic volume; it is an “apparent” volume that reflects the degree of distribution of the toxic agent in tissues. The volume of distribution for most toxic agents depends on its size, pH, protein binding, partition coefficients, and regional differences in blood flow and binding to special tissues.
D. Half-Time and Half-Life
The time it takes for the plasma concentration of a substance to be reduced by 50% is the half-time. For substances that are eliminated according to first-order kinetics, the time it takes to eliminate 50% of the substance is called the half-life. For a substance eliminated by first-order kinetics, about 90% of the amount in the body will be eliminated in 3.5 half-lives after the end of the period of exposure.