While the key to preparing and understanding a toxic tort case is working with a reputable toxicologist, once it is determined that a given chemical is in fact the cause of the victim’s injury or death, the services of an expert in pharmacokinetics are required. Pharmacokinetics studies the way animals absorb, distribute, metabolize and eliminate a chemical. While the field of toxicology measures the effect of a chemical on an animal, pharmacokinetics attempts to measure the effect of the animal on the chemical. Originally designed to assist doctors in evaluating the therapeutic use of drugs in humans, pharmacokinetic studies measure the processes of absorption, metabolism, distribution and elimination of a chemical in the body. Because the body is a dynamic system in which the concentration of chemicals in various locations changes with time, pharmacokinetics is often the refuge of the defense where it can introduce multiple additional parameters and confounders to create misunderstanding in an effort to mislead the jury into believing that a given, proven toxic is no more dangerous than other known chemicals. Understanding the terminology of pharmacokinetics is helpful in proving and defending a toxic tort case.
The term absorption refers to how fast a chemical enters the body, and how much of it enters the body. The absorption of a chemical into the body varies depending on the route of administration. For instance, most chemicals penetrate through the skin into the body more slowly than they penetrate through the stomach or intestinal tract. For these chemicals the skin can act to limit the chemical’s entry into the body. Other chemicals are readily absorbed by the skin which serves as a sponge, especially when the toxic solvent soaks clothing, gloves, or shoes, which serve as a continuously repeating application. Recent studies by dermatologists at the University of California confirm that skin absorption is a major route of entry. Chemicals absorbed in this fashion are usually undiluted and unchanged by the digestive process and readily lodge with lipid [fat] tissue. Dioxins and PCBs are readily found in fat samples.
An important concept is the distinction between exposure and dose. Exposure is the amount of chemical the body contacts externally. But all does not necessarily enter the body. Dose is the amount of chemical that actually penetrates into the body, and the effective dose ultimately determines toxicity.
Distribution refers to the dynamic movement and temporary storage of a chemical within the body. Virtually every chemical has a defined target organ, of which the most common are the brain, heart, lungs liver, kidney, and colon. Different kinds of tissues and organs take up and release chemicals at different rates. Sometimes distribution may have an effect on elimination. All chemicals move in and out of various bodily tissues at varying rates. Some are dissipated within hours, while others, especially those that bind with lipid tissue, may accumulate and remain for years.
The process of metabolism is the conversion within the body of the original chemical (parent) to a different chemical (metabolite). While not all chemicals are metabolized in the body, metabolites are helpful in assessing toxicity. While some chemicals are not toxic in certain animals, the metabolites in humans are found to be extremely toxins. A common class of metabolites are conjugates, which are combinations of the parent compound and other naturally-occurring chemicals in the body. Conjugates can be excreted more rapidly than the parent chemical.
Elimination refers to the process by which a chemical leaves the body, whether by perspiration, respiration, urine or feces. Metabolism and elimination are both ways the parent chemical can be discharged from the body. Most chemicals are eliminated or excreted from the body, but at greatly varying rates.
The rate is very important, because from the elimination rate, the half-life can be calculated. Half-life is the amount of time it takes to either eliminate or metabolize one-half of the amount of chemical dose to the body. For example, if the half-life for elimination of a chemical is one day, then one half of the dose will be eliminated during the first day. During the second day, one half of the amount remaining in the body (one-fourth of the original dose) will be eliminated. Therefore, after 2 days 75% would be eliminated; similarly, after 3 and 4 days, 87.5% and 93.75%, respectively, would be removed from the body.
Elimination or metabolic rates that are characterized by a half-life value are also called first order processes. First order processes are very common throughout nature, the law of radioactive decay being an example. Similarly, pesticide degradation often is expressed in half- lives.
Pharmacokinetic studies also determine how much chemical is in the body when an animal is exposed repeatedly or continuously to a chemical, similar to a workplace exposure. Under these conditions, the amount in the body (the body burden) will increase for a certain period of time. But, when the rate at which the chemical is entering the body equals the rate at which it is being eliminated, the amount in the body will no longer increase and absorption is at a maximum or saturation. With repeated and continuous exposure, the chemical’s body burden will level off at a constant value which is called the steady state level or body burden. The attainment of a steady state concentration of a chemical in the body upon repeated exposure is a consequence of the dynamic of the relationship between the body, the chemical and the fact that it is being eliminated.
The term bioaccumulation refers to the ratio between the amount of chemical in the body after a single dose, and the steady state amount in the body following repeated doses. Bioaccumulation factors vary and, even while bioaccumulation occurs, elimination also continues.
Most of the dynamic processes responsible for handling a chemical in the body are first order ones (i.e., they have a half-life). However, if the dose becomes too high the process will no longer be first order. High doses lead to saturation, and indicate that the capacity to metabolize or eliminate a chemical has been overwhelmed by high dose levels. At saturation levels or above, the internal concentrations of the chemical may no longer be proportional to the administered dose level, leading to higher body levels than would be predicted from data at lower, non-saturating doses.
Laboratory pharmacokinetic studies differ from a classic toxicology study. For example, a pharmacokinetic study is normally designed for small groups of three to six animals, and no control groups are needed. Moreover, pharmacokinetic studies typically measure different parameters than the classic toxicology study. Tracing, identifying and quantifying minute amounts of a chemical (and its possible metabolites) passing through a human or animal require great skill and often involve very intricate scientific detective work, which defense experts may not choose to exercise.
Design considerations include the identification of end products expected to be produced, the synergistic reaction of the chemical with the environment, the proper length of the study, the correct dosing regimen, the appropriate parameters to be measured, and the desirability of radioactive labeling as an aid to tracing the test chemical.
Following completion of an acceptable protocol, and selection of healthy subjects, the test chemical is administered. Blood samples typically are taken at regular periods. All urine and feces are collected and analyzed. With humans, careful pre-study and post-study physical examinations are made by physicians.
In animal studies, when dosing and sample collection are complete, the animals are sacrificed. Typically, liver, kidney, lungs, heart, brain, muscle, fat, carcass and other tissues are removed and analyzed, to identify the parent compound and any metabolites formed.
All of the samples collected are analyzed in order to quantify the levels found in each sample. Chemical levels found in excretory products and tissue samples are then compared to the total dose administered. Efforts should be made to recover all the dose administered. Even the air passing through the animal cage should be collected and analyzed, and the cages are washed down with a solvent for analysis.
Pharmacokinetic studies provide data useful in many ways. Clearly, pharmacokinetic data is valuable in gaining a better understanding of how an animal or human reacts to a chemical. For example, pharmacokinetic data are used to select proper dosages for therapeutic drugs. In addition, they can be utilized in assessing the hazards of chemical exposures.
Identification of chemical metabolites through pharmacokinetic studies is also important in making interspecies comparisons. If a chemical responds in a similar manner in several different species, then one species may be a good model for others. Identifying the existence of metabolites is also crucial in interpreting the results of environmental and human monitoring.
Finally, and perhaps most importantly, pharmacokinetic data on the rate of elimination in humans, coupled with accurate analytical measurements and knowledge of the time of exposure, allows the calculation of the dose actually received by an exposed victim.
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