Toxicology made easy: what every trial advocate should know.

• Author: Dukes, David E.
• Position: Coping with Science

TOXICOLOGY is commonly recognized as the study of poisons, and is properly defined as the study of adverse effects of chemical or physical agents on biological systems.(1) While toxicology's roots can be traced back to the use of poisons by early human beings in hunting for sustenance and survival, the recognition of toxicology as an independent science has come of age only in the second half of the 20th century. For some time, for instance, toxicology was viewed as a subdivision of the science of pharmacology.(2) With the formation of the Society of Toxicology in 1961, which has been suggested as the beginning of the national recognition of this science, toxicology finally emerged as an independent science.(3)

As the various scientific disciplines and regulatory agencies continue to struggle with this emerging and controversial science, lawyers face an ever-increasing need to utilize toxicological evidence and experts in both tort litigation and regulatory proceedings.(4) The challenge for defense counsel is to wade through the morass of scientific research methodologies for assessing toxicity, the conflicting opinions within the scientific community concerning the reliability of the data extracted from the various testing models, and the immense range of true expertise among today's "toxicologists."

BASICS OF TOXICOLOGY

One of the most fundamental principles of toxicology is the concept that all chemicals are toxic in large enough quantities. Since human beings obviously can tolerate more of a specific chemical before it becomes toxic than mice can, the quantity of a chemical must be considered in relation to the weight of the organism. This amount per weight is referred to as the "dose." For example, an equivalent dose of a tranquilizer of one ounce per 100 pounds would require a single ounce for a 100-pound person and 20 ounces for a 2,000-pound elephant. From this comes the basic tenet that "the dose makes the poison." This concept should be made clear to a jury in the very beginning, as many people have a preconceived notion that chemicals are either "toxic" or "non-toxic."

As the dosage increases, an organism's response to a particular chemical also will increase. This basic but foundational relationship is known in toxicology as the dose-response relationship. This relationship is best visualized by graphically plotting the level of response--no effect, moderate effect, death--against increasing dosages to create a dose-response curve. Much of toxicology is based on this direct relationship between dose and response and on toxicologists' attempts to identify the particular dose-response curve for human beings and specific chemicals.

While a given dose-response curve might illustrate what happens when a rat is exposed to chemical X, the ultimate goal is to determine, most likely through extrapolation, what the dose-response curve will look like when human beings are exposed to the same chemical. In other words, the science of toxicology simply encompasses an attempt to identify and distinguish the universe of dose-response curves, as each illustrates the relative toxicity of a chemical with various organisms and ultimately suggests the likely human dose-response curve for each of chemical.

RESEARCH METHODOLOGIES FOR TOXICITY ASSESSMENT

Since human beings simply cannot be exposed to varying dosages of a particular chemical to plot the dose-response curve, as ultimately the curve will include a lethal dosage, there are different methods for assessing the relative toxicity of chemicals. There are three basic methodologies, each of which produces a distinct type of toxicological evidence. It is critical in defending a case involving toxicological evidence for defense counsel to understand the basics of each of the testing methodologies, as they provide qualitatively distinct information concerning the toxicity of chemicals, with particular advantages and limitations that should be exploited.

The assessment methods can be categorized as

* in vitro studies, which employ short-term laboratory tests to examine the adverse effect of chemicals on bacteria, cells, organs or embryos;

* in vivo or animal toxicology studies; and

* epidemiological studies.

1. In Vitro Studies

   In vitro, or test-tube, studies, which usually are referred to as short-term screening assays or controlled clinical exposures, are recognized as a fairly inexpensive and quick method for testing whether a chemical is capable of causing mutagenicity or alterations in genetic material. At their simplest, these studies test bacteria and cells to determine whether specific chemicals induce mutagenicity. There are several short-term tests used for making quick assessments of the mutagenic/carcinogenic activity of a chemical. The more common are (1) bacterial mutagenesis assays--the most popular of which is the Ames test, a test for measuring the ability of a chemical to cause mutation of DNA in bacteria; (2) mammalian cell culture mutagenesis assays, which measure chemically induced mutations in cultured mammalian cells; and (3) cell transformation assays, which measure the ability of chemicals to transform cultured cells to a tumorigenic state (able to produce tumors).(5)

   Theoretically, this research focuses on the biochemical mechanisms in an attempt to better understand the cellular mechanics of a particular chemical's effect on human beings.(6) While the data often are useful in identifying which chemicals are good candidates for the next level of toxicological testing, the data generally are not regarded as useful for extrapolating to determine the possible effects on human beings.(7)

2. In Vivo Studies

   The second source of toxicological evidence in the hierarchy of methodologies used for assessing the toxicity of a chemical is in vivo studies, commonly referred to as animal bioassays or animal toxicity studies. At a rudimentary level, controlled laboratory studies are undertaken in which large numbers of animals, typically mice and rats, are exposed to varying doses of specific chemicals to generate statistical data and mathematical models used to identify the dose-response relationship.

   In defining the dose-response curve for various...