Causality in Illnesses Thought to Result from Toxic Exposures

Part I: Toxicology

Litigation in matters of toxic exposures usually hinges on proof of a causal link between exposure and illness. We have seen a few extreme (and unsustainable) positions taken by both plaintiffs and defendants in litigation, as well as a larger number of cases where degree of causation or level proof is legitimately debatable. This article is the first in a planned series outlining approaches useful in analyzing the question. The series will include an introduction to toxicology, an introduction to epidemiology, and a discussion of exposure and risk assessment.

Toxicology is the study of poisons or toxicants and their adverse effects on various organs and tissues of the body. The term "toxin" is often used as a synonym for poison, but some specialists prefer to reserve that name for poisons of biological origin, like snake venom or poison ivy. With advances in imaging technologies and in chemical measurement technologies, the scope of toxicology is progressively broadening to subsume more subtle, subclinical effects of toxicants.

Paracelsus was a medieval alchemist who is often recognized as both the "father of toxicology" and the "father of pharmacology" because of his pioneering work in systematizing the study of effects of chemicals and drugs. Paracelsus stated that all substances are poisons, and that only the dose differentiates a poison and a remedy. This notion of dose is critical for understanding toxic effects. At very low doses, even the most toxic chemicals known will cause no discernable effect on humans, while at very high doses, even essential substances like oxygen and water will harm or kill. In between, different amounts will cause different degrees of harm.

Exposure is a necessary but not sufficient condition for toxicity. This may seem trivial, but we have been astonished how often educated people overlook the fact. Before an illness can result from poisoning, enough of the poison must be absorbed into the body to cause harm. The mere presence of even a very potent poison (toxicant) in the vicinity of a person is not sufficient: chemicals do not magically leap from sealed containers, run out, and bite people. They can, however, escape those containers through a variety of mishaps and move through air, water, soil, or food to where a person is. Analysis of how poisons move from where they were created to where a person could be poisoned by them will be discussed in the article on exposure and risk assessment.

Toxic response is a function of the characteristics of the toxicant and of the exposure. Characteristics of toxicants that alter the response include the source, chemical form, and physical state of the toxicant. Arsenic provides an example of variation in toxicity with source and also with chemical form. Elemental arsenic may be found in high levels in the large piles of mine tailings at current and former copper mining and smelting sites throughout the western U.S. Methylated arsenic (an organic chemical form of arsenic) accumulates in exposed fish and seafood. Generally, toxicologists consider elemental arsenic to be much more potent than methylated arsenic in terms of causing cancer or neurotoxicity.

Physical state refers to whether the toxicant is in the form of a solid, liquid, or gas or vapor. An example of the influence of physical state on toxicity obtains from considering how vaporization of a liquid solvent increases likelihood of inhalation, rapid absorption into the body, and rapid onset of acute toxic effects.

Understanding toxicology requires recognition of the spectrum of toxic effects. The term "side effects" usually refers to low probability adverse effects that may occur with drugs or pharmacologic agents. In the U.S., the FDA requires an extensive process to determine drug efficacy and safety before marketing is permitted. Hence, the probability of adverse effects from use of these agents is very small. By contrast "adverse or toxic effects" result from exposure to chemicals that are not carefully screened for safety before marketing (like solvents and metals used in industrial settings.) Therefore, the probability of adverse effects from sufficiently high exposures tends to be much greater.

Carcinogenic (cancer-causing) effects include the generation of any type of cancer caused by toxicant exposure. The potential for a toxicant to cause carcinogenic effects is assessed by observing its ability to generate tumors in animal test systems. Non-carcinogenic effects include all toxic effects other than the generation of cancer.

Acute effects are adverse effects that occur immediately or shortly after exposure to a toxicant. Chronic effects occur after some delay or after a long period of chronic exposure. Carcinogenic effects for which there is characteristically a long latent period (typically two or more decades) between exposure and effect are included in chronic effects. Prolonged exposures that result in overt effects only after some time (like ongoing low-level lead exposure in drinking water causing peripheral neuropathy after several years) are also included in chronic effects. Beware of confusion resulting from these homographs. Acute and chronic refer both to duration or time of onset of effects and to duration of exposure. Although the words are the same, the meanings differ.

Target organs are the specific organs or tissues adversely affected by a particular toxicant. Organs may be more sensitive to certain poisons because of the way the poison is distributed in the body or because of the way the organ reacts with, responds to, or metabolizes the poison. Mechanism of action includes the biochemical, physiologic, and anatomic changes caused by a toxicant that result in its characteristic toxic effects.

Characteristics of exposure include: dose or amount received, the temporal characteristics of the exposure, the nature of the exposure or how the poison was presented to the body, and receptor characteristics. Dose for most poisons is measured as mass (weight) of the poison or better as mass of the poison per kilogram of body mass. The latter allows comparisons of expected activity on animals or people of different size. For gases or vapors, dose is estimated as a product of the concentration of the poison in air multiplied by the number of minutes the person breathed the contaminated air. If a person is breathing a constant volume of air each minute, then the amount of poison taken into the lungs can be doubled by either doubling the time in the same environment or by doubling the concentration with the same time. The product of concentration and time is usually written Ct and expressed in mg-min/m³ [(milligrams per cubic meter) x (minutes)]. We tend to think of all equal Ct exposures as equally toxic, but for a variety of reasons, shorter exposures at higher concentrations usually cause more damage.

Temporal characteristics refer to how long the exposure continued. Acute exposures are usually a single dose or a single period lasting from a few seconds to as long as a day or so. In animal studies, the amount of poison needed to kill half of the animals, called the LD₅₀ for lethal dose--50%, is the toxicologic datum most commonly available for a poison. It is determined by exposing or dosing small groups of animals to different amounts of poison, noting the number in each group that die, and determining a dose that would kill half of them. Chronic exposures extend for a substantial fraction of the animals lifetime: the experiments can be designed so that they are analogous to lifetime or 40-year working-life exposures in humans.

Nature of exposure refers to such questions as whether the chemical is pure or in a mixture, the route by which the poison enters the body, and the physical and chemical state of the toxicant. Receptor characteristics include individual susceptibility based on age, gender, or genetic make-up. Children, for example, may be more susceptible to lung irritants than adults owing to their small, easily-obstructed airways.

Different types of studies yield information on toxic responses. Animal studies provide most of our information because we cannot ethically expose humans to dangerous materials. The studies fall into categories by the length of time involved, by the animal species used, and by the illnesses or effects (end points) that the researchers looked for. Acute toxicity studies, yielding an LD₅₀, are the most common. The LD₅₀ is the bit of information most commonly available for substances. Acute toxicity studies also are often useful in identifying target organs and in providing some information on the reversibility and duration of effects and mechanism of action.

The term subacute studies, refers to investigations involving repeated administration of a toxicant to animals for two to four weeks. These studies are particularly useful to study irreversible (and hence cumulative) effects or the effects of accumulation of toxicants in the body.

In subchronic studies, investigators typically administer four to five different doses of toxicant to animals for 90 days. These studies establish a no-observable-adverse-effects level (NOAEL), which will be between the lowest dose at which adverse effects are observed and the next lowest dose. The NOAEL is the best estimate of the threshold for injury and is the basis for regulating non-carcinogens.

Carcinogenicity bioassays require administering the toxicant to groups of animals (usually rats and mice) to determine the number of tumors produced at each dose level tested. To be designated a proven animal carcinogen, a toxicant must cause tumors in two species.

Mutagenicity studies employ a wide variety of methods to determine adverse effects or alterations in the genetic material of cells. Mutations in somatic (non-reproductive) cells could cause adverse effects (like cancer) in the affected organism. Mutations in germinal cells (ova and sperm) may be passed on to subsequent generations.

Chronic non-carcinogenic effects studies administer toxicant to animals for an entire lifetime (typically, two years for rats and mice.) Chronic non-carcinogenic effects may be significant when a toxicant has a long half life in the body or when it has irreversible effects (and hence cumulative effects with ongoing exposure.)

Multi-generational reproductive and developmental effects studies continuously expose three generations of male and female animals to toxicant throughout gestation, lactation, development, and reproduction. Reproductive success of each generation is assessed. Necropsy evaluations of the first group of offspring of each generation and half of the pregnant females after each mating detect embryologic malformations, the number of embryos, and abnormalities of implantation or fetal development. Detection of teratogenic effects or adverse effects on female or male reproductive functions or capacity may be further evaluated by more specialized studies.

Human studies provide the information most relevant to evaluating human health risks from toxicant exposures. Human data come primarily from two sources: environmental or occupational epidemiologic studies and case reports. Both types will be discussed at greater length in the second article in this series. Environmental and occupational epidemiologic studies are done to observe the effects of unplanned exposures on groups of people. Case reports describe the clinical recognition, evaluation, and treatment of one or a few cases of poisoning resulting from exposures to particular toxicants.

Continue to Part II - Epidemiology by Clicking Here

Leslie J. Hutchinson, M.D., M.P.H.

Sanford S. Leffingwell, M.D., M.P.H.