Role of toxicology in toxic tort litigation: establishing causation.

• Author: James, Robert C.

TOXICOLOGISTS research the nature of any adverse health effects produced by a chemical and assess the probability of occurrence of these adverse effects. In applying their science to toxic torts, toxicologists establish the known effects of the chemical in human beings and determine whether the alleged dose experienced by plaintiffs was sufficient to have caused any of their alleged diseases. Called "causation analysis," this process utilizes a specific methodology to establish to a scientific degree of certainty whether plaintiffs' claims are valid.

Possibly the first effort to formalize this objective methodology occurred more than a century ago with the development of the Henle-Koch postulates for establishing the causes of infectious diseases. Sir Bradford Hill later defined a similar methodology for determining whether a particular chemical found in the workplace should be considered a human carcinogen. Now there are at least 10 criteria proposed as the basis of the scientific method for determining whether a chemical in fact does cause a specific disease in human beings.(1)

These criteria include:

1. The strength of the human association,

2. The consistency of the human association,

3. The specificity of the human association,

4. Temporal relationships,

5. Dose-response relationships,

6. Biological plausibility,

7. Experimental evidence in animals,

8. Structure activity analogy,

9. Confounding disease or risk factors, and

10. The coherence and weight of the evidence.

    Regulatory agencies are recognizing the importance of adhering to an established scientific methodology to determine risks. In its 1992 draft guidelines for carcinogen risk assessment, the Environmental Protection Agency cites seven criteria(2) adapted from Rothman(3) as those it recognizes as the scientific method that should be used to determine whether a chemical is a human carcinogen. These are:

1. Temporal relationship.

   This is the single absolute requirement. It does not prove causality itself, but it must be present if causality is to be considered. The disease must occur within a biologically reasonable time frame after the initial exposure. The initial period of exposure to the agent is the accepted starting point in most epidemiologic studies.

2. Consistency.

   Associations are observed in several independent studies of a similar exposure in different populations. This criterion also applies if the association occurs consistently for different subgroups in the same study.

3. Magnitude of the association. A causal

   relationship is more credible when the risk estimate is large and precise (narrow confidence intervals).

4. Biological gradient. The risk ratio is

   correlated positively with increasing exposure or dose. A strong dose-response relationship across several categories of exposure, latency and duration is supportive, although not conclusive, for causality, given that confounding is unlikely to be correlated with exposure. The absence of a dose-response relationship, however, should not be construed by itself as a lack of a causal relationship.

5. Specificity of the association. The

   likelihood of a causal interpretation is increased if a single exposure produces a unique effect (one or more cancers also found in other studies) or if a given effect has a unique exposure.

6. Biological plausibility. The association

   makes sense in terms of biological knowledge. Information from animal toxicology, pharmacokinetics, structure-activity relationship analysis and short-term studies of the agent's influence on events in the carcinogenic process are considered.

7. Coherence. The cause and effect

   interpretation is in logical agreement with what is known about the natural history and biology of the disease--that is, the entire body of knowledge about the agent.

   SCIENTIFIC METHOD AND TOXIC TORTS

   The criteria and scientific method for establishing the cause of a specific person's disease in a toxic tort case are based on essentially the same criteria as those used to determine what diseases a chemical is capable of causing. That is to say, before one can conclude to a reasonable degree of scientific or medical certainty that exposure to a specific chemical has resulted or will result in a specific disease, one must be able to demonstrate that a scientific basis for establishing causation does exist. Simply demonstrating exposure to a chemical, regardless of whether this exposure occurs in the workplace or some other environment, does not permit one to conclude to a reasonable degree of scientific or medical certainty that a given exposure to a specific chemical has resulted or will result in a specific disease.

   While the methodology for establishing the cause of a specific disease in a specific individual may be more exhaustive, the five basic conditions that must be met before causation can be established are:

1. The chemical in question is capable of producing the alleged medical condition in human beings.

2. The exposure was of sufficient magnitude to produce the alleged medical condition.

3. The chemical exposure was temporally related to the onset of the alleged medical condition.

4. Potential alternative causes of the medical condition (confounders) can be ruled out.

5. There is coherence and consistency in the evidence evaluated in this specific case.

   Thus, in toxic tort cases the burden of proof for plaintiffs is to demonstrate that these five criteria can be satisfied. In contrast, the objective of the defense is to (1) ensure that the court understands that failure to satisfy any of these five criteria is fatal to the plaintiff's case, and (2) demonstrate that one or more of these criteria cannot possibly be satisfied.

   Given that the two basic functions of toxicology are to examine the nature the adverse health effects produced by a chemical and to assess the probability of their occurrence, the role of the toxicologist is largely that of assessing the evidence and determining if either one or both of the first two criteria for establishing disease causation in a specific individual are satisfied by the alleged chemical exposure. Or stated another way, the role is largely that of helping establish the known toxicity of the chemical in human beings and of determining whether the dose experienced by plaintiffs was sufficient to have caused any of their alleged diseases.

   While for some chemicals there is sufficient data to describe the known toxicities for human beings and their dose-response relationships, there are many instances in which attorneys or expert witnesses attempt to use and extrapolate animal test data to support their allegations or conclusions regarding human beings. They also may use regulatory exposure standards that are often based on some extrapolation of animal data. Thus, a related issue often raised in toxic tort cases, either directly or indirectly, is the applicability of the assumptions used to generate regulatory standards and whether they are consistent with the decidedly different process of establishing and proving causation.

   The following sections focus on some of the issues raised when one attempts to rely on animal data and discuss some of the strengths and weaknesses of the animal-to-man extrapolations.

   1. Does the Chemical in Question Cause the Alleged Toxicity in Human

      Beings?

      For some chemicals there is sufficient data to describe adequately the known toxicities and expected dose-response relationships in human beings. The answer to the question of causation is rather straightforward for such compounds. An evaluation of the exposure history, the potential for the person to have received a dose and prior medical records can quickly give one a feel for the viability of the claim. For most chemicals, however, attorneys and expert witnesses will attempt to use and extrapolate animal test data as a means of supporting their allegations or conclusions. When this happens, the function of the toxicologist is to determine the validity of the claim if there are limited, equivocal or no human data but positive animal data suggestive of the compound's possible toxicities.

      Even in many cases where the human data are overwhelmingly negative, there might be a wealth, or even limited, positive animal evidence that claimants will use to support their contentions. This is often the case when cancer or fear of cancer is being alleged, as more than 90 percent of the compounds considered to be carcinogens are classified solely on the basis of animal studies.

   2. Animal-to-Man Extrapolations: Catch 22

      While it may be prudent to use animal data to predict what the human response might be when human data are unavailable, it should be remembered that when one makes an animal-to-man extrapolation, the basic assumption is that the animal response is both qualitatively and quantitatively the same as the human response. However, since two different species may respond differently, both qualitatively and quantitatively, to the same dosage of a particular chemical, any animal-to-man extrapolation is a Catch-22 situation.

      To know whether it is valid to extrapolate from a particular animal species to human beings requires prior knowledge of both outcomes. While toxicologists use animal data to predict possible human outcomes, the potential for significant qualitative and quantitative differences among species in their response to that chemical essentially requires that the human response first be known before an appropriate animal model can be selected for testing and extrapolation purposes. The selection of the appropriate animal model is complicated by the fact that innumerable and vast species differences exist. These differences are related primarily to the anatomical, physiological and biochemical differences among species and because these differences may produce significant differences in the metabolism and pharmacokinetics of the chemical.

      Differences in target organ concentrations and in the chemical intermediate present, combined...