Toxicogenomics: Toward the Future of Toxic Tort Causation

• Publication year: 2003
• Citation: Vol. 5 No. 2003

Jon R. Pierce and Terrence Sexton⁰

I. Introduction

Plaintiff suspects that a chemical in her city's water supply has caused her to develop a rare form of liver cancer. Defendant, a company in Plaintiff's city, has been discharging the chemical into the water for a number of years. Both parties in the toxic tort litigation are at the mercy of an unevenly developed and often-insufficient body of science to establish or rebut the required causation element.

This article will examine the current causation paradigm in toxic tort litigation, pointing out its specific weaknesses. The article will then introduce an emerging discipline, toxicogenomics, which will eventually make it possible to specifically describe the molecular pathways leading from exposure to injury, and in so doing will greatly improve the reliability of causation evidence in toxic tort cases to the benefit of both plaintiffs and defendants. To illustrate its potential usefulness, this article will walk through a hypothetical toxicogenomics experiment involving a suspected liver toxin. The article will conclude by suggesting that judges controlled by Daubert v. Merrell Dow Pharmaceuticals, Inc.¹ would be wise not to admit such evidence until more research can definitively link the described molecular pathways to the specific injury.

II. Current Causation Paradigm in Toxic Tort Litigation

It is a fundamental premise of tort law that a plaintiff must establish that the defendant's acts or omissions proximately caused her injury in order to prevail.² Historically, a variety of inexact tools have been used to attempt to establish a causal link between a substance and an adverse effect.³ A plaintiff in toxic tort litigation must prove, by a preponderance of the evidence, both that the substance at issue could cause the general type of injury suffered (general causation) and that it did cause her injury (specific or individual causation).⁴ Clearing both of these evidentiary hurdles currently is a significant challenge. It is often so daunting that some plaintiffs opt instead to pursue novel causes of action.⁵ If validated by the scientific community, toxicogenomics could become an important tool for plaintiffs and defendants alike.

A. General Causation

To prove general causation, plaintiffs often proffer epidemiological evidence. Indeed, some cases have even required epidemiology studies to satisfy the general causation burden.⁶ In any epidemiology study, "subsets or samples of populations" are examined "to determine whether there is an association between exposure to a substance or factor and subsequent disease or injury."⁷ In general, "large-scale" epidemiology studies can be probative as to whether a chemical or other potentially toxic substance can cause an injury since they involve either "comparing the incidence of adverse health outcomes in groups of exposed and non-exposed individuals, or comparing the incidence of exposure across injured and healthy groups."⁸

Unfortunately, epidemiology studies "are expensive, time-consuming, and require that a large number of people be exposed to the substance."⁹ Given the current capabilities and limitations of science, however, "the hazardous properties of [many] substance[s] often cannot be established" via any other mechanism.¹⁰ Simply put, the existence of epidemiology studies may be the only avenue to meet the general causation burden in a toxic tort case. Furthermore, unless and until a party establishes general causation, any evidence regarding specific or individual causation likely would be deemed irrelevant and inadmissible.¹¹

B. Specific Causation

Another major limitation of epidemiology studies is that they "are relevant only to general causation" since results from such studies cannot establish whether a particular exposure or series of exposures actually caused the disease or injury in a specific individual.¹² Determining specific causation often is much more difficult than establishing general causation.¹³ Additionally, the complex etiology of many diseases creates the possibility that any of a variety of factors could have caused the plaintiff's

injury.¹⁴

To sort through the myriad possible causes of injury, courts often rely on a physician performing a differential diagnosis¹⁵ where the physician, as an expert witness, considers and rules out potential causes of injury, finally stating an opinion as to whether the particular substance at issue caused the plaintiffs injury.¹⁶ Despite advances in medical science, there still are significant limitations to differential diagnoses¹⁷ and some commentators believe that the admissibility of such evidence has become even more difficult in the wake of Daubert.¹⁸ Given the current limitations regarding both general and specific causation, toxic tort litigants need a tool that can eliminate much of the guesswork by definitively linking a substance to the injury that it causes.

III. Toxicogenomics

Toxicogenomics is a relatively new science.¹⁹ Once fully developed, the discipline should greatly improve the current causation paradigm. A multidisciplinary²⁰ field focused on understanding the role of genes in responding to toxicants and other stressors,²¹ toxicogenomics will eventually advance toxicology beyond its current "gross endpoints."²²

Fundamental to toxicogenomics is the hypothesis that, following toxicant exposure and preceding any currently measurable adverse effect, gene expression is modulated in a specific and measurable way.²³ Once described, these patterns and sequences of gene expressions will constitute response "signatures" unique to specific toxicants or classes of toxicants.²⁴

Two recent studies strongly support this hypothesis.²⁵ in one, conducted by Zeytun et al., scientists administered a known toxicant, 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), to mice and then monitored eighty-three genes for a period following the exposure.²⁶ A "significant proportion" of the genes examined showed some form of altered expression following exposure.²⁷ By studying these patterns of altered expression, researchers may be able to identify "'finger print' genes, which could serve as biomarkers for predicting toxicity induced by a specific class of toxicants."²⁸ in an even more convincing study by Hamadeh, et al., researchers treated rats with several different chemicals and monitored a number of genes following the exposures.²⁹ The researchers successfully developed distinct gene expression profiles for each of the classes of chemicals tested, even though some of those chemicals had the exact same previously measurable exposure endpoint.³⁰ These two studies strongly support the hypothesis that following exposure to a specific toxic substance, gene modulation will occur in a manner that is both measurable and predictable.

The initial toxicogenomics studies suggest that the field holds great promise for toxic tort litigants. Eventually, it could reduce or eliminate much of the current causation guesswork by generating evidence that describes how a toxic substance would affect a person at the molecular level.³¹ As previously stated, the promise of toxicogenomics extends to all parties involved in toxic tort litigation. Commentators,³² defense groups,³³ and plaintiffs' groups³⁴ alike have already recognized its potential importance.

A. The Scientific Underpinnings of Toxicogenomics

in a relatively short period, scientists have made a remarkable amount of progress toward discovering and describing our molecular makeup.³⁵ From "[t]he rediscovery of Mendel's laws of heredity" early in the twentieth century, to the elucidation of the DNA double helix fifty years ago, and the sequencing and analysis of individual strands of DNA today, humans have expanded exponentially the frontiers of genetics over the past hundred years.³⁶ Two particular advances in the field promoted the emergence of toxicogenomics as a discipline.³⁷ First, the rapid development of DNA sequencing capabilities over the past two decades has allowed scientists to sequence entire genomes. Second, researchers are utilizing the vast information contained in these genome sequences via sophisticated DNA microarrays.

1. Gene Sequencing

One of science's most recent endeavors, and one that still is very much ongoing, is the development of methodologies and equipment for rapidly sequencing an organism's DNA. Sequencing a strand of DNA is a multi-step³⁸ process resulting in a comprehensive description of the organism's individual base sequence.³⁹ The sequence of bases in DNA is the most definitive means of distinguishing among species and among individuals within a species.⁴⁰

DNA sequencing is currently complete for hundreds of viruses, viroids, plasmids, and organelles, as well as for dozens of other simple organisms.⁴¹ in 1995, researchers completed the first DNA sequence of a free-living organism and the sequencing of a number of other more complex organisms rapidly followed.⁴²

The most ambitious DNA sequencing project by far is the collaborative⁴³ effort to map the human genome.⁴⁴ Scientists published a draft version of the human genome sequence in February 2001,⁴⁵ and announced that this enormous effort was finished on April 14, 2003.⁴⁶ The National Center for Biotechnology Information currently places the number of known human genes at about 24,000 not including the genes on the sex chromosomes.⁴⁷

2. Microarrays

Given the vast size of a DNA molecule⁴⁸ and the potential amount of information available therein, a research tool capable of exploiting such large quantities of information is necessary. Microarrays are such a tool.⁴⁹ A microarray is typically either a glass slide or a computer chip that has had a specific arrangement of known gene sequences either spotted onto it or engineered onto it, respectively.⁵⁰

Although the origins of microarrays can be traced to the mid to late 1980s,⁵¹ today's microarray is highly evolved and capable of vastly superior analytical feats. As one...