Genetics and Epidemiology in Environmental Regulation and the Courtroom: Beware the Genome Gnomes

Thomas Parker Redick
Gallop Johnson & Neuman, L.C.

Christina Galdos Bernstein
Maas, Miyamoto and Bernstein

Introduction

This article will survey of some of the legal issues that are likely to arise in environmental regulation and litigation involving epidemiology issues in the aftermath of the mapping of the human genome. The principal focus will be upon the emergence of newly foreseeable genetic susceptibilities and their impact in toxic tort trials on proof of medical causation of harm to people exposed to toxic chemicals.

While the phrase "paradigm shift" may be the most abused concept in the modern legal lexicon, it aptly describes the changes that will occur with the advent of "toxicogenomics." The shift to "genomic" approaches to assessing risk is already reshaping both regulatory policies and the expert opinions offered in support of toxic tort litigation. Regulation and litigation will rapidly "co-evolve" using genomic data, with advances in regulatory approaches driving new approaches to toxic tort litigation (e.g., newly lowered standards for exposure, based on rare genetic interactions). New approaches in toxic tort cases will use genetic evidence and drive reassessment of regulatory approaches to protection of workers and "bystanders" to chemical use.

The stars of this transformation will be a class of scientists with expertise in toxicogenomics - the "genome gnomes" - who arrive with new-found power to sort out baseless claims from existing classes of presumably affected plaintiffs with much more precision than modern population-based epidemiology. At the same time, these genome gnomes will open doors to heretofore undetected chemical-gene interactions. This new capability will drive an ongoing reassessment of regulatory protections.

First, a word about gnomes and the dual function they serve in folklore. Sometimes gnomes are beneficial to householders, tidying up and organizing their human's life. At other times these gnomes, for various mystifying reasons, would wreak havoc on the orderly lives of everyday people. The role of the toxicogenomic expert in litigation will probably feature both the order-creating and mischief-making models of gnomic intervention in human affairs.

Introducing the Environmental Genome Project: Home of the Gnomes

The National Institute of Environmental Health Sciences (NIEHS), an institute of the National Institutes of Health (NIH), initiated the Environmental Genome Project. http://www.niehs.nih.gov/envgenom/home.htm (site visited Feb. 20, 2002). This effort may identify genes important in making people susceptible to environmentally-associated diseases. The NIEHS will provide a steady stream of gene-chemical interactions over the coming years, causing some concern over the potential misuse of "junk science" genomics. Genome Study Maps Chemical Sensitivity, http://www.junkscience.com/news/egp.html. (Site visited Feb. 21, 2002).

NIEHS teams of "epidemiologists, biostatisticians, ethicists, molecular biologists experienced in using high through-put technologies, and toxicologists and/or other environmental health scientists" will undertake "molecular epidemiology studies of environmentally induced diseases such as asthma and other respiratory diseases, birth defects, neurological diseases, and cancer" - and may one day be retained as experts in the litigation that follows a finding of that a chemical causes disease in a susceptible population. At present, a suspected genetic link (e.g., the "snip"- a single nucleotide polymorphism "SNP") will be posted on the Internet shortly after discovery.

The NIEHS genome gnomes are acutely aware of the profound impact on the public that finding the SNP could have. NIEHS has begun discussions with industry concerning what to do with the volume of new toxicogenomic information NIEHS will generate in the next ten years. NIEHS has indicated an interest in generating partnerships and friendships with various interested industries. Having this new data will present more opportunities for successes, as well as conflict and opposition.

We will have a large amount of data that will be complex and confusing for awhile. We don't want interest groups and the press using the data prematurely to frighten the American public or to misinterpret the data - we want the data used wisely. We want to be able to agree on what some of the scientific issues are and maybe organize an "environmental court" or blue ribbon panel of experts to look at the data as they are being developed and interpret the information for the public and for policy makers.

National Advisory Environmental Health Sciences Council, Minutes of Meeting, Report of Dr. Olden, May 21, 2001. http://www.niehs.nih.gov/dert/council/2001/may2001.htm.

Given the deluge of toxicogenomic data that is on its way, there is a great deal of work to be done before the existing legal frameworks of litigation and environmental regulation are ready to accept this data. Those companies and other stakeholders with interests in reducing uncertainty about chemical health effects should begin now to assess their risks of increased exposure to litigation premised on epidemiological findings, and of increasing pressure to use "mechanistic" approaches to existing toxic substances (e.g., to reclassify substances as "known" carcinogens, as recently occurred to dioxin. See, Tozzi v. United States HHS, 271 F.3d 301, 2001 U.S. App. LEXIS 25093, 53 Env't Rep. Cas. (BNA) 1580 (D.C. Cir. 2001); see also, Alan C. Raul and Julie M. Zampa, Deeper Judicial Scrutiny Needed for Agencies' Use of Science, Washington Legal Foundation Legal Backgrounder, January 25, 2002 (critique of "mechanistic" approach to causation).

Toxicogenomics and the Mass Media: Erin Brockovich's Blue Genes

If the genome gnomes at NIEHS need a preview of the media's treatment of the "toxigene of the week" program that is to come, they need only stop by the video store. In the award-winning film Erin Brockovich, the word "genes" appears only twice - once for the defense and once for plaintiffs. First, the defense attorney smugly informs Erin Brockovich that the health problems plaintiffs are suffering from were caused by diet or "bad genes" - reflecting some mysterious genetic "alternative cause" theories. As new genetic causes of ordinary, everyday, non-toxicogenomic health problems are revealed by genomic data, defense attorneys will increasingly turn to genetic theories to demonstrate an alternative cause for the alleged injury. As will be discussed below, however, the tactical implications of raising a "genetic alternative cause" defense can be daunting.

Genes also made a second cameo appearance, this time for the plaintiffs. When Brockovich turns to an academic expert in toxicology for assistance, he informs her that the compound in question "gets in your genes, you pass it on to your kids." This particular genetic theory was actually adjudicated in the litigation that followed the settlement featured in the film. In the unpublished appellate decision addressing the "gets in your genes" theory espoused by the movie's expert witness (Adams v. Pacific Gas & Electric), the Court of Appeals affirmed the dismissal by Judge Rothschild (Los Angeles County Superior Court) of all "pre-conception" plaintiffs on the grounds that public policy and current science could not permit the claims to go forward. As far as current law and science are concerned, the compound in question did not get into anyone's genes nor was it passed on to the children involved.

A few compounds have crossed the generational boundaries that law and science erect (see, e.g., DES Cancer Network, DES Frequently Asked Questions, http://www.descancer.org/des.html (site visited Feb. 21, 2002) (Believed to prevent miscarriages,…DES has been associated with genital and reproductive tract abnormalities in the daughters and sons of the women who took DES…1 out of every 20 people, in the United States is a DES-exposed mother, daughter, or son."); Press Release, DES Daughters Had Increased Rates of Cancer; An Animal Study Shows 'DES Grand-Daughters' May Too, http://www.niehs.nih.gov/oc/news/desgds.htm). Most courts have been more reluctant, however, to open this "intergenerational" floodgate. The courts will have to determine whether toxicogenomics should turn that tide in favor of plaintiffs. This question will be fought on various fronts as the Environmental Genome Project "spills the genes" for all to see.

Identifying the Genetically Susceptible Subclass

The ability to define genetically susceptible subclasses will permanently alter a substantial part of the landscape of mass tort liability. This change will occur in any instance where a gene/chemical interaction can be documented to the satisfaction of a state or federal court. Genetic linkages will turn up in mass tort and other epidemiologically-based lawsuits as genetic tests developed for specific chemical interactions are created and marketed to potential plaintiffs. The marketing of these tests may precede scientific studies proving the hypothetical link to the "statistically significant" level of proof that scientific methodology would require. As a result, such litigation may drive faster acceptance of a gene/chemical hypothesis, with medical literature and regulatory action trailing behind.

While the mapping of the human genome is expected to open up new horizons in medicine, the most immediate benefit may well prove to be the sorting out of people who are genetically susceptible to the toxic effects of chemotherapy drugs. (See, Francis Collins, Implications of the Human Genome Project for Medical Science. http://jama.ama-ssn.org/issues/v285n5/ffull/jsc00413.html) ("common variants in genes involved in drug metabolism or drug action are associated with the likelihood of a good or bad response… such correlations will be found for many drugs over the next 10 years, including agents that are already on the market.").)

The implications for various types of litigation should be obvious. For every genetically susceptible child that is saved from toxicity by prompt testing, there may be another child who could have been detected, if he had only been tested in time to avoid the adverse reaction. This "eggshell gene" detection method, while breathtaking in its life-saving potential, opens a Pandora's Box of gene/chemical interactions that must be learned and added to medical and chemical warning procedures under product liability law. This also raises an interesting question: will the genetic revolution in medicine be preceded by, or at least accompanied by, a genetic revolution in medical causation for plaintiffs in toxic tort and other litigation premised on epidemiological findings?

There are a few genome gnomes publishing papers in the legal literature, tipping their methodological hand for counsel to see. A recent article in JURIMETRICS, a cross-disciplinary science/law journal published by the American Bar Association's Section on Science and Technology, features plaintiffs' experts promoting genetic methodologies for establishing medical causation, using "genotype stratification" to establish medical causation for susceptible groups. The authors state that this is a way to avoid a "doubling risk" general causation defense to claims for medical causation that are based on small increases in cancer risk. Sander Greenland and James M. Robins, Epidemiology, Justice and the Probability of Causation, 40 JURIMETRICS 321 at 335. (Greenland and Robins disclose their status as plaintiffs' toxic tort experts in footnote 5 of their article, but defense attorneys report having also retained Greenland.)
In recent years, epidemiology and the law have combined to create the "doubling risk" concept, which that also arises in the context of environmental risk assessment because it presents issues concerning the measurement of effects on human health. To cross this threshold, plaintiffs are sometimes asked to prove that their increased risk from chemical exposure is at least two times the background incidence of a given disease. In toxic tort cases, the court may require an initial showing of "general causation" (i.e., that scientific evidence shows an increased risk, with valid scientific studies to support that conclusion). These screening motions often use "doubling risk" as the dividing line. Once general causation is shown using the "doubling risk" screening device, then specific proof of each plaintiff's case ("specific causation") can be addressed through discovery and trial.

For example, the doubling risk doctrine would require, for a group of 100,000 persons, some proof that a background incidence of 100 cancers has doubled to 200 probable cancers in the exposed population. The reason for this is simple - the court will not know which of the persons with cancer before it are imposters if there are only 150 probable cancers. About 100 of these cancers will be part of the "background incidence" of cancer. The odds of one person having the cancer caused by the chemical will be much less than 50% - not within the "preponderance of evidence" standard for proof.

For the defense bar, the doubling risk has served as the bright line for medical causation in tort law applications of epidemiology, and many courts have embraced the idea as well. See, Frederick T. Smith, Daubert and Its Progeny: Scientific Evidence in Product Liability Litigation (Washington Legal Foundation, 2000).

Doubling risk as a judicial sorting device is admittedly crude, since a genetically susceptible person harmed by a chemical might fall through the cracks and elude detection. This shortcoming has led some courts to use doubling risk as only one factor to consider, with other factors entering in to permit causation to be proved even where doubling risk is lacking. See, e.g., In re Joint Eastern & Southern District Asbestos Litigation, 52 F. 3d 1124, 1134 (2d Cir. 1995); see also, Nicklas Akers and Nate Scott, Admissibility of Epidemiological Evidence Under Daubert, The Judicial Gatekeeping Project, http://cyber.law.harvard.edu/daubert/ ch6.htm; Cf. Dave Hitt, Epidemiology 101, http://www.davehitt.com/facts/epid.html (Sites visited Sept. 15, 2001).

The error factor cuts both ways. Doubling risk motions can also reward large numbers of unworthy plaintiffs in some cases. As Greenland and Robins note, "the 'all or nothing' rule" (referring to doubling risk) "can excessively reward plaintiffs." Greenland and Robins at 334. Greenland and Robins also suggest that this evidence will help courts avoid any unfair and arbitrary result. At present, some plaintiffs recover and others do not just because we do not understand the mechanism of causation. Genetic technologies could bring proof of toxic causation closer to "the truth."
With genetic susceptibility evidence, however, a medical causation expert can employ "genotype stratification" and separate the genetically susceptible into their own subclass. From that group of 100,000 persons, there might be 25 genetically susceptible persons who can show excess risk (2x background) from chemical exposure. These people can recover if the class is narrowed by excluding those who are not genetically susceptible. Thus, even if the risk is still marginal (i.e., just above the "doubling" risk for the genetically susceptible), it represents a risk that would have been lost like a needle in a haystack of 100,000 people using traditional epidemiology.

Over time, however, the genotype stratification approach could become standard operating procedure, as the environmental genome project produces more genomic evidence to link to particular compounds or disorders caused by environmental toxins.

Expert Retention, Discovery and Motion Practice
Given the potential for either side to play the genomic evidence card in this new game of "Genomic Poker" (imagine a poker game where someone declares wild cards that change in the middle of the game, and you get the general idea), we offer a few general guidelines for the attorney who is new to the genetic evidence game:

NAME YOUR GNOME - Counsel should retain genetic epidemiologists and specialists conversant in genomic issues (e.g., a neurologist expert that is familiar with relevant genetic disorders of the brain).

TRAIN YOUR GNOME - Plaintiff's counsel should be wary of genetic susceptibilities that are too hypothetical, and lack peer reviewed studies to support the causal connection.

BAN THEIR GNOME - Alert defense counsel may exclude genomic experts that use inadequate statistical evidence matching genotype (our genetic code) to phenotype (what we turn out to be). See, e.g., In Re: Paoli Railroad Yard PCB Litigation ("Paoli II"), U.S. Dist. LEXIS 2529 (3rd Cir. Case No. 86-2229, No. 87-1190, No. 87-1258, No. 87-3227, decided Mar. 7, 2000) (courtroom expert must employ the "same level of intellectual rigor [as] an expert in the relevant field"); Frederick T. Smith, Daubert and Its Progeny: Scientific evidence in Product Liability Litigation, (Washington Legal Foundation, 2000).

ISOLATE THE GENE - Both sides need to research defenses potentially applicable to genetic evidence. For example, consider either of the following defenses: the "state of the art" defense (see, e.g., Anderson v. Owens-Corning Fiberglas Corp., 53 Cal. 3d 987, 994 (Cal. Sup. Ct. 1991) (duty to warn of known or knowable risks in given the "state of art" for medical knowledge available at product distribution)); or the "idiosyncratic reaction" defense (see, e.g., Oakes v. E.I. Du Pont de Nemours & Co., Inc., 272 Cal. App. 2d 645 (Cal. App. 1969) (defendant only liable if it knew or should have known that weed killer would trigger allergic reaction)).

BEWARE "BAD GENE" BACKFIRE - Defense counsel should ask an expert consultant (not a designated witness subject to disclosure) to do research on any "alternative cause" genetic theory before putting opposing counsel on notice of a possible genetic defect. This process can begin by serving a notice of medical examination seeking genetic testing or by serving subpoenas for medical records of family members. (In some cases, an extended family tree complete with medical data will be required to confirm that there is a genetic alternative cause.) Some cases of genetic susceptibility will qualify as alternative causes, while others may only help to prove plaintiff's case.

FAMILY TREE IS KEY- To prove an alternative cause defense, defense counsel should promptly seek family medical evidence in discovery. Relatives of the plaintiff could oppose the subpoena. Protective orders allow information to be disclosed while minimizing adverse consequences (e.g., a "confidential counsel only" protective order).

GENETIC TESTING - If the defense seeks a genetic test, plaintiff's counsel should get a confidential research report from their expert on the implications of the gene should testing reveal one. In addition to the science, plaintiff's counsel may also want evidence (perhaps in expert opinion) of the potential social consequences of disclosure. There may be grounds to deny a medical examination on the grounds that the plaintiff's waiver of privacy for the claim does not merit such an intrusive procedure.

Conclusion

Perhaps the only certainty counsel can look forward to is the knowledge that the 21st century will feature a steady stream of genetic theories that push the boundaries of junk science, while counsel on both sides struggle to define those theories that will work best to prove harm, or alternative cause. On both sides of the bar, there will be "war stories" of winners and losers in the high stakes poker game.

The role of genetic information in calculating risk will increase over time. Both environmental regulators and toxic tort lawyers can expect to see more genetic evidence and expertise presented in the future. Over time, a policy preference for sorting out genetic susceptibilities in the context of litigation rather than regulation may evolve. For now, the toxic tort bar will need to be alert to opportunities for resolving disputes using genetic evidence. For counsel representing them or defending these claims, it will be a brave new world filled with many complex legal and technical challenges. For the general public, it may be a much more fearful world, as obscure impacts of various chemicals make their way onto the Internet, into the media, through regulatory rule-making, and ultimately into the courts.

Thomas Parker Redick is a member of the environmental practice group at Gallop Johnson & Neuman, L.C. in St. Louis and a vice chair of the Section's Toxic Tort and Environmental Litigation Committee (tpredick@gjn.com). Christina Galdos Bernstein is with Maas, Miyamoto and Bernstein in San Diego (cbernstein@maaslitigation.com).