Golru, Sara --- "Judging the genome: Using genetic evidence to support or refute causation" [2023] PrecedentAULA 19; (2023) 175 Precedent 28

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JUDGING THE GENOME

USING GENETIC EVIDENCE TO SUPPORT OR REFUTE CAUSATION

By Dr Sara Golru

This article explores the increasingly important role that genetic evidence is playing in toxic tort litigation, and indeed personal injury litigation more broadly, with reference to recent case law in both Australia and the United States. Genetic information can provide valuable evidence to support or dispute causation by showing genetic changes indicating a plaintiff’s exposure to a toxin and/or injury because of exposure to a toxin; genetic predisposition to disease; and genetic susceptibility to a toxin. This article also observes that, while courts can compel plaintiffs to undergo genetic testing as a means of shedding light on the issue of causation, caution is needed to balance the benefits to the administration of justice with the risks, which include misinterpretation and violation of individual and familial privacy and autonomy.

Imagine that a plaintiff alleges they were injured by a pollutant in their drinking water, toxic dust in their workplace, a pesticide used in their garden, or a vaccine or medication they were prescribed. In such a case, how can the plaintiff prove that their injury (be that a cancer, birth defect or brain damage) was caused by exposure to that specific toxin, rather than the myriad of other exposures they experience on a daily basis? The methods lawyers have used in attempts to prove or disprove causation in such toxic injury cases include epidemiological evidence, toxicological evidence and the developing field of genetic evidence.

EPIDEMIOLOGICAL EVIDENCE

Epidemiologists typically seek to determine whether certain substances are capable of causing disease in the general population, rather than whether a certain substance caused a specific individual’s disease. Conversely, tort lawyers seek to determine causation in order to assign responsibility for harm caused to specific individuals. Despite these conflicting aims, epidemiologic studies have proven to be particularly influential in toxic tort cases. For example, in the relatively recent PFAS/PFOA^[1] class actions, a ‘science panel’ of three epidemiologists was employed to survey 70,000 residents who resided in districts where the water had been contaminated by PFOA released from a DuPont manufacturing facility.^[2] However, this class action also highlighted the issues with efficiency, time and financial costs associated with epidemiological evidence, as the science panel did not make any determinations until eight years after the settlement.^[3]

Epidemiologic studies are often expensive and time consuming, and cannot feasibly be conducted in a number of cases, such as where there is an insufficient number of persons exposed to the relevant substance or the incidence of the disease is so rare that epidemiologic studies are inadequate to reveal the effect of the substance.^[4] In such cases, toxicological evidence is especially valuable.

TOXICOLOGICAL EVIDENCE

Toxicological studies (where an animal or cell is exposed to a toxin) can provide proof of the causal relationship between chemical exposure and development of disease in humans, especially when viewed in light of other evidence (including epidemiology and genetics). Toxicological evidence can contribute to ‘the weight of evidence supporting causal inferences by explaining how a chemical causes a specific disease through describing metabolic, cellular, and other physiological effects of exposure’.^[5] Such evidence can also reveal ‘the increased risk of contracting a disease at any given dose and help rule out other risk factors for the disease’.^[6] A primary advantage of toxicological evidence is that ‘[i]t is much easier, and more economical, to expose an animal to a chemical or to perform in vitro studies than it is to perform epidemiological studies’.^[7] Moreover, animal and cell studies can be ‘rigidly controlled in a way that is not possible in epidemiological studies’.^[8]

However, toxicological studies alone are rarely sufficient to provide direct evidence of the cause of a particular plaintiff’s harm. Such studies typically seek to determine the adverse impacts of a substance on general human populations or the environment, rather than on specific individuals. The utility of toxicological evidence has been limited by the difficulty of extrapolating results obtained from the artificial setting of animals and tissues in laboratories. For example, there can be difficulties in generalising from animal studies to humans where there is a:

• lack of similarity between species;

• lack of similarity between substances;

• lack of similarity between injuries;

• lack of similarity between doses;

• reliance on regulatory standards; and

• reliance on the no-threshold theory.^[9]

GENETIC EVIDENCE

Genetic evidence has been proposed as a means of addressing the shortcomings of toxicological and epidemiological evidence.^[10]

The use of genetic (and epigenetic) information to support or dispute causation in toxic tort litigation typically involves one or more of the following:

1. Genetic markers of exposure and/or effect: Evidence of a pattern in the plaintiff’s genetic makeup (their genome) that shows exposure to a specific toxin and/or a medically significant harmful effect as a result of exposure to that toxin.

2. Genetic markers of disease predisposition: Evidence of specific genetic mutations (changes) in the plaintiff showing they have a genetic predisposition to a disease.

3. Genetic markers of toxic susceptibility: Evidence of specific genetic mutations showing the plaintiff has a genetic susceptibility to a specific toxin.

Genetic markers of exposure and/or effect

In order to prove exposure to a toxic substance, plaintiffs can adduce evidence of biomarkers existing in their genome that indicate molecular changes to their cells as a result of exposure to a toxic substance. Genetic markers can either indicate exposure to any toxic substance or a specific substance where a pattern of specific mutations in an individual’s genes reveals precisely which toxic substance caused the mutation. In particular, exposure to a toxic substance may result in direct alteration of:

• Coding DNA sequence;

• chromosomal aberrations;

• epigenetic factors; and/or

• gene expression.

In toxic tort cases, ‘[s]uch alterations may serve as biomarkers of exposure, or, if the alterations indicate or accompany clinical manifestations, as biomarkers of effect’.^[11]

Gene expression profiles have proven to be a useful means of disproving causation in toxic torts where plaintiffs allege exposure to radiation caused their cancer. In Naomi Guzman v ExxonMobil Corp.,^[12] the plaintiff claimed that her thyroid cancer was caused by exposure to radioactive material. The defence expert was able to use gene expression profiling to show that the plaintiff’s cancer tissue had the ‘gene signature’ for sporadic thyroid cancer. This indicated that the cancer was not induced by radiation, but rather was idiopathic.

Genetic markers have also provided a useful method of proving or disproving causation in several cases where plaintiffs allege exposure to benzene caused their leukemia. Benzene is a substance found in crude oil, gasoline, cigarette smoke, and trace amounts have been found in consumer products (such as sunscreen). For example, in several benzene-leukemia cases, plaintiffs have argued that they have genetic markers that are specific to individuals who have been exposed to benzene and have leukemia.^[13]

Defendants have also harnessed genetic evidence in such cases, by arguing that plaintiffs did not have the type of genetic markers one would expect to see altered if they had been exposed to benzene.^[14] This evidence was excluded in the cases in the late 1990s primarily because the courts concluded the evidence was untested and not scientifically reliable.^[15] However, as the field of genetics has developed, the courts have become more open to accepting this evidence and it appears to have been outcome-determinative in some cases.^[16] Plaintiff and defence lawyers have also relied on genetic evidence to prove or disprove causation in tobacco cases by showing the presence/absence of specific markers in the plaintiff’s genome that are more common in smokers than in non-smokers.^[17]

Genetic markers of disease predisposition and toxic susceptibility

Genetics can also help to elucidate the considerable variability in each individual’s response to a given toxin. Inherited susceptibility genes can broadly be divided into two groups:

1. genetic markers of toxic susceptibility (those genes that increase risk only when there is exposure); and

2. genetic markers of disease predisposition (those genes that increase risk regardless of exposure).

The former can be used by plaintiffs to support causation and the latter can be used by defendants to refute causation.

There have been several ‘vaccinomics’ cases where plaintiffs allege that their injury (typically a form of epilepsy) was caused by the diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP).^[18] Evidence of genetic predisposition has been successful in disproving causation in these cases, so long as the plaintiff tested positive for the relevant mutation (for example, SCN1A mutations that have been linked to forms of epilepsy).^[19]

In relatively recent talcum powder litigation, counsel for the plaintiffs was able to effectively suggest plaintiffs whose genetic test results showed a BRCA1 or BRCA2 mutation were ‘move[d]...closer to the edge of the cliff [and were] in especially precarious situations for being exposed to significant levels of asbestos that might give [them] a shove’.^[20] The plaintiff’s expert testified that ‘[t]he last person you’d want to expose to asbestos with the most potent carcinogens is somebody who had any defect in their ability to repair DNA’.^[21] The plaintiff could therefore present the case that their genotype heightened their risk of developing ovarian cancer after exposure to talcum powder. It is likely that, as genetic testing becomes more routine, these arguments will become increasingly common. In response, defendants could argue the alleged exposure to talcum powder could not have a synergistic effect, and the plaintiff would have developed ovarian cancer regardless of toxic exposure. These issues are also not unique to BRCA1 and ovarian cancer, but are also increasingly relevant to other contexts, for example defendants have argued BAP1 gene mutations caused the plaintiff’s mesothelioma, and plaintiffs have argued the mutation merely made them more susceptible.^[22]

COURT-ORDERED GENETIC TESTING

If a defendant requests a plaintiff to undergo genetic testing and the plaintiff refuses to do so, courts are able to compel the plaintiff to undergo the testing.^[23] Courts can order a variety of genetic tests, including karyotyping, gene panel sequencing, single gene sequencing, microarrays, whole exome sequencing and/or whole genome sequencing.

Several courts have shown a willingness to grant motions to compel genetic testing in toxic tort cases and, in some, the results of the test have been detrimental to the plaintiff’s case.^[24] For example, in the case of Bowen v EI Dupont de Nemours & Co, the plaintiff alleged that her ‘retarded foetal growth and cell development’ was caused by exposure to Benlate (fungicide).^[25] They argued that there was in utero exposure while her mother was spraying houseplants in the early stages of pregnancy. The defendant alleged that there were no environmental causes and in fact a specific condition (CHARGE syndrome) and in particular a genetic variation (CHD7) was the cause of the plaintiff’s harm. The defendant was able to successfully obtain a court order to genetically test the plaintiff for that specific genetic variation and the genetic test revealed the plaintiff had the CHD7 variation. The genetic testing evidence was so powerful that it even prompted the plaintiff’s expert to change his opinion and support the defendant’s contention that CHARGE syndrome was the correct diagnosis and the CHD7 gene ‘played a substantial role in bringing about [the plaintiff’s] condition’.^[26]

The Court ultimately granted the defendant’s motion for summary dismissal and concluded that ‘[t]he position advocated by the defense is clear – the mutated CHD7 gene was the sole and proximate cause of [plaintiff’s] CHARGE syndrome’.^[27] The Court placed particular emphasis on the fact that the defence ‘theory ha[d] substantial support in the record in that it has been tested, peer reviewed and published, apparently without consequential dissent’.^[28] This case is a testament to the power of court-ordered genetic testing to disprove causation in toxic torts.

Despite the notable benefits of ordering genetic testing, courts should be wary of the issues with such testing. Although genetic testing could reveal a precise diagnosis, it could also simply reveal a pre-symptomatic, predictive diagnosis. There are still many genetic variants of uncertain significance where the functional importance of the genetic variant is unknown and/or is unable to be conclusively linked with a disease. So, we know these genes have a variation but we do not know the signification of this variation – it could be pathogenic (disease-causing) or it could be completely benign (and have no impact whatsoever on disease).

There are also differing interpretations of this evidence – for example, there is considerable variability in the estimated penetrance of BRCA1 mutations: some studies show the BRCA1 mutation increases the risk of breast cancer by 30 per cent and other studies show it increases the risk by 90 per cent but usually the accepted range is 40–70 per cent.^[29] Genetic evidence is still statistical/population-level data, which means it carries many of the problems associated with other forms of statistical data. However, if the relevant mutation is a highly penetrant, highly specific mutation that causes the disease at issue, the fact that the genetic data are population based is reduced to a triviality, that is, 100 per cent of mutation carriers develop the disease and 100 per cent of non-carriers do not, such as the Huntington’s disease mutation. In regard to SCN1A, ‘penetrance varies by phenotype’, for example, the penetrance is estimated ‘to be 70 per cent for the GEFS+ phenotype [but] 90 per cent for the familial simple febrile seizure phenotype’.^[30]

It is particularly difficult to attempt to predict the probability of the plaintiff developing a multifactorial disorder. Multifactorial disorders are caused by gene-environment interactions so they are by their very nature much harder to predict compared to a monogenic (single gene) disorder or even a polygenic (multiple genes) disorder. Genetic testing is usually more accurate in determining the probability of developing monogenic or polygenic genetic conditions because the manifestation of the disorder (such as Huntington’s disease) does not depend on environmental interactions. It is caused by genes and genes alone. However, even these monogenic or polygenic disorders are problematic. For example, the genetic test may be able to accurately predict the probability of developing a disease but it will usually be unable to account for how severe the symptoms will be and when the symptoms will occur, if at all. For example, just because a plaintiff has a BRCA1 mutation does not mean they will develop breast cancer. On the other hand, many individuals who do not have the relevant BRCA1 mutation will develop breast cancer.

Practically speaking, the threshold for compelling medical examinations is quite low, so courts have almost always concluded that reliability is a matter for trial.^[31] Courts will typically order the requested testing so long as it has the capacity to shed light on the issue of causation.

There are also notable individual and familial privacy violations that could result from court-ordered genetic testing. In order to avoid such violations, it is important that courts consider, for example, issuing adequate protective orders prohibiting redisclosure of the genetic test results. This could take the form of an implied undertaking and potentially also orders restricting publication.

Genetic data can also produce incidental findings such as an incurable condition (like Huntington’s disease) which can lead to stigma and/or discrimination, and potentially also have a deterrent effect by dissuading individuals from commencing personal injury litigation due to fear of discovering potentially traumatic information. It is certainly not every case that will turn up issues of stigma and discrimination – many genetic test results will likely reveal no relevant mutations, and lethal genetic conditions are rare. However, it is just as important to consider the emotional trauma of knowing and the right not to know as it is to consider issues of stigma and discrimination. It will therefore be up to the courts to determine, on the facts of each case, whether any detriment to the plaintiff outweighs the benefits of compelling testing to assist the truth-seeking mission of the court.

CONCLUSION

Ultimately, genetic evidence, like epidemiological and toxicological evidence, can provide a valuable method of proving or disproving causation in toxic tort litigation. It is crucial that the evidence is viewed as a whole, rather than considering each piece in isolation. Genetic markers will rarely provide conclusive evidence. However, such data can often provide probabilistic evidence that sheds light on causation, which can be useful if it helps litigants meet the more likely than not burden of proof.

Dr Sara Golru is a medical lawyer at HWL Ebsworth Lawyers and sessional academic at University of Sydney Law School. EMAIL [e-mail].

This is an edited excerpt of the thesis, Judging Your Genome: Adducing Genetic Evidence to Support or Refute Causation in Australian and American Toxic Tort Litigation, by Dr Sara Golru. The full thesis can be accessed at: <https://ses.library.usyd.edu.au/bitstream/handle/2123/29777/Golru_SG_Thesis.pdf?sequence=1&isAllowed=y>.

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^[1] PFAS describes a group of chemicals known as per- and poly-fluorinated alkyl substances. PFOA denotes perfluorooctanoic acid, also known as C8, a fluorocarbon used in the production of Teflon.

^[2] Leach v EI Du Pont de Nemours & Co (W Va, No 01-C-608, 2005). K Steenland, D Savitz and T Fletcher, ‘Class action lawsuits: Can they advance epidemiologic research?’, Epidemiology, Vol. 25, No. 2, 2014, 168. For epidemiological evidence in Australian PFAS/PFOA class actions, see, eg, Smith v Commonwealth of Australia (No 2) [2020] FCA 837, [5], [60].

^[3] Steenland, Savitz and Fletcher, above note 2, 168.

^[4] See, eg, ‘Reporter’s Note to Comment (c)(4)’ in Restatement of the Law Third, Torts, Liability for Physical and Emotional Harm, The American Law Institute, United States, 2010, s28.

^[5] Federal Judicial Center, Committee on the Development of the Third Edition of the Reference Manual on Scientific Evidence, National Research Council, Policy and Global Affairs, Reference Manual on Scientific Evidence, 3rd ed, National Academies Press, United States, 2011, 637.

^[6] Ibid.

^[7] Ibid, 659.

^[8] BD Goldstein, ‘Toxic torts: The devil is in the dose’, Journal of Law and Policy, Vol. 16, No. 2, 2008, 551.

^[9] S Golru, ‘The extrapolation dilemma: Toxicological evidence and toxic torts’, Torts Law Journal, Vol. 27, No. 3, 2022, 210.

^[10] See, eg, S Brice and W Christian, 'The use of genetic evidence to defend against toxic tort claims – Part I', Intellectual Property & Technology Law Journal, Vol. 29, No. 9, 2017, 3; G Marchant, 'Genetic data in toxic tort litigation', The Brief, Vol. 45, No. 2, 2016, 22.

^[11] S Gold, M Green and J Sanders, ‘Epidemiological evidence in toxic torts’ in MD Freeman and MP Zeegers (eds), Forensic Epidemiology: Principles and Practice, Academic Press, London, 2016, 55.

^[12] Naomi Guzman v ExxonMobil Corp, ExxonMobil Oil Corp, Humble Inc, and Intracoastal Tubular Services Inc (La Dist Ct, Jury Verdict, No 693–606, 2013).

^[13] Evers, Keith Leonard v Racecar Preparation and Management Pty Ltd [2013] VCC 517; Sutera v Perrier Group of America Inc, 986 F Supp 655 (D Mass, 1997); Harris v KEM Corp (SD NY, No 85 Civ 2127 (WK), 1989); Harris v Kem Corp (SD NY, No 85 Civ 2127 (WK), 1990); Milward v Acuity Specialty Products Group, Inc, 664 F Supp 2d 137, 143 (D Mass, 2009); Milward v Acuity Specialty Products Group, Inc, 639 F 3d 11, 22 (1st Dist, 2011); Milward v Acuity Specialty Products Group, Inc, 969 F Supp 2d 101, 116 (D Mass, 2013).

^[14] Farley-Smith v Repatriation Commission [2010] AATA 637; Wells v Shell Oil Co (DCE Tex, Jury Verdict, 2 March 1998); Lavender v Bayer Corp (W Va Cir, No 93-C-226-K, 29 May 1998); Edwards v Safety-Kleen Corp, 61 F Supp 2d, 1354, 1359–60 (SD Fla, 1999); Henricksen v ConocoPhillips Co, 605 F Supp 2d 1142, 1149 (ED Wash, 2009); Hallquist ex rel Hallquist v EI DuPont De Nemours (NJ Super, No A-6223-12T2, 10 October 2014); Walsh v BASF Corp, 234 A.3d 446 (Pa, 2020).

^[15] Ibid; S Golru, ‘The challenge of proving toxic tort causation: Genetic markers as the solution?’, University of Western Australia Law Review, Vol. 49, No. 1, 2022, 186.

^[16] Ibid.

^[17] Webb v Repatriation Commission [2001] AATA 633; Tompkin v American Tobacco Co (ND Ohio, No 94-CV-1302, 25 July 2001).

^[18] Sucher v Secretary of Health & Human Services, 2010 WL 1370627 (Fed Cl, 2010); Snyder v Secretary of Health & Human Services 553 Fed Appx 994, 996 (Fed Cl, 2014); Waters v Secretary of Health & Human Services (Fed Cl, No 08-76V, 7 January 2014); Deribeaux v Secretary of Health and Human Services 717 F 3d 1363, 1368 (Fed Cir, 2013). For a detailed analysis of Australian and American cases, see S Golru, ‘Deciphering the toxic tort causation problem: The emerging role of genetic susceptibility’, Tort Law Review (Forthcoming).

^[19] Ibid.

^[20] Gail Lucille Ingham et al v Johnson & Johnson et al (Trial Transcript, Cir Ct of the City of St Louis, vol 18A, 26 June 2018) 3573, (vol 18B) 3658–3659. The author thanks Kirk Hartley for bringing this case to her attention.

^[21] Ibid.

^[22] Ortwein v Certainteed Corp (Cal Sup Ct, No RG13-701633, 22 December 2014); Thrash v Boeing Co (ND Cal, No 17-CV-01501-JST(EDL), 2 March 2018) 2018 WL 2573097; Dustin W. Holsten, et al. v Amalgamated Sugar Co. LLC, et al. (Ill Cir, No. 18-L-1664, 30 August 2019); Cynthia Cowger v Qualitex Co (Ill Cir, No 2018-L-012099, 30 December 2020).

^[23] See, eg, Uniform Civil Procedure Rules 2005 (NSW) rr 23.1 23.4; Supreme Court (General Civil Procedure) Rules 2015 (Vic) rr 33.01–33.12; Uniform Civil Rules 2020 (SA) rr 112.9–112.10; Supreme Court Rules 1987 (NT) rr 33.01–33.13; Federal Rules of Civil Procedure (US) r 35.

^[24] S Golru, ‘Court-ordered genetic testing: The defendant’s right to examine the plaintiff’s genome?’, Journal of Civil Litigation and Practice, Vol. 10, No. 4, 2022, 171.

^[25] Bowen v EI DuPont de Nemours & Co, No 97C 06-194, WL 1952859 (Del Super Ct, 2005).

^[26] Ibid, 20.

^[27] Ibid, 41.

^[28] Ibid.

^[29] S Chen and G Parmigiani, ‘Meta-analysis of BRCA1 and BRCA2 penetrance’, Journal of Clinical Oncology, Vo. 25, No. 11, 2007, 1329; KB Kuchenbaecker, JL Hopper, DR Barnes et al, ‘Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers’, Journal of the American Medical Association, Vol. 317, No. 23, 2017, 2402; RL Milne and AC Antoniou, ‘Modifiers of breast and ovarian cancer Risks for BRCA1 and BRCA2 mutation carriers’, Endocrine-Related Cancer, Vol. 23, No. 10, 2016, T69.

^[30] I Miller and M Sotero de Menezes, ‘SCN1A Seizure Disorders’ in MP Adam, HH Ardinger et al (eds), Gene Reviews, University of Washington, Seattle, 1993, 2007–2022.

^[31] Golru, ‘Court-ordered genetic testing’, above note 24.