How many external sources have a role in cancer causation? And to what extent can scientists and lawyers parse these factors in today’s age of molecular investigation of cancers? For purposes of analysis, this post looks at a hypothetical bladder cancer case in which there are assertions regarding smoking, asbestosis, and occupational coal tar pitch exposure in the context of manufacturing of carbon graphite electrodes.
Assume that plaintiff’s industrial hygiene expert asserts that the bladder cancer was caused by polycyclic aromatic hydrocarbons (PAHs) occurring as a vapor and inhaled from the air and re-suspended into the air from settled coal dust. Assume that one PAH in particular (benzol(a)pyrene (BaP)) has been singled out by plaintiff as causally related to various cancers, including bladder cancer, in humans.
Bladder Cancer Risk factors
There can be, and often are, multiple factors involved in the development of any cancer. Focusing on the present hypothetical case, a savvy examiner can relatively quickly investigate how many factors are or may be involved in bladder cancers and how many are or may be relevant to the plaintiff in question?
The following factors have been proposed to increase the risk of bladder cancer:
- Increasing age
- Being white
- Being a man
- Exposure to certain chemicals (e.g., arsenic and chemicals used in the manufacture of dyes, rubber, leather, textiles and paint products)
- Previous cancer treatment
- Taking certain diabetes medications
- Chronic bladder inflammation
- Personal or family history of cancer
Obviously there are multiple potential factors to investigate with respect to the hypothetical bladder cancer. Initial discovery may be best focused on medical records and plaintiff’s life and work history in order to see which factor(s) appear most pertinent and worth the expense of further detailed investigation. Indeed, during the litigation process, key questions will emerge about which factors were ruled in or out by which experts and the reasons for the decisions. So, one important challenge is to preliminarily understand the science, the facts and law relevant to these factors.
Plaintiff Science Assertions
Let’s look at some of the evidence that might be marshalled by plaintiffs in support of the view that coal tar pitch is causally related to bladder cancer:
- IARC first reported in 1973 that coal tar pitch is carcinogenic in humans
- IARC affirmed the carcinogenicy of coal tar pitch in 1979
- ACGIH lists BaP as a human carcinogen and BaP is a marker for PAH exposure broadly
- Some say that adverse health effects of coal tar pitch (including its carcinogenicity) are due to its PAHs
- Exposure to and intake of PAHs can occur via dermal exposure as well as inhalation exposure
- Some human and animal studies demonstrate the carcinogenicity of coal tar pitch
As with most assertions of this type, confronting them is a matter of a detailed review of the statements, focusing on their underlying basis.
To start, IARC itself has been the subject of lucid criticisms about the extent to which the Agency applies the best science, and how one defines the “best science” (see, for example, this recent post by Geoffrey Kabat).
Another area of inquiry goes to the quantity and quality of the information about bladder cancer and the assertions that could be made. To understand the scale of available data, there is a need for general investigation about the body of data available from regulatory and advisory agencies. Indeed, IARC has repeatedly assessed and evaluated coal tar pitch and PAHs in the context of various occupational settings (undoubtedly, many more reports than those that will be cited by plaintiffs and their experts).
Importantly, IARC has made important distinctions in its assessment of the overall carcinogenicity of coal tar pitch in the specific setting of carbon electrode manufacturing. For example, in its 2010 evaluation, IARC concluded: “there is sufficient evidence in humans for the carcinogenicity of occupational exposures” during some occupational exposures (e.g., aluminum production). Yet they state that there is only “…limited evidence in humans for the carcinogenicity of occupational exposures during carbon electrode manufacture.” Plaintiffs and their experts are likely to focus on carcinogenicity in the aluminum production industry despite the fact that IARC itself makes a distinction in the carcinogenicity of coal tar pitch and its constituents depending on industry of exposure.
Thus, the statements made by IARC and the evidence reviewed must be thoroughly vetted and evaluated. Indeed, IARC followed up with an additional report on the carcinogenicity of coal tar pitch in 2012 (but that report is not likely to be cited by plaintiffs and their experts).
IARC, of course, is just one of multiple agencies that express views about the carcinogenicity of substances. Similarly detailed analyses should be conducted for ACGIH and any other regulatory assessments that may be used by experts.
Evaluation of Non-Agency Published Scientific Literature
The body of available data on “toxins” is growing every day, at in increasingly pace. For example, a quick literature search shows over 2800 scientific articles that mention “coal tar.” With so much data out there, a logical follow up question is: how to find rigorous and appropriate scientific answers without making a life’s work out of the necessary research? Does one go with a local, general toxicologist or a national expert with prior expertise in bladder cancer? And in what alleged exposure context does that expertise arise? Will conflicts of interest emerge?
Experts will say they need to analyze and compile the published scientific literature in animals and humans. In doing so, a topic that will drive costs is the level of investigation of the investigation of the literature. Is it critical to distinguish between the precise chemicals evaluated (e.g., coal tar pitch, PAHs, BaP, etc.). Another question will go to the relative value of determining what occupational settings the exposures were evaluated in as well as the levels of exposure.
BaP as the Agent of Interest – Epidemiology versus Molecular Analysis (or Both)
Plaintiff’s counsel presumably will suggest that BaP is the chemical agent of interest that causes bladder cancer. Yet no epidemiological data on BaP alone were available to a recent IARC Working Group. What is the plaintiff going to do for proof if there are zero or few epidemiologic studies that are in the ballpark? And what are the dimensions of that ballpark? Shall the defense proceed only on the basis of a possible lack of supporting epidemiologic data? Is that “enough” these days, after Milward v. Acuity? All sides will need to make choices after thinking about the law as it is developing. Some of the factors are discussed in this prior Goldberg Segalla article on the Milward decision, and other recent legal cases of relevance.
Assuming that epidemiologic papers alone are not – or may not – be “enough” for either side, it’s logical to look at the molecular science. When one looks at the molecular data, some might argue the genotoxic mechanism of BaP is reasonably well delineated. Indeed, IARC does consider BaP to be a clearly defined human carcinogen. Nevertheless, experts will ask, what is the evidence on whether BaP levels in the context of electrode manufacturing are capable of causing bladder cancer.
Exploring Bladder Cancer Causation and Alternative Causes, at the Molecular Level
Another line for investigation will be the role of relevant of cofactors and the molecular evidence. As noted above, a plaintiff with bladder cancer also may well have a history of smoking and may show at least some level of arguable or actual asbestosis exposure. However, one also needs to think about other less obvious possible causes. For many but not all cancers, molecular events related to cancer of a particular organ likely will have been widely investigated and many papers may exist. Importantly, knowledge of molecular events related to bladder cancer have been used to great effect by plaintiffs in litigation surrounding the antidiabetic drug Actos, leading to a 2.4 billion dollar settlement.
Specifically, plaintiff expert Jennifer Southgate, Ph.D. concluded in her report:
“In sum, and on the basis of the evidence discussed above, it is my opinion with a reasonable degree of scientific certainty that pioglitazone causes bladder cancer in rats and humans. It is also my opinion that there are biologically plausible mechanisms by which pioglitazone exerts carcinogenic effects on the urothelium chiefly through receptor-mediated effects that are relevant in humans.”
The strength and specificity of her language demonstrates the power of the molecular techniques that she used to come to her opinions. There is no reason why similar techniques cannot be brought to bear on the allegations in this case,– i.e., is there (or is there not) biological plausibility to support the view that BaP, PAHs, and/or coal tar pitch is linked to bladder cancer in humans, and if so, how compelling is the information?.
Cancer litigation today is increasingly complex due to the ongoing explosion of molecular knowledge about the how and why of some cancers. As the knowledge increases, analysis of cofactors is increasingly important, although the cofactors and importance will vary from case to case. Next month we will address a new paper that offers new hypotheses about evaluating external causes of cancers.
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