Mass Torts: State of the Art : Mass Torts Lawyer & Attorney : Vorys, Sater, Seymour & Pease Law Firm : Toxic Torts & Wrongful Death

Though riddled with clever falsehoods and logical fallacies, "The Story of Cosmetics" is brilliant rhetoric - which is to say it's extremely persuasive. The narrator comes across as everywoman - down to earth, smart, earnest, caring and fair yet resolute about protecting families; and, her conclusions follow obviously from her premises.The graphics are especially well done - they enhance what the narrator is saying and add humor and wit. Finally, and importantly, it's short. Before my first trial my Dad told me to "say what you need to say or ask what you need to ask and then sit down and shut up; too many lawyers babble on trying to prove how smart they think they are and accomplish nothing besides annoying the jury and obscuring whatever point they're trying to make." Two decades on I can confirm all aspects of that advice.

Deconstructing this work of rhetorical art needs to be done piecemeal (if only because I have a present ion to complete and thereafter a plane to catch) so let's start at the beginning (well, not the beginning beginning - that's just the anti-consumerism ideological waypoint - I mean the "are these products toxic" beginning). Anyway, the narrator says she loves her shampoo and one day got to wondering what was in it. The first thing she noticed upon reading the label was that it had chemicals in it; specifically sodium laureth sulfate, tetrasodium EDTA and methylisothiazolinone. So she took the list to some unidentified "scientists" who advised that her shampoo "contains a chemical linked to cancer!" Let's look at this claim.

As luck would have it the International Journal of Toxicology just published "Final Report of the Amended Safety Assessment of Sodium Laureth Sulfate and Related Salts of Sulfated Ethoxylated Alcohols". Not surprisingly it's a soap that may irritate your eyes but if properly formulated won't even do that. It's certainly not a carcinogen which is what the American Cancer Society, OSHA and EPA have been saying for years to anyone willing to ask.

And what about tetrasodium EDTA? Before I answer that one I'd bet it's probably not a coincidence that the first two chemicals mentioned have sodium in the name since sodium, as in sodium chloride, has become a politically incorrect element just as California's state rock has become a politically incorrect mineral. In any event there's no evidence that EDTA is a carcinogen. On the other hand, when your dentist uses it to inhibit biofilm formation in your mouth it's actually an anti-carcinogen. Then there's the fact that EDTA is used to remove toxic metals from the body. Hmmm.

Finally, there's methylisothiazolinone, a biocide that keeps fungi and bacteria from growing in your shampoo. A quick trip through the ether to the U.S. National Library of Medicine leads to the brand new "Final Report of the Safety Assessment of Methylisothiazolinone". Reaffirming previous findings the report concludes that in the doses used in personal care products methylisothiazolinone is safe. But there's something very important here that you'll miss if you're not paying attention to the big picture; and that something is the weight given in vivo versus in vitro data.

How should chemicals be tested for toxicity? Typically it's been done on animals but because of political opposition to animal testing and a 20th century belief in genetic determinism a big yet largely unnoticed push has been underway to have EPA, NTP, etc shift to doing toxicity testing on human cell lines in vitro. So far such cell line in vitro testing has repeatedly managed to find signs of cellular damage from a host of substances never before associated with toxicity. Methylisothiazolinone is one such example.

Despite the fact that neurotoxicity has never been associated with methylisothiazolinone in humans, rats, mice, etc in vitro testing found that it produced damage to a line of human neural cells. What gives?

What gives, of course, is that just as a bacterium responds to its environment differently depending on whether it's alone or in a biofilm so it's hardly a surprise that a single cell would respond to stimuli differently than would the entire organism of which it is but a vanishingly small part. Thus the decision that methylisothiazolinone is safe thanks to the weight of the in vivo data. Therefore, as we shift away from the tried and true methods of toxicity testing and towards a new model which, in light of recent discoveries regarding epigenetics and the microbiota which run a good portion of our lives, be prepared for many many more baseless health scares; and the worst part about it is that without the ability to test the hypotheses generated on actual animal models refuting even the most absurd claims will only get harder.

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The American Cancer Society is calling for new research to settle the issue of whether or not twenty different agents do indeed cause the types of cancer in which they've been implicated. The twenty are:

(1) Lead and lead compounds; (2) indium phosphide (used in many flat screen TVs); (3) cobalt with tungsten carbide; titanium dioxide; (4) welding fumes; (5) refractory ceramic fibers; (6) diesel exhaust; (7) carbon black; (8) styrene oxide and styrene; (9) propylene oxide; (10) formaldehyde (does it cause leukemia?); (11) acetaldehyde; (12) formaldehyde; (13) methylene chloride; (14) trichloroethylene; (15) tetrachloroethylene; (16) chloroform; (17) PCBs; (18) DEHP (a phthalate); (19) atrazine (a herbicide and the subject of a coordinated attack by various activists groups resulting in a new EPA review); and, (20) shift work (the presumed exposure being "light at night" leading to a disruption of circadian rhythms and the most commonly associated malignancy being breast cancer).

You can find the press release here: Report Outlines Knowledge Gaps for 20 Suspected Carcinogens; and you can find the IARC report summarizing past rationale for assigning these suspected carcinogens to groups 2A - 3, the new evidence forming the basis for the recommendation that the status be updated and the sorts of epidemiological and mechanistic studies necessary to answer the question of whether they ought to be added to the list of 107 Group 1 agents known to be carcinogenic to humans, here: Identification of Research Needs to Resolve the Carcinogenicity of High-Priority IARC Carcinogens.

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Sometimes The New York Times just publishes the press releases of zillionaire trial lawyers and fellow traveler advocacy groups in its Science and Health sections. Most of the time though, when power and money aren't apparently in play anyway, The Gray Lady does the best job in the business of reporting on scientific advances.

One advance that we've been covering for the last year is the staggering realization that most of the cells in "our" body aren't ours; that much of the heavy lifting that keeps us healthy is done by the aliens inside of us; and, that genetic determinism is a fairy tale.

Read "How Microbes Defend and Define Us" for an excellent introduction to the topic of the Mighty Microbe that saves the day.

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"'What we have heard back from drug companies is that, if it has the word 'PPAR' in it, it's dead,” says Bruce Spiegelman, a cell biologist at the Dana-Farber Cancer Institute." That's from "Diabetes Drug Woes Spell Trouble for the Entire Drug Family." The most famous PPAR-gamma drug out there is, of course, Avandia.

Why hope PPAR-gamma drugs aren't dead? Well, read "in Vitro and In Vivo Therapeutic Efficacy of the PPAR-gamma Agonist Troglitazone in Combination With Cisplatin Against Malignant Pleural Mesothelioma Cell Growth". The PPAR-gamma agonist not only inhibited malignant pleural mesothelioma cell growth it also lengthened survival.

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Remember the Ames test ? Test a substance and if it causes mutations then it ought to be a carcinogen, right? After all, isn't cancer the result of a mutation that causes a cell and its descendants to grow out of control? That was the thinking anyway. Unfortunately (or fortunately) lots of things that cause mutations don't cause cancer and as a result the Ames test sparked more than a few bogus health scares and plenty of baseless tort cases.

Now, in a flashback to the days of starting with an unproven premise about the origin of cancer and stacking inference upon inference upon inference until mass litigation over an industrial chemical emerges and metastasizes, molecular epidemiology gives us an association between trichloroethylene (TCE) and non-Hodgkin lymphoma (NHL). See: "Occupational Exposure to Trichloroethylene is Associated with a Decline in Lymphocyte Subsets and Soluble CD27 and CD30 Markers". 

So what of this association between TCE and NHL? Have workers with long occupational TCE exposures gotten NHL at a high rate? No. Has there been however a small but consistent increase in NHL among TCE workers? No. So the causal claim fails the two big prongs, strength and consistency of the association, of every causal inference test. End of story, right? Not anymore.

Cancer epidemiology had a great run. Uncovering the epidemics of cancer in chimney sweeps, smokers and many others were profoundly important discoveries. Yet a decade ago many were wondering if it was time to call it a day for epidemiology. The strong and consistent causes had already been rooted out while subtler causal associations like that of H. pylori and peptic ulcer disease were being missed and non-existent associations between electricity, peanut butter, etc and cancer were repeatedly being discovered one week only to be refuted the next.

But if the tools work why not apply them to the new and fertile ground of molecular biology? In other words, why not look for strong and consistent associations between molecules as a way to uncover the links in the causal chain from genotype to phenotype? It was a great idea but nature failed to cooperate.

First, the reductionist approach to genetics ran into trouble when it became clear that a gene doesn't do the equivalent of say executing schematics for an alternator but rather is part of a larger algorithm dedicated to finding a way to convert available mechanical energy into electrical energy. Second, it became apparent that within largely known biochemical pathways there were often so many other factors influencing outcomes that meaningful p-values might often end up having something like "x 10-6" appended to them - in other words you might want to consider rejecting the null hypothesis only if the odds of the results observed being due to chance alone fall below one in a million.

Sadly none of that will stop some from arguing that TCE causes NHL and citing the new paper referenced above. Read it through and here's what you'll learn: Eighty workers were exposed to TCE. None got sick. However, they had lowered levels of lymphocytes, some of which lymphocytes have something to do with some of the cells involved in the immune response. Meanwhile some other people with some unstated change in their immune response are sometimes at a somewhat increased risk for NHL. Therefore it's somewhat more biologically plausible that TCE is possibly a cause of NHL.

I kid you not. Nevertheless you can bet that this paper will be cited in courtrooms and the Federal Register for the proposition that TCE causes cancer just as the Ames test was cited for the proposition that coffee causes cancer.

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The current paradigm, some 40 or 50 years old now, would say it was the mutation. As the first plaintiff's expert witness I ever cross examined at the courthouse said of the chemical in question "it messes with your DNA and if your DNA is messed up anything, especially cancer, can happen". By the way, for the younger set, before Daubert and Robinson/Havner that's what all too often passed for "science" in the courtroom.

Yet in the new Million Women Study of breast cancer, mutations associated with higher risk and environmental insults associated with higher risk seem to have no relation with one another such that hormone replacement therapy doesn't increase the risk of breast cancer even in women with genes predisposing them to estrogen-receptor positive disease. How can that be?

Well, here's some food for thought. Where do we come from? Bacteria, way back when. How do bacteria talk to each other? Quorum sensing (by the way, don't you wish all your teachers had been like Bonnie Bassler?) So if our stem cells want to monitor how many undifferentiated cells they need to be making and if those cells want to monitor their path to differentiation might they not do it via the same signaling pathways that their ancestors employed? If that's the case then could it be that a disruption in signaling causes runaway production of immature cells (cancer) and that the mutations only occur later? There's more than a scintilla of evidence for it.

What recruits bone marrow cells to the gut where their signaling is disrupted? Is it significant that many of the benzene workers thought to have developed leukemia as a result of exposure lived not only in the same building but were roommates? Is the parallel between the fall in cancer mortality and the rise of antibiotic use suggestive? It's something to think about anyway.

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In "The Lancet: Neurology" you'll find "Vitamin D and Multiple Sclerosis"  as well as "Vitamin D: Hope on the Horizon for MS Prevention?" Could it be that  the old mocked wisdom of "a healthy dose of sunshine" wasn't so silly after all? Could it be that the health panic precipitated by activists who demanded everyone stay out of the sun actually caused horrific and needless suffering? Could be.

I just got back from a vacation in Destin, Florida. While there I learned that there are people who cover every exposed surface of their kids with zinc oxide before letting them out in the sun. These parents think they're doing the right thing. Their kids seemed about as happy as I'd have been sent out into the world in a powder blue leisure suit. But while powder blue leisure suits don't cause rickets and MS, vitamin D deficiency does. When disease strikes will there be a viable cause of action against the scaremongers who caused it? It's an interesting question.

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Smoking, asbestos, silica, hexavalent chromium, nickel and radon have all been blamed for cases of lung cancer. Now there's a new paper from the National Cancer Institute implicating C. pneumoniae: "Chlamydia pneumoniae Infection and Risk for Lung Cancer". Be sure to note the significance of the finding that it's the marker of chronic infection with which a significantly increased risk of lung cancer is associated.

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Can C. difficile be spread through the air? What does C. difficile have to do with COPD? How should physicians treat the new and especially virulent strain of C. difficile? At what temperature should you cook ground meat to kill C. difficile and its spores? Do alcohol-based gels kill it? Why do antacids administered in hospital increase the risk of infection? Are there new antibiotics that work against C. difficile?

Click on the links for a sense of current thinking on these issues.

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When you ask a physician or researcher how bacteria cause and/or promote cancer usually the only answer you get is "inflammation" and some hand waiving. It sort of makes sense. Lots of new and different stuff is going on, lots of new and different cells are running all around and lots of old cells are busily dividing and multiplying - surely a recipe for an accident.

But what if the bacteria are actively promoting the metastasis? That's the finding in "Bacteria Peptidoglycan Promoted Breast Cancer Cell Invasiveness and Adhesiveness by Targeting Toll-Like Receptor 2 in the Cancer Cells". Why, in the "what's in it for them" sense, would bacteria promote something that kills their host? Something to ponder over the weekend.

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E. coli O157:H7 produces Shiga toxin, a cause of dysentery, and in some cases hemolytic uremic syndrome followed by kidney failure, particularly in the young. The government and industry have become increasingly vigilant in screening food for the bacterium. But what about all the kissing cousins of this promiscuous bug?

According to a new article in the NYTimes the recent outbreak of illness caused by lettuce wasn't due to E. coli O157 but rather by E. coli O145. In the article the owner of an organic food farm is quoted as saying that E. coli O145 and a handful of other non-E. coli O157 relations are being found more and more often in even organic food. Read all about it: "In E. Coli Fight, Some Strains Are Largely Ignored".

Life evolves to exploit underexploited energy dense environments. To microbes, we're still walking, talking energy dense environments. The long war continues.

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Could the answer, at least in part, be inferred from the following?

Statins appear to reduce the risk of sepsis and nosocomial pneumonia ; Antimicrobial and Immunomodulatory Attributes of Statins ; Unexpected Antimicrobial Effect of Statins ; Fungal rDNA Signatures in Coronary Atherosclerotic Plaques

It's quite an eye-opener, to glance through all the articles being published demonstrating links between good health or disease and the vast previously unappreciated hordes of microbes that live in and on us. And it makes you wonder what the President's Panel on Cancer was thinking when it prepared its report since, to anyone caring to look, the evidence that our ancient nemeses are responsible not just for acute infections but for a large part of cardiac disease and cancer is overwhelming.

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While some fret that man-made nanoparticles may bear unanticipated hazards that won't manifest for decades cancer researchers press forward with the development of revolutionary nano-scale drugs. What are they? How will they work? Will they be regulated as drugs, devices or biologics? An excellent (and free) discussion can be found at Nature Reviews: Clinical Oncology in "Conscripts of the Infinite Armada: Systemic Cancer Therapy Using Nanomaterials".

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Cancer of the oropharynx in men is on the rise. Such cancers have traditionally been blamed on smoking and/or drinking so what accounts for its increase in a time of reduced rates of smoking and alcohol abuse? A virus; human papillomavirus (HPV). See "HPV-Associated Head and Neck Cancer: A Virus-Related Cancer Epidemic".

Remember, (1) the focus of this year's World Cancer Day was a call for greater awareness of the contribution of infectious disease to cancer; and, (2) the "age of receding panemics" never really passed - we just stopped looking for them.

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As we wrote yesterday, causal attribution in most toxic tort cases is hard and the discovery that life and many of its diseases are emergent rather than predetermined phenomena has made the exercise even more complex. That said, sometimes causal attribution is easy - as in the cases of falling, being shot or developing mesothelioma after exposure to erionite.

50.5% of all deaths were due to mesothelioma in one village in Turkey and of women who moved from areas without erionite to this same village 69% of all deaths were due to mesothelioma. Read about it in: "Endemic Malignant Mesothelioma: Exposure to Erionite is More Important Than Genetic Factors".

Is there any carcinogen as potent as erionite? What do these numbers suggest about the mode of action of erionite? It sure looks as though the biological insult from erionite is more akin to that of some physical trauma than from some molecular biological disruption as in the case of a genetic mutation.

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Causation seems to just get harder and harder. A recent case in point being the finding that Chinese with myelodysplastic syndrome don't seem to suffer -5 and/or -7 chromosomal abnormalities even after extraordinarily high exposures to benzene. So much for that paradigm. What gives?

As we've written before the reductionist ideal seems clearly to have failed of its promise. But that's not to say that cancer causation is impossibly complex. Instead, more and more it's looking like our relentlessly efficient ancestors were keen on finding what works and refining it. And when they found something that worked, whether from yeast or plants or whatever, they shamelessly violated all patents and made it their own.

If you don't read anything else today read this in the NYTimes. It's big. It's a part of the beginning of a new paradigm; a new metaphor; it's part of the beginning of the idea that our physical systems are not all that different from those of modern computer code - bits of borrowed script, some improvised, some archaic and artifactual, but most of it off-the-shelf modules tried and true and ready to be plugged in and used as, for example, a do while loop.

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Shiga toxin-producing E. coli infections are trending down and so are hospitalization and mortality rates. The same is true for Campylobacter, Listeria and Salmonella since 1996.

That said, the rates for Vibrio are increasing and plateaus for Campylobacter, Listeria and Salmonella show worrying trends towards leveling and rebuilding. Of course, if you've ever spent time looking at bacteria under a microscope you'll know that these bugs are like Rocky - sometimes they're down, but they're never out.

The long war continues. Read the latest dispatch from the CDC.

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You know all those immunohistochemical stains for different types of cancer; the ones that say what a patient has and what chemo works for her? Well, because we live in a time of discovery, and thus of great uncertainty, standards and scoring vary greatly from laboratory to laboratory. We know this from the leukemia, lung cancer and mesothelioma litigation. Now Gina Kolata has written about it in the breast cancer context in the NYTimes in: "Cancer Fight: Unclear Tests for New Drug"

Years from now, we hope, when it's all clear and obvious, historians will look back on this era and marvel at our tolerance for untested treatments, primitive diagnostics and a swing-for-the-fences approach to our health. For now though it's the best we can do.

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Chemo's dirty secret is that many patients, oftentimes most, will be made wretchedly sick yet receive no benefit in the bargain - they won't even be playing the remission lottery. That's because cancer isn't one disease called "cancer". It's a highly individualized disease. Yet because until now no one could identify who would respond to what everybody with a given type of cancer got whatever worked best for the most people.

Now, efforts at M.D. Anderson Cancer Center to identify biomakers that refine the diagnosis of the disease well beyond say small cell lung cancer are starting to pay off and drugs that might never have been prescribed because they only helped a tiny subset of victims can now be targeted at only those people who have the sort of lung cancer susceptible to the drug. Read about it at Bloomberg.

And how individualized will cancer turn out to be? Very, if things continue to go as they've gone with Vectibix, a colon cancer drug.

So much for economies of scale.

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It has been just over a decade since the human genome was sequenced. Now that we know the "code of life" cures for all sorts of maladies like cancer, birth defects and even aging are just around the corner, right? A missing or mutated gene causes a problem so provide the protein it would have produced or suppress the errant one it does or even use a virus to replace the faulty or missing gene with a new one, right? Well, it might have worked out like that if what everybody knew about DNA and gene regulation was true. Instead the discoveries of the last ten years have exploded one dogma after another and left many scientists despairing that life may be impossibly, incomprehensibly complex.

One of the biggest "Huh?!" moments came with the announcement by the folks running the ENCODE project that all that non-coding DNA, the allegedly meaningless flotsam and jetsam of 3 billion years of evolution, was, in fact, coding little bits of RNA which turned out to play mysterious yet essential regulatory roles.

And one of the most depressing "Uh Oh" moments seemed to come collectively when one day everyone began to look at all the pretty graphical images of signaling pathways, which look like a snapshot of the grand finale of a Fourth of July fireworks display, and to realize that just as a Martian could study such pictures forever and still never understand why we were shooting off fireworks, likewise researchers could never comprehend what was going on in a living organism just by studying simple causal nexuses.

There is an excellent write-up of these issues at Nature in a special and free report called "The Human Genome at Ten". Read it.

Yet just because things have turned out to be vastly more complex than hoped for and expected that doesn't mean truth can't at least be more closely approximated. More and more it's beginning to look to me like modular computer programming is a better metaphor for these biological processes than the older purely reductionist one. If so then most of what's going on research-wise today is replacing "FOR N = 1 TO 100" with "FOR N = 1 TO 85" and then trying to figure out just where, and what, in the game just got a little bit more or less likely. Once the principle, the function, of a cluster of effects is understood perhaps maladies like cancer will at last begin to yield to the enormous amount of effort expended. If so then perhaps the following is the better quote about wisdom:

"Patience is the companion of wisdom" - Saint Augustine

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Does diet soda cause Type II diabetes? There are a couple of studies that suggest as much and now a hypothesis, yet to be tested, about how un-sugar could trigger a response to chronically too much sugar has emerged.

In "Stomach's Sweet Tooth" published online at ScienceNews the author considers the evidence for the proposition that artificial sweeteners essentially cause confusion in the body's metabolic processes by sending one signal via the tongue and another via previously unknown taste receptors in the stomach and intestines. How the release of various hormones and enzymes in response to the stomach and intestines "tasting" sugar when none is present might lead to diabetes or metabolic syndrome is unknown but apparently a large amount of research into the question is underway.

The long under-appreciated gut is now thought to be the largest hormone-releasing organ and the body's "second brain" with more neurons than than the spinal cord. And there's a new word for the study of this system: Neurogastroenterology. Neurogastroenterology?! We certainly live in interesting times.

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In the newest edition of the journal Cancer Causes and Control you'll find a paper titled "Endotoxin Exposure and Lung Cancer Risk: A Systematic Review and Meta-Analysis of the Published Literature on Agriculture and Cotton Textile Workers". The authors examined 28 studies of workers occupationally exposed to high levels of endotoxins and their risk of developing lung cancer. Previous studies had suggested acute and chronic lung conditions could be caused by endotoxins.

Interestingly, endotoxin exposure was consistently associated with a large and statistically significant decrease in lung cancer. Furthermore, the protective effect was strengthened as dose was increased.

Also this month, in Cancer Epidemiology, Biomarkers & Prevention, you'll find "Lower Risk of Lung Cancer After Multiple Pneumonia Diagnoses". It turns out that getting pneumonia three or more times is even better than high exposure to endotoxins if you want to avoid lung cancer.

What is it about these biological challenges to the lung that leads to significant anti-lung cancer protective effect? It's anyone's guess but perhaps keeping your immune system tuned up is part of the answer.

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Read: "A Susceptibility Locus on Chromosome 6q Greatly Increases Lung Cancer Risk Among Light and Never Smokers". If you've got the gene your risk of lung cancer goes up nearly 500% even if you never smoke (in fact smoking only weakly increases your risk if you've got the gene). Interestingly, if you don't have the gene and you smoke your risk goes through the roof.

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Even though cells drawn from a pleural effusion stain positive for calretinin and negative for CEA that doesn't mean the person has mesothelioma. Those mesothelial cells may be non-malignant yet still react to immunohistochemical stains used to identify malignant mesothelioma.

Is there a way to distinguish between malignant and merely reactive cells? According to a new paper in Cancer Cytopathology, "The Use of Immunohistochemistry to Distinguish Reactive Mesothelial Cells From Malignant Mesothelioma in Cytologic Effusions", a positive epithelial membrane antigen (EMA) stain coupled with a negative desmin stain strongly points to mesothelioma while the opposite pattern strongly suggests reactive mesothelial cells and not mesothelioma.

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In "On to a Fifth Age? How About We Finish the Second?" we discussed a JAMA editorial wherein Dr. Michael Gaziano asserted we may be entering a fifth age of the so-called epidemiologic transition. These transitions are claimed to be changes in the primary causes of morbidity and mortality and Dr. Gaziano opined that we are moving into an era in which obesity and inactivity will drive preventable illness. We discussed the origin of the idea of epidemiologic transitions and questioned  whether we'd ever finished the second age which would have required the conquest of infectious diseases.

The so-called third age was supposed to be the "age of degenerative and man-made diseases" but it keeps turning out that many illnesses thought to be due to wear and tear, lifestyle or pollutants actually have an infectious disease process at their core. Now there's growing evidence that coronary heart diseases (CHD) may in many cases have more to do with a number of infections, including influenza, than with lifestyle or the environment.

Here's a link to a letter published in the Reflections section of The Lancet: Infectious Diseases that nicely summarizes the pre-1970 thinking that pointed to infections as the cause of CHD, the subsequent predominating narrative of chronic diseases not being caused by infections, and the new evidence that chronic diseases are in fact often caused by previously undetected infectious processes: "Inflammation as the Cause of Coronary Heart Disease". And here's a link to a written debate about "this nascent field associating chronic diseases with infections" from 2002 with the author of the recent Lancet paper cited above: "Debate on the Paper by Maria Ines Reinert Azambuja & Bruce B. Duncan".

Given the enormous renewed interest in infections as a possible cause of chronic illness and the ease with which scientists can now find traces of bacterial, fungal and viral DNA (or RNA) at the scene of the suspected microbial crime it's fair to assume that we'll be seeing many more such stories in the future.

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Mitochondrial DNA, or mtDNA, is increasingly assayed for early evidence of a disease which will eventually become manifest. Take a sample, amplify the DNA, examine it and look for change - makes sense, right? Your genes are the ones you're born with, right? And if they've changed that can't be good, right?

Well, it turns out that you, or your mitochondria at least, evolve or mutate within the course of your lifetime - and it's perfectly normal. We may have started out with Mom's mitochondria but it looks like by the time we're adults mitochondria in different parts of the body don't just express different genes, they have different genes. That's the conclusion of "Heteroplasmic Mitochondrial DNA Mutations in Normal and Tumour Cells" just published in Nature.

There's a great write-up of the findings at TheScientist.com and it makes two very important points for those of us dealing with litigation involving mtDNA biomarkers.

1) "we have to keep in mind [that] some of the changes we see may not really be [disease-related] mutations." - quote from author Nickolas Papadopoulos

2) "there's a big question mark about how early this increase in mtDNA variation appears in the blood. If it's only apparent once the cancer is well established then it isn't much use as a biomarker." - email from molecular biologist Ian Holt to The Scientist

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The genes belong to bacteria living in your gut. They, along with their fellow microbes in and on "your" body outnumber human cells 10 to 1. But their genes collectively outnumber yours 150 to 1. These findings are just part of what you'll find in "A Human Gut Microbial Gene Catalogue Established by Metagenomic Sequencing"  published in Nature and free online.

The authors conclude that  this catalogue of bacterial genes found in the human gut "will lead to a much more complete understanding of human biology than the one we presently have." I think it's fair to say that the realization that the microbes we host have so much control over our lives will lead to a revolution in how we think of ourselves and how we prevent, diagnose and treat conditions like obesity, diabetes and cancer.

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You can read about a new vaccine based therapy for mesothelioma that is both safe and, in some at least, effective in "Consolidative Dendritic Cell-Based Immunotherapy Elicits Cytotoxicity Against Malignant Mesothelioma"

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In May of 2006 PLOS One published an excellent paper summarizing the evidence that the reductionist approach embraced by medicine over the last century or so had done about as much as it could and was actually hindering further advances. You can find a free copy of that paper, "The Limits of Reductionism in Medicine: Could Systems Biology Offer An Alternative?" at PLOS One.

Modern medicine, the authors wrote, tends to assume (a) that each disease has a single cause; (b) that any deviation from homeostasis requires beating down levels of whatever is up and pumping up levels of whatever is down; (c) that a risk factor for disease in one person is a risk factor for disease in another person; and, (d) that in the case of multiple disease states they can each be treated separately rather than cumulatively. While this approach has been quite successful, particularly for certain diseases, the view of the body and its functions as a bunch of disconnected parts to be dealt with by hyperspecialized parts doctors is beginning to give way to a view that a deeper understanding of disease will occur only when when the complex systems governing the whole organism are understood.

Now there's another paper advancing this idea that afflictions of the body are more than just the sum of their signs and symptoms. In "Systems Biology as a Paradigm Shift in Clinical Research" available free at Oxford Journal of Nephrology Dialysis Transplantation. In particular the authors note the failed promise of biomarker identification to uncover either the causes of illness or effective treatments.

"Simply stated, molecules in a living cell are involved in networks of interactions that regulate the cell's basic functions ... [d]isruption of a partner in these interactions does not result in linear and definable effects but rather in global and often unpredicted perturbations of the whole network." The authors conclude with an overview of the systems biology approach and its promise particularly with regard to understanding and treating chronic diseases.

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At least that may be the case for parasitic worms, also known as helminths. In the review article "Parasitic Helminths: New Weapons against Immunological Disorders" its authors discuss the recent literature supporting the hygiene hypothesis - the idea that the modern hygienic lifestyles of children deprive them of the immune system priming necessary to provide protection later on against diseases like diabetes, allergies, arthritis, Crohn's disease and cancers like Hodgkin's. Later in the article they turn to the evidence showing that one especially unhygienic aspect of an infestation, the helminths laying eggs in your body, is especially good for you.

So what does this have to do with mass torts? Well, a number of ailments attributed to chemicals, diet or drugs may in fact have their roots in our having rather suddenly and dramatically distanced ourselves from the microbiological environment that shaped us over the eons. Thanks to the elucidation of the molecular pathways responsible it may now be possible to identify those plaintiffs whose unmatured immune systems are the real culprits.

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In an article just published in Diagnostic Cytopathology, "Podoplanin is a Useful Marker for Identifying Mesothelioma in Malignant Effusions", the authors conclude that calretinin plus podoplanin (part of an immunohistochemical staining panel) would significantly improve the specificity of pleural effusion diagnostics in suspected cases of malignant pleural mesothelioma (MPM). In other words, the suggested technique would do a better job of differentiating MPM from adenocarcinomas of the ovary, lung and breast.

As more and more putative mesothelioma cases have been filed, particularly by women plaintiffs with de minimis or even nonexistant amphibole exposures, battles over diagnosis have become more common. On the other hand, plaintiffs' counsel are now seeking to tie adenocarcinoma of the ovary to asbestos exposure. Perhaps both then are just new new levels in the never ending Whac-A-Mole game that is asbestos litigation.

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Reuters Health is reporting on a new study in the Journal of Investigative Dermatology in which British researchers publish the results of their study on Vitamin D deficiency and sunshine. The short version is: you were made to be exposed to sunlight, you can get sick without it but moderation, as in all things, is the key.

There's a lot more of interest in this study available free online at Nature.

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Tomorrow, February 4, is World Cancer Day and the International Union Against Cancer (UICC) is calling for greater awareness of the contribution of infectious disease to cancer cases around the world. "Cancer can be prevented too" is the theme of the effort. According to the press release the campaign is backed by a new scientific report: Protection Against Cancer Causing Infections which focuses on the nine known infections that can lead to cancer.

There's already a highly effective vaccine against human papillomavirus that prevents cervical cancer, a dreadful disease that took the life of one of my law school classmates within a year of her graduation, though it's still not widely given for a variety of reasons associated with culture and values. There's also a vaccine to protect against hepatitis B virus which causes a staggering number of cases of liver cancer worldwide yet it too is grossly underutilized. For more on World Cancer Day 2010 try these links: UICC World Cancer Campaign, World Health Organization,  European Hospital and this book: Infections Causing Human Cancer 

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"If there is one thing the history of evolution has taught us it's that life will not be contained. Life breaks free, expands to new territory, and crashes through barriers, painfully, maybe even dangerously." -Dr. Ian Malcom, Jurassic Park

That's the quote that came to mind when I read the story about infectious cancer in Tasmanian devils from The New York Times. It's about a cell that became "malignant" and then set out on its own to be parasitic on others of the species. So far, only one similar case has been found - that of canine transmissible venereal tumor in dogs. But then, how long have researchers been looking for cells that left the multicellular super organism of which they were once a part to set up shop and find a new way of growing and propagating?

The dogmatic view that chronic diseases like cancer must be due to chemicals or behavior is now yielding to an older view that many of our woes are instead due to a nature red in tooth and claw.

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The LATimes is reporting on a new study finding that neuroticism and extraversion in patients suffering from major depressive disorder are respectively alleviated and enhanced in patients taking Paxil. As compared to those taking placebos, Paxil patients not only experienced longer lasting relief from depression they also saw significant positive personality changes becoming less neurotic and more outgoing. "That is a dramatic change," said Robert McCrae, a leading researcher on personality, now retired. "If you were these patients or someone in their family, you'd notice a difference."
 

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Despite decades of emphasis on putative man-made carcinogens, and a corresponding tendency to dismiss nature's brutish side as a possible cause of cancer, the case for viruses in causing human cancers has only gotten stronger. In "Human tumor-associated viruses and new insights into the molecular mechanisms of cancer" the roll of Epstein-Barr virus (EBV), human papillomavirus (HPV), hepatitis B and C (HBV and HCV respectively), human T-cell lymphotropic virus (HTLV-1) and Kaposi's associated sarcoma virus (KSHV) in a significant percentage of human cancers is discussed along with insights into molecular biological mechanisms and some very interesting thoughts about how these insights might reveal other heretofore unsuspected viral-induced cancers, novel treatments and public health strategies to reduce cancer by preventing viral infections.

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In their paper "Benzene-induced mutational pattern in the tumour suppressor gene TP53 analysed by use of a functional assay, the functional analysis of separated alleles in yeast, in human lung cells" Billet et al hypothesize that benzene-induced leukemia is the result of one or more mutations in the tumor suppressor gene known as TP53. They then report on their efforts to identify mutations in TP53 caused by benzene or its metabolites. It turns out that of the mutations linked to benzene exposure it is those in which guanine is substituted for adenine (A>G) that produce a pattern similar to that seen in benzene-induced acute myelogenous leukemia.

The authors conclude by suggesting that such an A>G transition could be "a fingerprint of benzene" that might help identify cases of AML produced by very low levels of past benzene exposure.

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Why is the rate of lung cancer among nonsmokers increasing? In this paper published in Experimental Lung Research the authors not only found measles virus antigens in 83% of non-small cell lung cancer cases, they found that infection with the virus resulted in an excess of a protein typically seen in excess among lung cancer patients.

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It was only a matter of time before molecular biological methods allowing screening for past potentially toxic exposures were developed.  In "DNA Double Strand Breaks by Asbestos, Silica and Titanium dioxide: Possible Biomarker of Carcinogenic Potential?' the authors from NIOSH, Health Effects Laboratory Branch, report that crocidolite was much more likely to produce  DNA double strand breaks leading to a molecule that can be detected by fluorescent antibody.  What this will mean for mass torts is anyone's guess but its implications for cases involving medical monitoring claims or mesothelioma claims where the plaintiff has failed to identify any amphobile exposures are obvious.

Interestingly, while similar effects were seen for crystalline silica and titanium dioxide, they were significantly less pronounced than that induced by crocidolite.

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In this paper the authors, including Arnold Brody, report that carbon nanotubes are responsible for inflammation on the pleural surface of mice following a brief exposure.  A subsequent immune response lead to areas of pleural fibrosis.  Non-fiber shaped carbon nanoparticles failed to produce a similar outcome suggesting that the fibrous tube structure may be an important aspect of this phenomenon.  The authors suggest minimizing inhalation of nanotubes until longer term assessments are completed.

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This is cool: BioGene.

Hat tip: OpenHelix.

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A Japanese man who was diagnosed with advanced malignant pleural mesothelioma is disease-free more than two years after being treated with a mushroom extract containing agaricus blazei Murill Kyowa and a modified form of acupuncture. The authors, who note that the patient had undergone debulking and chemotherapy but thereafter, as is typically the case, fared poorly, conjecture that his remarkable recovery may be due to “some immunological reactions of the host to the tumor” induced by either or both of the alternative treatments. The free paper was published in the Journal of Medical Case Reports.

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Although the precise mechansim for mesothioma is currently unknown, one study has postulated that immunosupression plays a role in the pathogenesis of this cancer. Mesothelioma in an HIV/AIDS patient without history of asbestos exposure: possible role for immunosuppression in mesothelioma: a case report, involved the study was of 41-year-old man who had asthma, HIV with progression to AIDS in the past 3 years, and a 20-pack year smoking history, was diagnosed with malignant mesothelioma.  This individual had no occupational history of asbestos exposure but did have a brief history of assisting in the demolition of a house over an 8-hour period a year before his diagnosis but it was unknown if he was exposed to asbestos during that work.

The authors of the study noted that the polyoma virus SV-40 has been implicated as a participant in some cases of mesothelioma. Studies have postulated that since the virus inactivates anti-tumor genes such as retinoblastoma, it promotes immunosuppression that may lead to enhanced susceptibility to mesothelioma. Similar to SV-40 virus, HIV is also an oncovirus and therefore capable of inducing cancer. Because HIV suppresses the immune system the authors think that HIV increases the susceptible to mesothelioma.

The authors also noted that transplant patients are immunosuppressed due to administration of drugs to prevent transplant organ rejection and elderly patients undergo physiologic immunosenescence which is characterized by reduced immune responses. Mesothelioma has been reported in transplant patients, without notable asbestos exposure, and mesotheliomas are classically reported in elderly patients.

The study notes that mesothelioma may be more prevalent in SV-40 virus-infected patients, HIV/AIDS patients, organ transplant patients, and elderly patients, than in the general population. The study concludes the development of mesothelioma in patients with HIV/AIDS, SV-40 infection, organ transplant, or advanced age suggests that chronic immunosuppression enhances susceptibility to mesothelioma.

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US EPA has been working on a risk assessment of trichloroethylene (TCE) for some time now. Here’s a link to the EPA Issue Papers through 2005. Now a comprehensive review of the issues has been published in Critical Reviews in Toxicology. The article is entitled “Trichloroethylene risk assessment: A review and commentary” and it provides an excellent overview of the developing molecular biological and molecular epidemiological approach to causal attribution and risk; one we’re sure to see increasingly in asbestos, benzene and other mass tort litigation.

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There are some interesting articles in the scientific literature about a war of which you've likely never heard. It's the one going on inside your body. A war pitting microbe against microbe. A conflict in which chemical warfare, the secretion of toxins, may well result in collateral damage - with the collateral damagee being you and the damage being cancer. More about that in the coming days but for now, here's an article about colon cancer risk and some of the bacteria working night and day to keep you from developing it. Here's the link.

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Immortalized cells in a patient suffering from glioblastoma multiforme showed signs of infection by the SV40 virus. link. Further evidence of an alternate cause, particularly among who received the polio vaccine when it was contaminated with SV40, in brain cancer cases.

For the latest on the SV40 / mesothelioma debate see this article noting that both asbestos and SV40 cause calretinin (you remember - calretinin- from all those mesothelioma immunohistochemistry path reports you're always reading) to rush to the defense of mesothelial cells eventually, perhaps, exhausting some ill defined mechanism and leading to mesothelioma.

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Lots of things cause aneuploidy but does that mean they cause cancer? Could it be that it's actually protective?

Nat Rev Mol Cell Biol. 2009 Jul;10(7):478-87. Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis

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Here's an another article for the health conscious suggesting that Golden Delicious apples contain a chemical that inhibits the growth of a bacterium called helicobacter pylori (h. pylori).  H. pylori is known to cause MALT lymphoma and stomach cancer and is increasingly suspected as a causative agent in a host of other cancers often the subject of mass tort litigation.

Though IARC declared h. pylori a Class I human carcinogen for gastric cancer in 1994, unflinching efforts to demonstrate links between h. pylori and neoplasms as diverse as colon cancer and lymphoma commenced only recently.  

In another post on this topic I’ll discuss the big drum that always gets beat in mass tort cases, epidemiology, and how it fared in elucidating the real cause of gastric cancer.  Teaser: When it came to finding the real cause, h. pylori, epidemiology produced an epic failure.

See "Carotenoids with Anti-Helicobacter Pylori Activity from Golden Delicious Apple"

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Chronic beryllium disease may result from very low levels of exposure to beryllium which occurred decades before any manifestation of the illness. The mechanism is thought to be a delayed immune response triggered by unknown environmental and genetic factors but at its heart due to sensitization to beryllium.

In this paper the authors present a history of the disease and current knowledge of its molecular biochemical mechanisms. They conclude that the current very low OSHA exposure limits still do not protect workers and suggest screening methodologies to identify those at risk.

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Bloomberg is reporting in "Prostate Cancer’s Worst Form Linked to Gene-Influencing Virus" that a virus linked to the most aggressive form of prostate cancer, the XMRV virus, may insert itself in a cell's genome setting up shop next to genes coding for cell growth and thereby leading to uncontrolled growth.

Daily the 20th century scientist's belief that nature is benign yields to the wisdom:

Tho' Nature, red in tooth and claw
With ravine, shriek'd against his creed
 

  - In Memoriam A.H.H. - Alfred, Lord Tennyson

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In the hormone replacement therapy litigation there's obviously a fight over whether estrogen caused the plaintiff's breast cancer. Is the demarcation simply a line between those breast cancers fueled by estrogen and those that aren't? If so, are there alternate causes of estrogen-fueled breast cancers?

What about human papillomavirus? It's been identified as the cause of cervical as well as head and neck cancers. Now HPV has been suggested as a cause of breast cancer.  http://www.nature.com/bjc/journal/vaop/ncurrent/full/6605282a.html

But is HPV a cause independent of estrogen or does estrogen facilitate whatever HPV does that leads to breast cancer? And if it's the latter, how do you sort out causation?

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The idea that fungi, bacteria, viruses, etc. invade much more complex organisms and force them to do their bidding is not new but the extent of the control they can exert is just now beginning to be revealed.

For a good discussion of one method by which an organism invades another to create something new see this article - though perhaps the title of it needs to be altered slightly to read "how endosymbosis is changing life on earth".

But for a really interesting read about one life form hijacking another see this story about zombie ants.  Hat tip www.MycoRant.com.

And what does this have to do with mass torts?  1) Again, there's increasing evidence of a paradigm shift in the thinking about causes of cancer and a number of infectious disease processes are being associated with cancers seen in toxic tort cases; and, 2) infectious disease, maybe including those that decades later result in cancer, may soon be among the most massive of mass torts.

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Here's a link to the program and abstract book: http://www.tum-benzenesymposium.de/AbstractBook_FINAL_082509.pdf

Given the current state of benzene litigation among the most interesting presentations will be those pertaining to (1) latency (whether attributable cases drop dramatically after 10 years or so); (2) disease endpoints (just AML, just certain subtypes of AML, or NHL, MM and even ALL); (3) molecular biology/epidemiology (biomarkers and pathways) for assessing past exposures; and, (4) risk assessment.

Details to follow.

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Or would a better title be something like "Back to the Future"? When I got out of law school I worked on more PAHs, nitrosamine and butadiene cases than dust cases. Some early and fairly primitive epi studies had suggested causal associations with brain cancers in southeast Texas but the litigation never really went anywhere - or at least it didn't turn into the next asbestos. There were a few bladder cancer cases that got interesting but the literature on glioblastoma pretty uniformly concluded that it had no known etiology and the brain cancer cases died out.

See: Human exposure to selected animal neurocarcinogens: a biomarker-based assessment and implications for brain tumor epidemiology. You'll have to register (and pay) to get more than the abstract.

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From bisphenol-A to benzene some researchers are claiming that some toxic substances not only don't have a no observable effect level (NOEL) but also that the shape of the dose response curve for these substances at low levels is supralinear.  What that all means is that the bane of any toxic tort litigator, the linear dose response assumption implying that even one molecule poses some risk, understates the actual risk associated with very low levels of exposure.

In "Evidence That Humans Metabolize Benzene via Two Pathways" by Rappaport, et al. hypothesize that at low levels of benzene exposure (less than one ppm) humans metabolize  the aromatic molecule much more efficiently than at higher levels due to some as-yet unidentified metabolic pathway.  Consequently "true leukemia risks" from exposure to benzene at what are considered acceptable ambient levels may instead pose significantly greater risks than are currently contemplated by regulators, according to the authors.

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Distinguishing a mesothelioma from a lung adenocarcinoma is critical in asbestos malignancies. Over time, diagnoses made on the basis of morphology and the presence of asbestos bodies gave way to immunohistochemistry. Immunohistochemical staining panels keep changing and debates often rage over whether say a positive calretinen, etc. and negative CEA, etc. is enough or whether they merely show for example an adenoma of mesothelial origin. Now there's a new paper out discussing the use of epigenetic (your genes aren't so deterministic after all) profiles. Its title is "Differentiation of lung adenocarcinoma, pleural mesothelioma, and nonmalignant pulmonary tissues using DNA methylation profiles" and you can buy a copy of it there.

Of course all these new methodologies raise the obvious question of "What happens when you try to draw causal inferences about a case diagnosed today from epidemiological research conducted at a time long before these diagnostic techniques existed?" Will these then be, at least with regard to the litigation, distinctions without a difference?

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One contemporary narrative goes like this: most cancers are preventable because most cancers are the result of man’s disregard for “nature”; whether due to pollution or ad campaign-induced bad habits like eating too much. But what if it turns out that a group of microbes that set up shop in our bodies are the real cause of many if not most cancers? 

Lung cancer has been the injury at issue in a number of mass tort cases.  A host of recently published papers indicates that human papillomavirus may trail only cigarette smoking as the leading cause of lung cancer.  See "Incidence of Human Papilloma Virus in Lung Cancer" and "The Role of Human Papilloma Virus in Lung Cancer: A Review of the Evidence"

Human papillomavirus has been associated with lung cancer in numerous studies though there is considerable debate as to whether the correlation is coincidental or causative. The first article reviews the literature and argues for a causative role for HPV in lung cancer. The second article suggests a biologically plausible mechanism for the production of lung cancer by human papillomavirus.

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