Tau hyperphosphorylation is a pretty common finding in young and middle-aged people with no cognitive impairment and has many causes, including physical and emotional ones.
Extrapleural pneumonectomy: runs up the damages, runs down the patient.
Want to look and feel younger? Well, there's a properly done study, statistically significant at p < .05, showing that people who listen to The Beatles "When I'm Sixty-Four" actually became a year and a half younger! Far fetched? Sure, but no more so than umpteen conclusions published in the scientific literature every day purporting to establish some causal connection based on nothing more than a statistical analysis of a series of observations. That's the point demonstrated conclusively in False-Positive Psychology: Undisclosed Flexibility in Data Collection and Analysis Allows Presenting Anything as Significant.
Though a paper may validly claim that the likelihood of the reported causal connection being due to chance alone is 5% or less (i.e. p < .05), "False-Positive Psychology" demonstrates that researchers free to modify as few as four variables (such as the number of observations to be made, sorting those observed by gender or stratifying outcomes) more likely than not have "discovered" a causal association that doesn't exist. The harm done by publishing such false-positives are obvious. As the authors put it:
"First, once they appear in the literature, false positives are particularly persistent. Because null results have many possible causes, failures to replicate previous findings are never conclusive. Furthermore, because it is uncommon for prestigious journals to publish null findings or exact replications, researchers have little incentive to even attempt them. Second, false positives waste resources: They inspire investment in fruitless research programs and can lead to ineffective policy changes. Finally, a field known for publishing false positives risks losing its credibility."
To vaccinate against infecting the scientific literature with false-positives the authors conclude with suggestions similar to those we've seen elsewhere in efforts to promote evidence-based science. At the heart of the suggested approach is transparency from the moment the experiment is conceived all the way through publication. There are six for authors and four for reviewers; be sure to read them all.
Plaintiff's expert Martyn Smith has proposed a mechanism whereby benzene produces leukemia.
Night shift work modestly increases women's risk of obesity and thus their risk of diabetes.
Soy milk may make your baby girl grow up to be considerably less feminine.
I keep coming up with reasons to pass on my father-in-law's venison stew/boudin/sausage/etc.
It's not clear whether acetaminophen causes asthma or whether the flu is to blame.
Aspirin really does reduce the risk of colon cancer in those predisposed to it.
The new IOM report, "Breast Cancer and the Environment: A Life Course Approach", again emphasizes the difference between how scientific panels go about making a causal inference and the approach too often approved of by credulous judges often insecure about their own ability to think critically and mesmerized by the jargon-laden pronouncements of credentialed experts. Beginning on page 82 under "Hierarchy of Studies" and followed by "Categories of Evidence" the report does a great job of detailing what counts as evidence and the methods and criteria used by organizations like the International Agency for Research on Cancer, the National Toxicology Program, the World Cancer Research Fund / American Institute for Cancer Research in going about collecting, assessing and weighing evidence when making causal judgments. They even put together a helpful summary of the classification systems (see Appendix C, "Classifications Systems Used in Evidence Reviews" at page 312).
Here are a couple of takeaways: (1) "The criteria aim to be explicit about the weight, or relative importance, given to studies in humans and in animals or other experimental systems"; and (2) "Strong and consistent positive epidemiologic evidence in rigorously conducted studies is prima facie evidence that the substance is a risk factor." You will quickly note upon reviewing the summary of systems of causal inference that none support anything like the notion embraced by the court in Milward v. Acuity that an expert weighing a subset of the data (each piece of which is either weak, irrelevant or inconsistent) upon the scales of his personal scientific judgment can by "reasoning to the best explanation" reliably reach a causal inference - especially in the complete absence of any epidemiological evidence to support it. Indeed the "atomization" of evidence decried by the Milward court and those in the "public health movement" who promote mass tort litigation is exactly what IARC, IOM, NTP, EPA and WCRF/AICR do - they assess each piece of evidence, they do it transparently, they do it according to rules laid down before they even go looking for the evidence and then they weigh what's left; again, according to weighting systems that are explicit, consistent and established before the first piece of evidence is examined.
The idea that knowledge comes from scientists taking a "holistic approach to the data" and applying their personal judgment to it is, to be blunt, hooey. That may be a way to arrive at a testable conjecture but without the conjecture passing a test of its predictive power (e.g. a rigorous epidemiological study) it remains nothing but a bald, personal opinion with no foundation beyond the ipse dixit of the expert who induced it.
There's an epidemic of immune disorders in America. Allergies (especially food allergies), asthma, atopy, hypersensitivity disorders including Stevens Johnson Syndrome, Crohn's disease, type1 diabetes, obesity and more are being laid at the feet of perinatal use of antibiotics. Evidence is mounting rapidly that the use of antibiotics in newborns or their mothers disrupts the intestinal microbiota essential to a well-functioning immune system. The consequences are seen in the host of immune-related disorders which have become perhaps the most significant cause of morbidity and mortality in the United States today. For a new primer try: Perinatal Programming of Asthma: The Role of Gut Microbiota.
So what should we make of a drug that when first administered saved a young woman, allowing her to have a family and to live to 90* and yet which (because the role that gut bacteria play in generating a healthy immune system was decades away from being known) would eventually precipitate a wave of autoimmune disease in the United States? If antibiotics are indeed responsible for as many cases of debilitating illness as is now widely suspected, should we ban them and vilify their makers? Should their makers be driven to ruin by our tort system to ensure that nothing like penicillin is ever unleashed on the public again? Or should we instead finally recognize that we must take the good with the bad; that with every advance comes risk; and, that unintended consequences, the nature and extent of which may not be known for years to come, is the price of progress?
Apparently every risk is foreseeable in Iowa now that they've adopted the Restatement
Antibiotics taken during pregnancy may cause diseases as varied as asthma and diabetes
More and more the evidence is pointing to a causal relationship between viruses and NHL
Vaccinating your daughters against measles may do more good than they know
Post cheeseburger ergo propter cheeseburger is not enough to win an E. coli case
For want of an exit the restroom was lost
For want of a restroom decorum was lost
For want of decorum a tree was sought
For want of a tree the field was crossed
But the field's hidden hole bore a great cost
Yet because of a storm sight of it had been lost
Sadly the use of his leg was thus lost
And all for the want of an exit ramp
Apparently in Kentucky everything is foreseeable and "substantial factor" causation is nothing more than simple "but for" causation. See, Waldsachs v. Inland Marine Service, Inc.
To the followers of Mass Torts: State of the Art, apologies for our absence. Summer was unusually hectic and this fall has been a nightmare.
We were out the end of last week to attend and to speak at the DRI annual meeting in Washington. Here's our PowerPoint from the presentation on the Restatement (Third) re: duty, risk and causation (and how, and why, it got all mixed up). If you find some or all of it helpful feel free to use it. Attribution is always appreciated.
Aggregate settlements are all about the Benjamins, whatever the ALI may say.
Some cases of multiple myeloma and MDS/AML share a common etiology.
Trial by mathematics: better reasoning, not abdication of the duty to reason.
Third generation cephalosporin-resistant E. coli may make the MRSA problem look easy.
Individual genetic susceptibility explains beryllium sensitization at very low exposure levels.
"The exploration of the viral universe has only just begun."
People support evidence-based decision-making only so long as it supports their prior decisions.
Recurrence of SJS and TEN suggests predisposing factors.
Which came first, the C. albicans or the oral cancer?
In New York, the strength of a single epidemiological study is enough to support a causal inference.
Illinois' "consumer expectation test" does not excuse a plaintiff from proving causation.
Chinese chrysotile asbestos workers have more than a threefold increase in lung cancer risk.
What doesn't kill you makes you live longer.
Toxicology is rethinking recent dogma and its gaze is turning towards Goldilocks and hormesis.
Market economics explain otherwise inexplicable plant-fungi interactions.
What are they? They're responsible for massive worldwide die-offs of frogs and other amphibians. They're killing huge numbers of bats across the United States and threatening some local populations with outright extinction. They've also been convincingly associated with bee-colony collapse disorder which has wiped out 20 - 40 percent of U.S. honeybee colonies.
But they're not all bad. They invented penicillin and make other good things like beer and bread.
So, what are they? Read all about them in the Institute of Medicine's new report: "Fungal Diseases: An Emerging Threat to Human, Animal and Plant Health: Workshop Summary". The partial quote in our blog title comes from one of the participants, Arturo Casadevall, who said "Fungi are the only group of organisms that have been convincingly shown to cause extinction." And if you want more proof that infectious disease have most certainly not been conquered (and in fact have been invisible to investigators until now) be sure to read the story of the Cryptococcus gatti epidemic that emerged on Vancouver Island and has spread to the Northwestern U.S. killing 40 and sickening over 300 so far.
If you're interested in the issue of causation a great place to start is page 4 (through 9) of the Institute of Medicine's new report "Adverse Effects of Vaccines: Evidence and Causality". There's lots to consider. For example,support for the Texas Supreme Court's recent determination that plaintiff's will need two well done epi studies to support a claim of general causation:
"The committee does not consider a single epidemiologic study - regardless of how well it is designed, the size of the estimated effect, or the narrowness of the confidence interval - sufficient to merit a weight of 'high' or, in the absence of strong or intermediate mechanistic evidence, sufficient evidence to support a causality conclusion other than 'inadequate to accept or reject a causal relationship.' This requirement might seem overly rigorous to some readers. However, the Agency for Healthcare Research and Quality advises the Evidence-based Practice Centers that it has funded to produce evidence reports on important issues in health care to view an evidence base of a single study with caution (Owens et al., 2010). It does so due to the inability to judge consistency of results, an important contributor to a strength of evidence, because one cannot 'be certain that a single trial, no matter how large or well designed, presents the definitive picture of any particular clinical benefit or harm for a given treatment' (Owens et al., 2010)." (pg. 6)
You'll also get an introduction to the similar yet different GRADE v. EPC approaches to assessing and weighing scientific evidence when making causal judgments. Hopefully, as we've said in the past, courts will one day demand of experts the same sort of transparency in evidence accumulation, assessment and weight assignment that sound science demands.
Along the way you'll note the conspicuous absence of the pronouncements of experts among the things to be determinative in reaching causal judgments. By now that ought not be surprising. As Dr. Steven N. Goodman reported in his journal article "Judgment For Judges: What Traditional Statistics Don't Tell You About Causal Claims" the US Preventive Services Task Force, which is committed to evidence-based medicine, has ranked by reliability the different sorts of evidence that go into making supportable causal judgments. At the top of the list, the strongest sort of evidence, is the well done randomized controlled trial. Then comes the non-randomized controlled trial. Then cohort or case-control studies. Then multiple time series. Dead last, and weakest of all, comes "opinions of respected authorities ..." If science hasn't much use for the mere ipse dixit of credentialed experts it's hard to imagine why the law should hold otherwise.
Anyway, to find out what vaccines cause, and don't cause, and how sound causal judgments are made, this new IOM report is well worth your time.
Gina Kolata has another good read at the NYTimes in "The New Generation of Microbe Hunters". The word, as you can see, is quickly getting out; the old ways of thinking about the determinants of human health are crumbling as the discovery that we are "super-organisms", more bacterial than human - at least from a genetic perspective, sweeps away old notions about what makes us sick, what keeps us healthy and even what (and maybe who) we are.
For other dispatches from the revolution you might want to read about just how big a deal this is, how much we know, how much remains to be understood and the promise of biotherapeutics; or maybe, since there's a little Gilgamesh in each of us, how changing the bacteria in the gut of mice makes the rodents live significantly longer; then there's a dysregulated microbiome and rheumatoid arthritis; new insights into how H. pylori causes gastric cancer; and gut microbes can cause cancer of the liver and breast (in mice anyway); and changing the gut microbiota to treat type 2 diabetes and, and, and ... There's a torrent of literature but that'll give you an idea what's out there and what's coming.
None of that is to say "Eureka!" they've found the answer. Likely (as it's wise to hedge bets) the causation onion has many layers still uncovered. No, the point is twofold. First, the 40 year old idea championed by public health advocates pushing what they call social, or environmental, justice - that much if not most human suffering is due to bad industrial chemicals or the bad habits inculcated in consumers by nefarious corporations bent on selling them things they don't want or need - was never sound but now it's just silly. Second, if you've been paying attention, you'll understand that an awful lot of illness and suffering has been caused by stuff nobody, we presume, ever fretted about. But who knows? Maybe somebody somewhere has the disrupted microbiome version of the Sumner Simpson Papers. Wouldn't that be something?
As we've discussed previously, the Dallas Court of Appeals in Bostic made it logically impossible for a plaintiff injured as the result of multiple potentially causative exposures to recover from any of those responsible for the exposures. They did so by holding that a plaintiff must not only show that the aggregate dose was the "but for" cause of his injury, but also that each defendant's component dose was the "but for" cause of his injury. Thus, if plaintiff were exposed to two doses, each sufficient to have caused his injury, both defendants could argue with equal force under a "but for" standard "had my product never existed plaintiff would still have been injured because of the other guy's product and so my product cannot possibly have been the 'but for' cause of plaintiff's injury".
The source of the problem seems to originate in confusion over what the Texas Supreme Court means by "substantial factor", We've been arguing since our amicus in Borg-Warner that the essence of every court's discussion of foreseeability or proximate cause is risk. Since, as the National Academies put it in Science and Decisions, "[v]irtually every aspect of life involves risk", what courts have been doing is drawing boundaries between those risks for which the imposition of liability would be just and those for which the imposition of liability would be unjust. Substantial factor then means substantial risk and in toxic tort cases risk is measured by exposure, or dose. A plaintiff need only show that "but for" his exposure to asbestos (in the aggregate) he would not have developed mesothelioma but if he's to carry his burden of showing substantial factor causation he must estimate dose for each defendant's contribution to the overall dose. And that's what we thought Borg-Warner said.
Bostic argues in her brief however that any requirement that a plaintiff show what the dose received from an individual defendants product or premises was likely to have been would make it "scientifically impossible" for any plaintiff to prevail. She says that her expert Dr. Longo testified "that it would be scientifically impossible for him to calculate the precise dose of asbestos" that Bostic experienced as a result of his use of Georgia-Pacific's products. Of course Borg-Warner specifically says that a plaintiff is not required to state with mathematical precision the dose-contribution of each defendant. A supportable approximation is good enough. Bostic further implies that coming up with even an approximation of dose is impossible. Is it?
In 1995 Harvey Checkoway wrote: "Quantitative estimation of exposure has become a central focus in occupational epidemiology over the past decade as a result of the increasing emphasis put on exposure-response characterisation for occupational hazards." He concluded by writing: "Methods of assessment of exposure have been given much more attention in recent years. As a result, increasingly sophisticated approaches to retrospective assessment have been developed ... Nevertheless, no amount of foresight and prospective monitoring will replace the need for sound approaches to retrospective estimation of exposure, and the variety of methods now available provide a basis for that work." Not only have such methods been available to expert witnesses for years their use in benzene and other toxic tort litigation is nowadays utterly unexceptional.
Of course a supportable retrospective dose estimation is possible and it's done all the time. The attempt to substitute Dr. Longo's estimation of the highest dose from a one time use of Georgia-Pacific's product for Bostic's estimated total dose from its product is akin to substituting the amount of tar and other particulate generated by one cigarette for a plaintiff's pack-years of smoking - it evades the real question of "what was the risk?" and answers instead another question "was there any risk?" It's an effort to conflate risk and causation and so, without saying so, to get the Texas Supreme Court to adopt the Restatement (Third) of Torts and its attempt to substitute any risk for a substantial risk as the outer boundary of liability. Should they prevail they'll have knocked the cover off the ball.
The Supreme Court decided CSX v. McBride and here's our take. The majority held that whatever proximate cause might be it isn't a hurdle an FELA plaintiff must clear. Instead, without saying so, the court concluded that such a plaintiff has only the causation obstacle set out by the dissent in Palsgraf to deal with. Specifically, "but for", or counterfactual, causation plus the act of a not ordinarily prudent railroad company (requiring foreseeability of some, though not necessarily the, harm). A railroad company thus owes a duty not to the whole world but to its employees' whole future. Put another way, should a railroad do something "wrong" that produces not the harm the apprehension of which would have counseled a different course but which instead puts the employee in a place he otherwise wouldn't be so that he subsequently suffers a completely unforeseeable injury, the railroad is on the hook for the damages.
We are sad of course that the Court didn't take the opportunity to consider legal causation to be properly understood as "but for" causation plus risk. However, given the fact that the Court was interpreting a statute half a century old (one that Congress, by its steadfast refusal to change the Act's language regarding the causation standard, apparently doesn't consider to be the source of absurd or unjust results) the outcome isn't surprising. And it didn't help that the jury instruction on causation requested by CSX, "any cause which, in natural or probable sequence, produced the injury complained of", would shed no light on the distinction between pure "but for" causation and legal causation anyway. Most if not all proximate cause instructions indeed appear to be little more than, as one of our mock jurors muttered of the instruction, "typical lawyer BS".
Had Ms Palsgraf been an employee of the Long Island RR (and had the FELA's "played any part" causation standard been around) she would have prevailed. Bad news for the railroads but good news for anyone else not stuck with the FELA causation standard since whatever the court thinks proximate cause might be at least it's more than "played any part".
The ICNIRP (International Commission on Non-Ionizing Radiation Protection) Standing Committee on Epidemiology recently analyzed published research related to cell phones and brain cancer. This review concludes that evidence from a growing number of studies does not support the theory that cell phones raise the risk of brain cancer.
It's interesting to note that early on D. Savitz, a member of the ICNIRP Standing Committee on Epidemiology, was in the EMF causes childhood leukemia camp. In 1993 with the accumulation of additional data Savitz was able to concluded that “the evidence falls short of demonstrating a causal association between electric and magnetic fields and cancer.”
In 2004 the same members of the ICNIRP Standing Committee on Epidemiology published a detailed review of epidemiological studies of health effects from exposure to radio waves. The reviewers concluded that "results of these studies to date give no consistent or convincing evidence of a causal relation between RF exposure and any adverse health effect."
In 2009 the ICNIRP Standing Committee on Epidemiology published an update of their 2004 review. They noted that the number of papers on this topic had grown since 2004, but concluded that the available data does not suggest a causal association between mobile phone use and fast growing tumours in the brain such as malignant glioma. The similar absence of an association for slow growing tumours such as meningioma and acoustic neuroma is far less conclusive because the period of observation is simply too short.
With ICNIRP’s caveat “the possibility of a small or a longer term effect cannot be ruled out", I’m sure this isn't the end of the story. We’ll keep you posted.
That quote comes from the conclusion of Judge Cecilia Altonaga's Order granting defendant's motion to exclude plaintiffs' experts in In Re Denture Cream Products Liability Litigation. If you're interested in the problem of causation in toxic tort cases this little gem would make a great primer.
Of particular interest are the following: (a) the court's dissection of the experts' arrangement of bits of unrelated data into what to the casual observer might appear to be a sound deductive argument; (b) the court's discussion of causal inference via induction and its implicit requirement that experts assess ( weigh) and then disclose the strength of their belief in each premise of the argument; and, (c) the court's recognition of the problem of selection bias when paid experts are allowed to opine as to causation using a so-called differential diagnosis or differential etiology approach - they tend, presumably subconsciously, to populate the line-up of suspect causes with the defendant's product and three or four easily ruled-out alternatives.
We especially liked the following about the opinion of plaintiffs' experts: "This theory is not ridiculous, but neither is it necessarily true; it is ripe for testing." That's what we said about Milward. All the plaintiff had was a plausible yet untested (because, said her expert, it was untestable) theory. Traditionally, that hadn't been nearly enough.
There's a clear split between the circuits with most requiring evidence that a theory's prediction has been confirmed at least once before it can go to a jury while a couple of others require only plausibility and an expert willing to say that it's so based on his or her scientific judgment. So it's the empiricists vs. the epistemological anarchists; Popper v. Feyerabend. If the Supremes decide to have a look it'll be a very big deal.
A risk-based tax on rubber duckies?
Kentucky adopts the economic loss rule. (An especially well written opinion btw).
To be injured, you have to be injured. (Wis Ct of Appeals: another well-reasoned opinion worth reading)
Roggli shows that brake repair workers got their meso from commercial amphiboles.
BIC Pen Corp. v. Carter has been decided, again, and seemingly for the last time. The court previously disposed of the design defect claims and this time the tragic case of a little girl severely burned as a consequence of her five-year-old brother playing with a lighter was before the court on the issues of manufacturing defect and causation.
Given that BIC's own tests of the lighter involved in the accident showed that a flame was produced more readily (because less force was required) than designed the court steamrolled over BIC's manufacturing defect arguments. It gave especially short shrift to the manufacturing variance argument (which actually has a lot of merit). Thus, by the time the opinion gets to causation, a defect for which liability may be imposed having just been found, to the reader things look pretty grim for BIC.
The court focused immediately on the issue that decides causation. Since lighters are designed to be child-resistant and not child-proof (as otherwise lots of adults could not operate them) how do we know that Carter's brother wouldn't have been able to light it anyway? Which is to ask how do we know that but for the defect Carter's brother would not have started the fire? Clearly Carter has to produce some evidence that her brother was enabled by the defect since even if a lighter meets the CPSC standard for lighters it may still be usable by 15% of children his age.
First the court looks at evidence that the brother was developing more slowly than a typical boy his age. The idea is that if the boy was cognitively more like a four-year-old than like a five-year-old then it's more likely that he was indeed enabled by the defect. The court quite rightly decided that it was an apples to oranges assertion because the defect was in a feature meant to physically deter children whereas there was no defect found in the mechanism meant to confound them. Next the court turned to Carter's contention that she could prove her brother was enabled by the defect using the reasoning of Havner.
Carter points to data indicating that low-force-to-operate levels in lighters such as the one in question quadruple the likelihood of a child being able to produce a flame. If Havner requires a doubling of the risk isn't a quadrupling more than enough? Before we get to how the court decided this issue let's run the numbers. As best we can tell there is at least one good test showing that the number of children able to active the lighter goes from 4% to 16% when the physical deterrent to ignition (force) is reduced. Now, assuming that the lighter in question produced a reduction in force necessary to produce a flame similar to the one used in the test then we can calculate how likely it was that Carter's brother was enabled by the defect. Using Bayes' Rule, the likelihoods of ignition for as-designed lighters and reduced force lighters and our knowledge that the lighter in question was in fact defective we can calculated that the likelihood that Carter's brother would not have been able to start the fire (i.e. was enabled by the defect) but for the defect is 75% - a result easily clearing the "more likely than not" hurdle.
Now, the court could have decided that the quadrupling of risk of ignition involved a different level of force (which, in fact, it did) and that plaintiff had zip, zero, nada evidence that the reduction in force at issue (a very tiny one) has ever been shown to double, much less quadruple, risk (which, apparently, it has not). That would have preserved and extended to manufacturing defect cases the rational decision-making approach to uncertain cases established by the court in Havner. Instead, the court decided that probabilistic reasoning can't be used in manufacturing defect cases and gave an extraordinarily weak rationale for doing so.
The court held that "[t]he nature of the injury-causing activities and testing that would have to be done to show causation in this case are not similar to, nor do they pose the practical difficulties posed by, those we considered in Havner. In this case, testing of J-26 lighters posed no unreasonable risk of injury to the test subjects as would have been the case if testing of the drug on humans had been performed under the facts of Havner ... In such instances, tests are done with surrogate lighters that do not pose a risk of harm to the participating children. And testing was also performed on the Subject Lighter itself that posed no risk of injury. Thus we decline to adopt a Havner-type analysis as to causation in this case where manufacturing defects are the basis for the liability claim."
So, because the test subjects tested lighters that didn't contain butane and because the lighter in question posed no risk of burning children when it was tested in a lab post accident, modern techniques for inferring causation aren't appropriate? With all due deference that makes no sense whatsoever.
Maybe the court was worried about permitting Havner-esque analysis in manufacturing defect cases because eventually it would be deployed in a case where the allegedly defective product had been lost or destroyed. If so, a defendant's product could indeed be found to have been more likely than not the cause of the accident even though the product was lost or destroyed. But for that to happen one of two things would have to hold true. Either the defect was responsible for a huge percentage of all such accidents or a huge percentage of the product had been manufactured defectively. In this case, for example, had the lighter been destroyed in the fire plaintiff could not show "more likely than not" (even assuming a quadrupling of the risk) unless she could also show that at least two-thirds of all lighters had the reduced-force defect. Either way, imposing liability when a defect is almost always the cause of an accident or when almost all of the product involved has been defectively manufactured hardly seems an injustice.
Case by case for more than a decade the Texas Supreme Court has worked to produce a coherent and just approach to causation by demanding sound science and utilizing modern decision theory approaches when reasoning out the cases before it. Hopefully, given our fondness for Havner, the true meaning of BIC Pen Corp. v. Carter is exceptio probat regulam in casibus non exceptis.
No need to prove toxic dose in a pharma case.
Tort law: ending classical liberalism and becoming "the administrative state's backdrop"?
Uranium ore harbors lots of happy bacteria.
Vitamin D lowers risk of cardiovascular disease in men but not women.
The innate immune system may explain the unpredictability of Stevens-Johnson syndrome.
Pro/Pre/Pharma-biotics: from skepticism to conversion.
Our modern comforts and conveniences also provide significant health benefits.
If there are zombie ants and zombie mice why can't there be ....?
There's been considerable buzz about Betz v. Pneumo Abex; an asbestos case pending before the Pennsylvania Supreme Court. Recently several noted scientists underscored the importance of the case when they filed an amicus brief asking that the court reverse the Superior Court's ruling - a decision which would result in the plaintiff's expert being permitted to testify that each and every fiber of asbestos to which the plaintiff had been exposed was in fact a cause of his illness. The brief itself is somewhat odd and doesn't read much like the other works of the scientists involved; some scientific concepts having seemingly been lost in translation. They do however make one important point. Unfortunately, they don't address the fundamental issue that bedevil this litigation.
The point they make clearly is that the assertion that every fiber of asbestos is the cause of a subsequent disease is not a scientific one. Scientific claims require confirmation, which is to say that they're not merely hypotheses but are ideas that are testable, that have been tested and have survived those tests. In the case of the "every fiber" claim the scientists note that there's no evidence for it and that multiple studies involving exposure to low levels of asbestos have repeatedly refuted the claim. They make an especially strong plea for courts to remember the role that empiricism plays in the scientific method.
What remains unaddressed is what to do with a case in which the illness was allegedly caused by the aggregation of multiple small doses. In other words, as the plaintiffs frame the question, what is to be done when a camel is found with a broken back and a pile of straw the cause? Under what theory could any straw be absolved of blame?
Let's answer that question with some graphics. First up a typical modern case in which a plaintiff with mesothelioma had a combination of exposures from very high to very low. For the purposes of this discussion assume that 100 f yr/mL is a cumulative exposure that is recognized by plaintiffs and defendants as one that would have been sufficient to have caused plaintiff's illness. Here's what one such scenario might look like:
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Let's further define each exposure according to what we think the law is and ought to be with regard to what is called substantial factor analysis. Those exposures which in and of themselves are sufficient to have caused the illness are necessarily substantial factors. Those that pose a significantly increased risk, a question for the court and one that may vary from jurisdiction to jurisdiction, are also substantial factors. Those that produce only a remote or de minimis risk are not substantial factors. The graphic looks like this:
Our slide titled "How It Might Play Out" shows a case in which the court has defined the limits of liability and the jury has thereafter determined which of the substantial factors were foreseeable, which is to say risky in their estimation.
The harder case is the one in which plaintiffs argue that exposures that were substantial as well as those that were de minimis can just as arbitrarily be grouped into a subset of exposures the aggregate dose from which could clearly have been causative. It looks something like this:
As formerly peripheral defendants who were bit players in the asbestos industry have gone bankrupt we've increasingly seen cases with nothing but defendants whose conduct individually never produced more than a nearly infinitesimal risk of illness. And given that trend this is what plaintiffs' cases will look like in the future:
Assuming arguendo that multiple small doses of asbestos which have never been shown to have caused any illness whatsoever are in the aggregate capable of producing mesothelioma, how do defendants argue that they ought not be liable? The answer begins with the fact that an unwritten rule for asbestos litigation has evolved over the years. That rule is "causation equals liability". That was never the rule.
Now however, as with the circumstance of Ms. Palsgraf in which she could not recover because the risk to her created by a guard trying to help a stumbling passenger was too remote, courts wrestling with asbestos litigation are beginning to come to grips with the fact that many of the defendants left in the litigation are being sued for producing risks that were orders of magnitude smaller than those posed by everyday facets of life such as taking a shower, shaking a stranger's hand or eating an extra slice of pizza. And some courts are starting to apply the same rules that they apply to other cases in which the conduct was ordinary and the outcome remote - that it cannot be the law that any action a person takes, however benign or ordinary, subjects her to being hauled into court should she be that one in a million person whose ordinary conduct produces an extraordinary outcome.
And thus to the camel's claim. Ultimately the question is whether some conduct is so common and so unexceptional as to not, as a matter of law, subject the actor to liability; even though by way of one of life's tragic chances her simple action one day manifests in harm to another. The Restatement (Third) of Torts answers "no, never". On the other hand, in every context outside of asbestos litigation, American courts have overwhelmingly answered "yes". "Yes", because they recognize that we all make our way, with rare exceptions, as best we can through a world of inevitable and mostly unknown risks. They hold that the extra straw added to the camel's load then, in every case, asbestos or otherwise, ought not subject she who added it to massive and equally unpredictable liability.
When considering how legal outcomes may affect beliefs (think experts opining on general causation in the face of a lack of science), it is interesting to consider not just science but pure belief.
A beer joint in a small Texas town built an addition. A congregation prayed that it not be built. Lightning struck. The church rejoiced, firm in the belief of the power of prayer. The bar owner sued the church for causing, directly or indirectly, the lightning strike which smote his expansion. The church then denied the power of prayer. No really. True story.
Let’s again consider general causation and the power of process of elimination causation determinations.
The recent Milward opinion out of the U.S. First Circuit Court of Appeals notwithstanding, the subjective assessment of an expert, weighing whatever evidence he selects for consideration in the scales of his own "scientific judgment", is not how causal inferences should be reached. At least not according to the National Academy of Sciences (NAS).
Last Friday NAS released its report on EPA's Integrated Risk Information System (IRIS) assessment of formaldehyde. It wasn't impressed with the overlong and detailed discussions of each study the EPA had considered. Rather, it expressed its concern that all EPA had at the end of the day was a pile of studies and its scientific judgment. Specifically the NAS reiterated, as it has in the past, that data + a statement that proper methods of causal inference had been followed ≠ sound science.
Of the criticisms leveled against the EPA's report the most frequent was for a lack of transparency. The EPA hadn't made it at all clear how it was going to go about assembling data, how it was going to assess the data, by what criteria it would include or exclude a given piece of data or how, and by what standards, it was going to weigh the data it found worthy of consideration. How can another scientist assess the soundness of an expert's conclusion if she has nothing other than "I considered the following studies and reached the following conclusion using my best judgment" to go on? She can't.
So on page 115 the NAS reviews best practices for conducting and assessing comprehensive reviews. If you're dealing with an expert who says "I used the A.B. Hill criteria and my scientific judgment to reach my opinions" you'll find the discussion that follows full of great cross examination material. Where, for example, is the evidence table prepared by the expert? What weight does he assign to each datum? How did he come by it? If a particular study has a potential for bias by how much did he lessen the weight assigned, how did he come up with the number and in what other matter has he used the same modifier to account for possible bias?
Finally, the NAS took a particularly dim view of the EPA's conclusion that formaldehyde likely causes all lymphohematopoietic (LHP) cancers. (See pages 80 - 87). There's "[t]he grouping of 'all LHP cancers' includes at least 14 biologically distinct diagnoses in humans and should not be used in determinations of causality". And "there is no clearly articulated framework for establishing causation on the basis of the weight and strength of evidence". Finally "the conclusion of causation appears to be based on a subjective view of the overall data ... [t]he absence of a causation framework is especially problematic for the individual LHP cancers, given the highly variable epidemiologic literature and the high uncertainty of mode of action."
Bottom line: if you're going to use a "weight of the evidence" approach you have to say how you decided what to weigh and by what standards you weighed it. Pretty basic stuff really.
Systematic reviews and meta-analyses are considered to be perhaps the best evidence about treatments/exposures and outcomes from which causal inferences can be drawn. The problem is that they're susceptible to a variety of biases. See e.g. "Bias Due to Changes in Specified Outcomes During the Systematic Review Process".
In the litigation context we increasingly see a systematic review launched by an expert-to-be before the first suit is even filed. They will thus have already gone through the studies; used their "judgment" to select which ones ought to be considered (and which ought not); determined how much weight to give each; and established a protocol for conducting the review which, surprise surprise, demonstrates a causal link supporting the lawsuits. The strong suspicion is that selection bias (a form of the Texas Sharpshooter effect) is at work (and that, of course, is being charitable). And the biggest problem is that uncovering selection bias is notoriously difficult.
Now there's a move afoot to bring transparency to systematic reviews by requiring that plans, methods and protocols be registered before the systematic review is begun. See "Best Practice in Systematic Reviews: The Importance of Protocols and Registration"; "New Initiative to Make Systematic Review Protocols More Transparent" and "Open Medicine Endorses PROSPERO". Here's the press release from the Cochrane Collaboration and here's a link to PROSPERO.
Until we get courts to make experts disclose their methods and justifications for selecting, weighing and interpreting data before they develop their opinions articles like the following may come in handy: "How Can We Improve the Interpretation of Systematic Reviews?"
There's good epidemiological evidence that population mixing is responsible for several clusters of childhood leukemia (acute lymphocytic leukemia, or ALL). Some have hypothesized that viruses are to blame but there hasn't been much evidence to support that hypothesis; at least not until now.
In the current Journal of Pediatrics you'll find "Associations Between Vaccination and Childhood Cancers in Texas Regions" which compares the risk of ALL to vaccination rates in different public health regions. With all the caveats that must go along with hypotheses generated by statistical analysis it is nevertheless quite intriguing to see that children vaccinated against a wide range of viruses had a large and consistent reduction in their risk of ALL; so much so that it leading the researchers to conclude that "[s]ome common childhood vaccines appear to be protective against ALL at the population level."
Be sure to also note that 4 doses of diptheria-tetanus-pertussis, 3 doses of polio, 1 dose of measles-mumps-rubella, 3 doses of H. influenza, type B, 3 doses of hepatitis B and one dose of Varicella, the 4-3-1-3-3 vaccine regimen claimed by some anti-vaccine activists to be capable of "overloading young immune systems" and thereby (some-unstated-how) causing autism, produced a 38% decrease in the risk of a child developing leukemia.
Hopefully the anti-vaccine crowd is paying attention. The list of harms to children for which they may be made to answer is apparently growing.
It has been known for a couple of decades now that women who never have children (i.e. women who are nulliparous) and women who do have children but not until they are 30 or older suffer a striking increase in their risk of developing breast cancer. The evidence for the association between never giving birth or delaying having a child continues to accumulate and now it appears that the increased risk is focused on hornmone receptor-positive breast cancers. See "Associations of Breast Cancer Risk Factors With Tumor Subtypes: A Pooled Analysis From the Breast Cancer Association Consortium Studies" in the current issue of the Journal of the National Cancer Institute. So let's say you've got a nulliparous plaintiff alleging that your drug or device or chemical caused or accelerated her hormone receptor-positive breast cancer; how do you handle her status?
The first problem a defendant faces in such a case is the risk of inadvertently wandering into the minefield called "blaming the victim". The plaintiff has either freely made a choice or has tragically been unable to have a child. Either way the jury will react strongly and negatively to any discussion about parity status and causation that makes even the slightest trespass into the issue of fault. Keep the discussion limited to risk factors and their relative potency. But that leads to another problem.
In some of the jurisdictions in which I practice plaintiff's counsel will successfully argue to the trial court that only evidence about about the actual cause of plaintiff's injury is admissible. In other words, unless my expert is prepared to say e.g. that "to a reasonable degree of medical probability plaintiff's breast cancer was caused by her not having children when she was young" testimony about "mere risks" is irrelevant and so inadmissible. The practical effect of such a ruling is that only junk science is admissible on the issue of the actual cause of plaintiff's cancer since my experts tend to be modest about the claims science can make regarding the cause of any individual's cancer. We're stuck then trying to prove a negative, showing we acted reasonably and preserving error.
In this age in which much that was certain (e.g. that we've conquered infectious diseases) is proving not to be so it's time I think for courts to recognize not only that the reasonableness of actions can fairly and effectively be judged according to the risks they conferred but also that causation is in many cases most precisely weighed when competing risks are allowed to be compared against one another.
Finally, and hopefully still on topic, for more evidence of the complexity of causation see "Does Pregnancy Provide Vaccine-Like Protection Against Rheumatoid Arthritis?" Why would pregnancy protect against auto-immune disorders and what's the connection with breast cancer? There are a variety of hypotheses offered but so far no one knows.
It's very thorough and it's free, full text, in this month's Orphanet Journal of Rare Diseases.See "Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome".
SJS/TEN cases typically involve very high damages as the injury is akin to a severe burn. The article contains a list of known causative agents as well as standards for diagnosis and treatment.
The idea that a known cause of cancer, e.g. ionizing radiation, poses a risk of cancer at any dose, no matter how small, is a central thesis informing modern environmental and occupational regulations and modern, which is to say low dose, toxic tort cancer litigation. In the toxic tort context plaintiffs regularly employ the logical fallacy of the appeal to ignorance (argumentum ad ignorantiam) to prove that even the slightest exposure was risky. They say that because defendants cannot establish a safe level of exposure it follows that every exposure is necessarily unsafe. The formal name for the idea that risk doesn't drop to zero until exposure drops to zero is the linear no-threshold dose theory or LNT. The LNT theory, always longer on theory and politics than evidence is increasingly under attack. Now even NIOSH has had to concede that at least in some circumstances there is indeed a safe dose for a carcinogen.
In "Checking the Foundation: Recent Radiobiology and the Linear No-Threshold Theory" the author states "a large and rapidly growing body of radiobiological evidence indicates that cell and tissue level responses to [radiation damage], particularly at low doses and/or dose-rates, are nonlinear and may exhibit thresholds ... this evidence directly contradicts the assumptions upon which the microdosimetric [LNT] argument is based". The idea that a substance that is harmful at high levels can be harmless or better yet beneficial or protective (the idea of hormesis) at low levels is discussed at length in this month's issue of Human & Experimental Toxicology.
The claim that "if it takes an ounce to kill ten men then a drop will thousands" was itself just a theory based on the idea that carcinogenesis was a stochastic process. Getting cancer was sort of like hitting the anti-lottery and the more tickets you bought (exposures you sustained) the more likely you were to lose yet if you were unlucky enough just one ticket could do it. Like black box epidemiology LNT was simply a way to ignore the formerly incomprehensible molecular biological mechanisms responsible for cancer. Now that those mechanisms are being uncovered and understood they can no longer be ignored as they shatter one paradigm after another.
Biological causation gets more complex by the day and the simple, reductionist model of toxin in - disease out common to toxic tort cases gets more absurd by the day. Imagine what you'd have thought two years ago about this claim: the diet of a fruit fly changes the composition of the bacteria in its gut and those bacteria then change the pheromones she releases so that she will attract a male fruit fly with the same sort of bacteria in his gut resulting in a mating preference change that lasts up to 37 generations even if her offspring's diet changes along the way.
Thus, it's not just a matter of "They Are What You Eat"; it may well also be a matter of "You Are What Your Great Great Great Great Grandmother's Intestinal Bacteria Ate". See "Bacteria Can Drive the Evolution of New Species" in Nature News for the write-up and "Commensal Bacteria Play a Role in Mating Preference of Drosophila melanogaster" for the paper that heralds the discovery.
For more on the idea of a "hologenome" - i.e. the idea of thinking of "your" genetic code as consisting of the genes in your chromosomes plus those in the bacteria that live in and on you - see the following:
"Role of Microorganisms in the Evolution of Animals and Plants: the Hologenome Theory of Evolution"
"The Hologenome Theory of Evolution Contains Lamarckian Aspects Within a Darwinian Framework"
"Whole-Body Systems Approaches for Gut Microbiota-Targeted Preventive Healthcare"
Why are mice so much more susceptible to butadiene? Apparently it's because they metabolize it into potent mutagens at 200 times the rate of humans. As a result, while mice exposed to butadiene at current occupational levels promptly yield evidence of genotoxicity there's no evidence of genotoxicity in humans at current workplace exposure levels. See: "1,3-Butadiene: Biomarkers and Application to Risk Assessment".
Back when I was an associate we had a refinery client with a benzene unit and the unit generated litigation along with the benzene. Interestingly, the union knew that benzene could cause fatal blood diseases back when the unit was built in the late 1950s. The union even sent down a benzene safety poster which was framed and hung in the control room. The operators were issued cartridge respirators for aromatics and had blood samples taken for testing on a regular basis. Far from being a worry, even after the Emergency Temporary Standard for benzene came out the unit was a favorite of those union members with the seniority to bid on to it. So much so that women with the requisite seniority would have hysterectomies so they could get around the so-called fertile female policy that prevented them from working on it.
Some early, and I might add poorly done, studies had suggested that benzene might cause birth defects. Accordingly many companies adopted policies that kept women who were otherwise qualified from working with materials or in operations feared to be teratogenic. Eventually the U.S. Supreme Court struck down such policies. See: International Union, United Automobile, Aerospace & Agricultural Implement Workers of America, UAW, et al v. Johnson Controls, Inc.
Nothing ever came of the claim that benzene was a teratogen and even in southeast Texas where injury and illness would otherwise not exist but for deep pocketed corporations we never had any benzene birth defect claims.
Now however there's a new study in Environmental Health Perspectives that compares EPA estimates of benzene exposures in Texas and the rates of spina bifida among people living in those areas during a recent five year period. It found for the area with the highest exposure a 2.3-fold increase in spina bifida; an association which was statistically significant.
Read all about it (free) in "Maternal Exposure to Ambient Levels of Benzene and Neural Tube Defects Among Offspring, Texas, 1999 - 2004"
Hat tip: The Houston Chronicle
Industry and military scientists get rewarded when they come up with things that work. Academic scientists tend to get rewarded when they come up with narratives that generate more grant money. Ok, nothing new there. But what happens when an academic scientist suggests that a prevailing academic paradigm be subjected to the same criterion of falsifiability as any other claim to knowledge? Hilarity ensues, though only for those on the outside looking in at the absurdity of simultaneously dismissive and panicky academic internecine warfare.
Though she does not question the idea that man influences climate and may well do so harmfully, Judith Curry, from one of those few remaining institutions (e.g. the Ramblin' Wreck of Georgia Tech) that yet dare to question societal dogma has gathered the courage to question the prevailing groupthink of the Intergovernmental Panel on Climate Change (IPCC) and for her trouble has garnered the enmity of the Global Warming clergy and its laity.
Read all about it (free) at Scientific American in "Climate Heretic: Judith Curry Turns on Her Colleagues. Why Can't We Have a Civil Conversation About Climate?"
Do you comply with your doctor's orders? If you're on a daily medication do you always take it, every day, at the same time, with say the recommended glass of water? If you do, even if there's no medicine in the pill, your odds of living a long and healthy life are good and getting better and it's because you've made yourself the beneficiary of the compliance effect.
I was reminded of a recent study of the so-called compliance effect while reading "Secrets of the Centenarians" in today's NYTimes. In the Times piece the author examines the long life and sharp mind of Mrs Esther Tuttle and her particularly keen insight into the source of good health. She says:"If you respect what the doctors tell you to do, you can live a long life, but you have to do it. You can't ignore the advice."
Though currently inexplicable it turns out that people who follow their doctor's orders, even if it's just to take a sugar pill a day (they don't know it's a sugar pill, of course), do better than those who take a less disciplined approach to their health. The article of which I was reminded is: "The Relationship Between Bisphosphonate Adherence and Fracture: Is it the Behavior or the Medication? Results From the Placebo Arm of the Fracture Intervention Trial". In it the authors report the results of a study of the outcomes of those women on placebo in a drug trial for a drug designed to prevent bone loss (osteoporosis). Even though they didn't get any real medicine and even though they were on the same sugar pill as the women who didn't strictly adhere to their doctor's orders regarding the drug, those women who took their sugar pill religiously had significantly lower bone loss and fewer hip fractures.
This and other recent research on the compliance effect confirm what Mrs Tuttle somehow figured out: resolve (along with resourcefulness, resilience and a refusal to succumb to cynicism) somehow, some way, keeps you alive and keeps you healthy.
Workers exposed to trichloroethylene (TCE) who carry at least one copy of the GSTT1 allele are reported to have an 88% increase in risk of renal cancer in the new paper "Occupational Trichloroethylene Exposure and Renal Carcinoma Risk: Evidence of Genetic Susceptibility by Reductive Metabolism Gene Variants." Those workers without the polymorphism had a slight decrease in risk. Given that the allele occurs on a gene coding for cysteine β-lyase, which plays an important role in the metabolism of TCE among other molecules, the finding demonstrates biologic plausibility as well as increased risk.
So back to yesterday's post about risk : which risk, if any, would be relevant in a TCE toxic tort case? The risk given to all workers collectively; the risk at a particular range of exposure; the risk given to those carrying the polymorphism; or, the risk to those with the polymorphism exposed at high levels? And could it be the case that one risk is relevant to the question of whether a defendant's conduct was reasonable while another was relevant to the question of causation? How would that work?
However it works, as the causes of individual susceptibility are identified expect these sorts of challenges to multiply.
The Avandia witch hunt saga just gets more and more absurd. Guess what just popped up from the FDA's Division of Drug Information? Notice of an ongoing safety review of pioglitazone (the "safer alternative" generic pushed by those urging Avandia be pulled from the market.). Apparently "an increased risk of bladder cancer was observed among patients with the longest exposure to Actos (pioglitazone) as well as in those exposed to the highest cumulative dose of Actos."
So does this mean that pioglitazone ought to be banned? Does this mean that the ongoing study of pioglitazone users needs to be discontinued because it's unethical? That's what the anti-Avandia activists argued re: Avandia and the TIDE trial; they wanted everyone off Avandia, on pioglitazone and the experiment halted - pronto.
No; it ought not mean any of those things. What it does mean is that it's foolish to let our decisions be bound by the results of a single data dredge.
For more on the Avandia issue see: "Avandia: Burn Her Anyway?" For more on the perils of data mining see "Lies, Damned Lies and P-Values". Here's the full text of today's FDA missive on pioglitazone:
The Division of Drug Information (DDI) is CDER's focal point for public inquiries. We serve the public by providing information on human drug products and drug product regulation by FDA.
The U.S. Food and Drug Administration (FDA) is reviewing data from an ongoing, ten-year epidemiological study designed to evaluate whether Actos (pioglitazone), is associated with an increased risk of bladder cancer. Findings from studies in animals and humans suggest this is a potential safety risk that needs further study.
Actos is used along with diet and exercise to control blood sugar or improve control of blood sugar in adults with type 2 diabetes mellitus.
Bladder cancer is estimated to occur in 20 per 100,000 persons per year in the United States and is thought to be higher in diabetics.
The drug manufacturer, Takeda, has conducted a planned analysis of the study data at the five-year mark, and submitted their results to FDA. Overall, there was no statistically significant association between Actos exposure and bladder cancer risk. However, further analyses were also performed looking at how long patients were on Actos and the total amount of the drug they received during that time. An increased risk of bladder cancer was observed among patients with the longest exposure to Actos, as well as in those exposed to the highest cumulative dose of Actos.
At this time, FDA has not concluded that Actos increases the risk of bladder cancer. Its review is ongoing, and the Agency will update the public when it has additional information.
For more information, please visit: Actos
A new study, reviewing and pooling results from prior studies in prostate cancer screening, shows that screening men for prostate cancer does not increase life expectancy.
While the PSA test is effective at predicting which men may eventually get prostate cancer, it is ineffective in increasing life expectancy. This is because most men with a high PSA will not get prostate cancer in their lifetimes and will eventually die from something else. Many men, some of whom I have debated the value of a PSA test with, get a high PSA test result and live in fear of cancer for decades, even though prostate cancer never develops. Further, prostate cancer treatments, including surgery or radiation, can lead to incontinence and erectile dysfunction in about a third of patients. Unfortunately, some men get the treatments after a high PSA from fear of cancer which may never reach them in their lifetime. Other men get the treatments when they contract prostate cancer, even though this slow-growing tumor will not hurt them in their lifetimes. It is a case where the cure is sometimes worse than the cause.
The study is part of an effort to streamline which medical tests are effective, not just in detecting disease or the potential for disease, but for actually increasing life expectancy and increasing quality of life. A similar effort was undertaken to critically and empirically view breast cancer screening. The breast cancer screening recommendations were met with a flurry of criticism. Hopefully, this recommendation will not meet the same result.
In Tamraz v. Lincoln Electric Company, et al the 6th Circuit held that an expert could not stack speculation about mechanisms upon unseen and undetected lesions in the plaintiff to get from manganese exposure to his Parkinson's disease. Furthermore, the court ruled that you can't reasonably arrive at a causation opinion using what's erroneously called a differential diagnosis (it's more properly called simply a process of elimination) when you've no sound basis for ruling anything either in or out.
On the other hand, there's growing evidence that vitamin D deficiency is strongly associated with Parkinson's. Best of all, it makes sense. It looks like the enteric nervous system is first to be degraded in Parkinson's and that system is exquisitely sensitive to the gut mediated immune system which in turn is adversely affected by vitamin D deficiency. See: "Parkinson Disease: Could Sunlight Offer Protection from Parkinson Disease?"
Whenever epidemiological data is used to support a claim of causation in a toxic tort case a fight over causal inference invariably erupts and for the last twenty years or so that has meant an argument about whether Sir A. B. Hill's so-called causal criteria have been met. Long before Hill tried to prove that smoking causes lung cancer Robert Koch tried to find a defensible argument for the claim that microbes were the cause of anthrax. What he came up with are known as Koch's postulates and they've been around for well over one hundred years. Now, in an attempt to update them for a world in which often only bits of pathogens long gone remain an attempt to update the postulates has been published.
In "Microbe Hunting" the author summarizes the problem of causal attribution when the responsible bacteria can't be cultured or even found and when their role in disease is the result of an incredibly complex interplay between host, uncounted trillions of microbes and the external environment. He discusses the methods for teasing out pathogens from dense webs of causation and proposes a refined set of causal criteria. It's well worth reading because if you do mass torts you'll be dealing with this issue for years to come.
It has generally been assumed that bacteria evolve to overcome host defenses at a rate much slower than that of viruses. That assumption appears to be wrong. Helicobacter pylori, a cause of multiple cancers in humans, mutates at a rate similar to many viruses. See: "Microevolution of Helicobacter pylori During Prolonged Infection of Single Hosts and Within Families".
Just how fast can bacteria evolve? Would you be surprised to learn that within the lifetime of mice, bred to be free of gastrointestinal bacteria, bacteria from drinking water cannot only set up shop and colonize their hosts' guts but evolve into whole new species? If you are surprised, read: "Bacteria From Drinking Water Supply and Their Fate in Gastrointestinal Tracts of Germ-Free Mice: A Phylogenetic Comparison Study".
The long war continues, of course; and while we've been basking in our assumed victory over them for the last forty years our ancient enemies, descended from a long line of brilliant sappers, have been hard at work.
What does it mean, in the law of torts, for one to have caused another's injury? The standard legal account of causality has been that of the counterfactual put forward by David Hume as follows: "where, if the first object had not been, the second never had existed." (1748, Section VII). In the law it's the "but for" test and for our purposes then the courts tend to attach legal liability (assuming the existence of a duty and its breach) only upon the following: had Defendant done otherwise, Plaintiff would today be uninjured.
Generally speaking the "but for" test is easy to use and produces a nice clean binary answer of the sort favored by courts trying to resolve disputes. (e.g. "But for" Defendant having run the red light Plaintiff would have passed through the intersection without incident and would not have suffered the broken leg of which she complains.) Of course there are innumerable "but for" causes of the accident, including the Defendant's mother having given birth to him and the rudeness of the fellow with a cart full of groceries in the "10 items or less" line who slowed Plaintiff down so that she wound up in the intersection at the same moment as Defendant. Nevertheless, and almost invariably without much analysis, the parties settle on just one among the countless posibilities as the sine qua non act (or omission) to be subjected to the "but for" test.
However, when deployed in a case in which plaintiff's injury was caused by only one of several identical and indistinguishable acts (see e.g. Summers v. Tice) or by the cumulative effect of some subset of several identical and indistinguishable acts (see e.g. Landers v. East Texas Salt Water Disposal Co.) the "but for" test would, without some other rule, produce the jarring judgment that none of the defendants, considered individually, were more likely than not the sine qua non cause of the plaintiff's injury. In those cases, finding that the acts (divorced from the inquiry of whether they were actually causative) were tortious, the courts held that the defendants should bear the burden of proof that theirs was not the act that caused the plaintiff's injury. The instances in which such a rule would apply were surely few and even a century ago the idea of treating the defendants collectively and shifting the burden on to them was not unheard of. See 2 J. Wigmore, Select Cases on the Law of Torts Section 153, p. 865 (1912) ("When two or more persons by their acts are possibly the sole cause of a harm, or when two or more acts of the same person are possibly the sole cause, and the plaintiff has introduced evidence that one of the two persons, or one of the same person's two acts, is culpable, then the defendant has the burden of proving that the other person, or his other act, was the sole cause of the harm.")
An effort to distill all judicial reasoning about causation down to its essence and to make a rule of it has been underway for some time. Probably the most cited rule, a form of which is incorporated into the Restatement (Third) of Torts, is the NESS test. NESS stands for "necessary element of a sufficient set". The NESS test is itself a restatement of an older test in which a singular putative cause is said to indeed be causative if it, though insufficient, is nevertheless a necessary element of a precipitating event which event, though perhaps itself unnecessary, would nevertheless have been sufficient to have produced the outcome under investigation (see "Causes and Conditions" by J.L. Mackie). What in the world does any of that mean? In Mackie's example investigators of a fire are satisfied that a short-circuit was the cause of a house fire when conditions were such that the short circuit existed, flammable rags were nearby and those rags once ignited were sufficient to cause a conflagration that would burn down the house. The short-circuit alone was insufficient to burn down the house but it was necessary (other causes having been ruled out) to catch nearby flammable rags on fire. Lots of things can ignite and so burn down a house (so burning rags are not necessary to have a burning house) but burning rags are sufficient to torch the place. Whew.
"But for", causal analysis seems then to be about ruling things out and settling on what's left (the short-circuit). On the other hand, the investigation of the product of the remaining thing(s) (sufficient set) seems aimed towards the propensity of one condition (burning rags) to lead to another (burning house). It is out of this second analysis, of the propensity for one thing to lead to another, that queries about reasonableness and foreseeability and risk arise. More on that later though when I get to risk.
Anyway, the reductionist effort itself precipitated a debate about whether the NESS test accounts for all judicial causal reasoning that continues to this day. Take for instance the hypothetical case of the desert traveler. The desert traveler set off to hike across the desert with just enough water to make it to the other side. Unbeknownst to the desert traveler, defendant "A" had poisoned his water such once that he'd consumed all of it he would surely die. Along his way across the desert however, defendant "B" stole the desert traveler's water bottle. The desert traveler was found dead in the desert. If defendant "A's" conduct was not the cause of his death, why not?
Such conundrums would normally make for nothing more than an obscure niche in the law in which a few academics could regularly generate tedious and unread papers. Then forty one years ago Clarence Borel, dying of mesothelioma, filed a products liability claim in Beaumont, TX culminating in an opinion that would usher in the age of mass torts. Concluding that as it was impossible "to determine with absolute certainty which particular exposure to asbestos dust resulted in injury" and because "each exposure may result in an additional and separate injury" the 5th Circuit held in Borel v. Fibreboard that a jury could reasonably conclude "that each defendant was the cause in fact" of Borel's injury.
Twenty seven years after Johns Manville sank under the wave of litigation unleashed by Borel the practical effect of the ruling continues to drive companies into bankruptcy. The Restatement (Third) of Torts was awkwardly silent on the issue of "the mother of all mass torts" but recent musings by its Reporters and others suggest that they thought rather a lot about it and that its impact on the restatement effort was in fact profound. The shame of it is that they almost got it exactly right. All that was needed was to distinguish between risk and causation and to embrace Palsgraf's true meaning: that the risk imparted is the measure of the reasonableness of the man.
Next time: Risk.
Six hours a day, for five days, rats were exposed either to amosite or to joint compound with chrysotile. Over the course of a year subsets were sacrificed and their lungs examined. The rats exposed to amosite sustained an inflammatory response and by the end of four weeks had developed evidence of interstitial fibrosis and inflammation in the parietal pleura. Those rats exposed to chrysotile-containing joint compound never showed evidence of fibrosis and their bodies cleared the chrysotile fibers quickly. By the end of the year there was still no evidence of inflammation or migration.
Would you believe that an act that was neither sufficient nor even necessary to produce an injury could still be considered a legal cause of it simply because it had exposed an injured plaintiff to risk? You need to read Restatement (Third) of Torts: Liability for Physical Harm. Wherever adopted it will expand liability in asbestos cases against those that almost certainly had nothing to do with plaintiffs' injuries; it will extend asbestos litigation's special rules to any claim for a cumulative or indivisible injury due to toxic exposure; and, it will do it by standing modern thinking about causality and risk on its head.
To understand why Restatement 3rd will change everything you need to read "The Insubstantially of the 'Substantial Factor' Test for Causation". Among the authors are the Reporters for the Restatement (Third) of Torts and they specifically examine the problem of causation in asbestos cases. They survey the landscape of modern attempts to deal with the issue and settle on Lohrmann, Rutherford, Gregg and Flores as representative.
Concluding that Rutherford stands for the rule that "[p]laintiff need only prove that defendant contributed to the risk of disease by exposing the plaintiff to asbestos" the authors conclude: "[g]iven the reality of causal uncertainty, we believe the Rutherford solution to the problem is the best yet devised. The Rutherford approach of imposing liability for risk contribution is self correcting in the case of small doses, at least in jurisdictions with several liability. The defendant who contributes .05% of the dose to which the plaintiff was exposed will be liable for that same percentage of the plaintiff's damages."
What’s wrong with that? Well they've conflated risk and causation. They're defining cause as risk and risk as cause and imposing liability without regard to cause or even the degree of risk imparted. How so? By saying that dose, which is only an aspect of risk, is the measure of cause; and by saying that cause is simply the set of all proven doses (which is to say risks)- thus: 0.05% dose (risk) = 0.05% of the causation.
The authors make it clear that there is no lower limit above zero that could not be the basis for liability. Either each fiber was a necessary cause under the “straw that broke the camel’s back” view or each fiber was a member of some sufficient group or set of fibers thus satisfying the Restatements’ version of the NESS (Necessary Element of a Sufficient Set) test for causation. How do we know this? There is a “trivial-contribution exemption” that applies in situations where there are multiple sufficient causal sets but the authors state that this exemption does not apply in the asbestos context. How could that be so? They must have determined that asbestos doses are fungible and the disease the result of the dose such that the sufficient set of causes of say mesothelioma necessarily includes all asbestos exposures; and thus by extension, each fiber “a factual cause subject to liability”. Otherwise, calculating the answer to the "how many sufficient sets can we make out of the total dose" question would lead to the logical conclusion that it is impossible to say that any given defendant's contribution to dose was causative. To be sure that can't happen there's Section 27.
If you doubt that each fiber can be a legal cause or still doubt that that there's no lower limit of liability read section 27, especially comment f.
"Section 27. Multiple Sufficient Causes
If multiple acts occur, each of which alone would have been a factual cause under section 26 (what the Reporters say is the essence of causation, the "but for" test) of the physical harm at the same time in the absence of the other act(s), each act is regarded as a factual cause of the harm.
... comment f. The fact that an actor's conduct requires other conduct to be sufficient to cause another's harm does not obviate the applicability of this Section. Moreover, the fact that the other person's conduct is sufficient to cause the harm does not prevent the actor's conduct from being a factual cause of harm pursuant to this Section, if the actor's conduct is necessary to at least one causal set."
Basically, this is just the old game of "How do you know asbestos caused his mesothelioma? Because he was exposed to a sufficient dose. But how do you know he had a sufficient dose? Because he got mesothelioma. How do you know that every exposure contributed? Because otherwise he wouldn’t have had a sufficient dose. But how much was needed for a sufficient dose? Enough to cause his mesothelioma.”
If courts adopt such a rule it'll be a happy day indeed for plaintiffs' lawyers. Their refrain, and that of their experts, that "every dose is causative because the risk doesn't become zero until dose is zero" - the logical fallacy behind conflating risk and causation and behind the "one fiber" theory - will have become law; and the law will be deeply biased against defendants.
Next up, we'll discuss causation and risk and why the reasoning in Borg-Warner v. Flores best captures the essence of American tort jurisprudence. Hint: "the risk reasonably perceived defines the duty to be obeyed" is best understood as being about risk and the reasonable man, and not about foreseeability.
The incidence of food allergies in children is rising. Wheat, milk, egg, fish, peanut, walnut, shellfish and soy allergies have led to recalls of pork, turkey, cream of wheat mushroom soup, roast beef, ice cream and corn pasta in recent months. What's behind the increase in allergies?
There are at least two good hypotheses for which there's sound evidence. First, despite what our pediatrician told us, it's probably a good idea to introduce babies to e.g. cow milk sooner rather than later (see "Early Exposure to Cow's Milk Protein is Protective Against IgE-Mediated Cow's Milk Protein Allergy") and make sure they get a large enough dose to produce tolerance as it's apparently the low doses of say peanuts that lead to sensitization and allergy (see e.g. "Peanut Sensitization and Allergy: Influence of Early Life Exposure to Peanuts").
The second emerging hypothesis, another of the increasingly common "Grandma was right" sort of ideas, is that lack of sunshine is also responsible for the rise in food allergies in children. It turns out that vitamin D is crucial to a properly functioning immune system and without it you wind up with a gut full of the wrong sorts of bacteria behaving badly. (See "Potential Mechanisms for the Hypothesized Link Between Sunshine, Vitamin D, and Food Allergy in Children" and "The Role of the Gut Mucosal Immunity in the Development of Tolerance Versus Development of Allergy to Food").
And while we're on the topic of the consequences of this needless epidemic of vitamin D deficiency in the U.S. due to four decades of anti-sun/anti-reason activism you should also read: "North-South Differences in U.S. Emergency Department Visits for Acute Allergic Reactions", "Are Active Sun Exposure Habits Related to Lowering Risk of Type 2 Diabetes Mellitus in Women, a Prospective Cohort Study?" and "Vitamin D and Risk of Cognitive Decline in Elderly Persons" along with "Vitamin D: A Place in the Sun?" and "Vitamin D in Asthma: Panacea or True Promise?"
The takeaway here is that by overreacting to rare and likely uncontrollable risks we've been stampeded right into far more common and otherwise avoidable risks. So who should be liable to all of the eggshell plaintiffs manufactured out of junk science? Should it be the companies whose products would not have caused harm but for the activists or should the activists be called to account for what they have done?
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.
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.
On June 14, USEPA gave notice of a July 9, 2010 "listening session" related to its external review draft document entitled "EPA's Reanalysis of Key Issues Related to Dioxin Toxicity and Response to NAS Comments." The draft document includes new analyses on potential human effects from exposure to 2, 3, 7, 8 tetrachlorodibenzo-p-dioxin (TCDD). The draft document was also provided to EPA's Science Advisory Board for peer review.
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.
In Quillen v. Safety-Kleen Systems, Inc., 2010 WL 2044508 (E.D.Ky.) the court determined that plaintiff's expert, Dr. George Rogers, could properly attribute a case of myelodysplastic syndrome (MDS) to benzene by doing a differential diagnosis. That some courts have taken to using differential diagnosis to identify the root cause of say splenomegaly rather than to distinguish histoplasmosis induced splenomegaly from Hodgkin's disease induced splenomegaly would likely set many physicians' eyes rolling. Yet, that's apparently what the 6th Circuit said in Hardyman v. Norfolk & Western Railway Co., 243 F.3d255 (6th Cir. 2001) and thus the thinking by the Quillen court.
The point of doing a differential diagnosis, of course, is to rule out possible causes until just one is left - it's a process of elimination. But just because every other cause of splenomegaly has been ruled out in the case of a male patient that doesn't mean that it makes sense to conclude that the cause must be the remaining possibility - a metastatic ovarian cancer. To be considered for elimination in the first place the putative cause has to be one that makes sense. In Quillen though there was no effort to demonstrate that plaintiff's experience with benzene was the sort that would make benzene a reasonably plausible cause of his MDS.
Finally, please ponder the following. In response to the defendant's objection that plaintiff's expert had not ruled out ionizing radiation the court wrote: "Defendant points to nothing in the record demonstrating that Quillen was ever exposed to a statistically significant amount of such radiation." Somewhere an epidemiologist just fell out of her chair.
As a follow-up to our post on the death of the vaccine/autism litigation last week, we report the following news: Dr. Andrew Wakefield, the chief proponent of the now discredited junk science behind the MMR vaccine/autism link, has been banned from practicing medicine in his native UK.
Wakefield has moved to Texas and set up an autism clinic.
A brief synopsis of the whole sorry history of the MMR vaccine/autism scare is encapsulated in this prior post and comic strip which is eloquent in its brevity and accuracy.
The Court of Appeals for the Federal Circuit recently drove what we hope is the last nail in the coffin of the vaccine/autism litigation. Rarely has a toxic tort had the potential to cause so much harm based on such shoddy science. The history of this tort and its shortcomings have been reported in great detail.
In short, the scientific evidence that vaccines cause autism came from a discredited article by Andrew J. Wakefield and two follow-up articles. Dr. Wakefield’s article created a public health crisis with parents, including celebrity parents Jenny McCarthy and Jim Carey, urging parents not to get their children vaccinated. As a result, formerly endemic childhood diseases which had become effectively eradicated in the developed world began to make a reemergence. Wakefield’s article was finally withdrawn from the Lancet earlier this year after 10 of the 12 co-authors disavowed it. Wakefield, himself, refuses to withdraw the article even though it was found that he committed scientific misconduct and lied in the article. The UK’s General Medical counsel’s Fitness to Practice Panel issued a judgment against him for his vaccine/autism paper. Wakefield continues to testify. Others testify based on his work.
Thankfully, the vaccine litigation was consolidated in the federal Vaccine Court pursuant to The Vaccine Act (passed in response to the health scare where the DTP vaccine was accused of causing neurological damage and in response to lawsuits, stopped being manufactured). Plaintiffs in three bellwether cases all failed on causation. The Special Masters wrote massive opinions eviscerating Wakefield and the causation theories of Plaintiffs.
Hopefully parents can now rest assured that vaccines are not a risk for autism. And, they can recognize the far greater risks to their children and society from not vaccinating.
A World Heath Organization (WHO) study on cell phones and brain cancer has been published. It tracked 13,000 cell phone users over a number of years. The study showed no association between brain cancer and cell phone use. Statistically, people who used cell phones had a decreased rate of brain cancer.
Despite this, and despite every prior study showing no statistical evidence of an increased rate of brain cancer in cell phone users, the authors state that “[t]he results really don’t allow us to conclude that there is any risk associated with mobile phone use but it is also premature to say that there is no risk associated with it.”
This is true. It is just about impossible to prove a negative. This has not stopped the authors of the recently released President’s Cancer Panel from arguing for a “precautionary principle” to regulation. Their precautionary principle would have cell phones outlawed until they could be proven safe. Specifically, the panel argues that cell phones should be banned until there is no risk of cancer associated with them. The obvious question, however, is how to prove that there is no risk. Study after study finds no association but cannot prove the negative, an absolutely risk free product. All the freedoms and advances in wireless technology would be banned until a 30-year long term study showed there would be no risk. By 2040, what other life-changing technologies would we have missed?
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.
We've defended a few gastric lymphoma cases in which the alleged cause was benzene exposure. The discovery that Helicobacter pylori was was the cause of most instances of the disease made the litigation go away. Nevertheless there have continued to be cases of MALT lymphoma in patients without evidence of H. pylori infection. Could their cancers have been caused by something besides a bacteria?
In "Treatment Outcome of Localized Helicobacter pylori - Negative Low-Grade Gastric MALT Lymphoma" the authors report on what happened when they treated some MALT lymphoma patients who had no evidence of H. pylori infection with anti-H.pylori antibiotics. Complete remission was achieved in each case.
The authors offer the following hypotheses about why giving people a drug to kill a particular strain of bacteria that they don't have that bacteria might nevertheless cure them of lymphoma: (1) a first cousin, H. heilmannii, might actually be the causative organism; (2) unknown bacterial agents susceptible to the antibiotics caused the lymphoma; (3) H. pylori at populations too small to be detected are still enough to cause lymphoma; and, (4) antibiotics eradicate MALT lymphoma not by simply killing H. pylori but rather by altering the resident immune system - resetting the system as it were.
Unless the answer is (3) MALT lymphoma will serve as yet another example of the fact that, save for very rare instances like pleural mesothelioma and erionite, "but for" causal attribution in cancer cases is exceedingly difficult.
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.
Life would be so much simpler if causation were binary - e.g. stay out of the sun and never get melanoma or worship the sun and die young of skin cancer. That way we'd have real choice, the virtuous would be spared and the heedless would be plagued. It doesn't work that way, of course.
Shockingly (or not) most people who sunbathe, drink or smoke don't die of skin cancer, throat cancer or lung cancer. What gives? Maybe the numbers are wrong or maybe the statistics are just some trick of government / industry / academia / nefarious "other". Those are a few of the explanations offered up by the readers of the San Francisco Chronicle in response to its new article: "Vitamin D Levels Dip" in which the claim that sunbathing might be good for you is explored.
That biological cause and effect, even at the level of a single protein, can't be put into simple one-to-one correspondence doesn't just vex bloggers; it is profoundly troubling to researchers and it's prompting many to reexamine views about causality in biological systems that were being investigated decades ago but which fell out of favor in the modern reductionist era.
In "Order Without Design" Alexei Kurakin nicely sums up the evidence for life, and thus diseases of life, being emergent processes unexplainable by reducing the system to its parts and its inputs. Life (and its afflictions) instead seems to be a dynamic process driven essentially by economic competition for energy and materiel at the molecular level. What is the evidence for this claim? One very big piece of it is found in the amazing plasticity of proteins.
We've all been taught that proteins, especially cytokines, work like locks and keys. It's an easy to grasp metaphor and promised easy-ish cures for what ails us. Disease was the product of missing keys or broken locks. Supply the missing key, or one that worked the broken lock, and the door to good health was open again, right? Too often though it turned out that replacement keys didn't work as expected and that broken locks weren't actually broken - they were just performing other functions.
Closer examination revealed that proteins were often found far from where they were thought to do their work and were twisted and folded into completely unexpected shapes. Further investigations revealed that many if not most proteins exist not in some concrete form with concrete functionality but rather in a "disordered" state waiting to be shaped and directed not by some genetic program or external event but rather by the tides of energy and matter within the cell itself. And it is out of the ebb and flow of those tides that the organized activity of the cell emerges.
There's much more in the paper and those which it cites, of course, but for our purposes suffice it to say that the question of causation in biological systems cannot sensibly be asked, as we do in our courts, "Was chemical "X" a producing cause of Plaintiff's cancer?" Perhaps the question should be something more akin to "Given Plaintiff's condition before exposure to chemical "X" by how much was her risk of cancer increased by that exposure?" But then that doesn't really get it either. Take mesothelioma and amphibole exposure as an example.
It's commonly said that amphibole exposure is a risk factor for mesothelioma in humans. But if that's the case why didn't the other 95% of the workforce at say the unibestos plant in Tyler, Texas get mesothelioma? Is it that amphibole-induced mesothelioma is a purely stochastic process such that those who developed the disease were just unlucky? Or rather is it the case that causation, in the case of chronic diseases anyway, isn't generalizable? That's the takeaway - there may not be such a thing as what lawyers call "general causation".
IARC thinks so. Others have recently published papers claiming that breast cancers and melanomas are probably caused by exposure to electric lighting at night. However, a new study published in the American Journal of Epidemiology looked at 73,049 Chinese women and found no association between breast cancer and night-shift work, irrespective of frequency, duration or cumulative shift work. The authors conclude that "it may be premature to consider shift work a cause of cancer."
Back in the day, a doctor from deep East Texas opined as follows about an alleged carcinogen: "It messes with your DNA and everybody knows that if your DNA gets messed up it can lead to cancer." Multimillion dollar verdicts were founded on little more than that sort of speculation.
Yet, what if that which everybody knows about cancer is wrong? The prevailing paradigm, that cancer comes from a single cell that develops a mutation and then grows out of control, is beginning to show a lot of cracks. Why do cancer outbreaks mimic those of pathogenic epidemics? Why would population mixing lead to cancer? Read about it at Carcinogenesis in "Hypothesis: Towards the Origin of Cancer Epidemics and Pathogenesis".
What is the current state of the art for making an accurate diagnosis of asbestosis? See: "Pathology of Asbestosis - An Update of the Diagnostic Criteria: Report of the Asbestosis Committee of the College of American Pathologists and Pulmonary Pathology Society"
In "Perinatal Exposure to Bisphenol-A and the Development of Metabolic Syndrome in CD-1 Mice", just published in the journal Endocrinology, researchers tested the claim that exposure to a typical dose of BPA (1ppb via diet) increases the risk of high-fat diet-induced obesity and glucose intolerance. The experimental data did not support the claim. Interestingly, the BPA-fed mice grew a bit quicker early in life but by adulthood were the same size and body composition as the mice not fed BPA.
The New York Times reported today that EPA is adding Bisphenol-A (“BPA”) to its list of chemicals of concern. BPA is widely used in certain plastics, notably food packaging and baby bottles. New studies of concentrations of BPA in surface water, ground water and drinking water will be required. In addition, manufacturers using BPA in their products will be required to provide test data to help evaluate effects on growth, reproduction and development in aquatic organisms and wildlife.
Sometimes mass tort litigation feels a lot like being in the movie "Groundhog Day". The names and the products may change from day to day but the plaintiffs', the true believers' and the media's overarching narrative is always some aspect of the one refined in the tobacco litigation. One such narrative goes towards abrogating personal responsibility and does so by purporting to show that a product is both irresistibly addictive and insidiously malignant.
Today's vignette is thanks to a (free) paper just published in Nature Neuroscience titled "Dopamine D2 Receptors in Addiction-Like Reward Dysfunction and Compulsive Eating in Obese Rats". In the study being reported eleven rats got their fill of "bacon, sausage, cheesecake, pound cake, frosting and chocolate", eleven others got to pig out on "bacon, sausage ..." but for only one hour per day while nine other rats got nothing but "rat chow". Shockingly, the rats stuck in a cage all day with nothing to do but eat pound cake with frosting put on weight.
Various permutations of the experiment were run including some involving IHC staining with fluorescent proteins so that the now obligatory brilliantly colored photomicrographs could be produced. Some other rats considering pigging out were "punished" with electric foot shocks while yet others had "stimulating" electrodes implanted in their brains and held in place by four stainless steel skull screws.
The pound cake with frosting didn't affect life expectancy since all the rats were sacrificed two weeks after their 40 day food odyssey. However, the researchers found evidence of classic addiction response whereby reward mechanisms (pound cake with frosting makes you happy) were gradually suppressed by the body as it tried to adjust to the good times and maintain homeostasis so that more and more pound cake with frosting was needed to reproduce the initial reward level. The rat chow rats and the one hour per day bingers on the other hand lived out their 54 days in much slimmer bodies and with the normal compliment of dopamine receptors implying that living in a cage and eating rat chow is not excessively rewarding.
The quote above from Gene-Jack Wang, M.D. was found at The Situationist in its write-up of the Nature Neuroscience article. He's also quoted as saying that purified modern food makes people eat "unconsciously" and animals "eat like a drug abuser [uses drugs]". Wang is said to be the chair of the medical department at the U.S. Department of Energy's Brookhaven National Laboratory.
In "Odds Are, It's Wrong", Tom Siegfried lays out the argument for the proposition that much of what you read in the scientific literature is wrong because many of the claims being made rely on statistical significance. You see, an impressive sounding statement like "the association between exposure and disease was highly significant (P<0.05)" does NOT mean (a) that there's a 95% chance that the association is causal; (b) that the absence of an association can almost certainly be ruled out; nor does it necessarily mean that (c) the finding is momentous, compelling or even important. It doesn't even say that if the test were to be repeated that its results would likely hold. A P-value, the arbitrary judge of "statistical significance", won't, and can't, have anything to say about the likelihood that a given hypothesis is or is not true.
The fact of the matter is that if you have a bunch of data and can't find at least one statistically significant association it in only proves one thing - that you're not trying hard enough. The magical P-value level of 0.05 is nothing but a trade-off; a balancing act between finding associations that don't exist (false positives) and missing true associations that do (false negatives). As a result, false associations are not only possible, they're guaranteed when you have enough data and slice it enough ways.
Now, lawyers are getting into the act. And while it's bad enough that "[a] lot of scientists don't understand statistics" (Steven Goodman quote from the "Odds Are, It's Wrong" article) it gets awful when lawyers try to deploy statistics to support or rebut claims. Law review articles are littered with claims resting on nothing more than small P-values. Some purport to show that certain appellate courts are biased against accident victims; others that tort reform is good for your health. And hardly a week goes by that I don't see a brief or a pleading asserting that Texas "jurisprudence" requires an epidemiological study with a risk ratio greater than 2 and a P<0.05 before a plaintiff can recover on a toxic tort claim.
Apparently many lawyers, especially on the defense side, either forgot or never learned that it's easy to gin up false associations that meet the greater than 2 and less than 0.05 test. In fact, that's how most categories of toxic tort claims got started. Enshrining such a test in the law would turn out to be The Full Employment Act for toxic tort lawyers.
Causal inference from epidemiological statistical analysis is a crude method that nevertheless worked well for finding big effects like that of smoking on lung cancer risk and amphibole exposure on mesothelioma risk. On more subtle effects though, at the population level or molecular level, reliance on 20th century methods has produced so much bad science of late (bad only because statistics are routinely misused and abused and not because statistics aren't powerfully effective tools when properly used) that new methods of causal analysis are beginning to replace them. And these tools can answer the question of "how likely is it that drug A caused injury B?"
To see what the future of causal proof in toxic torts will look like read: "An Introduction to Causal Inference" by Judea Pearl.
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.
A new review of available toxicological, mineralogical and epidemiological data pertaining to talc mined in northern New York by R T Vanderbilt shows no support for the claim that exposure to it causes mesothelioma. See: "Industrial-Grade Talc Exposure and the Risk of Mesothelioma" just published in Critical Reviews in Toxicology.
See "Non-Occupational Exposure to Paint Fumes During Pregnancy and Fetal Growth in a General Population"
Though about half of the mothers surveyed said they'd been exposed to paint fumes in the home while they were pregnant the data suggested that the more fumes to which they'd remembered being exposed the lower the risk that their baby would be underweight. What? This study probably has more to say about the use of interview data as a proxy for exposure than it does about the relationship being examined.
In this recent article in JAMA(2010;303(10):943-950), the authors evaluate the impact of vaccinating children and adolescents on the incidence of influenza among non-vaccinated populations. They conclude that, if you vaccinate your children and teenagers, there is less disease among the rest of the population. Tell us something else that every parent already knew. Now, go wash your hands and come in to dinner.
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.
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.
Beta amyloid, aka abeta, builds up dramatically in the brains of patients with Alzheimer's. So, beta amyloid causes Alzheimer's, right? Or has something to do with causing it, right? At least it needs to be eliminated because people who don't have it don't have Alzheimer's so it must be bad somehow, right?
Maybe not. In a new report that demonstrates perfectly two (re-)emerging views about chronic diseases researchers at Massachusetts General Hospital have shown that beta amyloid is a potent antibiotic effective against fungi like Candida albicans and bacteria like Staphylococcus. They go on to hypothesize that far from being bad, beta amyloid may in fact be very good. It may well save you from brain infections that would otherwise kill you at a much younger age. An excellent write up can be found at Bloomberg and the article itself, "The Alzheimer's Disease-Associated Amyloid beta-Protein is an Antimicrobial Peptide", is at Plos One.
Oh, and those two (re-)emerging views about chronic diseases? The first is that too often scientists and physicians fall into the trap of assuming that the arrow of causation runs from biomarker to disease when in fact the body, with millions of years of fine tuning under the hood, has almost certainly some mechanism to deal with the build up of the by-products of its defenses such that fooling with that immune system, given our level of ignorance about how it works, is perilous at best. The second is that microbes, thought to have been essentially conquered 40 years ago, are in fact at the root of many if not most maladies commonly thought to be caused by man. Microbes it turns out have not been asleep over the eons nor even over the last 40 years. Almost weekly as new ways to culture and identify them are developed, new and heretofore unsuspected infections are identified. We're only beginning to understand the nature of the microbes that help us and prey upon us and so for now perhaps it's enough to consider the fact that in our own bodies they outnumber our human cells nine to one.
One last thing, isn't it interesting that many of the drugs currently being tested to determine their anti-aging potential are also potent anti-fungals? Correlation isn't, of course, causation, but it might be worth pondering.
Since 2007, the results of certain animal studies have fueled speculation that certain nanomaterials may behave in ways suspiciously similar to asbestos. In this article published in the journal Nanotoxicology this month, the authors report on their review of 746 articles published or pre-published in 2008 on the possible health effects of carbon- and metal-based nanomaterials. These particular types of nanomaterials are produced and used worldwide. The authors conclude: “Unfortunately, due to the large variability in materials used and methods used conflicting data are generated hampering the risk assessment.”
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
In a 1971 paper that profoundly influenced how scientists and policy makers approached public health issues Abdel Omran set out his theory of "The Epidemiologic Transition". He hypothesized that societies went through three different ages, or phases, that defined their experience with regard to mortality and life expectancy. In the first, the "age of pestilence and famine", life expectancy is low and episodes of widespread death are common. In the second, the "age of receding pandemics", infectious diseases are overcome and life expectancy increases dramatically. Finally, in the third, the "age of degenerative and man-made diseases", diseases of aging and self-inflicted suffering becomes the predominant determinant of mortality. Eventually others, noting the dramatic increase in life expectancy due to the rapid decline in deaths due to heart attack and stroke, posited a fourth age; essentially the same as the original third age but with cardiovascular disease removed from the "degenerative disease" category.
Now in an editorial in this month's JAMA Dr. Michael Gaziano asserts that we may be entering a fifth phase, or age, of the epidemiologic transition. We are now, he writes, entering the "age of obesity and inactivity" in which ailments due to gluttony and sloth predominate on death certificates. The editorial references two new articles in the same issue purporting to show Americans are fat and getting fatter; especially the children.
But wait a minute. The age of man-made diseases barely materialized. Certainly there have been many many cases of people suffering terribly as a result of some man-made health hazard. Look no further than the cases of mesothelioma among the men who served aboard amosite laden Navy ships. And smoking continues to exact its terrible toll. Yet if you throw all the deaths due to occupational diseases and every last lung cancer/COPD death into the same category you can't get to 10% using worst case estimates. More sober estimates put the percentage of deaths due to man-made diseases at considerably less than one. Nevertheless, this powerful meme - that most of our woes are self-inflicted and due to some failure to live in a natural way - still propels not only mass tort litigation but also much scientific and political thinking.
However, there's more than just AIDS to demonstrate that we never really saw the "disappearance" of infectious diseases. Go to www.pubmed.gov/ and do some searches on helicobacter pylori and humanpapilloma virus and you'll see just how many cancers are now being attributed to just these two organisms. Investigate mollicutes and you'll find that all sorts of microbes are suddenly being found associated with disease and they're only now being found because the technology to identify them is only now being refined.
Finally, remember to read the fascinating journey of Barry Marshall and Robin Warren from authors of an abstract rejected as one of the year's worst to winners of the Nobel Prize in Medicine for the very same work. In the end, the view, supported by the work of one of the world's preeminent public health researchers, that peptic ulcers were caused by that most modern of man-made insults, stress, only gave way to the understanding that the cause was in fact a bacteria when the evidence was irrefutable.
If a strong and consistent association between autism and a single chemical or vaccine were found in ten separate clusters around California you'd expect to read about it; and you'd expect the researchers to infer that the chemical or vaccine was, in fact, the cause of autism. But what if the only strong and consistent association wasn't between autism and exposure to some substance but was instead between autism and something complex, like "high parental education"? Well, you'd probably expect a lot of frustration; and you'd be pretty sure autism wouldn't be laid at the feet of higher education.
So what should we make of "Geographic Distribution of Autism in California: a Retrospective Birth Cohort Analysis" ? Why would the children of parents with college degrees be at a 400% increased risk of autism? Why aren't chemicals to blame?
The authors concede in interviews with Scientific American that the results tend to undermine claims that industrial pollution causes autism. Yet rather than explore the possible reasons why college-educated parents might be significantly more likely to have autistic children the authors speculate that their results may be biased. Perhaps, they suggest, the less educated aren't educated enough to take their autistic children in to be diagnosed. Or maybe, they wondered, the educated are much more likely to use some unknown household chemical which does, in fact, cause autism. Scientific American hastens to add that there's an unpublished study that shows a doubling of the risk of autism in mothers who use pet flea shampoos.
But why point to a much smaller effect allegedly to be found in an unpublished paper when a much larger effect published in a peer reviewed journal is in front of you?
First, people tend to prefer simple answers with readily implemented solutions, the blame for which, and the costs of which, get imposed on someone else.
Second, epidemiology, at least as practised in the West, tends to be reductionist. The triumph of linking tobacco to smoking led many epidemiologists to believe, or at least to want to believe, that indeed there are simple solutions to big problems and that silver bullets are out there just waiting to be found.
Finally, it's becoming increasingly clear that all sorts of ailments, from cancer to obesity, are highly complex and result in large part, from lifestyle, cultural and economic choices. Take breast cancer for example. One of the very best ways to reduce the risk of breast cancer is for a woman to bear children and to begin doing so in her late teens or early 20s. Yet no one wants to say that putting off children to get a degree and start a career is a cause of breast cancer.
And so, for now, the search is still on for the usual suspects.
The EPA says that radon, a colorless, odorless gas, is responsible for 20,000 American lung cancer deaths annually. Because January is the best time to test for the gas it has been designated "National Radon Action Month". You can read the EPA's press release here and find its radon information and testing site here.
Arguing that the target of benzene is a multipotent stem cell capable, when carrying the sort of mutations thought to be caused by benzene, of producing both myeloid and lymphoid malignancies, and that new classification systems are blurring the lines between previously thought distinct diseases, Goldstein's article concludes that there is now sufficient evidence to attribute lymphomas to benzene exposure.
That's the same argument made years ago in benzene litigation, though with different references. So what should we make of the intervening science? What about alkylating chemotherapeutics that produced similar genotoxicity and t-AMLs but not lymphomas? What about the epi studies that show increased risk for AML but not lymphomas?
In many respects last year's benzene conference in Munich served mainly to demonstrate how little is known about leukemogenesis and how staggeringly complex is the causal web that leads to lymphoproliferative malignancies.
One explanation for Genna v. Jackson (a new opinion out of the Michigan Court of Appeals) and Gass v. Marriott Hotel Services, Inc is that the courts thought about it and decided to shift the burden of proof regarding causation to the defendant any time a plaintiff suffers an injury that is consistent with the possible harm, as set out on a warning label or MSDS, associated with a potentially toxic material. In Genna the court reversed summary judgment in favor of the defendant in part because "[h]ere, like in Gass, defendant has not submitted any scientific evidence that the mold in her condominium could not have cause [sic] plaintiffs' injuries." In Gass the 6th Circuit noted "Defendants have offered no evidence to refute the MSDS's representation of Demand CS as a chemical which could have caused Plaintiffs' symptoms". The court later continued saying "[p]laintiffs are not required to produce expert testimony on causation where Defendants have failed to offer scientific evidence regarding the effects of Demand CS or Suspend SC."
The Genna court concluded, on the issue of causation, "[t]his is not a complicated case: the children were sick, the children were removed from the home, the mold was discovered, and the children recovered." Noting evidence that there was lots of mold and that mold in general had been reported to cause some of "the types of symptoms suffered by the children" the court concluded [i]t does not take an expert to conclude that, under these circumstances, defendant more likely than not is responsible for plaintiffs' injuries." (citing Gass). "Here, there was ample circumstantial evidence that would "facilitate reasonable inferences of causation, not mere speculation."
Under this view of an unannounced burden-shifting approach taken by these two courts it appears that in Michigan if a plaintiff develops ailments consistent with a those listed on a product's label or MSDS the jury is free to infer causation even in the absence of evidence of what dose produces those ailments and what dose plaintiff suffered and even in the absence of an expert to opine that the product in question caused the harm at issue.
Another explanation for these cases is that Michigan does not require toxic tort plaintiffs to show what some call specific causation - a concept common in cases in which causal inferences are derived from epidemiological evidence. The idea is that when dealing with an illness that has been associated with multiple causes, among which is the chemical at issue, the plaintiff must show that the putative cause was more likely than not the cause in fact of his illness. Evidence for this view can be found in the following passage from Genna: "Defendant urges this Court to adopt the requirement that, in order to prove causation in a toxic tort case, a plaintiff must show both that the alleged toxin is capable of causing injuries like those suffered by the plaintiff in human beings subjected to the same exposure as the plaintiff, and that the toxin was the cause of the plaintiff's injury. They urge this Court to find that direct expert testimony be required to establish the causal link, not inferences. We decline to adopt this requirement. There is no published Michigan case law on the subject."
A final explanation is that more attention to Aristotle's Rhetoric is needed. As Chief Judge Boggs, dissenting in Gass wrote the problem here is the logical fallacy behind post hoc, ergo propter hoc causal inferences such as those suggested by the plaintiffs in Genna and Gass. "It is the fallacy of saying that because effect A happened at some point after alleged cause B, the alleged cause was the actual cause. Such logic has never been enough to survive summary judgment. See, e.g., Abbott v. Federal Forge, ("[P]ost hoc, ergo propter hoc is not a rule of legal causation.") 912 F.2d 867, 875 (6th Cir.1990).
Equally importantly Chief Judge Boggs understands that lay juries are in no position to judge whether there has been a breach of the duty of care without evidence of what levels are harmful and the levels to which plaintiffs were actually exposed. If you don't know the dose you can't know what risk, if any, the defendant imposed on the plaintiff. He wrote: "Thus presented, the question is whether the plaintiffs needed expert testimony in this case to prove how much chemical exposure is too much chemical exposure or to prove whether the amount of exposure actually caused the alleged harmful consequence. In my view, the majority pays too little attention to this issue, rushing from the fact of exposure and odd symptoms to the legal conclusion of fault." He continued: "As I understand it, these cases require expert testimony in complex, professional, or scientific-based negligence cases in order to limit the dangers associated with indulging the post hoc impulse: it is too easy to charge an uncommon harm to the presence of a mysterious substance. Properly credentialed expert testimony operates as a bulwark against such fallacious attribution of guilt. As in the Daubert context, our concern in applying these cases should be to "assure that the powerful engine of tort liability ... points towards the right substances and does not destroy the wrong ones." General Electric v. Joiner, 522 U.S. 136, 148-49, 118 S.Ct. 512, 139 L.Ed.2d 508 (1997) (Breyer, J. concurring).
Whatever the explanation these cases will be a boon for Michigan toxic tort plaintiffs.
Have you been worrying that your water softener is significantly increasing your risk of dying from a heart attack? I didn't think so. But just because you haven't been feeling vulnerable around your water softener doesn't mean the WHO hasn't been fretting for you.
Thanks to epidemiological studies going back a decade or more (e.g. "Magnesium and Calcium in Drinking Water and Death from Acute Myocardial Infarction in Women") a worry arose that we were killing ourselves by eliminating the minerals naturally found in most drinking water. Yet subsequent studies have failed to confirm the finding including the just published "Effect of water hardness on cardiovascular mortality: an ecological time series approach". So what gives?
Well, what gives is that most of what gets published in peer reviewed journals is probably false; and when it comes to causal inferences drawn from epidemiological studies "the apparently indiscriminate indentification of particular aspects of daily life as dangerous to health" is, as witty programmers say, a feature, not a bug.
We live in strange times. Though whole genomes, of an individual as well as a malignant progenitor stem cell responsible for AML, have been sequenced and though modern medical diagnositic machinery and implantable devices increasingly look like things that Gene Roddenberry would have rejected as too futuristic, the fact is that scientists know very little about how our bodies work. Take C-reactive protein for example.
Let's say you decide to study heart attacks by measuring the levels of certain proteins in the blood and then later checking to see if there's been an association between the levels measured and an adverse event like a subsequent heart attack. Bingo! People with high levels of C-reactive protein have a high risk of heart attack. Wow!
Ok, let's assume the association is strong and consistent so that the finding probably reveals something about how the body works. But what?
Too often these sorts of findings have precipitated a Whac-A-Mole reaction from the medical community whereby drugs are promptly designed and thereafter prescribed to begin whacking the protein back down to "normal" levels. Causes precede effects, right? So this must be a cause, right?
Well, what if C-reactive protein is actually part of the body's response to accumulating plaque and inflammation? What if its level correlates with risk because it's part of the body's attempt to fix whatever is broken? What if it's not a cause of heart disease but is really an effect of heart disease? Reuters is reporting on a new analysis published in Lancet indicating that at least in the case of C-reactive protein earlier assumptions had indeed confused cause and effect. The authors conclude that it is unlikely that C-reactive protein is a cause of heart disease.
The American Cancer Society has published "The Global Burden of Cancer: Priorities for Prevention" this month in the journal Carcinogenesis. While tobacco use is discussed first and diet, obesity and lack of physical activity second, it's cancers related to chronic infections that gets the most coverage. "Persistent infection with various microbial organisms accounts for about 18 percent of cancers worldwide." Preventive approaches including the development of vaccines and lifestyle modifications are discussed in detail.
A series of lungs from California farm workers who died in accidents or from illness were examined for evidence of pneumoconiosis. Despite being young these Hispanic farm workers had significantly more evidence of interstitial fibrosis than did non-farm workers. A variety of analytical techniques demonstrated that those with pneumoconiosis had significant exposure to crystalline silica and aluminum silicate.
The article is "Pneumoconiosis from agricultural dust exposure among young California farmworkers". As for the source of mineral dust exposure the authors note "most agricultural soils are composed largely of silicate materials (e.g., feldspars, mica, clay minerals) and crystalline silica (CSi) (quartz)".
An important new study was recently released indicating that there is no causal association between ambient exposure to either solvents or benzene and the development of non-Hodgkin’s lymphoma (NHL). The report adds to a growing body of literature demonstrating no discernable risk for typical community benzene exposures.
Researchers from Mayo Clinic have published "An outbreak of neurological autoimmunity with polyradiculoneuropathy in workers exposed to aerosolised porcine neural tissue: a descriptive study" in The Lancet Neurology. Workers exposed to aerosolised pig brains (ugh) developed polyradiculoneuropathy - a painful and disabling autoimmune illness. Of the 24 workers affected 17 required immunomodulatory therapies, six improved after exposure ceased and one was lost to follow up.
In the on-going debate over when to start getting mammograms and how often to have them the assumption by many of those supporting an "early and often" policy has been that false positives lead to little more than worry and maybe a needle biopsy. Now The New York Times is reporting on a study that appears to demonstrate that young women already at heightened risk of breast cancer double that risk if they start getting mammograms early.
Five prior studies of women carrying a mutation that is thought to put them at increased risk of breast cancer were examined to determine whether low dose radiation exposures from mammograms further increased that risk. The results, which were statistically significant at a 95% confidence interval, showed that women carrying the breast cancer gene who started mammography early in life or who had five or more mammograms were more than twice as likely to develop breast cancer as women with the breast cancer gene who started getting mammogramps later and had fewer of them.
The working hypothesis is that mammography actually causes many cases of breast cancer in susceptible women. An alternate explanation, I suppose, is that about half of all breast cancers detected by mammography either aren't cancerous or were never going to develop into a malignancy.
Hopefully doctors are finally beginning to discuss the large and unsettling uncertainties associated with the diagnosis, treatment and causal attribution of poorly understood diseases like cancer.
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.
Articles published in the last several months raise the question whether microbes found in the gut are responsible for Parkinson's disease. In September researchers published an article titled "The Second Brain and Parkinson's disease" in which they reviewed and elaborated on emerging evidence that the enteric nervous system and the microbes that in part constitute it may, be responsible for precipitating Parkinson's disease. Another group published "Autoimmune Disease and risk for Parkinson disease" in which they failed to find support for the hypothesis that Parkinson's is an autoimmune disorder. Most recently in Medical Hypotheses Mark Lyte's "The Microbial Organ in the Gut as a Driver of Homeostatsis and Disease" speculates that the microbes living in our guts along with the enteric nervous system form a sort of organism within an organism that when disrupted can lead to diseases such as Parkinson's. For more on this unfolding understanding of the role of these microorganisms in our lives see "They Are What You Eat".
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.
Here's a case report of pericardial mesothelioma arising twenty-four years after the patient was treated with radiation therapy to the mediastinum for nodular sclerosing Hodgkin's disease.
In two weeks, representatives from 192 countries will assemble in Copenhagen for the purpose of setting global limits on carbon emissions. COP15, the official name of the climate change summit, referencing the 15th Conference of the Parties under the United Nations Framework Convention on Climate Change (UNFCCC), consists of environmental ministers who meet annually. The goal of the Copenhagen summit is “to secure binding emissions targets and overcome the division between the developed and developing world.” Apparently, despite high hopes among proponents, it appears unlikely that a deal will be reached this year.
World leaders have confirmed that time has run out to secure a legally binding agreement at the COP15. However, the United States and Britain hope to at least hammer out an outline of the commitments to be put in place rather than postpone the formulation of a plan for an entire year.
So what's behind the delay? Certainly the global economic turmoil makes it difficult for politicians to agree to changes that would at least in the short term cause even further job dislocations. More significant perhaps is an apparent waning of public interest in the issue of global warming/climate change.
Recent polling has shown a marked decrease in both the belief that climate change is occurring and that such change is due to human agency. What's behind this significant change in public opinion? Over at Yale Environment 360 you'll find an excellent article addressing the concern that years of increasingly dire climate predictions have resulted not in more widespread and more confidently held belief in human-caused climate change but rather "apocalypse fatigue".
We've written before about the dawning realization that the microbes that live in and on us can have a surprising degree of control over our lives. Today we learn that what we eat may control which microbes we host and whether we get fat or stay lean.
In a news release from Washington University titled "Junk food binge alters community of microbes in the gut in less than a day" researchers report that high fat / high sugar diets shift the distribution of bacteria in the intestines towards those bacteria which are exceedingly efficient at extracting calories from food. These super efficient microbes, once transplanted, could then cause weight gain and obesity even in mice fed a low-fat, plant-based diet. The shift towards the super efficient microbes occurred just 18 to 20 hours after the consumption of fatty/sugary foods.
Finally, gut microbes were demonstrated to be capable of being passed from mother to offspring.
Continue Reading...A study published last week in Occupational and Environmental Medicine estimated exposures to asbestos fibers of specific sizes of workers exposed to chrysotile using data from transmission electron microscopy (TEM) and investigated the extent to which the risk of lung cancer varies with fiber length and diameter. The study used a cohort of 3803 workers that were employed from January of 1950 and December of 1973 in manufacturing asbestos textile products. Workers’ exposures to asbestos fibers were estimated from work histories and over 3500 industrial hygiene measurements.
Fiber length and diameter were significantly associated with an increasing risk of lung cancer. Exposures to longer and thinner fibers tended to be most strongly associated with lung cancer. The results supported the investigators hypothesis that the risk of lung cancer among workers exposed to chrysotile asbestos increases with exposure to longer fibers.
In a study just published in the Oxford Journal of Toxicological Sciences the authors report that bisphenol A (BPA) produced no sexual developmental disorders in the laboratory animals tested. Pregnant rats were exposed to very low to low doses of BPA and their offspring were studied for any signs of sex morphology disruptions. The study was funded and conducted by Reproductive Toxicology Branch of the EPA.
Interestingly, ethinyl estradiol on the other hand even at very low doses produced numerous reproductive morphological disruptions. Ethinyl estradiol is a form of estrogen used in almost all modern formulations of the Pill.
The National Institute of Environmental Health Sciences has announced a $30 million, two-year research effort to study the health effects of exposure to bisphenol A (BPA). The funds for this effort were appropriated to the NIEHS as part of the American Recovery and Reinvestment Act.
BPA is an organic compound that is used in the production of polycarbonate plastics and epoxy resins. According to NIEHS’ press release in “2008, NTP [National Toxicology Program] and NIEHS concluded that there is evidence from animal studies that BPA may be causing adverse effects.” The press release continues that the “innovative two-year grants provided through the Recovery Act will support human and animal studies that address many of the research gaps identified by expert scientific panels, and provide a better understanding of how this chemical may impact human health.”
The maxim “the dose makes the poison” is regularly offered by defendants in toxic tort cases as a premise for the assertion that a particular dose was too small to have been toxic. To demonstrate the concept examples of toxicity due even to essential substances like water are deployed. I’ve done it myself and the retort from plaintiff’s counsel has been invariably mocking. Here are sixteen million reasons why they should reconsider.
John Cook at The Endeavor posted this comment by Mithat Gönen of Memorial Sloan-Kettering Cancer Center about a recent paper concerning Bayesian clinical drug trials of chemotherapeutics.
"While there are certainly some at other centers, the bulk of applied Bayesian clinical trial design in this country is largely confined to a single zip code."
That zip code is 77030 and it’s the zip code for M.D. Anderson Cancer Center. Here’s a great article about M.D. Anderson just published in the New York Times by Gina Kolata.
Bayesian decision-making approaches are proving their worth every day in a wide variety of fields and more than a few courts are starting to grasp and apply probabilistic decision rules. Expect to see more and more Bayes decision theory as courts take an increasingly modern approach to the question of causal inference in mass tort cases.
This question has been posed by coal ash’s recent notoriety, and the answer is without consensus. European scientists recently published a paper aimed at determining the levels of mercury in coal ash (one of coal's more dangerous components) and its potential to leach into the surrounding environment. The researchers concluded that concentrations of mercury or leaching values were not so high as to justify considering coal ash a hazardous waste by European standards. (The EPA has made a similar determination but it is being reviewed.)
Such findings, while restricted to mercury, seem to take the fire out of recent lawsuits filed by individuals affected by coal ash spills and/or disposal claiming coal ash mercury and other components are leaching into water sources at dangerous levels. While mercury, arsenic, lead and other compounds are undeniably harmful at certain exposure levels their concentration and propensity to leach are not so clear. Thus, the question of coal ash harmfulness is subject to debate and will be studied in greater detail by courts and administrative agencies grappling with this issue.
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.
After adjusting for smoking chronic obstructive pulmonary disease (COPD), chronic bronchitis and emphysema were associated with a doubling of the risk for lung cancer in this just published paper. It's part of the ongoing Environment and Genetics in Lung Cancer Etiology (EAGLE) study.
Noting that a family history of chronic bronchitis and emphysema alone have been associated with lung cancer, that COPD has been associated with lung cancer in never-smokers and that COPD is thought to be responsible for 10% of all lung cancers, the authors concluded that these findings support the hypothesis that COPD alone causes lung cancer and they further conjectured that chronic inflammation is the essential mechanism in COPD/emphysema-induced lung cancer.
The incidence rate for mesothelioma continues to rise in Alberta, Canada. This paper just published in Chronic Diseases in Canada reports a continuing and significant increase in reported cases of mesotheliomas among male Albertans and projects that the incidence of the disease may not peak for another 10 years.
An interesting issue touched upon but not worked out is the impact on current projections of past misdiagnoses. Think about what it would mean for these projections if past less refined diagnostic procedures understated the number of cases of mesothelioma; then think about what it would mean if reported cases of mesothelioma in the 1960s and 1970s were overstated.
What does it mean when an increase in cancer coincides with an increase in the ability to detect it? Nothing really, because correlation isn’t necessarily causation? Or something, because the new diagnostic technique has biased the data? Specifically, are doctors finding more cases of melanoma nowadays because they’re looking harder or are they finding more cases of melanoma because something else, maybe increased UV radiation, is causing more people to get it? Those are the questions raised by this New York Times article. Something similar happened with prostate cancer and something similar will likely happen in the future once methods of detecting cancers like mesothelioma and leukemia very early in the disease process are developed.
If you watch TV you’ll have noticed celebrities eager to tell you about their “digestive health”. They attribute their well being to regularity and their regularity to eating probiotics, which are live bacteria. The NYTimes also noticed and reported on the issue today. Especially of note to lawyers is the discussion of the $35 million Dannon, maker of probiotic product Activia, has agreed to pay to settle claims of mislabeling and deceptive marketing.
Interestingly, Dannon has agreed to “increase the visibility of the scientific names of the unique strains of probiotics that are in each of these products”. Pity the poor consumer who has enough trouble understanding the nutritional data already on food products – “hmmm, should I buy the yogurt with streptococcus thermophilus, lactobacillus acidophilus and a generic bifidobacterium or the one with just bifidobacterium regluaris?”
Then there’s the law of unintended consequences. The idea that certain strains of bacteria have been essentially domesticated and can be turned loose in the gut to work their magic without fear that they might mutate or disrupt an already balanced system seems overly hopeful. While the milk intolerant have been happily ingesting lactobacillus acidophilus for years and research on certain species of lactobacillus seems to support the theory that these “good” bacteria wage war in your guts against “bad” cancer-causing bacteria both directly and indirectly (e.g. by inducing intestinal epithelial cells to shore up their defenses) one wonders how long it will be before a good strain goes bad, a good strain is unmasked as a double agent or a good strain is demonstrated to have a dark side.
I was part of a panel discussion last week in San Francisco about what we in the law call "specific causation" - essentially the determination, in an individual case of causal attribution, when the disease in question has been associated with certain risk factors in the general population. It is, I think, a distinction without a difference but until courts move past 20th century science (epidemiology) and on to 21st century science (molecular biology) it's one we'll have to talk about. Here's my PowerPoint from the seminar.
Diets high in foods with large amounts of fructose sugar such as sweetened soft drinks increased blood pressure in men, according to a study presented September 23rd that also found that a drug for gout blocked the effect. Most sugar consumption in the U.S. comes from sweetened drinks and foods high in sugar or high fructose corn syrup. Fructose is the only common sugar known to increase uric acid levels.
Men in the study who ate a high-fructose diet had their blood pressure rise about 5 percent after two weeks, while those who also were given a gout treatment increased less than 1 percent. Eating great amounts of fructose without the treatment also raised the risk of developing metabolic syndrome, a risk factor associated with the development of heart disease and diabetes. The gout treatment lowered the body’s uric acid that is linked at elevated levels to high blood pressure, diabetes and heart disease. So, it’s possible that lowering uric acid levels could become a routine practice in the future, much like lowering cholesterol.
Here's a paper that reviews current knowledge regarding the causes of autism. Note the concerns about Vitamin D deficiency. Could it be that decades of sun-o-phobia has led to more than just increases in rickets and a host of cancers?
What is it in cigarette smoke that causes lung cancer? Tar? PNAHs? Exotic isotopes? What about bacteria and fungi? What if they're in part responsible for chronic inflammation associated with lung cancer? It turns out that when you inhale cigarette smoke you invite into your lungs a swarm of nasty germs. Here's a new article that'll introduce you to the issue and lay out the evidence.
Wouldn't it be interesting if there were similar microbes living in and on asbestos fibers? Actually ....
Senator Tom Harkin (D-IA), the new head of the Senate Committee on Health, Education, Labor and Pensions promised on Monday to probe deeply into any potential links between cell phone use and cancer. This issue has been extensively studied, particularly in Scandinavian countries where cell phone manufacturers such as Nokia and Ericson are headquartered. Each study to date has found no statistically significant association between cell phone use and cancer, including brain cancer.
However, there are still some who attribute brain cancer to cell phones on the theory that radio waves, a form of radiation, damage brain cells. The debate comes on the heels of the 1980's and 1990's controversy regarding the potential adverse health effects of electromagnetic fields EMFs emanating from power lines. While studies cleared EMFs they implicated population mixing likely via some sub-clinical infection as a cause of cancer in children. More on population mixing to come.
Wired has a new article about the placebo effect and evidence that placebos are becoming more increasingly more potent.
Years ago I was thinking about going to medical school and so hung on every word from a friend's father when he talked about what he did for a living. I remembered being fascinated by his stories about sugar pills and the patients to whom he prescribed them. He said that he'd learned years before that for some patients, the ones without any objective signs of treatable illness, he did his best work by being part priest and part witch doctor.
He'd listen to their stories, affirm their suffering, advise them to live better, forgive them their faults and prescribe powerful new magic - "penta-methyl-tri-something-or-another-cis-this-and-that". And it worked. He and his pharmacist friend had to be creative though as patients would compare pills and often return to demand stronger magic citing a neighbor's far milder symptoms. So they wound up having a number of different sugar pills in varying shapes and sizes. I don't recall him saying much about color other than that one lady, upon discovering that she'd been prescribed a very large red and white pill, returned to the office to say that she wasn't nearly as sick as the doctor apparently thought she was.
So what does this have to do with mass torts? Well, particularly in the realm of adverse effects from the use of psychotropic drugs, there's a huge risk of (or opportunity for) getting the causation arrow pointed in the wrong direction especially when so little is known about the causes of mental and emotional disorders and the mechanisms by which they are alleviated. After all, trial lawyers thrive in conditions of uncertainty.
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?
Never apologize for showing feeling. When you do so, you apologize for the truth.
- Benjamin Disraeli
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