What's Behind the Rise in Food Allergies?

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?

A Role For Observational Epidemiology?

The Institute of Medicine's "Ethical Issues in Studying the Safety of Approved Drugs: A Letter Report (2010)" is a slog punctuated by the occasional eye-roller. Perhaps because of the presence of undefined ethical issues, technical discussions of drug trials are interrupted with fawning nods to stakeholders "who have kinds of knowledge different from those of technical experts" and a promise to incorporate their different ways of knowing. Sheesh. Anyway, the report does suggest something profoundly important and that is a shift away from the randomized controlled trial (the so-called gold standard) to observational epidemiological studies when making decisions about whether an approved drug ought to be pulled from the market.

Observational epidemiology has been on life support for years. It worked very well on the big risks but when it was turned loose on smaller risks, or worse yet, simply unleashed upon mounds of raw data without any a priori hypothesis to be tested, it failed altogether and often as not wound up falsely indicting random aspects of daily life as wanton spree killers. The failures of course were due neither to the math nor the principles but rather to the misuses to which it was put - especially by expert witnesses who knew better. Nevertheless, finding a role for epidemiology in a world of small risks has been a topic of much debate. Online, and free, you can find the debate in full at "The Triumph of the Null Hypothesis: Epidemiology in an Age of Change" and Jan P Vandenbroucke's commentary, "Seen from Another Angle".

For the Institute of Medicine (IOM), at least given qualms about the ethics of randomized controlled trials particularly after questions have been raised about a drug, Vandenbroucke's view has apparently prevailed. The IOM concluded that "under specific circumstances, observational studies may be adequate to ... identify the presence of an important safety issue ..."; and further that such studies "could provide useful and valid estimates of the risk associated with a safety signal." And, when a drug trial is ongoing, e.g. TIDE, "if new evidence from any source, including the trial itself, is determined to be sufficiently compelling to ground a policy decision without waiting for additional new information, allowing the trial to continue would be unethical."

So, if observational epidemiology prompted by a potential signal of a serious risk were to suggest a small risk, the drug could be pulled from the market and the only test capable of answering the question of whether or not it actually posed a risk would be stopped and prohibited from being run? It sounds like it. If that's the case observational epidemiology has come roaring back to attain a position of power and prestige not held in many years.

Twenty Suspected Carcinogens

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 Doctor Doth Protest Too Much, Methinks

Today The New York Times, which dutifully fanned the flames of the 2007 "prescription drug crisis" started by those pushing for greater FDA powers and fewer new drugs, published "Caustic Government Report Deals Blow to Diabetes Drug". In essence it reports Dr. Thomas Marciniak's criticism of the RECORD study which in 2007 led the FDA, despite congressional histrionics, to vote 22 - 1 to keep Avandia on the market. What the NYTimes is talking about is this.

What sets off the alarms, to a mass tort lawyer anyway, is slide 22. Why, asks the good doctor, should you believe his numbers? After all he declares that he has "nothing to hide" and that "[n]either my job nor (for me) $100,000,000's are riding on the results." The other slides evidence an effort to dig, but not too much, into the data and upon finding seeming errors to imply, without saying so, that the manufacturer somehow managed to beguile honest researchers from around the world into signing off on bad science. It's the kind of drama you'd expect to see from a certain sort of expert witness testifying at the courthouse in Jefferson County; but hardly the sort of presentation typical of scientific gatherings. Then again the FDA has been hyper-politicized so maybe this is the new normal.

Anyway, the implication that this is the "Government Report" is highly misleading. It is in fact but one of many government reports (if by that we agree to mean presentations generated by government employees/contractors). Indeed, another "Government Report" addresses Dr. Marciniak's claims. You'll find it here.

Dr. Marciniak did the easy thing. Post hoc he rummaged around for evidence of errors that would undermine the RECORD study. When examining the outcomes of thousands of people based on many times that number of documents he found a few seeming inconsistencies. Anyone who does mass tort litigation knows that if a bad data point or two were enough to refute any study then we wouldn't have much to talk about down at the courthouse.

What's also interesting is the fact that throwing in the extra assumed heart attack episodes (even the ones for which there were no biomarkers confirming same) the study still only shows a small increase (1.38) that is statistically significant by the barest margin (C.I. 0.99 - 1.93) (i.e. "not") and still it does not support the Nissen hypothesis (to say nothing of the study of 227,000 Medicare patients that rejects it).

But most interesting of all is the data on the only question we really, ultimately, want answered. Do the people taking the medication live longer, or die sooner, than those who don't? By that measure, the protesting doctor's numbers still show that patients on Avandia were 14% less likely to die than those who weren't. By this most critical measure, even considering the data cherry picking of Dr. Marciniak, the results for Avandia are "reassuring" - according to that other government report.

Avandia: Burn Her Anyway?

Three years ago Dr. Steven Nissen published "Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes" in which he reported that those taking Rosiglitazone (Avandia) had about a 40% increased risk of acute myocardial infarction (heart attack). The study was a meta-analysis of published and unpublished data and drew extensively from the manufacturer's unpublished data.

The media simultaneously reported the findings and propagated the following narrative: The pharmaceutical companies collect vast quantities of data; publish only what supports their products; and are at best willfully ignorant of the risks of their products which risks are right before their eyes if only they would look. Dr. Nissen who "has a statistician’s zeal for drilling deep into clinical data, seeking signs that some widely used drugs pose undisclosed risks to patients" was made the hero of the drama. Congress got involved by beating the drums of safety and transparency and demanding that the FDA pay more attention to ensuring that pharmaceuticals are safe.

The FDA reassessed Avandia and panel members voted 21-3 to keep it on the market.

In February of this year, a Congressional investigation conferred near-martyr status on Dr. Nissen after it was revealed that he had secretly tape recorded a meeting with the representatives of the maker of Avandia. The same month, in European Heart Journal, he published the editorial "The Rise and Fall of Rosiglitazone". Meanwhile everyone was waiting for the results of a huge study of Avandia.

Last week that study, "Risk of Acute Myocardial Infarction, Stroke, Heart Failure, and Death in Elderly Medicare Patients Treated with Rosiglitazone or Pioglitazone" (interestingly, for several days JAMA made you click through an ad for a competitor's type 2 diabetes product to get to the article) was published. And what was the risk of heart attack among those elderly patients on Avandia? Essentially no different than those on the older medication - a statistically insignificant 1.06 increase - especially so given the fact that almost three quarters of all type 2 diabetics wind up dying of heart disease in any event. So, was Avandia cleared? Nope. In fact, the calls for removing it from the market have grown even louder.

The new study, while rejecting the original claim that Avandia causes heart attacks, raised the hypotheses that Avandia causes congestive heart failure and stroke and increases the rate of mortality overall. Yet even though the numbers of patients involved in the study (their records were simply culled from Medicare databases) was large (227,000) the increases were relatively small and by the time the increases appeared (after six to fifteen months of medication) only a small and rapidly decreasing fraction of the original cohort were actually still on one of the two medications.

At almost the same time Dr. Nissen published an updated meta-analysis ("Rosiglitazone Revisited: An Updated Meta-Analysis of Risk for Myocardial Infarction and Cardiovascular Mortality"  also free and also, though published in the Archives of Internal Medicine, only after an ad for the same competitor's type 2 diabetes product) that purports to show that Avandia increases the risk of heart attack but doesn't increase the risk of mortality. What? Hey, wait a second! How can ... So, siding with those advocating "safety over certainty" the New York Times quickly editorialized in favor of those demanding Avandia be removed from the market.

The LATimes went so far as to publish a piece calling for "an immediate moratorium on sales as soon as a credible study raises questions about safety." In that same piece the journalist was posed the following question by a researcher being interviewed: "Suppose a drug saves five people and kills one person. Do you keep it on the market?" His answer was "I know this: If that one person killed is my loved one - or yours - the answer is readily apparent."

Yikes. Really? If a data dredge shows any risk of a fatal outcome then the drug should be pulled from the market no matter how many people are killed in the process? We'll save for another day the question of how thinking about risk goes so badly astray. For now though consider how likely it is (yes likely - and in fact, if the number of endpoints examined are sufficiently large, how almost certain it is) that a risk will be found where none exists. Start with "Data Dredging, Bias, or Confounding: They Can All Get You Into the BMJ and the Friday Papers" and then for more on the perils of statistical deep drilling read "Your Intuitions Are Not Magic" and the links therein.

At the end of the day the issue isn't safety versus certainty. Claiming that pharmaceutical manufacturers are insisting upon certainty before warnings are issued or products are pulled is just a straw man argument. The usefulness of statistical analyses of medical outcomes has not been added to "death and taxes".The real question is which course is less uncertain - making vital judgments on the basis of large randomized controlled trials like the one due out on Avandia in 2015 or on the basis of data dredges? The answer ought to be obvious.

NHL is Not Associated With Exposure to Gasoline

Twenty one of twenty two studies in the English literature that have examined the risk of non-Hodgkin lymphoma (NHL) among petroleum workers exposed regularly to gasoline have found no association between the two. The overall relative risk across all such studies has been estimated to be just 1.02. See: "Occupational Exposure to Gasoline and the Risk of non-Hodgkin Lymphoma: A Review and Meta-Analysis of the Literature".

What Percentage of Mesothelioma Cases Are Due to Asbestos?

What Are The Risk Factors For Lung Cancer Among Those Who Never Smoked?

It doesn't appear to be second hand smoke; at least not from a brand new study of lung cancer cases in Toronto. On the other hand, having a family member diagnosed with lung cancer before age 50 significantly increased risk. So did a prior history of chronic lung disease. Similarly, occupational exposure to solvents, paints, thinners, soot, wood dust, grain dust and welding more than doubled the risk of lung cancer among non-smokers. Read all about it (for free) in "Lung Cancer Risk in Never-Smokers: A Population-Based Case-Control Study of Epidemiologic Risk Factors".

More Fuel for the Glargine Insulin Fire

A year ago a large European study implicated high doses of glargine insulin in certain cancers in diabetics. At the time endocrinologists urged causation in interpreting the results and advisory boards urged patients and physicians not to change their insulin regimens until further studies were completed. Now the results of those studies are starting to be published.

In "Doses of Insulin and its Analogues and Cancer Occurrence in Insulin-Treated Type 2 Diabetic Patients" the authors report the results of a nested case-control study of insulin-dependent diabetics. A five fold increase in cancer was found among those taking high doses of glargine. No such increase in risk was found among those diabetics taking other forms of insulin.

Vitamin D Deficiency and Multiple Sclerosis (MS): Who Pays?

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

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

Why Would Mining Protect Men From Prostate Cancer?

Nobody knows why but miners tend to be at a much lower risk of prostate cancer. In "Could Mining Be Protective Against Prostate Cancer? A Study and Literature Review" researchers from Australia document a huge decrease in this most common of all cancers afflicting men. Before anyone hauls out the "healthy worker effect" note that the risk of prostate cancer in these miners, only 35% that of non-miners, is much lower than would be predicted even from those studies in which a significantly decreased risk has been attributed to the effect.

Poultry Workers at Increased Risk of Certain Cancers

Workers exposed to chicken viruses at slaughtering and processing facilities were at increased risk of dying from cancers of the pharynx, lung, pancreas and brain as well as from hematopoietic malignancies. See: "Cancer Mortality in Poultry Slaughtering/Processing Plant Workers Belonging to a Union Pension Fund".

Chronic Chlamydia Pneumoniae Infection and Lung Cancer

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

Clostridium Difficile in the News

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

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

An Unusual Benzene/MDS Opinion

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.

Statins: A Little Sour With the Sweet

As evidence confirming the hypothesis that statins reduce the risk of cardiovascular disease piles up along with it comes data suggesting that some other risks may be elevated by taking statins. So far, however,  the benefits of statin treatment appear to easily outweigh the risks. Here's some of that data published in the last couple of weeks:

Lipid-lowering Agents and New Onset Diabetes Mellitus

Unintended Effects of Statins in Men and Women in England and Wales; Population Based Cohort Study Using the QResearch Database

Acute Renal Failure With the Combined Use of Rosuvastatin and Fenofibrate

Balancing the Intended and Unintended Effects of Statins

How is Multi-Drug Resistant Acinetobacter Baumannii Spread Through Hospitals?

It's not just unwashed hands nor even mostly unwashed hands. Gloves and gowns of healthcare workers are contaminated with A. baumanni more often than hands. Following contact with infected patients 38.7% of gloves/gowns were contaminated whereas hands only picked up the bacteria 4.5% of the time. A. baumannii looks to be more readily transmissible than even MRSA. See "Frequent Multidrug-Resitatant Acinetobacter Baumannii Contamination of Gloves, Gowns, and Hands of Healthcare Workers".

An Epidemic of Head and Neck Cancer

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.

 

Evidence For a Benzene-Leukemia Supralinear Dose Response?

What is the risk of leukemia in workers exposed to relatively low cumulative levels (<100 ppm yrs) of benzene? To get at the answer researchers examined nine published studies from which exposure-response data could be extracted. The exposure response curve that best fit the data shows a supralinear response, by which it is meant that the rate of response falls less rapidly for an interval before returning to its former rate of descent. The primary explanation offered for the deviation from the linear is that at some level the mechanism by which benzene is ordinarily metabolized is overwhelmed, or saturated, and metabolism by some other mechanism, one responsible for metabolites that cause leukemia, takes over until it too is saturated beyond which point risk rises at a lower rate.

The obvious problem with the best fitting curve graphed in the study is that it manages to predict a positive risk for benzene-induced leukemia even when the exposure to benzene is zero - an apparently absurd result. This best fitting model shows greater risk of benzene induced leukemias down to 10 ppm years than would be predicted by a typical linear no threshold model and a doubling of the risk level at just above 40ppm yrs. However, the second best fitting curve shows a sharp decline, especially below 40 ppm yrs and one which might be consistent with a threshold for risk at some non-zero level.

The paper is free and you can find it here: "Flexible Meta-Regression to Assess the Shape of the Benzene-Leukemia Exposure-Response Curve"

Libby Vermiculite and Death From Cardiovascular Disease

While examining the effect of cumulative fiber exposure on lung cancer and mesothelioma among Libby, MT vermiculite workers researchers from the ATSDR noticed dose related increase in deaths from cardiovascular disease. Using a "within-cohort comparison" they were able to demonstrate a significant dose response relationship at or above 44.0 f/cc years. See "Vermiculite Worker Mortality: Estimated Effects of Occupational Exposure to Libby Amphibole".

Breast Cancer and Diet: Good News and Bad News

in "Meat Mutagens and Breast Cancer in Postmenopausal Women - A Cohort Analysis" the researchers report the results of their study of breast cancer risk among women who consume meat cooked at temperatures high enough to produce heterocyclic amines (endocrine disruptors) and so-called "meat-derived mutagens". The good news is that the women were at no increased risk of estrogen-receptor positive breast cancer and at a slight decreased risk of estrogen-receptor negative breast cancer.

The bad news, if you've been forcing down lots of leafy greens in hopes of fending off breast cancer, is that cruciferous vegetable consumption seemed to have no effect, one way or the other, on breast cancer risk.

Was Estrogen-Progestin Hormone Replacement Therapy Responsible for High Rates of Breast Cancer in Marin County?

It certainly looks that way. Read: "Recent Trends in Hormone Therapy Utilization and Breast Cancer Incidence Rates in the High Incidence Population of Marin County, California".

There are three very interesting observations reported in the study. There's of course the strong correlation between the sharp drop in the incidence rate of invasive breast and the discontinuation of estrogen plus progestin hormone replacement therapy (EPHT). But there's also the fact that this group of well to do and well educated women apparently picked up on the HERS and WHI study results and almost overnight collectively and dramatically altered their preferences for a medical treatment. And then there's the discovery that hysterectomy rates varied wildly throughout the various counties in California.

As for the first finding, these and similar results continue to add to the overwhelming evidence that the breast cancer clusters in Marin County, CA and Long Island, NY are not due to environmental pollutants but instead are due to a mix of lifestyle, surgical procedures and medications along with a genetic component.

As for the second and third findings they reinforce the emerging view that comparing cancer rates from one county to those of other counties, to the state as a whole, or to national rates is perilous at best. Here Marin County women adopted EPHT early, did so at a high rate relative to women elsewhere in the state and underwent hysterectomies at a low rate relative to other women yet those causal factors were completely unaccounted for in early studies. As a result, activists and some researchers concluded that the cancer cluster had to do with the environment of Marin County rather than the lifestyle choices of its residents.

One of the underlying assumptions of epidemiological studies is that the population investigated and the group to which it's compared are the same. These results demonstrate that merely accounting for gender, race and age isn't enough and that lifestyle choices afforded by education and wealth can make a critical difference, both positive and negative.

But Sometimes Causation is Really, Really, Really Easy

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.

Huge Prospective Cohort Study Launched to Study Cell Phone Users

The Cohort Study on Mobile Communications (COSMOS) will follow more than a quarter milion people in Britain and Northern Europe over the next three decades to determine whether cell phone use poses any health risks. You can read about it at Reuters Health.

Given the accelerating changes technology has wrought over the last three decades I'd bet that a study of cell phones (at least the kind we currently use) will be as interesting to the people of 2040 as a study about the risks of using teleprinters would be to us today.

Does Shift Work Cause Cancer?

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."

Kidney Cancer: Cigarette Smoking, Obesity and Uncontrolled Blood Pressure

What causes kidney cancer? A lot of things have been proposed, especially substances and habits which are nowadays considered indicia of immorality such as using petrochemicals or having a Western lifestyle. However appealing to some, there's little to support such claims. On the other hand, smoking, being fat and not taking your blood pressure medicine are clearly the best ways to improve your odds of getting kidney cancer. Read about it in: "Contemporary Epidemiology of Renal Cell Carcinoma: Perspectives of Primary Prevention".

Another Study Concludes That Hormone Therapy Does Not Increase the Risk of Dying From Breast Cancer

See: "Hormone Therapy and Fatal Breast Cancer" finding no suggestive link between estrogen therapy and the risk of dying from breast cancer. Note that an increase in mortality from breast cancer among those taking both estrogen plus progestin could not be ruled out.

Lies, Damned Lies, and P-Values

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.

Occupational Exposure to Endotoxins: A Good Thing?

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.

No Association Between Industrial-Grade Talc and Mesothelioma

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.

Why Do So Many Non-Smokers Get Lung Cancer?

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

Everything is More Carcinogenic in China

"Tobacco smoking is responsible for one-third of the total cancer deaths among men." See "Estimation of Cancer Incidence and Mortality Attributable to Smoking in China". Secondary smoke exposure is said to be responsible for more than 11% of all cancer deaths in women.

Do you ever get the feeling that China is just going through what the U.S. went through in the 1960s, 1970s and 1980s when epidemiology and mass health panics were all the rage? If so, and if a "redistributional justice" model of tort law can be introduced in China, it may be deja vu all over again for classic mass tort litigation.

No Association Between Paint Fumes in the Home and Fetal Growth

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.

Long Term Smoking Significantly Reduces the Risk of Parkinson's Disease

A greater than 40% decrease in Parkinson's if you smoke more than 30 years? So it seems from this huge NIEHS study of 305,468 Americans. "Smoking Duration, Intensity, and Risk of Parkinson Disease".

Obviously the risk of getting lung cancer, emphysema, etc from smoking is much higher. Still, if you knew you had the genes that protects you from lung disease (whatever they are) but not the ones that protect you from Parkinson's (whatever they are) would you smoke?

 

Are There Occupational Risk Factors for Parkinson's?

According to "Occupational Factors and Risk of Parkinson's Disease: A Population-Based Case-Control Study" the risk of Parkinson's was not significantly affected by workplace exposures to  metals, solvents or pesticides.

It Doesn't Seem Logical But It Does Seem To Be So

If people with Type 2 diabetes are at a greatly increased risk of heart disease wouldn't it make sense to get their blood pressure and triglycerides down and their "good" cholesterol up? Quitting smoking and lowering "bad" cholesterol reduces the risk from very, very high to just very high so attacking these other presumed risk factors should help, right? Besides, pushing systolic blood pressure down closer to normal would obviously yield some benefits. And there's no way it could hurt. Right?

It turns out that these interventions, implemented on the basis of reasoning and not rigorous studies, either do no good, do no good and cause side effects, or do no good and increase the risk of heart attack by 50%. Be sure to read about the just published data and the reaction to it in an excellent write up by Gina Kolata in The New York Times.

How could this be? Well, what if the things everyone thinks are causes of heart disease in diabetics are really just other effects of the real cause? Or, and this is where it really gets scary, what if what everyone thinks is a cause in need of eradication is in fact part of the body's defense mechanism against the real cause? For a discussion about how obesity may be just such a protective mechanism see "One of the Scourges of Modern Life May Have Been Profoundly Misunderstood" in The Economist's Science and Technology section.

The takeaway from all this can be found in the first article. While these treatments seemed logical (and as noted in the article, at every meeting "some academic" would always be going on about how elevated blood sugar after a meal was dangerous and had to be lowered until eventually doctors had put thousands of people on these treatments) it turned out they were instead dangerous and ineffective. That'll always be the danger when we attempt to deduce solutions based on just the known variables of a complex and only partially understood system.

Many Parents of Children With ASD "Have Relied Upon Practitioners and Researchers Who Peddled Hope, Not Opinions Grounded in Science and Medicine"

Three more strikes against the claim that thimerosol causes autism spectrum disorders (ASD).

Mead v. Secretary of HHS

King v. Secretary of HHS

Dwyer v. Secretary of HHS (- the quote in the title can be found in this opinion)

Be sure to read the discussions of Petitioners' expert Sander Greenland and his opinions about the limits of epidemiology - at least on the "what it can't rule out" end of the spectrum. One wonders what his answer would have been if instead he'd been asked to formulate an "intervention policy" based on the same epidemiological studies - all of which show no association between thimerosol and ASD, and none of which show a "clearly regressive" subset of ASD. See "Epidemiologic Measures and Policy Formulations: Lessons From Potential Outcomes", by Sander Greenland, free online.

FDA Finds No Increased Risk of Femur Fractures in Women Taking Fosamax

The FDA has reported on its ongoing safety review of oral bisphophonates and atypical subtrochanteric femur fractures. "Recent news reports have raised the question about whether there is an increased risk of this type of fracture in patients with osteoporosis using these [Fosamax, Actonel, Boniva, Reclast] medications" "All available case reports and clinical trial data were requested. FDA's review of these data did not show an increase in this risk in women using these medications."

Coronary Heart Disease: Neither Degenerative Nor Man-Made?

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.

You Know Those Mass Screenings for Prostate Cancer? Nevermind.

According to the Houston Chronicle the American Cancer Society has finally come to grips with mounting evidence that indiscriminate screening for prostate cancer causes more harm than good thanks to (a) the inevitable morbidity resulting from needless biopsies and surgeries due to false positive tests; (b) the realization that an awful lot of people who consider themselves "cancer survivors" would never have known they had cancer but for the screening test as their cancers would have gone away on their own or would have grown so slowly that they'd have died of something else before the prostate cancer became threatening; and, (c) the unfortunate fact that early detection, despite what everybody has been led to believe, does not mean that aggressive cancers can be cured - it just means that we get to be treated for them, and worry about them, longer.

Here's a link to the new screening recommendations: "Revised Prostate Cancer Screening Guidelines: What Has -- and Hasn't -- Changed"

Also of interest may be the readers' comments over at the Chronicle and elsewhere. Predictably there are two dominant camps. One sees this change as a nefarious plot by Big Pharma and Big Medicine to prevent early detection so they can make more money by making people wait until they need more expensive medicines and surgeries. The other one sees the new guidelines as a nefarious plot by Big Government to save money by preventing early detection so it can save money on treatment and hasten the deaths of Americans thereby saving money on Social Security payments as the cherry on top. I've run across veniremen able to hold both views simultaneously. But that's a discussion for another day.

Loves Safranin, Hates People

The New York Times has an alarming article about the rise of gram-negative bacteria as the cause of a staggering amount of morbidity and mortality among hospital patients. The rogues' gallery of gram-negative "wretched beasties" includes Klebsiella pneumoniae, Legionella pneumophila, Pseudomonas aeruginosa, Escherichia coli, Enterobacter cloacae and Helicobacter pylori.

For more on the problem see: "How Can We Stem the Rising Tide of Multidrug-Resistant Gram-Negative Bacilli?" wherein you'll read: "... we know much less about how best to detect and prevent transmission of multidrug-resistent gram-negative bacilli. These organisms are relative newcomers to the healthcare-associated infections arena ..."

Does Estrogen + Progestin Increase the Risk of Lung Cancer?

According to "Lung Cancer and Hormone Replacement Therapy: Association in the Vitamins and Lifestyle Study" published in the Journal of Clinical Oncology, long term use of estrogen and progestin (> 10 yrs) produced a 48% increase in lung cancer and typically advanced disease at that. Interestingly, those taking estrogen alone experienced no increase in risk.

The hazard ratio was only 1.48 with a confidence interval from 1.03 to 2.12 meaning the reported result suggests at best a hypothesis for further testing and not a presumed causal relationship.

Possible Link Between Low Level Benzene Exposure and Birth Defects, Miscarriages

In this article in last month’s Envrionmental Health Perspectives, the authors reported an increased incidence of sperm aneuploidy (abnormal numbers of chromosomes) in men exposed at air levels close to the current 1ppm Permissible Exposure Level (PEL) recognized by EPA. The chromosomes studied have previously been associated with birth defects and miscarriages. This study is the first to associate sperm aneuploidy with levels of bezene exposure below the PEL. It may be pointed to as some indication that the current PEL in the United States insufficiently protective against reproductive harm.

Household Exposures to PAH from Coal Tar Driveway and Parking Lot Sealants

In a paper published last month in Environmental Science and Technology, the authors measured polycyclic aromatic hydrocarbons (PAH) in settled house dust (SHD) in 23 apartments in Austin, TX. Half of the apartments had parking lots sealed with coal tar based parking lot sealcoat and half of them did not. The authors report 530 times more PAH in SHD in the apartments with parking lots sealed with coal tar based sealants than in the other apartments. These findings suggest that coal tar based sealants may play a significant role in household exposures to PAH, notwithstanding the fact that PAH are ubiquitous in urban environments.

The High Cost of Infections Acquired in the Hospital

According to "Clinical and Economic Outcomes Attributable to Health Care-Associated Sepsis and Pneumonia" just published in Archives of Internal Medicine just two types of preventable hospital acquired infections, sepsis and pneumonia, killed an estimated 48,000 Americans in 2006 and added more than $8 billion to the cost of care. The article details the alarming number of infections due to simple lapses in sanitation, from poor hand washing habits to dirty surgical devices, and the spread of so-called "superbugs" which have acquired immunity to common antibiotics.

Another Meta-analysis of Benzene and NHL Studies Finds No Independent Association

In "Benzene Exposure and Non-Hodgkins Lymphoma: a Meta-Analysis of Epidemiologic Studies" published in the Journal of Occupational and Environmental Medicine the authors looked at 8 cohort and 14 case-control studies of benzene-exposed workers and their risk of developing non-Hodgkins lymphoma (NHL). Whether in the aggregate or looking just at those with the highest reported exposures the summary relative risk estimate remained almost exactly one. The authors conclude that these studies at least do not demonstrate that benzene is a risk factor for NHL

Determining Causation After an E. Coli Outbreak

In a case involving lots of infected meat all from the same plant and all infected with the same pathogen cultured from the victims and known (thanks to the deployment of Koch's postulates) to cause the illness in question, well, tracing the source isn't too hard. But that's not how it usually goes.

After an outbreak and after all the food has been tossed and the food areas washed down with Clorox how could you possibly find the source? Thanks to the robust sales data kept by more and more businesses it may be possible to construct a "virtual cohort" and thereafter through the usual epidemiological techniques trace an outbreak all the way back to "cooked beef topside" at a single delicatessen. The method is discussed in "The Use of a New Virtual Cohort Study Design to Investigate an Outbreak of E. coli O157 Linked to a Supermarket Delicatessen".

Six new Stevens-Johnson Syndrome Papers in a Month

Among the conclusions: mycoplasma pneumoniae causes Stevens-Johnson syndrome (SJS) but symptoms were less severe than those cases produced by drugs and biopsy specimens were distinguishable; treatments for vision-related pathologies are available if administered timely; NSAIDs are only weakly associated with SJS and perhaps not at all; the percentage of total body surface affected by SJS/TEN (TEN is toxic epidermal necrolysis) is the best predictor of whether a potentially deadly blood stream infection will occur thus informing and the types of bacteria typically responsible may guide clinicians regarding antibiotic therapy; and, Tamiflu, SJS and you.

Does Hormone Replacement Therapy Prevent Colon Cancer?

A study of 57,000 California teachers found that those on hormone replacement therapy (HRT) had a 36% lower risk of colon cancer than women who never used HRT. The study followed California teachers for a over a decade. The study, "Menopausal Hormone Therapy Use and Risk of Invasive Colon Cancer: The California Teachers Study" is published this month in the American Journal of Epidemiology.

The effect, and by the way a 36% decrease in one of the leading causes of cancer is a pretty big deal, held whether the women were active or not, obese or not, taking NSAIDs or not, consumers of alcohol or not and was especially strong among women with a family history of colorectal cancer. Interestingly, the protective effect disappeared after 15 years.

So what should a perimenopausal/postmenopausal woman do? Is it just a matter of picking her poison? I've no idea. But until someone figures out how cancer really works it looks like we're stuck in a "damned if you do, damned if you don't" dilemma.

Soft Drinks and Pancreatic Cancer: A Plausible Link?

Late last night the press began reporting on a press release from the authors of "Soft Drink and Juice Consumption and Risk of Pancreatic Cancer: The Singapore Chinese Health Study". By this afternoon the claim that drinking as few as two soft drinks a week may nearly double the risk of getting one of those "go get your affairs in order" cancers had appeared on nearly every major news site. So what to make of it?

First it's probably wise to read up on the Singapore Chinese Health Study. How was dose (number of soft drinks per week) determined? It looks as though it was done via questionnaire rather than any objective measurements. And how many cases were there? 140; which isn't many thereby pushing the reported hazard ratio of 1.87 to the "slight" end of the range of the scale used to weigh evidence when making causal inferences.

Second let's look at the other claims on which the authors rely to support their causal hypothesis: specifically, a) Increased sugar intake may stimulate tumor growth through effects of insulin; and b) Pancreatic cancer rates increased nearly twofold over the past several decades.

As we reported recently there is indeed evidence tending to show that chronic moderate to high levels of glucose in the blood are associated with an increased risk of pancreatic cancer. Sounds supportive, right? Only if drinking sweetened soda chronically elevates blood sugar levels. And here's an article that says that it doesn't - not in lean men, not in obese men and not even in type 2 diabetic men; and not even at 75 grams of sucrose per day (seven times the purported risk elevating level referenced in today's article under discussion). So maybe it's like the fat follies of the past few decades; eating fat makes you fat, right? Wrong. Similarly, maybe the association between consuming sugar and hyperglycemia isn't so simple. And isn't that doubt furthered by the finding that sugary fruit drinks were NOT associated with pancreatic cancer?

Finally, here's the SEER Stat Fact Sheet for cancer of the pancreas. As noted there are lots of ways to look at trends but from the SEER perspective the upward trend in pancreatic cancer incidence and mortality is quite recent and looks to be driven by an increase among women. Doesn't that suggest smoking? It is after all the most consistently identified causative factor in cancer of the pancreas.

New Meta-Analysis Finds No Causal Association Between Benzene and NHL

A meta-analysis of 22 studies found no evidence of a link between benzene and non-Hodgkin's lymphoma (NHL) even at the highest levels of benzene exposures. Sliced and diced three different ways the data all revealed a summary relative risk estimate of almost exactly one every single time.

The study is titled "Benzene Exposure and Non-Hodkin Lymphoma: A Meta-Analysis of Epidemiologic Studies" and will be published in February's Journal of Occupational and Environmental Medicine.

Does Trichloroethylene Cause Parkinson's?

"I think people will really move on this as quickly as possible now" said Dr. Samuel Goldman of the Parkinson's Institute in Sunnyvale, CA according to the LATimes. Goldman was interviewed about a soon to be released study indicating that while other industrial solvents like xylene, toluene and n-hexane were not associated with Parkinson's, trichloroethylene (TCE) was strongly and significantly associated with the malady.

The results are to be presented in April at a meeting of the American Academy of Neurology and so there's not much to assess at the moment save the large grain of salt to be taken with any science that makes its way into the popular media before it lands in a journal. Nevertheless, the finding, if borne out by subsequent population studies, would be significant. Many substances have been blamed for Parkinson's but none with the 5.5 relative risk reported in this, well, press release.

Speaking of Saturated Fat

Yesterday we reported on a new paper in JAMA counseling caution in the face of activist efforts to impose universal sodium salt reduction on the American populace. We reminded our readers that once upon a time activists demonized saturated fats and stampeded the country towards greater consumption of trans fats. Now there's a new study looking at the health outcomes of 384,000 Americans to see whether those who consumed lots of saturated fats were more likely to develop heart disease than those who avoided saturated fats.

Reuter's Health reports that the study,published in the American Journal of Clinical Nutrition, involved the combination and assessment of 21 large studies of people, their diets with regard to the consumption of saturated fat and whether or not they developed heart disease. It turns out there's no demonstrable association between saturated fat and your risk of heart disease. Eat a lot or eat a little, your risk remains the same. Somewhere my late great grandmother, who lived to 102 and who made the best pies and pastries thanks in part to lard, is smiling.

Does Chronic Elevated Blood Sugar Cause Cancer?

It very well might, according to "Diabetes Mellitus Type 2 - An Independant Risk Factor for Cancer?" More alarming is the finding that significant risk of cancer is incurred even at blood glucose levels simply on the high side of "normal". A doubling of the risk for the following cancers has been found among those with type 2 diabetes: colorectal, breast, endometrial, renal, liver and pancreatic.

On to a Fifth Age? How About We Finish the Second?

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.

A Critique: Recent Epi Studies of Motor Skills and Manganese

In "Risk Assessment of an Essential Element: Manganese" Annette Santamaria and Sandra Sulsky of ENVIRON critically review recent epidemiological literature associating a variety of abnormal psychometrics with relatively low levels of manganese exposure.  

The authors conclude that the available epidemiological data is generally flawed and unreliable at least for the purpose of doing risk assessment. Furthermore, they demonstrate that some exposure levels claimed to pose a risk of neurobehavioral injury produce effective doses well below the amount of manganese recommended in a healthy diet; they also elaborate on the adverse health effects of manganese deficiency. Santamaria and Sulsky conclude by suggesting that more accurate and defensible risk assessments for manganese will have to come from objective data such as the determination of manganese dose via inhalation and the subsequent development of physiologically based pharmacokinetic models to predict the consequences of exposure at various levels and by various routes.

An Explanation for the Quebec/South Carolina Chrysotile Conundrum?

Why is there such a disparity between health outcomes of the workers who mined chrysotile and the textile workers who used it? In "Comparing Milled Fiber, Quebec Ore, and Textile Factory Dust: Has Another Piece of the Asbestos Puzzle Fallen into Place?" Berman reports that the dusts encountered at the facilities vary in two important ways. First, whether assessed by PCM or TEM, samples revealed that mine and mill dusts contain only 67% asbestos. On the other hand, typical feedstock for the textile facility was 100% asbestos. Second, the feedstock asbestos fibers were significantly longer than those typically encountered by workers exposed to mined or even refined asbestos.

Thus, for a given quantity of dust textile workers would have an approximately 50% greater exposure to asbestos and that exposure, on a fiber per fiber basis, would be significantly riskier. The author also suggests a method for reconstructing past exposures which would more accurately estimate the risk posed by each of those exposures.

Does Education Cause Autism?

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.

 

 

Are Michigan Courts Shifting the Burden of Proof to Defendants?

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.

Don't Pitch the Water Softener

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.

 

Is Your Drinking Water Safe? If Not, Why Not?

The New York Times has run an extensive article about the nation's drinking water claiming that our public water is contaminated with thousands of chemicals, hundreds of which are "associated with a risk of cancer". It even has a link to the articles on which the claims are based. Unfortunately, or fortunately depending on your point of view, the evidence cited for the proposition that tap water is putting the citizenry at risk of cancer is pretty thin if that's all there is.

For example, under "Studies Regarding Illnesses and Drinking Water" (of which there are only eight) the only one to make a broad claim of tap water carcinogenesis is a 28 year old study titled "Cancer and Drinking Water in Louisiana: Colon and Rectum" which used the 1970 census to compare 692 rectal cancer deaths from 1969-1975 by where along the Mississippi River they and controls got their drinking water. The authors noted a small increase in risk as the source got closer to the Gulf of Mexico and suggested that the finding may have something to do with an increasing concentration of industries along the river as it approaches the Gulf. More importantly they wondered whether by-products of chlorination might have something to do with the finding.

The link suggests just four other papers that have cited the study and of those only two studied drinking water. Of the two, the first is a Canadian paper from 2000 (the first true Y2K victim I've ever run across - note: "Received 1999 Accepted 1900") which found no association with rectal cancer but a small one for colon cancer among males who drank "chlorinated surface water for 35-40 years".

Following the papers that cited the Canadian paper you quickly find another drinking water paper that finds a small protective effect for all leukemias combined, a large protective effect for chronic lymphocytic leukemia and a small but significant association with chronic myeloid leukemia.

The other papers are similarly all over the place and there appears to be no consensus that U.S. drinking water is a cause for concern about cancer from the perspective of chemical contaminants.

On the other hand, there's a growing body of literature associating drinking water contaminated by microorganisms with cancer. There's a new one discussing the waterborne transmission of helicobacter pylori to be published in next month's Journal of Water and Health and then there's this alarmingly titled paper in the same journal: "Free-living amoebae, Legionella and Mycobacterium in tap water supplied by a municipal drinking water utility in the USA

It's unclear why the NYTimes focused on trace levels of chemicals as a cause for concern when there does appear to be something to be worried about when it comes to bugs in our water.

Cancer: Annual Report to the Nation

There was more good news last week about Americans' incidence and rates of death due to cancer. The rates of new cases and the rates of death from all cancers combined are dropping and dropping steadily. For example, cancer deaths for all forms of cancer collectively dropped 1.6% per year for each of the last six years for which data is available (2001 - 2006). The progress being made against colorectal cancer was highlighted in the report.

While men continue to have higher rates than women their decline in rates was also higher. Decreases in deaths and incidence for lung, prostate and colorectal cancer drove the decline for men.

Among women, breast and colorectal rates declines lead the overall improvement.

The news was not uniformly good. In men, rates increased for myeloma, kidney, liver and esophageal cancer as well as multiple myeloma and leukemia. In women the expected increase in lung cancer rates was found along with increases for thyroid, pancreatic, bladder, melanoma and kidney cancers as well as for non-Hodgkin's lymphoma and leukemia.

The NIH press release can be found here.

IARC Assesses Evidence for Carcinogenicity and Genotoxicity of Formaldehyde

IARC has determined that there is strong evidence that formaldehyde is the cause of nasopharyngeal cancer and moderate evidence that it causes leukemia, especially of the myeloid variety. Here's the ungated table from "A review of human carcinogens - Part F: Chemical agents and related occupations".

Formaldehyde: A Cause of Leukemia?

In a new article in the Journal of the National Cancer Institute an association between embalming, as a proxy for exposure to formaldehyde, and myeloid leukemia was found to be strong, significant and dose dependent. In coming days we'll be discussing the controversial claim of a causal link between leukemia and formaldehyde and IARC's recent musings about it.

The article is Mortality From Lymphohematopoietic Malignancies and Brain Cancer Among Embalmers Exposed to Formaldehyde .

Interstitial Fibrosis Among Farmworkers Due to Agricultural Dust

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)".

Are Big Punitive Awards in HRT Cases Justified?

Law.com is reporting that Philadelphia juries have awarded a total of $103 million in punitive damages alone to two women in separate breast cancer product liability trials. The women claimed that hormone replacement therapy (HRT) was responsible for their subsequent development of breast cancer.

In light of the recent controversy over the use of Bayesian decision-making approaches to mammography and Pap testing in which probabilities of outcomes are estimated and benefits are then weighed against costs (including other bad outcomes) I thought it might be of interest to see if such an approach had been applied to HRT. Sure enough, "Bayesian Meta-analysis of Hormone Therapy and Mortality in Younger Postmenopausal Women" was just published in The American Journal of Medicine.

So what does it show? It shows that across a number of randomized controlled trials of HRT in postmenopausal women under 60 those women had a reduced overall mortality compared to those postmenopausal women under 60 who weren't on HRT.

As is often the case in these modern times science does not yield a cure but does allow one to pick one's poison as it were; not to avoid death but to influence the odds of whether you die of stroke instead of breast cancer.

O-toluidine and Aniline Again Associated with Bladder Cancer

A recently published study in Occupational and Environmental Medicine reanalyzed the results of a 1991 investigation conducted by NIOSH of 1749 workers potentially exposed to o-toluidine and aniline at a chemical manufacturing plant and the incidence of bladder cancer. In the reanalysis, the investigators used updated exposure categories based on additional information ascertained through plant visits, employee interviews, documents, and answers provided by company and union officials on specific questions. Increased risks of bladder cancer were observed the longer the exposed employee worked at the facility and the longer the latency period from the date the employee initially worked in a department in which exposure occurred.

The investigators concluded that the findings were comparable to the results reported in 1991 by NIOSH that workers at the plant have an increased risk of bladder cancer.
 

Sulfonamides and Nitrofurantoin Associated with Birth Defects

The New York Times is reporting on this study by Crider KS et al. in November’s Archives of Pediatrics and Adolescent Medicine which appears to demonstrate an association between certain antibiotics taken for urinary tract infections (used just prior to pregnancy or during the first trimester of gestation) and several common birth defects.

The antibiotics associated with the most pronounced increases in birth defects were  nitrofurantoin and the sulfonamides. Caution is in order when interpreting these results. First, it appears that the exposures were extrapolated from memory rather than measured quantitatively. Questionnaire epidemiology is notoriously prone to error. Second, there’s the question of where does the arrow of causal suspicion point. Maybe it’s the infection that’s responsible for the birth defects. Finally, this particular cohort would not appear to be a cross section of pregnant American women but instead is drawn from a narrower slice and is significantly homogeneous. Social structures and interactions are increasingly recognized as important independent causes of certain morbidities.
 

Good News on Styrene

A review of the studies of workers exposed to styrene found no evidence of a causal link between styrene exposure and cancer. The literature contains numerous studies of workers with exposures to styrene during its manufacture or use in synthetic rubber or plastics production. Though a couple of studies have found an increase in either non-Hodgkins lymphoma or esophageal cancer many others did not and no dose response was seen in the outliers. The authors conclude that the available epidemiologic literature does not support a causal inference for styrene and any form of cancer.

The paper, published in the October issue of Journal of Occupational and Environmental Medicine is titled “Epidemiologic Studies of Styrene and Cancer: A Review of the Literature” and was authored by Boffetta P, Adami HO, Cole P, Trichopoulos D and Mandel JS.

Mortality Among 127,266 Petroleum Company Employees

The Journal of Occupational and Environmental Medicine is publishing in its October issue the results of an epidemiological study of 127,266 men employed in the U.S. by a major petroleum company with at least one day of employment from 1979 through 2000. Standardized mortality ratios were calculated for 94 causes of death. Overall these workers had risks below, and often well below, those of typical American males of the same age. However, the mesothelioma rate was triple that expected (CI=1.15 – 1.90) but only for men hired before 1960. Overall, the rate for acute non-lymphocytic leukemia (including AML) was essentially as expected though a subgroup in the chemicals portion of the business did show a statistically significant increase. Interestingly, there was a statistically significant increase in mortality from melanoma among truck drivers.

As is typical of refinery worker studies, these employees fared quite well as a group. Whether that’s because, as a plaintiff attorney friend of mine speculates, the oil companies are especially good at spotting people who’ll be less likely to die of say stomach cancer or whether it’s because these workers tend to be better paid, have better access to health care and so tend to live healthier lives remains to be seen.

The article is titled “Mortality Patterns and Trends Among 127,266 U.S.-Based Men in a Petroleum Company: Update 1979-2000” and was authored by Huebner WW, Wojcik NC, Jorgensen G, Marcella SP and Nicolich MJ.

Trichloroethylene: A Risk Factor for Cancer?

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

If a Lead, Must It Bleed?

Over at Mind Hacks there’s a fun discussion about the media’s propensity to take epidemiological data regarding say the risk of some dread disease, to note the uncertainty inherent in such data and to then conclude that the risk could actually be much higher. Why not also note that the uncertainty also means the risk could be much lower? Is it just a matter of hyping a story to sell more newspapers?

I think it may be something else. I think it may have more to do with the product of the news industry – a narrative that customers want to buy. Accordingly, when the news seems not to fit with the readers’ worldviews (e.g. a report about the disparate outcomes between children in daycare versus those who stay home with their mothers) you can count on the reporter to note that the surprising result may be overstated. Thus, it may not be a matter of reporters not understanding such data or of wanting to fan the flames of a story but rather to pound the day’s news into a narrative to the liking of its readership.

Next week in Munich, Germany - The 2009 Benzene Symposium

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

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

Details to follow.

Diagnosing Mesothelioma

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?