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July 2009

Another misguided attack on phthalates

In yet another episode of "I can't figure out a legitimate research project, so I'll pick on phthalates," a group from Germany has concluded, based on minimal data and a host of confounding factors, that infusion systems containing the phthalate DEHP increase the risk for a certain liver disease in neonates.

This work appears in the August, 2009 issue of Pediatrics (von Rettberg et al.).

Let's start off by quoting from the article:

The etiology and pathogenesis of total parenteral nutrition-associated cholestasis (TPNAC), the hepatobiliary dysfunction in children during parenteral nutrition, is not yet fully understood. Many theories have been proposed to explain the causes of this serious disease.

TPNAC is especially frequent in pre-term infants and neonates who require intensive care medicine. Many previous studies have shown birth weight, low gestational age, long duration of total parenteral nutrition, and the number of surgical interventions, as well as systemic infections, to be risk factors for the development of cholestasis.

OK, here is a disease that is not well understood, and there are at least five other risk factors in play. Yet our intrepid team thinks that exposure to phthalates could be the key. Whatever gave them that idea?

The paper cites a few references as supposed inspirations, but perhaps the authors did not read them too carefully:

In support of their statement "preterm infants and neonates are susceptible to significant cholestasis from toxic injury," they cite a review article from the April, 2004 issue of Pediatrics (Piñerior-Carrero et al.). However, this work mentions "phthalate" once, and this referred only to rodent studies, as drawn from a textbook published in 1998.

It is worth noting that virtually all attempts to match rodent responses to phthalates (typically at high doses) to what happens in human exposure to these compounds have failed.

The authors contend that "DEHP is a substance that can lead to an increase in oxidative stress and toxicity, especially in preterm infants and neonates who receive intensive care."

In support of this they cite a 2004 rodent study, and another article in Pediatrics. While the Pediatrics work (Calafat et al., May, 2004) does deal with humans, it most certainly does not conclude anything regarding oxidative stress and toxicity. Rather, it does confirm that newborns who undergo intensive therapeutic medical interventions are exposed to higher concentrations of DEHP than the general population.

Inasmuch as these neonates are connected to any number of DEHP-softened tubes, this is hardly surprising. In fairness, the same reference calls for more research into potential health effects, but does not posit or prove any.

Enough of the preamble. Let's look at the results.

76 patients were studied, 30 of whom utilized DEHP-containing tubing, and 46 of whom used DEHP-free products. The touted finding is that 50% of the former group contracted TPNAC, compared to 13% of the latter group. However, one of the confounding factors mentioned above—long duration of total parenteral nutrition (TPN)—was very much in play!

The authors reveal that the DEHP group was fed intravenously for 4 days longer than the free group (26 versus 22 days on average), and also received 11 units of transfusion more than the DEHP patients. They themselves admit that these two differences are "statistically significant."

Despite the severe methodological limitations, including a self-identified "wide limits of confidence" in a portion of their statistical modeling, the authors boldly conclude that:

This study shows that the DEHP load caused by polyvinylchloride infusion systems for TPN constitutes an important factor in the occurrence of cholestasis. By changing infusion systems, the incidence of cholestasis in our department has been reduced significantly.

I would characterize the results a bit differently. The authors decided to jump on the anti-phthalates bandwagon, and have drastically overreached in their conclusions. The fact that the DEHP group was on TPN for four days longer than the free group would all by itself seem to invalidate their findings.

Sadly, though, this latest effort is little different from the sort of anti-phthalate "science" we have seen in the past.

Five Easy Pieces (1970) retrospective

This is the film that made Jack Nicholson a star, and seemed to have a big effect on many of us emerging from the 1960s. At its heart is conflict: Country music versus classical music; blue-collar life versus one of privilege and culture; and perseverance versus escape. Different views of escape are also explored.

Oddly, the pic is best remembered for a throwaway scene in a restaurant, in which Jack just can't get what he wants. As it happens, Jack hardly ever gets what he wants in this movie, and the one thing he wants most of all proves little different from what he is running away from.

Most of the acting is excellent, and that's a good thing, since there is not much plot, and no big character arcs. If a film like this were to be made today, it would be an indie production, but in 1970, Columbia was all over it.

Read my complete review.

Is that medical device safe and effective? Who knows?

In the wake of the ObTape mess—more on that later—people are finally beginning to take a hard look at just how the FDA approves medical devices.

Most consumers and many health care workers are unaware that there is a big difference in the approval process between drugs and devices. To market a new drug, the manufacturer must go through a lengthy and expensive process, generally involving clinical trials. Even that process is not always sufficient to spot dangerous side effects of the drugs, which may not appear for years.

Device approval is completely different. Medical devices are classified (Classes I, II, and III) based on the level of control necessary to assure the safety and effectiveness of the device—Class III being the most stringent. The FDA maintains an extensive database to determine which Class a device would fall into. Here are some typical examples:

  • Class I - tongue depressors, bedpans, elastic bandages
  • Class II - x-ray machines, powered wheelchairs, infusion pumps, surgical needles and suture material
  • Class III - heart valves, silicone gel-filled breast implants, implantable pacemaker pulse generators

Many Class I devices are exempt, and do not require so-called premarket review. In such cases, the manufacturer need only register its facility with the FDA. All other devices are subject to one of two types of FDA premarket review before they may be legally marketed in the United States.

Premarket approval [PMA]: The manufacturer must submit evidence, typically including clinical data, providing reasonable assurance that the new device is safe and effective. A successful submission results in FDA approval.

Premarket notification [510(k)—Based on section 510(k) of the Food, Drug, and Cosmetic Act]: The manufacturer must demonstrate to FDA that the new device is substantially equivalent to a device already legally on the market that does not require a PMA. A successful submission results in FDA clearance.


"Substantially equivalent" means that the device has the same intended use as another legally marketed device (the "predicate device") and the same technological characteristics, or different technological characteristics and submitted information demonstrates that the device is as safe and effective as the legally marketed device and does not raise different questions of safety or effectiveness.

Notably, it is not legal to advertise a 510(k) cleared device as "FDA-approved." Rather, it is "FDA-cleared."

For PMA, the device review user fee is $200,725 or $50,181 for a small business. For 510(k), the device review user fee is $3693 or $1847 for a small business. A "small business" has annual gross sales and revenues of $100 million or less. The PMA fee is waived for the first premarket application from firms with less than $30 million gross receipts or sales.

Not surprisingly, far more devices are cleared than approved. In the period 2003-2007 (based on FDA's fiscal year) 14,999 devices were cleared and 1001 were approved. Thus, it is true that most medical devices are not specifically tested for safety and effectiveness.

The key here is determining the validity of substantial equivalence in each case. Even then, the procedure can be gamed, if a device is in fact substantially equivalent, but will be marketed for other purposes. For example, several quack devices said to measure skin resistance are accompanied by software that fabricates diagnoses and recommends products.

Given the public's demand for more and better health care, the 510(k) process can streamline getting devices into the marketplace. But, as the old joke says: "There's low price, high quality, and quick delivery. Which two do you want?"

Regarding ObTape Vaginal Sling, until taken off the market, this was a medical device meant to stop the uncontrollable flow of urine as a result of urinary stress incontinence, a medical condition affecting about two million American women. FDA clearance was granted based on substantial equivalence to the urethral support tape products manufactured and marketed by Johnson & Johnson, 510(k) No: K974098 and American Medical Systems, 510(k) K013355.

As it happens, clearance for the Johnson & Johnson device was based on the Protegen sling, which was forced off the market, based on FDA findings that it was "adulterated and misbranded." Since proving substantial equivalency is all that is required for a 510(k) clearance, the clearance is not affected if some problem occurs with a predicate device.

Numerous adverse incident reports came into the FDA on the ObTape, starting in 2004. While adverse incidents do not necessarily mean that the product is defective—and the manufacturer still defends ObTape—in 2006, the product was withdrawn. Through litigation, expert opinion suggests that there were substantial differences between the ObTape and its predicate device, including being made of much more dense material, not porous enough to allow tissue and capillaries to grow through it so it is fully incorporated in the body, rather than becoming encapsulated and expelled.

Moreover, once clearance was granted, the manufacturer of ObTape began to promote its unique features, sufficient enough to get it patented! In other words, ObTape was substantially equivalent enough to be cleared, but substantially unique enough to earn a patent.

Beyond the equivalence issue is good old political pressure. Media sources have documented this sort of thing recently. In one case, a PMA was granted to a certain mammography device even though scientists at the agency recommended against approval, charging that the company had not sufficiently tested the device. In another, clearance was granted to a knee implant, that many felt should have gone through the PMA process instead.

Inasmuch as the FDA is a government agency, politics cannot be kept out of the equation. But it is clear that device clearance and approval has to be reformed. A first step would be much tighter guidelines on equivalency.

Good news on phthalates--from an EPA guy!

EPA researcher Dr. Robert Benson somehow found the hours to publish—on his own time, and independent of the Agency—a breakthrough human risk assessment on phthalates. Benson examined human exposure in the US and Germany to all the phthalates that have been implicated in bad rodent effects, to see how this stacks up with current EPA guidelines—replete with their enormous built-in safety factors.

Specifically, Benson looked at dibutyl phthalate, diisobutyl phthalate, butylbenzyl phthalate, diethylhexyl phthalate, dipentyl phthalate, and diisononyl phthalate. Those that recognize the names of these chemicals know that Benson's list is comprehensive.

His conclusion: It is unlikely that humans are suffering adverse developmental effects from current environmental exposure to these phthalate esters. In other words, average daily human exposure to all the measured phthalates combined, does not even reach the most stringent safety level set by the EPA.

This mirrors the Canadian government's recent pronouncement on BPA.

My latest HND piece covers this, along with a portion of the saga on endocrine disruptors (ED), including the tale of notorious scientific fraudster Steven Arnold. Arnold was such a true believer in the nonsensical theory of ED synergism, that he completely fabricated data in support of this hypothesis in a paper published in Science (1996). Not only was the paper retracted in August, 1997, but Arnold was banned from government sponsored research for five years. Many thought he should have been banned for life.

Don't feel bad if you never heard of Arnold's misdeeds. Given the non-PC nature of the story, the mainstream media largely took a pass.

Of course, Arnold's results not being replicated is hardly unique in ED work. It's just that his findings were so important, and so vital to the ED cause, that numerous researchers were compelled to jump into the fray. And, yes, he got caught. But, what about dozens of other efforts that purport to link ED exposure to all kinds of health effects, based largely on questionnaires and data cherry-picking? Such studies may not be Arnold type fraud, in that data exists, yet they are still unworthy of being published in once-reputable journals.

Considering that the EPA alone has spent more than $80 million on endocrine research since 1999, not to mention untold amounts on testing and regulation inspired largely by Arnold's fraudulent paper, isn't it time for Congress to investigate this entire matter?

Or are you OK with major scientific research and regulatory budgets being controlled by feckless chemophobes?

Sandy Szwarc separates fact from fiction on the latest calorie restriction findings

Leave it to Sandy, and her essential blog Junkfood Science to bring the light of truth to another case of science by press release.

She carefully analyzed the study and contrary to the media spin, and worse, contrary to the misleading conclusion given in the abstract of the published article, she notes that...

The long-awaited research on the effects of calorie restriction on aging in rhesus monkeys from the University of Wisconsin and Wisconsin National Primate Research Center have just been released. It found no statistically significant difference in the number of deaths among the monkeys who've been eating a calorie-restrictive diet for more than 20 years compared to the monkeys who've been allowed to eat ad lib all day as much as 20% over their normal calories.

A masterful job. Read her entire commentary.

This herbicide can also make corn more nutritious

My latest HND piece takes a look at an unexpected benefit coming from the herbicide mesotrione, used on corn. Ag scientists have found that corn treated with this chemical shows increased carotenoid levels.

The article also tries to make some sense of the term "sustainable agriculture," while exposing the fraud who coined it.

We quote the researcher who came up with the herbicide finding:

"The exact mechanisms of these increases are still unclear and warrant further study. However, results further emphasize the ability to enhance valuable phytochemicals in crop plants through careful management of cultural growing practices."

BPA "health effects": Reductio ad absurdum?

While the previous post describes excellent work that pretty much sets the record straight on human exposure to BPA—at actual real-world levels—we note that the University of Illinois is touting an unpublished fear-mongering study, by the very aptly named Dr. Jodi Flaws.

Under the rather sensational headline "Plastics chemical retards growth, function of adult reproductive cells," the press release from the university goes onto say that "Their study is the first to show that chronic exposure to low doses of BPA can impair the growth and function of adult reproductive cells."

You have to get deeper into the article to find that Flaws really WAS testing the effect of BPA on cells. She used cell cultures, not whole animals!

Cell cultures cannot metabolize and eliminate BPA, and the BPA concentration used—10 micrograms per milliliter—is hardly a "low dose." In fact, such levels are orders of magnitude higher than normal human exposure.

The press release begins with the bogus contention that "Bisphenol A, a chemical widely used in plastics and known to cause reproductive problems in the offspring of pregnant mice exposed to it." We would remind the good Dr. Flaws that numerous studies on lab animals (not just their cells) have failed to show evidence of fertility issues even at doses one million times higher than typical human exposures.

Of course, I don't know exactly what she means by "reproductive problems," and she doesn't define what she means, either.

Let's see, normal human exposure to BPA causes no problems. Let's try mice at extremely high levels, and get dubious results. I've got it! Let's try mouse cells—separate from the animal—at even higher levels.

For those of you who forgot their Latin, reductio ad absurdum is the disproof of a proposition by showing that it leads to absurd or untenable conclusions. In this case the reductio ad absurdum refers to the lab work, itself.

Thank you Dr. Flaws, and maybe you'll get some hard questions when you present this work at your poster session on July 19th in Pittsburgh.

More good news on BPA

Leave it to Health Canada to finally put a stake through the heart of the BPA fear-mongering nonsense. Those of you who have been following this issue have often read that Canada protects the health of its citizens ever so much better than our own FDA. Since EWG and NRDC are fond of promoting this idea, let's see what the good scientists at Health Canada discovered...

They tested the following classes of products for BPA:

In all cases, dozens of products and different brands were tested, and in all cases, levels were exceedingly low. This new data confirms Health Canada's previous conclusion that exposure to BPA through food packaging uses is not expected to pose a health risk to the general population, including newborns and young children.

In fact, Health Canada stated that an adult would have to drink approximately 1,000 liters (264 US gallons) of water from polycarbonate water cooler bottles every day to approach the science-based safe intake limit for BPA recently established in Canada.

While all of the glass water bottles showed BPA concentrations below the minimum detectable level, so did many of the plastic bottles and the one water can brand tested (Perrier).

No BPA was detected in any of the canned powdered infant formula samples tested. The level of BPA found in baby food packaged in jars clearly indicates that exposure to BPA through consumption of these products is extremely low.

Health Canada's new data provides further support for recent assessments from eleven regulatory bodies around the world that determined BPA is safe for use in food contact products. These regulatory bodies include: the European Food Safety Authority, German Federal Institute for Risk Assessment, Danish Environmental Protection Agency, French Food Safety Authority, Swiss Office for Public Health, and Food Standards Australia-New Zealand.

I hope that this latest round of data will convince the public, but as long as grants are given out to the likes of Freddie vom Saal, Shanna Swan, and the rest of the endocrine disruptor gang, this trumped-up issue—based almost entirely on over-interpretation of data in rodents—will be with us.

Why not reach out to the gang, and ask them what they think of these new findings?

Here's the contact information:

Fred vom Saal      [email protected]      (573) 882-4367

Shanna Swan      [email protected]      (585) 273-3521

And, while you're at it, drop a quick e-mail to the journos at the Milwaukee Journal Sentinel who did a big story on how bad BPA is, basing nearly the entire 30,000 word series on input from...Freddie vom Saal.

Susanne Rust      [email protected]

Meg Kissinger      [email protected]

If you think I'm being too hard on old Freddie, check out this direct quote:

"The science is clear and the findings are not just scary, they are horrific," vom Saal said. "When you feed a baby out of a clear, hard plastic bottle, it's like giving the baby a birth control pill."

That's just the kind of level-headed thinking that should be driving this issue, don't you think?

Remember CPSIA?

You know, the awful, awful Consumer Product Safety Improvement Act, of which we have written about in the past.

Good guy Rick Woldenberg comes up with an absolutely devastating piece on his blog. For fun, check out this posting on another blog by a true-believing Leftie, who is starting to wonder about big government--at last.

I guess it depends on whose ox is gored, right?

The National Fisheries Institute takes aim at lazy and biased journos

Yesterday, the gauntlet was thrown down by Mary Anne Hansan, Vice President of The National Fisheries Institute, a non-profit organization dedicated to education about seafood safety, sustainability, and nutrition.

Hansan admonishes the news media to apply "strict scrutiny" to activist claims about fish consumption, nutrition and sustainability. She cites numerous examples of journos going way wrong, including these...

In November 2007, USA Today's Larry Wheeler wrote: "As many as 600,000 babies may be born in the USA each year with irreversible brain damage because pregnant mothers ate mercury-contaminated fish, the U.S. Environmental Protection Agency (EPA) says." What Wheeler failed to mention was that EPA never made that claim, but that it was simply an extrapolation made by an agency employee whose questionable methodology and conclusions have been challenged by other scientists. A correction soon followed. Further, Wheeler made the above assertion despite the fact that science shows mothers who eat the most fish have babies with the highest cognitive outcomes.

In January 2008, New York Times reporter Marian Burros conducted her own analysis of mercury in sushi that included remarkably similar methodology and conclusions to a report from environmental activist group Oceana that was released on the very same day her story was printed. Burros' story contained multiple errors, distortions and omissions; most critically, misinterpretations of the EPA "reference dose" and the U.S. Food and Drug Administration's (FDA) "action level" for mercury, ignoring the fact that both standards contain a ten-fold cushion of safety. The paper's public editor was forced to admit that the story "required careful judgment...and missed." He added: "I thought the package was less balanced than it should have been, given the state of existing research. James Gorman, an editor in the science department who reviewed the article before publication, said he had raised several specific questions but that in retrospect, 'I should have raised more questions about the general presentation.'"

In January 2009, an Associated Press article on tuna and mercury included the erroneous claim that the EPA and FDA advise women who are pregnant or may become pregnant, nursing mothers and young children to avoid eating tuna because of its "high levels of mercury that can cause brain damage in babies," --- a demonstrable falsehood. In the very first paragraph of the federal seafood consumption advice it is clearly stated, "women and young children in particular should include fish or shellfish in their diets due to the many nutritional benefits." The advice then urges this sensitive subpopulation to avoid just four fish during pregnancy: shark, tilefish, swordfish, and king mackerel. Tuna is not included on the list of 4 species to avoid. The advice clearly states that it is safe and healthful for women and children to eat 12 ounces of light tuna per week or 6 ounces of white albacore per week. When confronted with the error, the AP was forced to issue a correction.

Hansan notes that "In many cases, reporters will uncritically pass along charges from activists, yet at the same time apply great skepticism to experts, including independent scientists, who take a pro-seafood stance."

"At times," she says, "It can be hard to tell the difference between a press release from an environmental activist and what passes as mainstream reporting."

There's much more. Check out the complete letter.

Hansan and the Institute are to be commended for issuing one of the most comprehensive rebuttals of rotten journalism that I have ever seen coming from a trade association.

Would that more trade groups follow their example.