Risk Policy Report
February 28, 2006
PHTHALATE SAFETY CONCERNS MERIT SUBSTITUTE PRODUCTS
[Rachel's introduction: When do we know enough to act? For sure when less-harmful alternatives are readily available. In the case of DEHP (a phthalate) in medical devices, good alternatives are available now. As physician Ted Schettler says, the Food & Drug Administration should use its authority to meet its public trust responsibility: require labeling of DEHP-containing PVC medical devices and move the medical device market to safer alternatives by requiring substitution where suitable alternatives exist. This is the "substitution principle" -- an important part of precautionary action.]
By Ted Schettler, MD, MPH
As evidence of the hazards of di-2-ethylhexyl phthalate (DEHP) continues to mount, the inevitable question arises, "When do we know enough to act to protect people from unnecessary and potentially harmful exposures?" Concerns about the safety of DEHP, a PVC plasticizer, have intensified since it became apparent that developing organisms are far more susceptible to DEHP exposures than adults. Hundreds of animal studies confirm the particular vulnerability of the developing male reproductive system and have begun to define mechanisms of toxicity, including impaired testosterone synthesis. Birth defects, pathologic testicular changes, decreased sperm production, and altered hormone levels are caused by developmental exposures to DEHP. Lowest adverse effect levels in developing organisms are orders of magnitude lower than doses necessary to cause reproductive system impacts in adults.
Human studies report ubiquitous DEHP exposures in the general population, with some concluding that the reference dose is exceeded among those who are most highly exposed. Studies of infants in neonatal intensive care units show even higher exposure levels from DEHP- containing medical devices. Based on animal tests, these exposures occur during developmental windows of heightened sensitivity. Measurements of newly identified metabolites of DEHP have enriched our understanding of mammalian toxicokinetics and suggest that previous estimates of DEHP exposure are too low. The first studies of DEHP exposure effects in infants are inconclusive but provocative.
Two expert panels of the National Toxicology Program (NTP), the US Food & Drug Administration (FDA), a Health Canada expert panel, and the European Union have all concluded that the animal studies of DEHP are likely to predict human health impacts and raise serious concerns. These government-sponsored panels say health care delivery with DEHP- containing PVC medical products can be a clinically significant source of DEHP exposure, and infants receiving intensive medical care are most at risk.
In 2002, FDA issued a Public Health Notification{1} warning health care providers to use available DEHP-free medical devices while treating certain vulnerable patient populations, including critically ill infants. In October 2005, a second NTP expert panel reviewed the last several years of research findings and again expressed "serious concern" regarding infants receiving intensive medical treatments with DEHP-containing devices.
Recent studies of infants receiving intensive medical therapy with PVC medical devices reported levels of DEHP metabolites in their urine similar to those associated with adverse impacts in laboratory animals. One of the studies also contained some good news. Comparing infants in two Harvard-affiliated Boston Neonatal Intensive Care Units, the study found significantly lower DEHP levels in the babies receiving care at the hospital that had switched to DEHP-free medical devices for some applications. Health care providers at that institution had taken prudent action to protect their vulnerable patients from unnecessary exposures to DEHP while continuing to provide high-quality care.
Defenders of PVC/DEHP products cite studies in marmosets that reportedly show no harm from DEHP exposures. Marmosets are members of a primate species with male hormonal regulatory systems that significantly differ from humans. For instance, testosterone levels are normally high in marmosets, and they are relatively insensitive to changes in steroid hormone levels, unlike humans. This is not a trivial detail when evaluating a chemical that interferes with testosterone synthesis. It limits the utility of marmosets as a model for studying DEHP toxicity in humans. Moreover, no study has ever examined the impacts of fetal or neonatal exposure to DEHP in non- human primates.
The recent NTP expert panel also reviewed a relatively new but unpublished, industry-sponsored marmoset study submitted by the American Chemistry Council's Phthalate Ester Panel. The NTP panel was unconvinced by the study authors' curious rationale for omitting from the data analysis some animals that apparently showed significant impacts from exposure. Subsequently, a reproductive biologist commissioned by the Phthalate Ester Panel to review that study and comment on the appropriateness of using marmosets as a relevant animal model was also unable to explain why those data were omitted from the analysis. He further commented on the study's poor design and execution{2}.
PVC/DEHP defenders also look for safe harbor in the lack of proof that DEHP harms humans. Human studies will require accurate DEHP exposure assessment in male fetuses and infants, followed by long-term follow- up as these children enter their reproductive years in order to find a potential relationship between early life exposures and later reproductive function. The prospects for such a study are slim, and the results would not be available for decades.
DEHP-free alternatives are readily available for nearly all uses in health care. Replacing DEHP with another plasticizer in a PVC device of course raises questions of the safety of the alternative. To be sure, other plasticizers must also undergo rigorous scrutiny and FDA approval. Some alternative polymers, however, such as polypropylene and polyethylene, among others, do not require plasticizer additives of any kind, and concern about their leaching is not an issue. A list of PVC-free medical devices, manufacturers, and alternative materials is available at http://www.noharm.org/us/pvcDehp/issue{3}.
Some major health care institutions are responding to the FDA's notification by phasing out PVC medical devices and seeking safer alternatives -- including Kaiser Permanente, the largest non-profit health care provider in the United States; Catholic Healthcare West, Miller Children's Hospital, Lucille Packard NICU at Stanford University, and many others. The largest group purchasing organizations in the health care industry have committed to support labeling of PVC and DEHP medical products and offer DEHP-free alternatives.
In the experience of clinical practitioners, DEHP-free alternatives have similar costs and are just as safe and effective. Valerie Briscoe, a neonatal clinical nurse specialist at John Muir Medical Center, a 550-bed hospital in Northern California with the busiest birth center in its county, was able to switch her hospital's NICU to safer non-DEHP medical devices within six months of FDA's public health notification.
"We found alternatives that were as adequate in providing therapy with no substantial cost impact to the hospital. This was a relatively easy process for me," Briscoe said. "I would say that 99 percent of the products have alternatives out there. I've been very successful in finding alternatives."
Catholic Healthcare West (CHW), the largest Catholic health-care system in the western United States, announced in November a five- year, $70 million contract to B. Braun Medical Inc. for PVC-free/DEHP- free intravenous bags, solutions and tubing.
"We have been actively advocating for PVC/DEHP-free supplies from our vendors since 1997. B. Braun has stepped up to the challenge as the first supplier with the capacity to deliver PVC- and DEHP-free supplies to all 40 of our hospitals," said Lloyd H. Dean, CHW president/chief executive officer, in a press release announcing the contract. CHW previously contracted with the nation's largest medical device manufacturer, Baxter International, which has yet to fulfill its 1999 promise to shareholders to develop a fully-expanded PVC-free product line.
Despite these promising developments, many hospitals across the country are unaware of concerns about DEHP and continue to use PVC medical devices, unnecessarily exposing vulnerable patients to high levels of DEHP. Given the weight of the evidence and the availability of safer alternatives, FDA's failure to require labeling of products containing DEHP and to move manufacturers toward safer product formulations is disturbing.
Because of widespread use of phthalates in a variety of consumer products and general environmental contamination, exposures are ubiquitous in the general population. Unfortunately, no regulatory agency looks at total exposures from all sources when making decisions. Phthalate-containing products are under the regulatory authority of the Environmental Protection Agency, which regulates industrial chemicals, the Consumer Product Safety Commission, and FDA. Even within FDA, which is responsible for food contaminants, pharmaceutical ingredients, medical devices, and cosmetics -- each of which may contain phthalates -- there is virtually no attempt to look at the bigger picture. The focus is generally on one source or one product at a time. When FDA's medical device division considers the safety of exposures to DEHP, it considers only medical devices and not the real world of population-wide exposures from the several million tons of phthalates released into the environment annually.
Even within this Balkanized regulatory system, however, justification for replacing of DEHP-containing medical products is sufficient. Despite that justification, FDA posted its "Public Health Notification: PVC devices containing the plasticizer DEHP" on its website with little publicity. The agency has yet to issue a guidance that would require labeling of DEHP-containing medical products and responsibly move the device-manufacturing sector toward a new generation of safer materials. As a result, even those health care providers who are aware of the concerns surrounding DEHP are often unable to identify potentially problematic devices in their inventory. Informed purchasing decisions require full disclosure of product contents.
We know enough to act. There is no longer any justification for hospitals to continue using PVC/DEHP devices where alternatives exist, particularly in vulnerable patients. Medical device manufacturers should provide PVC-free/DEHP-free devices that hospitals increasingly seek. And, FDA should use its authority to meet its public trust responsibility: require labeling of DEHP-containing PVC medical devices and move the medical device market to safer alternatives by requiring substitution where suitable alternatives exist.
Ted Schettler is the Science Director of the Science and Environmental Health Network{4}
Copyright Inside Washington Publishers
{1} http://www.fda.gov/cdrh/safety/dehp.html
{2} http://cerhr.niehs.nih.gov/chemicals/dehp/pubcomm/ACC%20Attach%201%20Schlatt%202-06.pdf
{3} http://www.noharm.org/us/pvcDehp/issue
{4} http://www.sehn.org