The chemical bisphenol A, commonly found in many plastic household items, has been linked to yet another health problem in animals—an increased frequency of arrhythmias, or , a new study found. The results, seen only in females, will be presented Saturday at The Endocrine Society’s 91st Annual Meeting in Washington, D.C.

Past animal studies show that bisphenol A, or BPA, can have harmful effects on the reproductive, nervous and immune systems. Also, a study in humans reported last year found an increased prevalence of cardiovascular disease in people with high levels of BPA in the urine.

However, the effects of BPA on the heart are unknown, said study co-author Scott Belcher, PhD, associate professor in the University of Cincinnati’s Department of Pharmacology and Cell Biophysics.

In the new study, funded by the National Institutes of Health, the University of Cincinnati researchers found that low-dose BPA and estrogen can act alone or in combination to increase harmful arrhythmias in female rats and mice. Because BPA has properties similar to the main female hormone estrogen, it is considered an “environmental estrogen.”

Mice and rats in the study had normal heart rhythms at baseline, before administration of BPA or estrogen (estradiol), Belcher said. The investigators studied heart rhythms in both the working heart and in cultured heart muscle cells. In both models, exposure to BPA increased the frequency of arrhythmias, compared to baseline, in females but not in male animals, the authors found. Administration of estrogen alone also increased the frequency of arrhythmias in females.

Arrhythmias were most frequent in the female rats and mice when they received both BPA and estrogen, at levels normally found in female humans.

“We have identified a new possible risk for female heart health, caused by increased levels of estrogens in the body and exposure to the environmental estrogen BPA,” Belcher said.

BPA is found in polycarbonate-plastic baby bottles, refillable water bottles and food containers as well as the linings of metal food cans. Last year the U.S. Food and Drug Administration said more research on the safety of BPA is needed.

Arrhythmias occur when the heart beats too slowly or too fast or when it skips heartbeats. These heart rhythm irregularities can cause fatigue, lightheadedness, fainting or sudden cardiac death. If a fast heart rate affects the heart’s ability to pump, it can cause a heart attack.

The study’s lead author, Hong-Sheng Wang, PhD, assistant professor at the University of Cincinnati, will present the results.

Reference: The Endocrine Society, Bisphenol A exposure increases risk of abnormal heart rhythms in female rodents, 10-Jun-2009

People are likely being exposed to the commonly used chemical bisphenol A (BPA) at levels much higher than the recommended safe daily dose, according to a new study in monkeys. The results will be presented Thursday at The Endocrine Society’s 91st Annual Meeting in Washington, D.C.

“BPA is now known to be a potent estrogen,” said Frederick vom Saal, PhD, a co-author of the new study and a professor of biological sciences at the University of Missouri-Columbia. “Human and animal studies indicate it could be related to diabetes, heart disease, liver abnormalities, miscarriage and other reproductive abnormalities, as well as prostate and breast cancer.”

The U.S. Food and Drug Administration (FDA) declared BPA is safe based on estimates that people consume only small amounts each day from food. However, recent research indicated that U.S. adults are exposed to more BPA from multiple sources than previously thought, vom Saal said.

BPA is found in polycarbonate plastic food and beverage containers, such as water and infant bottles, as well as in the epoxy resin lining of cans and other sources. The chemical can leach into food and beverages, according to the National Institutes of Health, which funded the study by vom Saal and colleagues.

“Between 8 and 9 billion pounds of BPA are used in products every year,” vom Saal said.

In their study, he and his colleagues fed five female adult monkeys an oral dose of BPA (400 micrograms per kilogram of body weight). This amount is more than 400 times higher than the amount that the U.S. Food and Drug Administration (FDA) estimates that human adults are exposed to and 8 times higher than the estimated safe daily amount to consume, according to vom Saal.

Yet the blood levels of biologically active BPA over the next 24 hours were lower in the monkeys than the average levels found in people in the United States and other developed countries, vom Saal said. For levels to be higher in people when measured, their exposure dose must be greater than that given to the monkeys, he explained.

“These results suggest that the average person is likely exposed to a daily dose of BPA that far exceeds the current estimated safe daily intake dose,” vom Saal said.

He said that BPA exposure must come from many unknown sources, in addition to food and beverage containers. Like drugs, BPA acts in pulses, with each exposure creating a high-level pulse before it is cleared in the urine, according to vom Saal.

The researchers are continuing the study in more monkeys, but vom Saal said they do not expect to get different findings because the data in the first five animals were “very consistent.” The species of monkey that they used (rhesus) metabolizes BPA similar to humans, he added.

Reference: The Endocrine Society, Our exposure to controversial chemical may be greater than dose considered safe, 10-Jun-2009

Patients with curable early-stage breast cancer died from chemotherapy solvent
A chemotherapy drug that is supposed to help save cancer patients’ lives, instead resulted in life-threatening and sometimes fatal allergic reactions.

A new study from the Research on Adverse Drug Events and Reports (RADAR) pharmacovigilance program at Northwestern University Feinberg School of Medicine identified 287 unique cases of hypersensitivity reactions submitted to the FDA’s Adverse Event Report System between 1997 and 2007 with 109 (38 percent) deaths in patients who received Cremophor-based paclitaxel, a solvent-administered taxane chemotherapy.

Adverse event reports generally only represent from 1 to 10 percent of actual incidence, so the number of hypersensitivity reactions and deaths is likely significantly higher. The severe allergic reactions are believed to be caused by Cremophor, the chemical solvent – a derivative of castor oil — that is used to dissolve some insoluble drugs before they can be injected into the blood stream.

Two patients who died from an allergic reaction had early-stage breast cancer, which had been surgically removed, and were being treated with Cremophor-containing paclitaxel to prevent the cancer from coming back. Both of these patients had received medications before the chemotherapy to reduce the risk of hypersensitivity reactions.

The study was led by Charles Bennett, M.D., RADAR program coordinator and a professor of hematology/oncology at Northwestern’s Feinberg School, and Dennis Raisch, a professor of pharmacy at the University of New Mexico.

“The deaths of women with early-stage breast cancer are particularly disturbing because without the adverse reaction, they could have likely had 40 years of life ahead of them,” Bennett said.

RADAR investigators also found that 22 percent of all fatalities occurred in patients despite patients having received premedication to prevent hypersensitivity reactions, while another 15 percent of such patients experienced life-threatening respiratory arrest.

The report was presented at the 45th Annual Meeting of the American Society of Clinical Oncology held recently in Orlando, Fla.

Cremophor-containing paclitaxel has been associated with hypersensitivity reactions, with responses ranging from mild skin conditions to more severe effects, including anaphylaxis and cardiac collapse. Current U.S. product labeling for Cremophor containing paclitaxel includes a black-box warning alerting physicians and patients of potential toxicity and recommending the use of corticosteroids and other medications before chemotherapy administration to reduce the risk of hypersensitivity reactions.

“The results of our review suggest that physicians should be vigilant in monitoring the safety of their patients undergoing chemotherapy treatment,” said Bennett, who also is the A.C. Buehler Professor in Economics and Aging at the Feinberg School and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

“Patients receiving Cremophor-based paclitaxel should be given medications to prevent hypersensitivity reactions, but what is sobering, as the study has shown and as the black-box warning indicates, women suffer anaphylaxis despite receiving steroid premedication,” Bennett said. “Physicians should be diligent in reporting adverse events to regulatory agencies to better monitor the impact of Cremophor on patient safety. Physicians may also want to consider exploring other alternative chemotherapy options that do not include Cremophor.”

In addition to the two women with early-stage breast cancer who died after treatment with the Cremophor-based paclitaxel, four other women with early-stage breast cancer experienced life-threatening anaphylaxis reactions. Each of them had received prior medications to prevent the reactions.

“The fatal outcomes observed in patients with early-stage breast cancer were particularly striking as this is a patient population with a good prognosis that is generally treated with curative intent,” said Raisch.

For the report, Bennett and Raisch reviewed adverse event reports submitted to regulatory agencies in the U.S., Europe and Japan. The most common cancer diagnosis for these patients with allergic reactions was lung cancer followed by breast cancer and ovarian cancer.

Reference: Northwestern University, Common chemotherapy drug triggers fatal allergic reactions, Press Release, 8-Jun-2009

Letter from Martin L. Pall, Saturday 6th June 2009:

I was delighted when I was asked by the three editors of the future publication, “General and Applied Toxicology, 3rd Edition” (John Wiley and Sons) to write a review on multiple chemical sensitivity (MCS) for this prestigious multivolume set. MCS, as I am sure you know, has been largely ignored by toxicologists in general and I was delighted that these three prominent scientists, all of whom had extensive published research on the actions of chemicals implicated in MCS, asked me to write such an article. This was important recognition not only for my own work on MCS but also that MCS is now recognized as a toxicological phenomenon.

The paper, entitled Multiple Chemical Sensitivity: Toxicological Questions and Mechanisms is the most extensively documented publication on MCS, and will be a 54 page chapter in this multivolume set. While the majority of this paper comes from my earlier publications on MCS, it also contains several very important sections that are largely novel.

1. There are seven classes of chemicals implicated in MCS and all seven of these can indirectly produce a common response in the body, increased NMDA activity. Furthermore, animal studies have shown that members of all seven of these classes of chemicals can have their toxic responses lowered by using an NMDA antagonist. This clearly demonstrates not only that they produce such increased NMDA activity but those increases play an important role in producing the toxic responses to these chemicals. Given that we previously had six types of evidence implicating excessive NMDA activity in MCS, we now have compelling evidence that this common response plays a key role in MCS.

2. The role of these chemicals acting as toxicants in MCS has been confirmed by four genetic studies, showing that genes that determine the rate of metabolism of these chemicals, influence susceptibility to MCS (only three were available when the review was written). These studies implicate six genes as determining such susceptibility, all of which have roles in the metabolism of chemicals otherwise implicated in initiating cases of MCS. It follows that the roles of chemicals in initiating cases of MCS is undeniable.

3. There have been a series of published studies reporting objectively measurable responses to low level chemical exposure among MCS cases that are distinct from any responses in normals. At least three of these should be practical specific biomarker tests that can be applied in clinical settings. All of these studies are consistent with the NO/ONOO- cycle mechanism as it is thought to play out in MCS and all provide, therefore, evidence supporting this mechanism. We have been in great need for such specific biomarker tests for MCS and these and other approaches to developing such tests must be further studied and may provide recognized specific biomarker tests in the near future, in my judgment.

4. All except one of the elements of the NO/ONOO- cycle as it is thought to play out in MCS have been studied in animal models and all elements studied are implicated in these animal models. It follows that one can make a strong case for a NO/ONOO- cycle mechanism based on animal model studies alone.

5. The paper finishes with a list of five areas of future research which are in most need of further study, in my judgment.

We do have observational evidence that a protocol based on down-regulating the NO/ONOO- cycle mechanism is helpful in the treatment of most cases of MCS as well as most cases of ME/CFS and most cases of fibromyalgia. However, at this point this treatment fails to produce any substantial number of cures and seems to be quite variable in the extent of improvements apparently produced by it. Nevertheless, this approach does produce substantial apparent improvements in many people who have been ill for one, two or more decades. It is my hope that we will be able to add a second phase to such treatment that may start to produce at least some such cures, but that is a hope at this point.

Autor: Martin L. Pall, Professor Emeritus of Biochemistry and  Basic Medical Sciences, Saturday 6th June 2009

(Letter reprinted by CSN with personal permission)

To determine which topical pharmaceutical products marketed in Belgium contain fragrances and to examine the nature of the fragrance allergens in specific pharmaceutical products having caused iatrogenic contact dermatitis.  

All topical pharmaceutical products marketed in Belgium, which is 3820 products, were examined as to their fragrance content as labelled. Data of 18, 960 patients investigated for contact allergy between 1978 and 2008 were retrieved from our database, including information on the nature of the topical pharmaceutical products used, the results of patch tests, and the sensitization sources.  

Three hundred and seventy (10%) of 3280 of the topical pharmaceutical products were found to contain a total of 66 fragrance substances. Among 3378 patients suffering from iatrogenic allergic contact dermatitis, 127 were found to react to 48 specific products, for which 38 different fragrance substances gave relevant positive reactions. Women were more affected than men, and legs, hands, and face were the most commonly affected body sites.  

Fragrances, the presence of which is in most cases unnecessary, do contribute to iatrogenic allergic contact dermatitis. Moreover, sensitized patients have difficulties in avoiding their specific allergens because standardized labelling of the ingredients in pharmaceutical products is lacking. 

Reference: Nardelli A, D’Hooghe E, Drieghe J, Dooms M, Goossens A., Allergic contact dermatitis from fragrance components in specific topical pharmaceutical products in Belgium, Department of Dermatology, University Hospital, Katholieke Universiteit Leuven, Leuven, Belgium, Contact Dermatitis. 2009 Jun; 60(6):303-13.