Response to ACC criticism of a study finding DEHP in medical devices increases likelihood of liver problems in premature infants

July 31, 2009 at 5:27 pm | Posted in Analysis | 2 Comments
It's not easy finding pictures to illustrate PVC-related posts. Image (c) Stefan gara

Image (c) Stefan Gara

Thanks to John Newby, PhD for substantial input.

Recently, the journal Pediatrics published a very important study finding an association between the use of PVC in total parenteral nutrition (TPN) infusion systems and an increased risk of developing a liver disorder, cholestasis.

The American Chemistry Council (ACC) was quick to respond to the study, questioning the validity of the conclusions on the grounds of confounding factors and the limitations of epidemiological studies.

At H&E we disagree with the ACC assessment on a number of points and believe it to be worthy of response because they are dismissing, on scientifically dubious grounds, a study which clearly identifies a risk factor which if eliminated could substantially improve patient welfare.

Previously, researchers have measured chemical exposures during medical treatment, and even determined the various risk factors relating to development of cholestasis (TPN featuring strongly here).

This study is a vital addition to the literature because it pinpoints the specific material used in the TPN infusion equipment (PVC containing DEHP) as an additional risk factor in cholestasis.

In their response to the study, the ACC argues that:

“the finding that ‘DEHP load caused by polyvinylchloride infusion systems for TPN constitutes an important factor in the occurrence of Cholestasis’ are not supported by the data.”

suggesting that:

“the study does not answer whether the development of Cholestasis in these seriously troubled infants was related to the presence of DEHP in the vinyl tubing, or to the more severe underlying conditions of the infants prior to initiation of TPN.”

The ACC also suggest that the study does not show any direct cause and effect, but rather includes a multitude of confounding factors.

In general we are unhappy with the response, but would like to highlight two important errors.

Firstly, since this was an epidemiological study the elucidation of a direct cause and effect is highly unlikely: no epidemiological study will provide evidence of a direct cause and effect.

Secondly, there is the issue of the so-called “confounding factors”. This is the most important error in the ACC critique, where they treat recognised additional risk factors as being on a par with confounding factors.

Cholestasis is very likely to be multifactorial in origin, rather than having just one cause. Therefore, a number of risk factors can contribute to development of the condition. The ACC argues that these risk factors are confounding factors which may bias the study and therefore invalidate the results.

This is incorrect: the authors of the study recognised the known risk factors for cholestasis and they assessed the strength of correlation for development of hepatobiliary dysfunction in the study, and put the results in Table 2. [article continues after table]

Risk factors for cholestasis. Click image to enlarge.

Risk factors for cholestasis. Click image to enlarge.

Each of the factors listed in the table increases the risk of developing cholestasis. TPN correlates with a p value of 0.04, surgical disease/intervention p <0.0001, and systemic inflammation p=0.0083.

The study finds that, on top of these existing risk factors, the use of PVC infusion systems is an additional risk factor, found to correlate with a p value of 0.0004. Risk factors such as surgical disease/intervention influence the outcome independent of DEHP-PVC, ergo it is plausible that DEHP-PVC tubing increases risk independent of other risk factors.

So, far from being “confounders”, these are additional risk factors which influence the health outcome independent of the use of PVC in the TPN equipment.

From a health perspective, this is why the study is so significant: cholestasis incidence in the PVC-free group in this study was 18% compared to 50% for the PVC group. The ACC’s swift rejection of the study is, at best, unhelpful in the ongoing effort to improve medical care.

Required reading for endocrinologists? Some key points from the Endocrine Society’s first Scientific Statement

July 23, 2009 at 8:21 am | Posted in Briefing | Leave a comment
Prostate cancer - one of many diseases linked to EDCs. Picture by National Institutes of Health.

Prostate cancer - one of many diseases linked to EDCs. Picture by National Institutes of Health.

Last month, the Endocrine Society published its first Scientific Statement on endocrine disrupting chemicals (EDCs). [Endocrine Reviews 30(4):293-342, Diamanti-Kandarakis E et al. – download here].

The importance of the Statement cannot be understated: this is a leading medical/scientific body publishing a definitive statement about what we know about the risks posed by EDCs and how best to limit and manage them.

Endocrine disruptors have been making the news recently, particularly in the form of the plastic packaging and food tin lining additive bisphenol-A (BPA), which interferes with oestrogen pathways in the body. There are, however, many other EDCs out there – unregulated, biologically active at extremely low concentrations, with unknown health consequences.

Some of the key points to understand about EDCs are outlined below. From the Society’s own summary of its report, the emphasis on complexity of EDC interactions in the body is very striking:

An endocrine-disrupting substance is a compound, either natural or synthetic, which through environmental or inappropriate developmental exposures alters the hormonal and homeostatic systems that enable the organism to communicate with and respond to its environment.

Issues key to understanding the mechanisms of action and consequences of exposure to endocrine disrupting chemicals include age at exposure, latency from exposure, the mixture of chemicals, dose-response dynamics, and long-term latent effects. [...]

The evidence for adverse reproductive outcomes (infertility, cancers, malformations) from exposure to endocrine disrupting chemicals is strong, and there is mounting evidence for effects on other endocrine systems, including thyroid, neuroendocrine, obesity and metabolism, and insulin and glucose homeostasis.

Michael Lerner, vice-chair of the Collaborative on Health and the Environment (CHE) and President of Commonweal, a health and environmental research institute, recently highlighted 13 points in the report which he considers of particular importance. Six of these are as follows (the full list is available on request):

Note: Michael highlighted the important sections via email to the CHE listservs. CHE is an excellent source of information and discussion. For more information about signing up, go here.

Chapter 3. Relevance to medicine. “The field of endocrine disruption has particular pertinence to endocrinologists…The properties of these substances are particulary well suited for study by endocrinologists.” (page 4)

Chapter 6. Impacts of EDCs on female reproduction. These include polycystic ovarian syndrome, aneuploidy, POF, reproductive tract anomalies, uterine fibroids, endometriosis, and ectopic gestation. A treasure-trove of the best science condensed into five pages (pages 8-13).

Chapter 8. Male reproductive and developmental health. The focus is on disrupted reproductive function, manifest as reduced semen quality and infertility, altered fetal development, including hypospadias and cryptorchidism, and testicular germ cell cancer. Pthalates, PCBs, dioxins, and pesticides are each discussed as they impact semen quality. (pages 16-19)

Chapter 9. Prostate cancer and benign prostatic hyperplasia. Pesticides, environmental estrogens including DES, BPA, PCBs, , UV filters in sunscreens, cadmium, arsenic, vinclozin, DDT/DDE, are each discussed, with a note box with recommendations for prostate cancer research. (pages 19-22)

Chapter 12. Environmental chemical, obesity and metabolism. A wide-ranging and important section which uses DES in rodent studies as a poster-child and illustrates non-linear dose/response curves for EDCs with an important cautionary section on phytoestrogens like genistein in soy. At low levels these inhibit lipogenesis but at high levels they promote it. (page 33)

Chapter 13. Recommendations for the future. The need to link basic research to clinical practice, EDCs and the public, the need for a robust program of prevention using the precautionary principle for guidance, a call to TES to lobby for regulation seeking to decrease human exposure to EDCs, and this final statement:

Our chemical policies at the local, state and national levels, as well as globally, need to be formulated, financed and implemented to ensure the best public health.

H&E maintains a news and science feed for endocrine disruptors, which you can view here at del.icio.us or monitor using this RSS feed.

Follow-up: More on how “weak” oestrogen BPA can act as a powerful endocrine disruptor

July 17, 2009 at 4:58 pm | Posted in Briefing | Leave a comment
John Peterson Myers

John Peterson Myers

Pete Myers, founder and CEO of Environmental Health Sciences and author of Our Stolen Future, helpfully pointed out a couple items (one from 2002) which follow the same line of thought we expressed in proposing a mechanism for how BPA can act as a powerful endocrine disruptor.

So in case you were wondering, the science isn’t that new. And OurStolenFuture.org is a great site – it isn’t exactly aesthetic, but there is a lot of great content. Over to Pete:

We’ve been covering this mechanism on OurStolenFuture.org and EnvironmentalHealthNews.org since 2002. Here is one example: BPA is not a weak estrogen.

What is of special interest is that the gene cascade which is initiated by phosphorylation of the transcription factor CREB, among other things, upregulates a gene central to converting stem cells into fat cells, and it also is involved in disregulation of insulin. Here’s where this work started.

The article in second link points out four key lessons from the CREB research from 2002 (it’s well worth noting this research is now seven years old, yet there is still very little action being taken to control public exposure to BPA, with most food safety bodies adament that low levels of the chemical pose no risk to health):

  1. It involves a new type of estrogen receptor, located on the surface of the cell membrane.
  2. It finds bisphenol A to be just as powerful as estradiol in binding with this new receptor.
  3. Binding and alteration of gene expression occurs at extremely low levels, low parts per billion, well within the range of bisphenol A [levels] found in people today.
  4. By activating the transcription factor CREB, bisphenol A has the potential of altering gene expression in several profoundly important systems that are vital for normal development and functioning.
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