Friday, April 15, 2005

Trouble in the House of Plastic

Fred vom Saal is a highly respected scientist at the University of Missouri. If he suffers any lack of respect it is in the House of Plastic. In the House of Science he's in good shape. So I take with a grain of, well, plastic, the fact that the Family of the House of Plastic is upset with his new paper, just published in Environmental Health Perspectives.

The paper reviews a large body of recent literature on low dose effects of a ubiquitous environmental chemical almost all of us carry around in our bodies. It has attracted media attention because he and his co-author, Claude Hughes, show quite clearly there is an iron-clad relationship between funding source and outcome of a particular body of literature. As striking as this is, there is much more of significance in this wide-ranging review, and I shall try to highlight a bit of it. For those interested, it is freely available on-line at EHP.

A bit of background. In 1997 vom Saal sounded the alarm about very low doses of estrogenic chemicals, including a chemical used to make plastics, bisphenol A (BPA). BPA monomer units are strung together to make polycarbonate plastic, a resin lining most food and beverage cans and the substance of certain types of plastic beverage bottles, including the popular tinted bottles used by joggers, outdoor enthusiasts and many others. It also appears as an additive in many other products and is produced in huge quantities worldwide (6.4 billion pound capacity and growth of over 6%/year). The ester linkages between the monomer units are relatively weak, however, and the heat of sterilizing cans or acid or basic foodstuffs can hydrolyze the linkages, breaking the chains apart and releasing BPA. Ninety-five percent of urine samples in a recent CDC population survey had measurable levels of BPA. Thus the thought that extremely low doses of this chemical could be a problem immediately raised the ire of the 15 companies that make or use BPA and their trade association (the American Plastics Council).

The low doses we are talking about are indeed low, so low that some people don't find it credible they could be harmful. In fact it is biologically quite plausible. Consider the developing fetus or a fetal organ like the central nervous system. The process of growth and development is extremely intricate and requires precise coordination between some cells that grow, others that don't and still others that commit suicide (programmed cell death or apoptosis). Remodeling an organ is an example where some cells die while others preferentially grow. Growth and development is like a delicate dance where the different tissues act and respond in specific ways and in a specific order. Even doing the same thing but in the wrong order can be a recipe for failure, like putting on your shoes first and your socks second.

For growth, development and many essential physiologic processes cells and tissues need a way to communicate. The two main signaling systems are electrical (the nervous system) and chemical (the endocrine or exocrine systems). The endocrine system involves secreting minute amounts of a signaling chemical (a hormone) which travels through the blood and interacts with a target tissue via receptors on the target tissue cell. The signalling hormones are active at extremely low doses, doses so low that it was only in recent decades that technology was available to measure them.

One of the main concerns about endocrine disrupting chemicals is that they are like noise or static disrupting this essential communication process. Consider sitting in a crowded bar, trying to say something important to a companion while crowd noise, a blaring TV and a band play close by. As we all know, the sea of noise makes communication difficult and error prone. The same thing happens when we are bathed in a sea of endocrine-like chemicals, a kind of hormonal noise. BPA is a large contributor to that noise.

In their paper vom Saal and Hughes review 115 published studies of BPA and report that 94 show biologically significant effects at low doses. The "source of funding" finding regarding these papers is the most quoted, so we'll do it too:
As of the end of 2004 we are aware of 21 studies reporting only negative results with low doses of BPA. Source of funding is highly correlated with positive or negative findings in published articles. For government-funded published studies, 94/104 (90%) report positive effects at doses of BPA below 50 mg/kg/day. No industry-funded studies (0/11 or 0%) report positive effects at these same doses.
The authors also analyze several of the industry studies, convincingly showing how the work was flawed. At the same time, they are highly critical of the use of conventional toxicological methods for endocrine-disruptor risk assessments:
The implications of these results extend beyond BPA, because they may lead to requirements that hazard assessments be designed to detect analogous low-dose impacts of other chemicals. Acknowledgement of the existence of the large number of studies showing unique low-dose effects of BPA could lead to the demand that in designing studies to assess the hazards of all chemicals for risk assessment purposes, a wider range of doses must be examined, as opposed to only a few very high doses based on the maximum tolerated dose. This would require accepting that extrapolation from data on effects at very high doses (based on the linear-threshold model) is not valid for endocrine disrupting chemicals.
They conclude a new risk assessment for BPA is overdue, based on:
1. The extensive new literature reporting adverse effects in animals at doses below the current reference dose,

2. The high rate of leaching of BPA from food and beverage containers, leading to widespread human exposure,

3. Reports that the median BPA level in human blood and tissues, including in human fetal blood, is higher than the level that causes adverse effects in mice, and

4. Recent epidemiological evidence [a case-control study of polycystic ovary in Japan] that BPA is related to disease in women.
Ironically, while the industry has been training their fire on vom Saal, the scientific community has been busy finding new and additional mechanisms of BPA biological action at extremely low dose (see, for example, Wozniak et al. in this month's EHP where effects on Ca+2 flux and prolactin release are demonstrated at pico- and nanomolar concentrations).

The paper by vom Saal and Hughes may represent a watershed in the scientific approach to endocrine disrupting chemicals. It is powerful and persuasive reading.