Monday, October 15, 2007

Polycarbonate plastics: if only toxicology could be that clear

An ongoing debate about the health impacts of bisphenol A (BPA), the ubiquitous chemical used in production of polycarbonate - that hard clear plastic we use for eating, drinking, and storing food – continues, according to a recent article by Janet Raloff published in the September 29 issue of Science News. Her analysis provides good insight into why we often hear conflicting reports when it comes to environmental and health impacts of chemicals.

Raloff reports on the conflicting results of two different panels recruited by the National Toxicology Program (NTP) and charged with reviewing and evaluating the potential developmental and reproductive impacts of BPA. While one panel “labeled ‘as confident’ its assessment that BPA at low doses has had negative effects on experimental animals,” and that such findings were suggestive of impacts in humans, the other panel “concluded that current BPA exposures appear to pose little risk to humans.”

According to Raloff, one of the differences cited in this analysis, leading to conclusions ranging from don’t use the stuff if you don’t have to, to it’s a non-issue, were concerns about the basic experimental design used by scientists evaluating BPA. When laboratory animals are exposed to experimental chemicals there is often a trade-off between ensuring exposure to the chemical, verses exposing the animal in a realistic manner. Way back when, when I was interested in the effects of PCBs in fish populations, I’d load up syringe and inject. Now unless fish were mainlining PCBs (and concentrations in some wild fish were certainly suggestive of that!) clearly this wasn’t realistic. But, what it did provide us with was an exposure where we were sure that PCBs got to where we wanted them to go. Confident of our exposures (we’d also do some chemical analysis – which was the most costly part of the study back then, and so something toxicologists would like to avoid if at all possible), we could more efficiently get down to our intended business, evaluating the effects. Our option would have been to develop food with amounts of PCBs that fish would eat in amounts that we could somehow measure (you ever watch fish eat? Biting off pieces of food, letting the rest drift to the bottom, possibly snatched up by less aggressive fishes), that wouldn’t leave us with gallons of toxic water to cleanse in the end. The fact is there are often good reasons to use the needle, although as pointed out by the panels, there are limitations to these kinds of unrealistic exposures, one of them is interpreting experimental results to a broader range of more realistic exposure scenarios.

Raloff outlines other differences in the panels, for example, she writes that the panel which concluded impacts are likely, had either worked with the chemical or similar chemicals, while the panel that came to nearly an opposite conclusion “were selected precisely because they had no direct BPA experience and, therefore, no obvious vested interest in judging the quality of the data on the chemical.” Fair enough, I suppose. You’d hope scientists can see past their own interests, although I’ve always thought it’d be interesting to see a study correlating the evaluation of experimental data with sustained funding for a particular subject over a period of time.

For more details on the subject, the article is available on the Science News site, and, according to Raloff, “ultimately, NTP will issue a single report that integrates conclusions from both panels, along with any new information on BPA that comes to light during the next few months.” Now that ought to be an interesting read.

Wednesday, October 10, 2007

Bodily defense: detoxification update

Years ago as a budding toxicologist I studied a fascinating system called cytochrome P450, so called because under certain conditions one could measure a peak at the light wavelengths of 450nm. What was so fascinating was that it was, at the time, one of the few recognized detoxification systems. That is, this system, which consists of various proteins, could metabolize certain toxic chemicals and send them on their way out of the body. Now almost two decades later a recent paper, published in Developmental Biology by Goldstone and others, presents the “chemical defensome,” described as an “integrated network of genes and pathways that allow an organism to mount an orchestrated defense against toxic chemicals.” Though it sounds like something that belongs on a football field, it’s a little more highly evolved than that.

Back in the simple days, before scientists had the capability to identify each and every gene in our bodies, toxicology students studied the fate of fairly simple chemicals like polyaromatic hydrocarbons – those ubiquitous chemicals found in combustion products from the tip of a cigarette to the tip of your tailpipe – chemicals that basically sealed their doom by activating the system responsible for their own destruction. You see this particular detoxification system required activation or binding to a receptor, sort of the old lock and key - now an obsolete analogy but still good enough to get the basic idea across. A chemical binds to a receptor, and opens the door for specific proteins to be produced, in this case specific cytochrome P450 enzymes, which then go to work metabolizing the chemical sending it on its way to eventual detoxification.

Learning the story of P450 and polyaromatic chemicals was a must for nascent toxicologists. That was back in the old days, before the cigarette industry acknowledged the connection between inhaling a lungful of chemicals and cancer, but even back then we all knew that once some of those chemicals entered the lungs, little PAH keys entered PAH locks, or what we called aryl hydrocarbon receptors, activating genes necessary for P450 induction all around the body, in lung cells, liver cells, and kidney cells. We also knew that this process presented the proverbial “double-edged sword.” That is, detoxification of some chemicals, particularly PAHs, required several steps – some of them resulting in activation of a chemical to a more toxic or reactive state – before eventual detoxification and finally excretion. And, in the case of PAH, activation meant that the reactive PAH could bind to genetic material in way that could promote formation of cancerous tumors. We also knew there was a genetic component - even if we didn't know much about the genetics of the system. We knew then that the detoxification pathway proceeded differently and to different extents in some folks compared with others.

But at that time we were aware of just a few kinds of P450 enzymes, and, we had no idea of the breadth of the detoxification system, or the basic genetics of a system we now know we share with creatures ranging from tunicates, our slimy cousins that still cling to rocks by the seashore, to the pesky fruit flies that zip around the bruised fruit in my kitchen.

It made sense though, that given the harsh earthly conditions in which they evolved, our ancestors would need to protect themselves from constant chemical assault. But even so, back then, toxicologists wondered if receptors like the aryl hydrocarbon or PAH receptor evolved as a defense mechanism, or if its role in detoxification of foreign chemicals was a surreptitious side effect. Maybe, the system had evolved to deal with what are called endogenous chemicals, a way to get rid of the body’s own powerful chemicals once they no longer serve their purpose, like steroids for example (which, at least in my teen seems toxic enough, though to be fair, without them we’d probably still be clinging to rocks in some tide pool alongside our tunicate cousins.)

Now, a decade and a half later, scientists have unveiled a diverse and sprawling system of detoxification, or defense mechanisms from a plethora of P450 enzymes to antioxidants responsible for quenching the highly reactive oxygen produced by many metabolic processes protecting us from a range of potentially deadly chemicals, including microbial and plant toxins, PAHs and heavy metals.

In a paper that goes into genetic detail way beyond what my tunicate brain can comprehend, J.V. Goldstone and others introduce these systems collectively as a “defensome,” a fascinating concept of protective mechanisms that we humans take for granted, as we challenge our bodies with ever more complex combinations of naturally occurring and manmade chemicals. Let's just hope that unlike the typical Superbowl blowouts, we won't suffer a similar defensome overload, leaving us at the mercy of our natural and unnatural environment.

All the genetic details (and a hint to the youthful secrets of elderly sea urchins) can be found in Goldstone, J.V. et al. “The chemical defensome: Environmental sensing and response genes in the Strongylocentrotus purpuratus genome,” Developmental Biology 300:366-384.

Monday, October 01, 2007

The fire-retardants, they are a’changing

Say goodbye to PBDEs (well... at least in some states, in some products in the near future.)

There’s one of those rare heartening reports just published in the this week's online News section of Environmental Science and Technology, Formulating Environmental Friendly Flame Retardants. It’s good to hear every once in a while that industrial processes can change, even if not completely voluntary, particularly when it comes to chemicals that we know are a problem.

Take for example, the polybrominated Diphenyl Ethers (PBDEs) that are commonly used as flame retardants when added to plastics including computer plastics, furniture plastics (polyurethane is highly flammable), plastic plastics, and other plastics. PBDE’s are just about every where now, from my neighbor’s breast milk here in Western Mass to big momma polar bear’s milk in Alaska, to overly thin, hyperactive, perpetually hungry hyperthyroid house cats.

According to ES&T, in response to legislative pressures (certain PBDEs have already been discontinued, others are now banned in a few states), and pressure from consumers and plastics' producers, “The industry is responding with new approaches for making flame retardants, and some design teams are actively adopting the tenets of green chemistry. In the long run, the work now under way could result in the development of materials that are inherently resistant to fire.”

As industry moves away from halogenated flame retardants ( chemicals like bromine, fluorine and chlorine) a positive move, and turns instead to phosphorus-based flame retardants, metal hydroxide flame retardants, and nanoclay flame retardants, let’s just hope there’s enough foresight, oversight and whatever else, such that the use and development of these new products won’t bypass careful environmental and health evaluation. Otherwise we might end up in another twenty or thirty years wondering why Isidora the house cat, after spending her life lounging around on the carpet, the new couch, or the new bed (the slim high def television will no longer be an option) isn't acting quite right.

UPDATE: A letter in the October 12 2007 issue of Science by biophysical chemist Arlene Blum addresses "The Fire Retardant Dilemma." While pointing out that replacements for pentabrominated fire-retardants may be no safer than the chemicals they replace, Blum calls for the United States to follow the example set by the Europeans. Writes Blum, "New European regualtions for the Registration, Evaluation, and Authorization of Chemicals (REACH) require industry to provide data to establish the safety of new and existing chemicals. The United States should follow suit." Adding that "Fire-retardant chemicals in our homes should not pose a greater hazard to our health and environment than the risk of the fires they are supposed to prevent."

Well said.