Friday, January 16, 2009

Musings of an obsolete toxicologist: nanotoxicology is a whole new world

This morning while walking across town to the Lady Killigrew , a small hipster cafĂ© located just around the corner from home, I was thinking about a report I’d just begun to draft. The focus was how to evaluate the toxicity of nanoparticles. I was wondering if I’d been too strong in my dismal assessment of toxicology and had hoped that a good slap of cold air (the thermometer outside our kitchen window read -25C) would weed out the dramatic, and clarify the reality.

I’ve pasted some key points below, and while the topic and eventual report are confidential – there’s nothing confidential about the sentiment – I, and many others have been writing about it for a while:

1) The field of nanotoxicology is in its infancy, yet is ever expanding as newly created nanomaterials require assessment of potential health and environmental impacts. I’ve never before had the experience where I’ve considered research from 2006 as “old,” and where, the majority of literature cited is 2008 and 2009. Yet development of a new field within toxicology provides opportunity, and at the same time demands that toxicologists use both hindsight and foresight as they develop the methodology appropriate for these new materials.

2) Hindsight provides us with a glimpse of toxicology as a field, in large part, focused on application as a science catering to the need for rapid assessment and cost-effective regulation. Standardized toxicity testing methodology was developed and implemented as a result, quickly becoming a rigid set of test procedures, a good deal of which, over the years have become obsolete.

3) In part, because of the difficulties with changing test methodologies associated with a regulatory framework (check out the timeline for reproductive and developmental testing – “in development” for what, at least 10 years?) - standardized toxicity testing, useful for screening out the obvious is insufficient for detecting more subtle adverse effects or revealing the impacts of the complex mixtures of contaminants, drugs and naturally occurring chemicals to which we are all exposed.

4) We have an opportunity to consider the history of toxicology as we move forward. Many have expressed concern that “business as usual” may result in failure to adequately evaluate toxicity of nanomaterials. Oberdorster et al., (2005) representing the International Life Sciences Institute Research Foundation/Risk Science Institute (ILSI/RSI) writes “There is a strong likelihood that biological activity of nanoparticles will depend on physicochemical parameters not routinely considered in toxicity screening studies.” Additionally different physicochemical parameters may also affect behavior of particles in media typically used in preparing for traditional toxicity testing, the ability of researchers to adequately evaluate exposure concentrations, and particle behavior in the body. Problems only occasionally encountered in the past.

5) When it comes to some nanomaterials, such as quantum dots and functionalized particles we’re potentially dealing with multiple organic and inorganic materials that may, or may not, be released over a period of time. How do we assess that?

Well, as I wondered if I was getting a bit too dramatic, after grabbing a cup of decaf and ordering a breadboard with mustard I settled in and checked my emails. Bingo. There in the inbox was a link to Peter Montague’s recent article entitled "Can Chemicals be Regulated?" published in Rachel’s Democracy and Health News. Read it and weep.

Or, read it and be hopeful. I really do think that we’re at the proverbial crossroads. We’ve seen the consequences of becoming too rigid, of constrained linear thinking. But this is a new multitasking interconnected networked “wisdom of the masses” kind of world, not just for me and my Lady K compatriots (the majority of whom – to the dismay of the management - are more attentive to their electronics than to their stomachs) but also for those laboring away in research laboratories around the globe.

Maybe I need another slap of cold air, but if we can embrace this new fluidity in information, knowledge, and thinking, perhaps we can embrace a new way of not only evaluating health and environmental impacts of new chemical products, but a new way of using that information wisely.


7 comments:

Dori said...

Emily,

I don't know much about nanotechnology/toxicology/ or even science for that matter, but I think you have put your finger on it: we have reached the age of complex systems, and old linear paradigms will not work. It's a bit of freefall, but it seems to me that the best way that the toxicity of nano materials can be assessed, for now, would be through collaborative virtual teams of experts in the various fields involved. It may only amount to a "best guess," but that may be the best we can do. And there is always the precautionary principle available to us...

Anonymous said...

Emily, I think you have hit the nail on the head. In many ways engineered nanomaterials are the poster child for what is wrong with regulatory toxicology as it is practiced today. It is clear to me that the current battery of toxicity tests is not adequate to capture the more subtle, but critical endpoints, such as endocrine disruption and epigenetic modifications that can impact multiple generations. I have found recent National Research Council reports on tox testing to be fascinating as they are also articulating this need for a new strategy that focuses more on the perturbation of biological pathways.

The EPA ToxCast Program (www.epa.gov/ncct/toxcast) is piloting high throughput testing as an alternative to the animal-intensive regulatory tox test battery. By starting with chemicals that already have a robust set of standard tox tests, the results of the high throughput testing can be “validated”. What will be really interesting is what will happen when new effects or endpoints are uncovered by the high throughput testing. Will they be dismissed because they have not been previously described by the conventional tests? I think it will depend on whether the EPA is committed to finding new test methods that capture a broader array of biological perturbations – including endocrine disruption and epigenetic modifications – or if they are simply looking for a faster, cheaper alternative to conventional tests. Perhaps my biggest concern is that without a discussion on how these alternative tests should be interpreted we may be doomed to repeat the endless debates over relevance that we have seen with the standard tox tests.

It is here where I think the research that is being conducted in Chris Portier’s lab at NIEHS (http://www.niehs.nih.gov/news/newsletter/2008/february/pathway.cfm) provides some intriguing ideas. Going beyond the results of individual high throughput assays, these folks are looking at the context of the pathways, and how they may interact. By constructing rules for interpreting the results of high throughput testing, they are actually in a better position for advancing the dialogue on how to interpret the results of these alternative testing methods.

In my view the bottom line is that we need not only new test methods but we also need to talk about what the results might mean in terms of our new understanding of the role of endocrine and epigenetic changes that challenge traditional interpretations.

So getting back to the nano tox testing question – I think we need to dive in and start testing nanomaterials using the new high throughput screening methods. Will it answer all the questions that we need to know about nano risks? No – it won’t necessarily help us understand the fate and transport of nanomaterials in the environment, or exposure to and the movement of nanomaterials in the body. But it will help us understand intrinsic hazard, which we need to know no matter what. First, it will help us to identify materials that are intrinsically less hazardous (and thus advance green chemistry). Second, we need to know because it is so hard to predict exposure. In fact, it is the notable failures in exposure assessment that have led to massive distrust in risk assessment, which is predicated on the integration of hazard assessment with exposure. Yes, research is needed to understand exposure, but this should be done in parallel with toxicity testing.

There is also a reluctance to test “new” chemicals (nano or otherwise) using the alternative methods until we know how to interpret the alternative methods. But I think the interpretation process will be iterative – we will be learning as we go along, so testing “new” and “conventional” substances simultaneously can help us “learn” to interpret the results. If we limit the interpretation of alternative test methods to what we already know, we run the risk of missing or dismissing perturbations that don’t fit into our current understanding. Testing nano can help us challenge the status quo in toxicity testing and clearly this shake-up is needed.

Cal Baier-Anderson

Emily Monosson said...

Thanks for pointing me to Chris Portier's work at NIEHS.

Just today I came across an interesting commentary by Vicki Colvin and Kristin Kulenowski, published in volume 104 of PNAS (2007,) they were commenting on research by Linse et al., (2007 published in the same PNAS volume.)

Linse et al., had just reported that nanoparticles can catalyze protein fibrillation. Protein fibrillation may be involved in human protein folding-diseases such as Parkinson's, Alzheimers and others.

"Given the incredible variety of nanoparticle sizes, shapes, surface coatings, and compositions, it would be remarkable to find any biological response that is universal;
however, this is a possible conclusion from Linse et al. (1), and this generality has implications for science policy. The current practices for evaluating nanobiological interactions rely on a case-by-case
framework that assesses the effects of particular nanostructures in the context of specific exposure scenarios. Although this is the best response to regulatory issues at this time, the case-by-case approach is time-consuming and ultimately impractical given the many ways chemists can alter NP surface properties, size, and function.
If more fundamental and general trends can be identified and validated, then specific and simple tests for screening new
NPs will be enabled; such work will highlight size or composition thresholds, for which deeper scrutiny is warranted. Ultimately,
such fundamental science would
lead to predictive models that would aid government agencies in their oversight functions, create faster commercialization pathways for emerging nanomedicines, and guide researchers to produce safe NP systems at the very earliest stages of design.

Governments worldwide are just
starting to develop research strategies that have such goals in mind (25–27). It is tempting to overinterpret the fascinating
science of Linse et al. (1) given the dearth of information about NP biological interactions and the growing desire of consumers and policymakers to have better
information about NP risks. In such
a climate and through no fault of the researchers themselves, single studies can become focal points for public scrutiny and be given far more significance than is
warranted. The observation that NPs can catalyze fibrillation is important and should make all of us think harder about how best to use these new materials.

Kyle said...

This is fantastic. I am glad I have found your blog.

My name is Kyle and I am a student studying nanotechnology. I recently began to take an interest in nanotoxicology when it became dreadfully apparent that the “functional side” of nano-structure engineering is related directly to the toxicological side of nano-structures. In fact, it became painfully apparent that to functionalized any particle for either chemical or physical properties always implied an attention towards that structure's interaction with the conditions of an ever shrinking environment. As we have gone deeper into the realm of nano to design our functions we have been struck with the vast complexity of interactions at this level. We are in essence standing within a vast hall that we can see no end to, and that hall contains many details of how matter behaves together, at the nano scale of course!

Regardless, we can agree that there are many possible nanostructures and that there are many possible chemical and physical properties at the nanoscale. But the question is, how do we get our throughput high enough to deal with studying with practical efficiency all of the new systems and structures we are observing and creating? You mention that the game needs to change, that we can no longer keep business as usual and expect to get meaningful and useful understanding of what we are discovering.
At the end you are left wondering if a blast of cold air will help bring more understanding to the problem... How do we study toxic effects of nanostructures?

The key is to realize that understanding the toxic effects of nanostructures is akin, if not identical, to the knowledge of pragmatic use of nanostructures. This might sound a bit absurd if we look from the old paradigm, for there are many effects which nanostructures could have upon biological life that would not lead directly to significant effects, but we need to consider systems on a smaller scale, if only to increase understanding. We cant look at large systems only for studying the toxic effects, we need to look at much smaller systems that might not produce the significant effects on the larger.

If we think, like you have been, of the instruments and procedures which might lead to an efficient standardized way of studying these effects we are met with some difficulties in imagining a cost effective and efficient model. However I feel that we might have some success in using current trends in micro and nanotechnology to create systems to study the effects of nanostructures. We need to design new tools to study these effects, and I think the best route is to make inventory of what we already have that is useful, and to consider some possible “near future” devices which could utilize nanotechnology and microtechnology in the name of beefing up efficiency and decreasing cost, as well as increasing versatility... for that is where the main blockage is right now.

As a blind step towards experimentation I have been constructing an at home lab to study the toxic effects of various nanoparticles upon plants. I have only just begun to research the literature on this topic and have only designed and built the preliminaries of my lab. I do not yet have any designed experiment although the general idea is that I will first study algae with very simple nanoparticle inoculations into the culture.

Emily Monosson said...

Hi Kyle, thank you for your thoughtful and insightful comments. I have been thinking a lot about the evolution of the toxic response in general these days. And your comment relates to that (I think.)

We've evolved to live with chemicals - but clearly there are times when our ability to respond is either overwhelmed or is exposed to a novel chemical or in this case a novel structure which may or may not be handled appropriately by living systems.

I think there is something in the paragraphs of yours that I've excerpted below -- only I'm not sure what! But it certainly makes me think a bit differently. So thanks again for your comments!

" As we have gone deeper into the realm of nano to design our functions we have been struck with the vast complexity of interactions at this level. We are in essence standing within a vast hall that we can see no end to, and that hall contains many details of how matter behaves together, at the nano scale of course! ......The key is to realize that understanding the toxic effects of nanostructures is akin, if not identical, to the knowledge of pragmatic use of nanostructures. This might sound a bit absurd if we look from the old paradigm, for there are many effects which nanostructures could have upon biological life that would not lead directly to significant effects, but we need to consider systems on a smaller scale, if only to increase understanding. We cant look at large systems only for studying the toxic effects, we need to look at much smaller systems that might not produce the significant effects on the larger."

Kyle said...

Emily,

Thank you for your response. Are you already familiar with literature concerning submonolayer measurements of adsorbed proteins in micro and nano fluidic channels?

Emily Monosson said...

Hi Kyle, sorry for the delay - there's been a lot of spam comments.

No I'm not familiar with that literature.

Since I tend to work project by project - and don't have any nano right now...I haven't really been keeping up with it.