Paraquat and Parkinson's Disease: Response by Dr. Miller

When I wrote my editorial (Miller, 2007), I had hoped that the expression of my views on the subject would promote discussion and debate and am glad to see that this has occurred. My original concern was that there had been an overemphasis on studying paraquat with respect to Parkinson’s disease (PD) at the expense of other, possibly more important toxicants. More importantly though, was that much of the reason for what I perceived as overemphasis has been based upon ‘‘the structural similarity to 1-methyl-4-phenylpyridinium (MPPþ),’’ which I continue to view as a red herring. In their letter to the editor, Cory-Slectha and colleagues correctly note (point 1) that some of the differences between paraquat and MPPþ were pointed out over 20 years ago. Why then do scientists from around the world continue to cite the structural similarity between the two as the basis for investigation two decades later? This is precisely why I felt compelled to compose the editorial. As I stated in my editorial, I do not think studying paraquat has been a waste of time, rather it has improved our understanding of how oxidative stress can lead to dopamine neuron damage. I agree that I was not able to evaluate all of the pertinent literature within the confines of an editorial. I also agree that over the past several years, administration of paraquat has been able to consistently kill a subset of dopamine neurons (the preferential vulnerability of this subpopulation is especially intriguing). The authors also criticize me for not specifically citing the ability of paraquat to increase alpha-synuclein expression. Again, I stated that paraquat research has been useful and this is another example of this. The authors also countered my views on animal models of the disease. Although I have been critical of animal models of PD in the past, including those employed in my laboratory, I did not offer such critiques in the published editorial. Nor, did I imply any sort of gold standard. Perhaps the authors are referring to comments I have made in other forums, which are obviously extraneous to the discussion before us. Admittedly, within the constraints of an editorial, I was not able to expound upon my single comment regarding the combination of paraquat with other pesticides not bringing clarity to the field, nor can I give it proper justice here. It would have been best for me to not to include that statement in the editorial (points 3 and 4). I was also not able to address interactions with other risk factors of PD within the confines of an editorial. In response to the authors’ opinion that I failed to appreciate the complex etiology of the disease, I should state that I do have deep appreciation of the complexity of the disease and, indeed, this is one of my greatest concerns for the field. In order for us to construct a comprehensive model that drives the field forward, the building blocks that go into the complex architecture of such a model must be generated with care. I am reminded of the essay entitled Chaos in the Brickyard by Forscher (1963). In this story bricks, which were once made with care and planning, are manufactured at a faster rate than they can be incorporated into a useful edifice by builders. What was once an efficient system for making bricks (data) for the express purpose of building buildings (scientific theories), ended up with chaos in the brickyard, where the myriad of findings are piled upon each other making it impossible to find a suitable location to build or the proper bricks to construct a sound edifice. My concern is that, although our brickyard may not yet be in chaos, our building/theories regarding environmental factors in PD are being built with a disproportionate number of paraquat-based bricks, creating a precarious toxicological foundation. That is to say, important issues such as exposure assessment, bioavailability, environmental fate and transport are being neglected in favor of data generated from laboratory models that bypass many of these issues. In summary, the purpose of an editorial is to express an opinion. Had I been composing a scientific review of the role of pesticides in PD, I would have included a comprehensive analysis of the literature. However, I wrote the editorial to make a point about an erroneous basis for investigation, that is, the structural similarity between MPPþ and paraquat. Lastly, I must respectfully disagree with two of the authors’ closing points. The first is that the views expressed in my editorial were from a limited personal perspective. Although I composed the letter independently, over the past few years I have had numerous conversations with other academic investigators in the field that share many of my opinions. The second is that my editorial does not serve the scientific community well. I believe that expressing one’s views in a scientific forum is an important aspect to the scientific method and that being skeptical of research findings (including my own) is essential to science. A young scientist reading my editorial and the response by my esteemed colleagues gets a balanced glimpse inside the true