Covering up a cause of polycythemia vera?

In my previous post about the federal Agency for Toxic Substances and Disease Registry's confirmation of clusters of polycythemia vera in Schuylkill, Luzerne and Carbon counties, I raised a number of questions I wanted to examine further. One was why the agency says in its report confirming the clusters that the "cause of PV is not known."

Of course, as the ATSDR itself acknowledges, scientists do know what environmental contaminants have been linked to an excess risk of PV: They are benzene and related hydrocarbons, formaldehyde and other solvents, petroleum refinery pollution, and radiation. Of course, saying a pollutant has been associated with a higher risk of a disease and saying it "causes" a disease are not the same thing. However, people living in the high-rate PV communities might want to avoid and mitigate those risky exposures as best they can. More on that to come.

But it turns out that scientists don't only know what's been associated with a higher risk of the cancer: They know of at least one type of pollutant that causes the genetic mutation associated with PV and similar blood disorders.

I'm no toxicologist -- just a reporter trying to understand what's happening to the environmental health of the Hometown area through people's stories and the public record. And the fact is, the public record on the local polycythemia vera problem to date does not offer a great deal of information about the toxicology of the disease. For example, the ATSDR's final findings do not once mention the word "toxicology" or "toxicologist," and no toxicologists made presentations during the two public meetings to discuss the study.

So I was surprised to receive via e-mail an anonymous tip recently about that very subject: the toxicology of PV. It opened by noting that most PV patients have a specific mutation that substitutes the amino acid phenylalanine for valine in position 617 of the JAK2 gene. The e-mail went on to explain that the DNA mutation that produces this amino acid substitution is a G->T transversion. It also said that this particular transversion is known to be associated with exposure to polycyclic aromatic hydrocarbons -- most notably the PAH benzo(a)pyrene. Formed during the burning of coal, oil, gas, garbage, and organic substances like tobacco or charbroiled meat, PAHs are a pollutant of concern with the fluidized bed combustion systems used in the waste-coal-burning power plants that are concentrated in the areas of Pennsylvania with unusually high PV rates.

But do PAHs actually cause PV? Let's break down the e-mailer's claims.

We'll start with the amino acid substitution typical of PV. An article titled "A Gain-of-Function Mutation of JAK2 in Myeloproliferative Disorders," which appeared in the April 28, 2005 issue of the New England Journal of Medicine, confirms that patients with PV "had a homozygous G->T transversion, causing phenylalanine to be substituted for valine at position 617 of JAK2 (V617F)."

We find the same information in a paper presented at last year's American Society of Clinical Oncology annual meeting, which reported that "the molecular pathogenesis of the myeloproliferative disorders (MPDs) polycythemia vera, essential thrombocythemia, and myelofibrosis with myeloid metaplasia has been strongly linked to an activating mutation of JAK2 (Janus Associated Kinase 2). A G-T transversion event in exon 14 that translates into a substitution of phenylalanine for valine at amino acid residue 617 leads to constitutive activation of JAK2V617F in a majority of these MPD cases."

So a G->T transversion is involved in PV. But do PAHs cause such a transversion? Let's turn to a report by Andreas Luch in the February 2005 issue of Nature Reviews Cancer titled "Nature and Nurture - Lessons From Chemical Carcinogenesis." On Page 121 of the article, Luch discusses the action of PAHs -- particularly benzo(a)pyrene (BP) -- on DNA, noting that it can "induce mutations, such as G->T transversions, during DNA replication."

Thus the e-mailer appears to be correct: PAHs -- and particularly benzo(a)pyrene -- cause G->T transversions, and G->T transversions cause PV. So it seems we can logically conclude that PAHs are a cause of PV.

Yet the ATSDR says the cause of PV is not known.

Why?


(Image of benzopyrene bonded to DNA by Zephyris)