J.C. McElveen, of Jones Day, wrote the following guest post, for which we thank him. As is always true of guest posts, the two of us had nothing to do with what follows; JC gets all the credit. (We alone, however, are to blame for not knowing how to create subscripts in blog posts. JC properly wrote the chemical name “V205” using subscripts for the numbers, and we’re just too ignorant to create that format here.):

The other day, as I was perusing (as I’m sure many of you do) “Environmental Health Perspectives,” “the peer-reviewed journal” of the National Institute of Environmental Health Sciences, I came across an article by Ehrlich, et al. titled “Inhalative Exposure to Vanadium Pentoxide Causes DNA Damage in Workers.” Environmental Health Perspectives; 116(12):1689-1693 (December 2008). Now, vanadium pentoxide (V205) is not one of those compounds that leaps trippingly off the tongue, but with a title like that, it was an almost irresistible read.

The study looked at peripheral white blood cells from vanadium production workers and controls and tested for several DNA damage endpoints: Micronuclei (MN), nucleoplasmic bridges (NPB), nuclear buds (Nbuds), oxidized purines and pyrimidines (oxidized bases), and some others. The concluding paragraph of the article then made the following statement:

Overall, our results show that inhalative exposure to V205 increases the levels of oxidized bases and of MN, NPB and Nbud frequencies in blood cells and affects their DNA repair capacity . . . . Because the aforementioned parameters are causally related to diseases including cancer, our findings strongly suggest that more protective measures and periodical monitoring of the workers are required. p.1692

I must admit that this is the first reference I have seen that says that these particular genetic changes are “causally related” to cancer, and my first reaction was “where is the footnote?” (I won’t talk about other diseases because the only other disease even mentioned in this article, and that only in passing, was cardiovascular disease). You would at least like a footnote for a statement like this one. There was no footnote, and, frankly, given what I had read in other parts of the paper, I was surprised that such an unequivocal statement would be made.

For example, earlier in the article, I saw this quote:

In this article we present the results of the first comprehensive study on the impact of occupational exposure to airborne V205 on DNA stability. p.1691

Since replication of results is a commonly accepted criterion for causation, it would have been nice for the results to have been replicated before such a “causally related” statement was made. In fact, the paper admits that two earlier studies, looking at V205 and different DNA endpoints, were negative. p.1689

Also, when you think about a statement that says “because the aforementioned parameters are causally related to . . . cancer . . . .” You ask yourself: “What cancers?” “In what species?”

The article actually had something to say about those subjects that made its conclusion even more unusual. It pointed out that the National Toxicology Program found V205 inhalation caused a (presumably statistically significant) increase in adenomas and carcinomas in mice, but not in rats, and it noted that IARC, in 2006, based in part on these data, classified V205 as a “possible” human carcinogen (Group 2B).

So, thus far, all we know is that V205 is an animal carcinogen in mice, but where does the conclusion “the aforementioned [DNA damage] parameters are causally related to . . . cancer. . . .” come from?

One of the statements made early in the article is this one:

Because DNA damage and aneugenic processes are known to play a role in the onset of human cancer (Duesberg, et al. 2005; Pitot, 1986), evidence of genetic damage in exposed humans would support the assumption of increased cancer risks. p.1689

Well, there are references as support for, at least, the first part of that quote. One is to Dr. Henry Pitot, in 1986 and one is to Dr. Peter Duesberg, and others, in 2005. Since the Pitot piece is 22 years old, I thought I would look at the 2005 Duesberg article: “The Chromosomal Basis of Cancer,” Cellular Oncology 27(2005) 293-318. However, that article was published under the heading “Opinion” and the first sentence of the article says:

Despite over 100 years of cancer research, the cause of cancer is still a matter of debate between theories postulating either mutation or chromosomal alteration or epigenetic events as causes of cancer. p.293

That sentence is followed by cites to 29 footnotes, so there is no help there for the assertion in the V205 article, it would seem.
Later in the V205 paper, the authors say, with respect to the micronucleus test, that

. . . a prospective study showed that MNs in peripheral blood lymphocytes are a valid biomarker for predicting an increased cancer risk in humans (Bonassi, et al. 2007). pp.1691-1692

Well, that is a lead, and it is supported by a footnote, so, off to the literature. The cited article, by Bonassi, et al., was entitled “An Increased Micronucleus Frequency in Peripheral Blood Lymphocytes Predicts the Risk of Cancer in Humans.” Carcinogenesis 28(3); 625-631 (2007). However, the abstract of that article is a little more circumspect. It says:

The results from the present study provide preliminary evidence that MN frequency in PBL (peripheral blood lymphocytes) is a predictive biomarker of cancer risk within a population of healthy subjects. p.625

And, later in that article, the statement is made:

Nevertheless, we acknowledge that the number of cancers per organ site is relatively small, and that the statistical estimates, which are suggestive of an association with MN, are likely to become more stable as further cancers accumulate with increasing age of the cohort. p.629

Well, maybe.And later:

A feature of this study is the non-linearity of the dose-response relationship between MN frequency and overall cancer incidence. p.629

And later:

The international multi-centre nature of this study [43 sites in 23 countries – the Human Micronucleus Project (HUMN)] may be considered among its strengths [for the reasons cited]. . . . On the other hand, this approach has also introduced a number of limitations. These include the large inter-laboratory variability of MN frequency which is most likely due to
technical differences in slide preparation and scoring, the heterogeneous quality of data in genotoxic exposures, such as cigarette smoking and occupational carcinogens or the availability of a single measure of MN per individual which may have resulted in misclassification among MN frequency levels. A further potential source of bias is the heterogeneousity in the cancer registration quality of the countries involved. p.630 Hello?

I would go on, but for the one or two of you still reading, I will simply observe this: the micronucleus test (or any of the other ones mentioned at the beginning of the V205 article) may turn out to predict human cancer. They may even turn out to predict particular human cancers. However, I don’t think the evidence I saw supports the proposition that they do so now, and I think that any plaintiff who brought a V205 worker cancer case to court, on the basis of genetic evidence alone, would be hard-pressed to survive summary judgment.