Tuesday, October 6, 2015

Up in Vapor: The Real Story Behind the Formaldehyde-Cancer Link

Vapers, rest easy about e-cigarettes and formaldehyde. 

As a pathologist with 28 years’ formaldehyde exposure via workplace inhalation, I have both a professional and a personal interest in whether formaldehyde causes cancer.  It turns out that the formaldehyde-cancer link is weak to nonexistent, and it has been grossly exaggerated by organizations like the International Agency for Research on Cancer (IARC) and the U.S. National Toxicology Program (NTP).  In many ways, formaldehyde has been treated much like smokeless tobacco, which the same agencies list as a carcinogen in spite of weak to nonexistent epidemiologic evidence (here).    

The fact is, IARC and NTP primarily base their formaldehyde carcinogen classification on a single National Cancer Institute (NCI) study claiming that the agent causes nasopharyngeal cancer, or NPC.  That study, published in 2004 by NCI’s Michael Hauptmann and colleagues, has been shown to be unreliable.

The Hauptmann study was based on 25,000 workers, most of whom were exposed to formaldehyde at 10 industrial plants over a 30-year period.  Compared with unexposed workers, Hauptmann et al. reported that formaldehyde-exposed workers had about a two-fold higher risk for NPC, based on eight cases.  No other increased cancer risks were observed.   

The Hauptmann data was reassessed in 2005 by Gary Marsh, Ph.D., a University of Pittsburgh statistician who was supported by the Formaldehyde Council, an industry group. 

Dr. Marsh reported (abstract here) that “reanalysis provided little evidence to support NCI’s suggestion of a causal association between formaldehyde exposure and mortality from NPC.”  He pointed out that Hauptmann had based his conclusion on an excess of NPC in only one plant, located in Wallingford, Connecticut.  In the other nine plants, formaldehyde-exposed workers had lower-than-expected NPC rates.

Dr. Marsh continued to investigate the NPC cancers at Wallingford.  In 2007, he published another study showing that the NPC excess at the Wallingford factory was probably not due to formaldehyde, but to workers’ exposure “to several suspected risk factors for upper respiratory system cancer (e.g., sulfuric acid mists, mineral acid, metal dusts and heat).”

The NCI team had also claimed that the highest exposures to formaldehyde resulted in the highest NPC risks.  Dr. Marsh showed that claim to be wrong in a third study published in 2007 (here).     

In 2010, Annette Bachand and colleagues conducted a comprehensive meta-analysis, which included “all relevant cohort and case-control studies published through May 2009.”  They found no overall increase in NPC risk after excluding Hauptmann’s Wallingford plant data.  Six case control studies produced a marginally elevated risk for NPC among formaldehyde-exposed workers (OR = 1.22, 95% Confidence Interval = 1.00 – 1.50), which may have been due to a failure to adjust for smoking, a known risk factor for NPC.  Seven cohort studies resulted in a lower NPC risk among exposed workers (OR = 0.72, CI = 0.40 – 1.29). Bachand’s results were in agreement with an earlier meta-analysis by Bosetti et al.

Inflated claims by NCI epidemiologists are not unprecedented; witness the 1981 assertion by Dr. Deborah Winn that all American smokeless tobacco users were at risk for mouth cancer (completely refuted here and here).

The only bright side of this story is that the NCI formaldehyde-cancer claim could be analyzed because the agency’s data was available to outside investigators.  In contrast, the Karolinska Institute and the American Cancer Society have issued warnings about smokeless tobacco but persist in withholding the underlying data (here and here) – a violation of data-sharing and research practice standards. 

Tuesday, September 29, 2015

ZERO U.S. & Canada Cancer Deaths from Smokeless Tobacco, British Researchers Report

A study published in BMC Medicine (here) estimates that the number of cancer deaths due to smokeless tobacco (ST) use in the U.S. and Canada is ZERO. 

The researchers, mainly from the UK, had bad news for ST users in Southeast Asia, where products have high levels of contaminants and are mixed with other toxic ingredients like betel.   Deaths in that region contributed the lion’s share of the worldwide toll of 267,000 annual deaths from cancer and heart disease among ST users. 

The researchers developed risk estimates based on epidemiologic studies from each region.  As I have discussed many times, the risk of cancer among Swedish and U.S. ST users is so small that it is not statistically significant.  Attributing no U.S. cancer deaths to smokeless tobacco use, the UK researchers confirmed this.

They also estimated deaths from ischemic heart disease among ST users.  I have noted that several studies document the risk of heart attack among smokeless users in the U.S. and Sweden as “next to nil” (here, here, here and here).  Ignoring these published risk estimates, the UK researchers declared that “no good country-specific risk estimates were available.”  They assigned a risk value of 1.6 based on an international heart attack study that included ST use data from countries like Bangladesh, India, Pakistan, Sri Lanka, Nigeria and Cameroon, but not the U.S. or Canada.  Due to this, the UK claim of 11,000 heart attack deaths in the U.S. and Canada from ST use is a gross overestimate.

The U.S. and Canadian public should ignore scaremongering about ST deaths, as the real threat lies with adulterated products from Southeast Asia.  For Western ST users, there is much to celebrate in this report.

Wednesday, September 23, 2015

Premarket Study Positive for Proposed Snus Warning Label Changes

The FDA is considering a request from Swedish Match to modify federally-mandated warnings on the company’s snus packages.  The company wants to remove the current mouth cancer and gum disease/tooth loss warnings; replace the not-safe-alternative warning with the more accurate “this product presents lower [or substantially lower] risks to health than cigarettes”; and retain the current addiction warning.

In support of its application, Swedish Match funded a premarket online survey to measure perceptions of current and proposed labels among 13,200 U.S. participants.  The company’s advisory board asked me and Nantaporn Plurphanswat, my University of Louisville colleague, to analyze the survey, together with University of Vermont psychiatrist John Hughes and Swedish tobacco/nicotine researcher Karl Fagerström.  Our results appear in Nicotine and Tobacco Research (abstract here).

We classified participants according to their tobacco use: smokers, former smokers, ST users, other [combustible] tobacco users and never users.  Participants viewed only one of the current or proposed warnings, after which they were asked if the warning was believable, if snus was harmful, and if they were likely to use snus or motivated to buy snus.  

Most participants, regardless of tobacco use status, found all the current ST warnings believable.  In contrast, they were not as likely to believe the more accurate proposed labels.  The vast majority of respondents also perceived that using snus is harmful.  The perceived odds of harm were mostly lower with the proposed labels, but these differences were not always statistically significant.

These results are not surprising. American health authorities have ignored the substantial body of evidence documenting that ST use is less harmful than smoking and have promoted the message that ST is not a safe alternative to cigarettes (Enter “misinformation” in the search box on this blog for numerous examples).  As a result, most of the population equates the risks of ST use with those of smoking.   

Compared with the current not-safe-alternative warning, smokers viewing the proposed labels were significantly more likely to use or buy snus; the same was true for ST users and other tobacco users viewing the substantially lower risk label. This indicates that the proposed labels could foster a transition from cigarettes and other combustible products to snus, a result that would represent a significant health advantage for individual smokers and public health generally.

Among former tobacco users, no increases in likelihood to use or motivation to buy were seen with the proposed labels. In never users, an increase in motivation to buy snus was noted for the substantially lower risk label; neither proposed label had higher odds for likelihood to use snus.

In summary, our analysis of this pre-marketing survey suggests that tobacco users viewing the proposed relative-risk labels are more likely to perceive snus as less harmful than cigarettes and may be more likely to use and buy snus.

Wednesday, September 16, 2015

E-Cigarettes – Gateway to Fatally Flawed, Federally Funded Research

The latest addition to a flood of biased, federally-funded e-cigarette research is a JAMA Pediatrics article (here) claiming that e-cig use leads to smoking among teens and young adults. 

First author Dr. Brian Primack (University of Pittsburgh) and colleagues analyzed a Dartmouth-based survey of 16-26 year olds.  As a baseline, they asked never smokers if they had “ever” used an e-cigarette; 16 said yes and 678 said no. 

A year later, Dr. Primack asked: “If one of your friends offered you a cigarette, would you try it?” and “Do you think you will smoke a cigarette sometime in the next year?”  Possible answers for both questions were “Definitely yes, probably yes, probably not or definitely not.”  Participants were at risk for smoking if they gave any of the first three answers – including probably not (see my blog post about probably not meaning yes).  Primack also asked if participants had “smoked at least1 puff of a cigarette in her or his lifetime.”  He did not ask about current smoking (in the past 30 days).  Of 16 people who had ever used an e-cig at baseline, five were “at risk” for smoking one year later, and six had smoked at least a puff. 

As Dr. Michael Siegel observed (here), the authors’ media campaign grossly distorted their data.  Their statements to the press were based on tiny numbers, distorted by “ever” e-cigarette use refashioned as “use”, and “thinking about smoking” or ever having taken a puff repositioned as “regular smoking”. 

In this analysis the authors.  Primack et al. claimed to include “characteristics that have been previously associated with cigarette smoking and could also be associated with e-cigarette use.”  However, they omitted characteristics that they had previously claimed were important predictors of smoking: use of snus and waterpipes.  Three of the authors – Primack, Samir Soneji and James Sargent – published a study earlier this year from the same survey in the same journal (here), dubiously claiming that snus use and waterpipe smoking are gateways to cigarette smoking. (As I wrote just last week, “If you have ever used one tobacco product, you are likely to have ever used another.”)  This omission is inexplicable.

In addition to Dr. Siegel’s critique, the Primack claims have been questioned by a thoughtful article at FiveThirtyEight aptly entitled, “Ignore The Headlines: We Don’t Know If E-Cigs Lead Kids To Real Cigs.  We do know that omitting important information is a fatal flaw in this study.    

Wednesday, September 9, 2015

Teen E-Cigarette Use & Smoking: Correlation, Not Causation

Here we go again.  Researchers funded by the National Institutes of Health issued a release saying that “teens who use e-cigarettes were more likely to transition to smokeable tobacco products. However, researchers cautioned that additional studies are needed to determine whether the association is causal.”  Their study appeared in JAMA (here).  

It may sound like the authors are denying a gateway claim, but lead author Adam Leventhal pushed the envelope in the press release: “E-cigarettes may be drawing a new generation of teens into recreational nicotine use because they are high-tech, can be purchased somewhat easily, come in enticing flavors and have a perception that they’re not harmful…If you enjoy the experience of inhaling nicotine in e-cigarettes, it makes sense that you would be open to trying other nicotine products, like cigarettes, hookah, and cigars.”

The media, naturally, saw the study as evidence that e-cigarettes are a “gateway” to smoking among teenagers.  This is a misrepresentation of the data. 

The researchers collected baseline information on “ever” lifetime use of e-cigarettes.  The 6- and 12-month follow-up outcomes were “any” use (even a few puffs) of several combustible tobacco products in the past 6 months.  It is unsurprising that the results revealed that “ever” use of e-cigarettes at baseline was associated with combustible use at follow-up.  It is well known that use of one tobacco product is associated with use of other products among teenagers, especially when the comparison group is composed of kids who have never used any tobacco product.

The bottom line: If you have “ever” used one tobacco product, you are likely to have “ever” used another.  That is correlation, not causation.  This phenomenon was also confirmed by information in Table 2 of the publication, which crosstabs students’ combustible tobacco use with their use of e-cigs at baseline.  Here are the results:

Number of Combustible Products Ever UsedNumber of StudentsNumber (%) Ever Using E-Cigs
02,558225 (9%)
1401156 (39%)
2233136 (58%)
3134100 (75%)

Among the 2,558 students who never smoked, e-cigs were only used by 8.8%.  Among students who had smoked one product, e-cig use was 39%.  Students using 2 and 3 products had e-cig usage rates of 58% and 75%, respectively.

This study shows that students who have “ever” used one tobacco product are likely to have “ever” used another, and that includes e-cigarettes.