Med Page claims that “Industry Studies Obscure Harm from Tobacco Additives”

Editor’s Note: Industry documents have been on public record for months if not years. At no time during the extensive public comment period provided by  the FDA did the aformentioned “researchers” surface these argments.–unlike CRE who not only  made all their arguments public but allowed the public to comment on them on this Interactive Public Docket.  Notwithstanding the constant flow of ‘hail mary” passes against menthol, CRE will read  the study and if warrants a review CRE will  conduct a detailed review  and report the findings herein. Interesting the “researchers” refuse to look at the toxic effects of contraband.
By Crystal Phend, Senior Staff Writer, MedPage Today     
Published: December 20, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.
Action Points  
  • Menthol and other additives substantially boost the toxicity of cigarettes, though industry studies suggested otherwise.
  • The tobacco industry had reported results of the studies as neutral because of post hoc changes to adjust away significance.

Menthol and other additives substantially boost the toxicity of cigarettes, though industry studies suggested otherwise, researchers found.

The smoke of cigarettes with flavor and other additives was significantly more toxic and higher in total particulate matter than that of plain, tobacco-only cigarettes, Stanton A. Glantz, director of the Center for Tobacco Control Research and Education at the University of California San Francisco, and colleagues reported.

That’s what they uncovered in the per-protocol analyses of the industry studies using documents obtained through litigation.

But the studies had been reported as neutral because of post-hoc changes to adjust away significance, Glantz’ group pointed out in the December issue of PLoS Medicine.

“These findings show that the tobacco industry scientific research on the use of cigarette additives cannot be taken at face value,” the editors of the journal summarized.

That should come as no surprise, Glantz’ group noted, pointing to the long history of big tobacco manipulating release of scientific results on secondhand smoke.

The FDA and other regulatory authorities could now use the industry’s own data to eliminate use of menthol and all the other cigarette additives studied, the group suggested.

Some additives make tobacco smoke less irritating to the respiratory system, while others make it more palatable. Altogether, these can impact bioavailability and impact of nicotine, as well as initiation and ability to quit smoking.

The FDA prohibited flavor additives in 2009 with the exception of menthol.

Philip Morris anticipated FDA regulation of tobacco decades before it was enacted in 2009, and started conducting research that could be used to shape any proposed regulation. Out of that came four “Project MIX” papers, published in 2002, that concluded no evidence of substantial toxicity from different combinations of 333 additives reflecting what was in commercially available cigarettes.

The research included chemical analysis of smoke, in vitro testing for effect on genetic mutations and toxicity to cells, and in vivo rat inhalation toxicology studies.

Glantz’ group combed through roughly 60 million pages of tobacco industry documents turned over in the course of litigation to uncover the original research methods and protocols.

“While the procedures to collect the data themselves appear sound, the way that the data were analyzed and interpreted is not,” they wrote.

The 51 constituents of smoke from the test and control cigarettes were subjectively chosen and excluded important polycyclic aromatic hydrocarbons of concern, such as carcinogens.

The studies also assessed, but did not publish, ammonia levels in the smoke. Internal reports pointed to significantly elevated levels with two groups of additives but significantly reduced levels with a third group that included menthol.

Ammonia “increases the pH of tobacco smoke, making it less acidic and therefore easier to smoke while increasing the bioavailability of the nicotine,” Glantz’ group noted.

The original research protocol originally called for analysis on a per-cigarette basis, but that was changed at the request of Philip Morris after the company found out that the additive cigarettes had a 10% higher total particulate matter and 20% higher levels of the toxin acrolein.

The published paper did include that data showing the additives together boosted total particulate matter by 13% to 28%, which would increase cardiovascular disease risk and contribute to slower wound healing, spontaneous abortion, preterm delivery, and other pregnancy problems.

But the researchers downplayed the biological importance of this and normalized the toxin results by total particulate matter (TPM).

“Thus, as long as the amount of a toxin in the smoke of a test cigarette increased by less than the amount TPM increased in that cigarette, the ratio would drop even if both the toxin and TPM increased with the additives,” Glantz’ group explained.

With this adjustment, only five of the 31 toxins increased with the additives and 15 showed decreases.

But smokers smoke whole cigarettes, generally to obtain a certain amount of nicotine, regardless of total particulate exposure, Glantz’ group argued.

On a per cigarette basis, 31 of 51 chemicals increased with at least one of the additive groups and 37 increased per unit nicotine (17 and nine decreased, respectively).

For 15 chemicals, the increase was 20% or more beyond that of the tobacco-only control cigarettes. This group included human and animal carcinogens including arsenic, formaldehyde, and polycyclic aromatic hydrocarbons as well as respiratory irritants and cellular toxins, such as carbon monoxide.

The in vivo toxicology was also done to match total particulate matter across the cigarette groups, which meant rats were exposed to lower relative toxin levels with the additive cigarettes than if exposure was matched on nicotine delivery.

Other problems with the smoke inhalation toxicity research were use of only nine rats per group and a short 90-day exposure period with 42 days of follow up, which likely underpowered it to find real effects.

The genotoxicity and cytotoxicity studies used only screening tests, not sensitive dose-response measures, and therefore couldn’t determine changes in potential harm with the additives.

The FDA and other regulators need to insist on receiving all drafts of tobacco-related study protocols from industry as well as the raw data to reduce problems like these in the future, Glantz’ group concluded.

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