Response to Muge Akpinar-Elci Letter to Editor re. Pierce et al., Diacetyl and 2,3-pentanedione exposures associated with cigarette smoking: implications for risk assessment of food and flavoring workers, Crit. Rev. Toxicol. 44(5):420–435, 2014

To the Editor:

My co-authors and I appreciate the opportunity to respond to the Letter to the Editor (Akpinar-Elci and Elci 2014) concerning our recent article (Pierce et al. 2014).

Akpinar-Elci and Elci suggest that we “falsely” claimed that “all of the cohorts evaluated had considerable smoking histories”. To support their assertion, they offer a non- sequitur: of the nine alleged cases of bronchiolitis obliterans in their cohort, a majority (6/9) were current or former smokers. Unfortunately, they seem to have confused the terms “cohort” and “case”. To reiterate, all food/flavoring cohorts studied to date had a significant fraction of current/former smokers, and indeed in the Akpinar-Elci et al. (2005, 2006) analyses of the Gilster-Mary Lee (GML) workers, nearly 50% of the study participants were current smokers.

They also appear to believe that, because most of the alleged cases of bronchiolitis obliterans in their cohort (8/9) were not current smokers, then smoking was not a confounder in their study. They have unintentionally reinforced our point. Cigarette smoke contains high levels of diacetyl, therefore workers who smoke have much higher diacetyl exposures than the non-smoking food/flavoring workers. More importantly, even though smokers arguably have the highest peak and cumulative diacetyl exposures of any definable cohort, smoking is not a risk factor for bronchiolitis obliterans. These observations argue against a relationship between diacetyl exposure and bronchiolitis obliterans. Finally, they have confused “controlling for the effects of smoking on respiratory function” (which they did do) versus “accounting for the relatively large diacetyl exposure from smoking when assessing the exposure-response relationship between diacetyl inhalation and respiratory function in food/flavoring workers” (which they certainly did not do).

Akpinar-Elci and Elci claim that “A cluster of such a rare disease as bronchiolitis obliterans indicates a possible risk factor related to the work environment”. As U.S. Supreme Court Justice Louis Brandeis noted when referring to the benefits of transparency, “sunlight is said to be the best of disinfectants”. Let us shed some sunlight onto the above claim. First, they failed to note that only three of their alleged nine cases of bronchiolitis obliterans underwent lung biopsy to allow for confirmation of the suspected diagnosis. Of these, only one had findings that supported a possible diagnosis of bronchiolitis obliterans. Second, although bronchiolitis obliterans is a fixed obstructive disease, there was no difference in the prevalence of obstruction between the diacetyl-exposed workers versus controls in either of the Akpinar-Elci et al. (2005, 2006) studies of GML workers. Oddly, in neither study do they note that these findings completely contradict those of Kreiss et al. (2002), who claimed to have observed a significant relationship between diacetyl exposure and obstruction prevalence in workers at the same facility. Given the fact that Kreiss et al. (2002) is considered by Akpinar-Elci et al. to be a seminal study, failure to replicate the results of Kreiss et al. (2002) in their studies should warrant some mention in their papers. Similarly, in neither study do the authors inform the reader that in the original GML cohort (Kreiss et al. 2002), 57% of the cohort claimed to have had off-site (mostly farming-related) exposures to “other possible causes of lung disease”, including known inducers of bronchiolitis obliterans, such as nitrogen oxides (silo gas).

Furthermore, the authors are mistaken in suggesting that had we “more carefully” reviewed the findings of their analyses, our conclusions would have been different. We have reviewed their studies at length, and believe that their claim of “findings that strongly indicate a relationship between occupational butter flavoring exposure and respiratory diseases among popcorn production workers” is desperately over-reaching. In fact, their own papers provide substantially more evidence to the contrary. For example, they found that:

(1)	Sputum characteristics were not related to pulmonary function.
(2)	There were no significant differences in spirometric values between highly exposed workers and the internal reference group.
(3)	The mean FEV1 and FEV1/FVC percent of predicted were both greater than 95% among all popcorn production workers (indicating a healthy workforce).

We find it disingenuous that Akpinar-Elci and Elci would attempt to cloak themselves in the Hippocratic oath. One could easily argue that a rush to judgment on diacetyl has ushered in the heavy use of replacement chemicals which NIOSH scientists themselves are now claiming appear to be similar to or even more potent than diacetyl (NIOSH 2011, Morgan et al. 2012, Zaccone et al. 2013).

In summary, we stand by our original premise, which is supported by Akpinar-Elci et al.'s own published findings: (1) all the food/flavoring cohorts had significant smoking histories, (2) cigarette smoke contains very high diacetyl levels, (3) none of the diacetyl exposure–response evaluations to date have accounted for this very large non-occupational source of diacetyl, therefore, (4) all such evaluations are inherently flawed (though unintentionally) and should be revisited.

Declaration of interest

All the authors are employed by Cardno ChemRisk, a consulting firm that provides scientific advice to the government, corporations, law firms and various scientific/professional organizations. Cardno ChemRisk has been engaged by several manufacturers and suppliers of diacetyl and diacetyl-containing flavorings in various litigation matters. However, no external funding was received for the study, the research supporting the analysis, nor the time needed to prepare the article, and this paper was prepared and written exclusively by the authors, without review or comment by any clients including, but not limited to manufacturers and suppliers of diacetyl and diacetyl-containing products and their counsel. It is likely that this work will be relied upon in scientific and medical research and litigation. Two of the authors (Drs. Pierce and Finley) have served and may be called upon in the future to serve as expert witnesses in diacetyl litigation. The authors have not been engaged by the tobacco industry or been involved in any tobacco-related litigation.