Assessing Popper Purity—Implications for the Regulation and Recreational Use of Alkyl Nitrites
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsI have reviewed the manuscript entitled "Assessing Popper Purity—Implications for the Regulation and Recreational Use of Alkyl Nitrites", which I found interesting. The study is well-designed.
The authors addressed the problem with nitrite "poppers" and the exposure to these even in some products where these compounds were not listed as present in them. FDA in 2021 made a call saying " Ingesting or Inhaling Nitrite "Poppers" Can Cause Severe Injury or Death", due to an increase in hospitalizations and deaths.
https://www.fda.gov/consumers/consumer-updates/ingesting-or-inhaling-nitrite-poppers-can-cause-severe-injury-or-death
https://www.fda.gov/food/alerts-advisories-safety-information/fda-advises-consumers-not-purchase-or-use-nitrite-poppers
Still, there are products that contain these nitrites, and they are not even listed on the label. This kind of manuscript could open a talk about regulation and warning since they are still available in the market and not completely banned.
They could also consider doing the analysis by LC-MS/MS if possible. This has been my only suggestion in the revision process. The only thing that I found that needs to be changed is the citation of the references in the text, which should be [1,2] instead of [1],[2] according to the rules of the journal.
They are questioning the market, their purity, their safety, and the gap in the regulation, proving all of these points with their data. The references are appropriate. The tables and figures are good.
Author Response
Comments 1: I have reviewed the manuscript entitled "Assessing Popper Purity—Implications for the Regulation and Recreational Use of Alkyl Nitrites", which I found interesting. The study is well-designed.
The authors addressed the problem with nitrite "poppers" and the exposure to these even in some products where these compounds were not listed as present in them. FDA in 2021 made a call saying " Ingesting or Inhaling Nitrite "Poppers" Can Cause Severe Injury or Death", due to an increase in hospitalizations and deaths.
https://www.fda.gov/consumers/consumer-updates/ingesting-or-inhaling-nitrite-poppers-can-cause-severe-injury-or-death
https://www.fda.gov/food/alerts-advisories-safety-information/fda-advises-consumers-not-purchase-or-use-nitrite-poppers
Still, there are products that contain these nitrites, and they are not even listed on the label. This kind of manuscript could open a talk about regulation and warning since they are still available in the market and not completely banned.
Response 1: Thank you for this excellent point and review, and we completely agree with the point. The mentioned reference is included as reference 29; however, on page 2, 4th paragraph, lines 79-80 we have added a line making more explicit the recognition that the FDA has issued warnings regarding alkyl nitrites in the past.
Comment 2: They could also consider doing the analysis by LC-MS/MS if possible. This has been my only suggestion in the revision process. T
Response 2: While a more complete analysis could be ideal, we do not have the samples. Further, the choice of NMR of LC-MS/MS was explicit as NMR better allows characterization of unknown compounds as NMR allows quantification without reference standards, and provides much more detailed information about the molecular structure, including arrangement of atoms, bond lengths, and angles than can be provided by LC-MS/MS; further LC-MS/MS requires prior separation of the samples while NMR does not which is particularly helpful in analyzing complex mixtures. We have added a line on page 3, paragraph 3 lines 131-134 to better explain this as this is likely going to be common question for readers, thank you.
Comment 3: The only thing that I found that needs to be changed is the citation of the references in the text, which should be [1,2] instead of [1],[2] according to the rules of the journal.
Response 3: We completely agree, and are thankful for having this noted. We have corrected all references in the paper, including further the formatting in the references section.
Reviewer 2 Report
Comments and Suggestions for AuthorsAuthors of the article "Assessing Popper Purity—Implications for the Regulation and Recreational Use of Alkyl Nitrites," Nathan Makarewicz, Brent Albertson, Twan Sia, and Anuj Aggarwal, analyzed samples using hydrogen-1 (¹H) and carbon-13 (¹³C) nuclear magnetic resonance spectroscopy to assess the presence of impurities. The authors claim that "Physical labels on all nine samples indicated the contents were 'pure' isobutyl nitrite, despite contradictory online marketing in several cases." Spectral results showed isobutyl nitrite was present in all popper samples. However, there was evidence that various unlabeled compounds were also present in all samples.
My immediate question is why the authors confined themselves only to ¹H NMR and ¹³C NMR? Did the authors consider other methods to confirm the impurities and illuminate the potential harm to human health, such as GC-MS? For example, isobutyl alcohol found in some samples as a concomitant could pose health risks. It would be useful to analyze some popper brands both qualitatively and quantitatively. This would increase the attractiveness and attention of health authorities. Besides this, the manuscript is well written and highlights some medical problems associated with the recreational use of psychoactive poppers.
Author Response
Comments 1: My immediate question is why the authors confined themselves only to ¹H NMR and ¹³C NMR? Did the authors consider other methods to confirm the impurities and illuminate the potential harm to human health, such as GC-MS? For example, isobutyl alcohol found in some samples as a concomitant could pose health risks. It would be useful to analyze some popper brands both qualitatively and quantitatively. This would increase the attractiveness and attention of health authorities. Besides this, the manuscript is well written and highlights some medical problems associated with the recreational use of psychoactive poppers.
Response 1: Thank you for the review and for the well written point regarding consideration of GC-MS or even to consider LC-MS/MS. While a more complete analysis could be ideal, we do not have the samples. Further, the choice of NMR of LC-MS/MS was explicit as NMR better allows characterization of unknown compounds as NMR allows quantification without reference standards, and provides much more detailed information about the molecular structure, including arrangement of atoms, bond lengths, and angles than can be provided by LC-MS/MS; further LC-MS/MS requires prior separation of the samples while NMR does not which is particularly helpful in analyzing complex mixtures. We have added a line on page 3, paragraph 3 lines 131-135 to better explain this as this is likely going to be common question for readers. Considering GC-MS, which can provide some structural information, when combined with the fragmentation patterns in the mass spectrometer, it tends not to offer the same level of detail about the molecular structure as NMR, hence the choice as well. We have incorporated this into page 3, paragraph 3, lines 131-135 as well, thank you!
