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More than two million American adults who smoked have switched completely away from deadly cigarettes with the help of JUUL products. And we are eager to switch millions more.
Our team has worked diligently to provide FDA with robust scientific data demonstrating that our authorized products are appropriate for the protection of public health. As part of our 2020 PMTAs, we submitted over 110 scientific studies to FDA covering nonclinical, clinical, and behavioral evidence. The below information provides a high-level overview of the science we submitted to FDA in our PMTAs. More detailed information, including scientific articles, presentations, and posters is available in our Publication Library.
Our nonclinical research examines the JUUL System aerosol through analytical chemistry, in vitro studies, and toxicological assessments. This includes:
Testing for Harmful and Potentially Harmful Constituents (HPHCs): Chemical analyses of JUUL System aerosol are conducted to quantitatively assess the presence of HPHCs identified by public health bodies such as the World Health Organization (WHO) and the FDA U.S. Food and Drug Administration as key toxicants of concern. We measure the levels of specific constituents in the aerosol and compare them to those found in combustible cigarette smoke.
Chemical analyses demonstrate that aerosols from the JUUL System contain fewer and substantially lower levels of harmful and potentially harmful constituents (HPHCs) than cigarette smoke. Average analyte reductions (excluding primary ingredients and water) for all four tobacco- and menthol-flavored JUUL System aerosols were greater than 98% lower than smoke from a reference cigarette (3R4F).
Additionally, the results from in vitro studies show that JUUL System aerosol condensate is not cytotoxic, mutagenic, or genotoxic under the conditions of the studies, and is, overall, comparable to or lower in toxicity than comparator vapor products and less toxic than cigarette smoke. Read our study here.
Our clinical research program examines the effect of the JUUL System on adults who smoke including the rate and level of nicotine absorption in the body and changes in exposure to tobacco-related harmful and potentially harmful constituents among adults who switch completely from smoking cigarettes to use of JUUL System products, such as:
Pharmacokinetic Studies: Pharmacokinetic studies assess the rate and level of nicotine absorption in the body as well as subjective effects of use of various products. During testing, we analyze regular blood nicotine measurements before, during, and after use of each product to assess nicotine delivery and to help us understand nicotine absorption rates compared to cigarettes and other nicotine-containing products.
Pharmacokinetic studies of the JUUL System demonstrate a nicotine delivery that is competitive with, but lower than combustible cigarettes, and within the range of other vapor products. See more here.
Biomarkers of Exposure Studies: Combustible cigarettes expose smokers to harmful and potentially harmful constituents known to cause disease. The analogs, degradants, and metabolites of these toxicants (known as biomarkers of exposure [BOEs]) are detectable in the urine and bloodstream of smokers and can be used to assess the reduction in exposure to harmful constituents associated with switching from cigarettes to noncombustible products like ENDS.
This study demonstrates that adults who switch completely from smoking cigarettes to use of the JUUL System substantially reduce their exposure to HPHCs associated with smoking-related diseases.
Juul Labs’ behavioral research program was developed to evaluate the behavioral effects of JUUL System products in the population as a whole, including adults who smoke cigarettes and those who do not use tobacco products. Experimental and real-world studies have directly evaluated the effects of JUUL System products on cigarette smoking behavior, specifically switching away from cigarettes, subjective responses, patterns of use, as well as abuse liability and dependence relative to combustible cigarettes and other ENDS products.
Juul Labs also conducted observational longitudinal cohort studies of adults who purchased the JUUL System in the United States. The studies assessed transitions in tobacco product use (e.g., past-30-day switching away from cigarettes, smoking reduction), patterns of JUUL System use over time, and levels of dependence on the JUUL System in real-world settings. The results of a 24-month study demonstrate that:
Read our 24-month study
Juul Labs employs a stepwise health-risk evaluation approach when assessing its products. This process begins with product characterization, progresses to the evaluation of information generated from the product and identification of potential hazards, and then integrates actual-use data into a whole product risk assessment.
The chemical, toxicological and clinical data integrated in the whole product risk assessment support that the individual health risks of the JUUL System are expected to be lower than cigarettes and within the range of currently marketed vapor products.
We will update our publication library with research on the JUUL System as we continue to report results from our studies.
Juul Labs submitted PMTAs for its on-market JUUL System products in July 2020, ahead of the court-mandated September 9, 2020, deadline for submission of deemed products’ PMTAs. The JUUL System PMTAs included over 110 scientific studies to FDA covering nonclinical, clinical, and behavioral evidence. In June 2022, FDA issued a marketing denial order (MDO) for these products. Juul Labs’ filed an administrative appeal, known as a 10.75 appeal. Shortly after, FDA stayed the MDO and placed the MDO under administrative review, acknowledging “scientific issues unique to this application that warrant additional review.” The administrative review period lasted nearly two years before FDA formally rescinded the MDO in June 2024 and returned the JUUL System PMTAs back to substantive scientific review, where they are currently pending. Juul Labs remains confident in the quality and substance of our applications and believes that a full review of the science and evidence will demonstrate that our products meet the statutory standard of being appropriate for the protection of public health.
In 2022, we made the decision to publish our 10.75 administrative appeal and related review materials in an effort to provide transparency on the process and educate stakeholders on the science supporting our PMTAs, as well as the bases for FDA’s decision. We also published FDA’s Marketing Denial Order and Technical Project Lead memorandum to provide additional context for our decision.
By necessity, the 10.75 appeal contains information and statements about the relative health risks of the JUUL System compared to combustible cigarettes, as well as other tobacco products. The information and statements in the 10.75 appeal are neither intended for nor directed to consumers and should not be relied upon as health claims, as they have not been authorized by the FDA.
The appeal explains the company’s position, based on science and evidence, that the MDO was substantively and procedurally flawed, as it:
Despite the wealth of data included in our PMTA, the MDO nonetheless focused on limited issues within a narrow subset of toxicological data instead of considering it in the context of the overall health risk evaluation. The four deficiencies identified in the MDO relate to toxicological signals and potential hazards that, while relevant, have been effectively ruled out or further characterized in a scientific manner beyond what is described in the MDO.
Deficiency 1: The MDO asserted that Juul Labs identified certain leachable constituents (constituents from the pod and related components that could transfer to the e-liquid) of potential toxicological concern in simulated e-liquid studies but did not evaluate the mainstream aerosol yields of those constituents to determine whether and at what level users could be exposed. As a result, the MDO claimed that FDA was precluded from making a determination of whether JUUL products are appropriate for the protection of public health.
But Juul Labs did provide these data in its PMTAs. Through non-targeted analysis of the JUUL System aerosol, the PMTAs showed that the leachables in question were not detected in the aerosol and thus do not pose a health risk to the user.
Deficiencies 2 and 3: The MDO asserted that Juul Labs did not provide reliable and valid data to assess the genotoxic (ie: causes damage to cells) potential of JUUL products and as compared to combustible cigarettes and other ENDS products. As a result, the MDO claimed that FDA was precluded from making a determination of whether JUUL products are appropriate for the protection of public health.
But the MDO focused on limited methodological differences in select in vitro and in vivo studies, from which Juul Labs did provide sufficient and reliable information to inform on the genotoxic potential of JUUL products. More importantly, the MDO did not account for the additional science and evidence in which a signal of potential genotoxicity from an in vitro study was further assessed by subsequent studies and incorporated into whole product risk assessments to characterize potential exposures and associated health risk from the use of the JUUL System.
FDA did just that for another authorized product. For IQOS, FDA found that “some of the chemicals are genotoxic or cytotoxic” in the product but “these chemicals are present in very low levels and potential effects are outweighed by the substantial decrease in the number and levels of HPHCs found in [combustible cigarettes].” It should have done the same here but chose otherwise.
Deficiency 4: The MDO asserted that Juul Labs provided data showing its Menthol 5.0% product is potentially mutagenic (ie: causes damage to cells). As a result, the MDO claimed that FDA was precluded from making a determination of whether JUUL products are appropriate for the protection of public health.
However, the in vitro Ames study showed that the product was not mutagenic, according to the study protocol, OECD guideline, and testing criteria for determining a positive or negative response. According to the study report, applying the correct criteria and analysis, Menthol 5.0% was “considered to be negative for inducing mutagenicity in this assay.”
We believe that all perceived limitations identified by the MDO could have been resolved by clarifications through the usual, iterative process that defines a full review of product applications. The alleged deficiencies, if anything, were limitations that warranted additional engagement and review and could have been reconciled with information already provided in the PMTAs.
During the nearly two-year review period for its PMTAs, Juul Labs received just one substantive request for additional information, which it addressed by providing additional information, data, and analysis to support FDA’s review in June 2021. From June 2021 until the MDO in June 2022, FDA did not raise any other questions or otherwise engage substantively with JLI.
This limited engagement is in direct contrast to FDA’s usual, iterative process that defines a full and complete review of product applications generally and how it has managed other PMTAs specifically, particularly those that it has authorized.
The marketing decision applied a new and different standard to the data, which appears to have been created for, and applied only to, our PMTAs. FDA had previously authorized new products that lacked toxicological data (VERVE), had genotoxic and mutagenic concerns (IQOS), presented toxicological risks from unknown leachable compounds (Logic), or showed a toxicological profile that was similar to a traditional cigarette (Moonlight VLN Cigarettes).
Below are examples of how FDA evaluated toxicological data for other applications. Here, FDA identified areas of concern but resolved those issues by accounting for other scientific findings to conclude that the products were appropriate for the protection of public health.
| Product | Toxicological Concern | Resolution |
| Verve¹ | “No original toxicology studies were submitted by the applicant for any of the VERVE products. The applicant provided toxicological assessments, which included hazard and exposure assessments of the ingredients associated with VERVE Discs and Chews. The exposure assessments relied on toxicity values intended for foods as derived by regulatory and industrial trade associations; as such, these values are not intended for tobacco products.” | “Nonetheless, based on the data from oral exposure studies and the estimated exposures to ingredients made by the applicant from the use of VERVE , the information supported the determination that the added ingredients were not of toxicological concern given the margins of exposure in relation to oral toxicity studies derived from published reference values.” |
| IQOS² | “Eleven chemicals were identified with genotoxic potential. Based on the available toxicological data and predictive toxicology modeling analysis submitted by the applicant, 20 of the 30 chemicals exhibit concerns for potential health effects.”
“Many of the chemicals do not have sufficient inhalation toxicity or genotoxicity/carcinogenicity data to inform the toxicological evaluation of heated tobacco products. The data provided by the applicant is not sufficient to support their conclusion that these compounds pose no risk to IQOS users . . . .” “Similar to the in vitro studies, it is difficult to determine the carcinogenic potential of long-term exposure to Heatstick aerosols from these evaluations. The data suggest there is potential for carcinogenic effects from Heatstick aerosols, but at much higher exposure levels than required for CC smoke.” |
“However, although there is potential for genotoxicity with some of these compounds, the exposure levels appear low and the available data does not preclude a conclusion the products are appropriate for the protection of public health.””Although some of the chemicals are genotoxic or cytotoxic, these chemicals are present in very low levels and potential effects are outweighed by the substantial decrease in the number and levels of HPHcs found in CC.” |
| Logic³ | “The applicant submitted a risk assessment for the identified, partially identified, and unknown simulated leachable compounds in the new products. The applicant concluded that the potential risks to consumers from identified and partially identified leachable compounds are acceptable but risk for the unknown leachable compound was above the benchmark value of 1.0 which indicates potential risks of concern.” | “Although simulated leachable compounds for all new products can be hazardous, at the low levels present, if there is any contribution towards cancer hazard, these risks are outweighed by decreases in HPHCs by 83–99% in all new products.” |
| Moonlight VLN Cigarettes⁴ | “HPHC data for both VLN™ cigarettes indicates that noncancer hazards and cancer risks are likely similar to or slightly lower than NNC cigarettes, based on HPHC comparisons to top market-share cigarettes.”
“The toxicology review determined that overall, based on ISO regimen HPHC data, the noncancer hazards due to use of the VLN™ cigarettes are likely similar to those with use of the commercially marketed NNC cigarette comparators. In addition, based on the ISO regimen HPHC data, cancer risks due to use of the VLN™ cigarettes are likely similar and may be less than those associated with use of the commercially marketed NNC cigarette comparators.” “The toxicology review noted that increases in acetaldehyde and acrylonitrile via the CI regimen likely do not raise cancer-risk-related concerns for the VLN™ cigarettes. Overall based on these CI regimen HPHC data, cancer risks are likely similar with use of VLN™ cigarettes and use of commercially marketed NNC cigarette comparators.” |
“As TPL, I agree with the toxicology review conclusion. After consideration of all the toxicological data presented, the overall toxicological risks of VLN™ cigarettes are likely similar to those associated with use of the six comparator products that represent a significant portion of the cigarette market. However, the potential for a relative benefit compared to NNC cigarettes exists for smokers who switch completely to VLN™ cigarettes, then reduce cigarette use, and eventually totally quit.” |
¹FDA TPL Review of 22nd Century Group Inc.’s PMTAs PM0000491–PM0000492, p. 15, 27, 28, 34.
²FDA TPL Review of Philip Morris Product S.A.’s PMTAs PM0000424–426, PM0000479, p. 32, 39, 42.
³FDA TPL Review of Logic Technology Development LLC’s PMTAs PM0000529.PD1– PM0000531.PD1, PM0000535.PD1–PM0000537.PD1, PM0000540.PD1–PM0000541.PD1, p. 37.
⁴FDA TPL Review of 22nd Century Group Inc.’s PMTAs PM0000491–PM0000492, p. 15, 27, 28, 34.