My colleagues at the UCSF TCORS have submitted this public comment to the FDA on additions to its Harmful and Potentially Harmful Constituents list.  We support the FDA's proposal to add 19 new constitutents to this list and suggest adding more, including menthol.  A PDF of the comment, including the appendix, is available here.  The regulations.goc tracking number is  1k3-9cij-8wgr.

 

In addition to the 19 constituents FDA proposes to add to the list of Harmful and Potentially Harmful Constituents, FDA should also add compounds that may be carcinogenic or cause pulmonary or cardiovascular harms when inhaled, especially oils and chemicals and chemical classes found in e-cigarette flavorants, and FDA should use as additional criteria California’s Proposition 65 list of carcinogens and reproductive toxicants and the California Air Resources Board’s list of Toxicant Air Contaminants

 

UCSF TCORS

 

Lauren K. Lempert, JD, MPH; Gideon St.Helen, PhD; Jeff Gotts, MD; Shannon Kozlovich, PhD;

Matthew Springer, PhD; Bonnie Halpern-Felsher, PhD; Stanton A. Glantz, PhD

 

Docket No. FDA-2012-N-0143

 

October 2, 2019

 

FDA is proposing to add the following 19 toxicants that may be found in tobacco products, including electronic cigarettes, to the list of HPHCs: acetic acid, acetoin, (also known as 3-hydroxy-2-butanon3), acetyl propionyl (also known as 2,3-pentanedione), benzyl acetate, butyraldehyde, diacetyl, diethylene glycol, ethyl acetate, ethyl acetoacetate, ethylene glycol, furfural, glycerol, glycidol, isoamyl acetate, isobutyl acetate, methyl acetate, n-butanol, propionic acid, propylene glycol. (These constituents are shown in Table 1 of FDA’s Notice and Request for Comments.)  We support adding these 19 toxicants to the HPHC list.

 

The proposed list, however, omits several important toxicants delivered by new products, notably e-cigarettes and heated tobacco products.  In addition to the 19 toxicants FDA proposed, the list should be expanded to include other important toxicants and chemical classes delivered by these products.  It its especially important for FDA to update the HPHC list to take into account the ingredients, additives, and smoke and aerosol constituents in e-cigarettes and other newly deemed tobacco products (including cigars, hookah, and heated tobacco products such as IQOS) that will likely be included in PMTAs filed in the coming months.

In particular, FDA’s failure to consider 56 of the chemicals reported by PMI[1] to be higher in IQOS emissions than in reference cigarette mainstream smoke that were not included in the current list of 93 HPHCs may have contributed to FDA’s inappropriate decision to approve the IQOS PMTA.[2]

FDA first established the HPHC list in April 2012, and the list currently contains 93 HPHCs.[3] FDA’s proposal appropriately recognizes that the HPHC list that was established in 2012 does not reflect the current range of tobacco products now subject to the Agency’s tobacco product authorities or their health effects, including electronic cigarettes, heated tobacco products, and their associated components and parts.

The 2012 HPHC list is heavily weighted towards carcinogens; however, the major health effects identified for e-cigarettes include cardiovascular[4] and pulmonary impacts.[5] Even before the recent reports of serious lung ailments and deaths in teens and young adults that may be associated with cannabis or nicotine e-cigarette vaping,[6] evidence mounted that e-cigarettes may have considerable cardiopulmonary effects.  An August 2019 peer-reviewed paper[7] concluded that using e-cigarettes induces nicotine-dependent protease release from resident pulmonary immune cells. Thus, chronic e-cigarette use disrupts the protease-antiprotease balance by increasing proteolysis in the lung, which may place e-cigarette users at risk of developing chronic lung disease. These data raise significant concern about how dangerous e-cigarettes are.

Also, the list does not include ultrafine particles or chemicals in flavoring agents used in e-liquids and flavored e-cigarettes which affect cardiovascular[8] and pulmonary systems.[9] The carcinogen pulegone, found in mint- and menthol-flavored e-cigarettes and smokeless tobacco,[10] may have health risks when inhaled.

 

Updating the HPHC list to consider effects beyond cancer is especially important in light of the July 2019 federal court order[11] requiring e-cigarette manufacturers to submit premarket tobacco product applications (PMTAs) by May 2020.  In determining whether new tobacco products will obtain marketing authorization, applicants are required to submit a “full statement of the components, ingredients, additives, and properties, and of the principle or principles of operation” of the new product.[12] The Guidance for PMTAs provides, “For each new tobacco product, you should report the levels of harmful and potentially harmful constituents (HPHC), including smoke constituents, as appropriate to the product.”[13] For new tobacco products that are smoke (e.g., cigarettes), quantitative levels should be determined in smoke generated using both the ISO and Canadian Intense smoking regimens.  If an alternative to these testing methods is used, you should provide the basis for your selection of the alternative method.” In its consideration of the potentially thousands of PMTAs that will be submitted within 7 months, FDA will need to analyze whether the ingredients, including flavors, additives, and smoke and aerosol constituents, are included on the list of HPHCs, and what effect they have on the health risks of that product. 

Compounds that may be safe to ingest are not necessarily safe to inhale.  The literature shows that some flavorants and other additives become lung irritants and potentially dangerous when inhaled, and compounds that may be safe when isolated can become harmful when they interact with other constituents. Several constituents of e-cigarettes may have cardiovascular and pulmonary as well as carcinogenic effects when they are heated and inhaled.

1. We support FDA’s proposed addition of glycidol and ethylene glycol to the HPHC list applying the criteria that were applied for the original list
   1. We support FDA’s addition of glycidol to the list of HPHCs

 

FDA has tentatively concluded that in revising the HPHC established list, the agency should continue to apply the criteria that were originally applied when determining whether a constituent should be put on the list. Following a review of the data concerning degradation of glycerol when heated, and observing that glycidol can form and appear in heated e-cigarette aerosol, FDA has applied the original criteria and tentatively concluded that glycidol should be included on the HPHC list.  FDA notes that the International Agency for Research on Cancer (IARC) has identified glycidol as a probable carcinogen.

 

We support FDA’s application of IARC criteria, and support the inclusion of glycidol on the HPHC list as a probable carcinogen. That said, as we discuss elsewhere in this comment, whether a chemical is a probable carcinogen should be one of several criteria FDA uses in determining whether to add a chemical to the HPHC list, and should not be the exclusive criterion.

 

1. 2.  We support FDA’s addition of ethylene glycol to the list of HPHCs

 

FDA has tentatively concluded that ethylene glycol should also be included on the HPHC list, noting that the California Environmental Protection Agency (Cal EPA) identified ethylene glycol (ingested) as a reproductive toxicant based on its developmental toxicity. 

 

We support FDA’s application of Cal EPA criteria, and agree that certain products identified by Cal EPA as reproductive toxicants should be added to the HPHC list. That said, as we discuss elsewhere in this comment, FDA must not only consider whether a product is toxic when ingested, but also must consider whether a product is toxic when inhaled, whether or not it is toxic when ingested.

 

2. FDA should also consider constituents identified by the National Institute for Occupational Safety and Health (NIOSH) as having adverse respiratory effects as an additional criterion for determining whether a constituent should be added to the HPHC list, and should include 17 additional constituents that meet this criterion

We agree with FDA’s proposal to use constituents identified by the National Institute for Occupational Safety and Health (NIOSH) as having adverse respiratory effects as an additional criterion for determining whether a constituent should be added to the HPHC list.  We support FDA’s proposal to add to the list 17 additional constituents that meet this criterion (acetic acid, acetoin, acetyl propionyl, benzyl acetate, butyraldehyde, diacetyl, ethyl acetate, ethyl acetoacetate, ethylene glycol (which also meets one of the criteria that were originally applied), furfural, glycerol, isoamyl acetate, isobutyl acetate, methyl acetate, n-butanol, propionic acid, and propylene glycol).  FDA already considers whether NIOSH has identified a constituent as a potential occupational carcinogen in determining whether that constituent should be included on the HPHC list.  But whether a constituent has adverse respiratory effects may be even more significant than its carcinogenic effects when considering the constituents in e-cigarettes and e-liquids that will be inhaled.

1. 1. We support FDA’s addition of propylene glycol and glycerol to the HPHC list

 

A large contributor to the exploding appeal of e-cigarettes among both adults and adolescents is the effective delivery of nicotine in the form of an aerosol composed of the vehicle solvents propylene glycol (PG) and glycerol. These solvents are used to generate the aerosol without tobacco combustion. While FDA uses the chemical term “glycerol” in its list of 19 proposed additions to the HPHC list, this e-cigarette ingredient is also frequently called “glycerin” or “vegetable glycerin” and is abbreviated as “VG,” and these terms are used interchangeably. We will use the term “VG” in these comments to refer to glycerol, glycerin, and/or vegetable glycerin because much of the scientific literature uses “VG,” consumers see the term “VG” because the PG/VG ratio is included in many descriptions of e-liquids currently on the market, and FDA uses the term “VG” in its proposed rule on Premarket Tobacco Product Applications (PMTAs).[14]

Short-term occupational exposure to PG causes irritation of the airways, likely by activation of the receptors TRRPV1 and TRPA1, which are known to promote inflammation linked to asthma development.[15] Consistent with this concept, Dow Chemical Company’s Material Safety Data Sheet[16] for PG states that “At room temperature, exposure to vapor is minimal due to low volatility. Mist may cause irritation of upper respiratory tract...” (emphasis added; “mist” is a synonym for aerosol).  PG/VG also causes increased expression of inflammatory mucous proteins such as MUC5AC in mice, an effect verified in users of e-cigarettes.[17]

A September 2019 peer-reviewed study[18] shows many ways in which exposure to PG and VG from e-cigarettes disrupts normal lung function.  In the study, researchers exposed mice to e-cigarette aerosol without and with nicotine and found that the aerosol altered the lipid (fat) balance in the lungs in ways that depressed the ability of the lung macrophages to fight infections and disrupted normal product of surfactants (chemicals in the lungs that help keep the air-sacs from collapsing). The authors conclude that chronic e-cigarette aerosol aberrantly alters the physiology of lung epithelial cells and resident immune cells and promotes poor response to infectious challenge.  Notably, they found that alterations in lipid homeostasis and immune impairment are independent of nicotine, thereby warranting more extensive investigations of the PG/VG and other chemicals used in e-cigarettes.

Exogenous lipoid pneumonia due to exposure to glycerin-based oils in e-cigarettes was reported as early as April 2012.[19] VG in e-liquids has been tied to lung damage and has been shown to form many toxic compounds when heated, including those on FDA’s list of HPHCs, such as formaldehyde, acetaldehyde, and acrolein.[20]

 

Because of these harms, PG and VG should be added to the HPHC list.

In its proposed rule for PMTAs,[21] FDA appropriately requires applicants to specify the PG/VG ratio in e-liquids and e-cigarettes to determine whether permitting the marketing of the product would be appropriate for the protection of the public health.  Most of the evidence of potential harm reported in the scientific literature has involved both of these compounds, and we are aware of no studies that allow proportioning health risk to the relative amount of one of these compounds as a proportion of another.[22] Nevertheless, the relative concentration of each humectant in the e-liquid influences the type and amount of thermal degradation products emitted, which may translate to differential health risk. For example, one study found that PG-based e-liquid generated higher levels of formaldehyde and acetaldehyde than VG-based e-liquid by a factor of 2 and 12, respectively.[23]

3. We support FDA’s addition of diethylene glycol to the HPHC list

FDA proposes to add diethylene glycol (DEG) to the HPHC because of concerns that a product that contains either VG or PG also could be contaminated by DEG, and the acute health consequences from exposure to DEG-contaminated products may be serious and irreversible. We agree.

4. FDA should add additional chemicals or chemical compounds to the existing HPHC list because they are harmful or potentially harmful to consumers when they are heated and inhaled in e-cigarettes, heated tobacco products, and other tobacco products.

The existing HPHC list focuses primarily on harmful constituents that are produced from combustible cigarettes.  However, since that list was established in 2012, products (including but not limited to e-cigarettes and IQOS) that electronically heat tobacco, nicotine, flavorants, and/or other additives are, or soon will be, marketed in the United States.  

1. 1. Pulegone should be added to the HPHC list

 

Pulegone, a constituent of oil extracts prepared from mint plants, is a carcinogen that causes hepatic carcinomas, pulmonary metaplasia, and other neoplasms in rodents, and can also cause liver and kidney failure. Although the FDA banned synthetic pulegone as a food additive in 2018 and the chemical is banned in the European Union and in the state of California, substantial amounts of pulegone have been detected in mint- and menthol-flavored e-cigarette liquids and smokeless tobacco products. A September 2019 analysis[24] measured daily pulegone exposure from e-cigarettes and smokeless tobacco at higher levels compared with exposure from menthol cigarettes and compared the risk associated with pulegone content in combustible menthol cigarettes to the pulegone content in mint- and menthol-flavored e-cigarettes and smokeless tobacco.

 

 The margin of exposure (MOE) is the measure used by the FDA and other regulatory agencies for cancer risk assessment of food additives, and cancer risk is inversely proportional to the MOE, with values of 10,000 or below requiring mitigation strategies. This study found that the MOE for all the products that were analyzed are below the accepted MOE threshold of 10,000 for carcinogens. This suggests that users of mint- and menthol-flavored e-cigarettes and smokeless tobacco are exposed to pulegone levels higher than the FDA considers unacceptable for intake of synthetic pulegone in food, and higher than in smokers of combustible menthol cigarettes. (March 2019 study[25] found that mint-, menthol-, and cucumber-flavored Juul pods, not studied in the Jabba/Jordt analysis, also contain pulegone.

 

Because these findings establish health risks associated with pulegone intake, especially in connection with use of mint- and menthol-flavored e-cigarettes and smokeless tobacco, FDA should add pulegone to the list of HPHCs. 

 

1. 2. Vitamin E acetate should be added to the HPHC list

 

On September 6. 2019 the New England Journal of Medicine (NEJM) published a report[26] describing 53 cases of severe pulmonary disease associated with the use of vaping products among generally young, healthy persons.  As of September 27, 2019, at least 805 cases of serious lung illness associated with the use of vaping products had been reported to the CDC[27] from 46 states and 1 U.S. territory, and 12 deaths have been confirmed in 10 states.

 

            While no single product is linked to all cases of lung disease, vitamin E acetate (tocopheryl acetate) may be responsible for some of the reported cases of severe pulmonary disease because it is used in cannabis (THC) oil vaporizers. The extent to which vitamin E acetate has been used in e-cigarettes is not known but cannot be ruled out due to a lack of oversight of e-cigarette manufacturing and the ease of product manipulation by retailers and users. Vitamin E acetate is not known to be harmful when ingested as a vitamin supplement or when applied to the skin, but data on its inhalation effects suggest that its oil-like properties could be associated with the observed pulmonary symptoms.[28] Exogenous lipoid pneumonia can occur when an oil is inhaled. Once inhaled into the lungs, the oil can cause an inflammatory reaction, and the severity of the reaction can depend on the length of exposure. Severe inflammation can permanently damage the lungs. Lipid-laden macrophages and acute lung injury associated with e-cigarette inhalation has been reported previously.[29]

 

The NEJM report states:

 

E-cigarette liquids and aerosols have been shown to contain a variety of chemical constituents that may have adverse health effects. [fn] Major declared constituents in nicotine-based e-cigarettes include propylene glycol and glycerin, [fn] in addition to nicotine. Identified contaminants include polycyclic aromatic hydrocarbons, nitrosamines, volatile organic chemicals, and inorganic chemicals such as toxic metals. [fn] Endotoxins and flavoring compounds such as diacetyl and 2,3-pentanedione have also been detected. [fn] The health risks of some constituents remain poorly characterized, and toxicologic assessment of these substances is an active area of ongoing research. [fn] In addition to nicotine, e-cigarette devices can be used to deliver a variety of other recreational drugs, including THC-based oils. [fn]

            Until more data are available and analyzed, FDA should adopt the precautionary principle and add to the HPHC list vitamin E acetate and other “oils” (fatty acids).

5. Flavorants and other additives in e-cigarettes, heated tobacco products, and other deemed tobacco products become lung irritants when inhaled, so FDA must consider the chemical reaction that occurs when these constituents are heated (even if not combusted) and inhaled.

When considering flavorants and other additives in e-cigarettes, heated tobacco products, and other products that produce inhaled aerosols, FDA must not rely on previously established designations that these constituents are “generally recognized as safe” (GRAS) for ingestion. Inhalation is a fundamentally different exposure mode than ingestion, so the fact that a substance is GRAS for ingestion provides no useful information regarding safety for inhalation.

Erythropel et al.’s October 2018 study[30] found flavor aldehyde PG acetals in commercial e-liquids, and concluded that e-liquids are potentially reactive chemical systems in which new compounds can form after mixing of constituents and during story, and these can have unexpected toxicological effects. Erythropel et al.’s 2019 study[31] reported the presence of flavor aldehyde VG acetals in e-liquids and aerosols, and found that the compounds present in some Juul e-liquids (e.g., crème brulee) are delivered efficiently to the aerosol when heated, exposing users to the PG and VG acetals of vanillin. Appreciable amounts of acetals were present in the aerosol which, if inhaled, may cause irritation and contribute to inflammatory responses. This study demonstrates that e-cigarette liquids can be chemically unstable, with reactions occurring between flavorant and solvent components immediately after mixing at room temperature. The resulting compounds have toxicological properties that differ from either the flavorants or solvent components. These findings suggest that the reporting of manufacturing ingredients of e-liquids (including the reporting of HPHCs) is not alone sufficient for a safety assessment. Rather, to effectively analyze the risks, FDA should require companies to establish an analytical workflow to detect newly formed compounds in e-liquids and their potential toxicological effects.²⁹

Omaiye et al.[32] studied the flavor chemical and nicotine concentrations in 8 currently marketed Juul e-cigarette pods to evaluate the cytotoxicity and potential health impacts. They identified 59 flavor chemicals in Juul pod fluids, and found that all pod fluids were cytotoxic at a 10% dilution, and most aerosols were cytotoxic at concentrations between 0.2 and 1.8%. The study demonstrated that not only are the Juul flavor pods attractive to youth, but the concentrations of nicotine and some flavor chemicals (e.g., ethyl maltol) are high enough to be cytotoxic in acute in vitro assays, suggesting that Juul products could lead to adverse health effects with chronic use.

 

As described above, Jordt and Jabba found[33] that mint- and menthol-flavored e-cigarettes contain extremely high levels of pulegon.

 

Further, a study by Khlystov and colleagues suggests that flavors are major contributors to emissions of toxic aldehydes from e-cigarettes.[34]

 

These findings build on a 2016 study[35] that investigated the cellular effects of exposure to e-cigarette aerosol and the impact of various product characteristics on potential inhalation toxicity of e-cigarette products. The researchers found that exposure to e-cigarette aerosol resulted in decreased metabolic activity and cell viability, and flavors in e-liquids can have an acute cytotoxic effect on respiratory cells. In this study, menthol, coffee, and strawberry flavors had a significant impact on overall cytotoxicity of e-cigarette products. (although the study did not look at which of the flavoring compounds caused this cytotoxicity and release of inflammatory mediators, and only one e-liquid product was tested for each flavor name. The study also confirmed that increasing the device power by increasing battery output voltage resulted in significantly higher overall toxicity of e-cigarette aerosol.

 

Earlier studies had already found that inhalation of complex mixtures like flavored e-cigarette aerosols can cause a wide range of adverse health effects, ranging from simple irritation to systemic diseases.[36] Cinnamon flavorings in refill fluids were found to be linked to cytotoxicity, which could adversely affect e-cigarette users.[37]

 

Clapp et al showed that inhalation of cinnamaldehyde in flavored e-cigarette liquids may increase the risk of respiratory infections in e-cigarette users.[38] Gerloff et al showed that flavorings such as acetoin (butter), diacetyl, pentanedione, maltol (malt), ortho-vanillin (vanilla), coumarin, and cinnamaldehyde in some flavored e-cigarette liquids and aerosols can cause significant loss of epithelial barrier function and proinflammatory response in lung cells.[39] Muthumalage et al found that commonly used e-cigarette flavoring chemicals, including diacetyl, cinnamaldehyde, acetoin, pentanedione, o-vanillin, maltol and coumarin, can trigger an inflammatory response in monocytes and increased oxidative stress, and mixing a variety of flavors results in greater cytotoxicity and oxidative stress and may be more harmful to users, providing insights into potential pulmonary toxicity and tissue damage in e-cigarette users.[40] Park et al found that two widely used e-cigarette flavoring chemicals, diacetyl (often used in butter flavors) and its substitute 2,3-pentanedione, impair the cilia function in airway epithelium and likely contribute to the adverse effects of e-cigarettes in the lung.[41]

 

1. 1. Flavored e-liquids exacerbate vascular endothelial dysfunction, which often precedes cardiovascular diseases

September 2019 study[42] investigated the effects of flavored e-liquids on endothelial health and endothelial cell-dependent macrophage activation. The study found that acute exposure of human-induced pluripotent stem cell-derived endothelial cells to e-liquids containing several popular flavors, or to serum from e-cigarette users, leads to changes in cellular properties indicative of endothelial dysfunction, which often precedes cardiovascular diseases. The data revealed a range of cytotoxicity of the e-liquids, with the cinnamon-flavored e-liquid being most toxic and leading to significantly decreased cell viability, increased reactive oxygen species (ROS) levels, caspase 3/7 activity, and low-density lipoprotein uptake, activation of oxidative stress-related pathway, which are all consistent with endothelial dysfunction. The ability of endothelial cells to form tubular networks, and cell migration into cell-free regions, were also impaired. Conditioned media from the endothelial cells after exposure to e-liquid induced macrophage polarization into a pro-inflammatory state, leading to the production of interleukin-1β and -6, and an increase in ROS. Exposure of endothelial cells to serum of e-cigarette users also increased ROS levels in the cells and impaired their pro-angiogenic properties. Inflammatory cytokine levels in the serum of e-cigarette users were increased. Other studies have also shown various kinds of cytotoxicity in vitro for common flavors.[43]^{, [44]}

 

In addition to continuing to apply the criteria that were originally applied when determining whether a constituent should be put on the 2012 list of HPHCs, which largely considered whether a chemical is carcinogenic, FDA should evaluate whether a chemical exacerbates endothelial dysfunction in particular, and in general whether exposure to a chemical may have cardiovascular effects.

 

In addition to continuing to apply the criteria that were originally applied when determining whether a constituent should be put on the 2012 list of HPHCs, FDA should also evaluate whether chemicals, especially those that are used in e-cigarette flavorings, are potentially harmful when inhaled, regardless of whether they are GRAS for ingestion.

 

 

6. Although menthol has not itself been shown to be toxic, FDA should include it on the HPHC list because of its interaction with nicotine and tobacco carcinogens

 

In addition to menthol-flavored conventional cigarettes (i.e., cigarettes marketed with “menthol” as a characterizing flavor, such as Newport or Kool), most cigarettes, even those that are not labeled menthol as a characterizing flavor, contain menthol as an ingredient.  Likewise, e-cigarette liquids and other tobacco products include menthol as an ingredient, even if they are not sold as “menthol-flavored.”

 

In 2011 the FDA Tobacco Products Scientific Advisory Committee (TPSAC) issued a report concluding that “removal of menthol cigarettes from the marketplace would benefit public health in the United States.”[45] FDA independently undertook a thorough review of the available science concerning menthol in cigarettes and issued its own report in 2013.  Using a “weight of scientific evidence” approach, FDA’s independent analysis found that: (1) menthol use is likely associated with increased smoking initiation by youth and young adults; (2) menthol in cigarettes is likely associated with greater addiction; (3) menthol smokers show greater signs of nicotine dependence and are less likely to successfully quit smoking; (4) menthol’s cooling and anesthetic properties can reduce the harshness of cigarette smoke; and (5) menthol cigarettes are marketed as a smoother alternative to non-menthol cigarettes.  Considering this combined evidence, FDA concluded that these findings “make it likely that menthol cigarettes pose a public health risk above that seen with non-menthol cigarettes.”[46]

 

Although menthol is not a direct cause of disease, menthol has an important indirect effect on disease risk because it interferes with the clearance of tobacco-specific carcinogens.  In particular, menthol biologically interacts with nicotine and tobacco carcinogens, and increases exposure to harmful carcinogens.[47] Tissues in the body that are directly exposed to tobacco are especially vulnerable to developing primary tobacco-related cancer tumors.[48] These tissues have difficulty with the biological clearance (removal) of tobacco carcinogens (e.g., NNAL), and the presence of menthol, even at low levels (below that needed to have menthol be a “characterizing flavor”), decreases the body’s ability to detoxify tobacco carcinogens.[49] 

 

This situation may explain why “menthol cigarettes” (i.e., cigarettes for which menthol is a characterizing flavor) have not been associated with increased cancer incidents over “non-menthol cigarettes” (i.e., cigarettes for which menthol is not a “characterizing flavor”). The high levels of menthol in “menthol cigarettes” may be having effects on blocking clearance of carcinogens similar to the low levels of menthol in “non-menthol” cigarettes. Because the levels of menthol in both “menthol” and “non-menthol” cigarettes both reduce clearance of tobacco carcinogens, comparing the effects of menthol and non-menthol cigarettes would not show any difference in risk, even though menthol is increasing carcinogen exposure in both classes of products.  Specifically, the failure to find an association between menthol and cancer risk may be due to the fact that menthol’s effects on carcinogen detoxification can occur at levels below that associated with menthol as a characterizing flavor.

 

Thus, menthol as an ingredient, even at levels below those needed to qualify menthol as a characterizing flavor, can increase cancer risk by slowing clearance of tobacco carcinogens from the body.

 

7. FDA should use the following additional criteria in deciding whether to add a constituent to the list of HPHCs:

 

1. 1. FDA should include on the HPHC list constituents identified by the State of California known to be human carcinogens or reproductive toxins (Proposition 65 list) or a toxic air contaminant

 

The State of California maintains a list of chemicals known to cause cancer or reproductive toxicity known as the “Proposition 65 list.”[50] (Appendix).  Chemicals go through an extensive review process, including public notice and comment, so are thoroughly vetted.[51]

 

The Proposition 65 list includes chemicals identified by the World Health Organization International Agency for Research on Cancer (IARC) as causing cancer in humans or laboratory animals.  It also includes chemicals identified by two California scientific committees, the Carcinogen Identification Committee and the Developmental and Reproductive Toxicant Identification Committee.  It also includes chemicals identified by “authoritative bodies” (the US Environmental Protection Agency, US Food and Drug Administration (US FDA), National Institute for Occupational Safety and Health, the National Toxicology Program of the US Department of Health and Human Services, and IARC.) 

 

The FDA should consider the California Proposition 65 list an authoritative body and include the full range of chemicals on the Proposition 65 list now and in the future as part of the updated FDA HPHC list.

 

1. 2. FDA should include on the HPHC list constituents identified by the California Air Resources Board (CARB) as “Toxic Air Contaminants” under the Toxic Air Contaminant Identification and Control Act

 

The California Air Resources Board (CARB) has identified and regulated “Toxic Air Contaminants” under the Toxic Air Contaminant Identification and Control Act (AB 1807, Tanner 1983).[52]  In selecting substances for review, the CARB must consider criteria relating to "the risk of harm to public health, amount or potential amount of emissions, manner of, and exposure to, usage of the substance in California, persistence in the atmosphere, and ambient concentrations in the community" [Health and Safety Code section 39666(f)]. The law establishes a two-step process of risk identification and risk management to address the potential health effects from air toxic substances and protect the public health of Californians. The first (identification) step is relevant for the FDA HPHC list.

 

The identification step begins with the CARB and the California Environmental Protection Agency Office of Environmental Health Hazard Assessment (OEHHA) determining if a substance should be formally identified as a toxic air contaminant (TAC) in California. During this process, the CARB and the OEHHA staff draft a report that serves as the basis for this determination. The CARB staff assesses the potential for human exposure to a substance and the OEHHA staff evaluates the health effects. A thorough public process assures accountability and public input through one. Staff conducts public workshops to allow for direct exchanges of information with interested constituencies, publishes the draft risk assessments, and widely distributes with a public notice requesting comments. The final risk assessment (identification) report includes a record of the public comments and how they were addressed. After the CARB and the OEHHA staff hold several comment periods and workshops, the report is then submitted to the independent, nine-member, Scientific Review Panel (SRP), who reviews the report for its scientific accuracy. After the SRP's approval, CARB staff prepare a hearing notice and draft regulation to formally identify the substance as a TAC. Based on the input from the public and the information gathered from the report, the Board decides whether to identify a substance as a TAC.

 

The current list of TACs[53] is

• Acetaldehyde
• Asbestos
• Benzene
• Benzo[a]pyrene
• 1,3-Butadiene
• Cadmium
• Carbon Tetrachloride
• Chlorinated Dioxins
• Chloroform
• Diesel Exhaust^a
• Ethylene Dibromide
• Ethylene Dichloride
• Ethylene Oxide
• Formaldehyde
• Hexavalent Chromium
• Inorganic Arsenic
• Inorganic Lead^b
• Methylene Chloride
• Methyl Tertiary Butyl Ether^c
• Naphthalene^d
• Nickel
• Perchloroethylene
• Trichloroethylene
• Vinyl Chloride

These chemicals list should be included in the updated FDA HPHC list and the California TAC list should become an authoritative body that FDA relies on for furture additions to the HPHL list. 

 

After a public process similar to that described for TACs, the SRP also approved a report identifying TACs that may disproportionately impact infants and children as required by California’s Children’s Environmental Health Protection Act (SB 25, Escutia; chaptered 1999).  These compounds, listed in Table 1 (copied from Table 4 of the report Prioritization of Toxic Air Contaminants Under the Children’s Environmental Health Protection Act) should be highlighted in FDA’s new HPHC list.[54] 

 

Table 1. TACs that may disproportionately impact infants and children.
Toxic Air Contaminant	Endpoints of Most Concern	Major Reasons Why Chosen
Tier 1 TACs
Acrolein	Respiratory Irritant	Exacerbation of asthma; modeling predictions indicate concentrations in urban air above cREL
Chlorinated dioxins and dibenzofurans (dioxins)	Developmental toxicity, immunotoxicity, endocrine disruption; thyroid effects	Widespread exposure; endocrine disruption, thyroid and immuno-toxicity at low body burden; young animals more susceptible than older animals
Lead and compounds	Developmental neurotoxicity/CNS effects	Children the most susceptible subpopulation due to developmental neurotoxicity.
Particulate Emissions from Diesel-fueled Engines (Diesel exhaust particulate matter)	Enhancement of allergic response; exacerbation of asthma; developmental effects, genotoxicity and lung cancer.	Enhancement of allergic response and implications for exacerbation and possible induction of asthma; Major source of ambient PAHs, PM10; exacerbation of asthma by PM10; PAH developmental toxicity and genotoxicity a concern.
Polycyclic Organic Matter (POM)	Developmental effects, genotoxicity and lung cancer	Animal studies indicate teratogenicity, and fetotoxicity; human studies indicate greater genotoxicity following in utero exposures.
Tier 2 TACs
Arsenic and compounds (inorganic)	Carcinogenicity; potential neurotoxicity	Evidence of increased susceptibility to carcinogenicity early in life; possible neurotoxicity
Benzene	Hematopoietic effects, carcinogen	Widespread exposure; studies suggest possible increased risk of childhood leukemia in children of benzene-exposed workers.
Carbon disulfide	Neurotoxic effects; possible developmental toxicity	Neurotoxicity a key toxicological endpoint for children; metabolism slow in neonate; lower lethal dose in neonatal mice.
Chlorine	Respiratory irritant	Exacerbation of asthma.
Formaldehyde	Respiratory irritant; carcinogen	Widespread exposure; cREL below urban ambient and indoor levels; exacerbation of asthma; indication that children more susceptible to lung function impacts.
Ethylene glycol ethers (EGEE, EGME, EGEEA, and EGMEA)	Developmental effects including teratogenicity	Teratogenic effects; large emissions of glycol ethers from stationary sources.
Manganese and compounds	Neurotoxicity	Neurotoxicity a key endpoint for infants and children.
Mercury and compounds	Developmental neurotoxicity	Children most susceptible subpopulation due to developmental neurotoxicity.
Methyl Bromide	Neurotoxicity	Infants and children are susceptible subpopulations for neurotoxicity.
Methylene chloride	Metabolized to carbon monoxide	Carbon monoxide has higher affinity for fetal hemoglobin; high emissions from stationary sources.
Polychlorinated Biphenyls (PCBs)	Developmental effects including neurotoxicity; thyroid effects; dioxin -like toxicity	Infants susceptible subpopulation for thyroid effects; infants and children for developmental neurotoxicity
Vinyl chloride	Carcinogenicity	Animal studies indicate much higher potency when exposure occurs in utero or perinatally than as mature animals.

 

8. The FDA should also consider classes of chemicals as well as specific chemicals

 

In addition to focusing on single chemicals that we know are toxic, FDA should also consider chemical classes. That is, inclusion unto the HPHC list should also be done based on the structure-activity relationships of chemicals for which their toxicity has not yet been specifically assessed but which are similar to known toxicants.  Absent such an approach FDA will continuously be engaged in a wild-goose chase for the toxicity of the thousands of chemicals that are potentially added into e-cigarette flavors or heated-tobacco products.

 

For example, compared to a ref cigarette, IQOS had higher levels of 56 chemicals. These chemicals were most likely flavor additives and their derivatives. We do not know the toxicology of most of them. But as St. Helen et al observed in their IQOS paper that some of these chemicals “belong to chemical classes that are known to have significant toxicity, such as α,β-unsaturated carbonyl compounds (eg, 2-cyclopentene-1,4-dione), 1,2-dicarbonyl compounds (eg, cyclohexane, 1,2-dioxo-), furans (eg, 2 (5H)-furanone) and epoxides (eg, anhydro linalool oxide).

 

The HPHC should, at a minimum, include:

 

• α,β-unsaturated carbonyl compounds
• 1,2-dicarbonyl compounds
• Furans
• Epoxides

 

It should also include “oils” (fatty acids), not just vitamin E acetate.

 

9. Conclusion  

 

FDA will soon be required to review possibly hundreds of premarket tobacco product applications (PMTAs) that will be filed by the May 2020 deadline for filing PMTAs for newly deemed products including e-cigarettes, heated tobacco products, cigars, and hookah. Therefore, FDA must update the existing list of Harmful and Potentially Harmful Constituents (HPHCs) to take into account the ingredients, additives, and smoke and aerosol constituents that are likely to be found in these products.

 

We support FDA’s 19 proposed additions to the HPHC list. In particular, we support the addition of the following chemicals that are frequently found in e-cigarette flavorants and additives:

• propylene glycol
• glycerol (also called “vegetable glycerin” or “glycerin”)
• diacetyl
• pentanedione (or “2,3-pentanedione”)

 

In addition to the 19 constituents FDA proposes to add to the HPHC list, FDA should also add other compounds that may be carcinogenic or cause pulmonary or cardiovascular harms when inhaled, especially chemicals found in e-cigarette flavorants. There is mounting scientific evidence suggesting that compounds that may be safe to ingest are not necessarily safe to inhale. The literature shows that some flavorants and other additives become lung irritants and potentially dangerous when inhaled, and compounds that may be safe when isolated can become harmful when they interact with other constituents. Several constituents of e-cigarettes may have cardiovascular, pulmonary, and carcinogenic effects when they are heated and inhaled.

 

In particular, FDA should add the following chemicals to the existing HPHC list:

 

• pulegone
• vitamin E acetate
• acetoin
• maltol
• ortho-vanillin (or “o-vanillin”)
• coumarin
• cinnamaldehyde
• menthol
• α,β-unsaturated carbonyl compounds
• 1,2-dicarbonyl compounds
• furans
• epoxides

 

Finally, FDA should use additional criteria for additions to the HPHC list.  FDA should add constituents identified by the State of California on its Proposition 65 list of constituents known to be human carcinogens and constituents identified by the California Air Resources Board (CARB) as “Toxic Air Contaminants” under the Toxic Air Contaminant Identification and Control Act.