TOXICOLOGICAL SCIENCES, 151(2), 2016, 347–364
doi: 10.1093/toxsci/kfw051
Advance Access Publication Date: March 11, 2016
Research Article
Proposed Mode of Action for Acrolein Respiratory
Toxicity Associated with Inhaled Tobacco Smoke
R. Philip Yeager,* Mary Kushman,* Susan Chemerynski,* Roxana Weil,*
Xin Fu,* Marcella White,† Priscilla Callahan-Lyon,‡ and Hans Rosenfeldt*,1
*Division of Nonclinical Science, Center for Tobacco Products, US Food and Drug Administration, Silver
Spring, Maryland 20993; †Division of Regulatory Project Management, Center for Tobacco Products, US Food
and Drug Administration, Silver Spring, Maryland 20993; and ‡Division of Individual Health Science, Center
for Tobacco Products, US Food and Drug Administration, Silver Spring, Maryland 20993
1
To whom correspondence should be addressed at Division of Nonclinical Science, Center for Tobacco Products, US Food and Drug Administration, 10903
New Hampshire Avenue, Silver Spring, Maryland 20993. Fax: (301) 847-8614. E-mail: [email protected].
Disclaimer: This information is not a formal dissemination of information by FDA and does not represent agency position or policy.
ABSTRACT
This article presents a mode of action (MOA) analysis that identifies key mechanisms in the respiratory toxicity of inhaled
acrolein and proposes key acrolein-related toxic events resulting from the inhalation of tobacco smoke. Smoking causes
chronic obstructive pulmonary disorder (COPD) and acrolein has been previously linked to the majority of smoking-induced
noncancer respiratory toxicity. In contrast to previous MOA analyses for acrolein, this MOA focuses on the toxicity of
acrolein in the lower respiratory system, reflecting the exposure that smokers experience upon tobacco smoke inhalation.
The key mechanisms of acrolein toxicity identified in this proposed MOA include (1) acrolein chemical reactivity with
proteins and other macromolecules of cells lining the respiratory tract, (2) cellular oxidative stress, including compromise
of the important anti-oxidant glutathione, (3) chronic inflammation, (4) necrotic cell death leading to a feedback loop where
necrosis-induced inflammation leads to more necrosis and oxidative damage and vice versa, (5) tissue remodeling and
destruction, and (6) loss of lung elasticity and enlarged lung airspaces. From these mechanisms, the proposed MOA analysis
identifies the key cellular processes in acrolein respiratory toxicity that consistently occur with the development of COPD:
inflammation and necrosis in the middle and lower regions of the respiratory tract. Moreover, the acrolein exposures that
occur as a result of smoking are well above exposures that induce both inflammation and necrosis in laboratory animals,
highlighting the importance of the role of acrolein in smoking-related respiratory disease.
Key words: acrolein; inhalation; tobacco smoke; mode of action; respiratory toxicity.
Acrolein is a highly reactive a,b-unsaturated aldehyde generated by the pyrolysis and combustion of tobacco products.
Acrolein is one of the volatile carbonyls noted in FDA’s list of
Harmful and Potentially Harmful Constituents that are in tobacco products or emitted when tobacco products are used
(Food and Drug Administration, 2012). Inhaled acrolein is considered to be the primary and most significant contributor to
noncancer respiratory effects from cigarette smoke (Agency for
Toxic Substances and Disease Registry [ASTDR], 2007;
Cunningham et al., 2011; Fowles and Dybing, 2003; Haussmann,
2012). ATSDR notes that smoke from various cigarettes contains
3–220 lg acrolein per cigarette (ATSDR, 2007). Importantly, the
wide range in reported acrolein levels may be attributed to the
machine smoking regime used in the various studies; smokers’
exposure to acrolein is likely greater than reported when using
the International Organization for Standardization (ISO)
method. The ISO method permits greater ventilation and has a
lower puff volume than the Massachusetts Department of
Public Health or Canadian Intense (CI) machine smoking methods and is generally considered to reflect the lowest levels of
Published by Oxford University Press on behalf of the Society of Toxicology 2016.
This work is written by US Government employees and is in the public domain in the US.
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tobacco smoke exposure that smokers experience (Counts et al.,
2004, 2005; Hammond et al., 2006; Roy et al., 2010). The air dilution that is allowed by open air vents in the ISO method, together with the lower puff volume specified in this machine
smoking method, results in the reporting of tobacco constituent
levels that are lower than those reported by the CI method. An
analysis of mainstream cigarette smoke conducted by
Haussmann estimates that among smoke constituents, acrolein
exposure represents 88.5% of the known noncancer hazard
(Haussmann, 2012). By comparison, Haussmann estimates the
relative noncancer hazards of hydrogen cyanide and acetylaldehyde to be 7.2 and 2.4%, respectively (Haussmann, 2010).
Similarly, Fowles and Dybing estimate that the ‘noncancer risk
index’ that they developed for respiratory irritation is orders of
magnitude higher for acrolein (172) compared with other known
toxic substances, such as acetylaldehyde (3.78) and formaldehyde (0.83) (Fowles and Dybing, 2003). Tobacco smoke has also
been shown to be suitable for predicting acrolein exposure in
humans, as was demonstrated by Alwis et al. (2015), who used
biomonitoring of the acrolein metabolites N-acetyl-S-[3-hydroxypropyl]-L-cysteine (3-HPMA) and N-acetyl-S-[3- carboxyethyl]L-cysteine (CEMA) to characterize acrolein levels in the U.S.
population. In this study, the ratio of 3-HPMA to CEMA was
found to be significantly greater in smokers than nonsmokers.
Thus, acrolein inhaled as a tobacco smoke constituent presents
a significant public health problem.
Several reviews have summarized the literature describing
the mechanisms and adverse effects of acrolein in vitro and
in vivo, including respiratory toxicity from inhalation exposure
(ATSDR, 2007; Beauchamp et al., 1985; Bein and Leikauf, 2011;
EPA, 2003; Ghilarducci and Tjeerdema, 1995; Moghe et al., 2015;
Stevens and Maier, 2008; World Health Organization [WHO],
2002). A variety of mechanisms of toxicity have been proposed
for acrolein, including protein adduction, oxidative stress, mitochondrial dysfunction, DNA adduction, endoplasmic reticulum
(ER) stress, structural and membrane effects, and inflammation
and other immune alterations (Bein and Leikauf, 2011; Moretto
et al., 2012a; Moghe et al., 2015). Although the roles that these detailed mechanisms play within the overall toxicity spectrum of
inhaled acrolein have been characterized, a mode of action
(MOA) approach (Boobis et al., 2008; Dellarco and Wiltse, 1998;
EPA, 2003, 2005; Julien et al., 2009) can sufficiently define the key
biological events and processes that are integral to acroleinrelated respiratory disease such that reasonable conclusions
about the effects of tobacco-related acrolein exposure can be
made. Therefore, the aim of this study is to provide evidence to
link acrolein as the causal agent in exposures from cigarette
smoke to key events resulting in COPD in smokers. For this purpose, we sought to develop an MOA analysis that specifically
addresses the role of acrolein respiratory toxicity in inhaled tobacco smoke.
Inhaled acrolein has multiple effects on mammals, including
cardiovascular and respiratory pathologies (ATSDR, 2007).
However, the existing scientific evidence provides more robust
evidentiary support for estimating a portal-of-entry threshold
effect in the respiratory system, while information about how
acrolein affects the cardiovascular system is currently sparse.
The public health problem examined in this analysis deals with
the morbidity and mortality associated with acrolein toxicity;
thus, this analysis places less emphasis on some of the less severe (nonlife-threatening) aspects of acrolein-induced toxicity,
such as eye irritation, and more emphasis on pulmonary toxicity that restricts lung function. In particular, noncancer effects
are of interest because, unlike cancer endpoints, they allow for
the identification of threshold values below which these effects
are not expected to occur. Accordingly, this proposed MOA analysis focuses on the adverse effects that occur in the lower regions of the respiratory system that can lead to chronic
obstructive pulmonary disorder (COPD), which is the most severe form of noncancer respiratory disease caused by smoking.
The MOA analysis presented here originated from a
prespecified research review of the publicly available literature
conducted to identify the toxicity of inhaled acrolein, including
respiratory and systemic effects. Analysis of publications identified in the research review, including the citations in their reference sections, indicate that acrolein respiratory toxicity is
perpetuated by two key events: inflammation and necrosis
within the tracheobronchial and pulmonary regions of the airway. Comparisons of acrolein concentrations present in tobacco
smoke to levels of acrolein tested in studies of acrolein respiratory effects indicate that acrolein exposures that result from
smoking are well above exposures that are sufficient to initiate
both inflammation and necrosis in the lower respiratory tract.
The analysis presented here represents the first MOA describing
the toxicity of a tobacco smoke constituent as it exerts its effect
during smoking.
MATERIALS AND METHODS
Prespecified Research Review
Overall framework
The design of the primary research review is based on the
framework described in Kushman et al. (2013) and on “Box 2-1:
Standard 2.6 Develop a systematic review protocol”, included in
the 2011 Institute of Medicine (IOM) report (IOM, 2011).
Timelines
The research review was conducted in two segments. The first
segment was conducted during January–March 2014. During this
time, databases were searched, selection criteria applied, and citation lists were created for articles published through March
2014. For the initial analysis, data were extracted from published
reviews and regulatory documents. A preliminary MOA for acrolein in tobacco smoke was built based on the available secondary
literature, including review articles published in scientific journals and findings published by government agencies such as the
U.S. Environmental Protection Agency (EPA) and the ATSDR.
References included in the secondary literature were used to
build the preliminary MOA. A structured literature search and
screening strategy allowed for analysis of concordance of results
across species, doses, and biological endpoints. After the MOA
analysis was completed, the second segment of the research review was conducted in March 2015. This second segment
included evaluation of primary articles that were identified in
the first segment as well as all literature published between
March 2014 and 2015. The secondary research review identified
any new publications relevant to the MOA analysis that was constructed based on the first segment of the research review.
Databases
A protocol utilizing PubMed (http://www.ncbi.nlm.nih.gov/
pubmed/), Web of Science (http://www.webofknowledge.com),
Embase (http://www.elsevier.com/online-tools/embase), Science
Direct (http://www.sciencedirect.com), and Google (http://www.
google.com) was devised to identify mechanistic toxicology studies and regulatory documents relevant to respiratory disease and
acrolein. This search strategy identified publications that could
YEAGER ET AL.
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contribute to an assessment of acrolein toxicity regarding toxic
endpoints, dose-response, and MOA.
HHS OR CDC OR NIOSH OR OSHA OR EU OR EPA OR ACGIH). The
first 100 hits in the Google search were recorded.
Key questions
The following queries were developed to direct the search:
Selection criteria
1. Is acrolein a major driver of tobacco smoke-related toxicity,
especially toxicity associated with respiratory disease,
including COPD?
2. What is the mode or mechanism of action by which acrolein
causes adverse health effects?
3. What acrolein-related toxic events lead to respiratory disease associated with smoking?
4. What are the key steps involved (eg, adduct formation, respiratory tract irritation, epithelial disruption, matrix protein alteration, and tissue remodeling) with regard to the set
of toxic events that comprise the mode or mechanism of
acrolein toxicity?
5. How would reduction of acrolein in tobacco smoke be expected to reduce the impact of smoking-related toxicity,
including respiratory toxicity?
6. Which toxic endpoints are the most relevant to human toxicity resulting from smoking?
7. What are the dose-response relationships between these
endpoints and acrolein exposure in relevant nonclinical species and in humans?
Search strings
Specific terms for database queries were based on information
from recent acrolein reviews (ATSDR, 2007; EPA, 2003; Stevens
and Maier, 2008). Key database-specific search terms for acrolein toxicology were developed for each database search. The
goal of the search strategy was to capture findings related to the
known toxicity of acrolein and its relationship to respiratory
and other tobacco smoke-related diseases. Documents were reviewed for information on toxic endpoints, relevant organ systems, mode or mechanism of action, and dose–response
relationships. These search strings are presented in Table 1 in
the PubMed format. The search terms used to query Google are
as follows: “public health” AND acrolein AND (WHO OR IARC OR
For each report retrieved, the title, abstract, and if necessary,
the journal website, were first evaluated for relevance to the
role of acrolein in respiratory toxicity. Relevant reports were
then subject to full-text scan to determine eligibility for inclusion. As literature was reviewed, if knowledge gaps were identified, subsequent literature searches were performed in order to
gather further relevant information, especially regarding disease states. Any additional keywords or search terms deemed
necessary to address knowledge gaps were added to the original
search string, and the searches were re-run to capture the pertinent information. Keyword searching was also supplemented
with snowball searching, in which references cited in articles
identified by the primary searches were reviewed for relevance
to the toxicity of acrolein in respiratory disease. Any additional
relevant articles were identified and added to the primary literature database. Three subject matter experts manually screened
all full text research articles to assess relevance for inclusion in
the MOA analysis. The studies identified from the primary and
the snowball searches were then used to construct the proposed
MOA for acrolein toxicity.
Conversion of Acrolein Concentrations from Ambient
Exposure and Mainstream Smoke Measurements
Calculations were required in order to compare acrolein concentrations in parts per million (ppm) from exposure studies in
animals, environmental acrolein concentrations in ambient and
indoor air, and acrolein concentrations in mainstream smoke.
Some environmental concentrations were already reported in
parts per billion (ppb) and no conversions were required.
Environmental acrolein concentrations reported in mg/m3 were
translated to mg/m3, and a concentration factor specific to acrolein was applied to convert from mg/m3 to ppm (concentration
factor at 2.328 mg/m3 per 1.0 ppm; ATSDR 2007). These environmental concentrations were then converted to ppb for presentation due to their magnitude. For acrolein concentrations in
TABLE 1. Search Terms Used To Query the PubMed, Embase, Web of Science, and Science Direct Databases
Search Description
1
Base Toxicology Terms
No
2
Base Acrolein Search Terms
No
3
Combined Base Toxicology/
Acrolein Terms
Combined Base Toxicology/
Acrolein/Mechanism
Combined Base Toxicology/
Acrolein/Respiratory
No
Toxicology[MeSH Terms] OR toxicology[MeSH Major Topic] OR toxic* OR hazard OR systemic OR POE OR ‘portal of entry’ OR respiratory OR pulmonary
OR cardiovascular OR hepatic OR hepatox* OR liver OR reproduct* OR development* OR hematol* OR blood OR renal OR kidney OR dermal OR buccal
OR alveolar OR bronchial OR nasal OR tracheal OR lung OR NOAEL OR
LOAEL OR BMD* OR LOEL OR NOEL OR MTD OR ADI OR TDI OR MOE OR
EC50 OR LC50 OR IC50 OR LD50 OR TD50 OR LT50 OR RD50 OR ‘half-maximal’ OR MOS OR FEV OR FLV OR Immune OR immunol* OR innate OR
acquired OR Thyroid OR endocrine* OR hormon* OR Cancer OR carcinogen*
(acrolein OR ‘107-02-8’ OR ‘prop 2 enal’ OR propenal OR acraldehyde OR
‘acrylic aldehyde’ OR ‘allyl aldehyde’ OR ‘ethylene aldehyde’)
Nos. 1 AND 2
Yes
Nos. 1 AND 2 AND (‘Mode of action’ OR ‘Mechanism of action’ OR MOA)
Yes
Nos. 1 AND 2 AND (alveolar OR bronchial OR nasal OR tracheal OR lung OR respiratory OR pulmonary OR larynx)
4
5
a
Evaluated in
Research Review?
Search Stringa
Search
Number
Search terms shown in Pubmed format, * denotes wildcard search.
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mainstream smoke, concentrations from reference cigarettes in
mg/cig were converted to ppm using machine smoking regimenspecific puff volumes (ISO or CI; in ml) and measurement-specific puff numbers were reported (Counts et al., 2005). Puff volumes were multiplied by puff numbers to yield total volume of
air from smoking in ml, which was converted to m3. Reported
mg amounts (per cigarette) were then divided by air volume in
m3 to achieve concentrations in mg/m3. Concentrations in mg/m3
were then translated to ppm, per the method described earlier.
Acrolein concentrations from in vivo toxicity assays were reported in ppm and required no conversions.
articles, for a total of 2500 articles retrieved through database
searching. After inclusion and exclusion criteria (eg, the requirement that reviewed literature be peer-reviewed and relevant to
acrolein toxicity) were applied, 501 full-text records, including
464 primary research articles and 37 reviews, were manually
screened for possible inclusion in the MOA synthesis. Figure 1
presents a flow diagram that illustrates the article search and
selection process, along with reasons for exclusion. A total of
306 full-text records were considered for inclusion, with 142
relevant to inflammation/immunosuppression, 86 relevant to
macromolecular damage, 52 relevant to tissue destruction/remodeling, and 26 review articles.
RESULTS
Overview of Research Review Results
The initial segment of the literature search conducted through
March 2014 yielded a total of 2187 articles, and the second segment conducted through March 2015 yielded a total of 313
Overview of the Proposed MOA for Acrolein Toxicity
Resulting from Cigarette Smoking
Previous work has established acrolein as the tobacco smoke constituent with the greatest contribution to the respiratory toxicity
FIG. 1. Article selection flow chart for acrolein toxicity MOA analysis. Progression is shown from the initial 2500 full-text records identified from database searching,
and from the regulatory documents retrieved through Google searching, to those relevant to acrolein included in the review.
YEAGER ET AL.
of tobacco smoke, but to date no study has systematically examined an MOA for acrolein toxicity in tobacco smoke-related
noncancer lower respiratory disease, the most severe of which is
COPD. We developed an MOA for acrolein that addresses the role
of this highly reactive aldehyde in the respiratory toxicity of
inhaled tobacco smoke. Inhaled acrolein has multiple effects in
mammals, including cardiovascular and respiratory pathologies,
but the existing scientific evidence provides more robust support
for toxic portal-of-entry effects in the respiratory system.
Therefore, an MOA analysis was developed specifically for acrolein respiratory toxicity that would form the basis for (1) a better
understanding of the causal role of acrolein in smoking-related
respiratory disease, and (2) the identification of the key events
that are required for acrolein respiratory toxicity to occur. This
MOA analysis is designed for the unique exposure scenario represented by smoking behavior and focuses on events occurring in
the lower respiratory tract relevant to smoking-related respiratory disease. Eye and nose irritation have been previously used
as endpoints that are considered to be protective of more serious
toxicity occurring at higher doses in the lower respiratory tract
(EPA, 2003). Moreover, eye and nose irritation usually result in
avoidance of a noxious substance like acrolein. Nevertheless,
smokers continue to inhale tobacco smoke into the lower respiratory tract despite significant eye and nose irritation and an
MOA for acrolein exposure due to smoking requires the consideration of endpoints in the lower airway.
The MOA, described in detail in the following sections, considers the adverse impacts of acrolein on the lower respiratory
tract, and demonstrates how acrolein is a major driver of tobacco smoke-related toxicity associated with lower respiratory
disease, including COPD. In this MOA, inhaled acrolein from cigarette smoke causes lower respiratory tract tissue destruction
and remodeling via inflammatory events that result from the
direct interaction of acrolein with cellular macromolecules and
concomitant oxidative stress. The MOA proposes a cyclical
feed-forward effect in which inflammation leads to cellular necrosis, which, in turn, induces and promotes more inflammation. This sustained inflammation and cellular necrosis results
in lower respiratory tract tissue destruction and remodeling following long-term exposure.
The proposed MOA stems from several toxic mechanisms of
acrolein that were identified in the research review. These include macromolecular-acrolein binding, oxidative stress, inflammation, cell death, and tissue destruction-remodeling. The first
and most basic of these mechanisms is the chemical reactivity of
acrolein. This mechanism triggers toxic processes within cells
that lead first to cell death and later to tissue destruction.
Acrolein binds to thiol and sulfhydryl groups on glutathione
(GSH), cellular proteins, and cell membranes, causing oxidative
stress that leads to cell damage and death. Oxidative stress, cell
damage and cell death cause further inflammation, which can
lead to more cell damage and cell death, and eventually tissue
destruction and remodeling deeper in the respiratory tract, particularly in the tracheobronchial and pulmonary regions. This tissue destruction and remodeling results in the loss of lung
elasticity and compliance, leading to the enlarged airspaces that
are the predominant pathological change associated with COPD
(Borchers et al., 2007; Costa et al.,1986; Wells et al., 2014).
Key Events in the Proposed MOA for Acrolein Toxicity
Direct interaction with cellular proteins and macromolecules
Although some inhaled acrolein reaches the systemic circulation and is metabolized and excreted, inhaled acrolein primarily
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has local effects on the respiratory system. These local toxic effects are related to acrolein’s chemical reactivity and high affinity for cellular sulfhydryls, including those on proteins and GSH
in cells that come in direct contact with this aldehyde
(Arumugam et al., 1999; Gurtoo et al., 1981; Haussmann and
Walk, 1989; Lam et al., 1985; Marinello et al., 1984; Mcnulty et al.,
1984; Walk and Haussmann, 1989). GSH, N-acetylcysteine, and
other sources of thiol and sulfhydryl groups may to some degree
protect the respiratory system from the direct effects of acrolein
(Dawson et al., 1984; Hellstern et al., 1985; Zhu et al., 2011); however, GSH is subject to depletion by direct acrolein binding (van
der Toorn et al., 2007). Specifically, administration of acrolein to
the respiratory tract results in the concentration-dependent depletion of GSH in the nasal and respiratory mucosa, with high
concentrations of acrolein potentially resulting in direct tissue
damage following the depletion of cellular thiols-based antioxidants (Arumugam et al., 1999; Gurtoo et al., 1981; Haussmann
and Walk, 1989; Hecht, 2011; Lam et al., 1985; Marinello et al.,
1984; Mcnulty et al., 1984; Walk and Haussmann, 1989).
Acrolein can alter any protein containing a nucleophilic
functional group, including lysine (Uchida, et al., 1998), histidine
(Maeshima et al., 2012), and cysteine, with cysteine being the
most vulnerable target for acrolein protein-binding interactions
(LoPachin et al., 2009). Acrolein adducts involve proteins that are
involved in a wide variety of cellular functions such as cellular
growth, differentiation, and maintenance of membrane integrity, which when perturbed can result in cytopathic effects
(Grafstrom et al., 1988). For example, acrolein covalently modifies cellular proteins involved in tumor suppressor activity (eg,
phosphatase tensin homolog on chromosome 10 [PTEN])
(Biswal et al., 2003; Covey et al., 2010) and redox homeostasis (eg,
loss of Sirtuin1 [SIRT1] protein) (Caito et al., 2010). Speiss et al.
(2011) revealed that many of the protein targets of acrolein are
stress proteins, cytoskeletal proteins (eg, actin, keratins), and
key proteins involved in redox signaling, further linking macromolecular modification by acrolein to biological effects associated with acrolein exposure (Burcham et al., 2010a,b; DalleDonne et al., 2007). Acrolein-protein binding may also affect the
toxicity of other chemicals. Direct, irreversible interaction of
acrolein with arylamine N-acetyltransferases suggests acrolein
impacts the metabolic fate of other toxicants involved in respiratory diseases (Bui et al., 2013).
Data also demonstrate that protein modification by acrolein
occurs in the context of tobacco smoke inhalation. In a study of
mice exposed to tobacco smoke, an increase in the abundance
and intensity of acrolein-protein adducts was found in the lungs
as compared with air-exposed controls (Conklin et al., 2009).
Protein carbonyl formation has also been shown to greatly increase after exposure to cigarette smoke and/or its individual
constituents. For example, exposure of human plasma to cigarette smoke over 3 h caused a 60% depletion of protein sulfhydryls
and an increase in protein carbonyls (Eiserich et al., 1995).
Acrolein binds to nucleic acids, with the resulting formation
of cyclic DNA adducts (Chung et al., 1984; Kawai et al., 2003;
Minetti et al., 2010; Tang et al., 2011) and DNA crosslinks
(Kozekov et al., 2003; Burcham et al., 2007), and enhances DNA
damage induced by other chemicals (Lam et al., 1985). Although
acrolein modifies DNA bases by forming cyclic adducts (Chung
et al., 1984), the mutagenic potential of these adducts is inconclusive (Kim et al., 2007). Others posit that the inconsistent results of acrolein mutagenicity may be due to the variety and
repair of adducts in diverse detection systems (Liu et al., 2010).
The most relevant interactions between acrolein and cellular
macromolecules appear to be those involving proteins and
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peptides such as GSH that are important to redox homeostasis
maintenance.
Acrolein-induced oxidative stress
Acrolein reactivity causes oxidative stress, which results in
increased activity of enzymes (eg, superoxide dismutase) and
oxidative damage, including lipid peroxidation, across the entire respiratory tract (Arumugam et al., 1999; Roy et al., 2009).
Oxidative stress is exacerbated as acrolein rapidly binds to GSH
and depletes GSH levels in the respiratory pathway (Adams and
Klaidman, 1993; Mcnulty et al., 1984). The GSH adduct of acrolein, glutathionylpropianaldehyde, has been shown to induce
formation of oxygen radicals that may be responsible for the induction of lipid peroxidation by acrolein (Adams and Klaidman,
1993). Furthermore, acrolein causes direct respiratory damage
and can also be generated as a by product of cellular processes
associated with oxidative stress and the inflammatory response, caused by the initial insult. Specifically, acrolein can be
formed endogenously as a by product of lipid peroxidation
(Uchida et al., 1998) and is produced during the oxidative deamination of polyamines such as spermine and spermidine by
amine oxidase (Tsutsui et al., 2014). During an inflammatory response, acrolein is primarily generated via enzymatic oxidation
of L-threonine by myeloperoxidase, a process mediated by activated leukocytes (Vasilyev et al., 2005). This can result in an indirect cascading effect that exacerbates acrolein’s direct effects
and contributes to the perpetuation of redox imbalance and inflammation (Moretto et al., 2009; Wells et al., 2014). Arumugam
et al. (1999) reported that rats exposed to 1 or 2 ppm acrolein for
4 h demonstrated extensive lung damage, likely as a result of
enhanced oxidative stress and lipid peroxidation, with several
markers of oxidative stress elevated in the bronchoalveolar lavage (BAL). In addition to GSH depletion and lipid peroxidation,
acrolein also inactivates enzymes involved in lung monoxygenase activities such as NADPH-cytochrome c reductase (Patel
et al., 1984) and GSH peroxidase (Staimer et al., 2012), thus exacerbating oxidative stress. Acrolein has also been shown to cause
a dose-dependent inhibition of the NADH- and succinate-linked
mitochondrial respiration chain, with selective inhibition of
mitochondrial complex I, II, pyruvate dehydrogenase, and
alpha-ketoglutarate dehydrogenase (Sun et al., 2006).
The cellular response to acrolein-mediated redox insult can
also lead to alterations in transcription factors that modulate
the expression of genes related to redox homeostasis. Acrolein
modulates the function of transcription factors such as AP-1,
Nf-KB, and Nrf2 differently in different cell types (Biswal et al.,
2002; Horton, et al.,1999; Tirumalai, et al., 2002). Some transcription factors have been shown to regulate genes relevant to oxidative stress. For example, heme oxygenase-1, a target of Nrf2,
is upregulated by acrolein (Zhang and Forman, 2008). Thus,
acrolein modulates genes in ways that can initiate oxidative
stress and inflammatory response in the lower respiratory tract.
Inflammation
Acrolein has proinflammatory action in vitro and in vivo (Comer
et al., 2014; Lyon et al., 1970; Wells et al., 2014), but there is evidence that acrolein both suppresses the immune response and
elicits inflammation (Astry and Jakab, 1983; Spiess et al., 2013).
The altered immune response resulting in suppression appears
to occur with acrolein-mediated decreases in interleukins (ILs)
(Lambert et al., 2005; Valacchi et al., 2005), in cytokines such as
Th1 (Kasahara et al., 2008), and by direct alkylation of c-Jun
N-terminal kinase (JNK) (Hristova et al., 2012) and Nf-kB binding
sites by acrolein (Horton et al., 1999, Lambert et al., 2007). The
differences reported in IL response following acrolein exposure
appear to depend on cell type and acrolein concentration, but
several animal species experience inflammation across the respiratory tract following exposure to acrolein vapor in whole
body exposure chambers (Feron et al., 1978; Lyon et al., 1970).The
immune response thus plays a key role in the development of
smoking-associated respiratory diseases, such as COPD.
The inflammatory response to acrolein and cigarette smoke
is complex; however, tobacco smoke elicits inflammatory effects that are similar to pure acrolein exposure. Multiple studies
show that several cells types—including human bronchial
endothelial cells, human primary nasal epithelial cells, normal
human lung fibroblasts (NHLF), small airway epithelial cells
(SAECs), human bronchial smooth muscle cells] human endothelial cells, and human lung mucoepidermoid carcinoma cells
(NCI-H292)—release IL-8, a neutrophil chemoattractant, following treatment with cigarette smoke extract (Mio et al., 1997;
Moretto et al., 2012b; Richter et al., 2002; Wang et al., 2000).
Exposure to acrolein has also been shown to cause IL-8 release
(Mio et al., 1997; Moretto et al., 2012b). Although all of the specific
events in the inflammatory response to cigarette smoke exposure are not fully understood, acrolein appears to be the a,b-unsaturated aldehyde in cigarette smoke responsible for the
release of IL-8 and other factors (ie, LTA4H modification) and
concomitant infiltration of neutrophils. The IL-8 inflammatory
response in NHLFs and SAECs is induced by acrolein (or cigarette smoke extract) at concentrations nontoxic to cells, appears
dependent on p38 MAPK- and ERK1/2 pathways, and may be
blocked by a,b-unsaturated aldehyde scavengers (Moretto et al.,
2009, 2012b). A study by Wells et al. (2014) proposed that acrolein
alone, like cigarette smoke, selectively inhibits leukotriene A4
hydrolase (LTA4H) aminopeptidase activity, resulting in a decrease of proline-glycine-proline (PGP, a collagen degradation
product) and an increase in leukotriene B4 (LT B4), both of which
are neutrophil chemoattractants. Furthermore, the loss in ability of LTA4H to degrade PGP remains and results in chronic inflammation long after the insult has ceased (Wells et al., 2014).
Some studies have identified specific markers associated
with the inflammatory response. In C57BL/6 mice, the inflammatory response in the lung as measured via BAL results in significant neutrophil influx, cytokine secretion (keratinocyte
chemoattractant [KC], tumor necrosis factor-a, macrophage inflammation proteins [MIP-2, MIP-1a], and monocyte chemoattractant protein-1 [MCP-1]), and gene changes (KC, MIP-2,
matrix metalloproteinase-12 [MMP12], and granulocyte macrophage colony-stimulating factor) following cigarette smoke exposure (John et al., 2014). In a 6-h acute exposure study in
humans, cigarette smoke increased systemic inflammatory
markers (c-reactive protein [CRP], fibrinogen, intercellular
adhesion marker-1 [ICAM-1], IL-6, isoprostanes, MCP-1 and
P-selectin) and decreased CD40L in smokers compared with
nonsmokers (Levitzky et al., 2008). In smokers, CRP, ICAM-1, IL6, and isoprostanes remained elevated even 6 h after smoking.
These inflammatory signals lead to oxidative stress and necrosis, which in turn lead to the involvement of immune cell responses concordant with COPD pathology. Neutrophils,
macrophages, and lymphocytes accumulate in the lungs of
acrolein exposed mice (Borchers et al., 2007) and smokers with
airflow limitations (Di Stefano et al., 1998). The infiltration of
cells in acrolein-exposed mice is accompanied by progressive
destruction of alveolar walls (Borchers et al., 2007), which is part
of the symptomatology observed in patients with COPD.
The inflammatory response to both acrolein and cigarette
smoke has been demonstrated in cells, animals, and humans.
YEAGER ET AL.
The inflammatory response induced by acrolein exposure results in a series of events starting with inflammation, leading to
exacerbated cell death and ultimately resulting in respiratory
tissue damage.
Cell death
The altered immune and inflammatory responses induced by
acrolein can result in increased cell death. Acrolein-mediated
cell death has been shown to occur via multiple pathways. At
low doses, acrolein can cause cell death via apoptosis; at concentrations relevant to inhaled cigarette smoke, the primary
pathway by which acrolein kills cells is through oncosis (cell
death by swelling) (Rudra and Krokan, 1999), resulting in dosedependent necrosis (Averill-Bates et al., 2009; Roy et al., 2010). In
vitro studies have reported that apoptotic responses occur via
the mitochondrial pathway, through a decrease in mitochondrial membrane potential, cytochrome c release, caspase-7 and
-9 activation, and cross-talk between the Fas receptor pathway
(Tanel and Averill-Bates, 2005, 2007). Averill-Bates et al. (2009)
and Roy et al. (2010) reported induction of primarily apoptosis by
acrolein at concentrations from 15 to 50 lM in A549 cells treated
up to 4 h. In contrast, Kern and Kehrer (2002) reported apoptotic
inhibition and oncosis at concentrations from 20 to 40 lM in
mouse lymphocytes treated for 30 min. Although acrolein is
toxic to the mitochondria, whether a cell becomes apoptotic or
oncotic appears to be a function of dose and cell type
(Finkelstein et al., 2005; Kern and Kehrer, 2002; Li et al., 1997).
The mechanism (ie, apoptosis versus oncosis) may be driven
by dose and cell type, but chronic administration of acrolein results in chronic inflammation and tissue damage, indicating
that oncosis plays a larger role than apoptosis (Moghe et al.,
2015) and that necrosis may play a role in both mechanisms of
cell death. Acrolein-mediated oncosis is expected to occur at
higher doses via decreased cellular ATP and binding to thiol
groups (possibly inactivating caspases); in turn, this process
leads to necrosis (changes secondary to cell death) (Kern and
Kehrer, 2002). This necrotic process may result in accumulation
of debris, and there is evidence that clearance from these necrotic areas is inhibited. For example, a finding of dose-dependent acrolein ciliotoxicity, accompanied by complete lung
necrosis, was observed in rabbit tracheal epithelium explants
(Romet et al., 1990).
The initial round of oncosis elicited by acrolein exposure can
release debris that leads to further inflammation, which in turn
leads to cellular necrosis and eventually tissue-level necrosis
mediated by immune cells (Kern and Kehrer, 2002; RydellTormanen et al., 2006). As several studies have pathological
findings of necrosis throughout the respiratory tract following
acrolein administration in whole body exposure chambers
(Costa et al., 1986; Feron et al., 1978; Kutzman et al., 1985; Lyon
et al., 1970), oncosis and necrosis are expected to occur, ultimately leading to tissue remodeling and destruction.
Tissue destruction/remodeling
Acrolein-induced tissue remodeling is caused by inadequate repair after cell loss and inflammation-mediated extracellular
matrix (ECM) damage. Acrolein affects two important aspects of
cell ECM interactions that are critical for respiratory tissue repair: cell attachment to the ECM and remodeling of the ECM.
Loss of proper cell attachment may lead to pathological tissue
repair (Carnevali et al., 1998). One experimental system in which
the cell-ECM interaction can be observed is the 3D collagen matrix system. Acrolein inhibits chemotaxis, proliferation, and
contraction of 3D collagen gels (Wang et al., 2001). Moreover,
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acrolein-mediated inhibition of fibroblast-mediated contraction
is reported to result from the inhibition of fibronectin secretion
(Carnevali et al., 1998). Carnevali et al. (1998) suggest that acrolein-mediated decreases in fibronectin secretion could be associated with impaired healing in the context of pulmonary
emphysema.
Another important acrolein effect on pulmonary tissue is remodeling of the ECM, and this has been studied in animal models. ECM remodeling has a significant effect on organ function.
Loss of elasticity results from replacement of elastin, a flexible
fiber that is normally a significant component of the lung ECM
with collagen, a much less elastic fiber. ECM protein levels, such
as elastin, collagen, and proteoglycans, are variable across both
human and animal populations, and elastin is reportedly crucial for lung function in both development and response to lung
injury (Shifren et al., 2007). This localized tissue matrix destruction has been reported to involve macrophage accumulation
due to a sustained local proinflammatory response mediated by
acrolein and contributes to respiratory pathogenesis
(Hautamaki et al., 1997; Kirkham et al., 2003). MMP-12 may be
associated with degradation of structural proteins in the lung
including elastin (Houghton et al., 2006), resulting in reduced
forced expiratory volumes and therefore constituting a risk factor for COPD (Hunninghake et al., 2009). Thus, changes in elastin
levels following acrolein exposure may additionally alter lung
function. In addition, at concentrations that can be found in
sputum from COPD patients, acrolein can activate matrix metalloproteinase 9 and 14 (MMP-9, MMP-14) in a cell-free system;
in vivo acrolein treatment also increased MMP-9 and MMP-14
protein and activity and mucin transcript and protein levels,
and decreased transcripts of an MMP-9 inhibitor in mouse lung
tissue (Deshmukh et al., 2008, 2009). Although Deshmukh et al.
(2008) did not find that acrolein exposure increased transcripts
of MMP-12 in mouse lung tissue, a greater increase of mucin
transcripts was observed in MMP12(þ/þ) mice as compared with
MMP12(/) mice after acrolein exposure (Borchers et al., 1999).
Increased MMP-12 levels have also been detected in the sputum
of smokers and ex-smokers with COPD, with disease severity
directly associated with sputum MMP-12 levels and activity
(Chaudhuri et al., 2012). Importantly, Chaudhuri et al. noted that
MMP-12 activity was higher in ex-smokers with COPD compared
with current smokers with COPD, suggesting that disease severity was associated with irreversibly dysregulated MMP-12 function, supporting the contention that imbalanced proteolytic/
antiproteolytic activity can contribute to COPD pathology.
Acrolein has been shown to cause necrosis and the sloughing
of cells in the bronchi and bronchioles (Kutzman, 1981). Rats
exposed to 4 ppm acrolein vapor in whole body chambers had
twice the amount of elastin of control groups, and lung collagen
or hydroxyproline (an indicator of collagen) were increased in
the lungs of rats exposed to 1.4 and 4 ppm acrolein (Kutzman,
1981). Moreover, respiratory insults from acrolein vapor exposure increase elastase and metalloprotease activity, which results
in tissue destruction and remodeling (ie, airspace enlargement)
and in turn alter lung function (eg, compliance, elasticity)
(Kitaguchi et al., 2012). Similarly, exposure to 4 ppm acrolein results in airway changes that suggest altered lung function, such
as greater rigidity of the small airways (Kutzman, 1981).
Mechanistic Feedback of Acrolein Toxicity Leading to
Tissue Destruction and Remodeling in Respiratory Disease
More broadly, the combination of the toxic mechanisms
described earlier leads to a self-perpetuating cycle of pulmonary
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inflammation and cell death that results in tissue remodeling
and impaired lung function. The link between mechanistic
events of this toxic cycle and the temporal association to acrolein respiratory toxicity is described below.
Relationship of mechanistic events
From the proposed MOA for smoking-induced acrolein respiratory toxicity, it is evident that acrolein produces both inflammation and necrosis in the respiratory tract and that these events
can continue in a cascading feedback relationship. In this relationship, the inflammation causes necrosis and necrosis causes
further inflammation (Majno and Joris, 1995; Mantell et al., 1999;
Rock and Kono, 2008), which can lead to alteration of respiratory
tissue. Acrolein-induced inflammatory responses also result in
increased airway mucin transcripts, hypersecretion, mucus cell
differentiation, and secondary necrosis, further contributing
to decreased clearance and airway obstruction, which are hallmarks of COPD (Borchers et al., 1998, 1999; Makris et al., 2009;
Rydell-Tormanen et al., 2006).
Figure 2 diagrams the key events and relationships between
the steps in the proposed acrolein respiratory toxicity MOA.
Overall, acrolein reacts with sulfhydryl and thiol groups in cells
to alter cell function, causes inflammation and altered immune
function, and results in cell death, tissue destruction, and impaired respiratory function. Acrolein depletes GSH levels and increases oxidative stress, causing inflammation and necrosis.
These effects are interrelated and likely result in feedback with
secondary adverse effects, thereby exacerbating the oxidative
damage, inflammation, and necrosis in respiratory tissue. In
the proposed MOA the inflammatory and necrotic events cause
direct tissue damage and also alter the levels of ECM proteins
such as elastin and collagen. These respective events result in
airspace enlargement (Borchers et al., 2007; Kitaguchi et al., 2012)
and likely result in altered lung functionality (Rydell-Tormanen
et al., 2006; Shifren et al., 2007; Wells et al., 2014).
The protective mechanisms presented in Figure 2 represent
saturable systems and provide a rationale for acrolein toxicity
thresholds. The MOA is based on the fact that across all species
for which data are available, acrolein doses producing acute respiratory inflammation eventually cause necrosis if they are repeated over time; doses below those causing acute
inflammation do not produce these changes (Costa et al., 1986;
Feron et al., 1978; Kutzman et al., 1985; Lyon et al., 1970).
However, Feron et al. (1978) identified a threshold atmospheric
acrolein concentration at which tracheo-bronchial inflammation occurs in the rabbit and tracheo-bronchial inflammation
and necrosis occurs in the rat (4.9 ppm). The EPA and ATSDR
quantified environmental exposure limits for acrolein and considered Feron et al. (1978) to be a critical study. Because the focus
of this MOA is on acrolein inhaled as a tobacco smoke constituent, the scope of this assessment was limited to events occurring in the lower regions of the respiratory system, which are
relevant to smoking-related respiratory toxicity. Although frank
toxicity was observed in the nasal cavity of these species at a
lower acrolein concentration (1.4 ppm), Feron et al. (1978) did not
record any adverse effects to the tracheo-bronchial region of
the respiratory system at 1.4 ppm. Feron et al. (1978) also investigated the effects of acrolein on hamsters, but no inflammation
or necrosis occurred in the lower respiratory tract of this species
at the highest dose given.
Temporal association
Temporally, acrolein exposure occurs prior to inflammation
and if acute insults are repeated chronically, inflammation
progresses to necrosis. Several events occur as parts of a cycle
in the process of COPD progression (ie, cell death, neutrophil infiltration, lipid perodixidation). Acrolein exposure from cigarette
smoke is expected to precede protein binding, oxidative damage, inflammation, cell death, and tissue destruction and remodeling, which is exacerbated with chronic exposure. The
progression of events is not completely linear, since lipid peroxidation, oxidative damage, cell death, inflammation, and neutrophil infiltration are expected to occur in a chronic
pathological cycle following repeated acrolein exposure.
Relevance of the Proposed MOA to Respiratory Disease,
Concordance of Toxicological Relationships, and
Relevance to Cigarette Smoke Concentrations
As noted, the toxic effects of acrolein have been shown to occur
in vitro and in vivo. Although no laboratory animal species recapitulates all pathologies associated with respiratory disease etiology in humans, acrolein exposure causes inflammatory
portal-of-entry effects on the respiratory system followed by tissue destruction in several mammalian species (ie, rat, guinea
pig, dog, rabbit, hamster, squirrel monkey). Furthermore, the
irritating effects of acrolein and inflammatory effects of cigarette smoke on the respiratory system have been noted in these
species and in humans. Several of the mechanisms described
earlier contribute to COPD pathogenesis, including oxidative
stress/damage, a robust inflammatory response, imbalanced
proteolytic/antiproteolytic activity, and structural cell destruction (Arumugam et al., 1999; Cardoso et al., 1993; Demedts et al.,
2006; Deshmukh et al., 2008, 2009; Wells et al., 2014). The respiratory tissue pathology observed in animal studies has been
shown to parallel the respiratory tissue damage observed in cigarette smokers with COPD. Thus, chronic inflammation from
inhaled acrolein in cigarette smoke is expected to alter the
structure and function of tissues in the lower respiratory tract,
eventually leading to COPD.
DISCUSSION
This MOA analysis evaluates acrolein as a major driver of tobacco smoke-related toxicity that causes respiratory disease,
particularly COPD, via respiratory portal-of-entry effects. This
evaluation is highly relevant to understanding the potential
public health impacts of acrolein exposure from inhaled tobacco
smoke, particularly since the acrolein concentrations in tobacco
smoke exceed the concentrations that, as a result of multiple
toxic mechanisms, are expected to cause inflammation and
lead to lower respiratory tissue damage. The range of toxic
mechanisms described in the MOA precipitate from the reactive
nature of acrolein. Acrolein-induced adverse effects are the result of direct chemical interactions with tissues that come in
contact with this aldehyde; no metabolism or systemic distribution is necessary for these effects to occur. This analysis resulted in an MOA for acrolein as a constituent of tobacco smoke.
No previous study or review to date proposes a complete causal
toxicological relationship between acrolein inhalation as a tobacco smoke constituent and adverse effects, including COPD,
in the lower respiratory system.
Based on the MOA, inhaled acrolein from cigarette smoke is
expected to result in COPD following chronic exposure to concentrations above threshold values that result in key steps of
acrolein respiratory toxicity: inflammation and necrosis; acrolein levels in ambient air are well below the threshold values
and are not expected to result in COPD (ATSDR, 2007). In
YEAGER ET AL.
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FIG. 2. Summary of key events in the proposed MOA for acrolein as a constituent of cigarette smoke. The primary effect of acrolein upon inhalation is macromolecule
adduction and binding that interferes with key cell signaling pathways and other key functions required for cellular homeostasis. This disruption of macromolecule
function leads to key mechanisms of acrolein toxicity identified in the MOA that form a cycle in which oxidative stress and damage, inflammation, and cell death and
necrosis induce each other in a feed-forward manner. Thus, oxidative stress and damage can induce inflammation, which in turn induces cell death and necrosis.
However, inflammation can also induce oxidative stress, which in turn can also induce cell death and necrosis. At the level of the whole organ, sustained inflammation
and cell death in the lower respiratory tract results in tissue destruction and remodeling, leading to enlarged lung airspaces and loss of elasticity and compliance—
hallmarks of COPD.
ambient air, acrolein is estimated to account for about 5–10% of
total aldehydes, which generally do not exceed 50 ppb (Leikauf,
1992). Acrolein urban ambient air concentrations are reported to
be an average value of 0.61 ppb (1.4 mg/m3) and indoor nonsmoking residential concentrations are reported to be an average value
of 2.6 ppb (6.0 mg/m3) (Seaman et al., 2007). Exposure to inhaled
acrolein can also occur from sources other than tobacco smoke,
such as wood combustion, emissions from mobile sources, and
while performing certain occupations such as firefighting
(Stevens and Maier 2008; Faroon et al., 2008a, b; Reinhardt and
Ottmar, 2000, 2004; Reinhardt et al., 2000). In comparison, acrolein
concentrations in smoke are several orders of magnitude higher;
eg, the acrolein concentrations from 1R4F reference cigarettes
have been reported to be 58.1 and 67.5 ppm under the ISO smoking regimen (38.5 and 46.3 mg/cig, respectively) and 79.9 and 85.6
ppm under CI conditions (111 and 122 mg/cig, respectively)
(Counts et al., 2005) (Table 2). Of note, these comparisons reflect
concentrations in ambient air and in cigarette smoke that would
be inhaled. Concentrations in the lower respiratory system and
in tissues would be much lower, due to absorption in the upper
respiratory system and concentration dilution into the lung’s
functional residual capacity, among other factors. Acrolein levels
in cigarette smoke are also far greater than the concentrations
administered to animals that result in lower respiratory
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TABLE 2. Acrolein Concentrations Across Exposure Conditions and Species Acrolein Concentrations Associated with Key Respiratory Toxicity
Events, Human Smoking, and Environmental Exposures
Key Event
Reference
Exposure Conditions
Species
Acrolein
Concentration
Rabbit (Dutch) Hamster
(Syrian Golden)
4.9 ppm
Rat (Sprague-Dawley)
Guinea Pig (Princeton
or Hartley) Dog (Beagle)
Guinea Pig (Princeton or
Hartley) Dog (Beagle)
0.7 ppm
Rat (Fischer 344)
1.4 ppm
Rat (Wistar)
4.9 ppm
Rat (Fischer 344)
4 ppm
Mouse (Swiss-Webster)
1.7 ppm
Rat (Wistar)
0.25 ppm
Rat (Wistar)
1 ppm
Chronic exposures
Inflammation
Feron et al. (1978)
Lyon et al. (1970)
Lyon et al. (1970)
Necrosis
Kutzman et al. (1985)
Necrosis (with
mortality)
Feron et al. (1978)
Costa et al. (1986)
Vapor, exposure chamber,
6 h/d, 5 days/week, 13
weeks
Vapor, exposure chamber,
8 h/d, 5 days/week, 6
weeks
Vapor, exposure chamber,
continuous, 24 h/d, 90
days
Vapor, exposure chamber,
6 h/d, 5 days/week, 62
days
Vapor, exposure chamber,
6 h/d, 5 days/week, 13
weeks
Vapor, exposure chamber,
6 h/d, 5 days/week, 62
days
0.22 ppm
Acute exposures
Necrosis
Buckley et al. (1984)
Cassee et al. (1996)
Inflammation
(lipid
peroxidation)
Arumugam et al. (1999)
Exposure chamber,
6 h/d, 5 days
Nose-only exposure chamber, 6 h/d, 5 days
Head-only exposure, 4 h
Environmental and user exposures
Practice
Reference
Exposure Conditions
Matrix/Source
Acrolein
Concentration
Smoking
Counts et al. (2005)
Machine smoking
ISO Method, 1R4F
Kentucky Reference
cigarettes
HC Method, 1R4F
Kentucky Reference
cigarettes
Mean outdoor air concentration range, EPA
Air Quality System
Indoor air concentration
range, including
smoking
Mean outdoor air concentrations,
afternoon
Mean indoor air concentrations, afternoon,
nonsmoking
67.5 ppm (R-E);
58.1 ppm (R-V)
Ambient exposures (USA)
ATSDR (2007)
Ambient air
Indoor air
Ambient exposures
(California)
Seaman et al. (2007)
Ambient air (semirural,
suburban, urban)
Indoor residental (semirural, suburban, urban)
inflammation and necrosis, which we have identified as key
steps in the MOA for acrolein respiratory toxicity (Table 2).
Application of the Bradford Hill Criteria
The Bradford Hill criteria for causality provide for a standard approach for analysis of an MOA between an exposure and an
85.6 ppm (R-E);
79.9 ppm (R-V)
0.5–3.19 ppbv
<0.02–12 ppb
0.27 ppb (all locations)
0.61 ppb (urban only)
2.63 ppb
effect (Bogdanffy et al., 2001; Boobis et al., 2008). These criteria
are applied to our MOA analysis below in order to further evaluate the relationship between acrolein exposure and the toxic
events identified in the MOA. The Bradford Hill criteria call for a
causal relationship to be evaluated in terms of strength, consistency, specificity, temporality, biological gradient, plausibility,
coherence, experimental evidence, and analogy to similar
YEAGER ET AL.
factors. This analysis begins with an examination of experimental evidence for the MOA and the temporality and concordance
of toxicological relationships described in the MOA. The other
elements of the Bradford Hill criteria are also discussed.
Experimental Evidence
As stated above, the MOA of acrolein respiratory toxicity resulting in COPD is based on experimental evidence across multiple
species, including rodents, dogs, and nonhuman primates.
Acrolein inhalation causes inflammation that then leads to necrosis in the lower respiratory region as toxic insults are repeated over time (Costa et al., 1986; Feron et al., 1978; Kutzman
et al., 1985; Lyon et al., 1970).
Temporality and Concordance
Temporality and concordance of toxicological relationships
were presented earlier. Briefly, acrolein exposure precedes inflammation and resulting tissue damage; similar pathological
effects have been observed in all species studied. Furthermore,
cigarette smoke and acrolein are known respiratory irritants
that cause inflammation, and exposure to these compounds
precedes inflammation and the resulting respiratory tissue
damage. These key events are known precursors to COPD (Bein
and Leikauf, 2011; Brusselle et al., 2011; Chung and Adcock, 2008;
Moretto et al., 2012a; Shapiro and Ingenito, 2005; Yoshida and
Tuder, 2007).
Strength
No human or animal studies provide a direct causal link between acrolein and COPD, although smoking is known to cause
COPD. Currently, there are 7.5 million persons in the United
States with smoking-attributable COPD (Rostron et al., 2014).
However, in all studies identified, experimental animals
exposed to acrolein develop respiratory inflammation and necrosis, which are both key events observed in acrolein respiratory toxicity and key events in the development of COPD.
Furthermore, acrolein is by far the greatest contributor to
noncancer respiratory toxicity in mainstream tobacco smoke
(ATSDR, 2007; Cunningham et al., 2011; Fowles and Dybing,
2003; Haussmann, 2012) and the levels of acrolein present in
tobacco smoke greatly exceed the levels of acrolein that produce the key respiratory toxicity steps identified in this MOA
(Table 2).
Consistency and Specificity
Available studies of acrolein inhalation toxicity provide the
basis for key events (respiratory inflammation and necrosis),
and these events in the MOA result in COPD upon chronic exposure. These acrolein effects are expected to occur within the
context of inhaled tobacco smoke and smoking causes respiratory disease, including COPD. Specifically, the 2010 Surgeon
General’s Report asserts that “evidence is sufficient to infer that
smoking is the dominant cause of COPD” (U.S. Department of
Health and Human Services, 2010) and furthermore the 2004
Surgeon General’s Report summarizes findings from previous
Surgeon General’s Reports including the causal link between tobacco smoke and COPD (as seen in Table 1.2 of U.S. Department
of Health and Human Services, 2004; U.S. Department of Health,
Education, and Welfare, 1964, 1967, 1969, 1971, 1973). Although
some toxic interactions with other smoke constituents (ie, particulates, other irritants) are expected to contribute to tobacco-
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related respiratory disease, aldehydes are considered a key inflammatory component in cigarette smoke (Moretto et al., 2009).
In addition, tobacco smoke constituents other than acrolein
may contribute indirectly, eg, by causing mucociliary escalator
paralysis and reducing clearance from the lung. Although other
constituents may contribute to the development of COPD, acrolein is considered to be the greatest contributor to noncancer respiratory toxicity and acrolein inhalation exposures in animals
parallels the respiratory pathology observed in smokers with
COPD (Moghe et al., 2015).
The nonsmoking subpopulation with COPD is much smaller
than the smoking-related subpopulation with COPD (Zeng et al.,
2012). Risk factors other than smoking may contribute to COPD
development in nonsmokers (eg, genetic factors, asthma, outdoor
air pollution, environmental tobacco smoke, biomass smoke, occupational exposure, diet, childhood respiratory infection), but
these factors do not contribute significantly to the COPD burden
in the United States (Zeng et al., 2012). The risk of COPD from
smoking is much greater than the risk of COPD from other factors
(U.S. Department of Health and Human Services, 2014).
Biological Gradient
Although no single human or animal study captures the toxicological relationship for cigarette smoke or acrolein and COPD,
human and animal studies have shown acrolein exposure has
an increasingly adverse effect on the respiratory tract with
increasing dose or repeated exposure (Feron et al., 1978; WeberTschopp et al., 1977). Moreover, exposure to cigarette smoke,
which contains acrolein concentrations that are several fold
above the levels required to induce the key steps in the MOA,
causes respiratory disease, including COPD (Table 2). As duration and amount of cigarette exposure increases (as measured
in smoking pack-years) the proportion of smokers with emphysema (form of COPD) increases (U.S. Department of Health and
Human Services, 2010).
The key events identified in the MOA represent a biological
gradient. Chronic inflammation and necrosis result in respiratory tissue damage, where time (duration of exposure and repetitive exposure) is a major factor contributing to the severity
of the gradient due to repeated inflammation. These two toxicological endpoints, respiratory tissue inflammation and necrosis,
are key steps in the MOA (Bein and Leikauf, 2011; Brusselle et al.,
2011; Chung and Adcock, 2008; Moretto et al., 2012a; Shapiro and
Ingenito, 2005; Yoshida and Tuder, 2007) that are linked to the
etiology and progression of COPD.
Biological Plausibility and Coherence
The key events of inflammation, necrosis, and tissue remodeling are plausible key steps caused by acrolein that result in
COPD. The pathology of COPD is complex. Due to the insidious
onset of symptomatology (progressive shortness of breath and
decreased exercise tolerance), it is often not diagnosed in the
early stages. Other common conditions cause similar symptoms
(eg, deconditioning, congestive heart failure, interstitial lung
disease), making it challenging to understand the full scope of
the population affected (American Thoracic Society and
European Respiratory Society Task Force, 2004; Rennard, 2015).
The Global Initiative for Chronic Obstructive Lung Disease, a
joint project of National Heart, Lung, and Blood Institute and
WHO, defines COPD as follows:
A common preventable and treatable disease, is characterized by persistent airflow limitation that is usually progressive and associated with an
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enhanced chronic inflammatory response in the airways and the lung to
noxious particles or gases. Exacerbations and comorbidities contribute to
the overall severity in individual patients (Global Initiative for Chronic
Obstructive Lung Disease (GOLD), 2015).
However, the progressive nature of inflammatory respiratory
disease, including disease states within the definition of COPD,
suggests that the toxic mechanisms identified in the MOA likely
occur in less severe respiratory disease and are exacerbated
with repeated toxic insults that lead to COPD. Thus, the MOA
may apply not just to COPD, but also to less severe forms of respiratory disease that can lead to COPD.
Acrolein effects on pulmonary tissue are implicated in COPD
pathogenesis (U.S. Department of Health and Human Services,
2014; Moretto et al., 2012a). Acrolein toxicity results from its
high reactivity with nucleophilic cellular targets and induction
of oxidative stress leading to cytotoxicity and physiological responses such as enhanced mucus production and the induction
of inflammatory responses in the lung. Although inflammation
is a protective mechanism and plays an important role in tissue
repair, inflammatory processes also enhance reactive oxygen
species (ROS) production and can exacerbate the pulmonary
redox imbalance. In addition to increasing the oxidative burden,
acrolein exposure also depletes key antioxidants such as GSH,
which further contributes to oxidative stress and tissue damage. Pulmonary oxidative stress enhances pro-inflammatory responses and tissue damage, and has been identified as one of
the key mechanisms involved in the pathophysiology and progression of COPD (Rahman, 2003, 2005; Chung and Adcock,
2008).
Acrolein in the respiratory tract causes protein adduct formation, oxidative stress, cell death, airway inflammation,
mucus hypersecretion, and protease/antiprotease dysfunction
(Comer et al., 2014; John et al., 2014; Moghe et al., 2015; Moretto
et al., 2009, 2012a; van der Vaart et al., 2004). These toxic events
also occur in the development and progression of COPD and are
linked with acrolein exposure by the key events described
earlier. Furthermore, acrolein is shown to have respiratory effects similar to cigarette smoke, consistent with the conclusion
that acrolein is the most significant contributor to noncancer
respiratory disease risk (ATSDR, 2007; Cunningham et al., 2011;
Fowles and Dybing, 2003; Haussmann, 2012).
Other Modes of Action and Analogy
Previously described modes of action
The scientific literature describes toxicological steps in the
mechanism of acrolein respiratory toxicity (ATSDR, 2007; Bein
and Leikauf, 2011; EPA, 2003; Kehrer and Biswal, 2000; Li and
Holian, 1998; Moghe et al., 2015; Moretto et al., 2012a; Stevens
and Maier, 2008) and, as described earlier, these mechanistic
steps are associated with the same adverse effects occurring in
the pathology of COPD. In considering other acrolein MOAs
described to date, the EPA and ATSDR proposed similar MOAs
for acrolein respiratory toxicity; however, they considered the
concentration at which upper respiratory effects occur as a
threshold that is protective of the effects that would occur in
the sensitive lower respiratory tract. Upper respiratory symptoms from acrolein inhalation generally occur at lower exposures than those that cause lower respiratory toxicity. ATSDR
proposed an acrolein toxicity mechanism in which the action of
a highly reactive compound binding to sulfhydryl groups on
macromolecules causes increased oxidative stress and results
in cell death and inflammation. ATSDR also proposed that
irritation in the nasal epithelium was consistent across several
species and applicable to humans (ATSDR, 2007). The EPA proposed an acute MOA, stating that acrolein toxicity results in
nasal and ocular irritation and in respiratory distress. The EPA
also proposed a longer-term MOA for acrolein as a highly reactive compound, which increases the formation of ROS and depletion of GSH, with concomitant effects including binding and
perturbation of cell membrane proteins and regulatory proteins.
Furthermore, in EPA’s long-term acrolein MOA, the deposition
of acrolein results in respiratory tract pathologies with increasing severity and respiratory system penetration as the dose increases, with the nasal mucosa being the initial critical target
site (EPA, 2003). Although the EPA and ATSDR MOAs share similar features with this MOA, the two crucial differences are that
this analysis focuses on: (1) cigarette smokers and not the general population, and (2) a different endpoint (lower respiratory
toxicity) that is specific to smoking exposure. Cigarette smokers
tolerate upper respiratory tract irritation and inhale tobacco
smoke deeply; therefore in this MOA we consider the greater respiratory tract penetration that cigarette smokers experience in
determining the relevant toxic effects.
Other Potential Modes of Action
The research review identified emerging literature describing
the cardiotoxicity of inhaled acrolein. However, the cardiovascular toxicity of acrolein is not as well studied as the respiratory
portal-of-entry effects of acrolein, and this MOA focuses on the
respiratory system. Because the cardiovascular system is a different organ system, a separate MOA for acrolein cardiovascular
toxicity would be independent from this evaluation (Boobis
et al., 2008). Briefly, cardiovascular toxicities observed after acrolein inhalation include effects on the heart muscle and blood
pressure changes. Nonspecific inflammatory heart lesions have
been observed in rats, dogs, monkeys, and guinea pigs (Lyon
et al., 1970). Heart weight changes have been observed in hamsters and rats but were not dose-dependent (Feron et al., 1978).
Blood pressure increase was seen in hypertension-sensitive rats
compared with hypertension-resistant rats following aerosol
administration of acrolein, but a dose-dependent response was
not reported (Kutzman et al., 1984). It has been suggested that
the cardiovascular effects of acrolein are secondary to the pulmonary stress caused by the respiratory damage incurred at the
portal-of-entry (ATSDR, 2007). A more recent study noted the
decrease in the sensitivity of the baroreflex receptor and increase in arrhythmia in rats following acute acrolein exposure
(3.0 ppm) (Hazari et al., 2014). The authors suggest that these
autonomic regulatory changes that occur immediately following exposure may persist (Hazari et al., 2014). Many factors influence cardiovascular pathologies (ie, multiple chemicals,
multiple mechanisms) and as such a threshold for these cardiovascular effects does not yet appear to have robust support (ie,
clearly established lowest observed adverse effect levels
[LOAELs], confirmation in other studies). In contrast, respiratory
portal-of-entry effects have been shown to have dose-dependence in multiple studies.
Analogy to MOA
Several mechanisms of acrolein toxicity are discussed in the literature, including oxidative stress, mitochondrial dysfunction,
DNA adduction, inflammation and immune alteration, ER
stress, structural and membrane effects, and deregulated signal
transduction (ATSDR, 2007; Beauchamp et al., 1985; Bein and
Leikauf, 2011; EPA, 2003; Ghilarducci and Tjeerdema, 1995;
Moghe et al., 2015; Stevens and Maier, 2008; WHO, 2002). Except
YEAGER ET AL.
for DNA adduction, each of these elements is considered to be
important in the MOA for acrolein proposed here. The role of
DNA adduction in acrolein toxicity is unclear. Although acrolein-DNA adducts are formed, (Yin et al., 2013; Zhang et al.,
2007), these adducts may not be genotoxic. Moreover, there is
no currently available evidence to suggest that these DNA adducts are involved in noncancer respiratory toxicity resulting
from acrolein exposure.
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359
hazard attributed to acrolein in these risk assessments.
Furthermore, the levels of acrolein in tobacco smoke are much
higher than the levels necessary to induce the key steps in acrolein respiratory toxicity. As tobacco smoke causes the majority
of COPD in the United States, this proposed MOA is a reasonable
description of the key events following acrolein exposure and
leading to COPD and provides the basis for the estimation of
threshold values below which these key events are not expected
to occur.
Uncertainties, Inconsistencies, and Data Gaps
The chronic lower respiratory toxicity following acrolein exposure from cigarette smoking implicates key steps leading to
COPD that form the components of a descriptive MOA. As noted
earlier, no human or animal studies provide a direct link between acrolein as the causal agent in cigarette smoke and
COPD, although smoking is known to cause COPD. Furthermore,
a dose–response relationship of smoker exposure to acrolein in
cigarette smoke with extent and severity of COPD is not established. More broadly, tobacco smoke is a complex mixture of
numerous constituents, many of which are toxic. This fact complicates the assessment of acrolein-related effects from cigarette smoke exposure.
Moreover, acrolein both produces inflammation and impairs
the immune response, introducing complexity to the assessment of the MOA. The immunologic response may be doserelated and temporally related, with an acute high dose causing
susceptibility to infection and a chronic low dose causing inflammation and tissue injury (Moghe et al., 2015). Inflammation
resulting from acrolein exposure causes cell death by a variety
of mechanisms, introducing further complexity, although the
end result is consistently cellular necrosis. Animal studies report inflammation, cell necrosis, tissue damage, and tissue necrosis after acrolein exposure but apoptosis is also observed
(Moghe et al., 2015). Whether acrolein induces apoptosis or
oncosis may be related to dose (Finkelstein et al., 2005; Li et al.,
1997; Moghe et al., 2015). Apoptosis is balanced with regeneration for structural cells (Demedts et al., 2006) but the immune
alterations in the lung may prevent appropriate clearance of
apoptotic cells and release of intracellular contents, leading to
tissue damage (Rovere-Querini and Dumitriu, 2003).
Simultaneous chronic inflammation and impaired immune cell
function (such as clearance of damaged tissue) may occur after
acrolein exposure. Impaired clearance of necrotic and apoptotic
cells induces further inflammation and results in the tissue
damage observed in animal studies.
Conclusion
This MOA provides evidence to link the effects of acrolein exposure from cigarette smoke to the hallmarks of COPD pathogenesis through a logical sequence of events based on the
synthesis of evidence from in vitro and in vivo studies. Acrolein’s
strong portal-of-entry effects across multiple species provide
confidence that inflammation and tissue destruction occurs in
humans following chronic exposure to acrolein, causing COPD.
Acrolein exposure from inhaling cigarette smoke results in a
cycle of oxidative damage, cell necrosis, and chronic inflammation that over time causes respiratory tissue remodeling and destruction, ultimately manifesting as COPD. Although many
other significant respiratory toxicants are present in tobacco
smoke, acrolein has been previously identified as the tobacco
constituent associated with the greatest noncancer respiratory
disease risk. This MOA provides insights regarding the degree of
ACKNOWLEDGMENTS
The authors are grateful for the assistance of the White Oak
FDA library staff members for their help with the research
review and for locating hard-to-find articles. The authors
thank FDA Technical Writer Deborah Neveleff for her assistance with editing this manuscript. The authors thank Dr.
Kimberly Benson, Director of the Division of Nonclinical
Science, CTP, FDA, for her support of these research
activities.
FUNDING
There are no sources of funding to report. The findings and
conclusions in this report are those of the authors and do
not necessarily represent FDA positions or policies.
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