RESIDENTIAL INDOOR AIR QUALITY GUIDELINES

ACROLEIN
Health Canada is the federal department responsible for helping the people of Canada maintain and improve
their health. Health Canada is committed to improving the lives of all of Canada's people and to making this
country's population among the healthiest in the world as measured by longevity, lifestyle and effective use
of the public health care system.

Également disponible en français sous le titre :

Lignes directrices sur la qualité de l’air intérieur résidentiel
ACROLÉINE

To obtain additional information, please contact:

Health Canada
Address Locator 0900C2
Ottawa, ON K1A 0K9
Tel.: 613-957-2991
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© Her Majesty the Queen in Right of Canada, as represented by the Minister of Health, 2021

Publication date: March 2021

This publication may be reproduced for personal or internal use only without permission provided the source
is fully acknowledged.

Cat.: H144-82/2021E-PDF
ISBN: 978-0-660-37462-8
Pub.: 200446
PREAMBLE
Health Canada assesses the health risks posed by specific indoor pollutants in residential
environments and provides recommendations on how to reduce those risks. Residential Indoor Air
Quality Guidelines (RIAQG) summarize the known health effects, pollutant sources, and exposure
levels in Canadian homes and characterize the risks to health, based on the best scientific data
available. Recommended exposure limits (also referred to as guideline values) for short- and/or
long-term exposure to the pollutant are developed, representing indoor air concentrations below
which health effects are unlikely to occur. The recommended exposure limits take into account the
reference concentrations (RfC) for the pollutant and the feasibility of achieving such levels through
control of indoor sources. The RIAQG also include recommendations for controlling sources or
other actions to reduce exposure to the pollutant.

For some pollutants, a recommended exposure limit may not be developed, although the available
scientific evidence justifies reducing Canadians’ exposure to the pollutant. In this case, a guidance
document that focuses on actions to control sources and reduce exposure is developed.

The RIAQG and guidance documents serve as a scientific basis for activities to evaluate and reduce
the risk from indoor air pollutants including, but not limited to:

• assessments by public health officials of health risks from indoor air pollutants in residential
or similar environments;

• performance standards that may be applied to pollutant-emitting materials, products, and

devices, so that their normal use does not lead to air concentrations of pollutants exceeding
the recommended exposure limits; and

• communication products informing Canadians of actions they can take to reduce their
exposure to indoor air pollutants and to help protect their health.

The RIAQG and guidance documents replace a series of exposure limit values for indoor air
pollutants from a report entitled Exposure Guidelines for Residential Indoor Air Quality (Health
Canada 1987). In addition to updates for the substances included in the 1987 report, guidelines or
guidance documents will be developed for other substances that are identified as having the
potential to affect human health in the indoor environment.

The focus of this document is acrolein, which was identified as a priority for the development of
RIAQG, because indoor air concentrations measured in Canadian homes were found to exceed the
indoor air reference level (IARL) of 0.35 µg/m3 (Health Canada 2017). The IARL is based on
respiratory epithelial lesions in rats from an assessment published by the California Environmental
Protection Agency (CalEPA 2008).

RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN ❘ i

In addition to relevant literature, the present document draws from a number of comprehensive
reviews of the health effects of acrolein, including:

• Proposition de valeurs guides de qualité d’air intérieur : L’acroléine, published by the Agence
nationale de sécurité sanitaire de l’alimentation, de l’environnement et du travail (ANSES;
France) in 2013

• Acrolein Reference Exposure Levels, published by the California Environmental Protection

Agency in 2008 (cited hereafter as CalEPA 2008)

• Toxicological Profile for Acrolein, published by the Agency for Toxic Substances and Disease
Registry in 2007 (cited hereafter as ATSDR 2007)

• Toxicological Review of Acrolein, published by the US Environmental Protection Agency in

2003 (cited hereafter as US EPA 2003)

• Concise International Chemical Assessment Document 43: Acrolein, published by the World
Health Organization in 2002 (cited hereafter as WHO 2002)

• Priority Substances List Assessment Report: Acrolein, published by Environment Canada and
Health Canada in 2000 (cited hereafter as Environment Canada and Health Canada 2000)

Relevant literature was identified through the aforementioned comprehensive reviews and a
web‑based search through October 2018, with an emphasis on those published since the most recent
comprehensive review (i.e., ANSES 2013). The original articles of direct relevance to evaluating
exposure to acrolein in the indoor environment and its associated health effects were reviewed.
The scope of this document is limited to the inhalation of acrolein, and does not consider dietary
sources or oral routes of exposure. Key studies underlying the derivation of the recommended
exposure limits are presented, and where appropriate, supporting information is summarized. In
addition, information on acrolein concentrations in Canadian homes as well as factors influencing
these concentrations was obtained from Health Canada research studies.

ii ❘ RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN

TABLE OF CONTENTS
EXECUTIVE SUMMARY. . ........................................................................................................................................... 1

1 PHYSICAL AND CHEMICAL CHARACTERISTICS. . ..................................................................................... 7

2 SOURCES IN THE AIR ........................................................................................................................................ 8

2.1 Outdoor Sources........................................................................................................................................... 8
2.2 Indoor Sources............................................................................................................................................... 8

3 CONCENTRATIONS IN INDOOR AND OUTDOOR AIR . . ..................................................................... 11

4 TOXICOKINETICS.. ............................................................................................................................................. 16
4.1 Absorption, Distribution, Metabolism, and Excretion....................................................................... 16
4.2 Physiologically Based Pharmacokinetic Modelling. . ........................................................................... 19

5 HEALTH EFFECTS............................................................................................................................................... 20
5.1 Effects in Humans. . ...................................................................................................................................... 20
5.1.1 Short-term exposure....................................................................................................................... 20
5.1.2 Long-term exposure....................................................................................................................... 22
5.1.3 Carcinogenicity................................................................................................................................ 23
5.2 Toxicological Studies. . ................................................................................................................................ 24
5.2.1 Respiratory effects......................................................................................................................... 24
5.2.2 Immunological effects.................................................................................................................. 28
5.2.3 Cardiovascular effects. . ................................................................................................................. 29
5.2.4 Reproductive and developmental effects. . .............................................................................. 29
5.2.5 Genotoxicity.................................................................................................................................... 30
5.2.6 Carcinogenicity. . ............................................................................................................................. 31
5.3 Summary of Health Effects and Mode of Action................................................................................. 31
5.4 Susceptible populations............................................................................................................................ 34

RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN ❘ i

6 DERIVATION OF SHORT- AND LONG-TERM REFERENCE CONCENTRATIONS.. ........................ 35
6.1 Short-Term Reference Concentration.................................................................................................... 35
6.2 Long-Term Reference Concentration..................................................................................................... 36
6.3 Exposure in Canadian Homes in Relation to Reference Concentration and Determination
of Recommended Exposure Limits................................................................................................................. 37
6.3.1 Short-term reference concentration and recommended exposure limit......................... 37
6.3.2 Long-term reference concentration and recommended exposure limit.. ........................ 38
6.4 Uncertainties ............................................................................................................................................... 38

7 GUIDELINES......................................................................................................................................................... 40
7.1 Recommended Exposure Limits. . ............................................................................................................ 40
7.2 Risk Management Recommendations................................................................................................... 40

8 REFERENCES....................................................................................................................................................... 42

APPENDICES.............................................................................................................................................................. 51
APPENDIX A: LIST OF ACRONYMS AND ABBREVIATIONS.................................................................. 51
APPENDIX B: HUMAN EXPOSURE STUDIES. . ............................................................................................ 53
APPENDIX C: TOXICOLOGICAL STUDIES................................................................................................. 56
APPENDIX D: OTHER GUIDELINES ............................................................................................................. 64
D1. Short-Term Exposure Guidelines................................................................................................... 64
D2. Exposure Guidelines for Non-Neoplastic Chronic Effects. . ..................................................... 65

ii ❘ RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN

LIST OF TABLES
Table 1. Physical and chemical properties of acrolein............................................................................. 7

Table 2. Concentrations (µg/m3) of acrolein in indoor and outdoor air in Canada........................ 13

Table 3. Recommended exposure limits for acrolein for indoor environments.............................. 40

Table B1. Short-term exposure . . ................................................................................................................ 53

Table B2. Epidemiological studies................................................................................................................ 54

Table C1. Acute (single) exposure studies................................................................................................... 56

Table C2. Repeat exposure studies (3 days to 6 weeks)........................................................................... 58

Table C3. Repeat exposure studies (6 weeks to 18 months)................................................................... 60

Table D1. Other short-term exposure guidelines...................................................................................... 65

Table D2. Other exposure guidelines for non-neoplastic chronic effects.. ......................................... 66

RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN ❘ iii

LIST OF FIGURES
Figure 1. Distribution of concentrations of acrolein in indoor air by season across
studies conducted by Health Canada. . ...................................................................................... 14
Figure 2. Distribution of I/O ratios by season across studies conducted by
Health Canada. . ................................................................................................................................ 15
Figure 3. Proposed pathway for the metabolism of acrolein (adapted from
WHO 2002 and Burcham 2016).................................................................................................... 18

iv ❘ RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN

EXECUTIVE SUMMARY

RESIDENTIAL INDOOR AIR QUALITY GUIDELINES FOR ACROLEIN

Recommended Concentration
Critical effect(s)
Exposure Limit µg/m3 ppb

Short-term (1 h) 38 17 Eye irritation in healthy volunteers

Long-term (24 h) 0.44 0.19 Lesions in the respiratory epithelium of the rat nasal cavity

The recommended short-term (one-hour) exposure limit for acrolein is 38 µg/m3 and the
recommended long-term exposure limit is 0.44 µg/m3 (based on 24-hour average).
Levels of acrolein in a typical Canadian home are likely below the short-term, but above the
long‑term exposure limits, and accordingly may pose a health risk, specifically related to adverse
respiratory effects. It is therefore recommended to reduce exposure to acrolein by ensuring
adequate ventilation and controlling indoor sources.

BACKGROUND
Acrolein is a very reactive and volatile α,β-unsaturated aldehyde, which is found in both indoor and
outdoor air. In the Priority Substances List Assessment Report: Acrolein published in 2000,
Environment Canada and Health Canada derived a tolerable concentration based on changes in
cells of the nasal respiratory epithelium of rats following inhalation exposure to acrolein. A number
of key studies have been published since the Priority Substances List Assessment Report, along with
health risk assessments from several international organizations. Health Canada established an
Indoor Air Reference Level (IARL) for acrolein in 2017. IARLs represent concentrations that are
associated with acceptable levels of risk after long-term exposure for a specific volatile organic
compound (VOC), as determined by the organization or jurisdiction that performed the risk
assessment. As levels in Canadian homes are generally higher than the recommended IARL, and in
order to more fully characterize sources of acrolein in the indoor environment and review recent
health effects literature, this substance was prioritized for a full health risk assessment and
development of Residential Indoor Air Quality Guidelines (RIAQG).

The RIAQG review the epidemiological, toxicological, and exposure research on acrolein as well as
the conclusions from a number of comprehensive reviews from internationally recognized health
and environmental organizations. They are intended to provide recommended short- and long-term
indoor air exposure limits for acrolein, which would minimize risks to human health, and to support
the development of actions to limit acrolein emissions. The RIAQG also show that levels in Canadian
houses may potentially present a health risk when compared to the exposure limits and recommend
various risk mitigation measures to reduce exposure to acrolein.

RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN ❘ 1

SOURCES AND EXPOSURE
Acrolein is ubiquitous throughout the ambient environment. The primary natural source of acrolein
is incomplete combustion of organic matter during forest fires. The principal anthropogenic source
of atmospheric acrolein is the combustion of organic matter and fuels, with motor vehicles
(including aircraft) generating most of the acrolein emissions. Industrial processes such as
incineration, pulp and paper and oriented-strand board production, and coal electricity generation
also contribute to acrolein emissions, though much less than mobile sources.

Acrolein levels in residential indoor air are generally greater than outdoor levels. Some of the
sources of acrolein in indoor air are smoking, using gas stoves, wood-burning fireplaces, burning
incense, cooking with oils, and secondary formation by oxidation of other VOCs from products and
building materials. However, no information is available on the relative contributions of these
various sources to the total indoor air concentration of acrolein.
Acrolein is one of the most difficult chemicals to measure in air due to its reactivity with other
chemicals. Health Canada studies have collected acrolein measurements in air using the following
two most common methods: 2,4-dinitrophenylhydrazine cartridges for sampling coupled with high
performance liquid chromatography for analysis; and passivated canisters for sampling coupled
with gas chromatography mass spectrometry for analysis. While both methods have limitations, the
scientific literature and work carried out by Environment and Climate Change Canada and Health
Canada suggest that passivated canisters provide the most accurate estimate of indoor acrolein
levels available.

Median acrolein levels measured using passivated canisters in Edmonton, Halifax, Regina, and
Windsor during winter and summer from 2005 to 2010 ranged from 1.3 to 8.1 µg/m3 indoors and
from 0.2 to 2.2 µg/m3 outdoors (Health Canada 2010a, 2010b, 2012, 2013). In Windsor, personal
exposure measurements were also collected, with a median range of 1.1 to 4.3 µg/m3. In these
studies, the ratio of indoor-to-outdoor acrolein concentrations was in general consistently above
2.5, which is indicative of a predominance of indoor sources of acrolein.

HEALTH EFFECTS
Health effects of exposure to acrolein have been examined in toxicological and controlled human
exposure studies, with very little epidemiological evidence related to indoor acrolein exposure.
Based on the evidence from these studies, the effects of short- and long-term acrolein inhalation
exposures are observed at the site of entry. Key health effects include eye and respiratory irritation,
and tissue damage in the respiratory tract.

In this assessment, the short-term exposure limit is derived from the results of a controlled human
exposure study, whereas the long-term exposure limit is based on toxicological data from a study
in a rodent model. Supporting evidence is provided by the results of other toxicological and
controlled human exposure studies.

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Human studies
Studies with human participants reported that acute exposure induced eye irritation at acrolein
concentrations as low as 0.21 mg/m3 (210 µg/m3), nasal irritation starting at 0.35 mg/m3 (350 µg/m3),
and respiratory irritation (measured by decreased respiration rate) starting at 0.69 mg/m3 (690 µg/
m3) (Darley et al. 1960; Weber-Tschopp et al. 1977; Dwivedi et al. 2015; Claeson and Lind 2016).
Epidemiological data on the long-term effects in humans are limited to two studies in France: one
study showed a positive association between acrolein levels in schools and allergic asthma in the
previous year, and between acrolein levels and exercise-induced asthma, but a negative association
between acrolein levels and non-allergic asthma (Annesi-Maesano et al. 2012); in the other study, no
significant relationship was identified between acrolein levels measured in homes and asthma in the
previous year (Billionnet et al. 2011). Neither study showed a relationship between acrolein levels
and rhinitis.

Toxicological studies
In laboratory animals, acute acrolein exposure induced irritant effects such as decreased respiration,
bronchoconstriction/increased flow resistance, and increased mucus secretion in multiple species at
concentrations as low as 0.7 mg/m3 (700 µg/m3). Changes in cell composition in the respiratory tracts
of guinea pigs, hamsters, and rats were observed at higher concentrations, starting at 2.1 mg/m3
(2100 µg/m3) (Leikauf 1991; Roemer et al. 1993; Cassee et al. 1996; Cassee, Groten and Feron 1996;
Arumugan et al. 1999; US EPA 2003; CalEPA 2008).
Repeated inhalation exposures to acrolein produced similar effects as single exposures. Studies
in mice and rats have shown that exposure to acrolein for 3 days to 13 weeks results in increased
mucus secretion, and inflammation and cell proliferation in the respiratory epithelium accompanied
by basal cell hyperplasia and squamous cell metaplasia (Lyon et al. 1970; Feron et al. 1978; Kutzman
et al. 1981, 1985; Costa 1986; Roemer et al. 1993; Cassee, Groten and Feron 1996; Dorman et al.
2008). The severity of the effects appears to increase with exposure concentration but not with
duration of exposure. In experimental animals, acrolein reacts mainly in the nasal area and upper
respiratory tract, but there may be increased penetration and damage to the lower respiratory tract
at higher concentrations. In most studies, effects were observed at the lowest test concentration,
starting at 0.9 mg/m3 (900 µg/m3); however, one study identified a no observed adverse effect level
(NOAEL) of 0.46 mg/m3 (460 µg/m3) for pathology of the rat nasal respiratory epithelium, including
inflammation, hyperplasia, and squamous metaplasia (Dorman et al. 2008).

Acrolein has been shown to be mutagenic and genotoxic in vitro, but there were no indications of
genotoxicity in limited in vivo studies (Kutzman 1981; Lam et al. 1985; Environment Canada and
Health Canada 2000; US EPA 2003; ATSDR 2007; Wang et al. 2012; Lee et al. 2014). Conclusions
regarding its carcinogenicity potential cannot be drawn from the limited studies available.

RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN ❘ 3

Susceptible populations
Sensitized individuals such as asthmatics as well as individuals with chronic pulmonary disease or
bronchitis may be more susceptible to the effects of acrolein on the respiratory tract. Children,
especially those with asthma, may be more likely to show adverse respiratory effects following
exposure to acrolein due to higher prevalence rates of asthma in children as compared to other
age groups, the small size and immature state of their airways, and the exacerbation that toxic air
contaminants have been demonstrated to have on asthma in children. In general, pre-existing
nasal allergies can also intensify the response to nasal irritants; and individuals with decreased
glutathione synthesis or impaired glutathione-S-transferase activity may be more susceptible to
the effects of acrolein.

Mode of action of toxicity

Acrolein is a sensory irritant that activates defense mechanisms to reduce penetration further into
the respiratory tract, such as a decrease in breathing rate, an increase in mucus secretion, and
bronchoconstriction. As it is highly reactive, acrolein becomes rapidly and irreversibly bound to
sulfhydryl groups at the site of first contact, causing a decrease in glutathione and other reducing
agents, as well as changes in enzyme activities resulting in a decrease in protective activity in the
respiratory nasal epithelium. These changes also induce an inflammatory response through the
recruitment of immune cells and stimulation of the production and/or release of proinflammatory
cytokines.

DERIVATION OF THE RECOMMENDED EXPOSURE LIMITS

The determination of the recommended exposure limits is carried out in two stages. First, a
reference concentration (RfC) is derived by applying uncertainty factors to the concentrations at
which the most sensitive adverse health endpoint was observed. The RfC approach is used for the
determination of recommended exposure limits to reduce potential health impacts such as those
observed in key toxicological, controlled human exposure, and indoor epidemiological studies.

For the short-term exposure RfC, the exposure period is specified; in the present case, one hour.
For the long-term exposure RfC, the exposure is considered to occur over months or years, up to a
lifetime.

In the second stage, the short- and long-term exposure RfCs are compared with measured
exposures in residential indoor air, and evaluated with respect to their technical feasibility. In
general, if the RfC is considered attainable where reasonable control measures are followed, the
recommended exposure limit is set equal to the RfC. If the RfC is considered unattainable with
currently available risk management technology and practices, the recommended exposure limit
may be set at a higher concentration. Setting the recommended exposure limit at a higher
concentration than the RfC results in a smaller margin of exposure between the recommended
exposure limit and the concentration at which effects have been observed in health studies.

4 ❘ RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN

Nonetheless, a recommended exposure limit derived in this manner does provide a measure of
health protection, while remaining an achievable target for improving indoor air quality when
evaluating risk management measures.

Recommended short-term residential indoor air quality exposure limit

For short-term exposure to acrolein, the most sensitive endpoint was eye irritation in studies with
healthy volunteers. A NOAEL of 115 µg/m3 was selected as the point of departure (Dwivedi et al.
2015) and an uncertainty factor of 3 was applied to account for sensitive individuals. Thus, the acute
RfC is 38 µg/m3.
The Health Canada residential indoor air exposure studies provide a 24-hour integrated sample of
acrolein measurements, which does not represent acute or peak exposure (Health Canada 2010a,
2010b, 2012, 2013). These 24-hour measurements show that the short-term reference exposure level is
higher than the range of median indoor air concentrations. Therefore, as this exposure limit is
achievable in Canadian homes, the recommended short-term exposure limit for acrolein is 38 µg/m3.
It is recommended that the short-term exposure limit be compared to a one-hour air sample.

Recommended long-term residential indoor air quality exposure limit

For long-term exposure to acrolein, the most sensitive endpoint was degenerative lesions in the
respiratory epithelium of the rat nasal cavity. A NOAEL of 460 µg/m3 was selected as the point of
departure, based on inflammation, hyperplasia, and squamous metaplasia at higher test
concentrations (Dorman et al. 2008). This concentration was adjusted for continuous exposure, and
toxicokinetic differences between rats and humans were accounted for by applying a regional gas
dose ratio, giving a human equivalent NOAEL of 11 µg/m3. Uncertainty factors of 2.5 for
toxicodynamic differences between rats and humans and 10 for sensitivity in the human population
were applied. Thus, the long-term RfC is 0.44 µg/m3.
Median acrolein concentrations measured inside Canadian homes from the Health Canada
residential indoor air exposure studies for a 24-hour averaging period ranged between 1.3 and
8.1 µg/m3, and the 95th percentile ranged between 3.5 and 21.0 µg/m3 (Health Canada 2010a, 2010b,
2012, 2013). This indicates that even considering uncertainties in the measurement of acrolein, there
will likely be Canadian homes in which the long-term RfC is exceeded. However, the RfC was
derived using the most recent scientific information, and is consistent with both the Health Canada
IARL of 0.35 µg/m3 and values from other jurisdictions (Environment Canada and Health Canada
2000, US EPA 2003, CalEPA 2008, ANSES 2013). In addition, reduction of acrolein levels in the home
through ventilation and source control is considered possible. Therefore, the recommended
long‑term exposure limit for acrolein is 0.44 µg/m3.
When comparing a measured acrolein concentration with the long-term exposure limit, the
sampling time should be at least 24 hours.

RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN ❘ 5

RISK MANAGEMENT RECOMMENDATIONS
Strategies for reducing indoor exposure to acrolein include the following:

• Increase ventilation by opening windows (when possible, and check the outdoor air quality
conditions in your region before opening windows: Air Quality Health Index) or by
employing mechanical ventilation strategies. More information on how ventilation can
improve indoor air quality can be found in the Factsheet: Ventilation and the indoor
environment (Health Canada 2018a).

• Use a range hood exhaust fan with outside venting, preferably on the high setting, when
cooking, especially with oils.

• While cooking, use back burners instead of front burners in addition to using a range hood
exhaust fan. If a range hood exhaust fan is not available, open windows or run the fan in the
furnace or ventilation system.
• Do not smoke or burn candles or incense inside the home, and ensure proper ventilation to
the outside during use of combustion appliances (e.g., gas stoves, woodstoves or fireplaces).

• Decrease volatile organic compound (VOC) levels in the home to reduce secondary
formation of acrolein. This can be done by choosing low-emission products whenever
possible; opening windows to ensure good ventilation when using products such as glues,
paints, varnishes, and cleaning products; and minimizing the use of scented products, such
as plug-in or aerosol deodorizers (air fresheners).

6 ❘ RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN

1 PHYSICAL AND CHEMICAL
CHARACTERISTICS
Acrolein is a clear or yellow flammable liquid with a burnt, sweet, pungent odour. It is a volatile
α,β-unsaturated aldehyde, with low water solubility and vapour pressure. Its physical and chemical
properties are summarized in Table 1 (US EPA 2003; CalEPA 2008).

Table 1. Physical and chemical properties of acrolein

Property Value Chemical structure

Molecular formula C3H4O

Molecular weight 56.06 g/mol

CAS registry number 107-02-8

Density 0.843 g/cm3

Vapour pressure 29.3 kPa at 20 °C

Solubility Soluble in ethanol and diethyl ether, and

up to ~20% w/v in water

Boiling point 52.3 °C at 101.3 kPa

Odour threshold 0.37 mg/m3 (370 µg/m3) (0.16 ppm)

Octanol/water partition coefficient –0.01

Common synonyms Acrylaldehyde, acrylic aldehyde,

allyl aldehyde, ethylene aldehyde,
2-propenal, prop-2-en-1-al

RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN ❘ 7

2 SOURCES IN THE AIR
This section focuses on sources of acrolein in outdoor and indoor air. Additional sources contribute
to exposure to acrolein in media other than air—such as food (Environment Canada and Health
Canada 2000)—but these are beyond the scope of this document.

2.1 OUTDOOR SOURCES

Acrolein is found throughout the ambient environment, emitted through both natural and
anthropogenic sources. The primary natural source of acrolein is incomplete combustion of organic
matter during forest fires. Acrolein is also formed as a photooxidation product of various hydrocarbon
pollutants found in air (including propylene and 1,3-butadiene) (ATSDR 2007; CalEPA 2008).
Fermentation and ripening processes also release small amounts of acrolein (Environment Canada
and Health Canada 2000).

The principal anthropogenic source of atmospheric acrolein is the combustion of organic matter
and fuels. On-road motor vehicles were estimated to emit up to 3 000 000 kg/year and off-road
motor vehicles (including aircraft) emit perhaps even greater amounts (Environment Canada and
Health Canada 2000). The use of biodiesel (soy and animal blends) increased the acrolein emissions
compared to petroleum-derived diesel (ultralow sulfur diesel) (Karavalakis et al. 2010; Cahill and
Okamoto 2012). Industrial processes such as incineration, pulp and paper, oriented-strand board
production, and coal electricity generation also contribute to acrolein emissions, though much less
than mobile sources (Health Canada and Environment Canada 2000). Between 2013 and 2015,
industrial air emissions of acrolein reported to the National Pollutant Release Inventory ranged
between 102 and 111 tonnes (NPRI 2017).

No information is available on the relative contributions of various sources to the total ambient air
concentration of acrolein.

2.2 INDOOR SOURCES

Acrolein levels in residential indoor air have been found to be between 2- and 20-fold greater than
outdoor levels (Environment Canada and Health Canada 2000; WHO 2002; ATSDR 2007; Health
Canada 2010a, 2010b, 2012, 2013). Some of the primary sources of acrolein in indoor air are from
activities such as smoking and cooking with oils (Environment Canada and Health Canada 2000;
WHO 2002). However, no information is available on the relative contributions of the various sources
to the total indoor air concentration of acrolein.

8 ❘ RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN

Tobacco smoke has been shown experimentally to generate 3 to 220 µg of acrolein per burned
cigarette, a large proportion of which can be inhaled in the mainstream smoke or increase the level
of acrolein in a typical room by 0.4 to 2 ppb (0.9–4.6 µg/m3) (WHO 2002; ATSDR 2007). In Canada,
studies in Prince Edward Island and Regina, Saskatchewan reported an association between
increased acrolein levels and the presence of environmental tobacco smoke in the home; however,
the differences were not statistically significant due to the small sample sizes, and there is some
uncertainty in the measurement methods used in these studies (see section 3) (Gilbert et al. 2005;
Héroux et al. 2010). Other studies have shown higher acrolein concentrations in indoor
environments where combustion of tobacco products occurs (ATSDR 2007). In addition, significantly
higher levels of acrolein metabolites were detected in the urine of tobacco smokers compared to
non-smokers in the general population of the United States (Alwis et al. 2015).

Recent studies have demonstrated that electronic cigarettes (e-cigarettes, vaping) emit acrolein at
less than 0.02 to 21 µg per puff in the mainstream vapour (Herrington and Myers 2015; McRobbie et
al. 2015; Gillman et al. 2016; Farsalinos and Gillman 2018; Farsalinos et al. 2018). A predictive model
reported that heavy use of an electronic cigarette in a residential setting contributed more than
0.88 ppb (2 µg/m3) to the indoor air levels (Logue et al. 2017). There are certain cases where
electronic cigarette emissions have been shown to exceed that of tobacco smoking, such as the
“dry puff,” where the electronic-cigarette liquid is overheated (Farsalinos and Gillman 2018).

The overheating of animal and vegetable fats or oils during cooking can result in acrolein emissions
(ATSDR 2007). Seaman et al. (2009) showed that cooking or frying several different types of foods in
a variety of cooking oils produced significantly greater acrolein emissions compared to frying foods
in a “no oil” control. The acrolein indoor air levels 5 minutes after frying food with these various
cooking oils in a small (188 m3), well ventilated apartment (sampling 6 metres from emissions source)
ranged from 26.4 to 64.5 µg/m3. In a study of commercial kitchens in Hong Kong, cooking with oil
was associated with acrolein in the kitchen range hood exhaust (Ho et al. 2006). Similarly, in a study
in homes in California, acrolein concentrations were correlated with cooking events (Seaman et al.
2007). The air exchange rate was found to be the most significant chemical removal process for
acrolein generated by cooking with oils (Seaman et al. 2009).

The presence of a gas stove in the residence has been identified as a predictor of increased acrolein
levels. The mean personal exposure to acrolein was significantly higher (p < 0.05) for participants
that lived in homes with gas stoves (2.68 µg/m3) compared to those with electric stoves (2.03 µg/m3)
(Stocco et al. 2008). Acrolein is also found in wood smoke and increased concentrations may be
associated with the use of wood stoves or wood-burning fireplaces (IARC 1995; Seaman et al. 2009).
The acrolein emission rate from burning paraffin candles was experimentally measured to be
0.18 µg/kg of candle consumed (Lau et al. 1997), an emission rate more than 1000 times less than
cigarettes. Burning incense also increases the acrolein concentration in indoor air (Ho and Yu 2002).

RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN ❘ 9

Contributions to the indoor air concentration of acrolein may also come from building materials
by off-gassing or secondary formation (oxidation of other volatile organic compounds emitted).
In chamber emissions testing in California, acrolein was found in emissions from some building
materials (paints and particle boards), lumber used in home construction, and newly built
uninhabited homes (Seaman et al. 2007). Similarly, in a Canadian study, acrolein was detected in
some wood, insulation, and paint products (Won et al. 2014). However, the study authors noted that
the presence of acrolein needs to be interpreted with caution due to the limitations of the sampling
methodology (i.e., the use of pentafluorophenylhydrazine-coated thermal desorption tubes), which
resulted in high background levels and low capturing efficiency (see section 3 for more information
on measurement methods).
The 14.4 hour half-life of acrolein in the indoor environment is similar to values found in the ambient
environment (15–20 hrs) (ASTDR 2007; Seaman et al. 2009).

10 ❘ RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN

3 CONCENTRATIONS IN INDOOR
AND OUTDOOR AIR
Acrolein is one of the most difficult chemicals to measure in air due to its high volatility and reactivity.
Health Canada studies (Health Canada 2010a, 2010b, 2012, 2013) have collected indoor residential
acrolein measurements using the following two most common methods: 2,4-dinitrophenylhydrazine
(DNPH) cartridges for sampling coupled with high-performance liquid chromatography for analysis;
and passivated canisters for sampling coupled with gas chromatography mass spectrometry for
analysis. Both methods have their limitations, as described below.

Numerous problems have been reported for the 2,4-DNPH method, including the instability of the
DNPH-acrolein hydrazone during collection and storage, reactions with chemicals such as ozone
that interfere with accurate acrolein measurements, and poor chromatographic separation of the
complex carbonyl mixtures typically found in air (Tejada 1986; Possanzini and Di Palo 1996; Schulte-
Ladbeck et al. 2001; Seaman et al. 2006; Knighton et al. 2007; Wang et al. 2009; Uchiyama et al.
2010; Ho et al. 2011; Herrington and Hays 2012). Data collected by Health Canada are consistent
with the findings reported in the literature, as approximately 80% of the samples collected were
found to be below the limit of detection (personal communication, Health Canada 2018,
unreferenced). The unreliability of this method for quantifying acrolein is well established, with the
US EPA issuing an addendum in 1999 to Method TO-11A for the removal of acrolein from the list of
analytes covered by this method. As a result of these issues, no Health Canada exposure data from
2,4-DNPH cartridges have been reported in this guideline document.

Issues with the passivated canister method have also been reported, with both acrolein growth
(Swift et al. 2007; US EPA 2010) and acrolein reductions (ERG 2005) in canisters over time being
reported. Furthermore, investigations have shown that background acrolein can be elevated in
cleaned canisters, which may lead to overestimates (US EPA 2010). Finally, canister cleaning
technique can also influence acrolein background concentrations and growth over time (Dann and
Wang 2007; Shelow et al. 2009). Despite these issues, the passivated canister method has been
deemed superior to the 2,4-DNPH method by the US EPA, and used in ambient sampling networks
such as the US EPA’s Urban Air Toxics Monitoring Program and National Air Toxics Trends Stations
program in the United States.

In order to ensure that the data collected by Health Canada through the passivated canister method
could be used as a reasonable estimate of true indoor air acrolein concentrations, some investigations
were conducted. The first one examined the effect of time to analysis (i.e., number of days between
canister collection and canister analysis by the analytical laboratory) in historical data. The results of
this investigation showed a small but statistically significant effect of time to analysis (0.66% increase
per day). Adjustment for air exchange rate, temperature, and indoor humidity at the collection site
resulted in a higher although still relatively small increase (1.22% increase per day). For the second

RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN ❘ 11

investigation, Health Canada and Environment and Climate Change Canada tested the stability of
acrolein in passivated canisters. Overall results demonstrated that measured concentrations were
generally slightly higher at day 21 compared with the known day 0 concentrations in both the
SummaTM and SiloniteTM canisters. The median absolute difference between day 0 and day 21 was
0.34 µg/m3 (0.11 to 5.8 µg/m3) for the SummaTM canisters and 0.44 µg/m3 (0.02 to 6.6 µg/m3) for the
SiloniteTM canisters. In both types of canisters, the greatest changes in acrolein concentrations
between day 0 and day 21 were observed at the highest concentration (12 μg/m3).
These results suggest that while there may be some measurement error associated with the
passivated canister method, they provide the most accurate estimate of indoor acrolein
concentrations available at this time. Canadian indoor and outdoor exposure concentrations of
acrolein from Health Canada studies are presented in Table 2. These studies, which collected data
from over 200 households in four cities across Canada in both summer and winter, are considered
to be the most recent and representative data available for quantifying long-term indoor exposure
to acrolein in Canadian single-family homes.

Median acrolein levels measured by Health Canada in Edmonton, Halifax, Regina, and Windsor
during winter and summer from 2005 to 2010 ranged from 1.3 to 8.1 µg/m3 indoors and from
0.2 to 2.2 µg/m3 outdoors. The 95th percentile values ranged from 3.5 to 21 µg/m3 indoors and
from 0.5 to 7.4 µg/m3 outdoors (Health Canada 2010a, 2010b, 2012, 2013). In Windsor, personal
exposure measurements were also collected in 2005, with a median range of 1.1 to 4.3 µg/m3 and
a 95th percentile range of 3.1 to 8.2 µg/m3 (Health Canada 2010b).

12 ❘ RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN

Table 2. Concentrations (µg/m3) of acrolein in indoor and outdoor air in Canada

Sampling No. of Smoking No. of Concentration (μg/m3)

Location Sampling methoda Season Reference
period homes status samplesb Median 95th % ile
INDOOR
Edmonton, 2010 Passivated canisters Summer 50 Non-smokers 328 8.1 21.0 Health Canada
Alberta (7 days × 24 hours) Winter 50 337 6.2 15.6 (2013)

Halifax, Nova 2009 Passivated canisters Summer 50 Non-smokers 331 4.1 11.4 Health Canada
Scotia (7 days × 24 hours) Winter 50 312 2.8 9.7 (2012)

Regina, 2007 Passivated canisters Summer 111 Non-smokers 91 4.3 11.3 Health Canada
Saskatchewan (24 hours) Winter 106 Smokers 13 7.0 16.0 (2010a)

Non-smokers 83 1.8 3.5

Smokers 21 2.5 10.1
Windsor, 2006 Passivated canisters Summer 46 Non-smokers 211 6.2 10.3 Health Canada
Ontario (5 days × 24 hours) Winter 47 224 1.6 3.5 (2010b)

Windsor, 2005 Passivated canisters Summer 45 Non-smokers 217 5.9 10.2 Health Canada
Ontario (5 days × 24 hours) Winter 48 232 1.3 3.5 (2010b)

Overall range
from all 1.3–8.1 3.5–21.0
studies
OUTDOOR
Edmonton, 2010 Passivated canisters Summer 50 — 324 2.2 7.4 Health Canada
Alberta (7 days × 24 hours) Winter 50 332 1.0 2.5 (2013)

Halifax, Nova 2009 Passivated canisters Summer 50 — 324 0.6 1.6 Health Canada
Scotia (7 days × 24 hours) Winter 50 286 0.6 1.4 (2012)

Regina, 2007 Passivated canisters Summer 111 — 108 1.0 1.9 Health Canada
Saskatchewan (24 hours) Winter 106 94 0.2 0.9 (2010a)

Windsor, 2006 Passivated canisters Summer 46 — 214 0.6 1.1 Health Canada
Ontario (5 days × 24 hours) Winter 47 215 0.3 0.5 (2010b)

Windsor, 2005 Passivated canisters Summer 45 — 216 0.6 1.2 Health Canada
Ontario (5 days × 24 hours) Winter 48 200 0.2 0.5 (2010b)

Overall range
from all 0.2–2.2 0.5–7.4
studies
PERSONAL
Windsor, 2005 Passivated canisters Summer 45 — 206 4.3 8.2 Health Canada
Ontario (5 days × 24 hours) Winter 48 225 1.1 3.1 (2010b)

Notes: MDL = minimum detection limit

a
Stainless steel evacuated passivated (Summa™) canisters (6.0 L) were used to non-selectively collect indoor and outdoor air samples over
24-hour periods, in both seasons, for analysis of constituent VOC concentrations. Detailed methodologies for air sampling, analysis, and
treatment of values below the detection limit can be found in the individual reports.
b
The number of samples represent total number of samples collected and analyzed.

RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN ❘ 13

The distribution of indoor acrolein concentrations in studies conducted by Health Canada is
presented in Figure 1. It should also be noted that for the studies in Edmonton, Halifax, and
Windsor, multiple measurements were made at each home and these values have been averaged
to present one value per home, while for the Regina study a single measurement was made at each
home. Acrolein levels were higher in the summer than in winter in each of the four cities (Health
Canada 2010a, 2010b, 2012, 2013). This is likely due to warmer temperatures in summer and is
consistent with data collected by the Canadian Health Measures Survey, which found that
aldehydes, ketones, and alcohols generally had higher levels in the warm months and lower
levels in the cold months (Li et al. 2019).

Figure 1. Distribution of concentrations of acrolein in indoor air by season across studies

conducted by Health Canada
Acrolein (µg/m3)

Source data: Health Canada (2010a, 2010b, 2012, 2013)

The 75th, 50 th, and 25th percentiles are represented by the top, middle, and bottom of the boxes. The whiskers represent the 90 th
and 10 th percentiles. Outlier measurements from Halifax were not used for this plot.

14 ❘ RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN

The distribution of indoor/outdoor (I/O) ratios for each home is presented in Figure 2. An I/O ratio
compares levels of acrolein measured inside a given home to levels measured directly outside the
same home. In these studies, the I/O ratios much greater than 2.5 were generally consistent across
cities and seasons and are indicative of a predominance of indoor sources of acrolein.

Figure 2. Distribution of I/O ratios by season across studies conducted by Health Canada

Source data: Health Canada (2010a, 2010b, 2012, 2013)

The 75th, 50 th, and 25th percentiles are represented by the top, middle, and bottom of the boxes. The whiskers represent the 90 th
and 10 th percentiles. Outlier measurements from Halifax were not used for this plot.

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4 TOXICOKINETICS

4.1 ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

It has been demonstrated in various animal species that acrolein is effectively removed from inhaled
air by the respiratory tract (ATSDR 2007). For example, Egle (1972) observed that acrolein uptake by
the entire respiratory tract of anaesthetized dogs averaged 80 to 85% of the inhaled dose; only
about 20% of the inhaled dose reached the lower respiratory tract (Egle 1972 cited in ATSDR 2007;
US EPA 2003). Similarly, in mice and rats, inhaled acrolein was absorbed almost entirely into the
upper respiratory tract (Morris 1996 cited in ATSDR 2007; Morris et al. 2003; Struve et al. 2008).

In rats, uptake of acrolein in the upper respiratory tract decreased with increasing exposure
concentration or flow rate, and the uptake efficiency also decreased over time during 40- or
80minute exposures (Morris 1996; Struve et al. 2008), suggesting a saturable process. Data in
multiple experimental animal species have shown that acrolein mainly reacts in the nasal area, but
can penetrate into the lower respiratory tract at higher concentrations (reviewed in US EPA 2003).
This may be due to the decreased removal of acrolein in the upper respiratory tract as
concentration increases. There are also likely to be species differences in the level of deposition in
the upper and lower respiratory tract: deposition is expected to be primarily in the nasal passages
for rodents as they are obligate nose breathers and have a large surface area in their nasal
passages, whereas some penetration may occur to the lower respiratory tract for humans during
mouth breathing (Kimbell et al. 2001; Overton et al. 2001; Corley et al. 2012).

In rats dosed with acrolein intravenously or orally by gavage, almost all of the administered
radiolabel was detected in the excreta within 24 hours, 54 to 59% of the radioactivity being found in
urine, 22 to 27% in expired carbon dioxide, and 1 to 12% in feces. Tissue concentrations were very
low (< 1.2%), indicating a lack of systemic distribution (Parent et al.1996, 1998 cited in US EPA 2003).
By inhalation, acrolein did not reduce the concentration of liver glutathione (GSH), again suggesting
a lack of systemic distribution (McNulty et al. 1984 cited in CalEPA 2008; Lam et al. 1985). No other
data on distribution following inhalation exposure were identified.

Consistent with the highly reactive nature of acrolein, following inhalation, the effects observed
tend to be restricted to the initial site of contact (i.e., the respiratory tract). Inhaled acrolein is
retained at the site of exposure, and becomes rapidly and irreversibly bound to protein and
non‑protein sulfhydryl groups and to primary and secondary amines in proteins and nucleic acids
(WHO 2002; US EPA 2003). More specifically, it is proposed that acrolein binds with protein cysteine
residues and GSH, forming a GSH-acrolein adduct (ATSDR 2007; CalEPA 2008).

The predominant metabolic pathway proposed for acrolein starts with the glutathione-S-transferase
(GST)-catalyzed addition of GSH to the activated double bond of acrolein. This is followed by
processing of the acrolein-GSH adducts to mercapturic acid derivatives by alcohol and aldehyde

16 ❘ RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN

dehydrogenases (reviewed in WHO 2002, US EPA 2003). The reduced mercapturic acid derivative,
3-hydroxypropylmercapturic acid (3-HPMA, see Figure 3), is the predominant metabolite and has
been detected in the urine of rats administered acrolein by inhalation or by intraperitoneal (IP) or
subcutaneous injection (Linhart et al. 1996 cited in US EPA 2003). Similarly, 3-HPMA was detected in
urine of mice exposed to acrolein by inhalation (Tully 2014; Conklin et al. 2017). Linhart et al. (1996)
also measured a minor metabolite in rat urine, 2-carboxethylmercapturic acid (CEMA, See Figure 3),
accounting for approximately 10% of the two mercapturic acids.

Two other proposed minor pathways involve either epoxidation of acrolein and addition of GSH
on the epoxide, or addition of water to acrolein to form 3-hydroxypropionaldehyde, which is
subsequently oxidized to malonic acid and oxalic acid (Parent et al. 1998).

Acrolein is formed endogenously as a product of lipid peroxidation and the metabolism of

α-hydroxyamino acids and polyamines. Lipid peroxidation occurs during inflammation, which is a
characteristic of some respiratory diseases such as chronic obstructive pulmonary disease and
asthma (reviewed in ATSDR 2007; Bein and Leikauf 2011; Burcham 2016). Acrolein has been detected
in expired breath condensate and induced sputum; concentrations were higher in subjects with
chronic obstructive pulmonary disease or asthma compared with healthy subjects (Deshmukh et al.
2008 cited in Bein and Leikauf 2011). Similarly, acrolein metabolites 3-HPMA and CEMA were detected
in the urine of over 98% of the general population of the United States, with significantly higher levels
among tobacco smokers (Alwis et al. 2015).

RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN ❘ 17

Figure 3. Proposed pathway for the metabolism of acrolein (adapted from WHO 2002 and
Burcham 2016)

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4.2 PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELLING
Schroeter et al. (2008) developed a combined computational fluid dynamics (CFD)-physiologically
based pharmacokinetic (PBPK) model for acrolein. The CFD model was based on three-dimensional
models of rat and human nasal passages; and a two-compartment PBPK model (mucus and
epithelial tissues; perfused subepithelial tissues) was applied. The rat model was optimized using
pharmacokinetic (PK) data from Struve et al. (2008) and Morris (1996) studies (i.e., PK parameters
were adjusted to better match empirical data from these studies), but not fully validated (i.e., model
results were not compared to any rat PK studies that were not also used in the calibration process).
As the model was not calibrated or validated for humans, the authors used the 99 th percentile
results to be conservative. Saturation or non-linear kinetics appear to exist at relevant
concentrations.

Corley et al. (2012) extended the Schroeter et al. (2008) CFD model to include both the upper and
lower respiratory tract. The two-compartment PBPK model was maintained, but a new value for the
maximal metabolic rate (Vmax) was derived to account for aldehyde dehydrogenase saturation.
Relative acrolein uptake in rats, monkeys, and humans were presented only for an air concentration
of 0.6 ppm (1.38 mg/m3), for nasal tissues, and for the entire respiratory tract (considering both nasal
and oral human models). Acrolein uptake in nasal tissues was lower in humans than animals (69.5%,
54.7%, and 24% in rats, monkeys, and humans, respectively at 0.6 ppm [1.38 mg/m3]). When the
entire airway was considered, humans had similarly low relative acrolein uptake (98.5%, 95.8%,
45.2%, and 34.8% in rat, monkey, human nasal, and human oral models, respectively, at 0.6 ppm
[1.38 mg/m3]). The model was calibrated against PK data from rat studies (Morris 1996; Struve et al.
2008), but was neither fully validated for rats, nor calibrated or validated for humans.

As formaldehyde is a related gas, the relative flux of formaldehyde has also been modelled in rats
and humans by Kimbell et al. (2001), who used three-dimensional, anatomically realistic, CFD
models to estimate flux in regions or “bins” of the nasal passages. The average flux across 20 bins
was approximately double in humans compared to rats; the peak flux was about 25% higher in rats
than in humans (see section 6.2).

RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN ❘ 19

5 HEALTH EFFECTS
This section provides a review of the effects of acrolein in humans (see section 5.1) as well as relevant
toxicological studies in experimental animals, with supporting information from in vitro test systems
(see section 5.2). A concise summary of the health effects of inhalation exposure to acrolein, along
with a discussion on the mode of action, is also presented (see section 5.3). Details of the human
exposure and toxicological studies presented below can also be found in appendices B and C.

Relevant studies on the health effects of acrolein published up to October 2018 were reviewed.
Although acrolein is a component of tobacco smoke, studies of tobacco smoke were excluded as
tobacco smoke is a complex mixture that contains many known toxins and carcinogens, and its
health effects are not addressed in this document. Other routes of exposure (i.e., ingestion and
dermal) were not considered physiologically relevant. Health Canada evaluated the original studies
identified as key in the derivation of these recommended exposure limits for acrolein (see
section 6). Other relevant information was drawn from previous authoritative reviews of the health
effects of acrolein: (a) ANSES’s (2013) Proposition de valeurs guides de qualité d’air intérieur :
L’acroléine; (b) CalEPA’s (2008) Acrolein Reference Exposure Levels; (c) ATSDR’s (2007) Toxicological
Profile for Acrolein; (d) US EPA’s (2003) Toxicological Review of Acrolein; (e) WHO’s (2002) Concise
International Chemical Assessment Document 43: Acrolein; and (f) Environment Canada and Health
Canada’s (2000) Priority Substances List Assessment Report: Acrolein.

5.1 EFFECTS IN HUMANS

5.1.1  Short-term exposure

Several studies describe the acute effects of acrolein on human volunteers. In these studies, eye
irritation was the most sensitive endpoint, occurring at concentrations of 0.06 to 0.1 ppm (0.14–
0.23 mg/m3) for exposure durations as short as 5 minutes (Darley et al. 1960; Weber-Tschopp et al.
1977; Dwivedi et al. 2015; Claeson and Lind 2016). Nasal, throat, and respiratory irritation occurred at
higher concentrations (Weber-Tschopp et al. 1977).

Darley et al. (1960) exposed the eyes only of 36 volunteers to acrolein for 5 minutes, at concentrations
of 0.06, 1.3 to 1.6, or 2.0 to 2.3 ppm (0.14, 2.99–3.68 or 4.60–5.29 mg/m3, respectively). Some subjects
reported eye irritation even at the lowest test concentration (0.14 mg/m3), but the overall irritation
score at this concentration was still considered in the range of “no irritation.”

In a first experiment, Weber-Tschopp et al. (1977; publication in German) exposed 53 volunteers to

continuously increasing acrolein concentrations for 40 minutes (up to 0.6 ppm [1.4 mg/m3]);
significantly higher incidence of eye irritation (as reported by subjects) was first observed at
0.09 ppm (0.21 mg/m3). Eye irritation as measured by eye blink frequency was observed starting at
0.26 ppm (0.60 mg/m3). The study authors also noted a significant increase in subjective reports of

20 ❘ RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN

nasal irritation starting at 0.15 to 0.26 ppm (0.35 to 0.60 mg/m3), throat irritation starting at 0.43 ppm
(1.0 mg/m3), and a decrease in respiration rate at 0.6 ppm (1.4 mg/m3). In a second experiment,
Weber-Tschopp et al. (1977) exposed 42 subjects to acrolein for 1.5 minutes at concentrations of
0.15 to 0.6 ppm (0.35 to 1.4 mg/m3), with a recovery period between exposures. The incidence of
volunteer-reported eye irritation was significantly increased at 0.3 ppm (0.69 mg/m3) and nasal
irritation was increased at 0.6 ppm (1.4 mg/m3). Finally, Weber-Tschopp et al. (1977) exposed
46 volunteers to acrolein for 60 minutes at 0.3 ppm (0.69 mg/m3). Eye, nose, and throat irritation
increased during the first 10 to 20 minutes, and there was a significant decrease in respiration rate
(Weber-Tschopp et al. 1977 cited in US EPA 2003).

Other studies reported similar effects. Sim and Pattle (1957) observed that exposures of 0.8 ppm
(1.84 mg/m3) for 10 minutes, or 1.2 ppm (2.76 mg/m3) for 5 minutes were “extremely irritating” and
caused lacrimation (Sim and Pattle 1957 cited in US EPA 2003). Claeson and Lind (2016) found that
volunteers reported eye irritation starting about 7 minutes into a 15-minute eye-only exposure to
0.36 mg/m3 acrolein. Irritation continued for 10 minutes after cessation of exposure. No difference
in eye irritation was found between control exposures and a 45-minute exposure to 0.16 mg/m3 or a
60-minute exposure to 0.07 mg/m3. Dwivedi et al. (2015) studied irritation in 18 subjects exposed to
0.05 or 0.1 ppm (0.12 or 0.23 mg/m3) acrolein for 2 hours. Subjective eye irritation and blink
frequency were slightly increased at 0.1 ppm (0.23 mg/m3) but not 0.05 ppm (0.12 mg/m3) acrolein.
There was no difference between control and exposed subjects in terms of breathing frequency,
pulmonary function, or inflammatory markers in blood or sputum.

All of these studies had small numbers of volunteers and used self-reporting for symptoms of
irritation.

Several case studies describe the effects of acute exposure to acrolein; however, exposures are
often to multiple substances, and acrolein concentrations are generally unknown. A two-year-old
boy was hospitalized for acute respiratory failure following exposure for about an hour to acrid
smoke from vegetable oil burning. Lung effects were still visible eighteen months following
exposure (Mahut et al. 1993 cited in CalEPA 2008). A chemical worker was exposed to a sudden
release of acrolein in the workplace, causing chemical pneumonia and eye irritation, both of which
were resolved with treatment (Champeix et al. 1966 cited in US EPA 2003). The Centers for Disease
Control and Prevention (CDC) (2013) conducted a review of acute poisonings to acrolein from
occupational use of pesticides and identified eight cases in the United States between 1993 and
2009. Symptoms observed included respiratory distress, eye irritation, headache, dyspnea, and skin
irritation/burns.

RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN ❘ 21

5.1.2 Long-term exposure
Several recent studies were identified which examined the relationship between acrolein air
concentrations and health effects in humans. It is important to note that no causality can be
determined as all of the available studies are cross-sectional. Two of the studies identified included
concentrations of acrolein in schools or homes in France, measured with DNPH-coated passive
diffusion samplers; however, subjects were exposed to multiple pollutants, and health endpoints
(asthma and rhinitis) were based on questionnaires rather than medical diagnoses (Billionnet et al.
2011; Annesi-Maesano et al. 2012). Another study modelled ambient acrolein levels based on
emissions data and compared these levels to the prevalence of asthma in different regions of the
United States (deCastro 2014). There were no actual exposures measured, and no individual asthma
cases or control subjects. Limitations of the acrolein measurement methods are described in
section 3. Additional details of these studies are outlined below.

Annesi-Maesano et al. (2012) measured concentrations of acrolein and other air contaminant in
401 primary school classrooms in 108 schools across six cities in France. The acrolein concentrations
were put into 3 tiers: low (< limit of detection (LOD)—not specified), medium (> LOD but < 1.55 µg/
m3), and high (> 1.55 µg/m3). Health endpoints were asthma and rhinitis, as measured by a health
questionnaire completed by parents and a medical visit that included a skin prick test for allergies
and a test for exercise-induced asthma. After adjustment for possible confounders (including
passive smoking and family history), odds ratios (OR) for asthma in the previous year were 1.23 (95%
confidence interval [CI] of 1.02 to 1.45) and 1.22 (95% CI 1.09 to 1.38) for medium and high acrolein
concentrations, respectively, compared to low concentration. When the subjects were separated by
skin prick reactivity, acrolein was positively related to allergic (atopic) asthma (OR of 1.22 and 1.28
for medium and high exposure groups, respectively), and negatively related to non-allergic (non-
atopic) asthma. Acrolein was also found to be significantly correlated with exercise-induced asthma
(p < 0.025). There was no association between acrolein concentration and rhinoconjunctivitis in the
previous year. This study has multiple limitations, including the narrow range of concentrations
measured, no information on distribution of classroom acrolein levels, short-term (5 day) monitoring
without accounting for exposure to acrolein in the home, and parental definition of asthma in the
previous year rather than medical diagnosis. Given the weak, non-significant association between
acrolein and asthma in the whole study group, and the inverse relationship between acrolein and
asthma in non-atopic children as well as the lack of concentration-response relationship, the
authors’ claim that acrolein plays a role in the development of asthma must be viewed with caution.

Billionnet et al. (2011) sampled air in 490 homes in France, and measured acrolein and other indoor
air contaminants over one week. Acrolein concentrations were divided into quartiles; the range of
concentrations was < LOD (0.1 µg/m3) to 12.9 µg/m3, with a median of 1.0 µg/m3. Concentrations
above the third quartile of distribution were considered “elevated” (1.51 µg/m3). Health endpoints
(asthma in the previous year and rhinitis in the past month) were evaluated by questionnaire. After
adjustment for possible confounders (including smoking status and home characteristics), no
significant relationship was identified between elevated acrolein level and asthma or rhinitis. The
main focus of the paper was the effects of combined pollutant concentrations.

22 ❘ RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN

A more recent study was identified, which looked at modelled ambient acrolein levels and
prevalence of asthma in the population in the United States. deCastro (2014) estimated acrolein
exposure concentrations in each census tract based on data from the National Emissions Inventory
and US EPA’s air monitoring, and models incorporating population density, physical topography,
and climate. The modelled concentrations were divided into quintiles, with the lowest being
0.00014 to 0.011 µg/m3 and the highest being 0.055 to 0.457 µg/m3. The authors then compared
these with the results of the National Health Interview Survey, which gives national estimates of
disease prevalence across the country by year and age group. There was an increase in the
12-month asthma attack prevalence OR in the top quintile relative to the lowest quintile for all
subjects (n = 271 348), never smokers, and never + former smokers; the authors defined the
increases as “marginally significant,” with p-values between 0.05 and 0.15. No trend was observed
for the lower four quintiles. A major limitation of this study is that acrolein concentrations were not
actually measured.
Two recent biomonitoring studies examined levels of 3-HPMA (main acrolein metabolite) in urine and
disease risk. Limitations of these studies include lack of acrolein exposure measurements or source
attribution (includes exposure from all sources, including endogenous production); and no actual
health endpoints were studied. DeJarnett et al. (2014) examined the concentration of 3HPMA in urine
and the risk of cardiovascular disease in 211 subjects with moderate-to-high cardiovascular disease
risk. After adjusting for confounders, urine 3-HPMA concentration was found to be significantly
associated with cardiovascular disease risk (higher Framingham Risk Score). The relationship was even
more pronounced in non-smokers. Park et al. (2015) measured urinary 3-HPMA in approximately
2200 adult smokers from five ethnic groups. After adjusting for possible confounders, 3-HPMA was
highest in Native Hawaiians and lowest in Latinos. The authors note that compared to white people,
Native Hawaiians have a higher risk of lung cancer and Latinos a lower risk, and suggest that
differences in acrolein metabolism may account for some of the differences in risk.

5.1.3 Carcinogenicity
The International Agency for Research on Cancer (IARC) considers acrolein “not classifiable as to its
carcinogenicity to humans” (Group 3; IARC 1995), due to inadequate evidence in both humans and
experimental animals. The US EPA also considers the acrolein database inadequate for the
assessment of its carcinogenicity potential (US EPA 2003).

One occupational case-control study was identified (Ott et al.1989 cited in IARC 1995 and US EPA
2003), in which worker exposure to multiple chemicals was classified as “ever” or “never” by job
category. Exposure to acrolein was reported for two men who had died with non-Hodgkin’s
lymphoma, one with multiple myeloma, and three with nonlymphocytic leukaemia. There was no
statistically significant increase in cancer cases for workers exposed to acrolein, and concurrent
exposure to chemicals other than acrolein is likely. Therefore, the results of this study are insufficient
to conclude on the carcinogenic potential of acrolein.

No additional studies on the carcinogenic potential of inhaled acrolein were identified in the
literature.

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5.2 TOXICOLOGICAL STUDIES

5.2.1 Respiratory effects

5.2.1.1 Acute (single) exposure

Acrolein has high acute toxicity, inducing acute inflammatory reactions, lung injury, and death in
rats, mice, guinea pigs, and rabbits following inhalation exposure (reviewed in US EPA 2003). The
LC50 for 4- or 6-hour exposures ranges from 8 to 66 ppm (18.4 to 151.8 mg/m3) for rats, mice, and
hamsters (Environment Canada and Health Canada 2000). At lower concentrations, acrolein is a
respiratory irritant, inducing effects such as decreased respiration, bronchoconstriction, and
increased mucus secretion.

The concentration of acrolein required to lower the respiration rate by 50% (RD50) (an indication of
the irritant potential, see Shusterman 2011) has been calculated as 1.0 to 2.9 ppm (2.3 to 6.7 mg/m3)
in mice and 4.6 to 9.2 ppm (10.6 to 21.2 mg/m3) in rats (US EPA 2003; CalEPA 2008), indicating that
mice are more sensitive than rats to the irritant effects. Co-exposure to acrolein with acetaldehyde
and/or formaldehyde led to a more pronounced breathing rate decrease (Cassee et al. 1996).

Decreased respiration rate, and increased flow resistance and tidal volume, were observed in
guinea pigs exposed to acrolein by inhalation at 0.35 to 17 ppm (0.8 to 39.1 mg/m3) (Murphy et al.
1963 cited in US EPA 2003; Davis et al. 1967 cited in US EPA 2003). The increased airway resistance
was transient at 0.3 ppm (0.7 mg/m3); however, following exposure to 0.9 ppm (2.1 mg/m3) acrolein,
bronchial hyperresponsiveness remained for at least 24 hours following cessation of exposure
(Leikauf 1991). In mice, a single acrolein exposure at 1.1 to 1.6 ppm (2.5 to 3.7 mg/m3) induced a
decrease in breathing frequency and an increase in airway flow resistance, effects which were
enhanced in mice previously sensitized by IP injection of ovalbumin (a model of allergic airway
disease), suggesting that sensitized animals may be more susceptible to the effects of acrolein on
the respiratory tract (Morris et al. 2003).

Changes in cell composition of the trachea were observed in guinea pigs exposed for 2 hours to
0.9 ppm (2.1 mg/m3) acrolein. These changes were transient, with recovery occurring within 24 hours
(Leikauf 1991). In hamsters, exfoliation in bronchi, proliferation of basal cells, irregular areas of
epithelium, and hyperplasia were observed 4 days after a 4-hour exposure to 6 ppm (13.8 mg/m3)
acrolein (Kilburn and McKenzie 1978 cited in US EPA 2003; Environment Canada and Health Canada
2000). In rats, Arumugan et al. (1999) observed desquamized and mononuclear cells in the
bronchioles, hyperemia, and emphysema following a 4-hour exposure to 2 ppm (4.6 mg/m3)
acrolein. Increased cell proliferation was observed in the nose, trachea, and lung of rats after a
6-hour exposure to 0.2 to 0.6 ppm (0.46 to 1.38 mg/m3) acrolein (Roemer et al.1993). These effects
were not replicated by Cassee, Groten and Feron (1996), who did not observe any nasal lesions or
cell proliferation in rats exposed for 6 hours to 0.67 or 1.4 ppm (1.54 or 3.22 mg/m3) acrolein.

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5.2.1.2 Repeat exposure
Repeated inhalation exposures to acrolein produced similar effects as single exposures. Studies in
mice and rats have shown that exposure to acrolein for 3 days to 13 weeks results in increased
mucus secretion, and inflammation and cell proliferation in the respiratory epithelium accompanied
by basal cell hyperplasia and squamous cell metaplasia. The severity of the effects appears to
increase with exposure concentration but not with duration of exposure.

Several short-term (3 days to 4 weeks) studies in mice and rats were identified. Effects observed
were consistent with a site-of-contact irritant exposure. In mice, a 4-day exposure (3 hours per day)
to 0.5 or 1.7 ppm (1.2 or 3.9 mg/m3) acrolein decreased the respiratory rate further than a single
exposure (Kane and Alarie 1977 cited in US EPA 2003). Buckley (1984) observed lesions (exfoliation,
erosion, ulceration, necrosis, inflammation, and squamous metaplasia in the respiratory epithelium)
in the upper, but not lower, respiratory tract of mice exposed to 1.7 ppm (3.9 mg/m3) acrolein for
6 hours per day for 5 days. In rats, similar effects were observed in a 3week exposure study (5 days
per week at 3 ppm [6.9 mg/m3]) (Leach et al. 1987). In mice and rats exposed to 2 to 3 ppm (4.6 to
6.9 mg/m3) acrolein for 2 to 4 weeks, mucus hypersecretion and goblet cell metaplasia were
observed in the lungs (Borchers et al. 1998 cited in US EPA 2003; Borchers, Carty and Leikauf 1999
cited in US EPA 2003; Borchers et al. 1999 cited in US EPA 2003; Borchers et al. 2008; Chen et al.
2010, 2013). Roemer et al. (1993) observed an increase in cell proliferation in rat nasal, tracheal, and
lung epithelium after a 3-day exposure (6 hours per day) to 0.2 or 0.6 ppm (0.46 or 1.38 mg/m3)
acrolein; effects were less pronounced than after a single exposure. Similarly, Cassee, Groten and
Feron (1996) reported an increase in cell proliferation in the rat nose following a nose-only 3-day
exposure (6 hours per day) to 0.25 or 0.67 ppm (0.57 or 1.54 mg/m3). The authors also observed
lesions in the nasal epithelium, which increased in incidence and severity with increasing
concentration (lowest observed adverse effect level (LOAEL) = 0.25 ppm [0.57 mg/m3], but no
NOAEL)]. The Government of Canada (Environment Canada and Health Canada 2000) has
previously derived benchmark concentrations (BMC05) of 0.14 mg/m3 for “disarrangement, necrosis,
thickening and desquamation of the respiratory/transitional epithelium,” and 0.68 mg/m3 for basal
cell hyperplasia. The BMC05 represents “the concentration associated with a 5% increase in the
incidence of lesions in the nasal respiratory epithelium.” The BMC05 for the most sensitive endpoint
was used to derive the tolerable concentration.

Several subchronic studies (6 to 13 weeks) of acrolein inhalation toxicity were identified, which
confirmed the effects observed in short-term and acute studies. In mice, rats, guinea pigs, rabbits,
hamsters, monkeys, and dogs, acrolein exposure caused irritant effects in the respiratory system, from
mild inflammation at low concentrations to metaplasia and hyperplasia at higher concentrations.
Depending on the species and exposure regimen, target tissues included both the upper and lower
respiratory tract. The most sensitive region appears to be the nasal cavity as a site of first contact.

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Lyon et al. (1970) exposed rats, guinea pigs, monkeys (males only), and dogs (males only) to acrolein
vapour at 0.7 or 3.7 ppm (1.6 or 8.5 mg/m3) for 6 weeks (8 hours per day, 5 days per week). In the low
concentration exposure group, all species showed eye and nasal irritation and discharge as well as
mild, chronic inflammation of the lung tissue. These effects were more pronounced in dogs and
monkeys. In the high concentration exposure group, dogs and monkeys had squamous metaplasia
and basal cell hyperplasia in the trachea; monkeys also had necrosis and squamous metaplasia in the
bronchi. In the same study, the investigators exposed animals continuously to acrolein vapour at
concentrations of 0.22, 1.0 or 1.8 ppm (0.5, 2.3 or 4.1 mg/m3) for 90 days. At the low concentration, two
out of four dogs showed moderate emphysema, acute lung congestion, focal vacuolization of
bronchiolar epithelial cells, and some constriction of bronchioles. In guinea pigs and rats, pulmonary
inflammation was observed starting at 1 ppm. Monkeys exposed to 1.8 ppm acrolein had squamous
metaplasia and basal cell hyperplasia in the trachea. According to the US EPA (2003), histopathology
of the nasal passages was not conducted in this study, and there were no concurrent controls.
In another multi-species study, Feron et al. (1978) exposed hamsters, rats, and rabbits to acrolein
vapour at 0, 0.4, 1.4 or 4.9 ppm (0, 0.9, 3.2 or 11.3 mg/m3) for 13 weeks (6 hours per day, 5 days per
week). Within the first four weeks of exposure, six rats in the high concentration group had died.
Autopsies revealed lung damage (hemorrhage, edema). Surviving rats in this group had severe lung
damage, including hemorrhage, edema, bronchopneumonia, bronchitis, hyperplasia, and
metaplasia of the bronchial epithelium. Rabbits exposed to the high concentration of acrolein had
lung lesions of similar types, but not as severe (authors ranked it as “moderate”). Hamster lungs
were not affected. All three species had lesions in the trachea at the high concentration; however,
the severity varied from slight hyperplasia in rabbits to moderate hyper- and metaplasia in
hamsters, to severe damage in rats. This study also included nasal histopathology (three sections).
At the low concentration, only one rat was affected, with metaplastic and inflammatory changes
observed. At the middle concentration, the lesions in rats were ranked as moderate (incidence data
were not shown), and hamsters also had slight changes. At the high concentration, rats and
hamsters had severe alterations, while rabbits had moderate changes. The US EPA (2003)
considered 0.4 ppm a minimal LOAEL for rats, the most sensitive species. This study was selected as
the critical study by the US EPA for derivation of an inhalation RfC. It was chosen over the 3-day
study by Cassee, Groten and Feron (1996) because of the greater number of test animals of multiple
species and both sexes, the longer exposure duration, the use of three test concentrations over a
wider range, and the characterization of multiple endpoints.

Several studies of acrolein exposure were conducted in F344 rats (Kutzman 1981; Kutzman et al.
1985; Costa et al. 1986). Male and female rats were exposed to 0, 0.4, 1.4 or 4.0 ppm (0, 0.9, 3.2 or
9.2 mg/m3) acrolein for 62 days (6 hours per day, 5 days per week). High mortality (56%) at the high
concentration was observed in males, while all females survived. Many of the animals that died had
severe acute bronchopneumonia. Surviving animals had lesions in the lung and trachea, of which
the severity varied highly between individual animals. Lesions included focal alveolar edema with
sloughed cells in bronchi and bronchioles, epithelial necrosis in bronchioles, and tracheal edema
with erosion of mucosal epithelium. The authors described the effects as obstructive lung disease,

26 ❘ RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN

as lesions were observed in both large and small airways. Lung function tests showed evidence of
decreased lung function. At the middle concentration, rat lungs showed necrosis and hyperplasia,
again with a high degree of variability; however, functionally, this group showed no difference from
the control group. No lung lesions were observed in the low concentration group; however, these
animals showed functional deficits suggestive of restrictive lung lesions. The authors noted that
functional tests appeared to be the most sensitive indicator of change, and that lung composition
tests supported functional observations. In the previous Health Canada risk assessment of acrolein,
a BMC05 of 0.76 mg/m3 for lesions in the rat nasal turbinates was derived from this study
(Environment Canada and Health Canada 2000).

Dorman et al. (2008) exposed male F344 rats to 0, 0.02, 0.06, 0.2, 0.6 or 1.8 ppm (0, 0.05, 0.14, 0.46,
1.4 or 4.1 mg/m3) acrolein for 13 weeks (6 hours per day, 5 days per week). Histopathology was
conducted on exposure days 4, 14, 30, and 65, and after a 60-day recovery period on six sections of
the nasal cavity. Lesions were graded for severity, and the number of animals affected in each group
was noted. Pathology of the nasal respiratory epithelium included inflammation, hyperplasia, and
squamous metaplasia, with mild effects at 0.6 ppm (1.4 mg/m3) and more severe effects at higher
concentrations. At the highest concentration, effects were observed within days of starting
exposure. At some sites, inflammation and hyperplasia were transient and were replaced by
metaplasia, which persisted even after exposure stopped. The authors determined a NOAEL of
0.2 ppm (0.46 mg/m3) for nasal pathology. Increased cell proliferation was also observed at 0.6 and
1.8 ppm (1.4 and 4.1 mg/m3), but not at 0.2 ppm (0.46 mg/m3). Pathology of the nasal olfactory
epithelium was observed at 1.8 ppm (4.1 mg/m3) and included inflammation, degeneration, and
atrophy. Squamous metaplasia was also seen in the larynx and trachea; however, this was mild and
reversible. No treatment-related pathology was observed in the lungs. This was the only acrolein
inhalation study identified for which both a NOAEL and a LOAEL could be determined. The NOAEL
of 0.2 ppm (0.46 mg/m3) was considered the critical effect level for long-term exposure in the risk
assessments of acrolein conducted by CalEPA (2008) and ANSES (2013).

The CFD-PBPK model by Schroeter et al. (2008) was applied for a dosimetric analysis of the 13week
rat inhalation toxicology study by Dorman et al. (2008). In the frontmost regions of the nasal
passages (Levels I and II), very high incidence of lesions occurred, so no correlation could be found
between predicted dose metrics and lesion incidence; however, strong correlations were observed
in Levels III and IV (at 1.8 ppm [4.14 mg/m3]), which led the authors to conclude that 0.6 ppm
(1.38 mg/m3) was a NOAEL and 1.8 ppm (4.14 mg/m3) a LOAEL. The threshold flux associated with
the NOAEL was 72 pg/cm2-s, which in humans was associated with a concentration of 45 ppb
(NOAELhec = 0.1 mg/m3).
Two additional studies were identified that examined acrolein exposure for at least one year. Feron
and Kruysse (1977) exposed hamsters to 4 ppm (9.2 mg/m3) acrolein for 52 weeks (7 hours per day,
5 days per week), with an additional 29-week recovery period. No tumours were found in the
respiratory tract or other organs; however, inflammation and epithelial metaplasia of the respiratory
tract were observed in about 20% of animals (IARC 1995). Le Bouffant et al. (1980) exposed rats to

RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN ❘ 27

acrolein for 18 months (1 hour a day at 8 ppm [18.4 mg/m3]) and found no tumours. These studies
are of limited value due to the single exposure concentration, the small number of animals per
group, and the limited endpoints examined.

5.2.2 Immunological effects

The inflammatory response induced by acrolein has been shown in several short-term studies and
includes recruitment of immune cells and stimulation of the production and/or release of
proinflammatory cytokines. A 3-hour exposure to 3 ppm (6.9 mg/m3) acrolein (but not 0.3 ppm;
0.69 mg/m3) increased lymphocytes in mouse bronchial alveolar lavage fluid (BALF) (Thompson
et al. 2017). The total cell number, and the number of neutrophils and eosinophils in the BALF
were unchanged. Macrophages accumulated in mouse BALF following a 3-week exposure to 3 ppm
(6.9 mg/m3) acrolein (Borchers, Carty and Leikauf 1999 cited in US EPA 2003; Borchers et al. 1999
cited in US EPA 2003).

Acrolein promotes sensitization in vitro and in vivo. Roux et al. (1999 cited in CalEPA 2008) showed
that in previously sensitized lung tissue, preincubation with acrolein significantly increased the
bronchiole contractile response to several antigens, including dust mites and histamine. In mice
exposed to 5 ppm (11.5 mg/m3) acrolein in addition to inhaled ovalbumin (OVA) during a 2-week
sensitization period followed by a 3-day challenge to OVA, O’Brien et al. (2016) observed an
increase in OVA-specific IgG and neutrophils (compared to exposure to OVA only). Lung
inflammation was also increased in animals exposed to acrolein and OVA compared to those
exposed to OVA only. The authors suggest that acrolein appears to promote sensitization to
inhaled OVA, as observed by the increased IgG, but they also note that because of the exposure
protocol (repeated exposures to two antigens), the results could also indicate inhalation tolerance.

Prior exposure to acrolein has also been shown to cause desensitization (tolerance). Preexposure of
mice to inhaled acrolein (3 days for 3 hours per day at 0.5 or 1.7 ppm [1.2 or 3.9 mg/m3]), followed by
a 10-minute challenge with 0.4 to 11.2 ppm (0.9 to 25.8 mg/m3) acrolein, increased the RD50 from
1.7 to 3 ppm (3.9 to 6.9 mg/m3) (Kane and Alarie 1977 cited in US EPA 2003). Similarly, in rats, prior
inhalation exposure to another aldehyde (9-day exposure to 15 ppm formaldehyde) increased the
RD50 by 5-fold (Babiuk et al. 1985 cited in US EPA 2003). A 4-hour exposure of mice to 5 ppm
(11.5 mg/m3) acrolein resulted in a decreased airway response to subsequent allergen challenge, as
measured by a decreased release of specific cytokines (IL-33, IL-25, and IL1a) in the BALF (Danyal
2016). A decrease in cytokine release in response to allergen challenge was also observed in vitro in
human and mouse epithelial cells that were pretreated with acrolein.

Acrolein can also reduce allergic inflammation in sensitized animals. In mice previously sensitized to
OVA by IP injection (allergic asthma model), a 4-day exposure to 5 ppm acrolein reduced allergic
airway inflammation (suppressed mucus production, leukocyte infiltration and cytokine levels).
Decreased goblet cell hyperplasia was also noted (Spiess et al. 2013).

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O’Brien et al. (2016) proposed an explanation for the conflicting observations: “Acrolein exposure
can affect allergic airway disease in different ways depending on when exposure occurs during the
course of disease pathogenesis,” suggesting it can promote allergic sensitization (as in asthma
development) and neutrophilic inflammation, but it can also suppress allergic inflammation (as in
ongoing asthma).

5.2.3 Cardiovascular effects

The blood pressure and heart rate of anesthetized rats exposed to acrolein for one minute
increased with exposure concentration from 22 ppm (50 mg/m3); however, at higher concentrations
of 1100 or 2200 ppm (2530 or 5060 mg/m3), the heart rate decreased (Egle and Hudgins 1974 cited
in US EPA 2003).

In rats exposed to 3 ppm (6.9 mg/m3) acrolein for 3 hours, an increased incidence of cardiac
arrhythmias was observed during exposure and one hour after exposure. Acrolein also depressed
the baroreflex sensitivity in both normotensive and spontaneously hypertensive rats (Hazari et al.
2014). In another study by the same researchers, a 3-hour exposure to 3 ppm (6.9 mg/m3) acrolein
was found to increase blood pressure compared to when the same rats were exposed to air (no
concurrent control animals were included in the study) (Perez et al.2013). Hypertensive rats were
more sensitive to acrolein exposure in these studies. Another recent study from Kurhanewicz et al.
(2017) showed that mice exposed to 3 ppm (6.9 mg/m3) acrolein for 3 to 4 hours had increased heart
rate variability and incidence of arrhythmias.

Thompson et al. (2017) reported that mice had decreased myocardial performance following a
3hour exposure to 0.3 ppm (0.69 mg/m3) acrolein. This effect was not observed when the acrolein
concentration was 3 ppm (6.9 mg/m3). However, at the higher concentration, stroke volume and
cardiac output increased. In addition, there was an increase in regional circumferential strain delay,
indicating intraventricular myocardial dyssynchrony.

5.2.4 Reproductive and developmental effects

The studies by Kutzman (1981) and Kutzman et al. (1985) included a reproductive toxicity
component. Six days after the 62-day exposure regime (see section 5.2.1.2 for details), treated rats
(male and female) were mated with untreated rats. There was no change in the pregnancy rate, and
the number of corpora lutea, viable embryos, fetal death or preimplantation loss. There were also
no morphological sperm abnormalities. Bouley et al. (1976) exposed rats (3 male and 21 female)
continuously to 0 or 0.55 ppm (1.3 mg/m3) acrolein for 4 days prior to mating and for an additional
22 days after mating. No difference was found in the number of pregnant animals and in the
number and weight of fetuses between exposed and control animals. These studies are limited by
the small number of animals and few endpoints. In addition, the study by Bouley et al. (1976) only
used a single exposure concentration.

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5.2.5 Genotoxicity
In vitro, acrolein has been shown to induce DNA mutations in bacteria; and mutations and DNA
damage, including chromosome aberrations (CA), sister chromatid exchange (SCE), and DNA
breaks and cross-links, in mammalian cells (reviewed in Environment Canada and Health Canada
2000; US EPA 2003; ATSDR 2007; Wang et al. 2011, 2012; Mohammad et al. 2012; Luo et al. 2013; Lee
et al. 2014). Often, genotoxicity was only observed under conditions which limit cytotoxicity.

Repair-deficient cells are more susceptible to acrolein-induced genotoxicity, and acrolein also
appears to inhibit DNA repair. Acrolein increased mutations in repair-deficient human fibroblast
cells, but not in repair-proficient cells (Curren et al. 1988 cited in US EPA 2003). It also induced
mutations in repair-deficient V79 cells (Chinese hamster lung), although normal V79 cells were not
tested (US EPA 2003). Wang et al. (2012) showed that acrolein decreased DNA repair in cultured
human bronchial epithelial cells and lung fibroblasts. Lee et al. (2014) found that acrolein inhibits
both nucleotide excision repair and base excision repair, and induces repair protein degradation in
urothelial cells.

A limited amount of in vivo genotoxicity data is available for acrolein. In particular, only two studies
were identified that examined genotoxicity endpoints following inhalation exposure. No evidence
of SCE or CA was observed in rat peripheral blood following a 62-day exposure to 4 ppm (9.2 mg/
m3) acrolein. Bone marrow was also negative for SCE (Kutzman 1981). No DNA-protein cross-linking
occurred in rat nasal mucosa following a 6-hour inhalation exposure to 2 ppm (4.6 mg/m3) acrolein
(Lam et al. 1985). Acrolein was also negative in a dominant lethal assay in mice (exposure by IP
injection) and in a sex-linked recessive lethal assay in drosophila (ATSDR 2007).

Acrolein forms adducts with DNA, and deoxyguanosine (dG), deoxyadenosine, and deoxycytidine
adducts with acrolein have been observed in mammalian cells in culture following incubation with
acrolein (US EPA 2003; Moghe et al. 2015; Randall et al. 2016). Some research suggests that adducts
form preferentially at CpG sites and that methylation at these sites enhances acrolein binding
(Wang et al. 2013). Acrolein-DNA adducts have been found in lungs of current and former smokers
(Zhang 2007 cited in Burcham 2016), and increased acrolein-dG adducts were also observed in
BALF, lung, and bladder of mice exposed to cigarette smoke (Lee et al. 2015). Feng et al. (2006)
found that the locations of acrolein-DNA adducts in the p53 tumour suppressor gene are similar to
the mutational hotspots observed in lung tumours of smokers. In a recent study comparing bladder
tumours with normal bladder tissue, Lee et al. (2014) found more acrolein-dG adducts in the
tumours compared to normal tissue; most of the tumours were from current or former smokers.
However, in another study, Zhang et al. (2011) found that the total acrolein-dG level in blood
leukocytes was the same in smokers and non-smokers. DNA-acrolein adducts have also been
identified in liver DNA of unexposed humans and rats, indicating some level of background acrolein
exposure or endogenous production (Nath et al. 1996 cited in US EPA 2003). DNA adducts were
observed in aortas of chickens exposed to 1 ppm (2.3 mg/m3) acrolein for 6 hours; however, 10 days
later, the levels of DNA adducts were comparable to controls, suggesting a repair mechanism (Penn
et al. 2001 cited in CalEPA 2008).

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5.2.6 Carcinogenicity
Few studies have been conducted on acrolein with exposure durations greater than 13 weeks.
Feron and Kruysse (1977) exposed hamsters to 4 ppm (9.2 mg/m3) acrolein for 52 weeks (7 hours per
day, 5 days per week). No tumours were found in the respiratory tract or any other organs after a
29-week recovery period. The authors also found that this acrolein inhalation regimen followed by
the 29-week recovery period did not increase the incidence of respiratory tract tumours in animals
co-exposed to benzo(a)pyrene by intratracheal instillation or N-nitrosodiethylamine by
subcutaneous injection (Feron and Kruysse 1977 cited in IARC 1995). Le Bouffant et al. (1980)
exposed rats to 8 ppm (18.4 mg/m3) acrolein for 18 months (1 hour a day) and found no tumours.
Conclusions regarding the carcinogenicity potential of acrolein cannot be drawn from these studies
due to their short durations and single exposure concentrations.

No evidence of carcinogenicity has been observed in several oral studies of acrolein exposure in
multiple species (reviewed in ATSDR 2007; IARC 1995). No treatment-related tumour increase was
observed in gavage studies in mice (18 months) or rats (24 months) (Parent et al. 1991, 1992 cited in
IARC 1995), or in a rat 24 to 28-month drinking water study (Lijinski and Reuber1987; Lijinski 1988,
both cited in IARC 1995).

In an initiation/promotion study in rats, IP injection of acrolein alone for 21 weeks did not induce
urinary bladder tumours. However, rats given acrolein injections twice weekly for 6 weeks followed by
20 weeks of uracil in the diet had a statistically significant increase in bladder papillomas compared to
the group given twice weekly injections of water for 6 weeks followed by 20 weeks of uracil in the diet
(incidence of 18/30 and 8/30 respectively, p < 0.05) (Cohen et al. 1992 cited in IARC 1995).

In vitro, Lee et al. (2015) found that acrolein induces anchorage-independent growth of human
bronchial epithelial and urothelial cells, indicating neoplastic transformation.

5.3 SUMMARY OF HEALTH EFFECTS AND MODE OF ACTION

Based on the evidence from human and animal toxicology studies, the effects of single and
repeated acrolein inhalation exposures are observed at the site of contact. More specifically, key
health effects are eye, nose, and respiratory tract irritation. Sensory irritants, including aldehydes,
act by directly stimulating trigeminal nerve endings in the nasal mucosa. This activates defense
mechanisms to reduce penetration further into the respiratory tract, such as a decrease in breathing
rate, an increase in mucus secretion, and bronchoconstriction. More severe damage to the
respiratory tract occurs with increasing exposure concentration.

In experimental animals, acrolein reacts mainly in the nasal area and upper respiratory tract, but at
higher concentrations, there may be increased penetration to the lower respiratory tract. In humans,
acrolein may reach the lower respiratory tract during mouth breathing. The uptake of acrolein
appears to be a saturable process.

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Due to its highly reactive (electrophilic) nature, acrolein becomes rapidly and irreversibly bound to
protein and non-protein sulfhydryl groups and to primary and secondary amines in proteins and
nucleic acids (WHO 2002; US EPA 2003). Acrolein causes a decrease in reduced GSH and other
reducing agents as well as changes in enzyme activities, resulting in an overall decrease in
protective activity in the respiratory nasal epithelium (US EPA 2003; CalEPA 2008).

In studies with human volunteers, a single exposure to acrolein induced irritation of the eyes, nose,
and throat. The most sensitive effect was eye irritation, reported by subjects at concentrations as
low as 0.14 to 0.36 mg/m3 following exposures of 5 to 60 minutes (Darley et al. 1960; Weber-Tschopp
et al. 1977, both cited in US EPA 2003 and CalEPA 2008; Dwivedi et al. 2015; Claeson and Lind 2016).
Subject-reported nasal irritation was observed starting at 0.35 to 0.60 mg/m3, throat irritation at 0.69
mg/m3, and respiratory irritation as measured by decreased respiration rate at 0.69 mg/m3 (10 to
15% decrease) and 1.4 mg/m3 (25% decrease) (Weber-Tschopp et al. 1977 cited in CalEPA 2008 and
US EPA 2003).

Epidemiological data on the long-term effects of acrolein on humans are limited to two French
cross-sectional studies on indoor air quality and asthma and rhinitis. Annesi-Maesano et al. (2012)
measured acrolein in school classrooms and found higher acrolein concentration (> LOD) was
associated with increased incidence of asthma, but not rhinoconjunctivitis in the previous year (as
reported by parents on a questionnaire), compared to lower acrolein concentration (< LOD). The
LOD was not specified, and most students (72%) had exposures < LOD. The authors also reported
a correlation between acrolein exposure and exercise-induced asthma. Billionnet et al. (2011) found
no significant relationship between acrolein levels in homes and asthma in the previous year or
rhinitis in the previous month (as reported on a questionnaire). These studies both have significant
limitations, which are described in section 5.1.2.

Signs of irritation as well as inflammation and damage to the airways occurred in laboratory animals
exposed to inhaled acrolein. In mice, rats, guinea pigs, rabbits, hamsters, monkeys, and dogs,
acrolein exposure caused irritant effects in the respiratory system, from mild inflammation at low
concentrations to metaplasia and hyperplasia at higher concentrations. Reduced respiration, as an
indication of sensory irritation, was observed in all species tested; the lowest RD50 identified for a
single exposure was 2.3 mg/m3 in mice (US EPA 2003; CalEPA 2008). Other respiratory irritant
effects observed were increased airway resistance and bronchial hyperresponsiveness in guinea
pigs, and mucus hypersecretion in mice and rats (Murphy 1963 cited in US EPA 2003; Leikauf 1991;
Borchers et al. 1998; Borchers et al. 1999 cited in US EPA 2003).

With respect to histopathology, the rat nasal respiratory epithelium is the most sensitive target
organ, with lesions observed at exposure concentrations as low as 0.46 to 1.38 mg/m3 in multiple
studies, from a single exposure to repeated exposure for up to 13 weeks (Feron et al. 1978; Roemer
et al. 1993; Cassee, Groten and Feron 1996; Dorman et al. 2008). Inflammatory, degenerative, and
metaplastic lesions in the rat nasal epithelium have been characterized as disarrangement, necrosis,
thickening, desquamation, basal cell hyperplasia, and squamous metaplasia; the severity of the
lesions increases with exposure concentration but not with duration of exposure (Feron et al. 1978;

32 ❘ RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN

Cassee, Groten and Feron 1996; Dorman et al. 2008). At low concentrations, effects are generally
limited to the nasal cavity; but at higher concentrations, damage to the lower respiratory tract
occurs, with lesions in the rat trachea and lung observed above 1.6 mg/m3 (Lyon et al. 1970; Feron
et al. 1978; Kutzman 1981; Arumugan et al. 1999; Dorman et al. 2008; Chen et al. 2010, 2013). Dorman
et al. (2008) also found inflammation, degeneration, and atrophy of rat nasal olfactory epithelia as
well as olfactory neuronal loss following exposure to 4.1 mg/m3 acrolein for 13 weeks. The authors
noted that the respiratory epithelium was the most sensitive tissue based on the observed NOAEL
and LOAEL; however, based on a dosimetry model from Schroeter et al. (2008), olfactory epithelium
actually had a lower delivered tissue dose.

Inflammation and histopathology in the lower respiratory tract (trachea and lungs) were also
reported in guinea pigs, hamsters, rabbits, dogs, and monkeys at exposure concentrations of
1.61 mg/m3 and above, and, as in rats, the severity of the lesions increased with concentration
(Lyon et al, 1970; Feron et al. 1978; Kilburn and McKenzie 1978 cited in US EPA 2003; Leikauf 1991).
In mice, similar lesions to rats (exfoliation, erosion, ulceration, necrosis, inflammation, and squamous
metaplasia in the respiratory epithelium) were observed in the upper, but not lower, respiratory
tract in a 5-day exposure study at 3.9 mg/m3 (Buckley 1984); indications of metaplasia in the lungs
were observed in a 4-week exposure study at 4.6 mg/m3 (Borchers et al. 2008). No lower
concentration studies were available in mice.

In vitro, acrolein has shown to be mutagenic, inhibit DNA repair, and cause DNA damage, including
DNA adducts, breaks and cross-links. However, limited information is available on the formation and
mutagenicity of DNA adducts in vivo. Inhalation of acrolein did not cause DNA damage (SCE or CA)
in rat blood or bone marrow in a 62-day exposure study (Kutzman 1981), and no DNA-protein
cross-linking occurred in rat nasal mucosa following a single inhalation exposure (Lam et al. 1985).

No evidence of acrolein-induced tumours was identified in limited carcinogenicity studies in

experimental animals. However, the related aldehydes, formaldehyde and acetaldehyde, induce
nasal tumours in rats. Mode of action analyses have determined that the tumorigenic responses to
these aldehydes are non-linear and result primarily from cytotoxicity and proliferation rather than
mutagenicity (Environment Canada and Health Canada 2000; Health Canada 2017). The same pattern
of tissue damage and cell proliferation induced by other aldehydes is also observed with acrolein
exposure in animal models. Cytotoxicity (degeneration), proliferation, and metaplasia in the
respiratory epithelium were consistently observed in laboratory animals exposed to inhaled acrolein,
in some cases after just a single exposure. Therefore, although inhalation of acrolein has not been
shown positively to induce tumours in the respiratory system and acrolein is not being considered a
carcinogen in this assessment, the carcinogenic potential of acrolein requires further investigation.

RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN ❘ 33

5.4 SUSCEPTIBLE POPULATIONS
Sensitized individuals such as asthmatics as well as individuals with chronic pulmonary disease
or bronchitis may be more susceptible to the effects of acrolein on the respiratory tract. Although
no human studies conducted in susceptible populations are available to show this for acrolein
specifically, it has been demonstrated for other aldehydes including acetaldehyde (Health Canada
2017), and formaldehyde (Health Canada 2006). Also, in general, pre-existing nasal allergies can
intensify the response to nasal irritants (Shusterman 2011).

Animal studies showing bronchial hyperresponsiveness and inflammation following acrolein

inhalation as well as in vitro studies indicating that acrolein increases mucin and pro-inflammatory
mediators provide evidence that acrolein can exacerbate asthma and that sensitized individuals
may be more susceptible to the adverse effects of acrolein. The effects of inhalation exposure to
acrolein, including a decrease in breathing rate, an increase in mucus secretion, and
bronchoconstriction, are enhanced in mice previously sensitized by IP injection of OVA (a model
of allergic airway disease) (Morris et al. 2003). Roux et al. (1999 cited in CalEPA 2008) showed that in
previously sensitized lung tissue, preincubation with acrolein significantly increased the bronchiole
contractile response to several antigens, including dust mites and histamine.

Children, especially those with asthma, may be more likely to show adverse respiratory effects
following exposure to acrolein due to higher prevalence rates of asthma in children as compared
to other age groups, the small size and immature state of their airways, and the exacerbation that
toxic air contaminants have been demonstrated to have on asthma in children (Delfino et al. 2003;
CalEPA 2008).

Individuals with hypertension may also be more susceptible to the effects of acrolein. Perez et al.
(2013) found that hypertensive rats had an increase in breathing frequency and minute volume at a
concentration that did not affect normotensive rats. The hypertensive rats were also more sensitive
to cardiovascular effects, including increased heart rate, blood pressure, and heart rate variability.

In a study with Dahl rats that were either resistant (DR) or susceptible (DS) to hypertension, DS rats
were found to be more sensitive to acrolein-induced mortality and lung lesions than DR rats
(Kutzman et al. 1984).

Contact lens wearers could be more susceptible to ocular exposure and irritation by acrolein, as
contact lenses can trap and concentrate volatile compounds, and extend the exposure time by
limiting the eye’s normal self-cleansing (CalEPA 2008).

Due to the key involvement of GSH in the detoxification of acrolein, individuals with decreased
GSH synthesis may be more susceptible to its effects. Similarly, some individuals may be more
susceptible to acrolein toxicity due to impaired GST activity. For example, one of the four allelic
variants of the GST P1-1 isoenzyme has a significantly lower catalytic efficiency in GSH conjugation
of acrolein (Pal et al. 2000 cited in Stevens and Maier 2008).

34 ❘ RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN

6 DERIVATION OF SHORT- AND
LONG-TERM REFERENCE
CONCENTRATIONS

6.1 SHORT-TERM REFERENCE CONCENTRATION

For short-term exposure to acrolein, several studies investigating eye and respiratory irritation in
human volunteers were available for consideration as the point of departure for a short-term
reference concentration (see section 5.1). The LOAELs for eye irritation identified in multiple studies
were similar, ranging from 0.21 to 0.36 mg/m3 (Weber-Tschopp et al. 1977; Dwivedi et al. 2015;
Claeson and Lind 2016). The study by Weber-Tschopp et al. (1977) used multiple exposure protocols,
including a 40-minute exposure with increasing acrolein concentrations (up to 1.4 mg/m3) and a
60-minute exposure to a fixed acrolein concentration (0.69 mg/m3). The original paper is in German;
therefore, the US EPA report is cited. No NOAEL for eye irritation was derived in this study as
subjects reported eye irritation at the lowest tested concentration of 0.21 mg/m3 (LOAEL). In a more
recent study, Dwivedi et al. (2015) exposed healthy volunteers to acrolein for 2 hours. There was a
slight increase in eye irritation at 0.23 mg/m3, but not 0.12 mg/m3 (LOAEL and NOAEL, respectively).
The NOAEL from this study was similar to those identified in two other eye-only exposure studies
(Darley et al. 1960 where the NOAEL = 0.14 mg/m3; Claeson and Lind 2016 where the
NOAEL = 0.16 mg/m3).
The lowest LOAEL for respiratory irritation is from the study by Weber-Tschopp et al. (1977). During
a 60-minute exposure to 0.69 mg/m3 acrolein, subjects reported eye, nose, and throat irritation, and
respiration rates were reduced by 10 to 15%, indicating a slight respiratory irritation. No NOAEL for
respiratory irritation was identified in this study. Dwivedi et al. (2015) noted there was no difference
in breathing frequency, pulmonary function, nasal swelling, or inflammatory markers in blood or
sputum after a 2-hour exposure to 0.23 mg/m3 (NOAEL). No LOAEL was identified for these effects.
Therefore, eye irritation is the most sensitive endpoint, and the lowest LOAELs identified for this
endpoint were 0.21 mg/m3 from Weber-Tschopp et al. (1977) and 0.23 mg/m3 from Dwivedi et al.
(2015). As Weber-Tschopp et al. (1977) did not identify a NOAEL, the NOAEL of 0.12 mg/m3 (115 µg/
m3) for eye irritation from Dwivedi et al. (2015) was selected as the point of departure for the acute
RfC. This point of departure is also below the LOAEL and NOAEL for respiratory effects observed
by Weber-Tschopp et al. (1977) and Dwivedi et al. (2015), respectively. An uncertainty factor (UF) of 3
was applied to account for sensitive individuals and is considered sufficient as eye irritation due to
contact is not expected to vary greatly across the population (NRC 2001; US EPA 2008). No UF for
database deficiencies was applied as the critical study and the database for acute toxicity were
adequate. Thus, the acute RfC is 38 µg/m3.

RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN ❘ 35

6.2 LONG-TERM REFERENCE CONCENTRATION
Few epidemiological studies have been conducted on acrolein and its health effects; and due to
study limitations, in particular the lack of causality established, none of the available studies were
appropriate for use as key studies for deriving a long-term reference value.

Inhalation studies in multiple species of laboratory animals have consistently shown respiratory tract
effects following exposures of 3 days to 13 weeks to acrolein concentrations in the range of 0.46 to
1.38 mg/m3. Effects were observed at the lowest test concentration in most studies; only one
13-week study was able to identify both a NOAEL and a LOAEL. Dorman et al. (2008) found a
NOAEL of 0.46 mg/m3 and a LOAEL of 1.38 mg/m3 for degenerative lesions in the respiratory
epithelium of the rat nasal cavity. A NOAEL of 1.38 mg/m3 and a LOAEL of 4.14 mg/m3 for olfactory
neuronal loss were also derived.

Dorman et al. (2008) noted that the modelled tissue dose in rats (from Schroeter et al. 2008)
associated with the effect on olfactory epithelium was lower than that of the respiratory epithelial
lesions. However, the NOAEL of 0.46 mg/m3 (460 µg/m3) for lesions of the respiratory epithelium was
selected as the point of departure because it was the lowest exposure concentration associated
with an adverse effect. This concentration was adjusted from the animal study exposure (6 hours
per day, 5 days per week) to continuous exposure (24 hours per day, 7 days per week), resulting in
an adjusted NOAEL of 82 µg/m3.
Toxicokinetic differences between rats and humans were accounted for by applying a regional gas
dose ratio (RGDR) of 0.13 for a Category 1 gas with extrathoracic respiratory effects (US EPA 1994),
giving a human equivalent NOAEL of 11 µg/m3. This approach was also used by the US EPA (2003)
and ANSES (2013) to derive RfCs for acrolein and is considered appropriate in the absence of
chemical-specific information. Although the CFD-PBPK model by Corley et al. (2012) showed that
acrolein uptake in the respiratory tract in humans was lower than in rats, this model was not applied
for interspecies extrapolation in this assessment as it has not been calibrated or validated for
humans. CalEPA (2008) used the dosimetric adjustment factor (DAF) for formaldehyde in their
derivation of an RfC for acrolein. This DAF was based on the average of the mean flux and peak flux
of formaldehyde in the upper respiratory tract of rats relative to humans (Kimbell et al. 2001). The
CalEPA approach introduces additional uncertainty due to the use of a chemical analogue (i.e.,
formaldehyde) as well as from the averaging of mean and peak flux.

Uncertainty factors (UFs) of 2.5 for toxicodynamic differences between rats and humans, and 10 for
sensitivity in the human population were applied to the point of departure (human equivalent
NOAEL of 11 µg/m3). Although the Dorman et al. (2008) study was of less than chronic duration, no
additional UF was applied, as there is no indication that the severity or incidence of lesions
increases with longer exposure durations; exposure concentration appears to be the driving factor.
Also, no UF for database deficiencies was applied as the critical study and the health effects
database were adequate. A detailed justification for the selection of UFs for the long-term RfC can
be found in Ritter et al. (2007). Thus, the long-term RfC is 0.44 µg/m3.

36 ❘ RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN

6.3 EXPOSURE IN CANADIAN HOMES IN RELATION TO
REFERENCE CONCENTRATION AND DETERMINATION
OF RECOMMENDED EXPOSURE LIMITS
In the past decade, Health Canada has completed several exposure studies in multiple Canadian
cities (Health Canada 2010a, 2010b, 2012, 2013). These studies are considered the most recent and
most representative data available for quantifying long-term levels of exposure in Canadian homes
(see section 3.0).

Short- and long-term RfCs are based on the characterization of the concentration–response
relationship and the application of UFs to account for variability and data gaps. The context within
which these RfCs are to be applied, technical feasibility, and availability of risk mitigation measures
do not enter into their determination. However, these issues are relevant to the determination of
short- and long-term exposure limits.
In order to determine the recommended exposure limits, the short- and long-term RfCs are first
compared to available exposure data from Canadian homes. The feasibility of achieving the RfC
through the control of indoor sources is then evaluated. If the RfC is judged to be feasible, the same
value is set as the recommended exposure limit. If not, a higher concentration may be selected, while
still targeting an exposure limit that is protective of health in consideration of current evidence.

In the present assessment, the criteria guiding the determination of the value for both the
recommended short- and long-term exposure limits for acrolein are:

• a value that is potentially achievable in Canadian homes in the absence of significant sources
of indoor acrolein; and

• a value that is not associated with appreciable health effects, considering the derived
reference exposure levels and currently available evidence.

6.3.1 Short-term reference concentration and recommended exposure limit

The literature database provided sufficient information on the effects in humans for development of
a short-term RfC, which was determined for acrolein to be 38 µg/m3. The range of median indoor air
acrolein concentrations measured in Canadian homes from the Health Canada residential indoor air
exposure studies for a 24-hour averaging period was 1.3 to 8.1 µg/m3, with the 95th percentile
ranging from 3.5 to 21.0 µg/m3 (see Table 2) (Health Canada 2010a, 2010b, 2012, 2013). The 24-hour
integrated samples collected in these studies do not represent acute or peak exposures. However,
short-term acrolein peaks may occur with behaviours such as smoking or cooking as well as with the
use of fireplaces and wood-burning stoves. Based on the 24-hour sampling data and the expected
sources present, the short-term RfC should be achievable in Canadian homes. Therefore, the
short-term exposure limit for acrolein is 38 µg/m3.

RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN ❘ 37

6.3.2 Long-term reference concentration and recommended exposure limit
From the literature database, a chronic RfC of 0.44 µg/m3 was derived based on lesions in the
respiratory epithelium. The Health Canada residential indoor air exposure studies (Health Canada
2010a, 2010b, 2012, 2013) provide the best measure of chronic exposure in Canadian homes although
uncertainty remains in terms of accuracy of exposure data due to methodological difficulties in
measuring acrolein in indoor air. The range of median indoor air acrolein concentrations measured in
Canadian homes from the Health Canada residential indoor air exposure studies for a 24-hour
averaging period was 1.3 to 8.1 µg/m3, with the 95th percentile ranging from 3.5 to 21.0 µg/m3 (see
Table 2) (Health Canada 2010a, 2010b, 2012, 2013). This indicates that even considering uncertainties in
the measurement of acrolein, there will likely be Canadian homes in which the RfC is exceeded.
However, the RfC was derived using the most recent scientific information, and is in line with the
Health Canada IARL of 0.35 µg/m3 and reference values from other jurisdictions (see Appendix D).
Sources of acrolein in Canadian homes include smoking, cooking with oils, and secondary formation
from reactions of other VOCs. Based on the limited available source information, reduction of acrolein
levels in the home through ventilation and source control is considered possible. Therefore, the
recommended long-term exposure limit for acrolein is 0.44 µg/m3.

6.4 UNCERTAINTIES
As only limited data were available on repeated inhalation exposure to acrolein in humans, animal
data were used as a point of departure when deriving the RfC. The evidence in multiple species
clearly shows that acrolein is a reactive substance which exerts effects at the site of first contact (i.e.,
the nasal cavity in rats). Various approaches for comparing the physiology of the respiratory tracts
to account for toxicokinetic differences between rats and humans were considered. Assumptions
are made in each approach, and each has uncertainties. There are limited data available on the
kinetics of acrolein deposition in humans. Moreover, data are lacking that would allow for the
calibration and validation of a human CFD-PBPK model in order to facilitate a chemical-specific
extrapolation between animals as well as intermittent to continuous exposure.

Although the nature of effects (irritation) is likely to be the same across species, quantitative
differences in sensitivity were accounted for using default values for the toxicodynamic UF (rats to
humans) and an intraspecies uncertainty factor (for sensitive individuals). No studies could be found
on the effects of acrolein in sensitive individuals such as asthmatics which would reduce the
uncertainty in the RfC.

Studies on the effects of long-term inhalation exposure to acrolein are limited. There were also
significant limitations, as described in section 5.1.2, to the few epidemiological studies examining
associations between acrolein exposure and asthma or rhinitis. Similarly, most studies in
experimental animals did not go beyond a subchronic duration, and those few chronic studies
available were inadequate to draw conclusions about the carcinogenicity of acrolein.

38 ❘ RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN

Existing exposure studies have evaluated 24-hour sampling times to give an average daily exposure.
Exposures to peak concentrations over shorter durations have not been evaluated. As described in
section 3, acrolein is difficult to quantify accurately, and available methods have limitations.
Therefore, there is uncertainty with respect to the actual concentration of acrolein in indoor air.
However, the Health Canada data collected by the passivated canister method are believed to
provide a realistic estimate of acrolein concentrations in Canadian homes.

Minimal data are available on quantitative estimates of indoor acrolein sources and source
attribution. Therefore, the effectiveness of various strategies for reducing indoor concentrations of
acrolein could not be quantified, and it cannot be determined with certainty whether the
recommended limits can be achieved in all Canadian homes.

RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN ❘ 39

7 GUIDELINES

7.1 RECOMMENDED EXPOSURE LIMITS

Table 3. Recommended exposure limits for acrolein for indoor environments

Concentration
Exposure Limit Critical effect(s)
µg/m3 ppb

Short-term (1 h) 38 17 Eye irritation in healthy volunteers

Long-term (24 h) 0.44 0.19 Lesions in the respiratory epithelium of the rat nasal cavity

It is recommended that the short-term (acute) exposure limit be compared to a 1-hour air sample.

When comparing a measured acrolein concentration with the long-term exposure limit, the
sampling time should be at least 24 hours, taken under normal conditions. Moreover, the averaging
of results of repeated samples taken at different times of the year will provide a more representative
estimate of the long-term exposure.

7.2 RISK MANAGEMENT RECOMMENDATIONS

Some homes in Canada may have levels of acrolein above the long-term reference exposure limit
derived for protection against respiratory irritation and degeneration of the respiratory epithelium.
Therefore, sources of acrolein in the home should be controlled to limit exposure as much as reasonably
possible, given that air quality testing in individual homes is neither practical nor recommended in most
instances. Furthermore, many of the measures outlined below will also contribute to reducing the
concentrations of other indoor air contaminants, generally improving indoor air quality.

Exposure to acrolein indoors can be reduced by ensuring adequate ventilation and controlling for
indoor sources. Strategies for reducing indoor sources of acrolein include the following:

• Increase ventilation:

– By opening windows (when possible, and check the outdoor air quality conditions in your
region before opening windows: Air Quality Health Index).

– By employing mechanical ventilation strategies.

– If it is not possible to open windows, use the strategies below to reduce other sources of
indoor air pollution.

– For more information, refer to the Factsheet: Ventilation and the indoor environment
(Health Canada 2018a).

40 ❘ RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN

• Use a range hood exhaust fan with outside venting (preferably on the high setting) when
cooking, especially with oils.

• While cooking, use back burners instead of front burners in addition to using a range hood
exhaust fan. If a range hood exhaust fan is not available, open windows or run the fan in the
furnace or ventilation system. For more information, refer to the Factsheet: Cooking and
Indoor Air Quality (Health Canada 2018b).

• Do not smoke or burn candles or incense inside the home, and ensure proper ventilation to
the outside during use of combustion appliances (e.g., gas stoves, woodstoves or fireplaces).

• Decrease VOC levels in the home to reduce secondary formation of acrolein. This can be
done by choosing low-emission products when possible; ventilate adequately when using
products such as glues, paints, varnishes, and cleaning products; and minimize the use of
scented products, such as plug-in or aerosol deodorizers (air fresheners).

• For more information on protecting indoor air quality when outdoor air quality is poor, refer
to Factsheet: Protecting your Indoor Air from Outdoor Pollutants (Health Canada, 2020).

RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN ❘ 41

8 REFERENCES
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Thompson, L.C., Ledbetter, A.D., Haykal-Coates, N., Cascio, W.E., Hazari, M.S. and Farraj, A.K. (2017) Acrolein
Inhalation Alters Myocardial Synchrony and Performance at and Below Exposure Concentrations that Cause
Ventilatory Responses. Cardiovascular Toxicology, 17(2): 97–108.

Tully, M., Zheng, L., Acosta, G., Tian, R. and Shi, R. (2014) Acute systemic accumulation of acrolein in mice by
inhalation at a concentration similar to that in cigarette smoke. Neuroscience Bulletin, 30(6): 1017–1024.

Uchiyama, S., Inaba, Y. and Kunugita, N. (2010) Determination of acrolein and other carbonyls in cigarette smoke
using coupled silica cartridges impregnated with hydroquinone and 2,4-dinitrophenylhydrazine. Journal of
Chromatography A, 1217(26): 4383–4388.

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US EPA (1994) Methods for derivation of inhalation reference concentrations and application of inhalation
dosimetry. EPA/600/8-90/066F.

US EPA (2003) Toxicological Review of Acrolein (107-02-8). In Support of Summary Information on the Integrated
Risk Information System (IRIS). EPA/635/R-03/003, United States Environmental Protection Agency, Washington,
D.C. http://cfpub.epa.gov/ncea/iris/iris_documents/documents/toxreviews/0364tr.pdf.

US EPA (2008) Reregistration Eligibility Decision: Acrolein. https://archive.epa.gov/pesticides/reregistration/web/

pdf/acrolein_red.pdf.

US EPA (2010) Data Quality Evaluation Guidelines for Ambient Air Acrolein Measurements. https://www3.epa.gov/
ttnamti1/files/ambient/airtox/20101217acroleindataqualityeval.pdf.

Wang, H.T., Hu, Y., Tong, D., Huang, J., Gu, L., Wu, X.R., Chung, F.L., Li, G.M. and Tang, M.S. (2012) Effect of
carcinogenic acrolein on DNA repair and mutagenic susceptibility. Journal of Biological Chemistry, 287(15):
12379–12386.

Wang, H.T., Weng, M.W., Chen, W.C., Yobin, M., Pan, J., Chung, F.L., Wu, X.R., Rom, W. and Tang, M.S. (2013) Effect
of CpG methylation at different sequence context on acrolein- and BPDE-DNA binding and mutagenesis.
Carcinogenesis, 34(1): 220–227.
Wang, H., Zhang, X. and Chen, Z. (2009) Development of DNPH/HPLC method for the measurement of carbonyl
compounds in the aqueous phase: Applications to laboratory simulation and field measurement. Environmental
Chemistry, 6(5): 389–397.

Wang, L., Sun, Y., Asahi, M. and Otsu, K. (2011) Acrolein, an Environmental Toxin, Induces Cardiomyocyte Apoptosis
via Elevated Intracellular Calcium and Free Radicals. Cell Biochemistry and Biophysics, 61(1): 131–136.

Weber-Tschopp, A., Fischer, T., Gierer, R. and Grandjean, E. (1977) Experimentally induced irritating effects of
acrolein on men (author’s transl). International Archives of Occupational and Environmental Health, 40(2): 117–130.

WHO (2002) Acrolein­— Concise International Chemical Assessment Document 43. World Health Organization,
Geneva.

Won, D., Nong, G., Yang, W. and Collins, P. (2014) Material Emissions Testing: VOCs from Wood, Paint, and
Insulation Materials. A1-000342.2, NRC Institute for Research in Construction, Ottawa, ON.

Zhang, S., Balbo, S., Wang, M. and Hecht, S.S. (2011) Analysis of acrolein-derived 1,N2-propanodeoxyguanosine
adducts in human leukocyte DNA from smokers and nonsmokers. Chemical Research in Toxicology, 24(1): 119–124.

Zhang, S., Villalta, P.W., Wang, M. and Hecht, S.S. (2007) Detection and quantitation of acrolein-derived 1,N2-
propanodeoxyguanosine adducts in human lung by liquid chromatography-electrospray ionization-tandem mass
spectrometry. Chemical Research in Toxicology, 20(4): 565–571.

50 ❘ RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN

APPENDICES

APPENDIX A: LIST OF ACRONYMS AND ABBREVIATIONS

ANSES Agence nationale de sécurité sanitaire de l’alimentation, de l’environnement
et du travail (France)

ATSDR Agency for Toxic Substances and Disease Registry

BALF Bronchioalveolar lavage fluid

BMC05 Benchmark concentrations associated with a 5% increase of an effect

CA Chromosome aberration

CalEPA California Environmental Protection Agency

CDC Centers for Disease Control and Prevention

CEMA 2-Carboxethylmercapturic acid

CFD Computational fluid dynamics

CI Confidence interval

DAF Dosimetric adjustment factor

dG Deoxyguanosine

DNA Deoxyribonucleic acid

DNPH Dinitrophenylhydrazine

GSH Glutathione (free or reduced)

GST Glutathione-S-transferase

HEC Human equivalent concentration

3-HPMA 3-Hydroxypropylmercapturic acid

I/O Indoor/outdoor

IARC International Agency for Research on Cancer

IARL Indoor air reference level

IP Intraperitoneal

LC50 Lethal concentration that kills 50% of the test population

LOAEL Lowest observed adverse effect level

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LOD Limit of detection

MDL Minimum detection limit

NOAEL No observed adverse effects level

OR Odds ratio

OVA Ovalbumin

PBPK Physiologically based pharmacokinetic

PK Pharmacokinetic

ppb Parts per billion

ppm Parts per million

RD50 Concentration required to reduce the respiratory rate by 50%

RfC Reference concentration

RGDR Regional gas dose ratio

RIAQG Residential Indoor Air Quality Guidelines

SCE Sister chromatid exchange

UF Uncertainty factor

US EPA United States Environmental Protection Agency

VOC Volatile organic compound

WHO World Health Organization

52 ❘ RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN

 APPENDIX B: HUMAN EXPOSURE STUDIES

Table B1. Short-term exposure

Study Participants Exposure Results NOAEL/LOAEL

Claeson and 26 volunteers (18 women, Eye-only exposure for 15, 45 or 60 min Eye irritation in more than half the NOAEL = 0.16 mg/m3
Lind 2016 8 men) to 0.07, 0.16, 0.36 mg/m3 acrolein subjects at 0.36 mg/m3 for 15 min LOAEL = 0.36 mg/m3
(starting at 6.8 min)
(eye irritation)
No difference at 0.16 mg/m3 for 45 min
or 0.07 mg/m3 for 60 min

Darley et al. 36 volunteers (26 men, Eye-only exposure for 5 min to 0, 0.06, Subjective measure of irritation LOAEL = 0.14 mg/m3 (slight eye irritation
1960 10 women) 1.3–1.6 or 2.0–2.3 ppm (0.14, 2.99–3.68 or (none = 0, medium = 1, severe = 2) at the lowest test concentration)
4.60–5.29 mg/m3) acrolein Average maximum irritation scores: Used in the derivation of an acute
air = 0.361, 0.06 ppm = 0.471, 1.3– reference level by CalEPA (2008)
1.6 ppm = 1.182, 2.0–2.3 ppm = 1.476

Dwivedi et al. 18 volunteers (9 women, Whole body exposure for 2 hours to Eye blink frequency and irritation NOAEL = 0.12 mg/m3
2015 9 men) 0.05 or 0.1 ppm (0.12 or 0.23 mg/m3) increased slightly at high but not low LOAEL = 0.23 mg/m3
acrolein concentration.
(slight eye irritation)
No difference in breathing frequency,
pulmonary function, nasal swelling, and
inflammatory markers in blood or
sputum.

Weber-Tschopp a) 53 volunteers Whole body exposures: a) Incidence of eye irritation complaints LOAEL = 0.21 mg/m3 (slight eye irritation
et al. 1977 (31 men, 22 women) a) 40-min exposure to continuously significantly higher at 0.09 ppm, at the lowest test concentration)
b) 42 volunteers increasing acrolein concentration, nasal irritation at 0.26 ppm, and Used in the derivation of an acute
(17 men, 25 women) from 0.09 up to 0.6 ppm (0.21 up to throat irritation at 0.43 ppm. Eye exposure guideline limit by US EPA
1.4 mg/m3) blink frequency at 0.26 ppm. (2010)
c) 46 volunteers
Respiration rate decrease by 25% at
(21 men, 25 women) b) 1.5-min exposure to each acrolein LOAEL = 0.69 mg/m3 (reduced
0.6 ppm
concentration with 8 min in between, respiration rate/irritation)
at 0.15 up to 0.6 ppm (0.35 up to b) Incidence of eye irritation complaints
Used in the derivation of an acute
1.4 mg/m3) significantly higher at 0.3 ppm, nasal
minimal risk level by ATSDR (2007)
irritation at 0.6 ppm
c) 60-min exposure to 0.3 ppm
(0.69 mg/m3) acrolein c) Ocular, nasal, and throat irritation,
reduced respiration rate (10–15%)

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 Table B2. Epidemiological studies

❘54
Study Participants Exposure Results NOAEL/LOAEL

Annesi- 6590 children in six cities Concentrations were measured “during Medical visit included skin prick test for None derived
Maesano et al. in France class time” (does not specify for how allergies and test for exercise-induced Authors suggest that acrolein plays a
2012 (401 classrooms in long although a “5-day mean” asthma. role in asthma development in atopic
108 primary schools) concentration is mentioned elsewhere). Health questionnaire completed by children.
All concentrations were put into 3 tiers: parents (rhinitis and asthma in the
low < LOD, medium = LOD-1.55 µg/m3, previous year).
high > 1.55 µg/m3 (LOD not specified). Confounders included passive smoking
and family history (adjusted).
Previous year rhinoconjunctivitis OR < 1
for medium/high, previous year asthma
OR = 1.23 for medium, and OR = 1.22
for high.
When population stratified by skin prick
reactivity, acrolein significantly related
to allergic asthma (atopic) (OR of 1.22
and 1.28 for medium and high,
p = 0.1665) and negatively associated
with non-allergic asthma (non-atopic)
(OR of 0.94 and 0.60, p = 0.0741). The
association with asthma was stronger
during the spring-summer (OR 1.37).
Acrolein was significantly correlated
with exercise-induced asthma

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(p < 0.025).

Billionnet et al. 1012 individuals Sampling in main (parents) bedroom for Questionnaire on home characteristics, None derived
2011 ( > = 15 years old) from one week; used mean for analysis activity level/time at home Results suggest no relationship
490 homes in France LOD 0.1, limit of quantification (LOQ) Questionnaire on asthma (previous year) between acrolein exposure above
0.3 µg/m3 and rhinitis (previous month)—diagnosis 1.5 µg/m3 and asthma in the previous
0.8% homes < LOD, 3.5% between LOD not confirmed by physician year.
and LOQ Controlled for confounders (including
Range: < LOD to 12.9 µg/m3 smoking, outdoor pollution, and pets)

Median = 1.0 µg/m3 No relationship between acrolein and

asthma (OR of 0.83, 95% CI 0.5–1.5)
3rd quartile = 1.51 µg/m3
No relationship between acrolein and
Threshold value of above 3rd quartile of rhinitis (OR of 1.08, 95% CI 0.8–1.7)
distribution (considered “elevated”
high/low)
 Study Participants Exposure Results NOAEL/LOAEL

deCastro 2014 ~270 000 subjects in the Examined ambient acrolein levels (2005 Interview of nationally representative None derived
U.S. National Air Toxics Assessment— cross-section of households, designed EPA estimates that outdoor acrolein is
National Health NATA—concentrations) to produce national estimates of responsible for about 75% of non-
Interview Survey (CDC) NATA: data from National Emissions disease prevalence (i.e., estimation of cancer respiratory health effects
Inventory and EPA’s air monitoring and asthma prevalence across the U.S. over attributable to air toxics in the U.S.
uses models to estimate outdoor time and age group).
concentrations (accounting for Included confounders (urban/rural,
population density and physical smoking).
topography of census tracts) then Self-reported asthma attacks in
exposure concentrations (considers previous year (standard CDC definition
demographics, activity, climate)—from for evaluating asthma attack
quintile 0.000138–0.010900 µg/m3 to prevalence).
quintile 0.0555101–0.457000 µg/m3.
Exposures geographically linked at
census tract level with residences of
participants.
Authors state “marginally significant”
(p = 0.1) increase in asthma attack in the
top quintile with OR 1.08 (95% CI
0.98–1.19) for all subjects, never smokers
(OR 1.13), and never + former smokers
(OR 1.09). No trend in lower 4 quintiles.

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 56
APPENDIX C: TOXICOLOGICAL STUDIES

❘
Table C1. Acute (single) exposure studies

Species, Sex and

Study Exposure Results NOAEL/LOAEL
Number

Arumugan et al. Male Wistar rats, 5 per 0, 1 or 2 ppm (2.3 or 4.6 mg/m3) acrolein In lungs: reduced GSH, ascorbic acid, LOAEL = 2.3 mg/m3
(1999) group for 4 hours (head only) atocopherol; decreased activity of (enzyme and cellular changes in
catalase, glutathione peroxidase; respiratory epithelium at the lowest test
desquamized and mononuclear cells in concentration)
bronchioles; hyperemia; emphysema

Cassee, Groten Male Wistar rats, 5–6 per 0, 0.25, 0.67 or 1.4 ppm (0.57, 1.54 or Decreased glutathione reductase LOAEL = 0.57 mg/m3
and Feron group 3.22 mg/m3) acrolein for 6 hours (nose activity in nasal respiratory epithelium (enzyme changes in respiratory
(1996) only) No nasal lesions or cell proliferation epithelium at the lowest test
concentration)

Lam et al. (1985) Male Fischer 344 rats, 0, 0.1, 0.5, 1.0, 2.5, 5 ppm (0.23, 1.2, 2.3, Dose-dependent depletion of non- LOAEL = 1.2 mg/m3
4 per group 5.8, 11.5 mg/m3) acrolein for 3 hours protein sulfhydryl groups in respiratory (depletion of sulfhydryl groups in
(nose only) mucosa (significant from 1.2 mg/m3) respiratory mucosa)
No DNA-protein cross linking in nasal
mucosa

Leikauf (1991) Male Hartley guinea 0, 0.31, 0.67, 0.91, 1.26 ppm (0.7, 1.54, 2.1, Bronchial hyperresponsiveness/ LOAEL = 0.7 mg/m3
pigs, 5–7 per group 2.9 mg/m3) for 2 hours (whole body) increased airway resistance transient at (bronchial hyperresponsiveness and
0.7 mg/m3, but remaining for at least

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increased airway resistance at the
24 hours following cessation of lowest test concentration)
exposure to 2.1 mg/m3
Histopathology of the trachea at 2.1 mg/
m3, with recovery occurring within
24 hours

Morris et al. C57Bl/6J mice, 3–8 per 0.3, 1.6, 3.9 ppm (0.69, 3.7, 9.0 mg/m3) Decrease in breathing frequency; None derived; no control group
(2003) group acrolein for 10 min (nose only) increase in airway flow resistance Effects seen at 0.69 mg/m3 (lowest test
Naive and sensitized (no separate control group) Effects enhanced in mice previously concentration)
(OVA) sensitized by IP injection of OVA
(number of males and
females per group not
specified)
 Species, Sex and
Study Exposure Results NOAEL/LOAEL
Number

Perez et al. Spontaneously 3 ppm (6.9 mg/m3) acrolein for 3 hours SH rats had increased heart rate, blood None derived; no control group
(2013) hypertensive (SH) and (whole body) pressure, heart rate variability (only at Effects seen at 6.9 mg/m3 (lowest test
Wistar Kyoto (no separate control group; 5 days hour 3), breathing frequency (only at concentration)
normotensive (NT) male between baseline test and exposure for hour 3), and minute volume (only at hour
rats, 6 per group individual animals) 3). NT rats had only increased blood
pressure during acrolein exposure, but
this increase was not as large as in SH
rats.

Roemer et al. Male Sprague Dawley 0, 0.2 or 0.6 ppm (0.46 or 1.4 mg/m3) Increased DNA synthesis and cell LOAEL = 0.46 mg/m3
(1993) rats, 3–5 per group acrolein for 6 hours (head only) proliferation in the nose, trachea and (proliferation in respiratory epithelium
lung at the lowest test concentration)

Thompson et Male C57Bl/6J mice, 0.3 or 3 ppm (0.7 or 6.9 mg/m3) acrolein At high but not low concentration, None derived; no control group
al. (2017) 6 per group for 3 hours (whole body) decreased respiration frequency, Effects seen at 0.7 mg/m3 (lowest test
(no separate control group; the 30 min increased tidal volume, increased concentration)
acclimation period was considered lymphocytes in lungs (no change in total
baseline for individual animals) cells, neutrophils, eosinophils);
increased stroke volume (20%) and
cardiac output (10%) at 24-hour
post-exposure; increased delay in
cardiac cycle “dyssynchrony” (i.e.,
change in timing of contractions) at
1-hour and 24-hour post exposure
At low but not high concentration,
decreased heart rate (5% at 1-hour but
not at 24-hour post-exposure),
decreased myocardial performance (at
1- and 24-hour post-exposure)

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 Table C2. Repeat exposure studies (3 days to 6 weeks)

❘58
Species, Sex and
Study Exposure Results NOAEL/LOAEL
Number

Borchers et al. Female C57Bl/6J mice, 0, 0.5 or 2 ppm (1.2 or 4.6 mg/m3) Increased mucus index (high LOAEL = 1.2 mg/m3
(2008) 8 per group acrolein, 6 hours per day for 1, 2 or concentration, 2 weeks, 4 weeks)— (changes in BALF at the lowest test
4 weeks (whole body) mucus cell metaplasia in lungs concentration)
Increased BAL epithelial cells (airway
damage) (high concentration, 1, 2,
4 weeks)
Macrophage accumulation (low and
high concentrations, 2 weeks and
4 weeks)

Bouley et al. SPF OFA rats (3 male and Continuous exposure to 0 or 0.55 ppm No difference was found in number of NOAEL (reproductive/developmental
(1976) 21 female) (1.3 mg/m3) acrolein for 4 days prior to pregnant animals, and number and toxicity) = 1.3 mg/m3 (single test
mating and for an additional 22 days weight of fetuses between exposed and concentration; limited endpoints
after mating control animals examined)

Buckley (1984) Male Swiss-Webster 0 or 1.7 ppm (3.9 mg/m3) acrolein, Exfoliation and squamous metaplasia in LOAEL = 3.9 mg/m3
mice, 16–24 per group 6 hours per day for 5 days (whole body) respiratory epithelium, and moderate (lesions in respiratory and olfactory
(8–10 in control) ulceration in the olfactory epithelium. epithelium at the lowest test
No lesions in lower respiratory tract. concentration)

Cassee, Groten Male Wistar rats, 5–6 per 0, 0.25, 0.67 or 1.4 ppm (0.57, 1.54 or Concentration-related histopathological LOAEL = 0.57 mg/m3
and Feron group 3.22 mg/m3) acrolein, 6 hours per day for changes (including disarrangement, (lesions in nasal respiratory epithelium
(1996) 3 days (nose only) necrosis, thickening, desquamation, and at the lowest test concentration)

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basal cell hyperplasia) in the nasal
Health Canada has previously derived a
respiratory/transitional epithelium, but
BMC05 of 0.14 mg/m3, which was used to
not in the olfactory epithelium. Severity
derive the tolerable concentration.
of lesions increased with concentration.
Glutathione reductase decreased at low
and mid concentrations. GST and
aldehyde dehydrogenase were reduced
at mid concentration.
Increased cell proliferation at low and
mid concentration.

Leach et al. Male SD rats, 40 per 0, 0.1, 1.0 or 3.0 ppm (0.23, 2.3 or 6.9 mg/ In the high concentration group, there None derived
(1987) group m3) acrolein, 6 hours per day, 5 days per was exfoliation, erosion, and necrosis in Only 12 rats from the control group and
week for 3 weeks the respiratory epithelium of the nasal 12 from the high concentration group
turbinates, squamous cell metaplasia, were used for histopathology testing.
but no lung histopathology changes.
 Species, Sex and
Study Exposure Results NOAEL/LOAEL
Number

O’Brien et al. Male C57BL/6 mice 0 or 5 ppm (11.5 mg/m3) acrolein, 4 hours Exposure to acrolein increased None derived
(2016) per day, 4 days per week for 2 weeks OVA-specific IgG compared to OVA Effects observed at 11.5 mg/m3 (single
(+OVA, also OVA alone—inhaled) alone (acrolein promotes sensitization). test concentration)
Challenged with 3 days inhaled OVA Exposure to acrolein increased lung
after 1 week recovery inflammation compared to OVA alone.
No differences in lung leukocyte
number, macrophage number or ILs,
TNFa in BAL in any group. Also, there
was no difference in lung tissue cytokine
mRNA
Increased lung IL-17F mRNA in acrolein
exposed animals (+/- OVA). The authors
state that this IL has been associated
with asthma.

Roemer et al. Male Sprague Dawley 0, 0.2 or 0.6 ppm (0.46 or 1.38 mg/m3) Increase in cell proliferation in rat nasal, LOAEL = 0.46 mg/m3
(1993) rats, 3–5 per group acrolein, 6 hours per day for 3 days tracheal, and lung epithelium; effects (cell proliferation in respiratory
(head only) were less pronounced than after a epithelium at the lowest test
single exposure. concentration)

Spiess et al. Male C57BL/6 mice 0 or 5 ppm (11.5 mg/m3) acrolein, 6 hours Acrolein exposure reduced allergic None derived
(2013) sensitized to OVA by IP per day for 4 days (whole body) airway inflammation (suppressed mucus Effects observed at 11.5 mg/m3 (single
injection, 3–4 per group (during challenge phase, animals were production, leukocyte infiltration and test concentration)
also exposed by inhalation to OVA for cytokine levels). Decreased goblet cell
30 min) hyperplasia was also noted.

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 Table C3. Repeat exposure studies (6 weeks to 18 months)

❘60
Study Species, Sex and Number Exposure Results NOAEL/LOAEL

Dorman et al. Male Fischer 344 rats, 12 per 0, 0.02, 0.06, 0.2, 0.6 or 1.8 ppm (0, Some body weight reductions— NOAEL = 0.46 mg/m3
(2008) group 0.05, 0.14, 0.46, 1.4 or 4.1 mg/m3) significant (20%) in high concentration LOAEL = 1.4 mg/m3
acrolein, 6 hours per day, 5 days per group. For all other exposed animals,
(lesions in the respiratory epithelium
week for 13 weeks (whole body) the reduction was less but significant
of the nasal cavity)
Histopathology of respiratory tract and remained throughout exposure.
Partial recovery after exposure. The NOAEL of 0.46 mg/m3 was
conducted at days 4, 14, 30, and 65 as
considered the critical effect level for
well as after a 60-day post-exposure Pathology of nasal respiratory
long-term exposure in the risk
recovery period. Lesions were graded epithelium: inflammation, hyperplasia,
assessments of acrolein conducted by
on a scale of 1 to 5 (minimal to severe). squamous metaplasia. Mild effects at
CalEPA (2008) and ANSES (2013).
Nasal cavity was divided into 1.4 mg/m3 at day 4 and later. More
6 sections. severe effects at higher NOAEL = 1.4 mg/m3
concentrations. At 4.1 mg/m3, effects LOAEL = 4.1 mg/m3
were observed within days of starting
(inflammation in the olfactory
exposure. At some sites, inflammation
epithelium)
and hyperplasia were transient and
were replaced by metaplasia, which
persisted even after exposure
stopped.
Increased cell proliferation was
observed at 1.4 or 4.1 mg/m3, but not
0.46 mg/m3.
Inflammatory response in olfactory
epithelium, degeneration and atrophy
at 4.1 mg/m3, starting at day 4

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Feron and Syrian golden hamsters, 0 or 4 ppm (9.2 mg/m3) acrolein, Decreased body weight, but None derived
Kruysse (1977) 18 per sex per exposure 7 hours per day, 5 days per week for difference began to disappear No evidence of carcinogenicity at
group 52 weeks (whole body) post-exposure 9.2 mg/m3
Additional animals were also +/- recovery period of 29 weeks Inflammation and epithelial metaplasia
given NaCl and benzo(a) in nasal cavity (slight to moderate).
pyrene by tracheal instillation Lesions still observed after recovery
weekly, or period in 20% of animals.
N-nitrosodiethylamine by No respiratory tract tumours
subcutaneous injection every
No clear enhancement of B(a)P
3 weeks.
induced tumours; no impact on DENA
induced tumours
 Study Species, Sex and Number Exposure Results NOAEL/LOAEL

Feron et al. Male and female Syrian 0, 0.4, 1.4 or 4.9 ppm (0.9, 3.2, 11.3 mg/ Significant weight gain reduction at LOAEL = 0.9 mg/m3 (lowest test
(1978) golden hamsters (20 per m3) acrolein, 6 hours per day, 5 days high concentration for hamsters and concentration)
group), Wistar rats (12 per per week for 13 weeks rabbits, and mid and high US EPA considered 0.9 mg/m3 a
group), Dutch rabbits (4 per (whole body) concentration for rats minimal LOAEL, which was used to
group) Nasal histopathology: at low derive an RfC
Histopathology of respiratory system
for all animals; lesions graded as concentration, one rat had metaplastic
slight, moderate or severe and inflammatory changes; at mid
concentration, there were changes in
rats (moderate; incidence not shown)
and hamsters (slight), but not rabbits;
at high concentration, rabbits
moderate, rats and hamsters severe
Tracheal epithelia histopathology: at
high concentration, slight hyperplasia
in rabbits; moderate hyperplasia and
metaplasia in hamsters; and severe
damage in rats
Lung histopathology: at high
concentration, severe hemorrhage,
edema, bronchopneumonia,
bronchitis, hyperplasia and metaplasia
of bronchi, and wide range of degree
of lesions between individuals in rats;
similar effects in rabbits but less
severe (moderate) than rats

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 62
Study Species, Sex and Number Exposure Results NOAEL/LOAEL

❘
Kutzman (1981); Fischer 344 rats: 24 males per 0, 0.4, 1.4 or 4.0 ppm (0.9, 3.2 or During exposure, body weights at LOAEL = 0.9 mg/m3 (decreased lung
Kutzman et al. group for pulmonary function 9.2 mg/m3) acrolein, 6 hours per day, high concentration were significantly function at the lowest test
(1985); Costa et testing and lung pathology; 5 days per week for 62 exposure days, less than controls; other concentration concentration)
al. (1986) 8 males per group for + 1 week recovery groups were not different from The US EPA considered 0.9 mg/m3
pathology only; 10 males per (whole body) controls. support for a minimal LOAEL, which
group for cytology; 8 males At high concentration, mortality was used to derive an RfC.
Histopathology on lung, trachea and
and 8 females per group for (bronchopneumonia), bronchiolar
nasal turbinates (no sections); lesions NOAEL = 9.2 mg/m3 (reproductive
reproductive test epithelial necrosis and sloughing, and
scored on 0–5 scale toxicity at the highest test
bronchiolar and pulmonary edema concentration;
were observed. Severity of tracheal
limited endpoints examined)
edema was highly variable. There was
decreased lung function, including in
animals with no histologic lesions.
There were no pulmonary lesions at
mid concentration. Some rats had
bronchiolar necrosis and hyperplasia,
but functionally they were the same as
controls.
Some functional deficits were
observed at low concentration, but no
lung lesions.
There were no sperm abnormalities,
and no change in pregnancy rate,
corpora lutea, viable embryos, fetal
death or preimplantation loss.

RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN

Kutzman et al. Female Dahl rats, 0, 0.4, 1.4 or 4.0 ppm (0.9, 3.2 or At high concentration, all DS rats died LOAEL = 0.9 mg/m3
(1984) hypertension susceptible (DS) 9.2 mg/m3) acrolein, 6 hours per day, within 11 days from severe airway (proliferative changes in respiratory
and resistant (DR), 10 per 5 days per week for 62 exposure days, epithelial necrosis with edema and tract and nasal inflammation at the
group + 1 week recovery haemorrhage. 4 out of 10 DR rats died lowest test concentration)
(whole body) by day 62; surviving rats lost weight
DS strain more susceptible than DR at
and developed primarily a proliferative
high concentration
change in lung tissue.
At mid and low concentrations, both
strains had mild bronchiolar epithelial
hyperplasia and squamous metaplasia
as well as acute inflammation in nasal
turbinates.

Le Bouffant et Female SD rats, 20 per group 8 ppm (18.4 mg/m3) acrolein, 1 hour No tumours, no body weight change None derived (study primarily on
al. (1980) per day, 5 days per week for 10 or cigarette smoke inhalation)
18 months (whole body)
 Study Species, Sex and Number Exposure Results NOAEL/LOAEL

Lyon et al. Male and female SD rats 0.7 or 3.7 ppm (1.6 or 8.5 mg/m3) 6-week study: None derived (no concurrent controls)
(1970) (15 per group), male and acrolein, 8 hours per day, 5 days per At 0.7 ppm, all animals had chronic Effects observed at 0.5 mg/m3 (lowest
female guinea pigs (15 per week for 6 weeks inflammation (mild, focal to diffuse, no test concentration)
group), male monkeys (9 per 0.22, 1.0 or 1.8 ppm (0.5, 2.3 or 4.1 mg/ definite alteration of respiratory
group), male dogs (2 per m3) acrolein, continuously for 90 days epithelium) and occasional
group) emphysema (mild, patchy), which were
more prominent in dogs and monkeys.
No concurrent controls In dogs and monkeys, significant
No nasal histopathology morphologic changes in trachea
Descriptive only, no scoring of lesions (squamous metaplasia and basal cell
hyperplasia). In monkeys, necrosis of
bronchi, squamous metaplasia in
lungs (bronchi), and repair and
regeneration of bronchi epithelium. 2
monkeys died (days 6 and 9), but
unclear if treatment related.
90 day study:
At 0.22 ppm, dogs had moderate
emphysema, acute lung congestion,
focal vacuolization of bronchiolar
epithelial cells, and some constriction
of bronchioles. There were non-
specific inflammatory changes in lungs
of monkeys, guinea pigs, and dogs,
and non-specific histopathology in
rats (only lung and trachea, not nasal
cavity, of only half the rats were
examined).
At 1 ppm, guinea pigs had pulmonary
inflammation, and one dog
bronchiolitis and early
bronchopneumonia.
At 1.8 ppm, monkeys had squamous
metaplasia and basal cell hyperplasia
in the trachea, and dogs
bronchopneumonia.

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❘63
APPENDIX D: OTHER GUIDELINES

D1. Short-Term Exposure Guidelines

In the Environment Canada and Health Canada’s Priority Substances List Assessment Report:
Acrolein, no guideline for short-term exposure to acrolein was derived (Environment Canada and
Health Canada 2000).

For acute exposures, the California EPA (CalEPA) (2008) derived an acute (1 hour) reference
exposure level of 2.5 µg/m3. This reference level is based on the geometric mean of effect levels for
eye irritation in humans from the following two studies: a LOAEL of 138 µg/m3 in a study of
36 volunteers exposed (eye only) to acrolein for 5 minutes (Darley et al. 1960), and a LOAEL of
210 µg/m3 in a study of 53 volunteers exposed to increasing acrolein concentrations for 40 minutes
(Weber-Tshopp et al. 1977). Uncertainty factors of 6 for the use of LOAELs and 10 for intraspecies
variation were applied, giving a total UF of 60.

The US EPA (2010) derived an acute exposure guideline limit (AEGL-1) of 70 µg/m3 for non-disabling
effects for timeframes of 10 minutes to 8 hours, based on eye irritation at 210 µg/m3 in humans
exposed to increasing acrolein concentrations for 40 minutes (Weber-Tschopp et al. 1977). An
uncertainty factor of 3 was applied to account for intraspecies variability.

In their pesticide evaluations, the US EPA (2008) and Health Canada’s Pest Management Regulatory
Agency (2016) derived a concentration of concern for short-term exposure of 7 µg/m3, using a
LOAEL of 210 µg/m3 for eye irritation with uncertainty factors of 10 for intraspecies sensitivity and 3
for lack of NOAEL, and a LOAEL of 700 µg/m3 for nasal and throat irritation with uncertainty factors
of 10 for intraspecies sensitivity and 10 for lack of NOAEL.

ANSES (2013) derived a short-term exposure guideline of 6.9 µg/m3 for a 1-hour time frame, based
on a LOAEL of 0.7 mg/m3 for eye, nose, and throat irritation in volunteers exposed to acrolein for
60 minutes (Weber-Tschopp et al. 1977). Uncertainty factors of 10 for the use of a LOAEL and 10 for
intraspecies variability were applied, giving a total UF of 100.

ATSDR (2007) derived an acute (1 to 14 day) minimal risk level of 3 ppb (6.9 µg/m3), based on a
LOAEL of 0.3 ppm (0.7 mg/m3) for an increase in eye, nose, and throat irritation, and a decrease in
respiration rate in a study of 46 volunteers exposed to acrolein for 60 minutes (Weber-Tschopp et al.
1977). Uncertainty factors of 10 for the use of a LOAEL and 10 for intraspecies variation were
applied, giving a total UF of 100.

64 ❘ RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN

Table D1. Other short-term exposure guidelines

Organization Exposure guideline Health effect

California EPA (2008) 2.5 µg/m3 (1 h) Eye irritation

US EPA (2010) 70 µg/m3 (10 min to 8 h) Eye irritation
US EPA (2008), Health Canada (2016) 7 µg/m3 Eye, nose, and throat irritation
ANSES (2013) 6.9 µg/m3 (1 h) Eye, nose, and throat irritation
ATSDR (2007) 6.9 µg/m3 (3 ppb) Eye, nose, throat, and
(1 to 14 days) respiratory irritation

D2. Exposure Guidelines for Non-Neoplastic Chronic Effects

Previous assessments have developed exposure limits for chronic or long-term acrolein exposure
based on lesions in the nasal respiratory epithelium in rats.

The Government of Canada (Health Canada and Environment Canada 2000) derived a tolerable
concentration of 0.4 µg/m3, based on a BMC05 of 0.14 mg/m3 from a 3-day study (Cassee, Groten
and Feron 1996), which was adjusted for continuous exposure (6 hours/24 hours). Uncertainty factors
of 10 for interspecies extrapolation and 10 for sensitive human populations were applied, giving a
total UF of 100.

The US EPA (2003) derived an inhalation RfC of 0.2 µg/m3, based on a LOAEL of 0.9 mg/m3 from a
13-week rat study (Feron et al. 1978). The LOAEL was adjusted for continuous exposure
(6 hours/14 hours and 5 days/7 days), and a human equivalent concentration (HEC) was calculated
using an RGDR conversion factor of 0.13 (HEC = 0.02 mg/m3). This ratio accounts for
pharmacokinetic but not pharmacodynamic differences between animals and humans; an
uncertainty factor of 3 was also applied for pharmacokinetic differences between species.
Uncertainty factors of 10 for sensitive human populations, 10 to account for the use of a subchronic
study, and 3 for the use of a LOAEL were also applied, giving a total UF of 1000.

The CalEPA (2008) derived a chronic reference exposure level of 0.35 µg/m3, based on a NOAEL of
0.46 mg/m3 in a 13-week study (Dorman et al. 2008). The NOAEL was adjusted for continuous
exposure (6 hours/14 hours and 5 days/7 days), and an HEC was calculated using a DAF of 0.85
based on a model for the analogue formaldehyde (HEC = 0.07 mg/m3). Uncertainty factors of 2 for
pharmacokinetics (use of a DAF from a chemical analogue), 3 for pharmacodynamics, 10 for
sensitive human populations, and 3 for use of a subchronic study, giving a total UF of 200.

ANSES (2013) also used the NOAEL of 0.46 mg/m3 from Dorman et al (2008) to derive a long-term
exposure guideline of 0.8 µg/m3. No duration adjustment was made, and an HEC was calculated
using an RGDR conversion factor of 0.13 (HEC = 60 µg/m3). This ratio accounts for pharmacokinetic
but not pharmacodynamic differences between animals and humans; an uncertainty factor of 2.5
was also applied for pharmacokinetics. Uncertainty factors of 10 for sensitive human populations
and 3 to account for the use of a subchronic study were also applied, giving a total UF of 75.

RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN ❘ 65

Table D2. Other exposure guidelines for non-neoplastic chronic effects

Organization Exposure guideline Health effect

Health Canada and Environment 0.4 µg/m3 Lesions in nasal respiratory epithelium
Canada (2000)

US EPA (2003) 0.2 µg/m3 Lesions in nasal respiratory epithelium

California EPA (2008) 0.35 µg/m3 Lesions in nasal respiratory epithelium

ANSES (2013) 0.8 µg/m3 Lesions in nasal respiratory epithelium

66 ❘ RESIDENTIAL INDOOR AIR QUALITY GUIDELINES ACROLEIN